Biology subjects

Zhou, J.

Publications and source records attributed to Zhou, J..

At least 343 records · Page 19Linked to original sources

bioRxiv2023

Demographic disequilibrium and growth-mortality asymmetry of forests across climate gradients

Forests are commonly believed to adapt themselves to environment and ultimately converge to demographic equilibrium characterized by a fixed size-structure. The expectation, however, has been lacking in mathematical rigor and been debating for evidential solidity. Here, by giving a general time-dynamic solution to the forest demographic model and verifying the prediction with worldwide forest inventory data, we show the inherent disequilibrium of forest demography with oscillations of forest-size-structure. Forests adapt to environment in a way of asymmetric growth-mortality tradeoff along climate gradients, which generates divergence to convergence oscillations of size-structure with rising temperature and precipitation. The demographic disequilibrium framework can provide a general basis for elucidating the variability of forest-size-structure with implications on intrinsic ecosystem instability, and for improving the Earth system modeling.

ecology↗

bioRxiv2023

Monitoring norepinephrine release in vivo using next-generation GRABNE sensors

Norepinephrine (NE) is an essential biogenic monoamine neurotransmitter, yet researches using prototype NE sensors were limited by their low sensitivities. Here, we developed next-generation versions of GPCR activation-based NE sensors (GRABNE2m and GRABNE2h) with a superior response, high sensitivity and selectivity to NE both in vitro and in vivo. Notably, these sensors can detect NE release triggered by either optogenetic or behavioral stimuli in freely moving mice, producing robust signals in the locus coeruleus and hypothalamus. With the development of a novel transgenic mouse line, we recorded both NE release and calcium dynamics with dual-color fiber photometry throughout the sleep-wake cycle; moreover, dual-color mesoscopic imaging revealed cell type-specific spatiotemporal dynamics of NE and calcium during sensory processing and locomotion. Thus, these new GRABNE sensors are valuable tools for monitoring the precise spatiotemporal release of NE in vivo, providing new insights into the physiological and pathophysiological roles of NE.

neuroscience↗

bioRxiv2023

The effect of circulation rate on the water quality of container-type recirculation aquaculture system under different feeding rates of Schizothorax wangchiachii

As an experimental fish, juvenile Schizothorax wangchiachii were fed different dosages (100, 300, or 500 g), and the changes in water quality in the inlet and outlet of the biofilter and in the aquaculture buckets were measured under different circulation rates (1.5, 3, or 4.5 m3/h; water samples were collected every 2 hours). With 100 g of feed and different circulation rates (1.5, 3, or 4.5 m3/h), the average removal rates of ammonia nitrogen and nitroso nitrogen by the biofilter were 40.4, 36.8, and 27.7% and 43.9, 36.9, and 29.8%, respectively. With 300 g of feed, the average removal rates of ammonia nitrogen and nitroso nitrogen were 42.3, 37.9, and 33.6% and 45.8, 32.7, and 21.7%, respectively. With 500 g of feed, the average removal rates of ammonia nitrogen and nitroso nitrogen by biofilters with different circulation rates were 53.5, 42.6, and 35.7% and 40.3, 26.5, and 18.1%, respectively. Therefore, when the feeding amounts were 100, 300, and 500 g, respectively, the optimal circulation rates were 1.5, 1.5, or 4.5 m3/h, which allowed the best management and reduction in energy consumption of the circulating aquaculture system. This research conclusion provides a reliable scientific reference for the promotion of a low-cost new model of industrial circular water aquaculture.

animal behavior and cognition↗

bioRxiv2023

Zona incerta distributes a broad movement signal that modulates behavior

The zona incerta is a subthalamic nucleus made up mostly of GABAergic neurons. It has wide- ranging inputs and outputs and is believed to have many integrative functions that link sensory stimuli with motor responses to guide behavior. However, its role is not well established perhaps because few studies have measured the activity of zona incerta neurons in behaving animals under different conditions. To record the activity of zona incerta neurons during exploratory and cue-driven goal-directed behaviors, we used electrophysiology in head-fixed mice moving on a spherical treadmill and fiber photometry in freely moving mice. We found two groups of neurons based on their sensitivity to movement, with a minority of neurons responding to whisker stimuli. Furthermore, zona incerta GABAergic neurons robustly code the occurrence of exploratory and goal-directed movements, but not their direction. To understand the function of these activations, we performed genetically targeted lesions and optogenetic manipulations of zona incerta GABAergic neurons during exploratory and goal-directed behaviors. The results showed that the zona incerta has a role in modulating the movement associated with these behaviors, but this has little impact on overall performance. Zona incerta neurons distribute a broad corollary signal of movement occurrence to their diverse projection sites, which regulates behavior.

neuroscience↗

bioRxiv2023

Quantifying and predicting chromatic thresholds

Perceptual thresholds measured in the two-dimensional chromatic diagram are elliptical in shape. Across different parts of the chromatic diagram, these ellipses vary in their sizes, their tilting angles, and in how much they elongate. Overall, the chromatic thresholds exhibit intriguing patterns that were reflected in McAdams measurements in 1942. Previously, da Fonseca and Samengo (2016) used a neural model combined with Fisher information (a quantification of perceptual thresholds) to predict the pattern of chromatic thresholds measured in human observers. The model assumes linear cone responses paired with Poisson noise. I furthered the analysis, and studied two additional aspects of chromatic perception. First, I quantified how the pattern of chromatic thresholds vary when the proportion of three cone types (short-, mid-, and long-wavelength) varies. This analysis potentially leads to efficient estimation of thresholds across the chromatic diagram. Second, I analyzed to what extent the assumption of Poisson noise contributes to the threshold predictions. Surprisingly, eliminating Poisson noise betters the model prediction. So in addition to Poisson noise, I examined three alternative noise assumptions, and achieved improved predictions to MacAdams data. At last, I examined an application using the improved model-predictions. The total number of cones, as well as the proportion of S cone vary across retinal eccentricities. I showed that these two variations predict chromatic threshold patterns across retinal eccentricities are drastically different.

neuroscience↗

bioRxiv2023

Targeting CD301+ macrophage inhibits endometrial fibrosis and improves pregnancy outcome

Macrophages are a key and heterogeneous cell population involved in endometrial repair and regeneration during the menstrual cycle, but their role in the development of intrauterine adhesion (IUA) and sequential endometrial fibrosis remains unclear. Here, we reported that CD301+ macrophages were significantly increased and showed their most active interaction with profibrotic cells in the endometria of IUA patients compared with the normal endometria by single-cell RNA sequencing, bulk RNA sequencing and experimental verification. Increasing CD301+ macrophages promoted the differentiation of endometrial stromal cells into myofibroblasts and resulted in extracellular matrix accumulation, which destroyed the physiological architecture of endometrial tissue, drove endometrial fibrosis and ultimately led to female infertility or adverse pregnancy outcomes. Mechanistically, CD301+ macrophages secreted GAS6 to activate the AXL/NF-{kappa}B pathway, up-regulating the profibrotic protein synthesis. Targeted deletion of CD301+ macrophages or inhibition of AXL by Bemcentinib blunted the pathology and improved the outcomes of pregnancy in mice, supporting the therapeutic potential of targeting CD301+ macrophages for treating endometrial fibrosis.

immunology↗

bioRxiv2023

The Genetic Architecture of Dietary Iron Overload and Associated Pathology in Mice

Tissue iron overload is a frequent pathologic finding in multiple disease states including non-alcoholic fatty liver disease (NAFLD), neurodegenerative disorders, cardiomyopathy, diabetes, and some forms of cancer. The role of iron, as a cause or consequence of disease progression and observed phenotypic manifestations, remains controversial. In addition, the impact of genetic variation on iron overload related phenotypes is unclear, and the identification of genetic modifiers is incomplete. Here, we used the Hybrid Mouse Diversity Panel (HMDP), consisting of over 100 genetically distinct mouse strains optimized for genome-wide association studies and systems genetics, to characterize the genetic architecture of dietary iron overload and pathology. Dietary iron overload was induced by feeding male mice (114 strains, 6-7 mice per strain on average) a high iron diet for six weeks, and then tissues were collected at 10-11 weeks of age. Liver metal levels and gene expression were measured by ICP-MS/ICP-AES and RNASeq, and lipids were measured by colorimetric assays. FaST-LMM was used for genetic mapping, and Metascape, WGCNA, and Mergeomics were used for pathway, module, and key driver bioinformatics analyses. Mice on the high iron diet accumulated iron in the liver, with a 6.5 fold difference across strain means. The iron loaded diet also led to a spectrum of copper deficiency and anemia, with liver copper levels highly positively correlated with red blood cell count, hemoglobin, and hematocrit. Hepatic steatosis of various severity was observed histologically, with 52.5 fold variation in triglyceride levels across the strains. Liver triglyceride and iron mapped most significantly to an overlapping locus on chromosome 7 that has not been previously associated with either trait. Based on network modeling, significant key drivers for both iron and triglyceride accumulation are involved in cholesterol biosynthesis and oxidative stress management. To make the full data set accessible and useable by others, we have made our data and analyses available on a resource website. Author summaryThe response to a high iron diet is determined in part by genetic factors. We now report the responses to such a diet in a diverse set of inbred strains of mice, known as the Hybrid Mouse Diversity Panel, that enables high resolution genetic mapping and systems genetics analyses. The levels of iron in the liver varied about >5 fold across the strains, with genetic variation explaining up to 74% of the variation in liver iron. Pathologies included copper deficiency, anemia, and fatty liver, with liver triglycerides varying over 50 fold among the strains. Genetic mapping and network modeling identified significant genetic loci and pathways underlying the response to diet.

genetics↗

bioRxiv2023

Accurate identification of structural variations from cancer samples

Structural variations (SVs) are commonly found in cancer genomes. They can cause gene amplification, deletion, and fusion, among other functional consequences. With an average read length of hundreds of kilobases, nano-channel-based optical DNA mapping is powerful in detecting large SVs. However, existing SV calling methods are not tailored for cancer samples, which have special properties such as mixed cell types and sub-clones. Here we propose the COMSV method that is specifically designed for cancer samples. It shows high sensitivity and specificity in benchmark comparisons. Applying to cancer cell lines and patient samples, COMSV identifies hundreds of novel SVs per sample.

genomics↗

bioRxiv2023

VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomes

Meningeal lymphatic vessels promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelium growth factor-C (VEGF-C) is essential for meningeal lymphatic development and maintenance and has therapeutic potential for treating neurological disorders, including ischemic stroke. We have investigated the effects of VEGF-C overexpression on brain fluid drainage, single cell transcriptome in the brain, and stroke outcomes in adult mice. Intra-cerebrospinal fluid administration of an adeno-associated virus expressing VEGF-C (AAV-VEGF-C) increases the CNS lymphatic network. Post-contrast T1 mapping of the head and neck showed that deep cervical lymph node size and drainage of CNS-derived fluids were increased. Single nuclei RNA sequencing revealed a neuro-supportive role of VEGF-C via upregulation of calcium and brain-derived neurotrophic factor (BDNF) signaling pathways in brain cells. In a mouse model of ischemic stroke, AAV-VEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage. AAV-VEGF-C thus promotes CNS-derived fluid and solute drainage, confers neuroprotection, and reduces ischemic stroke damage. Short abstractIntrathecal delivery of VEGF-C increases the lymphatic drainage of brain-derived fluids confers neuroprotection, and improves neurological outcomes after ischemic stroke.

neuroscience↗

bioRxiv2023

Shortcut barcoding and early pooling for scalable multiplex single-cell reduced-representation CpG methylation sequencing at single nucleotide resolution

DNA methylation is essential for a wide variety of biological processes, yet the development of a highly efficient and robust technology remains a challenge for routine single-cell analysis. We developed a multiplex scalable single-cell reduced representation bisulfite sequencing (msRRBS) technology with off-the-shelf reagents and equipment. It allows cell-specific barcoded DNA fragments of individual cells to be pooled before bisulfite conversion, free of enzymatic modification or physical capture of the DNA ends, and achieves unparalleled read mapping rates of 62.51%, covering 59.95% of CpG islands and 71.62% of promoters in K562 cells on average. Its reproducibility is shown in duplicates of bulk cells with near perfect correlation (R=0.97-99). At a low 1 Mb of clean reads, msRRBS provides consistent coverage of CpG islands and promoters, outperforming the conventional methods with orders of magnitude reduction in cost. Here, we use this method to characterize the distinct methylation patterns and cellular heterogeneity of 6 cell lines, and leukemia and hepatocellular carcinoma models. Taking 4 hours of hands-on time, msRRBS offers a unique, highly efficient approach for dissecting methylation heterogeneity in a variety of multicellular systems.

genomics↗

bioRxiv2023

Spatio-temporal patterns of ovarian development and VgR gene silencing reduced fecundity of parthenogenetic Artemia

Halophilic zooplankton brine shrimp Artemia has been used as an experimental animal in multidisciplinary research. However, the reproductive patterns and regulation mechanisms of Artemia remain a mystery. In this study, the ovarian development process of parthenogenetic Artemia (P. Artemia) was distinguished into five stages, and oogenesis or egg formation process was identified with six phases. The mode of oogenesis was assumed polytrophic. Moreover, we traced the dynamic translocation of germline stem cells (GSCs) by EdU labeling, elucidated several key cytological events in oogenesis through HE staining and florescent image. Notably, distinguished from the ovary structure of insects and crustaceans, P. Artemia germarium originated from ovariole buds and located in the base of the ovarioles. RNA-seq based on five stages of ovarian development revealed that 2657 up-regulated genes related to reproduction were obtained by pair-to-pair comparison of RNA-seq. Furthermore, Gbb, Dpp, piwi, vasa, nanos, VgA and VgR associated with GSCs recognition and reproductive development genes were screened and also verified by qPCR. Silencing of the VgR gene in P. Artemia (PA-VgR) at stage L of ovarian development led to a low level of gene expression (<10%) within five days, which resulted variations of oogenesis-related gene expression and significantly inhibited vitellogenesis, impeded oocyte maturation, and eventually decreased the offspring number. In conclusion, we illustrated the patterns of ovarian development, outlined the key spatio-temporal features of oogenesis and established a platform for gene function research using P. Artemia as an experimental animal. These results lay the foundation for studying the reproductive biology of invertebrates, may also provide a novel insight in the reproductive regulation mechanism of aquatic animals in extreme environments. SUMMARY STATEMENTArtemia is a novel experimental platform and potential "model" crustacean for studying specific process and mechanism of reproduction.

developmental biology↗

bioRxiv2023

Schema cell formation in orbitofrontal cortex is suppressed by hippocampal output

Both orbitofrontal cortex (OFC) and hippocampus (HC) are implicated in the formation of cognitive maps and their generalization into schemas. However how these areas interact in supporting this function remains an open question, with some proposals supporting a serial model in which OFC draws upon task representations created by HC to extract key behavioral features and others proposing a parallel model in which both regions construct representations that highlight different types of information. Here we tested between these two models by asking how schema correlates in OFC would be affected by inactivation of HC output, after learning and during transfer across problems. We found the prevalence and content of schema correlates were unaffected by inactivation after learning, while inactivation during learning accelerated their formation. These results contradict a serial model and favor the proposal that OFC and HC operate in parallel to extract different features defining cognitive maps and schemas.

neuroscience↗

bioRxiv2023

A leaky integrate-and-fire computational model based on the connectome of the entire adult Drosophila brain reveals insights into sensorimotor processing

The forthcoming assembly of the adult Drosophila melanogaster central brain connectome, containing over 125,000 neurons and 50 million synaptic connections, provides a template for examining sensory processing throughout the brain. Here, we create a leaky integrate-and-fire computational model of the entire Drosophila brain, based on neural connectivity and neurotransmitter identity, to study circuit properties of feeding and grooming behaviors. We show that activation of sugar-sensing or water-sensing gustatory neurons in the computational model accurately predicts neurons that respond to tastes and are required for feeding initiation. Computational activation of neurons in the feeding region of the Drosophila brain predicts those that elicit motor neuron firing, a testable hypothesis that we validate by optogenetic activation and behavioral studies. Moreover, computational activation of different classes of gustatory neurons makes accurate predictions of how multiple taste modalities interact, providing circuit-level insight into aversive and appetitive taste processing. Our computational model predicts that the sugar and water pathways form a partially shared appetitive feeding initiation pathway, which our calcium imaging and behavioral experiments confirm. Additionally, we applied this model to mechanosensory circuits and found that computational activation of mechanosensory neurons predicts activation of a small set of neurons comprising the antennal grooming circuit that do not overlap with gustatory circuits, and accurately describes the circuit response upon activation of different mechanosensory subtypes. Our results demonstrate that modeling brain circuits purely from connectivity and predicted neurotransmitter identity generates experimentally testable hypotheses and can accurately describe complete sensorimotor transformations.

neuroscience↗

bioRxiv2023

Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections

Single-cell genetic and epigenetic analyses parse the brains billions of neurons into thousands of "cell-type" clusters, each residing in different brain structures. Many of these cell types mediate their unique functions by virtue of targeted long-distance axonal projections to allow interactions between specific cell types. Here we have used Epi-Retro-Seq to link single cell epigenomes and associated cell types to their long-distance projections for 33,034 neurons dissected from 32 different source regions projecting to 24 different targets (225 source [->]target combinations) across the whole mouse brain. We highlight uses of this large data set for interrogating both overarching principles relating projection cell types to their transcriptomic and epigenomic properties and for addressing and developing specific hypotheses about cell types and connections as they relate to genetics. We provide an overall synthesis of the data set with 926 statistical comparisons of the discriminability of neurons projecting to each target for every dissected source region. We integrate this dataset into the larger, annotated BICCN cell type atlas composed of millions of neurons to link projection cell types to consensus clusters. Integration with spatial transcriptomic data further assigns projection-enriched clusters to much smaller source regions than afforded by the original dissections. We exemplify these capabilities by presenting in-depth analyses of neurons with identified projections from the hypothalamus, thalamus, hindbrain, amygdala, and midbrain to provide new insights into the properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription factor binding motifs, and neurotransmitter usage.

neuroscience↗

bioRxiv2023

Decoding human in vitro terminal erythropoiesis originating from umbilical cord blood mononuclear cells and pluripotent stem cells

Ex vivo RBC production generates unsatisfactory expansion, {beta}-globin expression, and maturation of erythroid cells. The underlying mechanisms behind these limitations and ex vivo terminal erythropoiesis from different origins are largely unexplained. In this study, we mapped an atlas of ex vivo terminally differentiated cells from umbilical cord blood mononuclear cells (UCBMNs) and pluripotent stem cells (PSCs), and observed the differential regulatory dynamics of erythropoiesis from these two origins at a single-cell resolution. We detected the presence of hematopoietic stem progenitor cells (HSPCs), erythroid progenitor (e.g., CFU-E), and non-erythroid cells (e.g., macrophages) in the terminal populations. We observed that UCBMN-derived erythropoiesis is more active than PSC-derived erythropoiesis in terms of the cell cycle, stress erythropoiesis, and autophagy at single cell resolution, which may provide new insights into the limitations in cell expansion, globin expression, and maturation in ex vivo RBC production, respectively. We verified that a stress-erythropoiesis-related gene, TRIB3, increases the expression of globin genes in ex vivo erythropoiesis. As the major unexpected component detected in terminally differentiated cells, CFU-E were further characterized as having high- or low- expansion capacity based on CD99 expression, which generally decreased over erythropoiesis. By inhibiting CD99 gene expression using antagonists, we increased reticulocyte production in the population. Heterogeneous CFU-Es also exist in bone marrow. Moreover, decreased CD99 expression mediates the interactions between macrophages and CFU-E during ex vivo erythropoiesis. Overall, our results provide a reference for facilitating the development of strategies to improve ex vivo RBC regeneration. HighlightsO_LIWe performed scRNA-seq and cell typing of late stage UCBMN- and PSC-derived cells C_LIO_LIStress erythropoiesis, autophagy and cell cycle related gene expression different in two origins C_LIO_LICD99high progenitor cells are a proliferating colony forming unit erythroid subpopulation C_LI

cell biology↗

bioRxiv2023

Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain

Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brains 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq1) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH2) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq3 dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brains cellular-spatial and regulatory genome diversity.

genomics↗

bioRxiv2023

Time-resolved single-cell and spatial gene regulatory atlas of plants under pathogen attack

Plant leaf intercellular space provides a nutrient-rich and heterogeneous niche for microbes that critically impacts plant health. However, how individual plant cells respond to heterogeneous microbial colonization remains largely elusive. Here, by time-resolved simultaneous single-cell transcriptome and epigenome profiling of plants (Arabidopsis thaliana) infected by virulent and avirulent bacterial pathogens (Pseudomonas syringae), we present cell atlases with gene regulatory logic involving transcription factors, putative cis-regulatory elements, and target genes associated with disease and immunity. We also identify previously uncharacterized cell populations with distinct immune gene expression within major developmental cell types. Furthermore, we employ time-resolved spatial transcriptomics to reveal spatial heterogeneity of plant immune responses linked to pathogen distribution. Integrating our single-cell multiomics and spatial omics data enables spatiotemporal mapping of defense gene regulatory logic with pathogen cells. Our study provides a molecularly-defined spatiotemporal map of plant-microbe interaction at the single-cell resolution.

plant biology↗

bioRxiv2023

Comparative single cell epigenomic analysis of gene regulatory programs in the rodent and primate neocortex

Sequence divergence of cis-regulatory elements drives species-specific traits, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains to be elucidated. We investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset, and mouse with single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome, and chromosomal conformation profiles from a total of over 180,000 cells. For each modality, we determined species-specific, divergent, and conserved gene expression and epigenetic features at multiple levels. We find that cell type-specific gene expression evolves more rapidly than broadly expressed genes and that epigenetic status at distal candidate cis-regulatory elements (cCREs) evolves faster than promoters. Strikingly, transposable elements (TEs) contribute to nearly 80% of the human-specific cCREs in cortical cells. Through machine learning, we develop sequence-based predictors of cCREs in different species and demonstrate that the genomic regulatory syntax is highly preserved from rodents to primates. Lastly, we show that epigenetic conservation combined with sequence similarity helps uncover functional cis-regulatory elements and enhances our ability to interpret genetic variants contributing to neurological disease and traits.

genomics↗