bioRxiv Science⌕ Search

Biology subjects

Yan, X.

Publications and source records attributed to Yan, X..

At least 109 records · Page 6Linked to original sources

Individual differences in sequential decision-making

1People differ widely in how they make decisions in uncertain environments. While many studies leverage this variability to measure differences in specific cognitive processes and parameters, the key dimension(s) of individual variability in uncertain decision-making tasks has not been identified. Here, we analyzed behavioral data from 1001 participants performing a restless three-armed bandit task, where reward probabilities fluctuated unpredictably over time. Using a novel analytical approach that controlled for the stochasticity in this tasks, we identified a dominant nonlinear axis of individual variability. We found that this primary axis of variability was strongly and selectively correlated with the probability of exploration, as inferred by latent state modeling. This suggests that the major factor shaping individual differences in bandit task performance is the tendency to explore (versus exploit), rather than personality characteristics, reinforcement learning model parameters, or low-level strategies. Certain demographic characteristics also predicted variance along this principle axis: participants at the exploratory end tended to be younger than participants at the exploitative end, and self-identified men were overrepresented at both extremes. Together, these findings offer a principled framework for understanding individual differences in task behavior while highlighting the cognitive and demographic factors that shape individual differences in decision-making under uncertainty.

neuroscience↗

Distinct alpha-synuclein strains derived from Parkinson's disease patient tissues trigger differential inclusion pathology in a novel biosensor cell model

Background-Synuclein (Syn) can misfold and aggregate to form fibrillar {beta}-sheet-rich aggregates ("strains") that are phosphorylated (p-Syn) and deposited into intracellular inclusions in the brain, the pathological hallmark of synucleinopathies including Parkinsons disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Previously, we reported that seed amplification assays such as real-time quaking-induced conversion (RT-QuIC) amplifies and detects Syn strains from the patient skin. However, whether skin-derived Syn strains induce disease-specific pathological features in a biological system is unknown. MethodsWe generated a U251 human glioblastoma cell line expressing fluorescently tagged Syn carrying the PD-linked A53T mutation and Forster resonance energy transfer (FRET)-based U251 biosensor cells. Using fluorescence microscopy coupled with in situ detergent extraction, FRET-Flow cytometry and high-content confocal imaging, we examined the pathological burden and morphology of p-Syn inclusions seeded by RT-QuIC-amplified patient skin and brain Syn strains in Syn-expressing U251 cells, FRET-based Syn biosensor cells and Syn biosensor cell-derived neurons. ResultsU251 cells allow robust and rapid in situ detection of detergent-insoluble intracellular Syn inclusions triggered by exogenous Syn seeds. In U251 FRET-based biosensor cells, PD skin-amplified strains induce a greater pathological burden and distinct p-Syn inclusion morphology from PD brain-amplified and DLB skin-amplified strains. Inclusion morphology of DLB and MSA skin- and brain-amplified strains are comparable. Furthermore, skin-amplified Syn strains induce neuronal inclusions and cause degeneration of induced neurons reprogrammed from the U251 biosensor cells. Finally, biosensor cell-propagated PD skin Syn strains induce higher seeding activity measured by RT-QuIC than PD brain and DLB skin Syn strains, linking intracellular pathological burden to in vitro seeding activity. ConclusionsWe report the detection of distinct PD strains derived from patient skin and brain tissues that trigger unique pathological phenotypes in U251 Syn biosensor cells and cause degeneration of reprogrammed neurons from the same cell lineage. Moreover, DLB and MSA skin Syn strains mimic pathological features of their brain Syn strains in these biosensor cells. Therefore, the U251 Syn biosensor cell model is a robust tool to potentially discriminate PD and DLB synucleinopathies and to study Syn tissue- and strain-specific etiology and pathogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/646513v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@acf0a5org.highwire.dtl.DTLVardef@1eb0d17org.highwire.dtl.DTLVardef@a89c75org.highwire.dtl.DTLVardef@1b7eca4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

EcDNA-borne PVT1 fusion stabilizes oncogenic mRNAs

Extrachromosomal DNA (ecDNA) amplifications are prevalent drivers of human cancers. We show that ecDNAs exhibit elevated structural variants leading to gene fusions that produce oncogene fusion transcripts. The long noncoding RNA (lncRNA) gene PVT1 is the most recurrent structural variant across cancer genomes, with PVT1-MYC fusions arising most frequently on ecDNA. PVT1 exon 1 is the predominant 5 partner fused to MYC or other oncogenes on the 3 end. Mechanistic studies demonstrate that PVT1 exon 1 confers enhanced RNA stability for fusion transcripts, which requires PVT1 exon 1 interaction with SRSF1 protein. Genetic rescue of MYC-addicted cancer models and isoform-specific single-cell RNA sequencing of tumors reveal that PVT1-MYC better supports MYC dependency and better activates MYC target genes in vivo. Thus, the mutagenic landscape of ecDNA contributes to genome instability and generates chimeric fusions of lncRNA and mRNA genes, selecting PVT1 5 region as a stabilizer of oncogene mRNAs.

cancer biology↗

A reference genome assembly of the alpine forage grass Elymus nutans

Elymus nutans Griseb. (Poaceae: Triticeae, 2n=6x=42) is a dominant perennial plant species in the Qinghai-Tibetan Plateau in China, which is an important forage resource in high-altitude and cold regions and is the most popular species used for high yield artificial grassland planting because of its rich nutritional value and good palatability for herbivorous ruminant animals. In this study, using advanced sequencing technology, we generated an allohexaploid reference genome for E. nutans, representing the three sets of chromosomes (subgenomes St, Y, and H). This is the first study to our knowledge to confirm the origin of the Y subgenome, which shares a close relationship with the V subgenome. We predict that E. nutans arose via two-step hybridization and that its speciation occurred [~]3.16 MYA. The whole genome in this study will update the Triticeae family genomics information and provide theoretical basis for the evolutionary of its related speicies.

plant biology↗

Unveiling the Hidden: Dissecting Liraglutide Oligomerization Dual Pathways via Direct Mass Technology, Electron-Capture Dissociation, and Molecular Dynamics

Peptide therapeutics have revolutionized drug design strategies, yet the inherent structural flexibility and conjugated moieties of drug molecules present challenges in discovery, rational design, and manufacturing. Liraglutide, a GLP-1 receptor agonist conjugated with palmitic acid at its lysine residue, exemplifies these challenges by forming oligomers, which may compromise efficacy through progressive formation of aggregates. Here, we incorporate native mass spectrometry platforms including electron-capture dissociation (ECD), direct mass technology (DMT), and molecular dynamics (MD) to capture the early oligomerization process of liraglutide. Our findings reveal a restricted C-terminal region upon oligomer formation, as indicated by the reduced release of z-ions in ECD analysis. Additionally, we identified the formation of higher-order oligomers (n=25-62) by DMT, primarily stabilized by hydrophilic interactions involving preformed stable oligomers (n=14). Together, these integrative mass spectrometry results delineate a dual-pathway oligomerization process for liraglutide, demonstrating the power of mass spectrometry in uncovering hidden pathways of self-association. This approach underscores the potential of mass spectrometry as a key tool in the rational design and optimization of peptide-based therapeutics.

biophysics↗

Hypoxia-Induced Cardiopulmonary Remodeling and Recovery: Critical Roles of the Proximal Pulmonary Artery, Macrophages, and Exercise

Hypoxemia impairs cardiopulmonary function. We investigated pulmonary artery remodeling in mice exposed to chronic hypoxia for up to five weeks and quantified associated changes in cardiac and lung function, without or with subsequent normoxic recovery in the absence or presence of exercise or pharmacological intervention. Hypoxia-induced stiffening of the proximal pulmonary artery stemmed primarily from remodeling of the adventitial collagen, which resulted in part from altered inter-cellular signaling associated with phenotypic changes in the mural smooth muscle cells and macrophages. Such stiffening appeared to precede and associate with both right ventricular and lung dysfunction, with changes emerging to similar degrees regardless of the age of onset of hypoxia during postnatal development. Key homeostatic target values of the wall mechanics were recovered by the pulmonary arteries with normoxic recovery while other values recovered only partially. Overall cardiopulmonary dysfunction due to hypoxia was similarly only partially reversible. Remodeling of the cardiopulmonary system due to hypoxia is a complex, multi-scale process that involves maladaptations of the proximal pulmonary artery.

physiology↗

Decoding yeast transcriptional regulation via a data- and mechanism-driven distributed large-scale network model

The complex transcriptional regulatory relationships among genes influence gene expression levels and play crucial roles in determining cellular phenotypes. Here, we present a novel distributed large-scale transcriptional regulatory neural network model (DLTRNM) by integrating prior knowledge into the reconstruction of pre-trained machine learning models followed with fine-tuning. Taken S. cerevisiae as the example, the transcriptional regulatory relationships, carefully compiled and documented, are utilized to define interactions between TFs and their TGs within DLTRNM. Subsequently, DLTRNM is pre-trained on pan-transcriptomic data and fine-tuned with time-series data, enabling it to accurately predict dynamic regulatory correlations between TFs and TGs, such as simulating TG responses by tuning the expression of TFs. In addition, DLTRNM can assist in identifying potential key TFs for a subset of genes, thus simplifying the complex and interrelated transcriptional regulatory networks (TRN). Based on the key TFs, it can also refine previously reported transcriptional regulatory subnetworks and highlight the core regulatory networks. DLTRNM offers a powerful tool for studying transcriptional regulation with reduced computational demands and enhanced interpretability. Thus, this study represents a significant step forward in systems biology for understanding the complicated transcriptional regulation within cells.

bioinformatics↗

Igf2 regulates early postnatal DPP4+ preadipocyte pool expansion

Adipose tissue is rapidly expanding early in life. Identifying the queues facilitating this process will advance our understanding of metabolically healthy obesity. Single-cell RNA sequencing revealed compositional differences between pre-wean and adult murine subcutaneous adipose tissue. We identify a dipeptidyl peptidase-4 (Dpp4) positive precursor population in pre-wean mice residing at the reticular interstitium of subcutaneous adipose tissue expressing insulin growth factor 2 (Igf2). We show that IGF2 drives proliferation rather than differentiation in these cells. Moreover, loss of Igf2 in Dpp4+ progenitor cells promotes adipogenesis. We show that expression of Igf2 at a limited timeframe during development promotes preadipocyte expansion.

developmental biology↗

Unraveling and overcoming the ammonia toxicity in methanotrophs for sustainable biomanufacturing and methane removal

Replacement of nitrate with ammonium at large scale cultivation of methanotrophs can improve the economic feasibility of these bacteria in methane-based biomanufacturing and methane removal. However, ammonia toxicity and N2O emission impede this option. The mechanism of ammonia oxidation in methanotrophs remains elusive, limiting the effort to detoxify ammonia via genetic engineering. Using an industrially promising methanotroph as a model, we identified a porin PorA that facilitated ammonium uptake. Inactivation of PorA remarkably relieved ammonia toxicity and reduced N2O production. Meanwhile, we demonstrated that haoA, cytL and hcp contributed to ammonia detoxification and cytL was involved in the conversion of NH2OH to N2O. A mutant strain with increased ammonium-utilizing ability and decreased N2O emission was constructed. High growth rate and cell biomass were achieved in fed-batch fermentation with this strain using ammonium. These results deepen our understanding of ammonia oxidation in methanotrophs and promote their applications in biomanufacturing and methane removal. IMPORTANCEM. buryatense 5GB1C is becoming a methanotrophic model for both fundamental research and practical applications. Here, the genetic determinants of ammonia toxicity were identified and a porin gene that facilitated ammonium uptake was described for the first time, providing new understanding regarding the mechanism of nitrification in methanotrophs. Moreover, this study dramatically reduced ammonia toxicity and N2O production in this strain and enabled the use of ammonium as nitrogen source in fermentation, improving the sustainability of this strain in practical applications.

microbiology↗

From spots to stripes: Evolution of pigmentation patterns in monkeyflowers via modulation of a reaction-diffusion system and its prepatterns

The reaction-diffusion (RD) system is widely assumed to account for many complex, self- organized pigmentation patterns in natural organisms. However, the specific configurations of such RD networks and how RD systems interact with positional information (i.e., prepatterns) that may specify the initiation conditions for the RD operation remain largely unknown. Here, we introduced a three-substance RD system underlying the formation of repetitive pigment spots and stripes in Mimulus flowers. It consists of an R2R3-MYB activator (NEGAN), an R3-MYB inhibitor (RTO), and a coactivator represented by two paralogous bHLH proteins. Through fine- scale genetic analyses, transgenic experiments, and computer simulations, we identified the causal loci contributing to the evolutionary transition from sparsely dispersed spots to longitudinal stripes. Genetic changes at these loci modulate the prepatterns of the activator and coactivator expression and the promoter activities of the inhibitor and one of the coactivator paralogs. Our findings highlight the importance of prepatterns towards a realistic description of RD systems in natural organisms, and reveal the genetic mechanism generating pattern variation through modulation of the kinetics of the RD system and its prepatterns.

developmental biology↗

High-pressure Golgi neuronal staining for X-ray whole-brain imaging

Whole-brain imaging has revolutionized neuroscience research, providing comprehensive insights into neural networks across the entire brain. This powerful approach has greatly advanced our understanding of brain functions and the mechanisms underlying various diseases. One primary challenge in whole-brain imaging technology is to achieve high-resolution observation of neural networks at large scales. Although Golgi method allows labeling random neurons in their entirety in the brain, visualizing individual dendritic trees, and tracing long-distance axonal projections, the lengthy processing time pose a limit on its use, i.e., staining a mouse whole-brain sample of just 300 mm3 takes over two weeks. Here, we developed a rapid staining technique for whole-brain neurons using high-pressure assisted Golgi (HP Golgi). This method significantly reduced the staining time for mouse whole-brain neurons from 16 days to only 4 days. We demonstrated the broad applicability of the HP Golgi method across various model organisms, achieving whole-brain neuronal staining in zebrafish, mice, and rats. Further, we successfully performed rapid staining of hippocampal neurons in an intact pig brain, which is difficult to achieve with the classic Golgi-Cox method. We also demonstrated that the combination of the HP Golgi method with synchrotron-based X-ray microscopy for high-resolution imaging of whole-brain neurons in mice. This HP Golgi method enables fast and high-resolution neuronal imaging in large model organisms, showcasing its broad applicability for diverse applications.

biophysics↗

Silicon-rhodamine-enabled Identification (SeeID) for Near-Infrared Light Controlled Proximity Labeling In Vitro and In Vivo

Advancement in fluorescence imaging techniques enables the study of protein dynamics and localization with unprecedented spatiotemporal resolution. However, current imaging tools are unable to elucidate dynamic protein interactomes underlying imaging observations. In contrast, proteomics tools such as proximity labeling enable the analysis of protein interactomes at a single time point but lack information about protein dynamics. We herein developed Silicon-rhodamine-enabled Identification (SeeID) for near-infrared light controlled proximity labeling that could bridge the gap between imaging and proximity labeling. SeeID was benchmarked through characterization of various organelle-specific proteomes and the KRAS protein interactome. The fluorogenic nature of SiR allows for intracellular proximity labeling with high subcellular specificity. Leveraging SiR as both a fluorophore and a photocatalyst, we developed a protocol that allows the study of dynamic protein interactomes of Parkin during mitophagy. We discovered the association of the proteasome complex with Parkin at early time points, indicating the involvement of the ubiquitin-proteasome system for protein degradation in the early phase of mitophagy. In addition, by virtue of the deep tissue penetration of near-infrared light, we achieved spatiotemporally controlled proximity labeling in vivo across the mouse brain cortex with a labeling depth of [~]2 mm using an off-the-shelf 660 nm LED light set-up.

molecular biology↗

ACE: a versatile contrastive learning framework for single-cell mosaic integration

The integration of single-cell multi-omics datasets is critical for deciphering cellular heterogeneities. Mosaic integration, the most general integration task, poses a greater challenge regarding disparity in modality abundance across datasets. Here, we present ACE, a mosaic integration framework that assembles two types of strategies to handle this problem: modality-alignment based strategy (ACE-align) and regression-based strategy (ACE-spec). ACE-align utilizes a novel contrastive learning objective for explicit modality alignment to uncover the shared latent representations behind modalities. ACE-spec combines the modality-alignment results and modality-specific representations to construct complete multi-omics representations for all datasets. Extensive experiments across various mosaic integration scenarios demonstrate the superiority of ACEs two strategies over existing methods. Application of ACE-spec to bi-modal and tri-modal integration scenarios showcases that ACE-spec is able to enhance the representation of cellular heterogeneities for datasets with incomplete modalities. The source code of ACE can be accessed at https://github.com/CSUBioGroup/ACE-main.

bioinformatics↗

Physiological, transcriptomic and metabolomic responses of the marine diatom Phaeodactylum tricornutum to auxin

Auxin, an essential phytohormone, is widely used to promote plant growth and development. However, the effect of auxin on diatoms and its mechanism remain underexplored. Here, we studied the impact of auxin 3-indoleacetic acid (IAA) on the marine diatom Phaeodactylum tricornutum and the underlying molecular mechanisms. We found that 5 g L-1 of IAA promotes the growth of P. tricornutum in a time- dependent manner. Treatment with IAA resulted in significant changes in photosynthetic pigments and malondialdehyde, chlorophyll fluorescence, and antioxidant enzyme activities. In addition, transcriptomics showed that IAA exposure leads to upregulation of a large number of differential genes (DEGs) in carbon fixation and porphyrin metabolism, several of which were verified by qPCR. Furthermore, corresponding metabolites of these pathways were also validated by metabolomic analysis. Thus, IAA exhibits growth-promotion effect on the diatom mainly through increasing photosynthetic carbon sequestration and the expression of genes in porphyrin synthesis. Our results provide key data on the action mechanism of IAA in promoting the growth of a diatom.

plant biology↗

Versatile Stain Transfer in Histopathology Using a Unified Diffusion Framework

Histological staining is vital in clinical pathology for visualizing tissue structures. However, these techniques are laborious and time-consuming. Digital virtual staining offers a promising solution, but existing methods typically rely on Generative Adversarial Networks (GANs), which may suffer from artifacts and mode collapse. Motivated by the success of diffusion models, we present DUST, a novel Diffusion-based Unified framework for versatile Stain Transfer in histopathology. To enhance domain awareness and task-specific performance, we propose a dual encoding strategy that integrates the stain types of both the source and target domains. Additionally, we introduce a dynamic dual-output head to address the unstable intensity issue encountered with conventional DDPM implementations. Validated on a curated fourstain kidney histopathological dataset (H&E, MT, PAS, and PASM), DUST demonstrates superior versatile stain transfer capabilities. Our research highlights the potential of diffusion models to advance virtual staining, paving the way for more efficient digital pathology analyses.

pathology↗

STEP: Deciphering Spatial Atlas at Single-Cell Level with Whole-Transcriptome Coverage

Recent advances in spatial transcriptomics have revolutionized our understanding of tissue spatial architecture and biological processes. However, many of these technologies face significant challenges in achieving either single-cell resolution or comprehensive whole-transcriptome profiling, hindering their capacity to fully elucidate intercellular interactions and the tissue microenvironment. To address these limitations, we present STEP, a hybrid framework that synergistically integrates probabilistic models with deep learning techniques for spatial transcriptome analysis. Through innovations in model and algorithm design, STEP not only enhances sequencing-based spatial transcriptome data to single-cell resolution but accurately infers transcriptome-wide expression levels for image-based spatial transcriptomic. By leveraging the nuclear features extracted from histological images, STEP achieves precise predictions of cell type and gene expression and effectively diffuses the discriminative ability to serial sections for modeling solid tissue landscapes. The capability is particularly advantageous for analyzing cells with distinctive characteristics, such as cancer cells, enabling cross-sample inference. In addition, STEP simulates intercellular communication through a spatially resolved cell-cell interaction network, uncovering intrinsic biological processes. Overall, STEP equips researchers with a powerful tool for understanding biological functions and unveiling spatial gene expression patterns, paving the way for advancements in spatial transcriptomics research. Code is available at https://github.com/childishHU/STEP.

bioinformatics↗

Chaperonin TRiC bridges radial spokes for folding proteins locally translated in mammalian sperm flagella

As animals evolved from external to internal fertilization, sperm flagella, which once transiently propelled sperm in water to reach nearby eggs, developed to beat for days or even longer within the female reproductive tract. How flagella were remodeled accordingly remains unclear. Unlike externally fertilizing zebrafish and sea urchin, mammalian sperm flagella feature a unique barrel-shaped bridge between axonemal radial spokes RS1 and RS2, though its components and function remain unknown. Here, using cryo-EM and cryo-ET combined with mass spectrometry and immunofluorescence staining, we reveal that this RS1-RS2 barrel (RRB) in mammalian sperm flagella is a group II chaperonin TRiC/CCT. We purified and resolved the unforeseen cryo-EM structure of TRiC from bovine sperm flagella, discovering that flagella TRiC contains the testis-specific CCT6B subunit. Additionally, we resolved the cryo-ET map of mouse sperm flagella RSs, containing the RRB, achieving unprecedented local resolution of 10-14 [A]. The in-situ RRB map displays two extra densities within its chambers in a polarized manner, suggesting the presence of folding substrates and a co-chaperone (likely phosducin-like 2). Notably, mammalian flagella also contain components of translation machineries and actively synthesize proteins. Our results suggest that the RRB TRiC folds locally translated proteins to sustain mammalian flagella, providing new insights into flagellar remodeling in internally fertilizing species. Our findings also shed lights on male fertility and potential treatments for infertility.

biophysics↗

A Novel Cyanine-Based Fluorescent Dye for Targeted Mitochondrial Imaging in Neurotoxic Conditions and In Vivo Brain Studies

Mitochondrial dysfunction is a key feature of neurodegenerative diseases, often preceding symptoms and influencing disease progression. However, real-time in vivo imaging of mitochondria in the brain is limited by existing dyes like MitoTrackers, which struggle with poor tissue penetration, phototoxicity, and inability to cross the blood-brain barrier (BBB). This study introduces Cy5-PEG4, a novel mitochondrial-targeting dye that overcomes these limitations, enabling high-resolution, non-invasive imaging of mitochondrial dynamics. Cy5-PEG4 effectively labels mitochondria in primary neuronal cells exposed to the SARS-CoV-2 RNYIAQVD peptide, revealing dose-dependent alterations in mitochondrial function that may contribute to COVID-19-related neurodegeneration. Importantly, Cy5-PEG4 crosses the BBB without causing neuroinflammation or toxicity, making it a safe tool for in vivo brain imaging and detailed studies of mitochondrial responses. In 3D cultured cells, Cy5-PEG4 captures dynamic changes in mitochondrial distribution and morphology as cell structures mature, highlighting its potential in neurobiological research, diagnostics, and therapeutic development. These findings support Cy5-PEG4 as a powerful tool for studying disease progression, identifying early biomarkers, and evaluating therapeutic strategies in neurodegenerative disorders and COVID-19.

neuroscience↗