Biology subjects

Yuan, L.

Publications and source records attributed to Yuan, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

PET imaging of an antisense oligonucleotide in the living non-human primate brain using click chemistry

Determination of a drugs biodistribution is critical to ensure it reaches the target tissue of interest. This is particularly challenging in the brain where invasive sampling methods may not be possible. Here, a pretargeted imaging methodology is disclosed that utilizes bioorthogonal click chemistry to determine the distribution of an antisense oligonucleotide in the living brain following intrathecal dosing. A novel PET tracer, [18F]BIO-687, bearing a click-reactive trans-cyclooctene (TCO) was discovered and tested in conjunction with a Malat1 antisense oligonucleotide (ASO) conjugated with a methyltetrazine (MeTz). PET imaging in rats demonstrated that the tracer possesses good kinetic properties for CNS imaging and can react to form a covalent linkage with high specificity to the MeTz-conjugated-ASO in vivo. Further, the amount of tracer reacted by cycloaddition with the Tz was determined to be dependent on the concentration of ASO-MeTz in tissue, as determined through comparison of the imaging signal with the LC-MS of the tissue homogenate. The system was evaluated in cynomolgus monkeys, with PET imaging showing favorable tracer kinetics and specific binding to the ASO in vivo. These results demonstrate that the tracer [18F]BIO-687 can image intrathecally-delivered ASO distribution in the brain, and future studies should leverage this technology to evaluate ASO distribution in human subjects to study distribution. One Sentence SummaryDistribution of an intrathecally administered antisense oligonucleotide can be imaged using a pretargeted approach in the living brains of non-human primates.

neuroscience↗

bioRxiv2025

Mental exploration of future choices during immobility theta oscillations

Mental exploration enables flexible evaluation of potential future choices, guiding decision-making without requiring direct real-world iterations. Although the hippocampus is known to be active while imagining the future, the precise mechanisms that support mental exploration of future choices remain unclear. In the hippocampus, the theta rhythm (4-12 Hz) is prevalent during movement and supports memory coding during real-world exploration by organizing neuronal activity patterns into short virtual path segments (theta sequences) around the rats location. We observed these theta-related neural activity patterns during movement in a hippocampus-dependent working memory task and also, unexpectedly, theta oscillations and theta-related neural activity during immobility. Compared to standard theta sequences during movement, theta sequences during immobility differed in that they occurred at a shifted theta phase and preferentially represented remote locations, in particular the next choice in the working memory task. Coding for future locations was also observed during awake sharp wave ripple, but these short-lasting events occurred rarely and were biased toward frequently visited locations. Therefore, our findings suggest that recurring bouts of theta oscillations during immobility, which are also observed in primates and humans, support the cognitive demands of mental exploration in the hippocampal network and facilitate ongoing predictions of future choices.

neuroscience↗

bioRxiv2025

GEI-17-Mediated SUMOylation of GDI-1 Regulates Apoptotic Cell Clearance

Apoptotic cell clearance represents the final stage of apoptosis, and involves phagosome formation, maturation, and digestion. Here, we found that SUMO modifications participate in apoptotic cell clearance by influencing phagosomal degradation activity in C. elegans. The SUMO E3 ligase, GEI-17, SUMOylates GDP dissociation inhibitor (GDI-1) at K270 to trigger phagosomal degradation. Upon SUMOylation, GDI-1 facilitates release of GDP-bound RAB-1, which is subsequently converted to the GTP-bound form in a manner dependent on GDI displacement factor, PRAF-3. RAB-1 conversion enables binding and translocation of RAB-7 from the endoplasmic reticulum to Golgi to promote phagosome maturation and degradation activity. In the absence of GDI-1 SUMOylation, GDI-1 binds to GDP-RAB-1, sequestering it in the cytoplasm, resulting in impaired phagosomal degradation. Furthermore, we found SUMOylation of GDI1 at a conserved site plays a crucial role in efferocytosis regulation in mammals. This study defines a previously unrecognized mechanism by which SUMOylation drives apoptotic cell clearance.

cell biology↗

bioRxiv2024

Metabolic tuning facilitates nociceptor resilience to excitotoxicity

The capsaicin receptor, TRPV1, mediates the detection of harmful chemical and thermal stimuli. Overactivation of TRPV1 can lead to cellular damage or death through excitotoxicity, a phenomenon associated with painful neuropathy and the paradoxical use of capsaicin as an analgesic. We exploited capsaicin-evoked death to conduct a systematic analysis of excitotoxicity through a genome-wide CRISPRi screen, thereby revealing a comprehensive network of regulatory pathways. We show that decreased expression of mitochondrial electron transport chain (ETC) components protects against capsaicin-induced toxicity by mitigating calcium imbalance and mitochondrial reactive oxygen species production via distinct pathways. Interestingly, TRPV1+ sensory neurons in adult mice maintain lower expression of ETC components and can better tolerate excitotoxicity and oxidative stress compared to other sensory neuron subtypes. We further confirm the regulatory roles of the ETC in sensory neurons through gain-of-function and loss-of-function experiments. These findings implicate ETC tuning as a cellular protective strategy against sensory excitotoxicity.

cell biology↗

bioRxiv2024

Compressive forces induce epigenetic activation of aged human dermal fibroblasts through ERK signalling pathway

Age-related changes in human dermal fibroblasts (HDFs) contribute to impaired wound healing and skin aging. While these changes result in altered mechanotransduction, the epigenetic basis of rejuvenating aging cells remains a significant challenge. This study investigates the effects of compressive forces on nuclear mechanotransduction and epigenetic rejuvenation in aged HDFs. Using a compressive force application model, the activation of HDFs through alpha-smooth muscle actin ([a]-SMA) is demonstrated. Sustained compressive forces induce significant epigenetic modifications, including chromatin remodeling and altered histone methylation patterns. These epigenetic changes correlate with enhanced cellular migration and rejuvenation. Small-scale drug screening identifies the extracellular signal-regulated kinase (ERK) signaling pathway as a key mediator of compression-induced epigenetic activation. Furthermore, implanting aged cell spheroids to an aged skin model and subjecting the tissue with compressing forces resulted in increased collagen I protein levels. Collectively, these findings demonstrate that applying compressive force to aged fibroblasts activates global epigenetic changes through the ERK signaling pathway, ultimately rejuvenating cellular functions with potential applications for wound healing and skin tissue regeneration. Significance StatementPartial rejuvenation of aging cells is desirable but is still a major challenge. In this paper, we demonstrate that aged human dermal fibroblasts, embedded in a 3D collagen hydrogel matrix as spheroids, subjected to external static compressive force exhibit partial rejuvenation. Through immunofluorescence, small-scale inhibitor screen and gene expression analysis, we identify some of the critical mechanotransduction pathways in this process. Collectively, our results provide compelling evidence that tissue compression results in the activation of potential rejuvenation pathways in aging cells.

cell biology↗

bioRxiv2024

PreDigs: a Database of Context-specific Cell-type Markers and Precise cell subtypes for Digestive Cell Annotation

Research on cell type markers aids investigators in exploring the diverse cellular compositions within gastrointestinal tumors, enhancing our understanding of tumor heterogeneity and its implications for disease progression and treatment response. However, issues such as the integration of large-scale datasets and the lack of standardized cell type identification hinder comprehensive characterization. Here, we developed a user-friendly web interface called PreDigs (Predicted Signatures in Digestive System), which offers 124 tailored scRNA-seq datasets available for download, encompassing over 3.4 million cells. After unsupervised clustering, we unified the identification and naming of subtype labels, ultimately constructing a cell ontology tree that includes 142 cell types, with up to eight hierarchical levels. Meanwhile, we calculated three different context-specific cell-type markers--Cell Markers, Subtype Markers, and TPN Markers--based on various application requirements within or across tissues. Through the integrated analysis of PreDigs gastrointestinal data, we identified distinct cell subpopulations exclusive to tumors, one of which corresponds to tumor-specific endothelial cells (TEC). Furthermore, PreDigs offers online cell annotation tools that empower users to perform single-cell classification with greater flexibility, accessible at https://www.biosino.org/predigs/.

bioinformatics↗

bioRxiv2024

Parameter-free clear image deconvolution (CLID) technique for single-frame live-cell super-resolution imaging

Advancing single-frame imaging techniques beyond the diffraction limit and upgrading traditional wide-field or confocal microscopes to super-resolution (SR) capabilities are greatly sought after by biologists. While enhancing image resolution by deconvolving noise-free images is beneficial, achieving a noise-free image that maintains the distribution of signal intensity poses a challenge. We first developed a denoising method utilizing reversibly switchable fluorescent proteins through synchronized signal switching (3S). Additionally, we introduced a denoising neural network technique, 3Snet, which combines supervised and self-supervised learning using 3S denoised images as the ground truth. These approaches effectively eliminate noise while maintaining fluorescence signal distribution across camera pixels. We then implemented clear image deconvolution (CLID) on both 3S and 3Snet denoised images to develop SR techniques, named 3S-CLID and 3Snet-CLID. Notably, 3Snet-CLID boosts the resolution of single fluorescence images from wide-field and spinning-disk confocal microscopies by up to 3.9 times, achieving a spatial resolution of 65 nm, the highest in such imaging scenarios without an additional SR module and complex parameter setting. 3Snet-CLID enables dual-color single-frame live-cell imaging of various subcellular structures labeled with conventional fluorescent proteins and/or dyes, allowing observations of dynamic cellular processes. We expect that these advancements will drive innovation and uncover new insights in biology.

biophysics↗

bioRxiv2024

Evolution and Diversification of the Aposematic Poison Frog, Oophaga pumilio, in Bocas del Toro

The aposematic strawberry poison frog, Oophaga pumilio, is an iconic model system for studying the evolution and maintenance of color variation. Through most of its range, this frog is red with blue limbs. However, frogs from the Bocas del Toro Province, Panama, show striking variance in color and pattern, both sympatrically and allopatrically. This observation contradicts standard models of the evolution of aposematism and has led to substantial speculation about its evolutionary and molecular causes. Since the enigma of O. pumilio phenotypic variation is partly unresolved because of its large, [~] 6.7 Gb genome, we here sequence exomes from 347 individuals from ten populations and map a number of genetic factors responsible for the color and pattern variation. The kit gene is the primary candidate underlying the blue-red polymorphism in Dolphin Bay, where an increase in melanosomes is correlated with blue coloration. Additionally, the ttc39b gene, a known enhancer of yellow-to-red carotenoid conversion in birds, is the primary factor behind the yellow-red polymorphism in the Bastimentos West area. The causal genetic regions show evidence of selective sweeps acting locally to spread the rare phenotype. Our analyses suggest an evolutionary model in which selection is driving the formation of new morphs in a dynamic system resulting from a trade-off between predation avoidance, intraspecific competition, and mate choice.

evolutionary biology↗

bioRxiv2024

Video Foundation Models for Animal Behavior Analysis

Computational approaches leveraging computer vision and machine learning have transformed the quantification of animal behavior from video. However, existing methods often rely on task-specific features or models, which struggle to generalize across diverse datasets and tasks. Recent advances in machine learning, particularly the emergence of vision foundation models, i.e., large-scale models pre-trained on massive, diverse visual repositories, offers a way to tackle these challenges. Here, we investigate the potential of frozen video foundation models across a range of behavior analysis tasks, including classification, retrieval, and localization. We use a single, frozen model to extract general-purpose representations from video data, and perform extensive evaluations on diverse open-sourced animal behavior datasets. Our results demonstrate that features with minimal adaptation from foundation models achieve competitive performance compared to existing methods specifically designed for each dataset, across species, behaviors, and experimental contexts. This highlights the potential of frozen video foundation models as a powerful and accessible backbone for automated behavior analysis, with the ability to accelerate research across diverse fields from neuroscience, to ethology, and to ecology.

animal behavior and cognition↗

bioRxiv2024

Transcriptional reprogramming deploys a compartmentalized "timebomb" in Catharanthus roseus to fend off chewing herbivores

The evolutionary arms-race between plants and insects has led to key adaptive innovations that drive diversification. Alkaloids are well-documented anti-herbivory compounds in plant chemical defenses, but how these specialized metabolites are allocated to cope with both biotic and abiotic stresses concomitantly is largely unknown. To examine how plants prioritize their metabolic resources responding to herbivory and cold, we integrated dietary toxicity bioassay in insects with co-expression analysis, hierarchical clustering, promoter assay, and protein-protein interaction in plants. Catharanthus roseus, a medicinal plant known for its insecticidal property against chewing herbivores, produces two terpenoid indole alkaloid monomers, vindoline and catharanthine. Individually, they exhibited negligible toxicity against Manduca sexta, a chewing herbivore; their condensed product, anhydrovinblastine, however, was highly toxic. Such unique insecticidal mode of action demonstrates that terpenoid indole alkaloid "timebomb" can only be activated when the two spatially isolated monomeric precursors are dimerized by herbivory. Without initial selection pressure and apparent fitness costs, this adaptive chemical defense against herbivory is innovative and sustainable. The biosynthesis of insecticidal terpenoid indole alkaloids is induced by herbivory but suppressed by cold. Here, we identified a transcription factor, Herbivore Induced Vindoline-gene Expression (HIVE), that coordinates the production of terpenoid indole alkaloids in response to herbivory and cold stress. The HIVE-mediated transcriptional reprogramming allows this herbaceous perennial to allocate their metabolic resources for chemical defense at a normal temperature, when herbivory pressure is high, but switches to cold tolerance under a cooler temperature, when insect infestation is secondary.

plant biology↗

bioRxiv2024

Post-flowering photoperiod sensitivity of soybean in pod-setting responses

The development of soybean (Glycine max) is regulated by photoperiod, with genes related to photoperiod sensitivity primarily focused on flowering time. However, their roles in post-flowering reproductive development and the mechanisms by which photoperiod affects them are not yet determined. In this study, we found that pod formation is sensitive to photoperiod. Long-day (LD) conditions tend to extend the time from flowering to pod formation (R1 to R3 stage), and the first wave of flowers tends to fall off. Additionally, photoperiod affects pistil morphology; under short-day (SD) conditions, the stigma has a curved hook-like structure that facilitates better interaction with the filaments when pollen is released, ultimately influencing the timing of pod formation. Photoperiod-insensitive mutants, lacking E1 family and Evening Complex genes, showed no difference in pod formation time under LD or SD conditions. Hormone content analysis and transcriptome data analysis indicated that various hormones, ROS signals, and the application of sucrose solution in vitro might influence floral organ abscission. HighlightPhotoperiod sensitivity after flowering affects the pod-setting time in soybean.

plant biology↗

bioRxiv2024

Rhizobial effector NopM ubiquitinates Nod factor receptor NFR5 and promotes rhizobial infection in Lotus japonicus

Bacterial pathogens and nitrogen-fixing rhizobia employ type III protein secretion system (T3SS) effectors as potent tools to manipulate plant signaling pathways, thereby facilitating infection and host colonization. However, the molecular mechanisms by which rhizobial effectors affect legume infection remain largely elusive. In this study, we investigated the symbiotic role of T3SS effectors in the interaction between Sinorhizobium fredii NGR234 and Lotus japonicus. Mutants deficient in the T3SS genes Tts1 or NopA showed enhanced rhizobial infection of L. japonicus roots. Further mutant analysis showed that the NopT effector negatively affects infection, while the NopM effector in the absence of NopT promotes infection. Notably, NopM interacts with the Nod factor receptors LjNFR1 and LjNFR5. NopM ubiquitinates LjNFR5 on ten lysine residues as identified using mass spectrometry. Expression of NopM in L. japonicus resulted in an approximately twofold increase in LjNFR5 protein levels and enhanced rhizobial infection. Our findings indicate that NopM directly interferes with the symbiotic signaling pathway through interaction and ubiquitination of Nod factor receptors, which likely benefits rhizobial infection of L. japonicus. Our research contributes to the intricate interplay between the Nod factor signaling pathway and rhizobial T3SS effectors delivered into host cells. Significance StatementThis study unravels intricate mechanisms underlying the symbiotic interaction between Sinorhizobium fredii NGR234 and Lotus japonicus. By focusing on the role of the rhizobial effector NopM, this research sheds light on how bacteria manipulate host symbiotic signaling to promote infection and colonization. NopM interacts with NFRs and ubiquitinates LjNFR5, suggesting a novel strategy employed by rhizobia to enhance symbiotic signaling.

microbiology↗

bioRxiv2024

Identifying and quantifying the contribution of maize plant traits to nitrogen uptake and use through plant modelling

Breeding for high nitrogen use efficient crops can contribute to maintaining or even increasing yield with less nitrogen. Nitrogen use is co-determined by N uptake and physiological use efficiency (PE, biomass per unit of N taken up), to which soil processes as well as plant architectural, physiological and developmental traits contribute. The relative contribution of these crop traits to N use is not well known but relevant to identify breeding targets in important crop species like maize. To quantify the contribution of component plant traits to maize N uptake and use, we used a functional-structural plant model. We evaluated the effect of varying both shoot and root traits on crop N uptake across a range of nitrogen levels. Root architectural traits were found to play a more important role in root N uptake than physiological traits. Phyllochron determined the structure of the shoot through changes in source: sink ratio over time which, in interaction with light and temperature, resulted in a significant effect on PE and N uptake. Photosynthesis traits were more relevant to biomass accumulation rather than yield, especially under high nitrogen conditions. The traits identified in this study are potential targets in maize breeding for improved crop N uptake and use. HighlightOur research provides insight into the relevance of a range of traits for maize N uptake and N use, and identifies several potential target traits based on underlying mechanisms to assist maize breeding.

plant biology↗

bioRxiv2024

An interpretable integration model improving disease-free survival prediction for gastric cancer based on CT images and clinical parameters

Preoperative prediction of disease-free survival of gastric cancer is significantly important in clinical practice. Existing studies showed the potentials of CT images in identifying predicting the disease-free survival of gastric cancer. However, no studies to date have combined deep features with radiomics features and clinical features. In this study, we proposed a model which embedded radiomics features and clinical features into deep learning model for improving the prediction performance. Our models showed a 3%-5% C-index improvement and 10% AUC improvement in predicting DFS and disease event. Interpretation analysis including T-SNE visualization and Grad-CAM visualization revealed that the model extract biologically meaning features, which are potentially useful in predicting disease trajectory and reveal tumor heterogeneity. The embedding of radiomics features and clinical features into deep learning model could guide the deep learning to learn biologically meaningful information and further improve the performance on the DFS prediction of gastric cancer. The proposed model would be extendable to related problems, at least in few-shot medical image learning. Key PointsO_LIAn integration model combining deep features, radiomics features and clinical parameters improved disease-free-survival prediction of gastric cancer by 3%-5% C-index. C_LIO_LIEmbedding radiomics and clinical features into deep learning model through concatenation and loss design improved feature extraction ability of deep network. C_LIO_LIThe model revealed disease progression trajectory and tumor heterogeneity. C_LI

cancer biology↗

bioRxiv2024

Metatranscriptomic Compendium of 55900 RNA Viruses Deciphers Human Health Implication and Ecological roles of RNA Virome in Global Wastewater Treatment Plants

RNA viruses are widely recognized for their roles in causing human diseases and shaping Earths biodiversity. Wastewater treatment plants (WWTPs) are eco-friendly biotechnological systems where the roles of RNA viruses in process engineering and sanitation remain unclear. This study analyzed RNA sequencing dataset (> 3.8 Tb) from global WWTPs to examine the diversity, host associations, and auxiliary metabolic functions of RNA viruses. We identified 11,414 RNA virus operational taxonomic units (vOTUs), expanding the known diversity of RNA viruses in WWTPs by 67%. The RNA viral community in WWTPs was dominated by prokaryotic viruses, including both established RNA phage lineages and novel clades with broad ecological distributions, highlighting their underestimated diversity and broad niche breadths. Notably, a vOTU from the base-Howeltoviricetes phage clade was associated with the pathogenic bacterium Aliarcobacter cryaerophilus, suggesting potential applications in RNA phage therapy. Furthermore, the examined distribution and fate of human RNA viruses emphasized the utility of quantitative metatranscriptomics-based wastewater surveillance for public health monitoring. The discovery of auxiliary metabolic genes encoded by RNA viruses further revealed their involvement in critical host metabolic pathways such as translation and cellular respiration. These findings underscore the multifaceted roles of RNA viruses in the critical engineered systems.

microbiology↗

bioRxiv2024

A Systematically Optimized Miniaturized Mesoscope (SOMM) for large-scale calcium imaging in freely moving mice

Understanding how neuronal dynamics gives rise to ethologically relevant behavior requires recording of neuronal population activity via technologies that are compatible with unconstrained animal behavior. However, realizations of cellular resolution head-mounted microscopes for mice have been based on conventional microscope designs that feature various forms of ad-hoc miniaturization and weight reduction measures necessary for compatibility with the weight-limits for free animal behavior. As a result, they have typically remained limited to a small field of view (FOV) or low resolution, a shallow depth range and often remain susceptible to motion-induced artifacts. Here, we present a systematically optimized miniaturized mesoscope (SOMM), a widefield, head-mounted fluorescent mesoscope based on a principled optimization approach that allows for mesoscale, cellular resolution imaging of neuroactivity while offering robustness against motion-induced artifacts. This is achieved by co-optimization of a compact diffractive optical element and the associated computational algorithm under form-factor and weight constraints while maximizing the obtainable FOV, depth of field (DOF), and resolution. SOMM enables recordings of neuronal population activity at up to 16 Hz within a FOV of 3.6 x 3.6 mm2 in the cortex of freely moving mice while featuring 4-{micro}m resolution, a DOF of 300 {micro}m at a weight of less than 2.5 g. We show SOMMs performance of recording large-scale neuronal population activity during social interactions, during conditioning-type experiments and by investigating neurovascular coupling using dual-color imaging.

neuroscience↗

bioRxiv2024

Identification and classification of the genomes of novel Microviruses in a poultry slaughterhouse

Microviridae is a family of phages with circular ssDNA genomes and they are widely found in various environments and organisms. In this study, Virome techniques were employed to explore potential members of Microviridae in poultry slaughterhouse, leading to the identification of 98 novel and complete microvirus genomes. Using a similarity clustering network classification approach, these viruses were found to belong to at least 6 new subfamilies within Microviridae and 3 higher-level taxonomic units. Analysis of their genomes found that the genome size, GC content and genome structure of these new taxa showed evident regularities, validating the rationality of our classification method. Compared with the 19 families classified by previous researchers for microviruses dataset, our method can divide microviruses into about 45 more detailed clusters, which may serve as a new standard for classifying Microviridae members. Furthermore, addressing the scarcity of host information for microviruses, this study significantly broadened their host range and discovered over 20 possible new hosts, including important pathogenic bacteria such as Helicobacter pylori and Vibrio cholerae, as well as different taxa demonstrated differential host specificity. The findings of this study effectively expand the diversity of the Microviridae, providing new insights for their classification and identification. Additionally, it offers a novel perspective for monitoring and controlling pathogenic microorganisms in poultry slaughterhouse environments.

microbiology↗

bioRxiv2024

EI24-RTRAF interaction represses Nox4 translation, vital for redox balance and insulin production

As a double-edged sword, the content of reactive oxygen species (ROS) is precisely controlled. Disordered actions of ROS contribute to deleterious effects, such as cancer and metabolic dysregulation associated with aging and obesity. Although it is well established that cells have developed evolutionarily conserved programs to sense and adapt to redox fluctuations, it remains unclear how to control the expression of key ROS-producing enzymes to regulate continued ROS production at healthy levels for cells such as neurons and pancreatic beta cells. These cells have weaker antioxidant defense systems but strong secretion ability. Here, we found that the endoplasmic reticulum membrane-localized protein, EI24, controls the translation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), which constitutively produces hydrogen peroxide (H2O2), by recruiting an RNA transcription, translation, and transport factor (RTRAF) to the 3-UTRs of Nox4. Depletion of EI24 causes RTRAF to relocate into the nucleus, releasing the brake on Nox4 mRNA translation, and thus, the uncontrolled translation of Nox4 leads to a substantial generation of intracellular H2O2. This suppresses the translation of V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), inhibits its binding to the Ins2 gene promoter, and ultimately hinders insulin transcription. Treatment with a specific NOX4 inhibitor or the antioxidant N-acetyl-cysteine (NAC) restored MafA translation and downstream insulin synthesis while alleviating the diabetic symptoms in pancreatic beta-cell specific Ei24-KO mice. In summary, our study revealed a molecular mechanism that controls the expression of NOX4, a key enzyme responsible for continuous ROS generation. This mechanism ensures low levels of H2O2 and normal biological functions under physiological conditions.

cell biology↗