Biology subjects

Li, Q.

Publications and source records attributed to Li, Q..

At least 289 records · Page 16Linked to original sources

bioRxiv2024

Computational Identification of Migrating T cells in Spatial Transcriptomics Data

T cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide novel insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T-cell trafficking display an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix (ECM) remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce a novel approach for studying T cell migration and interactions within the tumor microenvironment (TME), offering valuable insights into tumor-immune dynamics.

bioinformatics↗

bioRxiv2024

Overcoming artificial structures in resolution-enhanced Hi-C data by signal decomposition and multi-scale attention

Computational enhancement is an important strategy for inferring high-resolution features from genome-wide chromosome conformation capture (Hi-C) data, which typically have limited resolution. Deep learning has been highly successful in this task but we show that it creates prevalent artificial structures in the enhanced data due to the need to divide the large contact matrix into small patches. In addition, previous deep learning methods largely focus on local patterns, which cannot fully capture the complexity of Hi-C data. Here we propose Smooth, High-resolution, and Accurate Reconstruction of Patterns (SHARP) for enhancing Hi-C data. It uses the novel approach of decomposing the data into three types of signals, due to one-dimensional proximity, contiguous domains, and other fine structures, and applies deep learning only to the third type of signals, such that enhancement of the first two is unaffected by the patches. For the deep learning part, SHARP uses both local and global attention mechanisms to capture multi-scale contextual information. We compare SHARP with state-of-the-art methods extensively, including application to data from new samples and another species, and show that SHARP has superior performance in terms of resolution enhancement accuracy, avoiding creation of artificial structures, identifying significant interactions, and enrichment in chromatin states.

bioinformatics↗

bioRxiv2024

Comparative genomic analysis reveals reduced pathogenicity of Ralstonia spp. in water

Ralstonia spp., known for their adaptability across various habitats, are known to cause infections. The adaptive metabolic diversity of those inhabiting aquatic ecosystems remains poorly understood. We report four new Ralstonia pickettii genomes enriched in the cyanobacterial culture derived from bloom-forming cyanobacteria, Dolichospermum. A total of 228 complete genomes from the Ralstonia genus were utilized for phylogenetic inference, categorizing them based on isolation environment and host: water, soil, plant, and human groups. Meanwhile, the abundance of carbohydrate-active enzymes and secondary metabolites in water and human groups differed from the plant-host associate habitat. CeoB and two {beta}-lactamases types of OXA were identified in the water habitat, showing similarities to certain strains in the human-host but differences from other habitats. The infectivity within water habitats seems to diminish, as evidenced by the decreased abundance of T3SS virulence proteins. Moreover, a distinctive pyrimidine degradation pathway in water degrades exogenous pyrimidines to supply nitrogen and other compounds for energy metabolism to provide a potential for broader habitat adaptability. Fluorescence in situ hybridization results confirmed that R. pickettii rarely attached to cyanobacterial cells, indicating that they are not parasitic relationships. We postulate that the absence of T3SS and the unique metabolic profile represent adaptations of Ralstonia to an aquatic free-living lifestyle.

microbiology↗

bioRxiv2024

Toden-E: Topology-Based and Density-Based Ensembled Clustering for the Development of Super-PAG in Functional Genomics using PAG Network and LLM

The integrative analysis of gene sets, networks, and pathways is pivotal for deciphering omics data in translational biomedical research. To significantly increase gene coverage and enhance the utility of pathways, annotated gene lists, and gene signatures from diverse sources, we introduced pathways, annotated gene lists, and gene signatures (PAGs) enriched with metadata to represent biological functions. Furthermore, we established PAG-PAG networks by leveraging gene member similarity and gene regulations. However, in practice, high similarity in functional descriptions or gene membership often leads to redundant PAGs, hindering the interpretation from a fuzzy enriched PAG list. In this study, we developed todenE (topology-based and density-based ensemble) clustering, pioneering in integrating topology-based and density-based clustering methods to detect PAG communities leveraging the PAG network and Large Language Models (LLM). In computational genomics annotation, the genes can be grouped/clustered through the gene relationships and gene functions via guilt by association. Similarly, PAGs can be grouped into higher-level clusters, forming concise functional representations called Super-PAGs. TodenE captures PAG-PAG similarity and encapsulates functional information through LLM, in characterizing network-based functional Super-PAGs. In synthetic data, we introduced a metric called the Disparity Index (DI), measuring the connectivity of gene neighbors to gauge clusterability. We compared multiple clustering algorithms to identify the best method for generating performance-driven clusters. In non-simulated data (Gene Ontology), by leveraging transfer learning and LLM, we formed a language-based similarity embedding. TodenE utilizes this embedding together with the topology-based embedding to generate putative Super-PAGs with superior performance in semantic and gene member inclusiveness.

bioinformatics↗

bioRxiv2024

Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs and CD8+ T cells

Administration of selective serotonin reuptake inhibitors (SSRIs) is associated with a reduced cancer risk and shows significant anti-tumor effects across multiple tumor types, suggesting the potential for repurposing SSRIs in cancer therapy. Nonetheless, the specific molecular target and mechanism of action of SSRIs remain to be fully elucidated. Here, we reveal that citalopram exerts an immune-dependent anti-tumor effects in hepatocellular carcinoma (HCC). Interestingly, the anti-HCC effects of citalopram are not reliant on its conventional target, the serotonin transporter. Through various drug repurposing approaches, including global reverse gene expression profiling, drug affinity responsive target stability assay, and molecular docking, the complement component 5a receptor 1 (C5aR1) is identified as a new target of citalopram. C5aR1 is predominantly expressed by tumor-associated macrophages (TAMs), and citalopram treatment enhances local macrophage phagocytosis and elicits CD8+ T anti-tumor immunity. C5aR1 deficiency or depletion of CD8+ T cells hinders the anti-HCC effects of citalopram. Collectively, our study reveals the immunomodulatory roles of citalopram in inducing anti-tumor immunity, and provides a basis for considering the repurposing of SSRIs as promising anticancer agents for HCC treatment.

cancer biology↗

bioRxiv2024

Integration of the DD-genome reshapes gene transcription, chromatin architecture and metabolome of allohexaploid wheat leading to enhanced adaptability

The integration, through hybridization, of the DD genome into domesticated tetraploid wheat gave rise to allohexaploid wheat, the most cultivated wheat globally growing across diverse environmental conditions. However, the regulatory basis of this integration on increased environmental adaptability in allohexaploid remains largely unexplored. Here, we investigated the change of transcriptome, epigenome as well as the chromatin interactome, and metabolome in three independent polyploidization events representing DD genome integration. Our findings reveal that polyploidization events induce the activation of defense-related genes through comprehensive reorganization of epigenome and chromatin architecture. DD integration not only brings an additional gene copy but also activates the homoeologs existing in the A and B subgenomes through chromatin interactions. Furthermore, secondary metabolites represented by alkaloids and flavonoids that are crucial for environmental adaptation, are significantly enriched following polyploidization. Thus, hexaploid wheat exhibits enhanced tolerance to alkalinity, UV-B light stress and high salt conditions was observed. These results highlight the indispensable role of DD genome integration in the adaptability of allohexaploid wheat during its evolution.

plant biology↗

bioRxiv2024

Early-life antibiotic exposure leads to gut microbial dysbiosis associated with neurodevelopment and neuroregeneration

Early-life is a critical period for neurodevelopment and establishment of gut microbiota, which are highly susceptible to antibiotic exposure. Here, we aimed to investigate association between gut microbiota and metabolites with neurodevelopment and neuroregeneration in early-life after antibiotic exposure. To induce microbial dysbiosis in offspring, a broad-spectrum antibiotic cocktail was administered to mice dams. The prefrontal lobe, spinal cord tissues and gut sample of offspring were collected at different time with or without spinal cord crush injury. 16S rRNA sequencing and metabolomics were performed to analyze the gut microbiota and metabolites. NG2 glia were cultured and treated by mitochondrial fusion and fission compounds and metabolites. Maternal antibiotic exposure significantly affected neuronal maturation, NG2 glia proliferation, prefrontal cortex myelination and injured spinal cord neuroregeneration of offspring. Mice in antibiotic exposure group exhibited disruption of gut microbiota and metabolites, along with lower Ace, Chao and Shannon indexes, higher relative abundance of Enterobacter and Escherichia_Shigella, lower lactobacillus and Streptococcus genus, and downregulated Cyclo(Arg-Gly-Asp-D-Phe-Val), Ampicilloyl, DG(8:0/i-19:0/0:0), Petasinine and 6-Hydroxymelatonin glucuronide. These metabolites were enriched in alpha-Linolenic acid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, linoleic acid metabolism. 6-Hydroxymelatonin glucuronide, PC(20:3/0:0), PC(20:2/0:0), Ameltolide, DG(8:0/i-19:0/0:0), Inproquone, and Chorismate were the cores of networks between gut microbiota and metabolites and negatively associated with neurodevelopment and neuroregeneration. Additionally, gut microbiota metabolites promoted NG2 glia differentiation, partly through reversing the effects of mitochondrial fusion/fission compounds. Totally, antibiotic exposure in early-life changed the composition, abundance, and metabolites of gut microbiota in offspring, which was associated with neurodevelopment and neuroregeneration.

microbiology↗

bioRxiv2024

DDX3 regulates the cap-independent translation of the Japanese encephalitis virus via its interactions with PABP1 and the untranslated regions of the viral genome

The translation of global cellular proteins is almost completely repressed in cells with flavivirus infection, while viral translation remains efficient. The mechanisms of flaviviruses evade host translational shutoff are largely unknown. Here, we identified viral elements and host factors associated with JEV evasion of host shutoff. JEV 5'UTR lacked IRES or IRES-like activity, while noncapped 5'UTR initiated translation in the presence of 3'UTR. Furthermore, the elements DB2 and sHP-SL within 3'UTR were involved in the regulation of cap-independent translation, which is conserved in the genus Orthoflavivirus. By RNA affinity purification and mass spectrometry analysis, cellular DDX3 and PABP1 were identified as key factors in regulating cap-independent translation of JEV via their interactions with DB2 and sHP-SL RNA structures. Mechanistically, we revealed that DDX3 could bind to both 5'UTR and 3'UTR of the JEV genome to establish a closed-loop architecture, recruit eIF4G/eIF4A to form the DDX3/PABP1/eIF4G/eIF4A tetrameric complex via its interaction with PABP1, thereby recruiting 43S PIC to the 5'-end of the JEV genome to start translation. Our findings demonstrated a noncanonical translation strategy employed by JEV and further revealed the regulatory roles of DDX3 and PABP1 in this mechanism. These results expand our knowledge of the translation initiation regulation in flaviviruses under the state of host translational shutoff, which provides a conserved antiviral target against orthoflavivirus.

microbiology↗

bioRxiv2024

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/Slc16a1). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.

biochemistry↗

bioRxiv2024

Unraveling Integration-Segregation Imbalances in Schizophrenia Through Topological High-Order Functional Connectivity

BackgroundThe occurrence of brain disorders correlates with detectable dysfunctions in the specialization of brain connectomics. While extensive research has explored this relationship, there is a lack of studies specifically examining the statistical correlation between the integration and segregation of psychotic brain networks using high-order networks, given the limitations of low-order networks. Moreover, these dysfunctions are believed to be linked to information imbalances in brain functions. However, our understanding of how these imbalances give rise to specific psychotic symptoms remains limited. MethodsThis study aims to address this gap by investigating variations at the topological high-order level of the system with regard to specialization in both healthy individuals and those diagnosed with schizophrenia. By employing graph-theoretic brain network analysis, we systematically examine information integration and segregation to delineate system-level differences in the connectivity patterns of brain networks. ResultsThe findings indicate that topological high-order functional connectomics highlight differences in the connectome between healthy controls and schizophrenia, demonstrating increased cingulo-opercular task control and salience interactions, while the interaction between subcortical and default mode networks, dorsal attention and sensory/somatomotor mouth decreases in schizophrenia. Furthermore, we observed a reduction in the segregation of brain systems in healthy controls compared to individuals with schizophrenia, which means the balance between segregation and integration of brain networks is disrupted in schizophrenia, suggesting that restoring this balance may aid in the treatment of the disorder. Additionally, the increased segregation and decreased integration of brain systems in schizophrenia patients compared to healthy controls may serve as a novel indicator for early schizophrenia diagnosis. ConclusionWe discovered that topological high-order functional connectivity highlights brain network interactions compared to low-order functional connectivity. Furthermore, we observed alterations in specific brain regions associated with schizophrenia, as well as changes in brain network information integration and segregation in individuals with schizophrenia.

neuroscience↗

bioRxiv2024

Circulatory proteins shape microglia state and boost phagocytosis

Microglia, the brains immune cells, are highly responsive to their local environment. Given that circulatory proteins can enter the brain, we asked whether microglia are responsive to such proteins. Here, we identify a stable population of microglia specialized to take up circulatory proteins in a region-specific manner under physiological conditions; human hematopoietic stem cell-derived microglia replacing endogenous microglia in chimeric mice show similar regional specialization. Plasma-positive microglia are characterized by prominent expression of genes related to innate immunity and antigen presentation and exhibit high metabolic and phagocytic activity. This activity is dependent, in part, on microglial uptake and accumulation of circulatory Apolipoprotein AI (ApoA-I). Our findings thus identify a new model of communication between brain and periphery through specialized microglia.

neuroscience↗

bioRxiv2024

Temporal Dynamics of Nucleus Accumbens Neurons in Male Mice During Reward Seeking

The nucleus accumbens (NAc) regulates reward-motivated behavior, but the temporal dynamics of NAc neurons that enable "free-willed" animals to obtain rewards remain elusive. Here, we recorded Ca2+ activity from individual NAc neurons when mice performed self-paced lever-presses for sucrose. NAc neurons exhibited three temporally-sequenced clusters, defined by times at which they exhibited increased Ca2+ activity: approximately 0, -2.5 or -5 sec relative to the lever-pressing. Dopamine D1 receptor (D1)-expressing neurons and D2-neurons formed the majority of the -5-sec versus -2.5-sec clusters, respectively, while both neuronal subtypes were represented in the 0-sec cluster. We found that pre-press activity patterns of D1- or D2-neurons could predict subsequent lever-presses. Inhibiting D1-neurons at -5 sec or D2-neurons at -2.5 sec, but not at other timepoints, reduced sucrose-motivated lever-pressing. We propose that the time-specific activity of D1- and D2-neurons mediate key temporal features of the NAc through which reward motivation initiates reward-seeking behavior.

neuroscience↗

bioRxiv2024

An all-in-one AAV vector for cardiac-specific gene silencing by an adenine base editor

ABE editing outcomes are highly variable and unpredictable, depending on various factors. Therefore, the success rate of creating targeted A*T-to-G*C conversions using ABE is not high. But utilizing ABE to target RNA splicing sites for gene silencing has a higher success rate. Another challenge for base editing in the heart is that traditional ABE is too large in size, necessitating dual AAV delivery. Whether single AAV delivery can be achieved remains to be explored. In this study, we demonstrated how the diversity of Cas9 homologs and screening of sgRNAs can facilitate cardiac base editing. Single-AAV base editing outperformed dual-AAV systems in the heart, potentially benefiting from chromatin accessibility-guided sgRNA selection. These findings have important implications for the development of more effective and predictable base editing tools for cardiac gene therapy.

molecular biology↗

bioRxiv2024

Novel regulator Fpr2 controls immune homeostasis via CCL4-dependent neutrophils

Polymorphonuclear leukocytes (PMNs) in Fpr2-deficient mice have significantly impaired bactericidal activity, yet the precise mechanism remains elusive. Our research unveiled the cellular heterogeneity of peripheral blood PMNs through single-cell RNA-sequencing (scRNA-seq) and identified two new neutrophil clusters related to bacterial infection, including a sterilization cluster named Neu_CSTA and a regulation cluster named Neu_CCL4. The lack of Fpr2 leads to an immune regulation imbalance of Neu_CCL4 on other clusters in uninfected conditions, resulting in persistent instability of PMNs in peripheral blood, elevated inflammatory factors, and increased NOX2 expression. Furthermore, our findings corroborate that the regulatory function of Neu_CCL4 on PMNs immune balance is closely tied to its high expression of the anti-inflammatory ligand Anxa1. Regulon analysis inferred by scRNA-seq and ChIP-seq data suggested that a specific transcription factor Elf4, could modulate the expression of Anxa1, thereby facilitating its regulatory impact on other clusters. In the infection state, there was a noted increase in intercellular interactions across different clusters, leading to a general improvement in the bactericidal activity of PMNs. In summary, our research revealed distinct functional cellular sub-populations of PMNs, discovered the potential regulatory mechanisms, and elucidated the essential roles of Fpr2 in their ability to resist infection.

immunology↗

bioRxiv2024

Spatial Development of Brain Networks During The First Six Postnatal Months

The initial months of life constitute a crucial period for human development. A comprehensive understanding of this early phase is essential for unraveling the origins of neurodevelopmental disorders and promoting infant brain health. This study uniquely focuses on the spatial development of intrinsic brain connectivity networks during infancy, which has been less explored compared to functional connectivity. We utilized independent component analysis on resting-state fMRI data from 74 infants to assess how the spatial organization of infant brain networks evolves between birth and six months. Our findings reveal significant changes in spatial characteristics, including an a notable rise in the network-averaged spatial similarity across age, reflecting how closely each participant-specific spatial map aligns with the group-level map for each network. We also observed a marked reduction in the network engagement range by age, representing the extent of voxel intensity range fluctuation within each network. This suggests a continuing process of consolidation, where voxel contributions to the network become more uniform, as indicated by the narrowing of intensity values. The network strength, calculated as the average of all the voxel intensities in the network, indicating the degree of involvement to the specific functional network, increased across age in several networks, such as frontal-mPFC, primary, and secondary visual networks. The network size, along with the network center of mass, illustrating spatial distribution alterations of brain networks by age, varied across different networks. For instance, both metrics increased across age in the secondary visual network but decreased in the temporal network. Additionally, we examined the networks in relation to their linear versus non-linear developmental trajectories across all spatial characteristics, providing a deeper understanding of how these patterns evolve during early infancy. These findings contribute to early brain development understanding and offer insights into potential markers of consolidation and spatial reorganization in large-scale brain networks during infancy.

neuroscience↗

bioRxiv2024

Neural basis of collective social behavior during environmental challenge

Humans and animals have a remarkable capacity to collectively coordinate their behavior to respond to environmental challenges. However, the underlying neurobiology remains poorly understood. Here, we found that groups of mice self-organize into huddles at cold ambient temperature during the thermal challenge assay. We found that mice make active (self-initiated) and passive (partner-initiated) decisions to enter or exit a huddle. Using microendoscopic calcium imaging, we found that active and passive decisions are encoded distinctly within the dorsomedial prefrontal cortex (dmPFC). Silencing dmPFC activity in some mice reduced their active decision-making, but also induced a compensatory increase in active decisions by non-manipulated partners, conserving the groups overall huddle time. These findings reveal how collective behavior is implemented in neurobiological mechanisms to meet homeostatic needs during environmental challenges.

neuroscience↗

bioRxiv2024

Glutamatergic regulation of miRNA-containing exosome precursor trafficking and secretion from cortical neurons

Neuronal exosomes are emerging secreted signals that play important roles in the CNS. Currently little is known about how glutamatergic signaling affects the subcellular localization of exosome precursor intraluminal vesicles (ILVs), microRNA (miR) packaging into ILVs, and in vivo neuronal exosome spreading. By selectively labeling ILVs and exosomes with GFP-tagged human CD63 (hCD63-GFP) in cortical neurons, we found that glutamate stimulation significantly redistributes subcellular localization of hCD63-GFP+ ILVs especially decreases its co-localization with multi-vesicular body (MVB) marker Rab7 while substantially promoting exosome secretion. Interestingly, glutamate stimulation only modestly alters exosomal miR profiles based on small RNA sequencing. Subsequent in vivo cortical neuronal DREADD activation leads to significantly more widespread hCD63-GFP+ area in hCD63-GFPf/+ mice, consistently supporting the stimulatory effect of glutamatergic activation on neuronal exosome secretion and spreading. Moreover, in situ localization of hCD63-GFP+ ILVs and secreted exosomes from specialized Hb9+ and DAT+ neurons were also illustrated in the CNS.

neuroscience↗

bioRxiv2024

Functional MRI reveals regional changes of brain activity after five days of focal high-density theta burst stimulation (hdTBS) of the rat brain

BackgroundThe therapeutic effects of transcranial magnetic stimulation (TMS) likely stem from neuroplasticity induced by repeated sessions over time. While animal models offer insights into TMS-induced plasticity, a rodent model that faithfully replicates prolonged TMS conditions in humans is still lacking. Objective/HypothesisDevelop a rat model that mimics the spatial and temporal patterns of TMS in humans. MethodsExperiments were conducted on two cohorts of healthy adult rats (N=33). In cohort 1, rats underwent surgical implantation of microelectrodes for motor evoked potential (MEP) recording. With a rodent-specific coil and the high-density theta burst stimulation (hdTBS) paradigm, under awake condition, rats received daily TMS at 100% motor threshold for five days (days 1-5) to the hindlimb motor cortex. Cortical excitability was measured by input-output (I-O) curves on Day 0 (pre-hdTBS baseline) and Day 6 (post-hdTBS). The second cohort received identical TMS and underwent fMRI to map cerebral blood volume (CBV) on Days 0 and 6. ResultsDaily hdTBS session for 5 days significantly up-shifted I-O curves only in the TMS group (N=9), not in the sham group (N=7), indicating enhanced cortical excitability. fMRI data showed that, compared to sham group (N=9), rats receiving hdTBS (N=8) had increased basal CBV in several brain regions proximal and distal to the stimulation site, suggesting enhanced basal metabolism. Conclusion(s)Daily hdTBS session for 5 days focally delivered to the motor cortex of naive rats significantly altered basal brain activity in a network of brain regions, opening a novel platform for further investigating TMS-induced plasticity.

neuroscience↗