Biology subjects

Huang, C.

Publications and source records attributed to Huang, C..

16 recordsLinked to original sources

bioRxiv2018

Gating TrkB switch by methylglyoxal enables GLO1 as a target for depression

The endogenous metabolite methylglyoxal (MGO) has recently emerged as a potential mediator of psychiatric disorders, such as anxiety and depression, but its precise mechanism of action remains poorly understood. Here, we find that MGO concentrations are decreased in the prefrontal cortex and hippocampus in rats subjected to chronic stress, and low-dose MGO treatment remarkedly enhances resilience to stress and alleviates depression-like symptoms. This effect is achieved by MGOs promotion on the synaptic plasticity in prefrontal cortex and hippocampus. Both in vitro and in vivo experiments show that MGO provokes the dimerization and autophosphorylation of TrkB and the subsequent activation of downstream Akt/CREB signaling, which leads to a rapid and sustained expression of brain-derived neurotrophic factor (BDNF). We further demonstrate that MGO directly binds to the extracellular domain of TrkB, but not its intracellular domain. In addition, we also identify a natural product luteolin and its derivative lutD as potent inhibitors of Glyoxalase 1 and validate their antidepressant effects in chronic stress rat models. The antidepressant role of endogenous MGO provides a new basis for the understanding and therapeutic intervention design for stress-associated mental disorders.

neuroscience↗

bioRxiv2018

Distribution of duck-origin parvovirus in Cherry Valley ducks in vivo over time and histopathological investigation

In 2015, we successfully isolated a strain of duck-origin parvovirus from Cherry Valley ducks, which we named QH-L01. In this study, duck-origin parvovirus in Cherry Valley ducks was quantified and localized by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC), and pathological damage to the tissues and organs was observed by hematoxylin-eosin staining (HE staining). qPCR showed that the viral load was higher in the spleen, brain, lung, cecum, ileum, and duodenum over time. The results from IHC experiments showed positive reactions in hepatocytes, epithelium of the lung atrium, myocardial cells, goblet cells of the intestine, and brain cells. Primary histological examination revealed pulmonary lobule depletion and dilation in the lung as well as necrosis and erosion of the villus tips in the duodenum, ileum and cecum. This study is the first demonstration that duck-origin parvovirus can be transmitted from the spleen to the brain and lung, resulting in proliferation and dissemination of the virus to the cecum, ileum, duodenum and other tissues through the blood. The lung, duodenum, ileum and cecum may thus represent the main target tissues and organs for duck-origin parvovirus.

zoology↗

bioRxiv2018

Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans

Reduced protein homeostasis and increased protein instability is a common feature of aging. Yet it remains unclear whether protein instability is a cause of aging. In neurodegenerative diseases and amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological solid aggregates in a variety of tissues. More recently, widespread protein aggregation has been described during normal aging, in the absence of disease processes. Until now, an extensive characterization of the nature of age-dependent protein aggregation and its consequences for aging has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and contain amyloid-like structures similar to disease-associated protein aggregates. Moreover, we demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these finding reveal that the formation of amyloid aggregates is a generic problem of aging and likely to be an important target for strategies designed to maintain physiological functions in later stages of life.

cell biology↗

bioRxiv2018

Limits to anatomical accuracy of diffusion tractography using modern approaches

Diffusion MRI fiber tractography is widely used to probe the structural connectivity of thebrain, with a range of applications in both clinical and basic neuroscience. Despite widespread use, tractography has well-known pitfalls that limits the anatomical accuracy of this technique. Numerous modern methods have been developed to address these shortcomings through advances in acquisition, modeling, and computation. To test whether these advances improve tractography accuracy, we organized the ISBI 2018 3D Validation of Tractography with Experimental MRI (3D-VoTEM) challenge. We made available three unique independent tractography validation datasets - a physical phantom and two ex vivo brain specimens - resulting in 176 distinct submissions from 9 research groups. By comparing results over a wide range of fiber complexities and algorithmic strategies, this challenge provides a more comprehensive assessment of tractographys inherent limitations than has been reported previously. The central results were consistent across all sub-challenges in that, despite advances in tractography methods, the anatomical accuracy of tractography has not dramatically improved in recent years. Taken together, our results independently confirm findings from decades of tractography validation studies, demonstrate inherent limitations in reconstructing white matter pathways using diffusion MRI data alone, and highlight the need for alternative or combinatorial strategies to accurately map the fiber pathways of the brain.

neuroscience↗

bioRxiv2018

Study of Sterilization Effects on Marine Vibrio sp. using Interaction of Cavitation with Shock Wave in a Narrow Water Chamber

When underwater shock waves are generated by an electric discharge in a narrow water chamber, the instant release of a great amount of energy causes the propagation of a shear wave in wall material with the deformation of the chamber wall. The shear waves produce decompression in water and result in the growth of bubble nuclei. Subsequently, those oscillating cavitation bubbles are exposed to the shock pressures, and thus free radicals and rebound shock waves are generated due to their violent collapses. Eventually, marine bacteria around them are inactivated by these productions. In the present study, we investigate the sterilization effects of these oscillating bubbles and cavitation-shock interaction by bio-experiments, respectively. Furthermore, the chemical action of free radicals on marine bacteria is discussed. The generation of the OH radicals is clarified by measuring the concentration of the H2O2. To estimate the generation condition of the OH radicals, a bubble dynamic model consisting of an oscillation model for the growth of bubble nuclei and an impact model to describe the cavitation-shock interaction is developed. Finally, the theoretical estimation by the bubble dynamic model is discussed under the conditions of the present experiments.

biophysics↗

bioRxiv2018

Comprehensive analysis of immune evasion in breast cancer by single-cell RNA-seq

The tumor microenvironment is composed of numerous cell types, including tumor, immune and stromal cells. Cancer cells interact with the tumor microenvironment to suppress anticancer immunity. In this study, we molecularly dissected the tumor microenvironment of breast cancer by single-cell RNA-seq. We profiled the breast cancer tumor microenvironment by analyzing the single-cell transcriptomes of 52,163 cells from the tumor tissues of 15 breast cancer patients. The tumor cells and immune cells from individual patients were analyzed simultaneously at the single-cell level. This study explores the diversity of the cell types in the tumor microenvironment and provides information on the mechanisms of escape from clearance by immune cells in breast cancer.\n\nOne Sentence SummaryLandscape of tumor cells and immune cells in breast cancer by single cell RNA-seq

cancer biology↗

bioRxiv2018

Noninvasive Vagus Nerve Stimulation Alters Neural Response and Physiological Autonomic Tone to Noxious Thermal Challenge

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n=15 sham and n=15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group x time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group x time x GSR analysis showed a significantly decreased response in nVNS group (p < .0005) in bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.

neuroscience↗

bioRxiv2018

Novel mutations associated with autosomal dominant congenital cataract are identified in Chinese families

PurposeAs the leading cause of the impairment of vision of children, congenital cataract is considered as a hereditary disease, especially autosomal dominant congenital cataract (ADCC). The purpose of this study is to identify the genetic defect of six Chinese families with ADCC.\n\nSubjects and MethodsSix Chinese families with ADCC were recruited in the study. (103 members in total, 96 members alive, 27 patients in total) Genomic DNA samples extracting from probands peripheral blood cells were captured the mutations using a specific eye disease enrichment panel with next generation sequencing. After initial pathogenicity prediction, sites with specific pathogenicity were screened for further validation. Sanger sequencing was conducted in the other individuals in the families and other 100 normal controls. Mutations definitely related with ADCC will then be analyzed by bioinformatics analysis. The pathogenic effect of the amino acid changes and structural and functional changes of the proteins were finally analyzed by bioinformatics analysis.\n\nResultsSeven mutations in six candidate genes associated with ADCC of six families were detected (MYH9 c.4150G>C, CRYBA4 c.169T>C, RPGRRIP1 c.2669G>A, WFS1 c.1235T>C, CRYBA4 c.26C>T, EPHA2 c.2663+1G>A, and PAX6 c.11-2A>G). All the seven mutations were only detected on affected individuals in the families. Among them there are three novel mutations (MYH9 c.4150G>C, CRYBA4 c.169T>C, RPGRRIP1 c.2669G>A) and four that have been reported (WFS1 c.1235T>C, CRYBA4 c.26C>T, EPHA2 c.2663+1G>A, and PAX6 c.11-2A>G). RPGRIP1 (c.2669G>A) mutation and CRYBA4 (c.26C>T) mutation are predicted to be benign according to bioinformatics analysis while the other five mutations (EPHA2, PAX6, MYH9, CRYBA4 c.169T>C, WFS1) are thought to be pathogenic.\n\nConclusionWe report two novel heterozygous mutations (MYH9 c.4150G>C and CRYBA4 c.169T>C) in six Chinese families supporting their vital roles in causing ADCC.

genomics↗

bioRxiv2018

Sequencing of Panax notoginseng genome reveals genes involved in disease resistance and ginsenoside biosynthesis

Panax notoginseng is a traditional Chinese herb with high medicinal and economic value. There has been considerable research on the pharmacological activities of ginsenosides contained in Panax spp.; however, very little is known about the ginsenoside biosynthetic pathway. We reported the first de novo genome of 2.36 Gb of sequences from P. notoginseng with 35,451 protein-encoding genes. Compared to other plants, we found notable gene family contraction of disease-resistance genes in P. notoginseng, but notable expansion for several ATP-binding cassette (ABC) transporter subfamilies, such as the Gpdr subfamily, indicating that ABCs might be an additional mechanism for the plant to cope with biotic stress. Combining eight transcriptomes of roots and aerial parts, we identified several key genes, their transcription factor binding sites and all their family members involved in the synthesis pathway of ginsenosides in P. notoginseng, including dammarenediol synthase, CYP716 and UGT71. The complete genome analysis of P. notoginseng, the first in genus Panax, will serve as an important reference sequence for improving breeding and cultivation of this important nutraceutical and medicinal but vulnerable plant species.

genomics↗

bioRxiv2018

Local Polyploidy Phenomenon in Escherichia coli and its significance in genetic engineering

Classic Helmstetter & Cooper model asserted that the multifork phenomenon in the process of replication. However, the impacts of the multifork on the evolution and genetic engineering are still vague. Here, we employed CRISPR/Cas9 technology to knock-out eighteen Escherichia coli chromosomal fragments (over 50 kb) that represent all areas of the chromosome. We demonstrated that a single cell could have wild-type, color-reporter, and antibiotic-resistant genes simultaneously in the same locus of the different branches of the duplication forks after multiple rounds of deletions and replacements. This phenomenon that a single cell had different genotypes in its local polyploid chromosomes, which was similar to eukaryotic heterozygote, was named as local polyploidy. Under a defined selective pressure condition, offspring cells containing at least a copy of conditionally beneficial mutation could be enriched, and other alleles could be kept silently and peacefully in the duplication fork(s) of the same cell. The significance of this phenomenon in the genetic engineering was discussed.

microbiology↗

bioRxiv2018

The landscape and diagnostic potential of T and B cell repertoire in Immunoglobulin A Nephropathy

Immunoglobulin A Nephropathy (IgAN) is the most common glomerulonephritis worldwide. In IgAN, immune complex deposite in glomerular mesangium, which induce inflammation and affect the kidneys normal functions. However, the exact pathogenesis of IgAN is still incompletely understood. Further, in current practice the clinical diagnosis relies on needle biopsy on renal tissue. Therefore, a non-invasive method for clinical diagnosis and prognosis surveillance of the disease is in high demand. In this paper, we investigated both the T cell receptor bata chain (TCRB) and immunoglobulin heavy chain (IGH) repertoire of kidney infiltrating and circulating lymphocytes of IgAN patients by immune repertoire high throughput sequencing. We found that the features of TCRB and IGH in the renal tissues were remarkably different from that in blood, including a decreased repertoire diversity and increased IgA and IgG frequency, and more activated B cells. The CDR3 length of PBMC TCRB and IGH in patients is significantly shorter than that in healthy controls, which is the result of both VDJ rearrangement and clone selection. We also found that the IgA1 frequency in the PBMC of IgAN is significant higher than that in other Nephropathy (NIgAN) and healthy control, which is consistent with the previous reports on the level of IgA1 producing B cells and serum IgA1. Significantly, we identified a set of IgAN disease related TCRB and IGH CDR3s, which can be used to distinguish IgAN from NIgAN and healthy controls from the blood with high accuracy. These results indicated that TCRB and IGH repertoire can potentially serve as non-invasive biomarkers for IgAN diagnosis. The characteristics of kidney infiltrating and circulating lymphocytes repertoire shed light on IgAN detection, treatment and surveillance.

immunology↗

bioRxiv2018

Interaction of BIR2/3 of XIAP with E2F1/Sp1 Activates MMP2 and Bladder Cancer Invasion by Inhibiting Src Translation

Although X-linked inhibitor of apoptosis protein (XIAP) is associated with cancer cell behaviors, the structure-based function of XIAP in promotion human bladder cancer (BC) invasion is barely explored. Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and invasion in XIAP-deleted BC cells, while Src was further defined as a XIAP downstream negative regulator for MMP2 activation and BC invasion. The inhibition of Src expression by BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation resulting from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, consequently leading to fully activation of E2F1/Sp1. Our findings provide a novel insight into understanding of specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.

cancer biology↗

bioRxiv2017

An interlaboratory study of complex variant detection

Next-generation sequencing (NGS) is widely used and cost-effective. Depending on the specific methods, NGS can have limitations detecting certain technically challenging variant types even though they are both prevalent in patients and medically important. These types are underrepresented in validation studies, hindering the uniform assessment of test methodologies by laboratory directors and clinicians. Specimens containing such variants can be difficult to obtain; thus, we evaluated a novel solution to this problem in which a diverse set of technically challenging variants was synthesized and introduced into a known genomic background. This specimen was sequenced by 7 laboratories using 10 different NGS workflows. The specimen was compatible with all 10 workflows and presented biochemical and bioinformatic challenges similar to those of patient specimens. Only 10 of 22 challenging variants were correctly identified by all 10 workflows, and only 3 workflows detected all 22. Many, but not all, of the sensitivity limitations were bioinformatic in nature. We conclude that Synthetic controls can provide an efficient and informative mechanism to augment studies with technically challenging variants that are difficult to obtain otherwise. Data from such specimens can facilitate inter-laboratory methodologic comparisons and can help establish standards that improve communication between clinicians and laboratories.

genetics↗

bioRxiv2017

Circuit-based models of shared variability in cortical networks

Trial-to-trial variability is a reflection of the circuitry and cellular physiology that makeup a neuronal network. A pervasive yet puzzling feature of cortical circuits is that despite their complex wiring, population-wide shared spiking variability is low dimensional with all neurons fluctuating en masse. Previous model cortical networks are at loss to explain this global variability, and rather assume it is from external sources. We show that if the spatial and temporal scales of inhibitory coupling match known physiology, model spiking neurons internally generate low dimensional shared variability that captures the properties of in vivo population recordings along the visual pathway. Shifting spatial attention into the receptive field of visual neurons has been shown to reduce low dimensional shared variability within a brain area, yet increase the variability shared between areas. A top-down modulation of inhibitory neurons in our network provides a parsimonious mechanism for this attentional modulation, providing support for our theory of cortical variability. Our work provides a critical and previously missing mechanistic link between observed cortical circuit structure and realistic population-wide shared neuronal variability and its modulation.

neuroscience↗

bioRxiv2017

Heritability of regional brain volumes in large-scale neuroimaging and genetic studies

Brain genetics is an active research area. The degree to which genetic variants impact variations in brain structure and function remains largely unknown. We examined the heritability of regional brain volumes (p ~ 100) captured by single-nucleotide polymorphisms (SNPs) in UK Biobank (n ~ 9000). We found that regional brain volumes are highly heritable in this study population. We observed omni-genic impact across the genome as well as enrichment of SNPs in active chromatin regions. Principal components derived from regional volume data are also highly heritable, but the amount of variance in brain volume explained by the component did not seem to be related to its heritability. Heritability estimates vary substantially across large-scale functional networks and brain regions. The variation in heritability across regions was not related to measurement reliability. Heritability estimates exhibit a symmetric pattern across left and right hemispheres and are consistent in females and males. Our main findings in UK Biobank are consistent with those in Alzheimers Disease Neuroimaging Initiative (n ~ 1100), Philadelphia Neurodevelopmental Cohort (n ~ 600), and Pediatric Imaging, Neurocognition, and Genetics (n ~ 500) datasets, with more stable estimates in UK Biobank.

genetics↗

bioRxiv2017

DrugPattern: a web-based tool for drug set enrichment analysis

Set enrichment analysis based methods (e.g. gene set enrichment analysis) have provided great helps in mining patterns in biomedical datasets, however, tools for inferring regular patterns in drug-related datasets are still limited. For the above purpose, here we developed a web-based tool, DrugPattern. DrugPattern first collected and curated 7019 drug sets, including indications, adverse reaction, targets, pathways etc. For a list of interested drugs, DrugPattern then evaluates the significance of the enrichment of these drugs in each of the 7019 drug sets. To validate DrugPattern, we applied it to predict the potential protective roles of oxidized low-density lipoprotein (oxLDL), a widely accepted deleterious factor for the body. We predicted that oxLDL has beneficial effects on some diseases, most of which were supported by literature except type 2 diabetes (T2D), in which oxLDL was previously believed to be a risk factor. Animal experiments further validated that oxLDL indeed has beneficial effects on T2D. These data confirmed the prediction accuracy of our approach and revealed unexpected protective roles for oxLDL in various diseases including T2D. This study provides a tool to infer regular patterns in biomedical datasets based on drug set enrichment analysis.

bioinformatics↗