Biology subjects

Hu, H.

Publications and source records attributed to Hu, H..

At least 253 records · Page 14Linked to original sources

bioRxiv2020

Single-cell RNA-seq reveals identity and heterogeneity of malignant osteoblast cells and TME in osteosarcoma

Osteosarcoma (OS) has high heterogeneity and poor prognosis. In order to explore the molecular mechanism of OS and the tumor micro-environment (TME) on OS, we employed single-cell RNA-sequencing (scRNA-seq) on 110,745 individual cells from OS primary lesion, recurrent focal and metastatic tissues. We identified 5 main malignant subpopulations of OS cells, 3 clusters of osteoclast(OC) and 2 types of cancer-associated fibroblasts (CAFs). Further we found that the progenitor OC and, antigen presenting CAF (apCAF) were lower in lung metastatic and recurrent tumor tissues than in primary tumor tissue. M2-like macrophages were predominant in the TME myeloid cells. Inactivation state of tumor-infiltrating T cells, mainly the CD4-/CD8-T and Treg cells, existed in lung metastatic tissues. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) expressed in 11 samples. We then blocked TIGIT which significantly enhancd the cytotoxic effects of primary T cells on OS cell lines. Our report represents the first use of scRNA-seq for the transcriptomic profiling of OS cells. Thus, the findings in this study will serve as a valuable resource for deciphering the intra-tumoral heterogeneity in OS and provide potential therapeutic strategies for OS in clinic.

cancer biology↗

bioRxiv2020

Is Oculudentavis a bird or even archosaur?

Recent finding of a fossil - Oculudentavis khaungraae Xing et al. 2020, entombed in a Late Cretaceous amber - was claimed to represent a humming bird-sized dinosaur1. Regardless of the intriguing evolutionary hypotheses about the bauplan of Mesozoic dinosaurs (including birds) posited therein, this enigmatic animal demonstrates various morphologies resembling lizards. If Oculudentavis was a bird, it challenges several fundamental morphological differences between Lepidosauria and Archosauria. Here we reanalyze the original computed tomography scan data of Oculudentavis. Morphological evidences demonstrated here highly contradict the avian or even archosaurian phylogenetic placement of Oculudentavis. In contrast, our analysis revealed multiple synapomorphies of the Squamata in this taxon, including pleurodont marginal teeth and an open infratemporal fenestra, which suggests a squamate rather than avian or dinosaurian affinity of Oculudentavis.

evolutionary biology↗

bioRxiv2020

TMEM184B controls pruriceptor specification and function

Nociceptive and pruriceptive neurons in the dorsal root ganglia (DRG) convey sensations of pain and itch to the spinal cord, respectively. One subtype of mature DRG neurons, comprising about 5% of neurons in the ganglia, is responsible for sensing mediators of acute itch and atopic dermatitis, including the cytokine IL-31. How itch-sensitive (pruriceptive) neurons are specified is unclear. Here we show that Tmem184b, a gene with roles in axon degeneration and nerve terminal maintenance, is required for the expression of a large cohort of itch receptors, including those for IL-31, Leukotriene C4, and Histamine. Male and female mice lacking Tmem184b show reduced responses to IL-31, but maintain normal responses to pain and mechanical force, indicating a specific behavioral defect in pruriception. Calcium imaging experiments indicate that a reduction in IL-31 induced calcium entry is a likely contributor to this phenotype. We identify an early failure of proper Wnt-dependent transcriptional signatures and signaling components in Tmem184b mutant mice that may explain the improper DRG neuronal subtype specification. Accordingly, lentiviral re-expression of Tmem184b in mutant embryonic neurons restores Wnt signatures. Together, these data demonstrate that Tmem184b promotes adult somatosensation through developmental Wnt signaling and promotion of proper pruriceptive gene expression. Our data illuminate a new key regulatory step in the processes controlling the establishment of diversity in the somatosensory system.

neuroscience↗

bioRxiv2020

Interleukin-35 pretreatment attenuates lipopolysaccharide-induced heart injury by inhibition of inflammation, apoptosis and fibrosis

Previous studies have demonstrated that targeting inflammation is a promising strategy for treating lipopolysaccharide (LPS)-induced sepsis and related heart injury. Interleukin-35 (IL-35), which consists of two subunits, Epstein-Barr virus-induced gene 3 (EBI3) and p35, is an immunosuppressive cytokine of the IL-12 family and exhibits strong anti-inflammatory activity. However, the role of IL-35 in LPS-induced heart injury remains obscure. In this study, we explored the role of IL-35 in heart injury induced by LPS and its potential mechanisms. Mice were treated with a plasmid encoding IL-35 (pIL-35) and then injected intraperitoneally (ip) with LPS (10 mg/kg). Cardiac function was assessed by echocardiography 12 h later. LPS apparently decreased the expression of EBI3 and p35 and caused cardiac dysfunction and pathological changes, which were significantly improved by pIL-35 pretreatment. Moreover, pIL-35 pretreatment significantly decreased the levels of cardiac proinflammatory cytokines including TNF-, IL-6, and IL-1{beta}, and the NLRP3 inflammasome. Furthermore, increased BCL-2 levels and decreased BAX levels inhibited apoptosis, and LPS-induced upregulation of the expression of pro-fibrotic genes (MMP2 and MMP9) was inhibited. Further investigation indicated that pIL-35 pretreatment suppressed the activation of the cardiac NF-{kappa}Bp65 and TGF-{beta}1/Smad2/3 signaling pathways in LPS-treated mice. Similar cardioprotective effects of IL-35 pretreatment were observed in mouse myocardial fibroblasts challenged with LPS in vitro. In summary, IL-35 pretreatment can attenuate cardiac inflammation, apoptosis, and fibrosis induced by LPS, implicating IL-35 as a promising therapeutic target in sepsis-related cardiac injury.

molecular biology↗

bioRxiv2019

Compensatory guaiacyl lignin biosynthesis at the expense of syringyl lignin in 4CL1-knockout poplar

The lignin biosynthetic pathway is highly conserved in angiosperms, yet pathway manipulations give rise to a variety of taxon-specific outcomes. Knockout of lignin-associated 4-coumarate:CoA ligases (4CLs) in herbaceous species mainly reduces guaiacyl (G) lignin and enhances cell wall saccharification. Here we show that CRISPR-knockout of 4CL1 in Populus tremula x alba preferentially reduced syringyl (S) lignin, with negligible effects on biomass recalcitrance. Concordant with reduced S-lignin was downregulation of ferulate 5-hydroxylases (F5Hs). Lignification was largely sustained by 4CL5, a low-affinity paralog of 4CL1 typically with only minor xylem expression or activity. Levels of caffeate, the preferred substrate of 4CL5, increased in line with significant upregulation of caffeoyl shikimate esterase1. Upregulation of caffeoyl-CoA O-methyltransferase1 and downregulation of F5Hs are consistent with preferential funneling of 4CL5 products toward G-lignin biosynthesis at the expense of S-lignin. Thus, transcriptional and metabolic adaptations to 4CL1-knockout appear to have enabled 4CL5 catalysis at a level sufficient to sustain lignification. Finally, genes involved in sulfur assimilation, the glutathione-ascorbate cycle and various antioxidant systems were upregulated in the mutants, suggesting cascading responses to perturbed thioesterification in lignin biosynthesis. One sentence summaryKnockout of lignin-associated 4CL1 in Populus reveals a 4CL5-dependent, caffeate-modulated compensatory pathway for lignification with links to thiol redox balance and sulfur assimilation.

plant biology↗

bioRxiv2019

Arabidopsis PPC2 is crucial for growth at low CO2 by involvement in photorespiratory metabolism and integration of ABI5

Phosphoenolpyruvate carboxylase (PEPC) is a pivotal enzyme that plays a key role in photosynthetic CO2 fixation in C4. However, the function of C3 PEPCs and their roles at environmental CO2 changes are still limited. Here, we report the role of PPC2 in seedling growth at low CO2 by linking photorespiratory metabolism with primary metabolism and involvement of ABA and ABI5. Mutation of PPC2 caused seedling growth arrest, with reduced Fv/Fm, photosynthetic carbohydrates and ABA biosynthesis at low CO2. PPC2 is induced by low CO2 and the PEPC activity was greatly reduced in ppc2 leaves. Moreover, metabolic analyses showed the photorespiratory intermediates, glycine and serine, were greatly increased and primary metabolites were reduced. Application of sucrose, malate and ABA greatly rescued the growth arrest phenotype of ppc2. The expression of glycine/serine synthesis and metabolism related photorespiratory enzyme genes were decreased in ppc2 and regulated by ABI5 at low CO2 conditions. ppc2 and abi5 mature plants exhibited reduced A-Ci curves at relatively low CO2, which could be recovered by non-photorespiratory low oxygen conditions. ABI5 expression greatly rescued the growth arrest and A-Ci curves of ppc2 at low CO2. Our findings demonstrate the important role of C3 PEPCs in carbon fixation and metabolism.

plant biology↗

bioRxiv2019

Systematical analysis reveals the novel function of Cyp2c29 in liver injury

As a severe lethal cancer, hepatocellular carcinoma (HCC) usually originates from chronic liver injury and inflammation, in which the discovery of key genes is important for HCC prevention. Here, we analyzed the time serial (from 0 week to 30 weeks) transcriptome data of liver injury samples in diethylnitrosamine (DEN)-induced HCC mouse model. Through expression and function analyses, we identified that Cyp2c29 was a key gene continuously downregulated during liver injury. Overexpression of Cyp2c29 suppressed the NF-{kappa}B activation, proinflammatory cytokine production and hepatocyte proliferation by increasing its production 14,15-epoxyeicosatrienoic acid (14,15-EET). Furthermore, in vivo Cyp2c29 protected against liver inflammation in liver injury mice models by reversing the expression on functions of cell proliferation, metabolism and inflammation including suppressing NF-{kappa}B pathway and compensatory proliferation. CYP2C8 and CYP2C9, two human homologs of mouse Cyp2c29, were decreased in human HCC progression and positively correlated with HCC patient survival. Therefore, through systematical analysis and verification, we identified that Cyp2c29 is a novel gene in liver injury and inflammation, which may be a potential biomarker for HCC prevention and prognosis.

bioinformatics↗

bioRxiv2019

Considering founding and variable genomes is critical in studying polyploid evolution

A wide range of differences between the subgenomes, termed as subgenome asymmetry or SA, has been reported in various polyploids and different species seem to have different responses to polyploidization. We compared subgenome differences in gene ratio and relative diversity between artificial and natural genotypes of several allopolyploid species. Surprisingly, consistent differences in neither gene ratio nor relative diversity between the subgenomes were detected between these two types of polyploid genotypes although they differ in times exposed to evolutional selection. As expected, the estimated ratio of retained genes between a subgenome and its diploid donor was invariably higher for the artificial allopolyploid genotypes due likely to the presence of variable genome components (VGC). Clearly, the presence of VGC means that exaggerated differences between a donor and a subgenome in a polyploid are inevitable when random genotypes were used to represent species of either a polyploid or its donors. SA was also detected in genotypes before the completion of the polyploidization events as well as in those which were not formed via polyploidization. Considering that significant changes during and following polyploidization have been detected in previous studies, our results suggest that the influence of VGC needs to be considered in evaluating SA and that diploid donors may define changes in polyploid evolution.

evolutionary biology↗

bioRxiv2019

Dynamic 3D chromosomal landscapes in acute leukemia

Three-dimensional (3D) chromatin architectural changes can alter the integrity of topologically associated domains (TADs) and rewire specific enhancer-promoter interactions impacting gene expression. Recently, such alterations have been implicated in human disease, highlighting the need for a deeper understanding of their role. Here, we investigate the reorganization of chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) using primary human leukemia specimens and its dynamic responses to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-Seq and CTCF ChIP-Seq datasets revealed widespread changes in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD \"fusion\" event being associated with loss of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data show that small molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation reduce specific 3D interactions associated with transformation. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.\n\nOne Sentence Summary3D chromatin alterations in T cell leukemia are accompanied by changes in insulation and oncogene expression and can be partially restored by targeted drug treatments.

cancer biology↗

bioRxiv2019

Population genomics and pathotypic evaluation of the bacterial leaf blight pathogen of rice

Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight disease, which reduces crop yield by up to 50% in rice production. Despite its substantial threat on food production worldwide, knowledge about its population structure, virulence diversity and the relationship between them is limited. We used whole-genome sequencing to explore the diversity and evolution of Xoo during the past 30 years in the main rice-planting areas of China. Six separate lineages were revealed by phylogenomic analysis, with CX-5 and CX-6 predominating in the population for decades. The recent sporadic outbreaks were respectively caused by Xoo derived from these lineages especially the two major ones. The lineage and sub-lineage distribution of isolates strongly correlated to their geographical origin, which was found to be mainly determined by the planting of the two major rice subspecies, indica and japonica. Large-scale virulence testing was conducted to evaluate the diversity of pathogenicity for Xoo. We found rapid virulence dynamics against rice, and its determinant factors including genetic background of Xoo, rice resistance genes and the planting environment of rice. Genetic background was investigated deeply by comparative genomics, which indicates that transposition events contributing the most to evolution of the Xoo genome and the rapid diversification of virulence. This study provided a good model to understand the evolution and dynamics of plant pathogens in the context of interaction with their hosts which are influenced by both geographical conditions and farming practices.

genomics↗

bioRxiv2019

Heritable temporal gene expression patterns correlate with metabolomic seed content in developing hexaploid oat seed

Oat ranks sixth in world cereal production and has a higher content of health-promoting compounds compared to other cereals. However, there is neither a robust oat reference genome nor transcriptome. Using deeply sequenced full-length mRNA libraries of oat cultivar Ogle-C, a de novo high-quality and comprehensive oat seed transcriptome was assembled. With this reference transcriptome and QuantSeq 3 mRNA sequencing, gene expression was quantified during seed development from 22 diverse lines across six time points. Transcript expression showed higher correlations between adjacent time points. Based on differentially expressed genes, we identified 22 major temporal co-expression (TCoE) patterns of gene expression and revealed enriched gene ontology biological processes. Within each TCoE set, highly correlated transcripts, putatively commonly affected by genetic background, were clustered, and termed genetic co-expression (GCoE) sets. 17 of the 22 TCoE sets had GCoE sets with median heritabilities higher than 0.50, and these heritability estimates were much higher than that estimated from permutation analysis, with no divergence observed in cluster sizes between permutation and non-permutation analyses. Linear regression between 634 metabolites from mature seeds and the PC1 score of each of the GCoE sets showed significantly lower p-values than permutation analysis. Temporal expression patterns of oat avenanthramides and lipid biosynthetic genes were concordant with previous studies of avenanthramide biosynthetic enzyme activity and lipid accumulation. This study expands our understanding of physiological processes that occur during oat seed maturation and provides plant breeders the means to change oat seed composition through targeted manipulation of key pathways.

genetics↗

bioRxiv2019

Structural insights into ligand efficacy and activation of the glucagon receptor

The glucagon receptor family comprises Class B G protein-coupled receptors (GPCRs) that play a crucial role in regulating blood sugar levels. Receptors of this family represent important therapeutic targets for the treatment of diabetes and obesity. Despite intensive structural studies, we only have a poor understanding of the mechanism of peptide hormone-induced Class B receptor activation. This process involves the formation of a sharp kink in transmembrane helix 6 that moves out to allow formation of the nucleotide-free G protein complex. Here, we present the cryo-EM structure of the glucagon receptor (GCGR), a prototypical Class B GPCR, in complex with an engineered soluble glucagon derivative and the heterotrimeric G-protein, Gs. Comparison with the previously determined crystal structures of GCGR bound to a partial agonist reveals a structural framework to explain the molecular basis of ligand efficacy that is further supported by mutagenesis data.

biophysics↗

bioRxiv2019

Identification of microRNA-target interactions for antioxidant defense response under drought stress by high-throughput sequencing in Zanthoxylum bungeanum Maxim.

When the plant is in an unfavorable environment such as drought or high temperature, it will accumulate a large amount of active oxygen, which will seriously affect the normal growth and development of the plant. The antioxidant system can remove the reactive oxygen species produced under drought conditions and so mitigate oxidative damage. We examined the trends of antioxidant enzymes, miRNAs and their target genes in Zanthoxylum bungeanum under drought stress. According to the changes of antioxidant enzymes, miRNAs and their target genes expression patterns of Zanthoxylum bungeanum under drought stress, an interaction model was constructed to provide a reference for further understanding of plant antioxidant mechanism. The results indicate that under drought stress, POD, CAT, APX, proline, MDA and related genes all show positive responses to drought, while SOD and its genes showed a negative response. It is speculated that in the antioxidant process of Zanthoxylum bungeanum, POD, CAT, and APX play a major role, and SOD plays a supporting role. In addition, the expression levels of miRANs and their target genes were basically negatively correlated, indicating that miRNAs are involved in the regulation of the antioxidant system of Zanthoxylum bungeanum.

cell biology↗

bioRxiv2019

Homoploid hybridization signals due to ancestral subdivision: a case study on the D lineage in wheat

Homoploid hybrid speciation has been reported in a wide range of species since the exploitation of genome sequences in evolutionary studies. However, the interference of ancestral subdivision has not been adequately considered in many such investigations. Using the D lineage in wheat as an example, we showed clearly that ancestral subdivision has led to false detection of homoploid hybridization signals. We develop a novel statistical framework by examining the changes in shared ancestral variations and infer on the likelihood of speciation due to genuine homoploid hybridization or ancestral subdivisions. Applying this to wheat data, we found that homoploid hybridization was not involved in the origin of the D lineage contrary to the now widely held belief. This example indicates that the significance of homoploid hybrid speciation is likely exaggerated. The underlying methodology developed in this study should be valuable for clarifying whether homoploid hybridization has contributed to the speciation of many other species.

evolutionary biology↗

bioRxiv2019

Contrasting biogeographic patterns of bacterial and archaeal diversity in the top- and subsoils of temperate grasslands

Biogeographic patterns and drivers of soil microbial diversity have been extensively studied in the past few decades. However, most research has focused on the topsoil while the subsoil is assumed to have similar microbial diversity patterns as the topsoil. Here we compare patterns and drivers of microbial diversity in the top- (0-10 cm) versus subsoils (30-50 cm) of temperate grasslands in Inner Mongolia of China along an aridity gradient covering a ~1500-km transect from arid to mesic ecosystems. Counter to the conventional assumption, we find contrasting biogeographic patterns of diversity and influencing factors for different bacterial and archaeal groups and between depths. While bacterial diversity increases with increasing aridity, archaeal diversity decreases. Microbial diversity in the topsoil is most strongly influenced by aboveground vegetation, but is most strongly influenced by historical temperature anomaly since the Last Glacial Maximum (LGM) in the subsoil. Moreover, the biogeographic patterns of top-subsoil diversity difference varies for different microbial groups and is overall most strongly influenced by soil fertility difference between depths and historical temperature anomaly. These findings suggest that diversity patterns observed in the topsoil may not be readily applied to the subsoil horizons. For the subsoil in particular, historical climate plays a vital role in the distribution of various microbial groups. Overall, our study provides novel information for understanding and predicting soil microbial diversity patterns at depth.\n\nIMPORTANCEExploring the biogeographic patterns of soil microbial diversity is critical for understanding mechanisms underlying the response of soil processes to climate change. Using top- and subsoils from a ~1500-km temperature grassland transect, we find divergent patterns of microbial diversity and its determinants in the top-versus subsoils. Furthermore, we find important legacy effect of historical climate change on the microbial diversity of subsoil but not topsoil. Our findings challenge the conventional assumption of similar geographic patterns of soil microbial diversity along soil profiles and help to improve our understanding of how soil microbial communities may respond to future climate change in different regions with varied climate history.

microbiology↗

bioRxiv2019

Google searches accurately forecast RSV hospitalizations

BackgroundHospitalization of children with respiratory syncytial virus (RSV) is common and costly. Traditional sources of hospitalization data, useful for public health decision-makers and physicians to make decisions, are themselves costly to acquire and are subject to delays from gathering to publication. Here we use Google searches for RSV as a proxy for RSV hospitalizations.\n\nMethodsSearches for \"RSV\" and numbers of RSV hospitalizations in WA, MD, FL, and CT were examined from 2004-2018. Running correlation coefficients and phase angles between search and hospitalizations were calculated. Various machine learning models were compared to assess the ability of searches to forecast hospitalizations. Using search data from all 50 US states, we use K-means clustering to identify RSV transmission clusters. We calculate the timing of the optimal timing of RSV prophylaxis initiation as the week beginning the 24-week period covering 95% of all RSV cases.\n\nResultsHigh correlations (> 0.95) and low phase differences were seen between counts of hospitalizations and search volume in WA, MD, FL, and CT. Searching for RSV began in FL and radiated outward and three distinct transmission clusters were identified: the south and northeast, the northwest and Appalachia, and the center of the country. Calculated initiation dates for prophylaxis closely followed those calculated using traditional data sources (correlation = 0.84).\n\nConclusionsThis work validates searches as a proxy for RSV hospitalizations. Search query surveillance of RSV is a rapid and no-cost addition to traditional RSV hospitalization surveillance and may be useful for medical and public health decision-making.

epidemiology↗

bioRxiv2019

Alterations of the pulmonary immunity are independent of spontaneous pneumonia in an experimental model of ischemic stroke

Stroke-associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multi-factorial in nature, stroke-induced immunosuppression plays a key role in the development of SAP. Previous studies of focal ischemic stroke induction, using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that severe brain damage results in massive apoptosis and functional defects of lymphocytes in the spleen, thymus, and peripheral blood. However, how immune alternations in remote tissues lead to a greater susceptibility to lung infections is not well-understood. Importantly, how ischemic stroke alters immune-cell fates, and the expression of cytokines and chemokines in the lungs that directly impact pulmonary immunity, has not been characterized. We report here that ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b+ dendritic cells (DCs), but reduces the percentage of CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells, and eosinophils in the lungs. The depletion of immune cells in the lungs is not caused by apoptosis, cell infiltration to the brain, or spontaneous pneumonia following ischemic stroke as previously described, but correlates with a significant reduction in the levels of multiple chemokines in the lungs, including: CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. These findings suggest that ischemic stroke negatively impacts pulmonary immunity to become more susceptible for SAP development. Further investigation into the mechanisms that control pulmonary immune alternations following ischemic stroke may identify novel diagnostic or therapeutic targets for SAP.

immunology↗

bioRxiv2019

Drought Affects the Antioxidant System and Stomatal Aperture in Zanthoxylum bungeanum Maxim.

When under drought, plants activate a range of self-protective responses. Among these are activation of the antioxidant system and changes in stomatal aperture. The antioxidant system can remove the reactive oxygen species produced under drought conditions and so mitigate oxidative damage. Water becomes a severely limiting resource for plants suffering drought stress, so they generally close their stomata to reduce water loss. We examined changes in the activities of the antioxidant enzymes and altered gene expression patterns in Zanthoxylum bungeanum plants exposed to drought by irrigation with 20% PEG6000. We also recorded changes in stomatal aperture as the drought persisted. Relationships between the antioxidant system and stomatal aperture were analyzed in relation to gene expression. The results indicate that under drought stress, POD, CAT, APX, proline, MDA and related genes all show positive responses to drought, while SOD and its genes showed a negative response. The relationship between drought duration and stomatal aperture was considered. Stomatal aperture declines exponentially as drought duration increases.

cell biology↗