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Biology subjects

Ye, Z.

Publications and source records attributed to Ye, Z..

At least 73 records · Page 4Linked to original sources

Brain-wide topographic coordination of traveling spiral waves

Traveling waves of activity are a prevalent phenomenon within neural networks of diverse brain regions and species, and have been implicated in myriad brain functions including sensory perception, memory, spatial navigation, and motor control. However, their spatial organization, anatomical basis, and whether they are locally confined versus distributed across the brain, remains unclear. Here we used cortex-wide imaging and large-scale electrophysiology in awake mice to reveal the organization of traveling waves across spatial scales. Traveling waves formed spiral patterns predominantly centered on somatosensory cortex, sweeping across somatotopic maps. Strikingly, the local axonal architecture of neurons in sensory cortex exhibited a matching circular arrangement. At the cortex-wide scale, these spiral waves were mirrored between hemispheres and between sensory and motor cortex, reflecting topographic long-range axons. At the brain-wide scale, cortical spiral waves were coordinated with subcortical spiking patterns in the thalamus, striatum, and midbrain. These results establish that traveling waves are shaped by axonal pathways into coordinated spiral patterns that globally impact neural activity across diverse brain systems, revealing a distributed, multi-sensory organizational principle for propagating neural activity.

neuroscience↗

High-throughput and scalable single cell proteomics identifies over 5000 proteins per cell

The emergence of mass spectrometry (MS)-based single-cell proteomics (SCP) promise to revolutionize the study of cellular biology and biomedicine by providing an unparalleled view of the proteome in individual cells. Despite its groundbreaking potential, SCP is nascent and faces challenges including limited sequence depth, throughput, and reproducibility, which have constrained its broader utility. This study introduces key methodological advances, which considerably improve the sensitivity, coverage and dependability of protein identification from single cells. We developed an almost lossless SCP workflow encompassing sample preparation to MS analysis, doubling the number of identified proteins from roughly 2000 to over 5000 in individual HeLa cells. A comprehensive evaluation of analytical software tools, alongside strict false discovery rate (FDR) controls solidified the reliability of our results. These enhancements also facilitated the direct detection of post-translational modifications (PTMs) in single cells, negating the need for enrichment and thereby simplifying the analytical process. Although throughput in MS remains a challenge, our study demonstrates the feasibility of processing up to 80 label-free SCP samples per day. Moreover, an optimized tissue dissociation buffer enabled effective single cell disaggregation of drug-treated cancer cell spheroids, refining the overall proteomic analysis. Our workflow sets a new benchmark in SCP for sensitivity and throughput, with broad applications ranging from the study of cellular development to disease progression and the identification of cell type-specific markers and therapeutic targets.

systems biology↗

Three-dimensional visualization of blood vessels in human gliomas based on tissue clearing and deep learning

Gliomas, with their intricate and aggressive nature, call for a detailed visualization of their vasculature. While many studies lean towards 2D imaging of thin sections, this method often overlooks the full spatial heterogeneity inherent to tumors. To overcome this limitation, our study melded state-of-the-art techniques, encompassing tissue clearing technology, 3D confocal microscopy imaging, and deep learning-aided vessel extraction, resulting in a comprehensive 3D visualization of glioma vasculature in intact human tissue. Specifically, we treated formalin-fixed thick human glioma tissue sections (500 m) with OPTIClear for transparency and subsequently performed immunofluorescent labeling using CD31. Using confocal microscopy, we obtained 3D images of the glioma vasculature. For vessel extraction, we employed a specialized 3D U-Net, enriched with image preprocessing and post-processing methods, and benchmarked its performance against the Imaris software. Our findings indicated that OPTIClear-enabled tissue clearing yielded a holistic 3D representation of immunolabeled vessels in clinical human glioma samples. Impressively, our deep learning technique outshined the traditional Imaris approach in terms of accuracy and efficiency in vessel extraction. Further, discernible variations in vascular metrics, such as mean diameter, branching point count, and volume ratio, were observed between low-grade and high-grade gliomas. In essence, our innovative blend of tissue clearing and deep learning not only enables enhanced 3D visualization of human glioma vasculature but also underscores morphological disparities across glioma grades, potentially influencing pathological grading, therapeutic strategies, and prognostic evaluations.

neuroscience↗

DREDge: robust motion correction for high-density extracellular recordings across species

High-density microelectrode arrays (MEAs) have opened new possibilities for systems neuroscience in human and non-human animals, but brain tissue motion relative to the array poses a challenge for downstream analyses, particularly in human recordings. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm which is well suited for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from spikes in the action potential (AP) frequency band, DREDge enables automated tracking of motion at high temporal resolution in the local field potential (LFP) frequency band. In human intraoperative recordings, which often feature fast (period <1s) motion, DREDge correction in the LFP band enabled reliable recovery of evoked potentials, and significantly reduced single-unit spike shape variability and spike sorting error. Applying DREDge to recordings made during deep probe insertions in nonhuman primates demonstrated the possibility of tracking probe motion of centimeters across several brain regions while simultaneously mapping single unit electrophysiological features. DREDge reliably delivered improved motion correction in acute mouse recordings, especially in those made with an recent ultra-high density probe. We also implemented a procedure for applying DREDge to recordings made across tens of days in chronic implantations in mice, reliably yielding stable motion tracking despite changes in neural activity across experimental sessions. Together, these advances enable automated, scalable registration of electrophysiological data across multiple species, probe types, and drift cases, providing a stable foundation for downstream scientific analyses of these rich datasets.

neuroscience↗

APOE4 poses opposite effects of plasma LDL on white matter integrity in older adults

INTRODUCTIONAPOE4 is a strong genetic risk factor of Alzheimers disease and is associated with changes in metabolism. However, the interactive relationship between APOE4 and plasma metabolites on the brain remains largely unknown. MEHODSIn the UK Biobank, we investigated the moderation effects of APOE4 on the relationship between 249 plasma metabolites derived from nuclear magnetic resonance spectroscopy on whole-brain white matter integrity, measured by fractional anisotropy using diffusion magnetic resonance imaging. RESULTSThe increase in the concentration of metabolites, mainly LDL and VLDL, is associated with a decrease in white matter integrity (b= -0.12, CI= [-0.14, -0.10]) among older APOE4 carriers, whereas an increase (b= 0.05, CI= [0.04, 0.07]) among non-carriers, implying a significant moderation effect of APOE4 (b= -0.18, CI= [-0.20,-0.15]). DISCUSSIONThe results suggest that lipid metabolism functions differently in APOE4 carriers compared to non-carriers, which may inform the development of targeted interventions for APOE4 carriers to mitigate cognitive decline.

neuroscience↗

Spatial-Live: A lightweight and versatile tool for single cell spatial-omics data visualization

Single cell spatial-omics data visualization plays a pivotal role in unraveling the intricate spatial organization and heterogeneity of cellular systems. Although various software tools and packages have been developed for this purpose, challenges persist in terms of user-friendly accessibility, data integration, and interactivity. In this study, we introduce Spatial-Live, a lightweight and versatile viewer tool designed for flexible single-cell spatial-omics data visualization. Spatial-Live overcomes the fundamental limitations of two-dimensional (2D) orthographic modes by employing a layer-stacking strategy, enabling efficient rendering of diverse data types with interactive features, and enhancing visualization with richer information in a unified three-dimensional (3D) space.

bioinformatics↗

Spatiotemporal Proteomics Deciphers Functional Selectivity of EGFR ligands

The epidermal growth factor receptor (EGFR) induces different signaling outputs depending on ligand identity and biological context. This phenomenon is known as functional selectivity, but the underlying molecular mechanisms remain elusive. Here, we investigated this on a global scale and time-resolved by high-throughput multilayered proteomics integrating dynamic changes in the EGFR interaction network by proximity biotinylation using EGFR- TurboID, phosphoproteome, and proteome in response to stimulation with the six highest-affinity EGFR ligands. We obtained comprehensive temporal profiles of protein recruitment and phosphosite changes pinpointing signaling proteins differentially regulated by the six ligands with key impact on EGFR endocytic fate, e.g. degradation or recycling. Specifically, the Epsin family protein, Clint1 was identified to control the endocytic trafficking of EGFR towards degradation. Moreover, we characterized the protein interaction selectivity of EGFR C-terminally phosphorylated tyrosine residues using a panel of tyrosine mutated constructs showing STAT5 specificity for EGFR Y1173. These data provide a comprehensive resource deciphering functional selectivity of EGFR signaling to support discovery of novel drug targets.

molecular biology↗

Inferring cell trajectories of spatial transcriptomics via optimal transport analysis

The integration of cell transcriptomics and spatial coordinates to organize differentiation trajectories remains a challenge. Here we introduce spaTrack, a trajectory inference method using optimal transport to incorporate both transcriptomics and distance of spatial transcriptomics sequencing data into transition costs. spaTrack could construct fine spatial trajectories reflecting the true differentiation topology, as well as trace cell dynamics across multiple samples with temporal intervals. To capture the dynamic drivers, spaTrack models the cell fate as a function of expression profile along temporal intervals driven by transcription factors. Applying spaTrack, we successfully disentangle spatiotemporal trajectories of axolotl telencephalon regeneration and mouse midbrain development. Furthermore, we uncover diverse malignant lineages expanding in a primary tumor. One of the lineages with upregulated extracellular matrix organization implants to the metastatic site and subsequently colonizes to a secondary tumor. Overall, spaTrack greatly facilitates trajectory inference from spatial transcriptomics, providing insights in cell differentiation of broad areas.

bioinformatics↗

Ultra-high density electrodes improve detection, yield, and cell type specificity of brain recordings

To understand the neural basis of behavior, it is essential to sensitively and accurately measure neural activity at single neuron and single spike resolution. Extracellular electrophysiology delivers this, but it has biases in the neurons it detects and it imperfectly resolves their action potentials. To minimize these limitations, we developed a silicon probe with much smaller and denser recording sites than previous designs, called Neuropixels Ultra (NP Ultra). This device samples neuronal activity at ultra-high spatial density ([~]10 times higher than previous probes) with low noise levels, while trading off recording span. NP Ultra is effectively an implantable voltage-sensing camera that captures a planar image of a neurons electrical field. We use a spike sorting algorithm optimized for these probes to demonstrate that the yield of visually-responsive neurons in recordings from mouse visual cortex improves up to [~]3-fold. We show that NP Ultra can record from small neuronal structures including axons and dendrites. Recordings across multiple brain regions and four species revealed a subset of extracellular action potentials with unexpectedly small spatial spread and axon-like features. We share a large-scale dataset of these brain-wide recordings in mice as a resource for studies of neuronal biophysics. Finally, using ground-truth identification of three major inhibitory cortical cell types, we found that these cell types were discriminable with approximately 75% success, a significant improvement over lower-resolution recordings. NP Ultra improves spike sorting performance, detection of subcellular compartments, and cell type classification to enable more powerful dissection of neural circuit activity during behavior.

neuroscience↗

Epstein-Barr virus BRRF1 induces butyrophilin 2A1 in nasopharyngeal carcinoma cells via the IL-22/JAK3-STAT3 pathway

Epstein-Barr virus is highly associated with nasopharyngeal carcinoma (NPC) with genes expressed for tumor transformation or maintenance of viral latency, but there are certain genes that can modulate immune molecules. Butyrophilin 2A1 (BTN2A1) is an important activating protein for presenting phosphoantigen presentation for recognition by V{gamma}9V{delta}2 T cells to achieve anti-tumor activities. We have previously shown that V{gamma}9V{delta}2 T cells achieve efficacy against NPC when BTN2A1 and BTN3A1 are upregulated by stimulating EBV gene expression, particularly LMP1. Whilst BTN3A1 can be induced by LMP1 mediated IFN-{gamma}/JNK/NLRC5 pathway, the viral gene that can regulate BTN2A1 remains elusive. Here, we showed that BTN2A1 expression is directly mediated by EBV BRRF1, which can trigger BTN2A1 promoter and downstream JAK3-STAT3 pathway in NPC43 cells as enlightened by RNA-seq data and verified by inhibitor experiments. Further, BRRF1 downregulated IL-22 binding protein (IL-22RA2) to complement the EBNA1-targeting probe (P4) induced IL-22 expression. These functions act in concordance to enhance the expression of BTN2A1, which likely lead to increased tumor cell killing by V{gamma}9V{delta}2 T cells. Overall, this study elucidated a new mechanism of stimulating BTN2A1 expression in nasopharyngeal carcinoma cells by the EBV gene BRRF1. Summary statementThis study demonstrated a new function Epstein-Barr Virus BRRF1 to induce BTN2A1 in nasopharyngeal carcinoma via the IL-22/JAK3-STAT3 pathway, which potentiates V{gamma}9V{delta}2 T cells against NPC.

immunology↗

One-Tip enables comprehensive proteome coverage in minimal cells and single zygotes

We present One-Tip, a lossless proteomics methodology that seamlessly combines swift, one-pot sample preparation with narrow-window data-independent acquisition mass spectrometric analysis. With simplest sample processing, One-Tip reproducibly identifies > 9,000 proteins from [~]1000 cells and [~] 6,000 proteins in a single mouse zygote with a throughput of 40 samples-per-day. This easy-to-use method expands capabilities of proteomics research by enabling greater depth, scalability and throughput covering low to high input samples.

biochemistry↗

RPRM as a potential preventive and therapeutic target for radiation-induced brain injury via multiple mechanisms

Patients receiving cranial radiotherapy for primary and metastatic brain tumors may experience radiation-induced brain injury (RIBI). So far there is a lack of effective preventive and therapeutic strategies for RIBI. Due to its complicated underlying pathogenic mechanisms, it is rather difficult to develop a single approach to target them simultaneously. We have recently reported that Reprimo (RPRM), a tumor suppressor gene, is a critical player in DNA damage repair, and RPRM deletion significantly confers radioresistance to mice. Here in this study, by using RPRM knockout (KO) mouse model established in our laboratory, we found that RPRM deletion alleviated RIBI in mice via targeting its multiple underlying mechanisms. Specifically, RPRM knockout significantly reduced hippocampal DNA damage and apoptosis shortly after mice were exposed to whole brain irradiation (WBI). For the late-delayed effect of WBI, RPRM knockout obviously ameliorated radiation-induced decline in neurocognitive function and dramatically diminished WBI-induced neurogenesis inhibition. Moreover, RPRM KO mice exhibited a significantly lower level of acute and chronic inflammation response and microglial activation than wild type (WT) mice did post WBI. Finally, we uncovered that RPRM knockout not only protected microglia against radiation-induced damage, thus prevented microglial activation, but also protected neurons and decreased the induction of CCL2 in neurons after irradiation, in turn attenuating the activation of microglial cells nearby through paracrine CCL2. Taken together, Our results indicate that RPRM plays a crucial role in the occurrence of RIBI, suggesting that RPRM may serve as a novel potential target for the prevention and treatment of RIBI.

neuroscience↗

Narrow-window DIA: Ultra-fast quantitative analysis of comprehensive proteomes with high sequencing depth

Mass spectrometry (MS)-based proteomics aims to characterize comprehensive proteomes in a fast and reproducible manner. Here, we present an ultra-fast scanning data-independent acquisition (DIA) strategy consisting on 2-Th precursor isolation windows, dissolving the differences between data-dependent and independent methods. This is achieved by pairing a Quadrupole Orbitrap mass spectrometer with the asymmetric track lossless (Astral) analyzer that provides >200 Hz MS/MS scanning speed, high resolving power and sensitivity, as well as low ppm-mass accuracy. Narrow-window DIA enables profiling of up to 100 full yeast proteomes per day, or [~]10,000 human proteins in half-an-hour. Moreover, multi-shot acquisition of fractionated samples allows comprehensive coverage of human proteomes in [~]3h, showing comparable depth to next-generation RNA sequencing and with 10x higher throughput compared to current state-of-the-art MS. High quantitative precision and accuracy is demonstrated with high peptide coverage in a 3-species proteome mixture, quantifying 14,000+ proteins in a single run in half-an-hour. TeaserAccurate and precise label-free quantification with comprehensive proteome coverage using narrow-window DIA

systems biology↗

SIX4 Controls STING Expression Enhancing anti-PD-1 Efficacy

The cGAS/STING cytosolic DNA sensing pathway plays a central role in anti-tumor immunity. Expression of STING is tightly regulated and commonly reduced or defective in many types of cancer. We have identified SIX4 as a significant regulator of STING expression in colon cancer cells. We showed that knockout of SIX4 decreased STING expression at the mRNA and protein levels while ectopic expression of SIX4 increased STING expression. Depletion of SIX4 led to attenuated STING activation and downstream signaling. Re-expression of SIX4 or ectopic expression of STING in SIX4 knockout cells reversed the effect. Ectopic expression of SIX4 enhanced DMXAA and cGAMP-induced STING activation and downstream signaling. Importantly, decrease of SIX4 expression substantially decreased tumor infiltration of CD8+ T-cells and reduced the efficacy of PD-1 antibodies to diminish tumor growth in immune competent mice in vivo. Finally, analysis of TCGA colon cancer dataset indicated that tumors with high SIX4 expression were significantly enriched in the Inflammatory Response pathway. SIX4 expression also correlated with expression of multiple IFN-stimulated genes, inflammatory cytokines and CD8A. Taken together, our results implicate that SIX4 is a principal regulator of STING expression in colon cancer cells, providing an additional mechanism and genetic marker to predict effective immune checkpoint blockade therapy responses.

cancer biology↗

Evolutionary Genomics of Sister Species Differing in Effective Population Sizes and Recombination Rates

Studies of closely related species with known ecological differences provide exceptional opportunities for understanding the genetic mechanisms of evolution. Here, we compared population-genomics data between D. pulex and D. pulicaria, two reproductively compatible sister species experiencing ecological speciation, the first largely confined to intermittent ponds and the second to permanent lakes in the same geographic region. D. pulicaria has lower genome-wide nucleotide diversity, a smaller effective population size, higher incidence of private alleles, and substantially more linkage-disequilibrium than D. pulex. Functional enrichment analysis revealed that positively selected genes in D. pulicaria are enriched in potentially aging-related categories such as cellular homeostasis, which may explain the extended lifespan in D. pulicaria. We also found that opsin-related genes, which may mediate photoperiodic responses, are under different selection pressures in these two species. Additionally, genes involved in mitochondrial functions, ribosomes, and responses to environmental stimuli are found to be under positive selection in both species. Our results provide insights into the physiological traits that differ within this regionally sympatric sister-species pair that occupies unique microhabitats.

evolutionary biology↗

The Genome-wide Signature of Short-term Temporal Selection

Despite evolutionary biologys obsession with natural selection, few studies have evaluated multi-generational series of patterns of selection on a genome-wide scale in natural populations. Here, we report on a nine-year population-genomic survey of the microcrustacean Daphnia pulex. The genome-sequences of > 800 isolates provide insights into patterns of selection that cannot be obtained from long-term molecular-evolution studies, including the pervasiveness of near quasi-neutrality across the genome (mean net selection coefficients near zero, but with significant temporal variance about the mean, and little evidence of positive covariance of selection across time intervals), the preponderance of weak negative selection operating on minor alleles, and a genome-wide distribution of numerous small linkage islands of observable selection influencing levels of nucleotide diversity. These results suggest that fluctuating selection is a major determinant of standing levels of variation in natural populations, challenge the conventional paradigm for interpreting patterns of nucleotide diversity and divergence, and motivate the need for the development of new theoretical expressions for the interpretation of population-genomic data. SignificanceExcept for mono/oligogenic traits known in advance to be under strong selection, there is little information on genome-wide patterns of temporal dynamics of allele-frequency changes in well-defined and unmanipulated natural populations. A multi-year survey of a population of the microcrustacean Daphnia pulex provides insight into these matters. Genome-wide analysis of > 800 genetic isolates demonstrates that temporal variation in selection intensity is a major determinant of levels of nucleotide polymorphism and divergence. Most nucleotide sites experience fluctuating selection with mean selection coefficients near zero, with little covariance in the strength of selection across time intervals, and with selection distributed across large numbers of genomic islands of linked sites. These results raise challenges for the conventional interpretation of measures of nucleotide diversity and divergence as indicators of effective population sizes and intensities of positive/negative selection.

evolutionary biology↗

Colocalization of Protein and microRNA Markers Reveals Unique Extracellular Vesicle Sub-Populations for Early Cancer Detection

Extracellular vesicles (EVs) play important roles in cell-cell communication but they are highly heterogeneous, and each vesicle has dimensions smaller than 200 nm thus encapsulates very limited amounts of cargos. We report the technique of NanOstirBar (NOB)-EnabLed Single Particle Analysis (NOBEL-SPA) that utilizes NOBs, which are superparamagnetic nanorods easily handled by a magnet or a rotating magnetic field, to act as isolated "islands" for EV immobilization and cargo confinement. NOBEL-SPA permits rapid inspection of single EV with high confidence by confocal fluorescence microscopy, and can assess the colocalization of selected protein/microRNA (miRNA) pairs in the EVs produced by various cell lines or present in clinical sera samples. Specific EV sub-populations marked by the colocalization of unique protein and miRNA combinations have been revealed by the present work, which can differentiate the EVs by their cells or origin, as well as to detect early-stage breast cancer (BC). We believe NOBEL-SPA can be expanded to analyze the co-localization of other types of cargo molecules, and will be a powerful tool to study EV cargo loading and functions under different physiological conditions, and help discover distinct EV subgroups valuable in clinical examination and therapeutics development.

cancer biology↗