Biology subjects

Zhao, T.

Publications and source records attributed to Zhao, T..

176 records · Page 10Linked to original sources

bioRxiv2018

Mesenchymal stem cell derived exosomes enhance lymphangiogenesis via exosomal transfer of Ang-2/Tie2

Mesenchymal stem cell derived exosomes (MSC-Ex) are nanosized membrane-bound extracellular vesicles found in MSC conditioned medium, that have yielded beneficial effects in several experimental models of organ injury. However, the therapeutic value and mechanism of MSC-Ex in lymphedema is poorly understood. Here we find that human umbilical cord MSCs derived exosomes (hucMSC-Ex) treatment contributed to the regeneration of LYVE-1 positive lymphatic vessels and reduction of lymphedema in a mouse model of tail lymphedema. Following uptake, exosomal lymphangiogenic factors (angiopoietin (Ang)-2 and Tie2) are taken up by HDLECs and promoted HDLECs proliferation, migration, and tube formation in vitro. We also find that exosomal Ang-2 and Tie2 exert a prolymphangiogenic effect on HDLECs through upregulating Prox1 and VEGFR3/p-Akt expression. In conclusion, our result unravel a previously unappreciated prolymphangiogenic role of hucMSC-Ex in lymphedema therapy and provide a new mechanism of Ang-2 in therapeutic lymphangiogenesis.

bioengineering↗

bioRxiv2018

Synaptic circuits for irradiance coding by intrinsically photosensitive retinal ganglion cells

We have explored the synaptic networks responsible for the unique capacity of intrinsically photosensitive retinal ganglion cells (ipRGCs) to encode overall light intensity. This luminance signal is crucial for circadian, pupillary and related reflexive responses light. By combined glutamate-sensor imaging and patch recording of postsynaptic RGCs, we show that the capacity for intensity-encoding is widespread among cone bipolar types, including OFF types.\n\nNonetheless, the bipolar cells that drive ipRGCs appear to carry the strongest luminance signal. By serial electron microscopic reconstruction, we show that Type 6 ON cone bipolar cells are the dominant source of such input, with more modest input from Types 7, 8 and 9 and virtually none from Types 5i, 5o, 5t or rod bipolar cells. In conventional RGCs, the excitatory drive from bipolar cells is high-pass temporally filtered more than it is in ipRGCs. Amacrine-to-bipolar cell feedback seems to contribute surprisingly little to this filtering, implicating mostly postsynaptic mechanisms. Most ipRGCs sample from all bipolar terminals costratifying with their dendrites, but M1 cells avoid all OFF bipolar input and accept only ectopic ribbon synapses from ON cone bipolar axonal shafts. These are remarkable monad synapses, equipped with as many as a dozen ribbons and only one postsynaptic process.

neuroscience↗

bioRxiv2018

PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts and white matter changes

Exome sequencing of two sisters with congenital cataracts, short stature and white matter changes identified compound heterozygous variants in the PISD gene, encoding the phosphatidylserine decarboxylase enzyme that converts phosphatidylserine (PS) to phosphatidylethanolamine (PE) in the inner mitochondrial membrane (IMM). Decreased conversion of PS to PE, and depletion of total cellular PE levels in patient fibroblasts are consistent with impaired PISD enzyme activity. Meanwhile, as evidence for mitochondrial dysfunction, patient fibroblasts exhibited more fragmented mitochondrial networks, enlarged lysosomes, decreased maximal oxygen consumption rates and increased sensitivity to 2-deoxyglucose. Moreover, treatment with lyso-PE, which can replenish the mitochondrial pool of PE, restored mitochondrial and lysosome morphology in patient fibroblasts. Functional characterization of the PISD mutations demonstrates that the maternal variant causes an alternative splice product. Meanwhile, the paternal variant impairs autocatalytic self-processing of the PISD protein required for its activity. Finally, evidence for impaired activity of mitochondrial IMM proteases explains why the phenotypes of these PISD patients resemble recently described \"mitochondrial chaperonopathies\". Collectively, these findings demonstrate that PISD is a novel mitochondrial disease gene.

molecular biology↗

bioRxiv2018

Unbiased Age-Appropriate Structural Brain Atlases for Chinese Pediatrics

In magnetic resonance imaging (MRI) studies of children brain development, structural brain atlases usually serve as important references of pediatric population in which individual images are spatially normalized into a common or standard stereotactic space. However, the existing popular children brain atlases (e.g., National Institutes of Health pediatric atlases, NIH-PD atlases) are made mostly based on MR images from Western populations, and are thus insufficient to characterize the brains of Chinese children due to the neuroanatomical differences that are relevant to genetic and environmental factors. By collecting high-quality T1- and T2- weighted MR images from 328 typically developing Chinese children aged from 6 to 12 years old, we created a set of age-appropriate Chinese pediatric (CHN-PD) atlases using an unbiased template construction algorithm. The CHN-PD atlases included the head/brain templates, the symmetric brain template, the gender-specific brain templates and the corresponding tissue probability atlases. Moreover, the atlases contained multiple age-specific templates with a one-year interval. A direct comparison of the CHN-PD and the NIH-PD atlases revealed remarkable anatomical differences bilaterally in the lateral frontal and parietal regions and somatosensory cortex. While applying the CHN-PD atlases to two independent Chinese pediatric datasets (N = 114 and N = 71, respectively), machine-learning regression approaches revealed higher prediction accuracy on brain ages than the usage of NIH-PD atlases. These results suggest that the CHN-PD brain atlases are necessary and important for future typical and atypical developmental studies in Chinese pediatric population. Currently, the CHN-PD atlases have been released on the NITRC website (https://www.nitrc.org/projects/chn-pd).

neuroscience↗

bioRxiv2018

Cerebrovascular damages induce lymphatic invasion into brain parenchyma to guide vascular regeneration

Damage to regional cerebrovascular network and neuronal tissues occurs during acute cerebrovascular diseases, such as ischemic stroke. The promotion of vascular regeneration is the most promising therapeutic approach. To understand cellular and molecular mechanisms underlying brain vascular regeneration, we developed two zebrafish cerebrovascular injury models using genetic ablation and photochemical thrombosis. Although brain parenchyma is physiologically devoid of lymphatic vasculature, we found that cerebrovascular injuries induce rapid ingrowth of meningeal lymphatics into the injured parenchyma. The ingrown lymphatics on one hand become lumenized drain interstitial fluid to resolve brain edema, on the other hand act as \"growing tracks\" for nascent blood vessels. The ingrown lymphatic vessels undergo apoptosis and clearance after cerebrovascular regeneration. This study reveals a pathological function of meningeal lymphatics, through previously unexpected ingrowth into brain parenchyma and a newly identified lymphatic function as vascular \"growing tracks\".\n\nHIGHLIGHTSCerebrovascular injuries induce lymphatic ingrowth into the injured brain parenchyma The ingrown lymphatics drain interstitial fluid to resolve brain edema Nascent blood vessels use the ingrown lymphatic vessels as \"growing tracks\" The ingrown lymphatic vessels undergo apoptosis after vascular regeneration completes

developmental biology↗

bioRxiv2018

Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2

Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA on HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression of the lncRNA ANRIL was elevated in HTLV-1 infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knocking down of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2, and activated the NF-{kappa}B pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2, but required the formation of an ANRIL/EZH2/p65 ternary complex. Chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.\n\nIMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that lncRNA ANRIL was important for maintaining proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-{kappa}B signaling through forming a ternary complex with EZH2 and p65. Further, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1 associated human diseases.

cancer biology↗

bioRxiv2018

Mitochondria promote neuropeptide secretion in Caenorhabditis elegans by preventing activation of hypoxia inducible factor

Neurons are highly dependent on mitochondrial function, and mitochondrial damage has been implicated in many neurological and neurodegenerative diseases. Relatively little is known about how mitochondria regulate neuronal function. Here we show that axonal mitochondria are necessary for neuropeptide secretion in Caenorhabditis elegans, and that oxidative phosphorylation, but not mitochondrial calcium uptake, is required for secretion. Oxidative phosphorylation produces cellular ATP, reactive oxygen species, and consumes oxygen. Disrupting any of these functions could inhibit neuropeptide secretion. We show that blocking mitochondria transport into axons inhibits neuropeptide secretion through activation of the hypoxia inducible factor HIF-1. Our results suggest that axonal mitochondria modulate neuropeptide secretion by regulating transcriptional responses induced by metabolic stress.

neuroscience↗

bioRxiv2018

Loss of SDHB reprograms energy metabolisms and inhibits high fat diet induced metabolic syndromes

Mitochondrial respiratory complex II utilizes succinate, key substrate of the Krebs cycle, for oxidative phosphorylation, which is essential for glucose metabolism. Mutations of complex II cause cancers and mitochondrial diseases, raising a critical question of the (patho-)physiological functions. To address the fundamental role of complex II in systemic energy metabolism, we specifically knockout SDHB in mice liver, a key complex II subunit that tethers the catalytic SDHA subunit and transfers the electrons to ubiquinone, and found that SHDB deficiency abolishes the assembly of complex II without affecting other respiration complexes while largely retaining SDHA stability. SHDB ablation reprograms energy metabolism and hyperactivates the glycolysis, Krebs cycle and {beta}-oxidation pathways, leading to catastrophic energy deficit and early death. Strikingly, sucrose supplementation or high fat diet resumes both glucose and lipid metabolism and prevent early death. Also, SDHB deficient mice are completely resistant to high fat diet induced obesity. Our findings reveal that the unanticipated role of complex II orchestrating both lipid and glucose metabolisms, and suggest that SDHB is an ideal therapeutic target for combating obesity.

molecular biology↗

bioRxiv2018

Comparative Phylogenomic Synteny Network Analysis of Mammalian and Angiosperm Genomes

BackgroundSynteny analysis is a valuable approach for understanding eukaryotic gene and genome evolution, but still relies largely on pairwise or reference-based comparisons. Network approaches can be utilized to expand large-scale phylogenomic microsynteny studies. There is now a wealth of completed mammalian (animal) and angiosperm (plant) genomes, two very important lineages that have evolved and radiated over the last ~170 million years. Genomic organization and conservation differs greatly between these two groups; however, a systematic and comparative characterization of synteny between the two lineages using the same approaches and metrics has not been undertaken.\n\nResultsWe have built complete microsynteny networks for 87 mammalian and 107 angiosperm genomes, which contain 1,464,753 nodes (genes) and 49,426,268 edges (syntenic connections between genes) for mammals, and 2,234,461 nodes and 46,938,272 edges for angiosperms, respectively. Exploiting network statistics, we present the functional characteristics of extremely conserved and diversified gene families. We summarize the features of all syntenic gene clusters and present lineage-wide phylogenetic profiling, revealing intriguing sub-clade lineage-specific clusters. We depict several representative clusters of important developmental genes in humans, such as CENPJ, p53 and NFE2. Finally, we present the complete homeobox gene family networks for both mammals (including Hox and ParaHox gene clusters) and angiosperms.\n\nConclusionsOur results illustrate and quantify overall synteny conservation and diversification properties of all annotated genes for mammals and angiosperms and show that plant genomes are in general more dynamic.

evolutionary biology↗

bioRxiv2017

ShuTu: Open-Source Software for Efficient and Accurate Reconstruction of Dendritic Morphology

Neurons perform computations by integrating inputs from thousands of synapses - mostly in the dendritic tree - to drive action potential firing in the axon. One fruitful approach to understanding this process is to record from neurons using patch-clamp electrodes, fill the recorded neuron with a substance that allows subsequent staining, reconstruct the three-dimensional architecture of the dendrites, and use the resulting functional and structural data to develop computer models of dendritic integration. Accurately producing quantitative reconstructions of dendrites is typically a tedious process taking many hours of manual inspection and measurement. Here we present ShuTu, a new software package that facilitates accurate and efficient reconstruction of dendrites imaged using bright-field microscopy. The program operates in two steps: (1) automated identification of dendritic process, and (2) manual correction of errors in the automated reconstruction. This approach allows neurons with complex dendritic morphologies to be reconstructed rapidly and efficiently, thus facilitating the use of computer models to study dendritic structure-function relationships and the computations performed by single neurons.\n\nSignificance StatementWe developed a software package - ShuTu - that integrates automated reconstruction of stained neurons with manual error correction. This package facilitates rapid reconstruction of the three-dimensional geometry of neuronal dendritic trees, often needed for computational simulations of the functional properties of these structures.

neuroscience↗

bioRxiv2017

Viral hijacking of the nucleolar DNA-damage response machinery: a novel mechanism to regulate host cell biology

Recent landmark studies indicate that nucleoli play critical roles in the DNA-damage response (DDR) via interaction of DDR machinery including NBS1 with nucleolar Treacle protein, a key mediator of ribosomal RNA (rRNA) transcription and processing, implicated in Treacher-Collins syndrome. Here, using proteomics, confocal/super-resolution imaging, and infection under BSL-4 containment, we present the first report that this nucleolar DDR pathway is targeted by infectious pathogens. We find that Treacle has antiviral activity, but that matrix protein of Henipaviruses and P3 protein of rabies virus, highly pathogenic viruses of the order Mononegavirales, interact with Treacle and inhibit its function, thereby silencing rRNA biogenesis, consistent with mimicking NBS1-Treacle interaction during a DDR. These data identify a novel mechanism for viral modulation of host cells by appropriating the nucleolar DDR; this appears to have developed independently in different viruses, and represents, to our knowledge, the first direct intra-nucleolar function for proteins of any mononegavirus.

microbiology↗

bioRxiv2017

Structural network maturation of the preterm human brain

During the 3rd trimester, large-scale of neural circuits are formed in the human brain, resulting in the adult-like brain networks at birth. However, how the brain circuits develop into a highly efficient and segregated connectome during this period is unknown. We hypothesized that faster increases of connectivity efficiency and strength at the brain hubs and rich-club are critical for emergence of an efficient and segregated brain connectome. Here, using high resolution diffusion MRI of 77 preterm-born and term-born neonates scanned at 31-42 postmenstrual weeks (PMW), we constructed the structural connectivity matrices and performed graph-theory-based analyses. We found faster increases of nodal efficiency mainly at the brain hubs, distributed in primary sensorimotor regions, superior-middle frontal and posterior cingulate gyrus during 31-42PMW. The rich-club and within-module connections were characterized by higher rates of edge strength increases. Edge strength of short-range connections increased faster than that of long-range connections. The nodal efficiencies of the hubs predicted individual postmenstrual ages more accurately than those of non-hubs. Collectively, these findings revealed regionally differentiated maturation in the baby brain structural connectome and more rapid increases of the hub and rich-club connections, which underlie network segregation and differentiated brain function emergence.

neuroscience↗

bioRxiv2017

Phylogenomic Synteny Network Analysis Reveals an Ancient MADS-Box Transcription Factor Tandem Duplication and Lineage-Specific Transpositions

Conserved genomic context (or synteny) provides critical information for comparative evolutionary analysis, such as the inference of ancient polyploidy events, recurrent genomic rearrangements across species and gene ancestry. With the increase of sequenced and assembled plant genomes, we now have the opportunity to use synteny to analyze the dynamics of gene family expansion and contraction across broad phylogenetic groups. Here we present an integrated approach to organize plant kingdom-wide gene synteny networks using k-clique percolation. As an example, we analyzed the gene synteny network of the MADS-box transcription factor family based on fifty-one completed plant genomes. We conclude from two massive gene clusters that one of the two Type II MADS-box gene clades evolved from an ancient tandem gene duplication likely predating the radiation of seed plants, which then expanded by polyploidy events and sub-functionalization. This gene clade now contains key regulators of major phenotypes of angiosperms including flower development. Moreover, we find lineage-specific gene clusters derived from transposition events. For example, lineage-specific clusters in the Brassicales containing genes that are well-known for their function in controlling flower morphology (AP3 and PI). Our phylogenomic synteny network approach can be applied to any group of species to gain new insights into the evolution and dynamics of any set of genes.

genomics↗

bioRxiv2016

Automatic Tracing of Ultra-Volume of Neuronal Images

Despite substantial advancement in the automatic tracing of neurons' morphology in recent years, it is challenging to apply the existing algorithms to very large image datasets containing billions or more voxels. We introduce UltraTracer, a solution designed to extend any base neuron-tracing algorithm to be able to trace virtually unlimited data volumes. We applied this approach to neuron-tracing algorithms with completely different design principles and tested on challenging human and mouse neuron datasets that have hundreds of billions of voxels. Results indicate that UltraTracer is scalable, accurate, and about 3 to 6 times more efficient compared to other state-of-the-art approaches.

bioinformatics↗