Biology subjects

Huang, Z.

Publications and source records attributed to Huang, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

A Hymenoptera-restricted gene mediating ant castes co-opts deeply conserved machinery to control organ size

Lineage-specific genes are widespread and have been implicated as phenotypic innovation inducers, but how they acquire complex developmental functions remains poorly understood. Ant queens and workers develop dramatically different organ sizes from identical genomes under juvenile hormone (JH) control, yet the molecular effectors translating JH signalling into caste-specific organ growth remain unknown. Here we identify torch, a Hymenoptera-restricted gene, as the most consistently gyne-biased and JH-responsive gene across 68 ant species. Knockdown of torch in virgin queens of Monomorium pharaonis produces a worker-like, multi-organ growth-restricted phenotype. Mechanistically, torch harbours an E-box-like motif activated by the JH receptor Gce-Tai and acts as a GA-repeat-binding transcription factor that regulates Hippo signalling, the deeply conserved organ-size control pathway in animals. Expressing torch heterologously in mice and a growth-restricted Drosophila background shows that the gene retained its general growth-promoting activity across more than 700 million years of animal evolution in lineages that lack the gene, establishing that its function is mediated through conserved rather than ant-specific machinery. A lineage-specific gene can therefore acquire complex morphogenetic function by co-opting ancient organ-size circuitry, providing a general route by which novel genes can drive phenotypic innovation.

evolutionary biology↗

bioRxiv2018

Molecular profiles and mutation burden analysis in Chinese patients with gastric carcinoma

The goal of this work was to investigate the molecular profiles and mutation burden in Chinese patients with gastric carcinoma (GC). In total, we performed whole exome sequencing (WES) on 74 GC patients with tumor and adjacent normal formalin-fixed, paraffin-embedded (FFPE) tissue samples. The mutation spectrum of these samples showed a high concordance with TCGA and other studies on GC. We found the alterations of 17 DNA repair genes (including BRCA2, POLE and MSH3, etc.) were strongly correlated with the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) of GC patients. Patients with mutations of these genes tend to have high TMB (median of TMB = 12.77, p=2.3e-6) and TNB (median of TNB = 5.97, p= 2.8e-3). In addition, younger GC patients (age < 60) have lower TMB (p = 0.0021) and TNB (p = 0.034) than older patients (age >= 60). Furthermore, we found a list of 18 genes and two genomic regions (1p36.21 and Xq26.3) were associated with peritoneal metastasis (PM) of GC, and patients with amplification of 1p36.21 and Xq26.3 have a worse prognosis (p=0.002, 0.01, respectively). Our analysis provides GC patients with potential markers for single and combination therapies.

cancer biology↗

bioRxiv2018

BDNF/TrkB signaling in pancreatic islet beta cells

Adrenergic signaling is a well-known input into pancreatic islet function. Specifically, the insulin-secreting islet {beta} cell expresses the Gi/o-linked 2-adrenergic receptor, which upon activation suppresses insulin secretion. The use of adrenergic agonist epinephrine at micromolar doses may have supraphysiological effects. We found that pretreating {beta} cells with micromolar concentrations of epinephrine differentially inhibited activation of receptor tyrosine kinases. We chose TrkB as an example because of its relative sensitivity to the effects of epinephrine and due to its potential regulatory role in the {beta} cell. Our characterization of brain-derived neurotrophic factor (BDNF)-TrkB signaling in MIN6 {beta} cells showed that TrkB is activated by BDNF as expected, leading to canonical TrkB autophosphorylation and subsequent downstream signaling, as well as chronic effects on {beta} cell growth. Micromolar, but not nanomolar, concentrations of epinephrine blocked BDNF-induced TrkB autophosphorylation and downstream mitogen-activated protein kinase pathway activation, suggesting an inhibitory phenomenon at the receptor level. We determined epinephrine-mediated inhibition of TrkB activation to be Gi/o-dependent using pertussis toxin, arguing against an off-target effect of high dose epinephrine. Published data suggested that inhibition of potassium channels or phosphoinositide-3-kinase signaling may abrogate the negative effects of epinephrine, however these did not rescue TrkB signaling in our experiments. Taken together, these results show that 1) TrkB kinase signaling occurs in {beta} cells and 2) use of epinephrine in studies of insulin secretion requires careful consideration of concentration-dependent effects. BDNF-TrkB signaling in {beta} cells may underlie pro-survival or growth signaling and warrants further study.

cell biology↗

bioRxiv2018

Curcumin inhibits cystogenesis in autosomal dominant polycystic kidney disease cells via altering JAK2/STAT3 activity.

Dysregulated JAK/STAT signalling is implicated in polycystic kidney disease, which is a common genetic disease leading to renal failure. However, the mechanisms underlying JAK/STAT-mediated cystogenesis arepoorlyunderstood.TheroleofJAK2wasinvestigated immunohistochemically in a murine model of cystic disease (Pkd1nl/nl). In the normal kidney, JAK2 is restricted to tubular epithelial and vascular cells with lesser staining in bowmans capsule and is undetectable in the interstitium. By contrast, in the diseased kidney JAK2 appears stronger in cyst-lining cells when compared to normal tubules and appears mislocalised in the interstitium. Given that JAK2 is a major tyrosine kinase activating JAK/STAT, we considered whether its inhibition can attenuate cystic growth in vitro. To assess this we used curcumin, a natural phytochemical, which significantly reduced JAK2 levels and STAT3 activity. Consistently, reduced JAK2/STAT3 activity was correlated with reduced cystic growth of cystic cells in three-dimensional cyst assays. Taken together, our results suggest that JAK2 is a key signalling molecule that functions to inhibit cystic growth in cystic tubular epithelial cells, thus providing the foundation for its development as a novel therapeutic in polycystic kidney disease.

cell biology↗

bioRxiv2018

The Structural Extraction of Chinese Medical Narratives

Medical narratives document a vast amount of clinical data. This data has a valuable secondary purpose, as it may be used to optimize health service delivery and improve the quality of medical care. However, medical narratives are typically recorded in an unstructured manner, which complicates the process of extracting the structured information required for optimization. In this paper, we address this problem by applying and comparing two models, a rule-based model and a model based on conditional random fields (CRFs), to a data set of Chinese medical narratives. Among 4626 manually annotated Chinese medical narratives, collected from Shanxi Dayi Hospital in China, the rule-based model achieved 95.87% precision, 69.82% recall, and an F-score of 80.80%, and the CRF-based model realized 95.99% precision, 65.11% recall, and a 77.59% F-score. These experimental results demonstrate the efficacy of both proposed models for structural extraction from Chinese medical narratives.

bioinformatics↗

bioRxiv2018

Mucosal immunoglobulins protect the olfactory organ of teleost fish against parasitic infection

The olfactory organ of vertebrates receives chemical cues present in the air or water and, at the same time, they are exposed to invading pathogens. Nasal-associated lymphoid tissue (NALT), which serves as a mucosal inductive site for humoral immune responses against antigen stimulation, is present in teleosts and mammals. IgT in teleosts is responsible for similar functions to those carried by IgA in mammals. Moreover, teleost NALT is known to contain B-cells and teleost nasal mucus contains immunoglobulins (Igs). Yet, whether nasal B cells and Igs respond to infection remains unknown. We hypothesized that water-borne parasites can invade the nasal cavity of fish and elicit local specific immune responses. To address this hypothesis, we developed a model of bath infection with the Ichthyophthirius multifiliis (Ich) parasite in rainbow trout, Oncorhynchus mykiss, an ancient bony fish, and investigated the nasal adaptive immune response against this parasite. Critically, we found that Ich parasites in water could be reach the nasal cavity and successfully invade the nasal mucosa. Moreover, strong parasite-specific IgT responses were exclusively detected in the nasal mucus, and the accumulation of IgT+ B-cells was noted in the nasal epidermis after Ich infection. Strikingly, local IgT+ B-cell proliferation and parasite-specific IgT generation were found in the trout olfactory organ, providing new evidence that nasal-specific immune responses were induced locally by a parasitic challenge. Overall, our findings suggest that nasal mucosal adaptive immune responses are similar to those reported in other fish mucosal sites and that an antibody system with a dedicated mucosal Ig performs evolutionary conserved functions across vertebrate mucosal surfaces.\n\nAuthor SummaryThe olfactory organ is a vitally important chemosensory organ in vertebrates but it is also continuously stimulated by pathogenic microorganisms in the external environment. In mammals and birds, nasopharynx-associated lymphoid tissue (NALT) is considered the first line of immune defense against inhaled antigens and in bony fish, protecting against water-borne infections. However, although B-cells and immunoglobulins (Igs) have been found in teleost NALT, the defensive mechanisms of parasite-specific immune responses after pathogen challenge in the olfactory organ of teleost fish remain poorly understood. Considering that the NALT of all vertebrates has been subjected to similar evolutionary forces, we hypothesize that mucosal Igs play a critical role in the defense of olfactory systems against parasites. To confirm this hypothesis, we show the local proliferation of IgT+ B-cells and production of pathogen-specific IgT within the nasal mucosa upon parasite infection, indicating that parasite-specific IgT is the main Ig isotype specialized for nasal-adaptive immune responses. From an evolutionary perspective, our findings contribute to expanding our view of nasal immune systems and determining the fate of the host-pathogen interaction.

immunology↗

bioRxiv2018

The draft genome sequence of mandrill (Mandrillus sphinx)

BackgroundMandrill (Mandrillus sphinx) is a primate species which belong to Old World monkey (Cercopithecidae) family. It is closely related to human, serving as model for some human diseases researches. However, genetic researches and genomic resources of mandrill were limited, especially comparing to other primate species.\n\nFindingsHere we sequenced 284 Gb data, providing 96-fold coverage (considering the estimate genome size of 2.9 Gb), to construct a reference genome for mandrill. The assembled draft genome was 2.79 Gb with contig N50 of 20.48 Kb and scaffold N50 of 3.56 Mb. We annotated the mandrill genome to find 43.83% repeat elements, as well as 21,906 protein coding genes. We found good quality of the draft genome and gene annotation by BUSCO analysis which revealed 98% coverage of the BUSCOs.\n\nConclusionsWe established the first draft genome sequence of mandrill, which is valuable resource for future evolutionary and human diseases studies.

genomics↗

bioRxiv2018

Glutamic acid is a carrier for hydrazine during the biosyntheses of fosfazinomycin and kinamycin

Fosfazinomycin and kinamycin are natural products that contain nitrogen-nitrogen (N-N) bonds but that are otherwise structurally unrelated. Despite their considerable structural differences, their biosynthetic gene clusters share a set of genes predicted to facilitate N-N bond formation. In this study, we show that for both compounds, one of the nitrogen atoms in the N-N bond originates from nitrous acid. Furthermore, we show that for both compounds, an acetylhydrazine biosynthetic synthon is generated first and then funneled via a glutamyl carrier into the respective biosynthetic pathways. Therefore, unlike other pathways to NN bond-containing natural products wherein the N-N bond is formed directly on a biosynthetic intermediate, during the biosyntheses of fosfazinomycin, kinamycin, and related compounds, the N-N bond is made in an independent pathway that forms a branch of a convergent route to structurally complex natural products.

biochemistry↗

bioRxiv2018

Unique molecular markers for GC-D-expressing olfactory sensory neurons and chemosensory neurons of the Grueneberg ganglion

The main olfactory bulb (MOB) is differentiated into subregions based on their innervation by molecularly distinct chemosensory neurons. For example, olfactory sensory neurons (OSNs) that employ a cGMP-mediated transduction cascade - guanylyl-cyclase D-expressing (GC-D+) OSNs of the main olfactory epithelium (MOE) and chemosensory neurons of the Grueneberg ganglion (GGNs) - project to distinct groups of \"necklace\" glomeruli encircling the caudal MOB. To better understand the unique functionality and neural circuitry of the necklace glomeruli and their associated sensory neurons, we sought to identify additional molecular markers that would differentiate GC-D+ OSNs and GGNs as well as their target glomeruli. We found in mouse that GC-D+ OSNs, but not other MOE OSNs or GGNs, express the neuropeptide CART (cocaine- and amphetamine-regulated transcript). Both GC-D+ OSNs and GGNs, but not other MOE OSNs, express the Ca2+/calmodulin-dependent phosphodiesterase Pde1a, which is immunolocalized throughout the dendrites, somata and axons of these neurons. Stronger Pde1a immunolabeling in necklace glomeruli innervated by GGNs than in those innervated by GC-D+ OSNs suggests either greater Pde1a expression in individual GGNs than in GC-D+ OSNs or a difference in sensory neuron innervation density between the two types of necklace glomeruli. Together, the unique molecular signatures of GC-D+ OSNs, GGNs and their MOB targets offer important tools for understanding the processing of chemosensory information by olfactory subsystems associated with the necklace glomeruli.

neuroscience↗

bioRxiv2018

Autophagy Decreases Alveolar Epithelial Cell Injury by Suppressing the NF-κB Signaling Pathway and Regulating the Release of Inflammatory Mediators

To research the impact of autophagy on alveolar epithelial cell inflammation and its possible mechanism in early stages of hypoxia, we established a cell hypoxia-reoxygenation model and orthotopic left lung ischemia-reperfusion model. Rat alveolar epithelial cells stably expressing GFP-LC3 were treated with an autophagy inhibitor (3-methyladenine, 3-MA) or autophagy promoter (rapamycin), followed by hypoxia-reoxygenation treatment at 2, 4 and 6h in vitro. In vivo, twenty-four male Sprague-Dawley rats were randomly divided into four groups (model group: no blocking of hilum in the left lung; control group: blocking of hilum in the left lung for 1h with DMSO lavage; 3-MA group: blocking of hilum in the left lung for 1h with 100ml/kg of 3-MA (5mol/L) solution lavage; rapamycin group: blocking of hilum in the left lung for 1h with 100ml/kg of rapamycin (250nmol/L) solution lavage) to establish an orthotopic left lung ischemia model. This study demonstrated that rapamycin significantly suppressed the NF-{kappa}B signaling pathway, restrained the expression of pro-inflammatory factors. A contrary result was confirmed by 3-MA pretreatment. These findings indicate that autophagy reduces ischemia-reperfusion injury by repressing inflammatory signaling pathways in the early stage of hypoxia in vitro and in vivo. This could be a new protective method for lung ischemia-reperfusion injury.

cell biology↗

bioRxiv2018

scQuery: a web server for comparative analysis of single-cell RNA-seq data

Single cell RNA-Seq (scRNA-seq) studies often profile upward of thousands of cells in heterogeneous environments. Current methods for characterizing cells perform unsupervised analysis followed by assignment using a small set of known marker genes. Such approaches are limited to a few, well characterized cell types. To enable large scale supervised characterization we developed an automated pipeline to download, process, and annotate publicly available scRNA-seq datasets. We extended supervised neural networks to obtain efficient and accurate representations for scRNA-seq data. We applied our pipeline to analyze data from over 500 different studies with over 300 unique cell types and show that supervised methods greatly outperform unsupervised methods for cell type identification. A case study of neural degeneration data highlights the ability of these methods to identify differences between cell type distributions in healthy and diseased mice. We implemented a web server that compares new datasets to collected data employing fast matching methods in order to determine cell types, key genes, similar prior studies, and more.

bioinformatics↗

bioRxiv2018

Further expansion of methane metabolism in the Archaea

The recent discovery of key methane-metabolizing genes in the genomes from the archaeal phyla Bathyarchaeota and Verstraetearchaeota has expanded our understanding of the distribution of methane metabolism outside of the phylum Euryarchaeota. Here, we recovered two near-complete crenarchaeotal metagenome-assembled genomes (MAGs) from circumneutral hot springs that contain genes for methanogenesis, including the genes that encode for the key methyl-coenzyme M reductase (MCR) complex. These newly recovered archaea phylogenetically cluster with Geoarchaeota (deep lineage of archaeal order Thermoproteales), and the MCR-encoding genes clustered with the recently reported methanogens within the Verstraetearchaeota. In addition, genes encoding hydroxybutyryl-CoA dehydratase were identified in the newly recovered methanogens, indicating they might carry out the {beta}-oxidation process. Together, our findings further expanded the methane metabolism outside the phylum Euryarchaeota.

microbiology↗

bioRxiv2018

Inter-annual variation in seasonal dengue epidemics driven bymultiple interacting factors in Guangzhou, China

Vector-borne diseases display wide inter-annual variation in seasonal epidemic size due to their complex dependence on temporally variable environmental conditions and other factors. In 2014, Guangzhou, China experienced its worst dengue epidemic on record, with incidence exceeding the historical average by two orders of magnitude. To disentangle contributions from multiple factors to inter-annual variation in epidemic size, we fitted a semi-mechanistic model to time series data from 2005-2015 and performed a series of factorial simulation experiments in which seasonal epidemics were simulated under all combinations of year-specific patterns of four time-varying factors: imported cases, mosquito density, temperature, and residual variation in local conditions not explicitly represented in the model. Our results indicate that while epidemics in most years were limited by unfavorable conditions with respect to one or more factors, the epidemic in 2014 was made possible by the combination of favorable conditions for all factors considered in our analysis.

epidemiology↗

bioRxiv2018

In vivo Chemical Reprogramming of Astrocytes into Functional Neurons

Mammals lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced reprogramming is a spatiotemporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for the in vivo reprogramming in organs with poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram resident astrocytes into functional neurons. The in situ chemically induced neurons (CiNs) resemble endogenous neurons in terms of neuron-specific marker expression and electrophysiological properties. Importantly, these CiNs can integrate into the mouse brain. Our study, for the first time, demonstrates in vivo chemical reprogramming in the adult brain, which could be a novel path for generating desired cells in situ for regenerative medicine.

cell biology↗

bioRxiv2018

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

Oncogenic MYC activation promotes cellular proliferation in Burkitt lymphoma (BL), but also induces cell cycle arrest and apoptosis mediated by TP53, a tumor suppressor gene that is mutated in 40% of BL cases. To identify therapeutic targets in BL, we investigated molecular dependencies in BL cell lines using RNAi-based, loss-of-function screening. By integrating genotypic and RNAi data, we identified a number of genotype-specific dependencies including the dependence of TCF3/ID3 mutant cell lines on TCF3 and of MYD88 mutant cell lines on TLR signaling. TP53 wild-type (TP53wt) BL were dependent on MDM4, a negative regulator of TP53. In BL cell lines, MDM4 knockdown induced cell cycle arrest and decreased tumor growth in a xenograft model in a p53-dependent manner, while small molecule inhibition of the MDM4-p53 interaction restored p53 activity resulting in cell cycle arrest. Consistent with the pathogenic effect of MDM4 upregulation in BL, we found that TP53wt BL samples were enriched for gain of chromosome 1q which includes the MDM4 locus. 1q gain was also enriched across non-BL cancer cell lines (n=789) without TP53 mutation (23% in TP53wt and 12% in TP53mut, p<0.001). In a set of 216 cell lines representing 19 cancer entities from the Achilles project, MDM4 was the strongest genetic dependency in TP53wt cell lines (p<0.001).\n\nOur findings show that in TP53wt BL, MDM4-mediated inhibition of p53 is a mechanism to evade cell cycle arrest. The data highlight the critical role of p53 as a tumor suppressor in BL, and identifies MDM4 as a key functional target of 1q gain in a wide range of cancers, which is therapeutically targetable.

cancer biology↗

bioRxiv2018

Inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates seizures by enhancing A-type potassium currents

The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report that Hsp70 exerts an unexpected deleterious role in kainic acid (KA)-induced seizures, and inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates both acute and chronic seizures via enhancing A-type potassium currents primarily formed by Kv4 -subunits and auxiliary KChIPs. Proteosomal degradation of Kv4-KChIP4a channel complexes is enhanced by Hsp70, which can be reversed by the Hsp70 inhibitors, 2-phenylethynesulfonamide (PES) and VER-155008 (VER). In cultured hippocampal neurons, either PES or VER can increase A-type Kv4 current to suppress neuronal hyperexcitability. Mechanistically, Hsp70-CHIP complexes directly bind to the N-terminus of auxiliary KChIP4a and target Kv4-KChIP4a complexes to the proteasome. Our findings reveal a previously unrecognized role of Hsp70 in mediating degradation of Kv4-KChIP4a complexes and regulating neuronal excitability, thus highlighting a therapeutic potential for hyperexcitability-related neurological disorders through Hsp70 inhibition.

neuroscience↗

bioRxiv2017

confFuse: high-confidence fusion gene detection across tumor entities

BackgroundFusion genes play an important role in the tumorigenesis of many cancers. Next-generation sequencing (NGS) technologies have been successfully applied in fusion gene detection for the last several years, and a number of NGS-based tools have been developed for identifying fusion genes during this period. Most fusion gene detection tools based on RNA-seq data report a large number of candidates (mostly false positives), making it hard to prioritize candidates for experimental validation and further analysis. Selection of reliable fusion genes for downstream analysis becomes very important in cancer research. We therefore developed confFuse, a scoring algorithm to reliably select high-confidence fusion genes which are likely to be biologically relevant.\n\nResultsConfFuse takes multiple parameters into account in order to assign each fusion candidate a confidence score, of which score [≥]8 indicates high-confidence fusion gene predictions. These parameters were manually curated based on our experience and on certain structural motifs of fusion genes. Compared with alternative tools, based on 96 published RNA-seq samples from different tumor entities, our method can significantly reduce the number of fusion candidates (301 high-confidence from 8,083 total predicted fusion genes) and keep high detection accuracy (recovery rate 85.7%). Validation of 18 novel, high-confidence fusions detected in three breast tumor samples resulted in a 100% validation rate.\n\nConclusionsConfFuse is a novel downstream filtering method that allows selection of highly reliable fusion gene candidates for further downstream analysis and experimental validations. confFuse is available at https://github.com/Zhiqin-HUANG/confFuse.

bioinformatics↗

bioRxiv2017

Welfare of zebra finches used in research

Over the past 50 years, songbirds have become a valuable model organism for scientists studying vocal communication from its behavioral, hormonal, neuronal, and genetic perspectives. Many advances in our understanding of vocal learning result from research using the zebra finch, a close-ended vocal learner. We review some of the manipulations used in zebra finch research, such as isolate housing, transient/irreversible impairment of hearing/vocal organs, implantation of small devices for chronic electrophysiology, head fixation for imaging, aversive song conditioning using sound playback, and mounting of miniature backpacks for behavioral monitoring. We highlight the use of these manipulations in scientific research, and estimate their impact on animal welfare, based on the literature and on data from our past and ongoing work. The assessment of harm-benefits tradeoffs is a legal prerequisite for animal research in Switzerland. We conclude that a diverse set of known stressors reliably lead to suppressed singing rate, and that by contraposition, increased singing rate may be a useful indicator of welfare. We hope that our study can contribute to answering some of the most burning questions about zebra finch welfare in research on vocal behaviors.

animal behavior and cognition↗