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Zhang, L.

Publications and source records attributed to Zhang, L..

At least 1,585 records · Page 88Linked to original sources
bioRxiv2018

The rice G protein γ subunit qPE9-1 positively regulates grain-filling process by interacting with abscisic acid and auxin

The rice genome contains a single G (RGA1) and G{beta} (RGB1) and five G{gamma} subunits. Recent genetic studies have shown that DEP1/qPE9-1, an atypical putative G{gamma} protein, is responsible for dense and erect panicles, but the biochemical and molecular mechanisms underlying control of grain size are not well understood. Here, we report that plants carrying qPE9-1 have more endosperm cells per grain than plants contain the qpe9-1 allele. The qPE9-1 line has a higher rate and longer period of starch accumulation than the qpe9-1 line. Additionally, the expression of several key genes encoding enzymes catalyzing sucrose metabolism and starch biosynthesis is higher in the qPE9-1 line than in the qpe9-1 line, especially from the mid to late grain-filling stage. Grains of the qPE9-1 line also have higher contents of two phytohormones, ABA and IAA. Exogenous application of ABA or IAA enhanced starch accumulation and the expression of genes encoding grain-filling-related enzymes in the grains of qPE9-1, whereas only IAA produced these effects in qpe9-1. Based on these results, we conclude that qPE9-1 promotes endosperm cell proliferation and positively regulates starch accumulation largely through ABA and IAA, which enhance the expression of genes encoding starch biosynthesis during the late grain-filling stage.

plant biology↗
bioRxiv2018

Establishment and imaging evaluation of Guangxi Ba-Ma mini pigs as a model of cerebral hernia induced by acute intracranial hypertension

In order to establish an animal model of cerebral hernia induced by acute intracranial hypertension for subsequent research in emergency medicine. Six Guangxi Ba-Ma mini-pigs which were injected with autologous arterial blood by micropump to induce intracranial hematoma in the frontal and temporal parietal lobes. Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP) and cerebral perfusion pressure (CPP)were observed during hematoma formation. Morphological changes and the occupying effects of intracranial hematoma were analyzed using computed tomography (CT) and magnetic resonance imaging (MRI) of the head. ICP, MAP and CPP gradually increased during blood injection, and they began to slowly decrease at 10 min after injection, though they remained higher than before injection. These three parameters were significantly different before blood injection, immediately after injection and at 10 min after injection (P< 0.05). Head CT and MRI showed cerebral hernia induced by acute intracranial hypertension. These results demonstrate micropump injection of autologous arterial blood can lead to acute intracranial hypertension in mini-pigs, which may be a useful model of cerebral hernia.

neuroscience↗
bioRxiv2018

Dynamic urinary proteomic analysis in a Walker 256 intracerebral tumor model

Patients with primary and metastatic brain cancer have an extremely poor prognosis, mostly due to the late diagnosis of disease. Urine, which lacks homeostatic mechanisms, is an ideal biomarker source that accumulates early and highly sensitive changes to provides information about the early stage of disease. A rat model mimicking the local tumor growth process in the brain was established with intracerebral Walker 256 (W256) cell injection. Urine samples were collected on days 3, 5 and 8 after injection and then analyzed by LC-MS/MS. In the intracerebral W256 model, no obvious clinical manifestations changes or abnormal MRI signals were found on days 3 and 5; at these time points, nine proteins were changed significantly in the urine of all 8 tumor rats. On day 8, when tumors were detected by MRI, twenty-five differential proteins were identified, including 10 proteins that have been reported to be closely related to tumor metastasis or brain tumors. The differential urinary proteomes were compared with those from the subcutaneous W256 model and the intracerebral C6 model. Few differential proteins overlapped. Specific differential protein patterns were observed among the three models, indicating that the urinary proteome can reflect the difference when tumor cells with different growth characteristics are inoculated into the brain and when identical tumor cells are inoculated into different areas, specifically, the subcutis and the brain.

cancer biology↗
bioRxiv2018

Transcriptional suppression from KMT2D loss disrupts cell cycle and hypoxic responses in neurodevelopmental models of Kabuki syndrome

Chromatin modifiers act to coordinate gene expression changes critical to neuronal differentiation from neural stem/progenitor cells (NSPCs). Lysine-specific methyltransferase 2D (KMT2D) encodes a histone methyltransferase that promotes transcriptional activation, and is frequently mutated in cancers and in the majority (>70%) of patients diagnosed with the congenital, multisystem intellectual disability (ID) disorder Kabuki syndrome 1 (KS1). Critical roles for KMT2D are established in various non-neural tissues, but the effects of KMT2D loss in brain cell development have not been described. We conducted parallel studies of proliferation, differentiation, transcription, and chromatin profiling in KMT2D-deficient human and mouse models to define KMT2D-regulated functions in neurodevelopmental contexts, including adult-born hippocampal NSPCs in vivo and in vitro. We report cell-autonomous defects in proliferation, cell cycle, and survival, accompanied by early NSPC maturation in several KMT2D-deficient model systems. Transcriptional suppression in KMT2D-deficient cells indicated strong perturbation of hypoxia-responsive metabolism pathways. Functional experiments confirmed abnormalities of cellular hypoxia responses in KMT2D-deficient neural cells, and accelerated NSPC maturation in vivo. Together, our findings support a model in which loss of KMT2D function suppresses expression of oxygen-responsive gene programs important to neural progenitor maintenance, resulting in precocious neuronal differentiation in a mouse model of KS1.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC=\"FIGDIR/small/484410v3_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (22K):\norg.highwire.dtl.DTLVardef@55dd1aorg.highwire.dtl.DTLVardef@1270c80org.highwire.dtl.DTLVardef@a5bda2org.highwire.dtl.DTLVardef@144df37_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗
bioRxiv2018

Early detection of retinal alteration by visible and near-infrared optical coherence tomography (vnOCT) in a dexamethasone-induced ocular hypertension mouse model

PurposeTo apply a novel visible and near-infrared optical coherence tomography (vnOCT) in the dexa-methasone-induced ocular hypertension mouse model, and test the capability of four optical markers, peri-papillary retinal nerve fiber layer (RNFL) thickness, total retinal blood flow, VN ratio and hemoglobin oxygen saturation (sO2), in detecting retinal ganglion cell (RGC) damage in association with ocular hyper-tension.\n\nMethodsTwelve mice (C57BL/6J) were separated into a control (n=6) and a dexamethasone group (n=6) receiving twice daily saline or dexamethasone eye drops, respectively, for 7 weeks. Intraocular pressure (IOP) measurements were taken at baseline and weekly. Optical measurements by vnOCT were longitudinally taken at baseline, 4 weeks and 7 weeks. Following week 7, ex vivo RGC counting was performed by immunostaining.\n\nResultsThe dexamethasone group showed a measurable rise in IOP by week 2. Despite the IOP differences between the dexamethasone and control groups, there was not a statistical difference in RNFL thickness or total blood flow over 7 weeks. The dexamethasone group did show an increase in retinal arteriovenous sO2 difference (A-V sO2) that was significant at week 4 and 7. The RNFL VN ratio showed a significant decrease at week 4 and 7 in dexamethasone group associated with a decreased RGC count.\n\nConclusionsRNFL VN ratio and A-V sO2 are capable of detecting early retinal alterations in the dexamethasone-induced ocular hypertension mouse model. Data analysis suggests VN ratio and A-V sO2 are corralated with RGC loss secondary to ocular hypertension, while being independent of IOP.

bioengineering↗
bioRxiv2018

A critical role of the T3SS effector EseJ in intracellular trafficking and replication of Edwardsiella piscicida in non-phagocytic cells

Edwardsiella piscicida (E. piscicida) is an intracellular pathogen within a broad spectrum of hosts. Essential to E. piscicida virulence is its ability to survive and replicate inside host cells, yet the underlying mechanisms and the nature of the replicative compartment remain unclear. Here, we characterized its intracellular lifestyle in non-phagocytic cells and showed that intracellular replication of E. piscicida in non-phagocytic cells is dependent on its type III secretion system. Following internalization, E. piscicida is contained in vacuoles that transiently mature into early endosomes, but subsequently bypasses the classical endosome pathway and fusion with lysosomes which depends on its T3SS. Following a rapid escape from the degradative pathway, E. piscicida was found to create a specialized replication-permissive niche characterized by endoplasmic reticulum (ER) markers. We also found that a T3SS effector EseJ is responsible for intracellular replication of E. piscicida by preventing endosome/lysosome fusion. Furthermore, in vivo experiments confirmed that EseJ is necessary for bacterial colonization of E. piscicida in both mice and zebrafish. Thus, this work elucidates the strategies used by E. piscicida to survive and proliferate within host non-phagocytic cells.\n\nAuthor summaryE. piscicida is a facultative intracellular bacterium associated with septicemia and fatal infections in many animals, including fish and humans. However, little is known about its intracellular life, which is important for successful invasion of the host. The present study is the first comprehensive characterization of E. piscicidas intracellular life-style in host cells. Upon internalization, E. piscicida is transiently contained in Rab5-positive vacuoles, but the pathogen prevents further endosome maturation and fusion with lysosomes by utilizing an T3SS effector EseJ. In addition, the bacterium creates an specialized replication niche for rapid growth via an interaction with the ER. Our study provides new insights into the strategies used by E. piscicida to successfully establishes an intracellular lifestyle that contributes to its survival and dissemination during infection.

pathology↗
bioRxiv2018

A SIMPLE APPROXIMATION TO THE BIAS IN THE GENETIC EFFECT ESTIMATES WHEN MULTIPLE DISEASE STATES SHARE A CLINICAL DIAGNOSIS

Case-control genome-wide association (CC-GWAS) studies might provide valuable clues to the underlying pathophysiologic mechanisms of complex diseases, such as neurodegenerative disease, cancer. A commonly overlooked complication is that multiple distinct disease states might present with the same set of symptoms and hence share a clinical diagnosis. These disease states can only be distinguished in a biomarker evaluation that might not be feasible on the whole set of cases in the large number of samples that are typically needed for CC-GWAS. Instead, the biomarkers are measured on a subset of cases. Or an external reliability study estimates frequencies of the disease states of interest within the clinically diagnosed set of cases. These frequencies often vary by the genetic and/or non-genetic variables. We derive a simple approximation that relates the genetic effect estimates obtained in a logistic regression model with the clinical diagnosis as an outcome variable to the estimates in the relationship to the true disease state of interest. We performed simulation studies to assess accuracy of the approximation that weve derived. We next applied the derived approximation to the analysis of the genetic basis of innate immune system of Alzheimers disease.

genetics↗
bioRxiv2018

NanoARG: A web service for identification of antimicrobial resistance elements from nanopore-derived environmental metagenomes

Direct selection pressures imposed by antibiotics, indirect pressures by co-selective agents, and horizontal gene transfer are fundamental drivers of the evolution and spread of antibiotic resistance. Therefore, effective environmental monitoring tools should ideally capture not only antibiotic resistance genes (ARGs), but also mobile genetic elements (MGEs) and indicators of co-selective forces, such as metal resistance genes (MRGs). Further, a major challenge towards characterizing potential human risk is the ability to identify bacterial host organisms, especially human pathogens. Historically, short reads yielded by next-generation sequencing technology has hampered confidence in assemblies for achieving these purposes. Here we introduce NanoARG, an online computational resource that takes advantage of long reads produced by MinION nanopore sequencing. Specifically, long nanopore reads enable identification of ARGs in the context of relevant neighboring genes, providing relevant insight into mobility, co-selection, and pathogenicity. NanoARG allows users to upload sequence data online and provides various means to analyze and visualize the data, including quantitative and simultaneous profiling of ARG, MRG, MGE, and pathogens. NanoARG is publicly available and freely accessible at http://bench.cs.vt.edu/nanoARG.

bioinformatics↗
bioRxiv2018

DeepCapTail: A Deep Learning Framework to Predict Capsid and Tail Proteins of Phage Genomes

The capsid and tail proteins are considered the main structural proteins for phages and also their footprint since they exist only in phage genomes. These proteins are known to lack sequence conservation, making them extremely diverse and thus posing a major challenge to identify and annotate them in genomic sequences. In this study, we aim to overcome this challenge and predict these proteins by using deep neural networks with composition-based features. We develop two models trained with k-mer features to predict capsid and tail proteins respectively. Evaluating the models on two different testing sets shows that they outperform state-of-the-art methods with improved F-1 scores.

bioinformatics↗
bioRxiv2018

Effects of Biogas Slurry on Fruit Economic Traits and Soil Nutrient of Camellia oleifera Abel

Soil nutrients play a principal role in Camellia oleifera Abel (oil-seed camellia) production. Camellia oleifera absorbs nutrients from surrounding soils and its production is highly influenced by nutrients or fertilization. In this study, we investigated the effects of biogas slurry applications on soil nutrients and economic traits of C. oleifera fruits. Five different amounts of fertilizing biogas slurry (0, 10, 20, 30, or 40 kg/plant/year from three applications per year) were applied to C. oleifera plants in 2015 and 2016. Rhizosphere soil nutrients and C. oleifera fruit economic traits (yield, seed rate, and oil yield)were measured. Fertilization with biogas slurryincreasedsoil organic matter, available nitrogen (N), phosphorus (P), and potassium (K) in both 2015 and 2016. Increases in soil available N, P, and Kwere largest at the highest slurry application rate and second largest at the second highest application rate. Fruit economic traits were maximized at the two highest application rates. Oil yield was correlated withsoil available P in 2015 and 2016, and soil organic matter in 2015. Fertilization with biogas slurry decreased saturated fatty acid content in fruit but had no effect on unsaturated fatty acid content. In conclusion, fertilization with biogas slurry increases rhizosphere soil nutrients and fruit economic traits of C. oleifera with the rates of at least 30 kg/plant/year having the most positive effects.

plant biology↗
bioRxiv2018

On ‘Reverse’ Regression for Robust Genetic Association Studies and Allele Frequency Estimation with Related Individuals

For genetic association studies with related individuals, standard linear mixed-effect model is the most popular approach. The model treats a complex trait (phenotype) as the response variable while a genetic variant (genotype) as a covariate. An alternative approach is to reverse the roles of phenotype and genotype. This class of tests includes quasi-likelihood based score tests. In this work, after reviewing these existing methods, we propose a general, unifying reverse regression framework. We then show that the proposed method can also explicitly adjust for potential departure from Hardy-Weinberg equilibrium. Lastly, we demonstrate the additional flexibility of the proposed model on allele frequency estimation, as well as its connection with earlier work of best linear unbiased allele-frequency estimator. We conclude the paper with supporting evidence from simulation and application studies.

genetics↗
bioRxiv2018

Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by abundant infiltration of tumor associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, the front-line chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Additionally, we report pyrimidine release is a general function of anti-inflammatory myeloid cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

cancer biology↗
bioRxiv2018

Intraflagellar transport protein 74 is essential for mouse spermatogenesis and male fertility by regulating axonemal microtubule assembly in mice

IFT74 is a component of the core intraflagellar transport (IFT) complex, a bidirectional movement of large particles along the axoneme microtubules for cilia formation. In this study, we investigated its role in sperm flagella formation and discovered that mice deficiency in IFT74 in male germ cells were infertile associated with low sperm counts and immotile sperm. The few developed spermatozoa displayed misshaped heads and short tails. Transmission electron microscopy revealed abnormal flagellar axoneme in the seminiferous tubules where sperm are made. Clusters of unassembled microtubules were present in the spermatids. Testicular expression levels of IFT27, IFT57, IFT81, IFT88 and IFT140 were significantly reduced in the mutant mice, with the exception of IFT20 and IFT25. The levels of ODF2 and SPAG16L proteins were also not changed. However, the processed AKAP4 protein, a major component of the fibrous sheath, a unique structure of sperm tail, was significantly reduced. Our study demonstrates that IFT74 is essential for mouse sperm formation, probably through assembly of the core axoneme and fibrous sheath, and highlights a potential genetic factor (IFT74) that contributes to human infertility in men.

developmental biology↗
bioRxiv2018

Umbelliprenin isolated from Ferula sinkiangensis inhibits tumor growth and migration through the disturbance of Wnt signaling pathway in gastric cancer

The traditional herb medicine Ferula sinkiangensis K. M. Shen (F. sinkiangensis) has been used to treat stomach disorders in Xinjiang District for centuries. Umbelliprenin is the effective component isolated from F. sinkiangensis which is particularly found in plants of the family Ferula. We previously reported the promising effects of Umbelliprenin against gastric cancer cells, but its anti-migration effect remained unknown. Here we investigated the anti-migration effect and mechanism of Umbelliprenin in human gastric cancer cells. In SRB assay, Umbelliprenin showed cytotoxic activities in the gastric cancer cell lines AGS and BGC-823 in a dose-and-time-dependent manner, while it showed lower cytotoxic activity in the normal gastric epithelium cell line GES-1. During transwell, scratch and colony assays, the migration of tumor cells was inhibited by Umbelliprenin treatment. The expression levels of the Wnt-associated signaling pathway proteins were analyzed with western blots, and the results showed that Umbelliprenin decreased the expression levels of proteins of the Wnt signalling pathway, such as Wnt-2, {beta}-catenin, GSK-3{beta}, p-GSK-3{beta}, Survivin and c-myc. The translocation of {beta}-catenin to the nucleus was also inhibited by Umbelliprenin treatment. In TCF reporter assay, the transcriptional activity of T-cell factor/lymphoid enhancer factor (TCF/LEF) was decreased after Umbelliprenin treatment. The in vivo results suggested that Umbelliprenin induced little to no harm in the lung, heart and kidney. Overall, these data provided evidence that Umbelliprenin may inhibit the growth, invasion and migration of gastric cancer cells by disturbing the Wnt signaling pathway.

molecular biology↗
bioRxiv2018

Pentatricopeptide repeat poly(A) binding protein from mitochondria of trypanosomes

In Trypanosoma brucei, most mitochondrial mRNAs undergo U-insertion/deletion editing, and 3' adenylation and uridylation. The internal sequence changes and terminal extensions are coordinated: Pre-editing addition of the short (A) tail protects the edited transcript against 3'-5' degradation, while post-editing A/U-tailing renders mRNA competent for ribosome recruitment. Participation of a poly(A) binding protein (PABP) in coupling of editing and 3' modification processes has been inferred, but its identity and mechanism of action remained elusive. We report identification of KPAF4, a pentatricopeptide repeat-containing PABP which sequesters the A-tail and impedes exonucleolytic degradation. Conversely, KPAF4 inhibits uridylation of A-tailed transcripts and, therefore, premature A/U-tailing of partially-edited mRNAs. This quality check point prevents translation of incompletely edited mRNAs. Our findings also implicate the RNA editing substrate binding complex (RESC) in mediating the interaction between the 5' end bound pyrophosphohydrolase MERS1 and 3' end associated KPAF4 to enable mRNA circularization. This event is critical for transcript stability during the editing process.

biochemistry↗
bioRxiv2018

Drosophila scribble mutant tumors undergo a transition from a growth arrest state to a proliferative state over time

The Drosophila neoplastic tumor suppressor gene (nTSG) mutant tumors have successfully modeled many aspects of human tumor progression. However, the fly nTSG mutant tumors progress rapidly over days. This is in contrast with most human tumors which develop slowly, harbor heterogeneous cell populations for selection and undergo an evolution-like process. Whether the fast-growing fly nTSG mutant tumors have capacity for evolution remains unclear. Through quantitative analysis of the scrib mutant tumor growth, we found that the scrib mutant tumors evolve to display different growth rates and cell cycle profiles over time. Multiple growth-regulatory signaling pathways show quantitative differences in early versus late scrib mutant tumors. These data suggest that the scrib mutant tumors undergo a transition from a growth arrest state to a proliferative state. Through longitudinal single cell RNA (scRNA) data analysis we found that the scrib mutant tumors harbor heterogeneous cell populations likely of distinct proliferative states, which are available for potential selection. This study raises the possibility of studying tumor evolution in a genetically accessible and fast-growing invertebrate tumor model.

developmental biology↗
bioRxiv2018

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Ciliopathies manifested in part by a dysfunction of several phosphoinositide 5phosphatases constitute Lowes, Dent disease 2 and Joubert syndromes through critical involvement of properly functioning primary cilia (PC). We showed that deletion of INPP5E under the control of OMP-Cre in mature mouse olfactory sensory neurons (OSNs) led to a dramatic redistribution of PI(4,5)P2 (PIP2) in cilia, significant reduction of PI(3,4)P2 and enrichment of PI(3,4,5)P3 in knobs. Redistribution of the phospholipids accompanied marked elongation of cilia in INPP5E-OMP knockout (KO) OSNs. Such a dramatic remodeling of phospholipid composition however did not affect other integral membrane lipids (cholesterol, sphingomyelin, glycosylated phosphaditylinositol, phosphatidylserine). Proteins known to bind with high affinity PIP2 entered the cilia of the KO OSNs. Loss of INPP5E did not affect ciliary localization of endogenous olfactory receptor M71/M72 or distribution and movement of IFT122 particles implicating independent of phospholipids mechanism of retrograde protein transport in cilia of mature OSNs. Net odor sensitivity and response magnitude as measured by EOG was not affected by the mutation. However, odor adaptation in the KO mouse was significantly impaired resulting in less efficient recovery and altered inactivation kinetics of the odor response at the EOG and single-cell level. These findings implicate phosphoinositide-dependent regulation of active Ca2+ extrusion in OSNs whereby controlling the rate of sensory adaptation.\n\nSignificance statementCurrently there are little if any available treatment to cure congenital ciliopathies. This is in part due to lack of basic knowledge of cilia biology. Olfactory cilia as well as primary cilia appear to be a phospholipid privileged organelle distinct from the rest of plasma membrane albeit sharing its continuity. We characterized distribution of several critically important for cell biology phospholipids and showed that their balance, especially of PIP2, is disrupted in Joubert syndrome animal model and has functional implications. Virally assisted delivery of wild type INPP5E to the mutant OSNs was able to restore localization of PIP2 and rescued impaired response to odor.

neuroscience↗