Biology subjects

Li, S.

Publications and source records attributed to Li, S..

At least 631 records · Page 35Linked to original sources

bioRxiv2024

STING Licensing of Type I Dendritic Cells Potentiates Antitumor Immunity

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a "shock-and-lock" dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells (Tmem173-/-) is important for antitumor efficacy. Specific depletion of cDC1 (Batf3-/-) or STING deficiency in cDC1 (XCR1creSTINGfl/fl) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wildtype cDC1 in Batf3-/- mice restored antitumor efficacy while transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wildtype but not Batf3-/- mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival while also showing increased expressions after neoadjuvant pembrolizumab therapy in non-small cell lung cancer patients. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis. One Sentence SummaryA "shock-and-lock" nanoparticle agonist induces direct STING signaling in type 1 conventional dendritic cells to drive antitumor immunity with defined biomarkers

immunology↗

bioRxiv2024

Spindle Oscillation Emerges at the Critical State of the Electrically Coupled Network in Thalamic Reticular Nucleus

Spindle oscillation is a waxing-and-waning neural oscillation observed in the brain, initiated at the thalamic reticular nucleus (TRN) and typically occurring at 7-15 Hz. Experiments have shown that in the adult brain, electrical synapses, rather than chemical synapses, dominate between TRN neurons, suggesting that the traditional view of spindle generation via chemical synapses may need reconsideration. Based on known experimental data, we develop a computational model of the TRN network, where heterogeneous neurons are connected by electrical synapses. The model shows that the interplay between synchronizing electrical synapses and desynchro-nizing heterogeneity leads to multiple synchronized clusters with slightly different oscillation frequencies, whose summed activity produces spindle oscillation as seen in local field potentials. Our results suggest that during spindle oscillation, the network operates at the critical state, which is known for facilitating efficient information processing. This study provides insights into the underlying mechanism of spindle oscillation and its functional significance.

neuroscience↗

bioRxiv2023

A spectrum of altered non-rapid eye movement sleep in schizophrenia

BackgroundMultiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations (SO), are altered in individuals with schizophrenia (SCZ). However, beyond group-level analyses which treat all patients as a unitary set, the extent to which NREM deficits vary among patients is unclear, as are their relationships to other sources of heterogeneity including clinical factors, illness duration and ageing, cognitive profiles and medication regimens. Using newly collected high density sleep EEG data on 103 individuals with SCZ and 68 controls, we first sought to replicate our previously reported (Kozhemiako et. al, 2022) group-level mean differences between patients and controls (original N=130). Then in the combined sample (N=301 including 175 patients), we characterized patient-to-patient variability in NREM neurophysiology. ResultsWe replicated all group-level mean differences and confirmed the high accuracy of our predictive model (Area Under the ROC Curve, AUC = 0.93 for diagnosis). Compared to controls, patients showed significantly increased between-individual variability across many (26%) sleep metrics, with patterns only partially recapitulating those for group-level mean differences. Although multiple clinical and cognitive factors were associated with NREM metrics including spindle density, collectively they did not account for much of the general increase in patient-to-patient variability. Medication regimen was a greater (albeit still partial) contributor to variability, although original group mean differences persisted after controlling for medications. Some sleep metrics including fast spindle density showed exaggerated age-related effects in SCZ, and patients exhibited older predicted biological ages based on an independent model of ageing and the sleep EEG. ConclusionWe demonstrated robust and replicable alterations in sleep neurophysiology in individuals with SCZ and highlighted distinct patterns of effects contrasting between-group means versus within-group variances. We further documented and controlled for a major effect of medication use, and pointed to greater age-related change in NREM sleep in patients. That increased NREM heterogeneity was not explained by standard clinical or cognitive patient assessments suggests the sleep EEG provides novel, nonredundant information to support the goals of personalized medicine. Collectively, our results point to a spectrum of NREM sleep deficits among SCZ patients that can be measured objectively and at scale, and that may offer a unique window on the etiological and genetic diversity that underlies SCZ risk, treatment response and prognosis.

neuroscience↗

bioRxiv2023

Distributed evidence accumulation across macaque large-scale neocortical networks during perceptual decision making

Despite the traditional view of parietal cortex as an important region for perceptual decision-making, recent evidence suggests that sensory accumulation occurs simultaneously across many cortical regions. We explored this hypothesis by integrating connectivity, cellular and receptor density datasets and building a large-scale macaque cortical model able to integrate conflicting sensory signals and perform a decision-making task. Our results reveal sensory evidence accumulation supported by a distributed network of temporal, parietal and frontal regions, with flexible sequential bottom-up or top-down modulation pathways depending on task difficulty. The model replicates experimental lesioning effects and reveals that the causal irrelevance of parietal areas like LIP for decision performance is explained by compensatory mechanisms within a distributed integration process. The model also reproduces observed temporal gating effects of distractor timing during and after the integration process. Overall, our work hints at perceptual integration during decision-making as a broad distributed phenomenon, providing multiple testable predictions.

neuroscience↗

bioRxiv2023

Role of the metallo-reductase FADING and vacuolinos in anthocyanin degradation in flowers and fruits.

Anthocyanins are vacuolar pigments that confer red-violet colors to plant tissues. Pigmentation patterns result from spatio-temporally regulated anthocyanin synthesis and degradation. Mutational inactivation of a conserved MYB-bHLH-WDrepeat-WRKY transcriptional complex (MBWW) causes degradation of anthocyanins and fading of flower color via a pathway that involves FADING (FA). Here we show that FA encodes a vacuolar membrane Fe-reductase-oxidase that promotes anthocyanin degradation. In wild type petals anthocyanins in the central vacuole (CV) are stable, because FA-GFP is upheld in small vacuoles (vacuolinos) and kept away from the CV, indicating that vacuolinos act as gatekeepers in protein trafficking. In cells lacking vacuolinos, including mbww- mutant petals, FA-GFP reaches the CV and triggers anthocyanin degradation. Virus-induced gene silencing (VIGS) of an FA-homolog in pepper fruits prevented the "fading" of anthocyanins during fruit maturation. These findings provide new insights to breed ornamental and food crops with increased anthocyanin-content and enhanced nutritional value of edible parts.

plant biology↗

bioRxiv2023

Neratinib Synergizes with Trastuzumab Antibody Drug Conjugate or with Vinorelbine to Treat HER2 Mutated Breast Cancer Patient Derived Xenografts and Organoids.

HER2 (ERBB2) is a major therapeutic drug target in breast cancer and The Cancer Genome Atlas (TCGA) Breast Cancer project and other studies have identified HER2 activating mutations in breast cancers without HER2 gene amplification. HER2 activating mutations occur in 2-5% of metastatic breast cancer patients (MBC), and clinical trials have shown that the irreversible pan-HER tyrosine kinase inhibitor, neratinib, produces a 31-40% clinical benefit rate for HER2 mutated MBC patients. We developed breast cancer patient-derived xenografts (PDX) from ER+, HER2 mutated MBC patients and used them to test neratinib-based drug combinations. Using organoid culture of these PDX breast cancer cells, we performed rapid, high-throughput ex vivo screening assays to test novel drug combinations. These organoid culture experiments identified drug synergy with the neratinib plus ado-trastuzumab emtansine (T-DM1) and neratinib plus vinorelbine combinations and we validated these results with in vivo PDX experiments. Statement of SignificancePDXs are a ready source of human cancer organoids, and with thousands of PDXs already available worldwide, PDX derived organoids (PDxOs) can dramatically accelerate cancer drug testing. This strategy of PDxO drug testing is particularly useful for rare cancer subtypes or mutations to identify the most promising treatment strategies for clinical trials testing.

cancer biology↗

bioRxiv2023

Macrophages control pathological interferon responses during viral respiratory infection

Antiviral immune mediators, including interferons and their downstream effectors, are critical for host defense yet can become detrimental when uncontrolled. Here, we identify a macrophage-mediated anti-inflammatory mechanism that limits type I interferon (IFN-I) responses. Specifically, we found that cellular stress and pathogen recognition induce Oncostatin M (OSM) production by macrophages. OSM-deficient mice succumbed to challenge with influenza or a viral mimic due to heightened IFN-I activation. Macrophage-derived OSM restricted excessive IFN-I production by lung epithelial cells following viral stimulation. Furthermore, reconstitution of OSM in the respiratory tract was sufficient to protect mice lacking macrophage-derived OSM against morbidity, indicating the importance of local OSM production. This work reveals a host strategy to dampen inflammation in the lung through the negative regulation of IFN-I by macrophages. One-Sentence SummaryType I interferons induced by viral stimuli are negatively regulated by macrophage-derived Oncostatin M.

immunology↗

bioRxiv2023

Quorum Sensing Positively Regulates CPS-dependent Autographiviridae Phages Infection in Vibrio alginolyticus

Quorum sensing (QS) orchestrates many bacterial behaviors, such as virulence and biofilm formation, across bacterial populations. Nevertheless, the underlying mechanism of QS regulating CPS-dependent phage-bacterium interactions remains unclear. In the present study, we report that QS upregulated the expression of CPS-dependent phage receptors, thus increasing phage adsorption and infection rates in V. alginolyticus. We found that QS upregulated the expression of the ugd gene, leading to increased synthesis of Autographiviridae phage receptor capsular polysaccharide (CPS) synthesis in V. alginolyticus. The signal molecule autoinducer-2 (AI-2) released by V. alginolyticus from different sources can potentially enhance CPS-dependent phage infection. Therefore, our data suggest that inhibiting quorum sensing may reduce rather than improve the therapeutic efficacy of CPS-specific phages. IMPORTANCEPhage resistance is a direct threat to phage therapy, and understanding phage-host interactions, especially bacteria block phage infection, is essential for developing successful phage therapy. In the present study, we demonstrate for the first time that V. alginolyticus uses QS to promote CPS-specific phage infection by upregulating the expression of ugd, which is necessary for the synthesis of Autographiviridae phage receptor capsular polysaccharide (CPS). Although increased CPS-specific phage susceptibility is a novel trade-off mediated by QS, it results in the upregulation of virulence factors, promoting biofilm development and enhanced capsular polysaccharide production in V. alginolyticus. This suggests that inhibiting QS may improve the effectiveness of antibiotic treatment, but it may also reduce the efficacy of phage therapy.

microbiology↗

bioRxiv2023

Conformational Space Profile Enhances Generic Molecular Representation Learning

The molecular representation model is a neural network that converts molecular representations (SMILES, Graph) into feature vectors, that carries the potential to be applied across a wide scope of drug discovery scenarios. However, current molecular representation models have been limited to 2D or static 3D structures, overlooking the dynamic nature of small molecules in solution and their ability to adopt flexible conformational changes crucial for drug-target interactions. To address this limitation, we propose a novel strategy that incorporates the conformational space profile into molecular representation learning. By capturing the intricate interplay between molecular structure and conformational space, our strategy enhances the representational capacity of our model named GeminiMol. Consequently, when pre-trained on a miniaturized molecular dataset, the GeminiMol model demonstrates a balanced and superior performance not only on traditional molecular property prediction tasks but also on zero-shot learning tasks, including virtual screening and target identification. By capturing the dynamic behavior of small molecules, our strategy paves the way for rapid exploration of chemical space, facilitating the transformation of drug design paradigms.

bioinformatics↗

bioRxiv2023

Regulation of blood pressure by METTL3 via RUNX1b-eNOS pathway in endothelial cells

BackgroundEndothelial cells regulate vascular tone to control the blood pressure (BP) by producing both relaxing and contracting factors. Previously, we identified methyltransferase-like 3 (METTL3), a primary N6-methyladenosine (m6A) methyltransferase, as a key player in alleviating endothelial atherogenic progression. However, its involvement in BP regulation remains unclear. MethodsTo evaluate the role of METTL3 in vivo, mice with EC specific METTL3 deficiency (EC-Mettl3KO) with or without Ang II infusion were used to create a hypertensive model. Functional and MeRIP sequencing analysis were performed to explore the mechanism of METTL3-mediated hypertension. ResultsWe observed a reduction in endothelial METTL3 activity by Ang II in vitro and in vivo. Endothelial METTL3-deficient mice exhibited higher BP than controls, both before and after Ang II infusion. Through m6A sequencing and functional analysis, we identified m6A modification of various RUNX1 monomers resulted in endothelial dysfunction. Mutations in the 3'UTR region of RUNX1b abolished its luciferase reporter activity, and enhanced eNOS promoter luciferase reporter activity with or without METTL3 overexpression. Overexpression of METTL3 by adeno-associated virus reduced Ang II-induced BP elevation. ConclusionThis study reveals that METTL3 alleviates hypertension through m6A-dependent stabilization of RUNX1b mRNA, leading to upregulation of eNOS, thus underscoring the pivotal role of RNA transcriptomics in the regulation of hypertension.

cell biology↗

bioRxiv2023

Two transcriptional cascades orchestrate cockroach leg regeneration

The mystery of appendage regeneration has fascinated humans for centuries, while the regulatory mechanisms remain unclear. In this study, a transcriptional landscape of regenerating leg was established in the American cockroach, Periplaneta americana, an ideal model for appendage regeneration with remarkable regeneration capacity. Through a large-scale in vivo screening, we identified multiple signaling pathways and transcription factors (TFs) controlling leg regeneration. Specifically, zfh-2 and bowl, which have not been previously implicated in appendage regeneration, contributes to blastema proliferation and morphogenesis in two novel transcriptional cascades BMP/JAK-STAT-zfh-2-bab1/B-H2/Lim1 and Notch-drm/bowl-bab1. Notably, zfh-2 was found working as a direct target of BMP signaling to promote cell proliferation in the blastema. These mechanisms might be conserved in the appendage regeneration of vertebrates from an evolutionary perspective. Overall, our findings reveal that two crucial transcriptional cascades orchestrate distinct cockroach leg regeneration processes, significantly advancing the comprehension of molecular mechanism in appendage regeneration.

developmental biology↗

bioRxiv2023

A phosphorylation-dependent switch of the lysosomal V-ATPase assembly regulates α-synuclein clearance in glia

Glia serve as double-edged swords to modulate neuropathology in Parkinsons disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating -synuclein (-syn) inclusions, remains elusive. Here we present evidence that dAuxilin (dAux), the Drosophila homolog of the PD risk factor Cyclin G-associated kinase (GAK), regulates the lysosomal degradation of -syn in glia. Lack of glial Gak/dAux increases the lysosome number and size, regulates lysosomal acidification and hydrolase activity, and ultimately blocks the degradation of substrates including -syn. Whereas -syn accumulated prominently in lysosomes devoid of glial dAux, levels of injected -syn preformed fibrils also further enhanced in the absence of microglial Gak. Mechanistically, dAux mediates phosphorylation at the serine 543 of Vha44, the V1C subunit of the vacuolar H+-ATPase (V-ATPase), regulates its assembly to control proper acidification of the lysosomal milieu. Expression of Vha44, but not the Vha44 variant lacking S543 phosphorylation, restores lysosome acidity, locomotor deficits, and DA neurodegeneration upon glial dAux depletion, linking this pathway to PD. Our findings identify a phosphorylation-dependent switch controlling the V-ATPase assembly for lysosomal -syn degradation in glia. Targeting the clearance of glial -syn inclusions via this lysosomal pathway could potentially be a therapeutical approach to ameliorate the disease progression in PD.

neuroscience↗

bioRxiv2023

Trying harder: how cognitive effort sculpts neural representations during working memory

The neural mechanisms by which motivational factors influence cognition remain unknown. Using fMRI, we tested how cognitive effort impacts working memory (WM). Participants were precued whether WM difficulty would be hard or easy. Hard trials demanded more effort as a later decision required finer mnemonic precision. Behaviorally, pupil size was larger and response times were slower on hard trials suggesting our manipulation of effort succeeded. Neurally, we observed robust persistent activity in prefrontal cortex, especially during hard trials. We found strong decoding of location in visual cortex, where accuracy was higher on hard trials. Connecting these across-region effects, we found that the amplitude of delay period activity in frontal cortex predicted decoded accuracy in visual cortex on a trial-wise basis. We conclude that the gain of persistent activity in frontal cortex may be the source of effort-related feedback signals that improve the quality of WM representations stored in visual cortex.

neuroscience↗

bioRxiv2023

Spatially resolved molecular and cellular atlas of the mouse brain

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding function of the brain. Here, using snRNA-seq and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters with single-cell resolution involving over 6 million cells as well as for 29,655 genes. We have identified new astrocyte clusters, and demonstrated that distinct cell clusters exhibit preference for cortical subregions. In addition, we identified 155 genes exhibiting regional specificity in the brainstem, and 513 long non-coding RNA exhibited regional specificity in the adult brain. Parcellation of brain regions based on spatial transcriptomic information showed large overlap with that by traditional method. Furthermore, we have uncovered 411 transcription factor regulons with spatiotemporal specificity during development. Thus, our study has discovered genes and regulon with spatiotemporal specificity, and provided a high-resolution spatial transcriptomic atlas of the mouse brain.

neuroscience↗

bioRxiv2023

Stereopy: modeling comparative and spatiotemporal cellular heterogeneity via multi-sample spatial transcriptomics

Tracing cellular dynamic changes across conditions, time, and space is crucial for understanding the molecular mechanisms underlying complex biological systems. However, integrating multi-sample data in a unified and flexible way to explore cellular heterogeneity remains a major challenge. Here, we present Stereopy, a flexible and versatile framework for modeling and dissecting comparative and spatiotemporal patterns in multi-sample spatial transcriptomics with interactive data visualization. To optimize this flexible framework, we have developed three key components: a multi-sample tailored data container, a scope controller, and an analysis transformer. Furthermore, Stereopy showcases three transformative applications supported by pivotal algorithms. Firstly, the multi-sample cell community detection (CCD) algorithm introduces an innovative capability to detect specific cell communities and identify genes responsible for pathological changes in comparable datasets. Secondly, the spatially resolved temporal gene pattern inference (TGPI) algorithm represents a notable advancement in detecting important spatiotemporal gene patterns while concurrently considering spatial and temporal features, which enhances the identification of important genes, domains and regulatory factors closely associated with temporal datasets. Finally, the 3D niche-based regulation inference tool, named NicheReg3D, reconstructs the 3D cell niches to enable the inference of cell-gene interaction network within the spatial texture, thus bridging intercellular communications and intracellular regulations to unravel the intricate regulatory mechanisms that govern cellular behavior. Overall, Stereopy serves as both a bioinformatics toolbox and an extensible framework that provides researchers with enhanced data interpretation abilities and new perspectives for mining multi-sample spatial transcriptomics data.

bioinformatics↗

bioRxiv2023

Comparative analysis of methodologies for detecting extrachromosomal circular DNA

Extrachromosomal circular DNA (eccDNA) is crucial in oncogene amplification, gene transcription regulation, and intratumor heterogeneity. While various analysis pipelines and experimental methods have been developed for eccDNA identification, their detection efficiencies have not been systematically assessed. To address this, we evaluated the performance of 7 analysis pipelines using three simulated datasets, in terms of accuracy, similarity, duplication rate, and computational resource consumption. We also compared the eccDNA detection efficiency of 7 experimental methods through twenty-one real sequencing datasets. Our results identified Circle-Map and CReSIL as the most effective pipelines for eccDNA detection through short-read and long-read sequencing data, respectively. Moreover, third-generation sequencing-based Circle-Seq showed superior efficiency in detecting copy number-amplified eccDNA over 10 kb in length. These results offer valuable insights for researchers in choosing the most suitable methods for eccDNA research.

cancer biology↗

bioRxiv2023

Phylogeny-metabolism dual-directed single-cell genomics for dissecting and mining ecosystem function

Although microbiome-wide association studies (MWAS) have uncovered many marker organisms for an ecosystem trait, mechanisms of most microbiota-mediated processes remain elusive, due to challenges in validating the markers in situ metabolic activities and tracing such activities to individual genomes. Here we introduced a phylogeny-metabolism dual-directed single-cell genomics approach called Fluorescence-In-Situ-Hybridization-guided Single-Cell Raman-activated Sorting and Sequencing (FISH-scRACS-Seq). It directly localizes individual cells from target taxon via a FISH probe for marker organism, profiles their in situ metabolic functions via single-cell Raman spectra, sorts cells of target taxonomy and target metabolism, and produces indexed, high-coverage and precisely-one-cell genomes. From cyclohexane-contaminated seawater, cells representing the MWAS-derived marker taxon of {gamma}-Proteobacteria and that are actively degrading cyclohexane in situ were directly identified via FISH and Raman respectively, then sorted and sequenced for one-cell full genomes. In such a Pseudoalteromonas fuliginea cell, we discovered a three-component cytochrome P450 system that can convert cyclohexane to cyclohexanol in vitro, representing a previously unknown group of cyclohexane-degrading enzymes and organisms. By culture-independently unveiling enzymes, pathways, genomes and their in situ functions specifically for those single-cells with ecological relevance, FISH-scRACS-Seq is a rational and generally applicable approach for dissecting and mining microbiota functions. TeaserFISH-scRACS-Seq is a new strategy to dissect microbiota functional mechanism at single-cell resolution.

microbiology↗

bioRxiv2023

Integration of ATAC-seq and RNA-seq identifies novel candidate genes associated with drought tolerance in Zoysia japonica Steud.

HighlightIntegration of ATAC-seq and RNA-seq identifies novel candidate genes associated with drought tolerance in Zoysia japonica Steud. The warm-season turfgrass Zoysia japonica is renowned for its drought resistance and serves as an exceptional domestic turfgrass in China. In order to unlock the potential of this native grass, identify drought-resistant genes, enhance the genetic transformation system, and maximize its utilization benefits, we conducted physiological characterization, multi-omics analysis, and RT-qPCR experimental verification in Zoysia japonica. This study suggested that 63 high-confidence genes related to drought stress and 6 motifs regulating drought responses were identified using a combined omics approach and RT-qPCR validation. The study discovered a positive correlation between ATAC-Seq peak intensity and gene expression levels. The expression of high-confidence genes was linked to Zoysia japonica resistance evaluation and phenotypic traits, implying that these genes are involved in responding to external drought stress. This study combined ATAC-seq and RNA-seq technologies for the first time to identify drought-related genes in Zoysia japonica, elucidating the grasss adaptation to environmental stress and the regulatory mechanisms underlying stress responses, and laying the groundwork for Zoysia japonica improvement and breeding.

genomics↗