Biology subjects

Ying, Y.

Publications and source records attributed to Ying, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Cytoskeletal-nuclear control of alveolar fibroblast identity directs lung regeneration

Respiratory mechanics direct cell fate in the lung, but the mechanisms by which these mechanical signals are sensed and transmitted to the nucleus to control cell state remain unclear. We paired in vivo perturbations of respiratory mechanics with single-cell genomics and found that alveolar fibroblasts are highly sensitive to physical changes in their microenvironment, exhibiting persistent shifts in their transcriptional identity after injury. Surprisingly, transmission of these signals through the nuclear envelope was not essential for maintaining transcriptional or epigenetic stability during homeostasis. However, severing mechanical-nuclear signaling promoted the normalization of alveolar fibroblast identity after acute injury, resulting in improved epithelial regeneration and reduced dysplastic remodeling. These studies reveal the importance of mechanical-nuclear signaling in the regulation of alveolar cell identity and function and reveal that targeting this complex can enhance tissue regeneration.

cell biology↗

bioRxiv2025

Membrane bending energy selects for compact growth of protein assemblies

Remodeling of cell membranes into vesicles is essential for receptor transport into cells and viral escape from infected cells. Membranes must be forced into these highly curved vesicles, and this is primarily driven through a structured assembly of multiple, multivalent interacting protein subunits forming a lattice. Lattice assembly from these subunits is a stochastic process, and intermediate structures formed during growth can vary in both structure and stability. Here we show that the membrane bending energy cost per protein rises significantly when remodeling is driven by lattice intermediates that deviate from compact, ideal spherical structures. We use a continuum membrane mechanics model coupled to lattice intermediates assembled from stochastic rigid-body simulations of HIV-1 Gag lattice assembly to quantify the bending energy as it systematically varies with lattice eccentricity. Our results show that highly eccentric lattices induce a higher bending energy cost because the lattices still deform the membrane into an approximate spherical cap, but the radius of the cap is larger due to the imperfect lattice geometry. These quantitative trends are also nearly independent of the density of links to the membrane, emphasizing the importance of the lattice perimeter shape instead. Rescaling thus recovers an approximately universal bending energy cost when evaluated relative to the circumscribing sphere of the lattice intermediates. These results show that assembly pathways coupled to membrane remodeling face much stronger selection pressure for highly compact growth compared to solution assembly pathways due to bending energy costs and provide a tool to characterize these pathways during processes like viral budding and endocytosis.

biophysics↗

bioRxiv2025

Modular Inter-brain Synchrony Network Associated with Social Difficulty in Autism Spectrum Disorder: a Graph Neural Network-Driven Hyperscanning Study

Understanding social difficulties in Autism Spectrum Disorder (ASD) remains challenging due to its neurobiological heterogeneity and the limited ecological validity of conventional neuroimaging methods in capturing dynamic social interactions. Hyperscanning analysis based on functional near-infrared spectroscopy (fNIRS), which measures inter-brain synchrony (IBS) during dyadic interaction, offers a novel avenue to address these challenges. However, prior studies on ASD have reported inconsistent findings, primarily focusing on intra-regional synchronization while overlooking cross-regional network dynamics. To bridge this gap, we proposed an interpretable graph neural network (GNN) model to systematically identify ASD-specific IBS modular network between child-caregiver dyads during naturalistic cooperative puzzle-solving and free-talking tasks. We identified distinctive key IBS sub-networks for the cooperative puzzle-solving task and free-talking task, with the frontal eye field (FEF) of caregivers, the dorsal lateral prefrontal cortex (DLPFC) and the motor region of children highlighted. Furthermore, the key IBS sub-networks were found to be able to predict multiple domains of the core ASD symptoms. By integrating hyperscanning with GNN-driven analysis, this work uncovers task-dependent inter-brain neural mechanisms underlying social difficulties in ASD. These findings advance the field by proposing a data-driven framework to identify IBS biomarkers tied to clinical profiles, paving the way for personalized interventions that integrate computational neuroscience with clinical practice.

neuroscience↗

bioRxiv2025

Mechanical force-mediated cellular crosstalk maintains the integrity of the lung gas exchange niche

Respiratory motion imposes a constant mechanical strain that has important but poorly defined impact on tissue niches in the lung. We developed a reversible bronchial ligation model to induce and reverse unilateral blockade of lung mechanical motion in vivo and show that this leads to transcriptomic changes in multiple cell lineages that are not normalized upon reinitiation of respiratory motion. Perturbation of mechanosignaling specifically in alveolar epithelial type I (AT1) cells alters the transcriptomic state and fate of their niche neighbors, demonstrating that AT1 cells act as a node that propagates a mechanical cascade throughout the lung alveolus. Mechanically perturbed AT1 cells induce a distinct capillary endothelial cell state that persists after reactivation of respiratory motion, which is mediated by an integrin/TGF-{beta} network within the alveolus that is vulnerable to pharmacological intervention. Importantly, AT1 mechanosignaling and intercellular communication are altered in chronic human lung diseases, highlighting the critical role of an AT1-driven mechanosensing network in lung disease biology. Thus, mechanosensing cells propagate biophysical signals that regulate tissue function and program tissue responses in disease.

cell biology↗

bioRxiv2024

Seed sequences mediate off-target activity in the CRISPR-interference (CRISPRi) system

The CRISPR interference (CRISPRi) system is a powerful tool that is widely used to selectively and efficiently silence genes in functional genomics research applications. However, the extent of off-target activity associated with the CRISPRi system has not been systematically investigated. Here, we utilized a genome-wide CRISPRi Cas9 single guide RNA (sgRNA) library to investigate the presence of off-target activity and its effects on gene expression. Our findings suggest that off-target effects in CRISPRi are quite pervasive and have direct and indirect impact on gene expression. Most of the identified off-target activities can be accounted for by complementarity of the PAM-proximal genomic sequence with the 3 half of the sgRNA spacer sequence, the seed sequence. We also report that not all PAM proximal positions are equally important for binding of sgRNA to the DNA and that mismatches in the PAM-proximal regions can be tolerated depending on the sequence context.

bioinformatics↗

bioRxiv2024

Role of non-coding RNA hsa_circ_0001495 in 16HBE cellular inflammation induced by PM2.5 and O3 combined exposure

BackgroundPM2.5 and O3 are the main air pollutants in China, and inflammation of the respiratory system is one of their main toxic effects. Cyclic RNAs are involved in many pathophysiological processes, but their relationship to the combined exposure to PM2.5 and O3 has not yet been investigated. ObjectiveTo elucidate the biological function played by hsa_circ_0001495 in the induction of 16HBE cellular inflammation by combined exposure to PM2.5 and O3. MethodDetection of cell survival after 24h exposure of 16HBE cells to a combination of PM2.5 and O3 by CCK8. RT-qPCR and ELISA were used to detect inflammatory factors in 16HBE cells after co-exposing to PM2.5 and O3. CircRNA was screened using high throughput sequencing and bioinformatics analysis approaches. RNaseR experiments were carried out to verify the circular RNA properties of the circRNAs. Cytoplasmic-nuclear subcellular localisation assays and fish assays were used to verify the distribution of circRNAs in the nucleus versus the cytoplasm of the cell. To validate functions related with circRNA,RT-qPCR and ELISA were employed. ResultCombined exposure to PM2.5 and O3 resulted in decreased cell viability.Combined exposure to PM2.5 and O3 resulted in 16HBE inflammation. High throughput sequencing and RT-qPCR results showed that the expression of hsa_circ_0001495 was significantly downregulated in 16HBE exposed to PM2.5 and O3 in combination. Hsa_circ_0001495 is not easily digested by RNaseR enzymes and has the properties of a circular RNA. Hsa_circ_0001495 is expressed in the cytoplasm as well as in the nucleus, but its distribution is predominantly in the cytoplasm. ConclusionIn 16HBE cells, combined exposure to PM2.5 and O3 can induce an inflammatory response.hsa_circ_0001495 plays an inhibitory role in the inflammatory response of 16HBE cells that can be induced by combined exposure to PM2.5 and O3.

molecular biology↗

bioRxiv2023

On Casein Kinase-2 (CK2) deregulation in NSCLC: an enzyme subunit-centered approach

CK2 is considered a constitutively active protein kinase promoting/supporting several neoplastic properties and inducing a so-called non-oncogene addiction in tumor cells. Compared to the extensive body of pre-clinical research, the translational and clinical information on CK2 is still limited. The holoenzyme, composed by a tetrameric array of two catalytic (CSNK2A1 and/or CSNK2A1) and two regulatory (CSNK2B) subunits, remains to be clinically validated. Herein, we interrogated available cancer multiomics databases to unravel CK2 deregulated expression in NSCLC. We focused our analysis on individual CK2 subunits assuming subunit-specific tumor supportive roles across cancers and particularly, within two major NSCLC subtypes. Moreover, we performed meta-analysis to uncover associations between CK2 expression and patient survival, as well as further correlations analysis with components of the tumor-microenvironment. The genomic and transcriptomic data analysis was complemented by IHC evaluation of CSNK2A1, CSNK2A2 and CSNK2B subunit expression, and CK2 enzymatic activity thereof. Overall, our data suggests that epigenetic, transcriptional and post-transcriptional regulatory mechanisms rather than mutational/gene amplification events may account for differential CK2 subunits expression/activity in NSCLC. Of note, CSNK2A1 and CSNK2B mRNA up-regulation consistently determine a worse patient prognosis in LUAD and correlated with increased infiltration of MDSCs/CAFs. Importantly, we corroborated that CK2 protein subunits levels and enzymatic activity are significantly exacerbated in LUAD and LUSC, but only CSNK2A1 positively correlated with tumor size and disease stage in the analyzed patient cohort, thus supporting our transcriptomic-based correlation analysis. Finally, we concluded that CSNK2A1 alone and/or the homo-tetramer thereof may be more instrumental to support NSCLC than CSNK2A2; thus, tailored drugs against these molecular CK2 entities may achieve better therapeutic windows at least for advanced lung cancer treatment.

cancer biology↗

bioRxiv2023

Fluorescence Image Data with Sparse and Low-Rank Poisson Regression

Multispectral biological fluorescence microscopy has enabled the identification of multiple targets in complex samples. The accuracy in the unmixing result degrades (1) as the number of fluorophores used in any experiment increases and (2) as the signal-to-noise ratio in the recorded images decreases. Further, the availability of prior knowledge regarding the expected spatial distributions of fluorophores in images of labeled cells provides an opportunity to improve the accuracy of fluorophore identification and abundance. We propose a regularized sparse and low-rank Poisson unmixing approach (SL-PRU) to deconvolve spectral images labeled with highly overlapping fluorophores which are recorded in low signal-to-noise regimes. Firstly, SL-PRU implements multi-penalty terms when pursuing sparseness and spatial correlation of the resulting abundances in small neighborhoods simultaneously. Secondly, SL-PRU makes use of Poisson regression for unmixing instead of least squares regression to better estimate photon abundance. Thirdly, we propose a method to tune the SL-PRU parameters involved in the unmixing procedure in the absence of knowledge of the ground truth abundance information in a recorded image. By validating on simulated and real-world images, we show that our proposed method leads to improved accuracy in unmixing fluorophores with highly overlapping spectra.

bioinformatics↗

bioRxiv2022

Microglial process dynamics enhance neuronal activity by shielding GABAergic synaptic inputs

Microglia are resident immune cells of the central nervous system (CNS) and play key roles in brain homeostasis. During anesthesia, microglia increase their dynamic process surveillance and interact more closely with neurons. However, the functional significance of microglial process dynamics and neuronal interaction has remained unclear. Using in vivo two-photon imaging in awake mice, we discover that microglia enhance neuronal activity after the cessation of general anesthesia. Hyperactive neuron somata are directly contacted by microglial processes, which specifically co-localize with GABAergic boutons. Electron microscopy-based synaptic reconstruction after two-photon imaging reveals that microglial processes enter into the synaptic cleft to shield GABAergic inputs. Microglial ablation or loss of microglial {beta}2-adrenergic receptors prevent post-anesthesia neuronal hyperactivity. Together, our study demonstrates a previously unappreciated function of microglial process dynamics, which allow microglia to transiently boost neuronal activity by physically shielding inhibitory inputs.

neuroscience↗

bioRxiv2022

Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1

Alveolar epithelial type 2 (AT2) cells harbor the facultative progenitor capacity in the lung alveolus to drive regeneration after lung injury. Using single cell transcriptomics, software-guided segmentation of tissue damage, and in vivo lineage tracing, we have identified the grainyhead transcription factor Tfcp2l1 as a key regulator of this regenerative process. Tfcp2l1 expression is initiated late in lung development and restricted to the AT2 cell population in the postnatal lung. Loss of Tfcp2l1 in adult AT2 cells decreased self-renewal and enhanced AT2-AT1 differentiation during active tissue regeneration. Conversely, Tfcp2l1 blunts the proliferative response to inflammatory signaling during the early acute phase after injury. This ability of Tfcp2l1 to temporally regulate the balance of AT2 self-renewal and differentiation is spatially restricted to zones undergoing active alveolar regeneration. Single-cell transcriptomics and lineage tracing reveal that Tfcp2l1 regulates cell fate dynamics by balancing the traffic across the AT2-AT1 differentiation axis and restricting the inflammatory program in AT2 cells. Organoid modeling shows that these cell fate dynamics are controlled by Tfcp2l1 regulation of IL-1 receptor expression and activity in AT2 cells. Together, these studies reveal the critical importance of properly staging lung alveolar regeneration and the integral role of Tfcp2l1 plays in balancing epithelial cell self-renewal and differentiation in this process.

cell biology↗

bioRxiv2022

Guided construction of single cell reference for human and mouse lung

Accurate cell type identification is a key and rate-limiting step in single cell data analysis. Single cell references with comprehensive cell types, reproducible and functional validated cell identities, and common nomenclatures are much needed by the research community to optimize automated cell type annotation and facilitate data integration, sharing, and collaboration. In the present study, we developed a novel computational pipeline to utilize the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples and constructed "LungMAP CellRef" and "LungMAP CellRef Seed" for both normal human and mouse lungs. "CellRef Seed" has an equivalent prediction power and produces consistent cell annotation as does "CellRef" but improves computational efficiency and simplifies its utilization for fast automated cell type annotation and online visualization. This atlas set incorporates 48 human and 40 mouse well-defined lung cell types catalogued from diverse anatomic locations and developmental time points. Using independent datasets, we demonstrated the utility of our CellRefs for automated cell type annotation analysis of both normal and disease lungs. User-friendly web interfaces were developed to support easy access and maximal utilization of the LungMAP CellRefs. LungMAP CellRefs are freely available to the pulmonary research community through fast interactive web interfaces to facilitate hypothesis generation, research discovery, and identification of cell type alterations in disease conditions.

bioinformatics↗

bioRxiv2022

Fluorescence visualization of deep-buried hollow organs

High-definition fluorescence imaging of deep-buried organs is still challenging. Here, we develop bright fluorophores emitting to 1700 nm by enhancing electron donating ability and reducing donor-acceptor distance. In parallel, the heavy water functions as the solvent of the delicately designed fluorophores, effectively reducing the fluorescent signal loss caused by the absorption by water. The near-infrared-II (NIR-II, 900-1880 nm) emission is eventually recovered and extended beyond 1400 nm. Compared with the spectral range beyond 1500 nm, the one beyond 1400 nm gives a more accurate fluorescence visualization of the hollow organs, owing to the absorption-induced scattering suppression. In addition, the intraluminal lesions containing much water are simultaneously negatively stained, leading to a stark contrast for precise diagnosis. Eventually, the intraluminally perfused fluorescent probes are excreted from mice and thus no obvious side effects emerge. This general method can provide new avenues for future biomedical imaging of deep and highly scattering tissues.

bioengineering↗

bioRxiv2021

Perfecting and extending the near-infrared biological window

In vivo fluorescence imaging in the second near-infrared window (NIR-II) has been considered as a promising technique for visualizing the mammals. However, the definition of the NIR-II region and the mechanism accounting for the excellent performance still need to be perfected. Herein, we simulated bioimaging in the NIR spectral range (to 2340 nm), confirmed the positive contribution of moderate light absorption by water in intravital imaging and perfected the NIR-II window as 900-1880 nm, where the 1400-1500 nm was defined as NIR-IIx region and the 1700-1880 nm was defined as NIR-IIc region, respectively. Moreover, the 2080-2340 nm was newly proposed as the third near-infrared (NIR-III) window, which was believed to provide the best imaging quality. The wide-field fluorescence microscopy in brain, in addition, was performed around NIR-IIx region with excellent optical sectioning strength and the largest imaging depth of in vivo NIR-II fluorescence microscopy to date. We also proposed 1400 nm long-pass detection in off-peak NIR-II imaging whose profits exceeded those of NIR-IIb imaging, using bright fluorophores with short peak emission wavelength.

bioengineering↗

bioRxiv2021

Aggregation-induced emission dots assisted non-invasive fluorescence hysterography in near-infrared IIb window

Uterine diseases seriously threaten the physical and mental health of women. The main principle, when clinicians adopt examinations, is to achieve efficient diagnosis without negative effect on the physical function including fertility. Hysterography in near-infrared (NIR) IIb window (1500-1700 nm) presents perceptibly enhanced signal to background ratio (SBR) and higher penetration capability compared with those beyond 1000 nm and 1300 nm, but lays down high requirements for the biosafety of fluorophores at the same time. Assisted by the biologically excretable aggregation-induced emission (AIE) dots, non-invasive NIR-IIb fluorescence hysterography visualized typical Y-shaped uteruses, real-time uterine peristalsis or the uterine lesions (mimetic disease statuses in clinic) in mouse models. Significantly, after intrauterine perfusion, the reproductive capacity was unimpaired via fertility assessment and histological analysis. This work could inspire some new ideas for non-invasive clinical diagnosis of uterine diseases and effectively promote the clinical translation of AIE dots.

bioengineering↗

bioRxiv2021

Adipocyte lipolysis abrogates skin fibrosis in a Wnt/DPP4-dependent manner

Tissue fibrosis in many organs results from altered and excessive extracellular matrix (ECM) protein deposition 1. Concomitant with ECM expansion, resident lipid-filled cells including mature adipocytes are lost in human and mouse fibrosis2-5, yet the mechanisms that drive mature adipocyte lipid loss and their contribution to tissue fibrosis are unknown. Here, we identify an early, fibro-protective role of mature adipocyte lipolysis driven by Wnt signaling during fibrosis onset. Using chemical and genetic mouse models of skin fibrosis, we show that fibrotic stimuli induce and maintain lipolysis in mature dermal adipocytes. Loss of the lipolytic rate-limiting enzyme adipocyte triglyceride lipase (ATGL)6,7 in murine dermal adipocytes exacerbates bleomycin-induced fibrosis development. Adipocyte lipolysis is stimulated in the early stages of Wnt signaling-induced skin fibrosis and by Wnt agonists in vitro. Furthermore, deletion or inhibition of the Wnt target gene, CD26/Dipeptidyl peptidase 4 (DPP4) prevented Wnt-induced lipolysis and skin fibrosis in mice. Notably, DPP4 expression correlates with skin fibrosis severity in human patients. Thus, we propose that adipocyte-derived fatty acids and the Wnt-DPP4 axis act as essential regulators of ECM homeostasis within tissues and provide a therapeutic avenue to manipulate fibrosis.

cell biology↗

bioRxiv2020

Optogenetic activation of spinal microglia triggers chronic pain in mice

Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in neuropathic pain. However, there has not been any direct evidence showing selective microglial activation in vivo is sufficient to induce chronic pain. Here we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity lasting for 5-7 days. In addition, activation of microglial ReaChR upregulated neuronal c-fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased IL-1{beta} production. IL-1 receptor antagonist was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.

neuroscience↗

bioRxiv2019

Microglial Calcium Signaling is Attuned to Neuronal Activity

Microglial calcium signaling underlies a number of key physiological processes in situ, but has not been studied in vivo in an awake animal where neuronal function is preserved. Using multiple GCaMP6 variants targeted to microglia, we assessed how microglial calcium signaling responds to alterations in neuronal activity across a wide physiological range. We find that only a small subset of microglial somata and processes exhibited spontaneous calcium transients. However, hyperactive and hypoactive shifts in neuronal activity trigger increased microglial process calcium signaling, often concomitant with process extension. On the other hand, changes in somatic calcium activity are only observed days after severe seizures. Our work reveals that microglia have highly distinct microdomain signaling, and that processes specifically respond to bi-directional shifts in neuronal activity through calcium signaling.

neuroscience↗

bioRxiv2019

Degradations of tannin and saponin during co-composting of shell and seed cake of Camellia oleifera Abel

The degradation processes were studied in this paper of tannin and saponin during the co-composting of the shell and seed cake of Camellia oleifera Abel. Four treatments were designed with the dry weight of the seed cake accounting for 1/3(A1), 1/4(A2), 1/5(A3), and 1/10(A4) of the shell. The proportion of the seed cake is positively correlated with the duration of thermophilic phase, highest temperature and degradation rate of tannin and saponin whose maximum were in A1, but negatively correlated with C/N ratio and tannin content which were least in A1 of the final products. The content of saponin were all about 2% finally. The final content of saponin and tannin decreased 68.92-75.22% and 34.57-59.52%. The organic matters, total nutrient (N, P2O5 and K2O) increased with the rising proportion of the seed cake. Overall, the addition of the seed cake promoted the stability, fertilizer efficiency and safety of the co-compost product.

pathology↗