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Sample records for inter-species liver co-expression

  1. Characterization of Chemically Induced Liver Injuries Using Gene Co-Expression Modules

    PubMed Central

    Tawa, Gregory J.; AbdulHameed, Mohamed Diwan M.; Yu, Xueping; Kumar, Kamal; Ippolito, Danielle L.; Lewis, John A.; Stallings, Jonathan D.; Wallqvist, Anders

    2014-01-01

    Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules) specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1) known biochemical pathways associated with liver injuries and 2) clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20%) genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects. PMID:25226513

  2. Co-expression network analysis identifies transcriptional modules in the mouse liver.

    PubMed

    Liu, Wei; Ye, Hua

    2014-10-01

    The mouse liver transcriptome has been extensively studied but little is known about the global hepatic gene network of the mouse under normal physiological conditions. Understanding this will help reveal the transcriptional organization of the liver and elucidate its functional complexity. Here, weighted gene co-expression network analysis (WGCNA) was carried out to explore gene co-expression networks using large-scale microarray data from normal mouse livers. A total of 7,203 genes were parsed into 16 gene modules associated with protein catabolism, RNA processing, muscle contraction, transcriptional regulation, oxidation reduction, sterol biosynthesis, translation, fatty acid metabolism, immune response and others. The modules were organized into higher order co-expression groups. Hub genes in each module were found to be critical for module function. In sum, the analyses revealed the gene modular map of the mouse liver under normal physiological condition. These results provide a systems-level framework to help understand the complexity of the mouse liver at the molecular level, and should be beneficial in annotating uncharacterized genes. PMID:24816893

  3. Uncovering the liver's role in immunity through RNA co-expression networks.

    PubMed

    Harrall, Kylie K; Kechris, Katerina J; Tabakoff, Boris; Hoffman, Paula L; Hines, Lisa M; Tsukamoto, Hidekazu; Pravenec, Michal; Printz, Morton; Saba, Laura M

    2016-10-01

    Gene co-expression analysis has proven to be a powerful tool for ascertaining the organization of gene products into networks that are important for organ function. An organ, such as the liver, engages in a multitude of functions important for the survival of humans, rats, and other animals; these liver functions include energy metabolism, metabolism of xenobiotics, immune system function, and hormonal homeostasis. With the availability of organ-specific transcriptomes, we can now examine the role of RNA transcripts (both protein-coding and non-coding) in these functions. A systems genetic approach for identifying and characterizing liver gene networks within a recombinant inbred panel of rats was used to identify genetically regulated transcriptional networks (modules). For these modules, biological consensus was found between functional enrichment analysis and publicly available phenotypic quantitative trait loci (QTL). In particular, the biological function of two liver modules could be linked to immune response. The eigengene QTLs for these co-expression modules were located at genomic regions coincident with highly significant phenotypic QTLs; these phenotypes were related to rheumatoid arthritis, food preference, and basal corticosterone levels in rats. Our analysis illustrates that genetically and biologically driven RNA-based networks, such as the ones identified as part of this research, provide insight into the genetic influences on organ functions. These networks can pinpoint phenotypes that manifest through the interaction of many organs/tissues and can identify unannotated or under-annotated RNA transcripts that play a role in these phenotypes. PMID:27401171

  4. Systems toxicology of chemically induced liver and kidney injuries: histopathology-associated gene co-expression modules.

    PubMed

    Te, Jerez A; AbdulHameed, Mohamed Diwan M; Wallqvist, Anders

    2016-09-01

    Organ injuries caused by environmental chemical exposures or use of pharmaceutical drugs pose a serious health risk that may be difficult to assess because of a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific histopathology outcomes via biomarkers will provide a foundation for designing precise and robust diagnostic tests. We identified co-expressed genes (modules) specific to injury endpoints using the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) - a toxicogenomics database containing organ-specific gene expression data matched to dose- and time-dependent chemical exposures and adverse histopathology assessments in Sprague-Dawley rats. We proposed a protocol for selecting gene modules associated with chemical-induced injuries that classify 11 liver and eight kidney histopathology endpoints based on dose-dependent activation of the identified modules. We showed that the activation of the modules for a particular chemical exposure condition, i.e., chemical-time-dose combination, correlated with the severity of histopathological damage in a dose-dependent manner. Furthermore, the modules could distinguish different types of injuries caused by chemical exposures as well as determine whether the injury module activation was specific to the tissue of origin (liver and kidney). The generated modules provide a link between toxic chemical exposures, different molecular initiating events among underlying molecular pathways and resultant organ damage. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Journal of Applied Toxicology published by John Wiley & Sons, Ltd. PMID:26725466

  5. Rat Hepatocytes Weighted Gene Co-Expression Network Analysis Identifies Specific Modules and Hub Genes Related to Liver Regeneration after Partial Hepatectomy

    PubMed Central

    Zhou, Yun; Xu, Jiucheng; Liu, Yunqing; Li, Juntao; Chang, Cuifang; Xu, Cunshuan

    2014-01-01

    The recovery of liver mass is mainly mediated by proliferation of hepatocytes after 2/3 partial hepatectomy (PH) in rats. Studying the gene expression profiles of hepatocytes after 2/3 PH will be helpful to investigate the molecular mechanisms of liver regeneration (LR). We report here the first application of weighted gene co-expression network analysis (WGCNA) to analyze the biological implications of gene expression changes associated with LR. WGCNA identifies 12 specific gene modules and some hub genes from hepatocytes genome-scale microarray data in rat LR. The results suggest that upregulated MCM5 may promote hepatocytes proliferation during LR; BCL3 may play an important role by activating or inhibiting NF-kB pathway; MAPK9 may play a permissible role in DNA replication by p38 MAPK inactivation in hepatocytes proliferation stage. Thus, WGCNA can provide novel insight into understanding the molecular mechanisms of LR. PMID:24743545

  6. Weighted gene co-expression network analysis of colorectal cancer liver metastasis genome sequencing data and screening of anti-metastasis drugs.

    PubMed

    Gao, Bo; Shao, Qin; Choudhry, Hani; Marcus, Victoria; Dong, Kung; Ragoussis, Jiannis; Gao, Zu-Hua

    2016-09-01

    Approximately 9% of cancer-related deaths are caused by colorectal cancer (CRC). CRC patients are prone to liver metastasis, which is the most important cause for the high CRC mortality rate. Understanding the molecular mechanism of CRC liver metastasis could help us to find novel targets for the effective treatment of this deadly disease. Using weighted gene co-expression network analysis on the sequencing data of CRC with and with metastasis, we identified 5 colorectal cancer liver metastasis related modules which were labeled as brown, blue, grey, yellow and turquoise. In the brown module, which represents the metastatic tumor in the liver, gene ontology (GO) analysis revealed functions including the G-protein coupled receptor protein signaling pathway, epithelial cell differentiation and cell surface receptor linked signal transduction. In the blue module, which represents the primary CRC that has metastasized, GO analysis showed that the genes were mainly enriched in GO terms including G-protein coupled receptor protein signaling pathway, cell surface receptor linked signal transduction, and negative regulation of cell differentiation. In the yellow and turquoise modules, which represent the primary non-metastatic CRC, 13 downregulated CRC liver metastasis-related candidate miRNAs were identified (e.g. hsa-miR-204, hsa-miR-455, etc.). Furthermore, analyzing the DrugBank database and mining the literature identified 25 and 12 candidate drugs that could potentially block the metastatic processes of the primary tumor and inhibit the progression of metastatic tumors in the liver, respectively. Data generated from this study not only furthers our understanding of the genetic alterations that drive the metastatic process, but also guides the development of molecular-targeted therapy of colorectal cancer liver metastasis. PMID:27571956

  7. Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha.

    PubMed Central

    Santoni-Rugiu, E.; Nagy, P.; Jensen, M. R.; Factor, V. M.; Thorgeirsson, S. S.

    1996-01-01

    We have previously shown that co-expression of c-myc and transforming growth factor (TGF)-alpha as transgenes in mouse liver results in major enhancement of neoplastic development in this organ as compared with expression of either of these transgenes alone. In this report we describe in detail the progression from liver cell dysplasia to hepatocellular carcinomas (HCCs) occurring in the liver of c-myc/TGF-alpha and c-myc transgenic mice. Despite morphological similarities in the sequence of events between the two transgenic lines, the dramatic acceleration, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice clearly demonstrated the synergistic effects of this transgenic combination. Although c-myc/TGF-alpha and c-myc females displayed longer latency and lower tumor incidence, the pathological changes were the same as those seen in the male mice, including the formation of HCCs, which are absent in TGF-alpha single-transgenic females. Tumors in single- and double-transgenic mice showed induction of the endogenous c-myc and TGF-alpha and, most frequently, unchanged or decreased epidermal growth factor receptor, further indicating the collaborative role of c-myc and TGF-alpha in providing a selective growth advantage to tumor cells independently of the epidermal growth factor receptor levels. To identify possible tumor precursors, we focused particularly on the dysplastic changes preceding and accompanying the appearance of preneoplastic and neoplastic lesions in the double-transgenic mice. Early on, these changes were characterized by the appearance of large dysplastic hepatocytes, mostly pericentrally, expressing high levels of TGF-alpha and uPA, as well as TGF-beta 1, particularly in apoptotic cells. After a short period of replication and expansion into the liver parenchyma, as well as penetration into the central veins, these cells underwent apoptotic cell death while preneoplastic and neoplastic lesions were forming. The peritumorous tissues also

  8. Inter-species interconnections in acid mine drainage microbial communities

    PubMed Central

    Comolli, Luis R.; Banfield, Jill F.

    2014-01-01

    Metagenomic studies are revolutionizing our understanding of microbes in the biosphere. They have uncovered numerous proteins of unknown function in tens of essentially unstudied lineages that lack cultivated representatives. Notably, few of these microorganisms have been visualized, and even fewer have been described ultra-structurally in their essentially intact, physiologically relevant states. Here, we present cryogenic transmission electron microscope (cryo-TEM) 2D images and 3D tomographic datasets for archaeal species from natural acid mine drainage (AMD) microbial communities. Ultrastructural findings indicate the importance of microbial interconnectedness via a range of mechanisms, including direct cytoplasmic bridges and pervasive pili. The data also suggest a variety of biological structures associated with cell-cell interfaces that lack explanation. Some may play roles in inter-species interactions. Interdependences amongst the archaea may have confounded prior isolation efforts. Overall, the findings underline knowledge gaps related to archaeal cell components and highlight the likely importance of co-evolution in shaping microbial lineages. PMID:25120533

  9. Inter-species entanglement of Bose–Bose mixtures trapped in optical lattices

    NASA Astrophysics Data System (ADS)

    (王 巍, Wei Wang; Penna, Vittorio; Capogrosso-Sansone, Barbara

    2016-06-01

    In the present work we discuss inter-species entanglement in Bose–Bose mixtures trapped in optical lattices. This work is motivated by the observation that, in the presence of a second component, the MI lobe shifts differently on the hole- and particle-side with respect to the Mott lobe of the single species system (Guglielmino et al 2010 Phys. Rev. A 82 021601; Capogrosso-Sansone et al 2011 Laser Phys. 21 1443). We use perturbation theory, formulated in a Hilbert space decomposed by means of lattice symmetries, in order to show that the nonuniform shift of the Mott lobe is a manifestation of inter-species entanglement which differs in the lowest excited states to remove and add a particle. Our results indicate that inter-species entanglement in mixtures can provide a new perspective in understanding quantum phase transitions. To validate our approach, we compare our results from perturbation theory with quantum Monte Carlo simulations.

  10. Contributions of ancestral inter-species recombination to the genetic diversity of extant Streptomyces lineages.

    PubMed

    Andam, Cheryl P; Choudoir, Mallory J; Vinh Nguyen, Anh; Sol Park, Han; Buckley, Daniel H

    2016-07-01

    Streptomyces species produce many important antibiotics and have a crucial role in soil nutrient cycling. However, their evolutionary history remains poorly characterized. We have evaluated the impact of homologous recombination on the evolution of Streptomyces using multi-locus sequence analysis of 234 strains that represent at least 11 species clusters. Evidence of inter-species recombination is widespread but not uniform within the genus and levels of mosaicism vary between species clusters. Most phylogenetically incongruent loci are monophyletic at the scale of species clusters and their subclades, suggesting that these recombination events occurred in shared ancestral lineages. Further investigation of two mosaic species clusters suggests that genes acquired by inter-species recombination may have become fixed in these lineages during periods of demographic expansion; implicating a role for phylogeography in determining contemporary patterns of genetic diversity. Only by examining the phylogeny at the scale of the genus is apparent that widespread phylogenetically incongruent loci in Streptomyces are derived from a far smaller number of ancestral inter-species recombination events. PMID:26849310

  11. Automated aural classification used for inter-species discrimination of cetaceans.

    PubMed

    Binder, Carolyn M; Hines, Paul C

    2014-04-01

    Passive acoustic methods are in widespread use to detect and classify cetacean species; however, passive acoustic systems often suffer from large false detection rates resulting from numerous transient sources. To reduce the acoustic analyst workload, automatic recognition methods may be implemented in a two-stage process. First, a general automatic detector is implemented that produces many detections to ensure cetacean presence is noted. Then an automatic classifier is used to significantly reduce the number of false detections and classify the cetacean species. This process requires development of a robust classifier capable of performing inter-species classification. Because human analysts can aurally discriminate species, an automated aural classifier that uses perceptual signal features was tested on a cetacean data set. The classifier successfully discriminated between four species of cetaceans-bowhead, humpback, North Atlantic right, and sperm whales-with 85% accuracy. It also performed well (100% accuracy) for discriminating sperm whale clicks from right whale gunshots. An accuracy of 92% and area under the receiver operating characteristic curve of 0.97 were obtained for the relatively challenging bowhead and humpback recognition case. These results demonstrated that the perceptual features employed by the aural classifier provided powerful discrimination cues for inter-species classification of cetaceans. PMID:25235008

  12. A RANKL mutant used as an inter-species vaccine for efficient immunotherapy of osteoporosis

    PubMed Central

    Liu, Changzhen; Zhao, Yunfeng; He, Wen; Wang, Wei; Chen, Yuan; Zhang, Shiqian; Ma, Yijing; Gohda, Jin; Ishida, Takaomi; Walter, Thomas S.; Owens, Raymond J.; Stuart, David I.; Ren, Jingshan; Gao, Bin

    2015-01-01

    Anti-cytokine therapeutic antibodies have been demonstrated to be effective in the treatment of several auto-immune disorders. However, The problems in antibody manufacture and the immunogenicity caused by multiple doses of antibodies inspire people to use auto-cytokine as immunogen to induce anti-cytokine antibodies. Nevertheless, the tolerance for inducing immune response against self-antigen has hindered the wide application of the strategy. To overcome the tolerance, here we proposed a strategy using the inter-species cytokine as immunogen for active immunization (TISCAI) to induce anti-cytokine antibody. As a proof of concept, an inter-species cytokine RANKL was successfully used as immunogen to induce anti-RANKL immune response. Furthermore, to prevent undesirable side-effects, the human RANKL was mutated based on the crystal structure of the complex of human RANKL and its rodent counterpart receptor RANK. We found, the antibodies produced blocked the osteoclast development in vitro and osteoporosis in OVX rat models. The results demonstrated this strategy adopted is very useful for general anti-cytokine immunotherapy for different diseases settings. PMID:26412210

  13. Plant inter-species effects on rhizosphere priming effect and nitrogen acquisition by plants

    NASA Astrophysics Data System (ADS)

    Sun, Yue; Xu, Xingliang; Yang, Baijie; Kuzyakov, Yakov

    2015-04-01

    Rhizosphere interactions play a central role linking roots-soil system and regulate various aspects of nutrient cycling. Rhizodeposition inputs are known to change soil organic matter (SOM) decomposition via rhizosphere priming effects (RPEs) through enhancing soil biological activity and altering microbial community structure. The magnitude of RPEs varies widely among plant-species and root biomass possibly due to different quality and quantity of rhizodeposits. However, it is virtually unknown whether the RPEs are influenced by plant inter-species interactions and how these processes affect N mineralization and available N for plants. Monocultures of maize (M) and soybean (S), and mixed cultures of maize/maize (MM), soybean/soybean (SS), maize/soybean (MS) were grown over a 45-day greenhouse experiment. We labeled them with plant litter that was enriched in13C and 15N. The 15N distributions in plants and microbial biomass were measured at 14, 35, and 45days after labeling. The RPEs were positive under all plants, ranging from 11.7% to 138.3% and gradually decreased with plant growth. The RPE in the SS was significantly higher than these in others treatments at 14 days, while at 45 days it was higher in the MS than these from their monocultures, suggesting that the RPE was enhanced by the inter-species effects of maize and soybean. The litter decomposition ratio and 15N recovery of plants and microorganism increased with the root growth across all plants. The 15N recovery of plants in the MS (14.2%) was higher than these in the MM (12.3%) and SS(9.7%) at 45 days. Similarly, the 15N recovery of microorganism in the corresponding treatments was 6.7%, 2.2%, and 6.8%, respectively. The MS showed higher soil organic N mineralization amount than that from all soybean and maize monocultures at 45 days. We conclude that plant inter-species interactions may have significant effect on rhizosphere priming and modify the plant N uptake from litter resource and SOM.

  14. Plant inter-species effects on rhizosphere priming of soil organic matter decomposition

    NASA Astrophysics Data System (ADS)

    Pausch, Johanna; Zhu, Biao; Cheng, Weixin

    2015-04-01

    Living roots and their rhizodeposits can stimulate microbial activity and soil organic matter (SOM) decomposition up to several folds. This so-called rhizosphere priming effect (RPE) varies widely among plant species possibly due to species-specific differences in the quality and quantity of rhizodeposits and other root functions. However, whether the RPE is influenced by plant inter-species interactions remains largely unexplored, even though these interactions can fundamentally shape plant functions such as carbon allocation and nutrient uptake. In a 60-day greenhouse experiment, we continuously labeled monocultures and mixtures of sunflower, soybean and wheat with 13C-depleted CO2 and partitioned total CO2 efflux released from soil at two stages of plant development for SOM- and root-derived CO2. The RPE was calculated as the difference in SOM-derived CO2 between the planted and the unplanted soil, and was compared among the monocultures and mixtures. We found that the RPE was positive under all plants, ranging from 43% to 136% increase above the unplanted control. There were no significant differences in RPE at the vegetative stage. At the flowering stage however, the RPE in the soybean-wheat mixture was significantly higher than those in the sunflower monoculture, the sunflower-wheat mixture, and the sunflower-soybean mixture. These results indicated that the influence of plant inter-specific interactions on the RPE is case-specific and phenology-dependent. To evaluate the intensity of inter-specific effects on priming, we calculated an expected RPE for the mixtures based on the RPE of the monocultures weighted by their root biomass and compared it to the measured RPE under mixtures. At flowering, the measured RPE was significantly lower for the sunflower-wheat mixture than what can be expected from their monocultures, suggesting that RPE was significantly reduced by the inter-species effects of sunflower and wheat. In summary, our results clearly demonstrated

  15. Intra- and inter-species spread of carbapenemase genes in a non-hospitalized patient.

    PubMed

    Sorlí, L; Miró, E; Segura, C; Navarro, F; Grau, S; Salvado, M; Horcajada, J P

    2011-12-01

    The purpose of this study was to report intra- and inter-species spread of carbapenemase genes between gram negative rods isolated from a non-hospitalized patient with bacteremia. The approach included chart review, antibiotic susceptibility testing and phenotypic screening for metallo-β-lactamase (MBL) detection, PCR and sequencing of bla, aac(6')-Ib and qnr genes, and plasmid analysis by PCR-based replicon typing. The clonal relationships between the isolates were analysed by comparing PFGE profiles. A non-hospitalized patient presented bacteraemia due to wild type Enterobacter cloacae (4.08), a VIM-1-producing E. cloacae (5.08), a VIM-1- and CTX-M-9-producing E. cloacae (7.08), a VIM-2-producing Pseudomonas aeruginosa, and catheter colonization by VIM-1-producing Klebsiella oxytoca. The patient had no previous hospitalization but had recently undergone an ambulatory colonoscopy. In E. cloacae 7.08 and K. oxytoca isolates, the bla(VIM-1) gene was located on a transferable plasmid of 48.5 kb, while in E. cloacae 5.08 the bla(VIM-1) gene was encoded on a 194 kb non-transferable plasmid. The bla(CTX-M-9) gene detected in E. cloacae was encoded on an HI2 plasmid of 290 kb. To date the prevalence of VIM-1 enzymes in the community is low. This molecular finding suggests an intra-species and/or inter-species horizontal spread of the MBL gene in the same non-hospitalized patient. PMID:21491175

  16. Discovering the Recondite Secondary Metabolome Spectrum of Salinispora Species: A Study of Inter-Species Diversity

    PubMed Central

    Bose, Utpal; Hewavitharana, Amitha K.; Vidgen, Miranda E.; Ng, Yi Kai; Shaw, P. Nicholas; Fuerst, John A.; Hodson, Mark P.

    2014-01-01

    Patterns of inter-species secondary metabolite production by bacteria can provide valuable information relating to species ecology and evolution. The complex nature of this chemical diversity has previously been probed via directed analyses of a small number of compounds, identified through targeted assays rather than more comprehensive biochemical profiling approaches such as metabolomics. Insights into ecological and evolutionary relationships within bacterial genera can be derived through comparative analysis of broader secondary metabolite patterns, and this can also eventually assist biodiscovery search strategies for new natural products. Here, we investigated the species-level chemical diversity of the two marine actinobacterial species Salinispora arenicola and Salinispora pacifica, isolated from sponges distributed across the Great Barrier Reef (GBR), via their secondary metabolite profiles using LC-MS-based metabolomics. The chemical profiles of these two species were obtained by UHPLC-QToF-MS based metabolic profiling. The resultant data were interrogated using multivariate data analysis methods to compare their (bio)chemical profiles. We found a high level of inter-species diversity in strains from these two bacterial species. We also found rifamycins and saliniketals were produced exclusively by S. arenicola species, as the main secondary metabolites differentiating the two species. Furthermore, the discovery of 57 candidate compounds greatly increases the small number of secondary metabolites previously known to be produced by these species. In addition, we report the production of rifamycin O and W, a key group of ansamycin compounds, in S. arenicola for the first time. Species of the marine actinobacteria harbour a much wider spectrum of secondary metabolites than suspected, and this knowledge may prove a rich field for biodiscovery as well as a database for understanding relationships between speciation, evolution and chemical ecology. PMID

  17. Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides.

    PubMed

    Roberts, Ashley; Lynch, Barry; Rogerson, Rebecca; Renwick, Andrew; Kern, Hua; Coffee, Matthew; Cuellar-Kingston, Nicole; Eapen, Alex; Crincoli, Christine; Pugh, George; Bhusari, Sachin; Purkayastha, Sidd; Carakostas, Michael

    2016-08-01

    The acceptable daily intake (ADI) of commercially available steviol glycosides is currently 0-4 mg/kg body weight (bw)/day, based on application of a 100-fold uncertainty factor to a no-observed-adverse-effect-level value from a chronic rat study. Within the 100-fold uncertainty factor is a 10-fold uncertainty factor to account for inter-species differences in toxicokinetics (4-fold) and toxicodynamics (2.5-fold). Single dose pharmacokinetics of stevioside were studied in rats (40 and 1000 mg/kg bw) and in male human subjects (40 mg/kg bw) to generate a chemical-specific, inter-species toxicokinetic adjustment factor. Tmax values for steviol were at ∼8 and ∼20 h after administration in rats and humans, respectively. Peak concentrations of steviol were similar in rats and humans, while steviol glucuronide concentrations were significantly higher in humans. Glucuronidation in rats was not saturated over the dose range 40-1000 mg/kg bw. The AUC0-last for steviol was approximately 2.8-fold greater in humans compared to rats. Chemical-specific adjustment factors for extrapolating toxicokinetics from rat to human of 1 and 2.8 were established based on Cmax and AUC0-last data respectively. Because these factors are lower than the default value of 4.0, a higher ADI for steviol glycosides of between 6 and 16 mg/kg bw/d is justified. PMID:27181453

  18. Collisionless inter-species energy transfer and turbulent heating in drift wave turbulence

    SciTech Connect

    Zhao, L.; Diamond, P. H.

    2012-08-15

    We reconsider the classic problems of calculating 'turbulent heating' and collisionless inter-species transfer of energy in drift wave turbulence. These issues are of interest for low collisionality, electron heated plasmas, such as ITER, where collisionless energy transfer from electrons to ions is likely to be significant. From the wave Poynting theorem at steady state, a volume integral over an annulus r{sub 1}=-S{sub r}|{sub r{sub 1}{sup r{sub 2}}}{ne}0. Here S{sub r} is the wave energy density flux in the radial direction. Thus, a wave energy flux differential across an annular region indeed gives rise to a net heating, in contrast to previous predictions. This heating is related to the Reynolds work by the zonal flow, since S{sub r} is directly linked to the zonal flow drive. In addition to net heating, there is inter-species heat transfer. For collisionless electron drift waves, the total turbulent energy source for collisionless heat transfer is due to quasilinear electron cooling. Subsequent quasilinear ion heating occurs through linear ion Landau damping. In addition, perpendicular heating via ion polarization currents contributes to ion heating. Since at steady state, Reynolds work of the turbulence on the zonal flow must balance zonal flow frictional damping ({approx}{nu}{sub ii}{sup 2}{approx}|(e{phi}(tilde sign)/T)|{sup 4}), it is no surprise that zonal flow friction appears as an important channel for ion heating. This process of energy transfer via zonal flow has not previously been accounted for in analyses of energy transfer. As an application, we compare the rate of turbulent energy transfer in a low collisionality plasma with the rate of the energy transfer by collisions. The result shows that the collisionless turbulent energy transfer is a significant energy coupling process for ITER plasma.

  19. Intra- and inter-species interactions within biofilms of important foodborne bacterial pathogens.

    PubMed

    Giaouris, Efstathios; Heir, Even; Desvaux, Mickaël; Hébraud, Michel; Møretrø, Trond; Langsrud, Solveig; Doulgeraki, Agapi; Nychas, George-John; Kačániová, Miroslava; Czaczyk, Katarzyna; Ölmez, Hülya; Simões, Manuel

    2015-01-01

    A community-based sessile life style is the normal mode of growth and survival for many bacterial species. Under such conditions, cell-to-cell interactions are inevitable and ultimately lead to the establishment of dense, complex and highly structured biofilm populations encapsulated in a self-produced extracellular matrix and capable of coordinated and collective behavior. Remarkably, in food processing environments, a variety of different bacteria may attach to surfaces, survive, grow, and form biofilms. Salmonella enterica, Listeria monocytogenes, Escherichia coli, and Staphylococcus aureus are important bacterial pathogens commonly implicated in outbreaks of foodborne diseases, while all are known to be able to create biofilms on both abiotic and biotic surfaces. Particularly challenging is the attempt to understand the complexity of inter-bacterial interactions that can be encountered in such unwanted consortia, such as competitive and cooperative ones, together with their impact on the final outcome of these communities (e.g., maturation, physiology, antimicrobial resistance, virulence, dispersal). In this review, up-to-date data on both the intra- and inter-species interactions encountered in biofilms of these pathogens are presented. A better understanding of these interactions, both at molecular and biophysical levels, could lead to novel intervention strategies for controlling pathogenic biofilm formation in food processing environments and thus improve food safety. PMID:26347727

  20. Intra- and inter-species interactions within biofilms of important foodborne bacterial pathogens

    PubMed Central

    Giaouris, Efstathios; Heir, Even; Desvaux, Mickaël; Hébraud, Michel; Møretrø, Trond; Langsrud, Solveig; Doulgeraki, Agapi; Nychas, George-John; Kačániová, Miroslava; Czaczyk, Katarzyna; Ölmez, Hülya; Simões, Manuel

    2015-01-01

    A community-based sessile life style is the normal mode of growth and survival for many bacterial species. Under such conditions, cell-to-cell interactions are inevitable and ultimately lead to the establishment of dense, complex and highly structured biofilm populations encapsulated in a self-produced extracellular matrix and capable of coordinated and collective behavior. Remarkably, in food processing environments, a variety of different bacteria may attach to surfaces, survive, grow, and form biofilms. Salmonella enterica, Listeria monocytogenes, Escherichia coli, and Staphylococcus aureus are important bacterial pathogens commonly implicated in outbreaks of foodborne diseases, while all are known to be able to create biofilms on both abiotic and biotic surfaces. Particularly challenging is the attempt to understand the complexity of inter-bacterial interactions that can be encountered in such unwanted consortia, such as competitive and cooperative ones, together with their impact on the final outcome of these communities (e.g., maturation, physiology, antimicrobial resistance, virulence, dispersal). In this review, up-to-date data on both the intra- and inter-species interactions encountered in biofilms of these pathogens are presented. A better understanding of these interactions, both at molecular and biophysical levels, could lead to novel intervention strategies for controlling pathogenic biofilm formation in food processing environments and thus improve food safety. PMID:26347727

  1. Inter-species prediction of protein phosphorylation in the sbv IMPROVER species translation challenge

    PubMed Central

    Biehl, Michael; Sadowski, Peter; Bhanot, Gyan; Bilal, Erhan; Dayarian, Adel; Meyer, Pablo; Norel, Raquel; Rhrissorrakrai, Kahn; Zeller, Michael D.; Hormoz, Sahand

    2015-01-01

    Motivation: Animal models are widely used in biomedical research for reasons ranging from practical to ethical. An important issue is whether rodent models are predictive of human biology. This has been addressed recently in the framework of a series of challenges designed by the systems biology verification for Industrial Methodology for Process Verification in Research (sbv IMPROVER) initiative. In particular, one of the sub-challenges was devoted to the prediction of protein phosphorylation responses in human bronchial epithelial cells, exposed to a number of different chemical stimuli, given the responses in rat bronchial epithelial cells. Participating teams were asked to make inter-species predictions on the basis of available training examples, comprising transcriptomics and phosphoproteomics data. Results: Here, the two best performing teams present their data-driven approaches and computational methods. In addition, post hoc analyses of the datasets and challenge results were performed by the participants and challenge organizers. The challenge outcome indicates that successful prediction of protein phosphorylation status in human based on rat phosphorylation levels is feasible. However, within the limitations of the computational tools used, the inclusion of gene expression data does not improve the prediction quality. The post hoc analysis of time-specific measurements sheds light on the signaling pathways in both species. Availability and implementation: A detailed description of the dataset, challenge design and outcome is available at www.sbvimprover.com. The code used by team IGB is provided under http://github.com/uci-igb/improver2013. Implementations of the algorithms applied by team AMG are available at http://bhanot.biomaps.rutgers.edu/wiki/AMG-sc2-code.zip. Contact: meikelbiehl@gmail.com PMID:24994890

  2. Inter-species pathway perturbation prediction via data-driven detection of functional homology

    PubMed Central

    Hafemeister, Christoph; Romero, Roberto; Bilal, Erhan; Meyer, Pablo; Norel, Raquel; Rhrissorrakrai, Kahn; Bonneau, Richard; Tarca, Adi L.

    2015-01-01

    Motivation: Experiments in animal models are often conducted to infer how humans will respond to stimuli by assuming that the same biological pathways will be affected in both organisms. The limitations of this assumption were tested in the IMPROVER Species Translation Challenge, where 52 stimuli were applied to both human and rat cells and perturbed pathways were identified. In the Inter-species Pathway Perturbation Prediction sub-challenge, multiple teams proposed methods to use rat transcription data from 26 stimuli to predict human gene set and pathway activity under the same perturbations. Submissions were evaluated using three performance metrics on data from the remaining 26 stimuli. Results: We present two approaches, ranked second in this challenge, that do not rely on sequence-based orthology between rat and human genes to translate pathway perturbation state but instead identify transcriptional response orthologs across a set of training conditions. The translation from rat to human accomplished by these so-called direct methods is not dependent on the particular analysis method used to identify perturbed gene sets. In contrast, machine learning-based methods require performing a pathway analysis initially and then mapping the pathway activity between organisms. Unlike most machine learning approaches, direct methods can be used to predict the activation of a human pathway for a new (test) stimuli, even when that pathway was never activated by a training stimuli. Availability: Gene expression data are available from ArrayExpress (accession E-MTAB-2091), while software implementations are available from http://bioinformaticsprb.med.wayne.edu?p=50 and http://goo.gl/hJny3h. Contact: christoph.hafemeister@nyu.edu or atarca@med.wayne.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25150249

  3. Inter-Species Comparative Analysis of Components of Soluble Sugar Concentration in Fleshy Fruits

    PubMed Central

    Dai, Zhanwu; Wu, Huan; Baldazzi, Valentina; van Leeuwen, Cornelis; Bertin, Nadia; Gautier, Hélène; Wu, Benhong; Duchêne, Eric; Gomès, Eric; Delrot, Serge; Lescourret, Françoise; Génard, Michel

    2016-01-01

    The soluble sugar concentration of fleshy fruit is a key determinant of fleshy fruit quality. It affects directly the sweetness of fresh fruits and indirectly the properties of processed products (e.g., alcohol content in wine). Despite considerable divergence among species, soluble sugar accumulation in a fruit results from the complex interplay of three main processes, namely sugar import, sugar metabolism, and water dilution. Therefore, inter-species comparison would help to identify common and/or species-specific modes of regulation in sugar accumulation. For this purpose, a process-based mathematical framework was used to compare soluble sugar accumulation in three fruits: grape, tomato, and peach. Representative datasets covering the time course of sugar accumulation during fruit development were collected. They encompassed 104 combinations of species (3), genotypes (30), and growing conditions (19 years and 16 nutrient and environmental treatments). At maturity, grape showed the highest soluble sugar concentrations (16.5–26.3 g/100 g FW), followed by peach (2.2 to 20 g/100 g FW) and tomato (1.4 to 5 g/100 g FW). Main processes determining soluble sugar concentration were decomposed into sugar importation, metabolism, and water dilution with the process-based analysis. Different regulation modes of soluble sugar concentration were then identified, showing either import-based, dilution-based, or import and dilution dual-based. Firstly, the higher soluble sugar concentration in grape than in tomato is a result of higher sugar importation. Secondly, the higher soluble sugar concentration in grape than in peach is due to a lower water dilution. The third mode of regulation is more complicated than the first two, with differences both in sugar importation and water dilution (grape vs. cherry tomato; cherry tomato vs. peach; peach vs. tomato). On the other hand, carbon utilization for synthesis of non-soluble sugar compounds (namely metabolism) was conserved

  4. Inter-Species Comparative Analysis of Components of Soluble Sugar Concentration in Fleshy Fruits.

    PubMed

    Dai, Zhanwu; Wu, Huan; Baldazzi, Valentina; van Leeuwen, Cornelis; Bertin, Nadia; Gautier, Hélène; Wu, Benhong; Duchêne, Eric; Gomès, Eric; Delrot, Serge; Lescourret, Françoise; Génard, Michel

    2016-01-01

    The soluble sugar concentration of fleshy fruit is a key determinant of fleshy fruit quality. It affects directly the sweetness of fresh fruits and indirectly the properties of processed products (e.g., alcohol content in wine). Despite considerable divergence among species, soluble sugar accumulation in a fruit results from the complex interplay of three main processes, namely sugar import, sugar metabolism, and water dilution. Therefore, inter-species comparison would help to identify common and/or species-specific modes of regulation in sugar accumulation. For this purpose, a process-based mathematical framework was used to compare soluble sugar accumulation in three fruits: grape, tomato, and peach. Representative datasets covering the time course of sugar accumulation during fruit development were collected. They encompassed 104 combinations of species (3), genotypes (30), and growing conditions (19 years and 16 nutrient and environmental treatments). At maturity, grape showed the highest soluble sugar concentrations (16.5-26.3 g/100 g FW), followed by peach (2.2 to 20 g/100 g FW) and tomato (1.4 to 5 g/100 g FW). Main processes determining soluble sugar concentration were decomposed into sugar importation, metabolism, and water dilution with the process-based analysis. Different regulation modes of soluble sugar concentration were then identified, showing either import-based, dilution-based, or import and dilution dual-based. Firstly, the higher soluble sugar concentration in grape than in tomato is a result of higher sugar importation. Secondly, the higher soluble sugar concentration in grape than in peach is due to a lower water dilution. The third mode of regulation is more complicated than the first two, with differences both in sugar importation and water dilution (grape vs. cherry tomato; cherry tomato vs. peach; peach vs. tomato). On the other hand, carbon utilization for synthesis of non-soluble sugar compounds (namely metabolism) was conserved among

  5. Inter-Species Grafting Caused Extensive and Heritable Alterations of DNA Methylation in Solanaceae Plants

    PubMed Central

    Lin, Yan; Ma, Yiqiao; Liu, Gang; Yu, Xiaoming; Zhong, Silin; Liu, Bao

    2013-01-01

    Background Grafting has been extensively used to enhance the performance of horticultural crops. Since Charles Darwin coined the term “graft hybrid” meaning that asexual combination of different plant species may generate products that are genetically distinct, highly discrepant opinions exist supporting or against the concept. Recent studies have documented that grafting enables exchanges of both RNA and DNA molecules between the grafting partners, thus providing a molecular basis for grafting-induced genetic variation. DNA methylation is known as prone to alterations as a result of perturbation of internal and external conditions. Given characteristics of grafting, it is interesting to test whether the process may cause an alteration of this epigenetic marker in the grafted organismal products. Methodology/Principal Findings We analyzed relative global DNA methylation levels and locus-specific methylation patterns by the MSAP marker and locus-specific bisulfite-sequencing in the seed plants (wild-type controls), self- and hetero-grafted scions/rootstocks, selfed progenies of scions and their seed-plant controls, involving three Solanaceae species. We quantified expression of putative genes involved in establishing and/or maintaining DNA methylation by q-(RT)-PCR. We found that (1) hetero-grafting caused extensive alteration of DNA methylation patterns in a locus-specific manner, especially in scions, although relative methylation levels remain largely unaltered; (2) the altered methylation patterns in the hetero-grafting-derived scions could be inherited to sexual progenies with some sites showing further alterations or revisions; (3) hetero-grafting caused dynamic changes in steady-state transcript abundance of genes encoding for a set of enzymes functionally relevant to DNA methylation. Conclusions/Significance Our results demonstrate that inter-species grafting in plants could produce extensive and heritable alterations in DNA methylation. We suggest that

  6. A study of inter-species ion suppression in electrospray ionization-mass spectrometry of some phospholipid classes.

    PubMed

    Khoury, Spiro; El Banna, Nadine; Tfaili, Sana; Chaminade, Pierre

    2016-02-01

    Phospholipid quantification in biological samples is crucial and is increasingly studied in lipidomics. Quantitative studies are often performed using commercially available standards of phospholipid classes in order to mimic the composition of biological samples. For this, studies are conducted by liquid chromatography coupled to electrospray ionization-mass spectrometry. In liquid chromatography coupled to mass spectrometry (LC-MS) analysis, the matrix components and the co-elution of several phospholipid species lead to the phenomenon of ion suppression. As a result, a decrease in the response of phospholipid species in mass spectrometry MS is observed. In fact, inter-species ion suppression affects the efficiency of phospholipid (PL) ionization and might also influence the quantitative results. The aim of this work is to study the PL inter-species ion suppression phenomenon in electrospray ionization (ESI)-mass spectrometry on a triple quadrupole TQ and an LTQ-Orbitrap in order to improve quantification in natural and biological samples. Thus, the phospholipid MS response was evaluated to study the effect of acyl chain length, the degree, and the position of unsaturation on acyl chain and the effect of the polar head group structure. A number of saturated and unsaturated phospholipid species and mixtures were analyzed in different ionization modes to a better understanding of inter-species ion suppression phenomenon. PL molecular species responded differently according to the length of fatty acid chains, the number of unsaturation, and the nature of the polar head group. Fatty acid chain length showed to have the most marked effect on MS response. PMID:26780707

  7. Multiscale Embedded Gene Co-expression Network Analysis

    PubMed Central

    Song, Won-Min; Zhang, Bin

    2015-01-01

    Gene co-expression network analysis has been shown effective in identifying functional co-expressed gene modules associated with complex human diseases. However, existing techniques to construct co-expression networks require some critical prior information such as predefined number of clusters, numerical thresholds for defining co-expression/interaction, or do not naturally reproduce the hallmarks of complex systems such as the scale-free degree distribution of small-worldness. Previously, a graph filtering technique called Planar Maximally Filtered Graph (PMFG) has been applied to many real-world data sets such as financial stock prices and gene expression to extract meaningful and relevant interactions. However, PMFG is not suitable for large-scale genomic data due to several drawbacks, such as the high computation complexity O(|V|3), the presence of false-positives due to the maximal planarity constraint, and the inadequacy of the clustering framework. Here, we developed a new co-expression network analysis framework called Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) by: i) introducing quality control of co-expression similarities, ii) parallelizing embedded network construction, and iii) developing a novel clustering technique to identify multi-scale clustering structures in Planar Filtered Networks (PFNs). We applied MEGENA to a series of simulated data and the gene expression data in breast carcinoma and lung adenocarcinoma from The Cancer Genome Atlas (TCGA). MEGENA showed improved performance over well-established clustering methods and co-expression network construction approaches. MEGENA revealed not only meaningful multi-scale organizations of co-expressed gene clusters but also novel targets in breast carcinoma and lung adenocarcinoma. PMID:26618778

  8. Liver.

    PubMed

    Kim, W R; Lake, J R; Smith, J M; Skeans, M A; Schladt, D P; Edwards, E B; Harper, A M; Wainright, J L; Snyder, J J; Israni, A K; Kasiske, B L

    2016-01-01

    The median waiting time for patients with MELD ≥ 35 decreased from 18 days in 2012 to 9 days in 2014, after implementation of the Share 35 policy in June 2013. Similarly, mortality among candidates listed with MELD ≥ 35 decreased from 366 per 100 waitlist years in 2012 to 315 in 2014. The number of new active candidates added to the pediatric liver transplant waiting list in 2014 was 655, down from a peak of 826 in 2005. The number of prevalent candidates (on the list on December 31 of the given year) continued to decline, 401 active and 173 inactive. The number of deceased donor pediatric liver transplants peaked at 542 in 2008 and was 478 in 2014. The number of living donor liver pediatric transplants was 52 in 2014; most were from donors closely related to the recipients. Graft survival continued to improve among pediatric recipients of deceased donor and living donor livers. PMID:26755264

  9. Detection of Salmonella enterica in Magellanic penguins (Spheniscus magellanicus) of Chilean Patagonia: evidences of inter-species transmission.

    PubMed

    Dougnac, C; Pardo, C; Meza, K; Arredondo, C; Blank, O; Abalos, P; Vidal, R; Fernandez, A; Fredes, F; Retamal, P

    2015-04-01

    Patagonia in southern South America is among the few world regions where direct human impact is still limited but progressively increasing, mainly represented by tourism, farming, fishing and mining activities. The sanitary condition of Patagonian wildlife is unknown, in spite of being critical for the assessment of anthropogenic effects there. The aim of this study was the characterization of Salmonella enterica strains isolated from wild colonies of Magellanic penguins (Spheniscus magellanicus) located in Magdalena Island and Otway Sound, in Chilean Patagonia. Eight isolates of Salmonella were found, belonging to Agona and Enteritidis serotypes, with an infection rate of 0·38%. Resistance to ampicillin, cefotaxime, ceftiofur and tetracycline antimicrobials were detected, and some of these strains showed genotypic similarity with Salmonella strains isolated from humans and gulls, suggesting inter-species transmission cycles and strengthening the role of penguins as sanitary sentinels in the Patagonian ecosystem. PMID:25148565

  10. Learning from Co-expression Networks: Possibilities and Challenges

    PubMed Central

    Serin, Elise A. R.; Nijveen, Harm; Hilhorst, Henk W. M.; Ligterink, Wilco

    2016-01-01

    Plants are fascinating and complex organisms. A comprehensive understanding of the organization, function and evolution of plant genes is essential to disentangle important biological processes and to advance crop engineering and breeding strategies. The ultimate aim in deciphering complex biological processes is the discovery of causal genes and regulatory mechanisms controlling these processes. The recent surge of omics data has opened the door to a system-wide understanding of the flow of biological information underlying complex traits. However, dealing with the corresponding large data sets represents a challenging endeavor that calls for the development of powerful bioinformatics methods. A popular approach is the construction and analysis of gene networks. Such networks are often used for genome-wide representation of the complex functional organization of biological systems. Network based on similarity in gene expression are called (gene) co-expression networks. One of the major application of gene co-expression networks is the functional annotation of unknown genes. Constructing co-expression networks is generally straightforward. In contrast, the resulting network of connected genes can become very complex, which limits its biological interpretation. Several strategies can be employed to enhance the interpretation of the networks. A strategy in coherence with the biological question addressed needs to be established to infer reliable networks. Additional benefits can be gained from network-based strategies using prior knowledge and data integration to further enhance the elucidation of gene regulatory relationships. As a result, biological networks provide many more applications beyond the simple visualization of co-expressed genes. In this study we review the different approaches for co-expression network inference in plants. We analyse integrative genomics strategies used in recent studies that successfully identified candidate genes taking advantage of

  11. Inter-species and Seasonal Variability in Mg / Ca in Larger Benthic Foraminifera: Implications for Paleo-proxy

    NASA Astrophysics Data System (ADS)

    Singh, A.; Saraswati, P. K.; Pande, K.; Sanyal, P.

    2015-12-01

    The reports of inter-species variability to intra-test heterogeneity in Mg/Ca in several species of foraminifera have raised question about its use in estimation of seawater temperatures and necessitate field and culture studies to verify it for species from different habitats. In this study, we attempt to investigate if Mg/Ca in larger benthic foraminifera (LBF) could be a potential proxy of seawater temperatures for shallow marine carbonates. The samples were collected in different seasons from coral reef at Akajima (Okinawa, Japan). The Ca and Mg of 13 species of LBF and small benthic foraminifera from the same season were determined to examine variation in Mg/Ca among the species calcified under presumably the same temperature and salinity conditions. We also analyzed Amphistegina lessoni from different seasons for Ca, Mg and δ18O to determine variation in Mg/Ca with temperature and see how the two proxies of temperatures, Mg/Ca and δ18O, correlate in the same species. The species cluster about two distinctly separated Mg/Ca values. The first group comprising species of Amphistegina, Gypsina, Ammonia and Elphidium have relatively lower Mg/Ca, varying from 30 to 45 mmol/mol. The second group, having average Mg/Ca ranging from ~110 to 170 mmol/mol, includes species of Schlumbergerella, Baculogypsinoides, Baculogypsina, Heterostegina, Operculina, Calcarina, Amphisorus, Alveolinella and Poroeponides. The result suggests large interspecies variability implying vital effect in foraminiferal Mg/Ca. There is no distinct difference in Mg/Ca values between porcelaneous and hyaline types or symbiont-bearing and symbiont-free types. In Amphistegina lessoni the variation in Mg/Ca between individuals of the same season is as large as variation across the seasons. There is no correlation between Mg/Ca and seawater temperature. Lack of correlation between Mg/Ca and δ18O further suggests that Mg/Ca in the species is not primarily controlled by temperature.

  12. Hemodynamic (fNIRS) and EEG (N200) correlates of emotional inter-species interactions modulated by visual and auditory stimulation

    PubMed Central

    Balconi, Michela; Vanutelli, Maria Elide

    2016-01-01

    The brain activity, considered in its hemodynamic (optical imaging: functional Near-Infrared Spectroscopy, fNIRS) and electrophysiological components (event-related potentials, ERPs, N200) was monitored when subjects observed (visual stimulation, V) or observed and heard (visual + auditory stimulation, VU) situations which represented inter-species (human-animal) interactions, with an emotional positive (cooperative) or negative (uncooperative) content. In addition, the cortical lateralization effect (more left or right dorsolateral prefrontal cortex, DLPFC) was explored. Both ERP and fNIRS showed significant effects due to emotional interactions which were discussed at light of cross-modal integration effects. The significance of inter-species effect for the emotional behavior was considered. In addition, hemodynamic and EEG consonant results and their value as integrated measures were discussed at light of valence effect. PMID:26976052

  13. Dynamic Visualization of Co-expression in Systems Genetics Data

    SciTech Connect

    New, Joshua Ryan; Huang, Jian; Chesler, Elissa J

    2008-01-01

    Biologists hope to address grand scientific challenges by exploring the abundance of data made available through modern microarray technology and other high-throughput techniques. The impact of this data, however, is limited unless researchers can effectively assimilate such complex information and integrate it into their daily research; interactive visualization tools are called for to support the effort. Specifically, typical studies of gene co-expression require novel visualization tools that enable the dynamic formulation and fine-tuning of hypotheses to aid the process of evaluating sensitivity of key parameters. These tools should allow biologists to develop an intuitive understanding of the structure of biological networks and discover genes which reside in critical positions in networks and pathways. By using a graph as a universal data representation of correlation in gene expression data, our novel visualization tool employs several techniques that when used in an integrated manner provide innovative analytical capabilities. Our tool for interacting with gene co-expression data integrates techniques such as: graph layout, qualitative subgraph extraction through a novel 2D user interface, quantitative subgraph extraction using graph-theoretic algorithms or by querying an optimized b-tree, dynamic level-of-detail graph abstraction, and template-based fuzzy classification using neural networks. We demonstrate our system using a real-world workflow from a large-scale, systems genetics study of mammalian gene co-expression.

  14. Protein Co-Expression Network Analysis (ProCoNA)

    SciTech Connect

    Gibbs, David L.; Baratt, Arie; Baric, Ralph; Kawaoka, Yoshihiro; Smith, Richard D.; Orwoll, Eric S.; Katze, Michael G.; Mcweeney, Shannon K.

    2013-06-01

    Biological networks are important for elucidating disease etiology due to their ability to model complex high dimensional data and biological systems. Proteomics provides a critical data source for such models, but currently lacks robust de novo methods for network construction, which could bring important insights in systems biology. We have evaluated the construction of network models using methods derived from weighted gene co-expression network analysis (WGCNA). We show that approximately scale-free peptide networks, composed of statistically significant modules, are feasible and biologically meaningful using two mouse lung experiments and one human plasma experiment. Within each network, peptides derived from the same protein are shown to have a statistically higher topological overlap and concordance in abundance, which is potentially important for inferring protein abundance. The module representatives, called eigenpeptides, correlate significantly with biological phenotypes. Furthermore, within modules, we find significant enrichment for biological function and known interactions (gene ontology and protein-protein interactions). Biological networks are important tools in the analysis of complex systems. In this paper we evaluate the application of weighted co-expression network analysis to quantitative proteomics data. Protein co-expression networks allow novel approaches for biological interpretation, quality control, inference of protein abundance, a framework for potentially resolving degenerate peptide-protein mappings, and a biomarker signature discovery.

  15. Arabidopsis gene co-expression network and its functional modules

    PubMed Central

    Mao, Linyong; Van Hemert, John L; Dash, Sudhansu; Dickerson, Julie A

    2009-01-01

    Background Biological networks characterize the interactions of biomolecules at a systems-level. One important property of biological networks is the modular structure, in which nodes are densely connected with each other, but between which there are only sparse connections. In this report, we attempted to find the relationship between the network topology and formation of modular structure by comparing gene co-expression networks with random networks. The organization of gene functional modules was also investigated. Results We constructed a genome-wide Arabidopsis gene co-expression network (AGCN) by using 1094 microarrays. We then analyzed the topological properties of AGCN and partitioned the network into modules by using an efficient graph clustering algorithm. In the AGCN, 382 hub genes formed a clique, and they were densely connected only to a small subset of the network. At the module level, the network clustering results provide a systems-level understanding of the gene modules that coordinate multiple biological processes to carry out specific biological functions. For instance, the photosynthesis module in AGCN involves a very large number (> 1000) of genes which participate in various biological processes including photosynthesis, electron transport, pigment metabolism, chloroplast organization and biogenesis, cofactor metabolism, protein biosynthesis, and vitamin metabolism. The cell cycle module orchestrated the coordinated expression of hundreds of genes involved in cell cycle, DNA metabolism, and cytoskeleton organization and biogenesis. We also compared the AGCN constructed in this study with a graphical Gaussian model (GGM) based Arabidopsis gene network. The photosynthesis, protein biosynthesis, and cell cycle modules identified from the GGM network had much smaller module sizes compared with the modules found in the AGCN, respectively. Conclusion This study reveals new insight into the topological properties of biological networks. The

  16. Relating specific connexin co-expression ratio to connexon composition and gap junction function.

    PubMed

    Desplantez, T; Grikscheit, K; Thomas, N M; Peters, N S; Severs, N J; Dupont, E

    2015-12-01

    Cardiac connexin 43 (Cx43), Cx40 and Cx45 are co-expressed at distinct ratios in myocytes. This pattern is considered a key factor in regulating the gap junction channels composition, properties and function and remains poorly understood. This work aims to correlate gap junction function with the connexin composition of the channels at accurate ratios Cx43:Cx40 and Cx43:Cx45. Rat liver epithelial cells that endogenously express Cx43 were stably transfected to induce expression of accurate levels of Cx40 or Cx45 that may be present in various areas of the heart (e.g. atria and ventricular conduction system). Induction of Cx40 does not increase the amounts of junctional connexins (Cx43 and Cx40), whereas induction of Cx45 increases the amounts of junctional connexins (Cx43 and Cx45). Interestingly, the non-junctional fraction of Cx43 remains unaffected upon induction of Cx40 and Cx45. Co-immunoprecipitation studies show low level of Cx40/Cx43 heteromerisation and undetectable Cx45/Cx43 heteromerisation. Functional characterisation shows that induction of Cx40 and Cx45 decreases Lucifer Yellow transfer. Electrical coupling is decreased by Cx45 induction, whereas it is decreased at low induction of Cx40 and increased at high induction. These data indicate a fine regulation of the gap junction channel make-up in function of the type and the ratio of co-expressed Cxs that specifically regulates chemical and electrical coupling. This reflects specific gap junction function in regulating impulse propagation in the healthy heart, and a pro-arrhythmic potential of connexin remodelling in the diseased heart. PMID:26550940

  17. Co-expression of glutaminase K and L isoenzymes in human tumour cells

    PubMed Central

    2004-01-01

    The pattern of expression of glutaminase isoenzymes in tumour cells has been investigated to clarify its role in the malignant transformation and the prospect of its use as a clinically relevant factor. Using leukaemia cells from medullar blood of human patients and several established human cancer cell lines, we have developed a competitive RT (reverse transcriptase)-PCR assay to quantify simultaneously K-type (kidney-type) and L-type (liver-type) glutaminase mRNAs. Co-expression of both transcripts and higher amounts of L-type mRNA were always found in all cancer cell types analysed. However, mature lymphocytes from the medullar blood of a patient suffering aplasia did not express the K-type transcript and showed a 15-fold increase of L-type transcript. Co-expression was also confirmed at the protein level using isoform-specific antibodies; nevertheless, it did not correlate with the relative abundance of glutaminase transcripts and strong K-type protein signals were detected. On the other hand, marked differences were found with regard to glutamate inhibition and phosphate activation of tumour glutaminase activity. Taken together, the protein data suggest that K isoform would account for the majority of glutaminase activity in these human tumour cells. The results confirm that simultaneous expression of both isoenzymes in human cancer cells is a more frequent event than previously thought. Furthermore, the present work and other previous data suggest that K isoform is up-regulated with increased rates of proliferation, whereas prevalence of the L isoform seems to be related with resting or quiescent cell states. PMID:15496140

  18. KL/KIT co-expression in mouse fetal oocytes.

    PubMed

    Doneda, Luisa; Klinger, Francesca-Gioia; Larizza, Lidia; De Felici, Massimo

    2002-12-01

    The tyrosine kinase receptor, KIT, and its ligand, KL are important regulators of germ cell development. The aim of this study was to examine in detail the expression of the genes encoding these proteins (White and Steel, respectively) during the fetal period (14.5-18.5 days post coitum, dpc) and the two weeks after birth in mouse ovaries using the highly sensitive in situ reverse-transcriptase polymerase chain reaction (in situ RT-PCR). KL and KIT mRNAs were not detected in 14.5-15.5 dpc ovaries but, between 16.5 and 17.5 dpc, most of the oocytes in the outer regions of the ovaries positively stained for both mRNAs. The majority of the co-expressing oocytes were identified at the zygotene/pachytene stage of meiotic prophase I. At 18.5 dpc, positive staining for KL mRNA was present only in the somatic cells in the outer regions of the ovaries. At birth, faint KL mRNA-labelled somatic cells were mainly found in the central region of the ovaries and, by P7-14, a higher level of expression was detected in the follicle cells of one- and two-layered growing follicles. Between 17.5 dpc and birth, most of the oocytes expressed KIT mRNA and, from P7 onward, there was a considerable accumulation of transcripts in the growing oocytes. The results of in situ RT-PCR were confirmed by RT-PCR on purified populations of oocytes, and at protein level by means of immunohistochemistry. The co-expression of KL and KIT in a fraction of fetal oocytes suggests that the KL/KIT system, besides the well known paracrine functions on germ cells, may exert a novel autocrine role during the mid-stage of the oocyte meiotic prophase. The possibility that this autocrine loop plays a role in sustaining the survival of fetal oocytes in this stage is supported by the finding that the addition to the culture medium of anti-KL or anti-KIT antibodies led to a significant increase in oocyte apoptosis in the absence of exogenous KL. PMID:12533025

  19. Investigating the Combinatory Effects of Biological Networks on Gene Co-expression

    PubMed Central

    Zhang, Cheng; Lee, Sunjae; Mardinoglu, Adil; Hua, Qiang

    2016-01-01

    Co-expressed genes often share similar functions, and gene co-expression networks have been widely used in studying the functionality of gene modules. Previous analysis indicated that genes are more likely to be co-expressed if they are either regulated by the same transcription factors, forming protein complexes or sharing similar topological properties in protein-protein interaction networks. Here, we reconstructed transcriptional regulatory and protein-protein networks for Saccharomyces cerevisiae using well-established databases, and we evaluated their co-expression activities using publically available gene expression data. Based on our network-dependent analysis, we found that genes that were co-regulated in the transcription regulatory networks and shared similar neighbors in the protein-protein networks were more likely to be co-expressed. Moreover, their biological functions were closely related. PMID:27445830

  20. Emotions and BIS/BAS components affect brain activity (ERPs and fNIRS) in observing intra-species and inter-species interactions.

    PubMed

    Balconi, Michela; Vanutelli, Maria Elide

    2016-09-01

    Affective response to observation of intra-species and inter-species interactions was considered in the present research. The brain activity (optical imaging: functional Near-Infrared Spectroscopy, fNIRS; and event-related potentials, ERPs, N200) was monitored when subjects observed interactive situations (human-human, HH; human-animal, HA) with a positive (cooperative), negative (uncooperative) or neutral (no emotional) content. In addition, cortical lateralization (more left or right prefrontal activity) and personality component (Behavioral Activation System, BAS; Behavioral Inhibition System, BIS) effects were explored. Both ERP and fNIRS showed significant brain activity increasing in response to positive and negative compared with neutral interactions for HH and HA. However, some differences were found between HH (more "negative valence" effect) and HA (more "positive valence" effect). Finally BAS and BIS were related respectively to more left (positive conditions) or right (negative conditions) hemispheric activity. These results supported the significance of affective behavior differentiating the species-specific and species-aspecific relationships. PMID:26319406

  1. Liver metastases

    MedlinePlus

    Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic; Colorectal cancer - liver metastases; Colon cancer - liver metastases; Esophageal cancer - liver metastases; Lung cancer - liver metastases; Melanoma - liver metastases

  2. From SNP co-association to RNA co-expression: Novel insights into gene networks for intramuscular fatty acid composition in porcine

    PubMed Central

    2014-01-01

    Background Fatty acids (FA) play a critical role in energy homeostasis and metabolic diseases; in the context of livestock species, their profile also impacts on meat quality for healthy human consumption. Molecular pathways controlling lipid metabolism are highly interconnected and are not fully understood. Elucidating these molecular processes will aid technological development towards improvement of pork meat quality and increased knowledge of FA metabolism, underpinning metabolic diseases in humans. Results The results from genome-wide association studies (GWAS) across 15 phenotypes were subjected to an Association Weight Matrix (AWM) approach to predict a network of 1,096 genes related to intramuscular FA composition in pigs. To identify the key regulators of FA metabolism, we focused on the minimal set of transcription factors (TF) that the explored the majority of the network topology. Pathway and network analyses pointed towards a trio of TF as key regulators of FA metabolism: NCOA2, FHL2 and EP300. Promoter sequence analyses confirmed that these TF have binding sites for some well-know regulators of lipid and carbohydrate metabolism. For the first time in a non-model species, some of the co-associations observed at the genetic level were validated through co-expression at the transcriptomic level based on real-time PCR of 40 genes in adipose tissue, and a further 55 genes in liver. In particular, liver expression of NCOA2 and EP300 differed between pig breeds (Iberian and Landrace) extreme in terms of fat deposition. Highly clustered co-expression networks in both liver and adipose tissues were observed. EP300 and NCOA2 showed centrality parameters above average in the both networks. Over all genes, co-expression analyses confirmed 28.9% of the AWM predicted gene-gene interactions in liver and 33.0% in adipose tissue. The magnitude of this validation varied across genes, with up to 60.8% of the connections of NCOA2 in adipose tissue being validated via co-expression

  3. Skipping the co-expression problem: the new 2A "CHYSEL" technology.

    PubMed

    de Felipe, Pablo

    2004-09-13

    The rapid progress in the field of genomics is increasing our knowledge of multi-gene diseases. However, any realistic hope of gene therapy treatment for those diseases needs first to address the problem of co-ordinately co-expressing several transgenes. Currently, the use of internal ribosomal entry sites (IRESs) is the strategy chosen by many researchers to ensure co-expression. The large sizes of the IRESs (~0.5 kb), and the difficulties of ensuring a well-balanced co-expression, have prompted several researchers to imitate a co-expression strategy used by many viruses: to express several proteins as a polyprotein. A small peptide of 18 amino acids (2A) from the foot-and-mouth disease virus (FMDV) is being used to avoid the need of proteinases to process the polyprotein. FMDV 2A is introduced as a linker between two proteins to allow autonomous intra-ribosomal self-processing of polyproteins. Recent reports have shown that this sequence is compatible with different sub-cellular targeting signals and can be used to co-express up to four proteins from a single retroviral vector. This short peptide provides a tool to allow the co-expression of multiple proteins from a single vector, a useful technology for those working with heteromultimeric proteins, biochemical pathways or combined/synergistic phenomena. PMID:15363111

  4. ImmuCo: a database of gene co-expression in immune cells.

    PubMed

    Wang, Pingzhang; Qi, Huiying; Song, Shibin; Li, Shuang; Huang, Ningyu; Han, Wenling; Ma, Dalong

    2015-01-01

    Current gene co-expression databases and correlation networks do not support cell-specific analysis. Gene co-expression and expression correlation are subtly different phenomena, although both are likely to be functionally significant. Here, we report a new database, ImmuCo (http://immuco.bjmu.edu.cn), which is a cell-specific database that contains information about gene co-expression in immune cells, identifying co-expression and correlation between any two genes. The strength of co-expression of queried genes is indicated by signal values and detection calls, whereas expression correlation and strength are reflected by Pearson correlation coefficients. A scatter plot of the signal values is provided to directly illustrate the extent of co-expression and correlation. In addition, the database allows the analysis of cell-specific gene expression profile across multiple experimental conditions and can generate a list of genes that are highly correlated with the queried genes. Currently, the database covers 18 human cell groups and 10 mouse cell groups, including 20,283 human genes and 20,963 mouse genes. More than 8.6 × 10(8) and 7.4 × 10(8) probe set combinations are provided for querying each human and mouse cell group, respectively. Sample applications support the distinctive advantages of the database. PMID:25326331

  5. Assessment of total and organic vanadium levels and their bioaccumulation in edible sea cucumbers: tissues distribution, inter-species-specific, locational differences and seasonal variations.

    PubMed

    Liu, Yanjun; Zhou, Qingxin; Xu, Jie; Xue, Yong; Liu, Xiaofang; Wang, Jingfeng; Xue, Changhu

    2016-02-01

    The objective of this study is to investigate the levels, inter-species-specific, locational differences and seasonal variations of vanadium in sea cucumbers and to validate further several potential factors controlling the distribution of metals in sea cucumbers. Vanadium levels were evaluated in samples of edible sea cucumbers and were demonstrated exhibit differences in different seasons, species and sampling sites. High vanadium concentrations were measured in the sea cucumbers, and all of the vanadium detected was in an organic form. Mean vanadium concentrations were considerably higher in the blood (sea cucumber) than in the other studied tissues. The highest concentration of vanadium (2.56 μg g(-1)), as well as a higher degree of organic vanadium (85.5 %), was observed in the Holothuria scabra samples compared with all other samples. Vanadium levels in Apostichopus japonicus from Bohai Bay and Yellow Sea have marked seasonal variations. Average values of 1.09 μg g(-1) of total vanadium and 0.79 μg g(-1) of organic vanadium were obtained in various species of sea cucumbers. Significant positive correlations between vanadium in the seawater and V org in the sea cucumber (r = 81.67 %, p = 0.00), as well as between vanadium in the sediment and V org in the sea cucumber (r = 77.98 %, p = 0.00), were observed. Vanadium concentrations depend on the seasons (salinity, temperature), species, sampling sites and seawater environment (seawater, sediment). Given the adverse toxicological effects of inorganic vanadium and positive roles in controlling the development of diabetes in humans, a regular monitoring programme of vanadium content in edible sea cucumbers can be recommended. PMID:25732906

  6. In Search of the E. coli Compounds that Change the Antibiotic Production Pattern of Streptomyces coelicolor During Inter-species Interaction.

    PubMed

    Mavituna, Ferda; Luti, Khalid Jaber Kadhum; Gu, Lixing

    2016-08-01

    The aim of this work was to investigate the interaction between E.coli and Streptomyces coelicolor A3 (2) for the increased production of undecylprodigiosin and identify the E. coli actives mediating this inter-species interaction. The antibiotics of interest were the red-pigmented undecylprodigiosin and blue-pigmented actinorhodin. Pure cultures of S. coelicolor in a defined medium produced higher concentrations of actinorhodin compared to those of undecylprodigiosin. The latter however, is more important due to its immunosuppressive and antitumor properties. As a strategy to increase undecylprodigiosin production, we added separately, live cells and heat-killed cells of E. coli C600, and the cell-free supernatant of E. coli culture to S. coelicolor cultures in shake flasks. The interaction with live cells of E. coli altered the antibiotic production pattern and undecylprodigiosin production was enhanced by 3.5-fold compared to the pure cultures of S. coelicolor and actinorhodin decreased by 15-fold. The heat-killed cells of E. coli however, had no effect on antibiotic production. In all cases, growth and glucose consumption of S. coelicolor remained almost the same as those observed in the pure culture indicating that the changes in antibiotic production were not due to nutritional stress. Results with cell-free supernatant of E. coli culture indicated that the interaction between S. coelicolor and E. coli was mediated via diffusible molecule(s). Using a set of extraction procedures and agar-well diffusion bioassays, we isolated and preliminarily identified a class of compounds. For the preliminary verification, we added the compound which was the common chemical structural moiety in this class of compounds to the pure S. coelicolor cultures. We observed similar effects on antibiotic production as with the live E. coli cells and their supernatant indicating that this class of compounds secreted by E. coli indeed could act as actives during interspecies

  7. Evolution and Emergence of Enteroviruses through Intra- and Inter-species Recombination: Plasticity and Phenotypic Impact of Modular Genetic Exchanges in the 5’ Untranslated Region

    PubMed Central

    Muslin, Claire; Joffret, Marie-Line; Pelletier, Isabelle; Blondel, Bruno; Delpeyroux, Francis

    2015-01-01

    Genetic recombination shapes the diversity of RNA viruses, including enteroviruses (EVs), which frequently have mosaic genomes. Pathogenic circulating vaccine-derived poliovirus (cVDPV) genomes consist of mutated vaccine poliovirus (PV) sequences encoding capsid proteins, and sequences encoding nonstructural proteins derived from other species’ C EVs, including certain coxsackieviruses A (CV-A) in particular. Many cVDPV genomes also have an exogenous 5’ untranslated region (5’ UTR). This region is involved in virulence and includes the cloverleaf (CL) and the internal ribosomal entry site, which play major roles in replication and the initiation of translation, respectively. We investigated the plasticity of the PV genome in terms of recombination in the 5’ UTR, by developing an experimental model involving the rescue of a bipartite PV/CV-A cVDPV genome rendered defective by mutations in the CL, following the co-transfection of cells with 5’ UTR RNAs from each of the four human EV species (EV-A to -D). The defective cVDPV was rescued by recombination with 5’ UTR sequences from the four EV species. Homologous and nonhomologous recombinants with large deletions or insertions in three hotspots were isolated, revealing a striking plasticity of the 5’ UTR. By contrast to the recombination of the cVDPV with the 5’ UTR of group II (EV-A and -B), which can decrease viral replication and virulence, recombination with the 5’ UTRs of group I (EV-C and -D) appeared to be evolutionarily neutral or associated with a gain in fitness. This study illustrates how the genomes of positive-strand RNA viruses can evolve into mosaic recombinant genomes through intra- or inter-species modular genetic exchanges, favoring the emergence of new recombinant lineages. PMID:26562151

  8. Trace/minor element:calcium ratios in cultured benthic foraminifera. Part I: Inter-species and inter-individual variability

    NASA Astrophysics Data System (ADS)

    Hintz, Christopher J.; Shaw, Timothy J.; Chandler, G. Thomas; Bernhard, Joan M.; McCorkle, Daniel C.; Blanks, Jessica K.

    2006-04-01

    Trace/minor element signatures ( DCd, DBa, DMg, and DSr) were measured in the tests (shells) of benthic foraminifera cultured in a trace-metal-concentration-controlled system. The culture system was constructed of inert materials and designed to limit microhabitat effects. This system ensured that variation observed in cultured foraminiferal element:calcium (TE/Ca) signatures was due to biologically mediated (vital) effects only. Two species, Bulimina aculeata and Rosalina vilardeboana, reproduced prolifically during two 4-to-8-month culture periods. In every case (i.e., for both species and each element), the inter-individual variability was larger than the analytical precision. Mean (±1 standard deviation) DE signatures for B. aculeata were: DCd: 1.5 ± 0.4, DBa × 10: 2.1 ± 0.7, DMg × 1000: 0.62 ± 0.15, and DSr × 10: 1.5 ± 0.1. Cultured B. aculeata DMg, calibrated from culture and core-top (live) field specimens, predicted temperatures within ±2.0 °C. The observed inter-individual variability from culture specimens was as large or larger than comparable results from core-top investigations. R. vilardeboana DCd signatures were significantly lower, while DBa, DMg, and DSr signatures were significantly higher than B. aculeata values. Since our culture system minimizes microhabitat variability, the variation in measured TE/Ca ratios suggests that biological processes are a significant factor in inter-individual and inter-species variability. Comparison of cultured and field-collected foraminiferal DBa signatures supports previous findings that pore-water chemistry is a major environmental influence on foraminiferal test chemistry.

  9. Elucidating gene function and function evolution through comparison of co-expression networks of plants

    PubMed Central

    Hansen, Bjoern O.; Vaid, Neha; Musialak-Lange, Magdalena; Janowski, Marcin; Mutwil, Marek

    2014-01-01

    The analysis of gene expression data has shown that transcriptionally coordinated (co-expressed) genes are often functionally related, enabling scientists to use expression data in gene function prediction. This Focused Review discusses our original paper (Large-scale co-expression approach to dissect secondary cell wall formation across plant species, Frontiers in Plant Science 2:23). In this paper we applied cross-species analysis to co-expression networks of genes involved in cellulose biosynthesis. We showed that the co-expression networks from different species are highly similar, indicating that whole biological pathways are conserved across species. This finding has two important implications. First, the analysis can transfer gene function annotation from well-studied plants, such as Arabidopsis, to other, uncharacterized plant species. As the analysis finds genes that have similar sequence and similar expression pattern across different organisms, functionally equivalent genes can be identified. Second, since co-expression analyses are often noisy, a comparative analysis should have higher performance, as parts of co-expression networks that are conserved are more likely to be functionally relevant. In this Focused Review, we outline the comparative analysis done in the original paper and comment on the recent advances and approaches that allow comparative analyses of co-function networks. We hypothesize that in comparison to simple co-expression analysis, comparative analysis would yield more accurate gene function predictions. Finally, by combining comparative analysis with genomic information of green plants, we propose a possible composition of cellulose biosynthesis machinery during earlier stages of plant evolution. PMID:25191328

  10. Analysis of bHLH coding genes using gene co-expression network approach.

    PubMed

    Srivastava, Swati; Sanchita; Singh, Garima; Singh, Noopur; Srivastava, Gaurava; Sharma, Ashok

    2016-07-01

    Network analysis provides a powerful framework for the interpretation of data. It uses novel reference network-based metrices for module evolution. These could be used to identify module of highly connected genes showing variation in co-expression network. In this study, a co-expression network-based approach was used for analyzing the genes from microarray data. Our approach consists of a simple but robust rank-based network construction. The publicly available gene expression data of Solanum tuberosum under cold and heat stresses were considered to create and analyze a gene co-expression network. The analysis provide highly co-expressed module of bHLH coding genes based on correlation values. Our approach was to analyze the variation of genes expression, according to the time period of stress through co-expression network approach. As the result, the seed genes were identified showing multiple connections with other genes in the same cluster. Seed genes were found to be vary in different time periods of stress. These analyzed seed genes may be utilized further as marker genes for developing the stress tolerant plant species. PMID:27178572

  11. Hi-C Chromatin Interaction Networks Predict Co-expression in the Mouse Cortex

    PubMed Central

    Hulsman, Marc; Lelieveldt, Boudewijn P. F.; de Ridder, Jeroen; Reinders, Marcel

    2015-01-01

    The three dimensional conformation of the genome in the cell nucleus influences important biological processes such as gene expression regulation. Recent studies have shown a strong correlation between chromatin interactions and gene co-expression. However, predicting gene co-expression from frequent long-range chromatin interactions remains challenging. We address this by characterizing the topology of the cortical chromatin interaction network using scale-aware topological measures. We demonstrate that based on these characterizations it is possible to accurately predict spatial co-expression between genes in the mouse cortex. Consistent with previous findings, we find that the chromatin interaction profile of a gene-pair is a good predictor of their spatial co-expression. However, the accuracy of the prediction can be substantially improved when chromatin interactions are described using scale-aware topological measures of the multi-resolution chromatin interaction network. We conclude that, for co-expression prediction, it is necessary to take into account different levels of chromatin interactions ranging from direct interaction between genes (i.e. small-scale) to chromatin compartment interactions (i.e. large-scale). PMID:25965262

  12. Chromatographic speciation of Cr(III)-species, inter-species equilibrium isotope fractionation and improved chemical purification strategies for high-precision isotope analysis

    PubMed Central

    Larsen, K.K.; Wielandt, D.; Schiller, M.; Bizzarro, M.

    2016-01-01

    Chromatographic purification of chromium (Cr), which is required for high-precision isotope analysis, is complicated by the presence of multiple Cr-species with different effective charges in the acid digested sample aliquots. The differing ion exchange selectivity and sluggish reaction rates of these species can result in incomplete Cr recovery during chromatographic purification. Because of large mass-dependent inter-species isotope fractionation, incomplete recovery can affect the accuracy of high-precision Cr isotope analysis. Here, we demonstrate widely differing cation distribution coefficients of Cr(III)-species (Cr3+, CrCl2+ and CrCl2+) with equilibrium mass-dependent isotope fractionation spanning a range of ~1‰/amu and consistent with theory. The heaviest isotopes partition into Cr3+, intermediates in CrCl2+ and the lightest in CrCl2+/CrCl3°. Thus, for a typical reported loss of ~25% Cr (in the form of Cr3+) through chromatographic purification, this translates into 185 ppm/amu offset in the stable Cr isotope ratio of the residual sample. Depending on the validity of the mass-bias correction during isotope analysis, this further results in artificial mass-independent effects in the mass-bias corrected 53Cr/52Cr (μ53 Cr* of 5.2 ppm) and 54Cr/52Cr (μ54Cr* of 13.5 ppm) components used to infer chronometric and nucleosynthetic information in meteorites. To mitigate these fractionation effects, we developed strategic chemical sample pre-treatment procedures that ensure high and reproducible Cr recovery. This is achieved either through 1) effective promotion of Cr3+ by >5 days exposure to HNO3 —H2O2 solutions at room temperature, resulting in >~98% Cr recovery for most types of sample matrices tested using a cationic chromatographic retention strategy, or 2) formation of Cr(III)-Cl complexes through exposure to concentrated HCl at high temperature (>120 °C) for several hours, resulting in >97.5% Cr recovery using a chromatographic elution strategy that

  13. Comparative Inter-Species Pharmacokinetics of Phenoxyacetic Acid Herbicides and Related Organic Acids. Evidence that the Dog is Not a Relevant Species for Evaluation of Human Health Risk.

    SciTech Connect

    Timchalk, Chuck

    2004-07-15

    Phenoxyacetic acids including 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxyacetic acid (MCPA) are widely utilized organic acid herbicides that have undergone extensive toxicity and pharmacokinetic analyses. The dog is particularly susceptible to the toxicity of phenoxyacetic acids and related organic acids relative to other species. Active renal clearance mechanisms for organic acids are ubiquitous in mammalian species, and thus a likely mechanism responsible for the increased sensitivity of the dog to these agents is linked to a lower capacity to secrete organic acids from the kidney. Using published data describing the pharmacokinetics of phenoxyacetic and structurally related organic acids in a variety of species including humans, inter-species comparative pharmacokinetics were evaluated using allometic parameter scaling. For both 2,4-D and MCPA the dog plasma half-life (t1/2) and renal clearance (Clr; ml hr-1) rates did not scale as a function of body weight across species; whereas for all other species evaluated, including humans, these pharmacokinetic parameters reasonably scaled. This exceptional response in the dog is clearly illustrated by comparing the plasma t1/2 at comparable doses of 2,4-D and MCPA, across several species. At a dosage of 5 mg/kg, in dogs the plasma t1/2 for 2,4-D and MCPA were {approx}92 - 106 hr and 63 hr, respectively, which is substantially longer than in the rat ({approx}1 and 6 hr, respectively) or in humans (12 and 11 hr, respectively). This longer t1/2, and slower elimination in the dog, results in substantially higher body burdens of these organic acids, at comparable doses, relative to other species. Although these results indicate the important role of renal transport clearance mechanisms as determinants of the clearance and potential toxicity outcomes of phenoxyacetic acid herbicides across several species, other contributing mechanisms such as reabsorption from the renal tubules is highly likely. These

  14. Chromatographic speciation of Cr(III)-species, inter-species equilibrium isotope fractionation and improved chemical purification strategies for high-precision isotope analysis.

    PubMed

    Larsen, K K; Wielandt, D; Schiller, M; Bizzarro, M

    2016-04-22

    Chromatographic purification of chromium (Cr), which is required for high-precision isotope analysis, is complicated by the presence of multiple Cr-species with different effective charges in the acid digested sample aliquots. The differing ion exchange selectivity and sluggish reaction rates of these species can result in incomplete Cr recovery during chromatographic purification. Because of large mass-dependent inter-species isotope fractionation, incomplete recovery can affect the accuracy of high-precision Cr isotope analysis. Here, we demonstrate widely differing cation distribution coefficients of Cr(III)-species (Cr(3+), CrCl(2+) and CrCl2(+)) with equilibrium mass-dependent isotope fractionation spanning a range of ∼1‰/amu and consistent with theory. The heaviest isotopes partition into Cr(3+), intermediates in CrCl(2+) and the lightest in CrCl2(+)/CrCl3°. Thus, for a typical reported loss of ∼25% Cr (in the form of Cr(3+)) through chromatographic purification, this translates into 185ppm/amu offset in the stable Cr isotope ratio of the residual sample. Depending on the validity of the mass-bias correction during isotope analysis, this further results in artificial mass-independent effects in the mass-bias corrected (53)Cr/(52)Cr (μ(53)Cr* of 5.2ppm) and (54)Cr/(52)Cr (μ(54)Cr* of 13.5ppm) components used to infer chronometric and nucleosynthetic information in meteorites. To mitigate these fractionation effects, we developed strategic chemical sample pre-treatment procedures that ensure high and reproducible Cr recovery. This is achieved either through 1) effective promotion of Cr(3+) by >5 days exposure to HNO3H2O2 solutions at room temperature, resulting in >∼98% Cr recovery for most types of sample matrices tested using a cationic chromatographic retention strategy, or 2) formation of Cr(III)-Cl complexes through exposure to concentrated HCl at high temperature (>120°C) for several hours, resulting in >97.5% Cr recovery using a

  15. A novel method to identify pathways associated with renal cell carcinoma based on a gene co-expression network.

    PubMed

    Ruan, Xiyun; Li, Hongyun; Liu, Bo; Chen, Jie; Zhang, Shibao; Sun, Zeqiang; Liu, Shuangqing; Sun, Fahai; Liu, Qingyong

    2015-08-01

    The aim of the present study was to develop a novel method for identifying pathways associated with renal cell carcinoma (RCC) based on a gene co-expression network. A framework was established where a co-expression network was derived from the database as well as various co-expression approaches. First, the backbone of the network based on differentially expressed (DE) genes between RCC patients and normal controls was constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The differentially co-expressed links were detected by Pearson's correlation, the empirical Bayesian (EB) approach and Weighted Gene Co-expression Network Analysis (WGCNA). The co-expressed gene pairs were merged by a rank-based algorithm. We obtained 842; 371; 2,883 and 1,595 co-expressed gene pairs from the co-expression networks of the STRING database, Pearson's correlation EB method and WGCNA, respectively. Two hundred and eighty-one differentially co-expressed (DC) gene pairs were obtained from the merged network using this novel method. Pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the network enrichment analysis (NEA) method were performed to verify feasibility of the merged method. Results of the KEGG and NEA pathway analyses showed that the network was associated with RCC. The suggested method was computationally efficient to identify pathways associated with RCC and has been identified as a useful complement to traditional co-expression analysis. PMID:26058425

  16. Human transcriptional interactome of chromatin contribute to gene co-expression

    PubMed Central

    2010-01-01

    Background Transcriptional interactome of chromatin is one of the important mechanisms in gene transcription regulation. By chromatin conformation capture and 3D FISH experiments, several chromatin interactions cases among sequence-distant genes or even inter-chromatin genes were reported. However, on genomics level, there is still little evidence to support these mechanisms. Recently based on Hi-C experiment, a genome-wide picture of chromatin interactions in human cells was presented. It provides a useful material for analysing whether the mechanism of transcriptional interactome is common. Results The main work here is to demonstrate whether the effects of transcriptional interactome on gene co-expression exist on genomic level. While controlling the effects of transcription factors control similarities (TCS), we tested the correlation between Hi-C interaction and the mutual ranks of gene co-expression rates (provided by COXPRESdb) of intra-chromatin gene pairs. We used 6,084 genes with both TF annotation and co-expression information, and matched them into 273,458 pairs with similar Hi-C interaction ranks in different cell types. The results illustrate that co-expression is strongly associated with chromatin interaction. Further analysis using GO annotation reveals potential correlation between gene function similarity, Hi-C interaction and their co-expression. Conclusions According to the results in this research, the intra-chromatin interactome may have relation to gene function and associate with co-expression. This study provides evidence for illustrating the effect of transcriptional interactome on transcription regulation. PMID:21156067

  17. Identification of hub genes and pathways associated with retinoblastoma based on co-expression network analysis.

    PubMed

    Wang, Q L; Chen, X; Zhang, M H; Shen, Q H; Qin, Z M

    2015-01-01

    The objective of this paper was to identify hub genes and pathways associated with retinoblastoma using centrality analysis of the co-expression network and pathway-enrichment analysis. The co-expression network of retinoblastoma was constructed by weighted gene co-expression network analysis (WGCNA) based on differentially expressed (DE) genes, and clusters were obtained through the molecular complex detection (MCODE) algorithm. Degree centrality analysis of the co-expression network was performed to explore hub genes present in retinoblastoma. Pathway-enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Validation of hub gene expression in retinoblastoma was performed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. The co-expression network based on 221 DE genes between retinoblastoma and normal controls consisted of 210 nodes and 3965 edges, and 5 clusters of the network were evaluated. By assessing the centrality analysis of the co-expression network, 21 hub genes were identified, such as SNORD115-41, RASSF2, and SNORD115-44. According to RT-PCR analysis, 16 of the 21 hub genes were differently expressed, including RASSF2 and CDCA7, and 5 were not differently expressed in retinoblastoma compared to normal controls. Pathway analysis showed that genes in 2 clusters were enriched in 3 pathways: purine metabolism, p53 signaling pathway, and melanogenesis. In this study, we successfully identified 16 hub genes and 3 pathways associated with retinoblastoma, which may be potential biomarkers for early detection and therapy for retinoblastoma. PMID:26662407

  18. Toxicity of lead (Pb) to freshwater green algae: development and validation of a bioavailability model and inter-species sensitivity comparison.

    PubMed

    De Schamphelaere, K A C; Nys, C; Janssen, C R

    2014-10-01

    model to reduce uncertainty in site-specific risk assessment. A model-based comparison with other species indicated that the sensitivity difference between P. subcapitata and two of the most chronically Pb-sensitive aquatic invertebrates (the crustacean Ceriodaphnia dubia and the snail Lymnaea stagnalis) is strongly pH dependent, with P. subcapitata becoming the most sensitive of the three at pH > 7.4. This indicates that inter-species differences in Pb bioavailability relationships should be accounted for in risk assessment and in the derivation of water quality criteria or environmental quality standards for Pb. The chronic toxicity data with three algae species and the bioavailability model presented here will help to provide a stronger scientific basis for evaluating ecological effects of Pb in the freshwater environment. PMID:25089923

  19. Single-Cell Co-expression Analysis Reveals Distinct Functional Modules, Co-regulation Mechanisms and Clinical Outcomes

    PubMed Central

    Wang, Jie; Xia, Shuli; Arand, Brian; Zhu, Heng; Machiraju, Raghu; Huang, Kun; Ji, Hongkai; Qian, Jiang

    2016-01-01

    Co-expression analysis has been employed to predict gene function, identify functional modules, and determine tumor subtypes. Previous co-expression analysis was mainly conducted at bulk tissue level. It is unclear whether co-expression analysis at the single-cell level will provide novel insights into transcriptional regulation. Here we developed a computational approach to compare glioblastoma expression profiles at the single-cell level with those obtained from bulk tumors. We found that the co-expressed genes observed in single cells and bulk tumors have little overlap and show distinct characteristics. The co-expressed genes identified in bulk tumors tend to have similar biological functions, and are enriched for intrachromosomal interactions with synchronized promoter activity. In contrast, single-cell co-expressed genes are enriched for known protein-protein interactions, and are regulated through interchromosomal interactions. Moreover, gene members of some protein complexes are co-expressed only at the bulk level, while those of other complexes are co-expressed at both single-cell and bulk levels. Finally, we identified a set of co-expressed genes that can predict the survival of glioblastoma patients. Our study highlights that comparative analyses of single-cell and bulk gene expression profiles enable us to identify functional modules that are regulated at different levels and hold great translational potential. PMID:27100869

  20. The Detection of Metabolite-Mediated Gene Module Co-Expression Using Multivariate Linear Models

    PubMed Central

    Padayachee, Trishanta; Khamiakova, Tatsiana; Shkedy, Ziv; Perola, Markus; Salo, Perttu; Burzykowski, Tomasz

    2016-01-01

    Investigating whether metabolites regulate the co-expression of a predefined gene module is one of the relevant questions posed in the integrative analysis of metabolomic and transcriptomic data. This article concerns the integrative analysis of the two high-dimensional datasets by means of multivariate models and statistical tests for the dependence between metabolites and the co-expression of a gene module. The general linear model (GLM) for correlated data that we propose models the dependence between adjusted gene expression values through a block-diagonal variance-covariance structure formed by metabolic-subset specific general variance-covariance blocks. Performance of statistical tests for the inference of conditional co-expression are evaluated through a simulation study. The proposed methodology is applied to the gene expression data of the previously characterized lipid-leukocyte module. Our results show that the GLM approach improves on a previous approach by being less prone to the detection of spurious conditional co-expression. PMID:26918614

  1. Improved expression of recombinant human factor IX by co-expression of GGCX, VKOR and furin.

    PubMed

    Liu, Jianming; Jonebring, Anna; Hagström, Jonas; Nyström, Ann-Christin; Lövgren, Ann

    2014-04-01

    Recombinant human FIX concentrates (rhFIX) are essential in the treatment and prevention of bleeding in the bleeding disorder haemophilia B. However, due to the complex nature of FIX production yields are low which leads to high treatment costs. Here we report the production of rhFIX with substantially higher yield by co-expressing human FIX with GGCX (γ-glutamyl carboxylase), VKOR (vitamin K epoxide reductase) and furin (paired basic amino acid cleaving enzyme) in Chinese hamster ovary (CHO) cells. Our results show that controlled co-expression of GGCX with FIX is critical to obtain high rhFIX titre, and, that co-expression of VKOR further increased the yield of active rhFIX. Furin co-expression improved processing of the leader peptide of rhFIX but had a minor effect on yield of active rhFIX. The optimal expression level of GGCX was surprisingly low and required unusual engineering of expression vector elements. For VKOR and furin the control of expression was less critical and could be achieved by standard vector element. Using our expression vectors an rhFIX-producing clone with an expression level of up to 30 mg/L of active rhFIX was obtained. In addition an efficient single step purification method was developed to obtain pure and active rhFIX with up to 94% yield. PMID:24567122

  2. Genome-Wide Tissue-Specific Gene Expression, Co-expression and Regulation of Co-expressed Genes in Adult Nematode Ascaris suum

    PubMed Central

    Rosa, Bruce A.; Jasmer, Douglas P.; Mitreva, Makedonka

    2014-01-01

    Background Caenorhabditis elegans has traditionally been used as a model for studying nematode biology, but its small size limits the ability for researchers to perform some experiments such as high-throughput tissue-specific gene expression studies. However, the dissection of individual tissues is possible in the parasitic nematode Ascaris suum due to its relatively large size. Here, we take advantage of the recent genome sequencing of Ascaris suum and the ability to physically dissect its separate tissues to produce a wide-scale tissue-specific nematode RNA-seq datasets, including data on three non-reproductive tissues (head, pharynx, and intestine) in both male and female worms, as well as four reproductive tissues (testis, seminal vesicle, ovary, and uterus). We obtained fundamental information about the biology of diverse cell types and potential interactions among tissues within this multicellular organism. Methodology/Principal Findings Overexpression and functional enrichment analyses identified many putative biological functions enriched in each tissue studied, including functions which have not been previously studied in detail in nematodes. Putative tissue-specific transcriptional factors and corresponding binding motifs that regulate expression in each tissue were identified, including the intestine-enriched ELT-2 motif/transcription factor previously described in nematode intestines. Constitutively expressed and novel genes were also characterized, with the largest number of novel genes found to be overexpressed in the testis. Finally, a putative acetylcholine-mediated transcriptional network connecting biological activity in the head to the male reproductive system is described using co-expression networks, along with a similar ecdysone-mediated system in the female. Conclusions/Significance The expression profiles, co-expression networks and co-expression regulation of the 10 tissues studied and the tissue-specific analysis presented here are a

  3. CoExpNetViz: Comparative Co-Expression Networks Construction and Visualization Tool

    PubMed Central

    Tzfadia, Oren; Diels, Tim; De Meyer, Sam; Vandepoele, Klaas; Aharoni, Asaph; Van de Peer, Yves

    2016-01-01

    Motivation: Comparative transcriptomics is a common approach in functional gene discovery efforts. It allows for finding conserved co-expression patterns between orthologous genes in closely related plant species, suggesting that these genes potentially share similar function and regulation. Several efficient co-expression-based tools have been commonly used in plant research but most of these pipelines are limited to data from model systems, which greatly limit their utility. Moreover, in addition, none of the existing pipelines allow plant researchers to make use of their own unpublished gene expression data for performing a comparative co-expression analysis and generate multi-species co-expression networks. Results: We introduce CoExpNetViz, a computational tool that uses a set of query or “bait” genes as an input (chosen by the user) and a minimum of one pre-processed gene expression dataset. The CoExpNetViz algorithm proceeds in three main steps; (i) for every bait gene submitted, co-expression values are calculated using mutual information and Pearson correlation coefficients, (ii) non-bait (or target) genes are grouped based on cross-species orthology, and (iii) output files are generated and results can be visualized as network graphs in Cytoscape. Availability: The CoExpNetViz tool is freely available both as a PHP web server (link: http://bioinformatics.psb.ugent.be/webtools/coexpr/) (implemented in C++) and as a Cytoscape plugin (implemented in Java). Both versions of the CoExpNetViz tool support LINUX and Windows platforms. PMID:26779228

  4. Differential co-expression analysis of venous thromboembolism based on gene expression profile data

    PubMed Central

    MING, ZHIBING; DING, WENBIN; YUAN, RUIFAN; JIN, JIE; LI, XIAOQIANG

    2016-01-01

    The aim of the present study was to screen differentially co-expressed genes and the involved transcription factors (TFs) and microRNAs (miRNAs) in venous thromboembolism (VTE). Microarray data of GSE19151 were downloaded from Gene Expression Omnibus, including 70 patients with VTE and 63 healthy controls. Principal component analysis (PCA) was performed using R software. Differential co-expression analysis was performed using R, followed by screening of modules using Cytoscape. Functional annotation was performed using Database for Annotation, Visualization, and Integrated Discovery. Moreover, Fisher test was used to screen key TFs and miRNAs for the modules. PCA revealed the disease and healthy samples could not be distinguished at the gene expression level. A total of 4,796 upregulated differentially co-expressed genes (e.g. zinc finger protein 264, electron-transfer-flavoprotein, beta polypeptide and Janus kinase 2) and 3,629 downregulated differentially co-expressed genes (e.g. adenylate cyclase 7 and single-stranded DNA binding protein 2) were identified, which were further mined to obtain 17 and eight modules separately. Functional annotation revealed that the largest upregulated module was primarily associated with acetylation and the largest downregulated module was mainly involved in mitochondrion. Moreover, 48 TFs and 62 miRNA families were screened for the 17 upregulated modules, such as E2F transcription factor 4, miR-30 and miR-135 regulating the largest module. Conversely, 35 TFs and 18 miRNA families were identified for the 8 downregulated modules, including mitochondrial ribosomal protein S12 and miR-23 regulating the largest module. Differentially co-expressed genes regulated by TFs and miRNAs may jointly contribute to the abnormal acetylation and mitochondrion presentation in the progression of VTE. PMID:27284300

  5. Comparison of co-expression measures: mutual information, correlation, and model based indices

    PubMed Central

    2012-01-01

    Background Co-expression measures are often used to define networks among genes. Mutual information (MI) is often used as a generalized correlation measure. It is not clear how much MI adds beyond standard (robust) correlation measures or regression model based association measures. Further, it is important to assess what transformations of these and other co-expression measures lead to biologically meaningful modules (clusters of genes). Results We provide a comprehensive comparison between mutual information and several correlation measures in 8 empirical data sets and in simulations. We also study different approaches for transforming an adjacency matrix, e.g. using the topological overlap measure. Overall, we confirm close relationships between MI and correlation in all data sets which reflects the fact that most gene pairs satisfy linear or monotonic relationships. We discuss rare situations when the two measures disagree. We also compare correlation and MI based approaches when it comes to defining co-expression network modules. We show that a robust measure of correlation (the biweight midcorrelation transformed via the topological overlap transformation) leads to modules that are superior to MI based modules and maximal information coefficient (MIC) based modules in terms of gene ontology enrichment. We present a function that relates correlation to mutual information which can be used to approximate the mutual information from the corresponding correlation coefficient. We propose the use of polynomial or spline regression models as an alternative to MI for capturing non-linear relationships between quantitative variables. Conclusion The biweight midcorrelation outperforms MI in terms of elucidating gene pairwise relationships. Coupled with the topological overlap matrix transformation, it often leads to more significantly enriched co-expression modules. Spline and polynomial networks form attractive alternatives to MI in case of non-linear relationships

  6. Intra-and-Inter Species Biomass Prediction in a Plantation Forest: Testing the Utility of High Spatial Resolution Spaceborne Multispectral RapidEye Sensor and Advanced Machine Learning Algorithms

    PubMed Central

    Dube, Timothy; Mutanga, Onisimo; Adam, Elhadi; Ismail, Riyad

    2014-01-01

    The quantification of aboveground biomass using remote sensing is critical for better understanding the role of forests in carbon sequestration and for informed sustainable management. Although remote sensing techniques have been proven useful in assessing forest biomass in general, more is required to investigate their capabilities in predicting intra-and-inter species biomass which are mainly characterised by non-linear relationships. In this study, we tested two machine learning algorithms, Stochastic Gradient Boosting (SGB) and Random Forest (RF) regression trees to predict intra-and-inter species biomass using high resolution RapidEye reflectance bands as well as the derived vegetation indices in a commercial plantation. The results showed that the SGB algorithm yielded the best performance for intra-and-inter species biomass prediction; using all the predictor variables as well as based on the most important selected variables. For example using the most important variables the algorithm produced an R2 of 0.80 and RMSE of 16.93 t·ha−1 for E. grandis; R2 of 0.79, RMSE of 17.27 t·ha−1 for P. taeda and R2 of 0.61, RMSE of 43.39 t·ha−1 for the combined species data sets. Comparatively, RF yielded plausible results only for E. dunii (R2 of 0.79; RMSE of 7.18 t·ha−1). We demonstrated that although the two statistical methods were able to predict biomass accurately, RF produced weaker results as compared to SGB when applied to combined species dataset. The result underscores the relevance of stochastic models in predicting biomass drawn from different species and genera using the new generation high resolution RapidEye sensor with strategically positioned bands. PMID:25140631

  7. Motif discovery in promoters of genes co-localized and co-expressed during myeloid cells differentiation

    PubMed Central

    Coppe, Alessandro; Ferrari, Francesco; Bisognin, Andrea; Danieli, Gian Antonio; Ferrari, Sergio; Bicciato, Silvio; Bortoluzzi, Stefania

    2009-01-01

    Genes co-expressed may be under similar promoter-based and/or position-based regulation. Although data on expression, position and function of human genes are available, their true integration still represents a challenge for computational biology, hampering the identification of regulatory mechanisms. We carried out an integrative analysis of genomic position, functional annotation and promoters of genes expressed in myeloid cells. Promoter analysis was conducted by a novel multi-step method for discovering putative regulatory elements, i.e. over-represented motifs, in a selected set of promoters, as compared with a background model. The combination of transcriptional, structural and functional data allowed the identification of sets of promoters pertaining to groups of genes co-expressed and co-localized in regions of the human genome. The application of motif discovery to 26 groups of genes co-expressed in myeloid cells differentiation and co-localized in the genome showed that there are more over-represented motifs in promoters of co-expressed and co-localized genes than in promoters of simply co-expressed genes (CEG). Motifs, which are similar to the binding sequences of known transcription factors, non-uniformly distributed along promoter sequences and/or occurring in highly co-expressed subset of genes were identified. Co-expressed and co-localized gene sets were grouped in two co-expressed genomic meta-regions, putatively representing functional domains of a high-level expression regulation. PMID:19059999

  8. VTCdb: a gene co-expression database for the crop species Vitis vinifera (grapevine)

    PubMed Central

    2013-01-01

    Background Gene expression datasets in model plants such as Arabidopsis have contributed to our understanding of gene function and how a single underlying biological process can be governed by a diverse network of genes. The accumulation of publicly available microarray data encompassing a wide range of biological and environmental conditions has enabled the development of additional capabilities including gene co-expression analysis (GCA). GCA is based on the understanding that genes encoding proteins involved in similar and/or related biological processes may exhibit comparable expression patterns over a range of experimental conditions, developmental stages and tissues. We present an open access database for the investigation of gene co-expression networks within the cultivated grapevine, Vitis vinifera. Description The new gene co-expression database, VTCdb (http://vtcdb.adelaide.edu.au/Home.aspx), offers an online platform for transcriptional regulatory inference in the cultivated grapevine. Using condition-independent and condition-dependent approaches, grapevine co-expression networks were constructed using the latest publicly available microarray datasets from diverse experimental series, utilising the Affymetrix Vitis vinifera GeneChip (16 K) and the NimbleGen Grape Whole-genome microarray chip (29 K), thus making it possible to profile approximately 29,000 genes (95% of the predicted grapevine transcriptome). Applications available with the online platform include the use of gene names, probesets, modules or biological processes to query the co-expression networks, with the option to choose between Affymetrix or Nimblegen datasets and between multiple co-expression measures. Alternatively, the user can browse existing network modules using interactive network visualisation and analysis via CytoscapeWeb. To demonstrate the utility of the database, we present examples from three fundamental biological processes (berry development, photosynthesis and

  9. Liver Cancer

    MedlinePlus

    ... body digest food, store energy, and remove poisons. Primary liver cancer starts in the liver. Metastatic liver ... and spreads to your liver. Risk factors for primary liver cancer include Having hepatitis B or C ...

  10. Liver scan

    MedlinePlus

    ... hyperplasia or adenoma of the liver Abscess Budd-Chiari syndrome Infection Liver disease (such as cirrhosis or ... Amebic liver abscess Cirrhosis Hepatic vein obstruction (Budd-Chiari) Hepatitis Liver cancer - hepatocellular carcinoma Liver disease Splenic ...

  11. Co-expression network-based analysis of hippocampal expression data associated with Alzheimer's disease using a novel algorithm

    PubMed Central

    YUE, HONG; YANG, BO; YANG, FANG; HU, XIAO-LI; KONG, FAN-BIN

    2016-01-01

    Recent progress in bioinformatics has facilitated the clarification of biological processes associated with complex diseases. Numerous methods of co-expression analysis have been proposed for use in the study of pairwise relationships among genes. In the present study, a combined network based on gene pairs was constructed following the conversion and combination of gene pair score values using a novel algorithm across multiple approaches. Three hippocampal expression profiles of patients with Alzheimer's disease (AD) and normal controls were extracted from the ArrayExpress database, and a total of 144 differentially expressed (DE) genes across multiple studies were identified by a rank product (RP) method. Five groups of co-expression gene pairs and five networks were identified and constructed using four existing methods [weighted gene co-expression network analysis (WGCNA), empirical Bayesian (EB), differentially co-expressed genes and links (DCGL), search tool for the retrieval of interacting genes/proteins database (STRING)] and a novel rank-based algorithm with combined score, respectively. Topological analysis indicated that the co-expression network constructed by the WGCNA method had the tendency to exhibit small-world characteristics, and the combined co-expression network was confirmed to be a scale-free network. Functional analysis of the co-expression gene pairs was conducted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The co-expression gene pairs were mostly enriched in five pathways, namely proteasome, oxidative phosphorylation, Parkinson's disease, Huntington's disease and AD. This study provides a new perspective to co-expression analysis. Since different methods of analysis often present varying abilities, the novel combination algorithm may provide a more credible and robust outcome, and could be used to complement to traditional co-expression analysis. PMID:27168792

  12. A novel method to identify pathways associated with renal cell carcinoma based on a gene co-expression network

    PubMed Central

    RUAN, XIYUN; LI, HONGYUN; LIU, BO; CHEN, JIE; ZHANG, SHIBAO; SUN, ZEQIANG; LIU, SHUANGQING; SUN, FAHAI; LIU, QINGYONG

    2015-01-01

    The aim of the present study was to develop a novel method for identifying pathways associated with renal cell carcinoma (RCC) based on a gene co-expression network. A framework was established where a co-expression network was derived from the database as well as various co-expression approaches. First, the backbone of the network based on differentially expressed (DE) genes between RCC patients and normal controls was constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The differentially co-expressed links were detected by Pearson’s correlation, the empirical Bayesian (EB) approach and Weighted Gene Co-expression Network Analysis (WGCNA). The co-expressed gene pairs were merged by a rank-based algorithm. We obtained 842; 371; 2,883 and 1,595 co-expressed gene pairs from the co-expression networks of the STRING database, Pearson’s correlation EB method and WGCNA, respectively. Two hundred and eighty-one differentially co-expressed (DC) gene pairs were obtained from the merged network using this novel method. Pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the network enrichment analysis (NEA) method were performed to verify feasibility of the merged method. Results of the KEGG and NEA pathway analyses showed that the network was associated with RCC. The suggested method was computationally efficient to identify pathways associated with RCC and has been identified as a useful complement to traditional co-expression analysis. PMID:26058425

  13. Strategies and Methodologies for the Co-expression of Multiple Proteins in Plants.

    PubMed

    Ferrer, Albert; Arró, Monserrat; Manzano, David; Altabella, Teresa

    2016-01-01

    The first transgenes were introduced in a plant genome more than 30 years ago. Since then, the capabilities of the plant scientific community to engineer the genome of plants have progressed at an unparalleled speed. Plant genetic engineering has become a central technology that has dramatically incremented our basic knowledge of plant biology and has enabled the translation of this knowledge into a number of increasingly complex and sophisticated biotechnological applications, which in most cases rely on the simultaneous co-expression of multiple recombinant proteins from different origins. To meet the new challenges of modern plant biotechnology, the plant scientific community has developed a vast arsenal of innovative molecular tools and genome engineering strategies. In this chapter we review a variety of tools, technologies, and strategies developed to transfer and simultaneously co-express multiple transgenes and proteins in a plant host. Their potential advantages, disadvantages, and future prospects are also discussed. PMID:27165331

  14. An extensive (co-)expression analysis tool for the cytochrome P450 superfamily in Arabidopsis thaliana

    PubMed Central

    Ehlting, Jürgen; Sauveplane, Vincent; Olry, Alexandre; Ginglinger, Jean-François; Provart, Nicholas J; Werck-Reichhart, Danièle

    2008-01-01

    Background Sequencing of the first plant genomes has revealed that cytochromes P450 have evolved to become the largest family of enzymes in secondary metabolism. The proportion of P450 enzymes with characterized biochemical function(s) is however very small. If P450 diversification mirrors evolution of chemical diversity, this points to an unexpectedly poor understanding of plant metabolism. We assumed that extensive analysis of gene expression might guide towards the function of P450 enzymes, and highlight overlooked aspects of plant metabolism. Results We have created a comprehensive database, 'CYPedia', describing P450 gene expression in four data sets: organs and tissues, stress response, hormone response, and mutants of Arabidopsis thaliana, based on public Affymetrix ATH1 microarray expression data. P450 expression was then combined with the expression of 4,130 re-annotated genes, predicted to act in plant metabolism, for co-expression analyses. Based on the annotation of co-expressed genes from diverse pathway annotation databases, co-expressed pathways were identified. Predictions were validated for most P450s with known functions. As examples, co-expression results for P450s related to plastidial functions/photosynthesis, and to phenylpropanoid, triterpenoid and jasmonate metabolism are highlighted here. Conclusion The large scale hypothesis generation tools presented here provide leads to new pathways, unexpected functions, and regulatory networks for many P450s in plant metabolism. These can now be exploited by the community to validate the proposed functions experimentally using reverse genetics, biochemistry, and metabolic profiling. PMID:18433503

  15. Genome-wide patterns of promoter sharing and co-expression in bovine skeletal muscle

    PubMed Central

    2011-01-01

    Background Gene regulation by transcription factors (TF) is species, tissue and time specific. To better understand how the genetic code controls gene expression in bovine muscle we associated gene expression data from developing Longissimus thoracis et lumborum skeletal muscle with bovine promoter sequence information. Results We created a highly conserved genome-wide promoter landscape comprising 87,408 interactions relating 333 TFs with their 9,242 predicted target genes (TGs). We discovered that the complete set of predicted TGs share an average of 2.75 predicted TF binding sites (TFBSs) and that the average co-expression between a TF and its predicted TGs is higher than the average co-expression between the same TF and all genes. Conversely, pairs of TFs sharing predicted TGs showed a co-expression correlation higher that pairs of TFs not sharing TGs. Finally, we exploited the co-occurrence of predicted TFBS in the context of muscle-derived functionally-coherent modules including cell cycle, mitochondria, immune system, fat metabolism, muscle/glycolysis, and ribosome. Our findings enabled us to reverse engineer a regulatory network of core processes, and correctly identified the involvement of E2F1, GATA2 and NFKB1 in the regulation of cell cycle, fat, and muscle/glycolysis, respectively. Conclusion The pivotal implication of our research is two-fold: (1) there exists a robust genome-wide expression signal between TFs and their predicted TGs in cattle muscle consistent with the extent of promoter sharing; and (2) this signal can be exploited to recover the cellular mechanisms underpinning transcription regulation of muscle structure and development in bovine. Our study represents the first genome-wide report linking tissue specific co-expression to co-regulation in a non-model vertebrate. PMID:21226902

  16. Gene Co-Expression Analysis Predicts Genetic Variants Associated with Drug Responsiveness in Lung Cancer

    PubMed Central

    Shroff, Sanaya; Zhang, Jie; Huang, Kun

    2016-01-01

    Responsiveness to drugs is an important concern in designing personalized treatment for cancer patients. Currently genetic markers are often used to guide targeted therapy. However, deeper understanding of the molecular basis for drug responses and discovery of new predictive biomarkers for drug sensitivity are much needed. In this paper, we present a workflow for identifying condition-specific gene co-expression networks associated with responses to the tyrosine kinase inhibitor, Erlotinib, in lung adenocarcinoma cell lines using data from the Cancer Cell Line Encyclopedia by combining network mining and statistical analysis. Particularly, we have identified multiple gene modules specifically co-expressed in the drug responsive cell lines but not in the unresponsive group. Interestingly, most of these modules are enriched on specific cytobands, suggesting potential copy number variation events on these loci. Our results therefore imply that there are multiple genetic loci with copy number variations associated with the Erlotinib responses. The existence of CNVs in these loci is also confirmed in lung cancer tissue samples using the TCGA data. Since these structural variations are inferred from functional genomics data, these CNVs are functional variations. These results suggest the condition specific gene co- expression network mining approach is an effective approach in predicting candidate biomarkers for drug responses. PMID:27570645

  17. Massive-Scale Gene Co-Expression Network Construction and Robustness Testing Using Random Matrix Theory

    PubMed Central

    Isaacson, Sven; Luo, Feng; Feltus, Frank A.; Smith, Melissa C.

    2013-01-01

    The study of gene relationships and their effect on biological function and phenotype is a focal point in systems biology. Gene co-expression networks built using microarray expression profiles are one technique for discovering and interpreting gene relationships. A knowledge-independent thresholding technique, such as Random Matrix Theory (RMT), is useful for identifying meaningful relationships. Highly connected genes in the thresholded network are then grouped into modules that provide insight into their collective functionality. While it has been shown that co-expression networks are biologically relevant, it has not been determined to what extent any given network is functionally robust given perturbations in the input sample set. For such a test, hundreds of networks are needed and hence a tool to rapidly construct these networks. To examine functional robustness of networks with varying input, we enhanced an existing RMT implementation for improved scalability and tested functional robustness of human (Homo sapiens), rice (Oryza sativa) and budding yeast (Saccharomyces cerevisiae). We demonstrate dramatic decrease in network construction time and computational requirements and show that despite some variation in global properties between networks, functional similarity remains high. Moreover, the biological function captured by co-expression networks thresholded by RMT is highly robust. PMID:23409071

  18. WeGET: predicting new genes for molecular systems by weighted co-expression.

    PubMed

    Szklarczyk, Radek; Megchelenbrink, Wout; Cizek, Pavel; Ledent, Marie; Velemans, Gonny; Szklarczyk, Damian; Huynen, Martijn A

    2016-01-01

    We have developed the Weighted Gene Expression Tool and database (WeGET, http://weget.cmbi.umcn.nl) for the prediction of new genes of a molecular system by correlated gene expression. WeGET utilizes a compendium of 465 human and 560 murine gene expression datasets that have been collected from multiple tissues under a wide range of experimental conditions. It exploits this abundance of expression data by assigning a high weight to datasets in which the known genes of a molecular system are harmoniously up- and down-regulated. WeGET ranks new candidate genes by calculating their weighted co-expression with that system. A weighted rank is calculated for human genes and their mouse orthologs. Then, an integrated gene rank and p-value is computed using a rank-order statistic. We applied our method to predict novel genes that have a high degree of co-expression with Gene Ontology terms and pathways from KEGG and Reactome. For each query set we provide a list of predicted novel genes, computed weights for transcription datasets used and cell and tissue types that contributed to the final predictions. The performance for each query set is assessed by 10-fold cross-validation. Finally, users can use the WeGET to predict novel genes that co-express with a custom query set. PMID:26582928

  19. Context Specific and Differential Gene Co-expression Networks via Bayesian Biclustering.

    PubMed

    Gao, Chuan; McDowell, Ian C; Zhao, Shiwen; Brown, Christopher D; Engelhardt, Barbara E

    2016-07-01

    Identifying latent structure in high-dimensional genomic data is essential for exploring biological processes. Here, we consider recovering gene co-expression networks from gene expression data, where each network encodes relationships between genes that are co-regulated by shared biological mechanisms. To do this, we develop a Bayesian statistical model for biclustering to infer subsets of co-regulated genes that covary in all of the samples or in only a subset of the samples. Our biclustering method, BicMix, allows overcomplete representations of the data, computational tractability, and joint modeling of unknown confounders and biological signals. Compared with related biclustering methods, BicMix recovers latent structure with higher precision across diverse simulation scenarios as compared to state-of-the-art biclustering methods. Further, we develop a principled method to recover context specific gene co-expression networks from the estimated sparse biclustering matrices. We apply BicMix to breast cancer gene expression data and to gene expression data from a cardiovascular study cohort, and we recover gene co-expression networks that are differential across ER+ and ER- samples and across male and female samples. We apply BicMix to the Genotype-Tissue Expression (GTEx) pilot data, and we find tissue specific gene networks. We validate these findings by using our tissue specific networks to identify trans-eQTLs specific to one of four primary tissues. PMID:27467526

  20. WeGET: predicting new genes for molecular systems by weighted co-expression

    PubMed Central

    Szklarczyk, Radek; Megchelenbrink, Wout; Cizek, Pavel; Ledent, Marie; Velemans, Gonny; Szklarczyk, Damian; Huynen, Martijn A.

    2016-01-01

    We have developed the Weighted Gene Expression Tool and database (WeGET, http://weget.cmbi.umcn.nl) for the prediction of new genes of a molecular system by correlated gene expression. WeGET utilizes a compendium of 465 human and 560 murine gene expression datasets that have been collected from multiple tissues under a wide range of experimental conditions. It exploits this abundance of expression data by assigning a high weight to datasets in which the known genes of a molecular system are harmoniously up- and down-regulated. WeGET ranks new candidate genes by calculating their weighted co-expression with that system. A weighted rank is calculated for human genes and their mouse orthologs. Then, an integrated gene rank and p-value is computed using a rank-order statistic. We applied our method to predict novel genes that have a high degree of co-expression with Gene Ontology terms and pathways from KEGG and Reactome. For each query set we provide a list of predicted novel genes, computed weights for transcription datasets used and cell and tissue types that contributed to the final predictions. The performance for each query set is assessed by 10-fold cross-validation. Finally, users can use the WeGET to predict novel genes that co-express with a custom query set. PMID:26582928

  1. Gene Co-Expression Analysis Predicts Genetic Variants Associated with Drug Responsiveness in Lung Cancer.

    PubMed

    Shroff, Sanaya; Zhang, Jie; Huang, Kun

    2016-01-01

    Responsiveness to drugs is an important concern in designing personalized treatment for cancer patients. Currently genetic markers are often used to guide targeted therapy. However, deeper understanding of the molecular basis for drug responses and discovery of new predictive biomarkers for drug sensitivity are much needed. In this paper, we present a workflow for identifying condition-specific gene co-expression networks associated with responses to the tyrosine kinase inhibitor, Erlotinib, in lung adenocarcinoma cell lines using data from the Cancer Cell Line Encyclopedia by combining network mining and statistical analysis. Particularly, we have identified multiple gene modules specifically co-expressed in the drug responsive cell lines but not in the unresponsive group. Interestingly, most of these modules are enriched on specific cytobands, suggesting potential copy number variation events on these loci. Our results therefore imply that there are multiple genetic loci with copy number variations associated with the Erlotinib responses. The existence of CNVs in these loci is also confirmed in lung cancer tissue samples using the TCGA data. Since these structural variations are inferred from functional genomics data, these CNVs are functional variations. These results suggest the condition specific gene co- expression network mining approach is an effective approach in predicting candidate biomarkers for drug responses. PMID:27570645

  2. Context Specific and Differential Gene Co-expression Networks via Bayesian Biclustering

    PubMed Central

    McDowell, Ian C.; Zhao, Shiwen; Brown, Christopher D.; Engelhardt, Barbara E.

    2016-01-01

    Identifying latent structure in high-dimensional genomic data is essential for exploring biological processes. Here, we consider recovering gene co-expression networks from gene expression data, where each network encodes relationships between genes that are co-regulated by shared biological mechanisms. To do this, we develop a Bayesian statistical model for biclustering to infer subsets of co-regulated genes that covary in all of the samples or in only a subset of the samples. Our biclustering method, BicMix, allows overcomplete representations of the data, computational tractability, and joint modeling of unknown confounders and biological signals. Compared with related biclustering methods, BicMix recovers latent structure with higher precision across diverse simulation scenarios as compared to state-of-the-art biclustering methods. Further, we develop a principled method to recover context specific gene co-expression networks from the estimated sparse biclustering matrices. We apply BicMix to breast cancer gene expression data and to gene expression data from a cardiovascular study cohort, and we recover gene co-expression networks that are differential across ER+ and ER- samples and across male and female samples. We apply BicMix to the Genotype-Tissue Expression (GTEx) pilot data, and we find tissue specific gene networks. We validate these findings by using our tissue specific networks to identify trans-eQTLs specific to one of four primary tissues. PMID:27467526

  3. Co-expression of soybean Dicer-like genes in response to stress and development.

    PubMed

    Curtin, Shaun J; Kantar, Michael B; Yoon, Han W; Whaley, Adam M; Schlueter, Jessica A; Stupar, Robert M

    2012-11-01

    Regulation of gene transcription and post-transcriptional processes is critical for proper development, genome integrity, and stress responses in plants. Many genes involved in the key processes of transcriptional and post-transcriptional regulation have been well studied in model diploid organisms. However, gene and genome duplication may alter the function of the genes involved in these processes. To address this question, we assayed the stress-induced transcription patterns of duplicated gene pairs involved in RNAi and DNA methylation processes in the paleopolyploid soybean. Real-time quantitative PCR and Sequenom MassARRAY expression assays were used to profile the relative expression ratios of eight gene pairs across eight different biotic and abiotic stress conditions. The transcriptional responses to stress for genes involved in DNA methylation, RNAi processing, and miRNA processing were compared. The strongest evidence for pairwise co-expression in response to stresses was exhibited by non-paralogous Dicer-like (DCL) genes GmDCL2a-GmDCL3a and GmDCL1b-GmDCL2b, most profoundly in root tissues. Among homoeologous or paralogous DCL genes, the Dicer-like 2 (DCL2) gene pair exhibited the strongest response to stress and most conserved co-expression pattern. This was surprising because the DCL2 duplication event is more ancient than the other DCL duplications. Possible mechanisms that may be driving the DCL2 co-expression are discussed. PMID:22527487

  4. Reconstruction of gene co-expression network from microarray data using local expression patterns

    PubMed Central

    2014-01-01

    Background Biological networks connect genes, gene products to one another. A network of co-regulated genes may form gene clusters that can encode proteins and take part in common biological processes. A gene co-expression network describes inter-relationships among genes. Existing techniques generally depend on proximity measures based on global similarity to draw the relationship between genes. It has been observed that expression profiles are sharing local similarity rather than global similarity. We propose an expression pattern based method called GeCON to extract Gene CO-expression Network from microarray data. Pair-wise supports are computed for each pair of genes based on changing tendencies and regulation patterns of the gene expression. Gene pairs showing negative or positive co-regulation under a given number of conditions are used to construct such gene co-expression network. We construct co-expression network with signed edges to reflect up- and down-regulation between pairs of genes. Most existing techniques do not emphasize computational efficiency. We exploit a fast correlogram matrix based technique for capturing the support of each gene pair to construct the network. Results We apply GeCON to both real and synthetic gene expression data. We compare our results using the DREAM (Dialogue for Reverse Engineering Assessments and Methods) Challenge data with three well known algorithms, viz., ARACNE, CLR and MRNET. Our method outperforms other algorithms based on in silico regulatory network reconstruction. Experimental results show that GeCON can extract functionally enriched network modules from real expression data. Conclusions In view of the results over several in-silico and real expression datasets, the proposed GeCON shows satisfactory performance in predicting co-expression network in a computationally inexpensive way. We further establish that a simple expression pattern matching is helpful in finding biologically relevant gene network. In

  5. Annotation of gene function in citrus using gene expression information and co-expression networks

    PubMed Central

    2014-01-01

    Background The genus Citrus encompasses major cultivated plants such as sweet orange, mandarin, lemon and grapefruit, among the world’s most economically important fruit crops. With increasing volumes of transcriptomics data available for these species, Gene Co-expression Network (GCN) analysis is a viable option for predicting gene function at a genome-wide scale. GCN analysis is based on a “guilt-by-association” principle whereby genes encoding proteins involved in similar and/or related biological processes may exhibit similar expression patterns across diverse sets of experimental conditions. While bioinformatics resources such as GCN analysis are widely available for efficient gene function prediction in model plant species including Arabidopsis, soybean and rice, in citrus these tools are not yet developed. Results We have constructed a comprehensive GCN for citrus inferred from 297 publicly available Affymetrix Genechip Citrus Genome microarray datasets, providing gene co-expression relationships at a genome-wide scale (33,000 transcripts). The comprehensive citrus GCN consists of a global GCN (condition-independent) and four condition-dependent GCNs that survey the sweet orange species only, all citrus fruit tissues, all citrus leaf tissues, or stress-exposed plants. All of these GCNs are clustered using genome-wide, gene-centric (guide) and graph clustering algorithms for flexibility of gene function prediction. For each putative cluster, gene ontology (GO) enrichment and gene expression specificity analyses were performed to enhance gene function, expression and regulation pattern prediction. The guide-gene approach was used to infer novel roles of genes involved in disease susceptibility and vitamin C metabolism, and graph-clustering approaches were used to investigate isoprenoid/phenylpropanoid metabolism in citrus peel, and citric acid catabolism via the GABA shunt in citrus fruit. Conclusions Integration of citrus gene co-expression networks

  6. [Liver and artificial liver].

    PubMed

    Chamuleau, R A

    1998-06-01

    Despite good results of orthotopic liver transplantation in patients with fulminant hepatic failure the need still exists for an effective and safe artificial liver, able to temporarily take over the complex liver function so as to bridge the gap with transplantation or regeneration. Attempts to develop non-biological artificial livers have failed, mostly when controlled clinical trials were performed. In the last decade several different types of bioartificial livers have been devised, in which the biocomponent consists of freshly isolated porcine hepatocytes or a human hepatoblastoma cell line. The majority use semipermeable hollow fibers known from artificial kidney devices. The liver cells may lie either inside or outside the lumen of these fibers. In vitro analysis of liver function and animal experimental work showing that the bioartificial liver increases survival justify clinical application. Bioartificial livers are connected to patients extracorporeally by means of plasmapheresis circuit for periods of about 6 hours. In different trials about 40 patients with severe liver failure have been treated. No important adverse effects have not been reported in these phase I trials. Results of controlled studies are urgently needed. As long as no satisfactory immortalised human liver cell line with good function is available, porcine hepatocytes will remain the first choice, provided transmission of porcine pathogens to man is prevented. PMID:9752034

  7. Better Alone or in Ill Company? The Effect of Migration and Inter-Species Comingling on Fascioloides magna Infection in Elk

    PubMed Central

    Pruvot, Mathieu; Lejeune, Manigandan; Kutz, Susan; Hutchins, Wendy; Musiani, Marco; Massolo, Alessandro; Orsel, Karin

    2016-01-01

    Migratory movements and alteration of host communities through livestock production are examples of ecological processes that may have consequences on wildlife pathogens. We studied the effect of co-grazing of cattle and wild elk, and of elk migratory behaviour on the occurrence of the giant liver fluke, Fascioloides magna, in elk. Migratory elk and elk herds with a higher proportion of migratory individuals were significantly less likely to be infected with F. magna. This may indicate a decreased risk of infection for migratory individuals, known as the “migratory escape” hypothesis. Elk herds overlapping with higher cattle densities also had a lower prevalence of this parasite, even after adjustment for landscape and climate variables known to influence its life cycle. Serological evidence suggests that even in low-prevalence areas, F. magna is circulating in both elk and cattle. Cattle are “dead-end” hosts for F. magna, and this may, therefore, indicate a dilution effect where cattle and elk are co-grazing. Migratory behaviour and host community composition have significant effects on the dynamics of this wildlife parasite; emphasizing the potential impacts of decisions regarding the management of migratory corridors and livestock-wildlife interface. PMID:27462721

  8. Better Alone or in Ill Company? The Effect of Migration and Inter-Species Comingling on Fascioloides magna Infection in Elk.

    PubMed

    Pruvot, Mathieu; Lejeune, Manigandan; Kutz, Susan; Hutchins, Wendy; Musiani, Marco; Massolo, Alessandro; Orsel, Karin

    2016-01-01

    Migratory movements and alteration of host communities through livestock production are examples of ecological processes that may have consequences on wildlife pathogens. We studied the effect of co-grazing of cattle and wild elk, and of elk migratory behaviour on the occurrence of the giant liver fluke, Fascioloides magna, in elk. Migratory elk and elk herds with a higher proportion of migratory individuals were significantly less likely to be infected with F. magna. This may indicate a decreased risk of infection for migratory individuals, known as the "migratory escape" hypothesis. Elk herds overlapping with higher cattle densities also had a lower prevalence of this parasite, even after adjustment for landscape and climate variables known to influence its life cycle. Serological evidence suggests that even in low-prevalence areas, F. magna is circulating in both elk and cattle. Cattle are "dead-end" hosts for F. magna, and this may, therefore, indicate a dilution effect where cattle and elk are co-grazing. Migratory behaviour and host community composition have significant effects on the dynamics of this wildlife parasite; emphasizing the potential impacts of decisions regarding the management of migratory corridors and livestock-wildlife interface. PMID:27462721

  9. Co-expression analysis reveals a group of genes potentially involved in regulation of plant response to iron-deficiency.

    PubMed

    Li, Hua; Wang, Lei; Yang, Zhi Min

    2015-01-01

    Iron (Fe) is an essential element for plant growth and development. Iron deficiency results in abnormal metabolisms from respiration to photosynthesis. Exploration of Fe-deficient responsive genes and their networks is critically important to understand molecular mechanisms leading to the plant adaptation to soil Fe-limitation. Co-expression genes are a cluster of genes that have a similar expression pattern to execute relatively biological functions at a stage of development or under a certain environmental condition. They may share a common regulatory mechanism. In this study, we investigated Fe-starved-related co-expression genes from Arabidopsis. From the biological process GO annotation of TAIR (The Arabidopsis Information Resource), 180 iron-deficient responsive genes were detected. Using ATTED-II database, we generated six gene co-expression networks. Among these, two modules of PYE and IRT1 were successfully constructed. There are 30 co-expression genes that are incorporated in the two modules (12 in PYE-module and 18 in IRT1-module). Sixteen of the co-expression genes were well characterized. The remaining genes (14) are poorly or not functionally identified with iron stress. Validation of the 14 genes using real-time PCR showed differential expression under iron-deficiency. Most of the co-expression genes (23/30) could be validated in pye and fit mutant plants with iron-deficiency. We further identified iron-responsive cis-elements upstream of the co-expression genes and found that 22 out of 30 genes contain the iron-responsive motif IDE1. Furthermore, some auxin and ethylene-responsive elements were detected in the promoters of the co-expression genes. These results suggest that some of the genes can be also involved in iron stress response through the phytohormone-responsive pathways. PMID:25300251

  10. Conserved Units of Co-Expression in Bacterial Genomes: An Evolutionary Insight into Transcriptional Regulation

    PubMed Central

    Junier, Ivan; Rivoire, Olivier

    2016-01-01

    Genome-wide measurements of transcriptional activity in bacteria indicate that the transcription of successive genes is strongly correlated beyond the scale of operons. Here, we analyze hundreds of bacterial genomes to identify supra-operonic segments of genes that are proximal in a large number of genomes. We show that these synteny segments correspond to genomic units of strong transcriptional co-expression. Structurally, the segments contain operons with specific relative orientations (co-directional or divergent) and nucleoid-associated proteins are found to bind at their boundaries. Functionally, operons inside a same segment are highly co-expressed even in the apparent absence of regulatory factors at their promoter regions. Remote operons along DNA can also be co-expressed if their corresponding segments share a transcriptional or sigma factor, without requiring these factors to bind directly to the promoters of the operons. As evidence that these results apply across the bacterial kingdom, we demonstrate them both in the Gram-negative bacterium Escherichia coli and in the Gram-positive bacterium Bacillus subtilis. The underlying process that we propose involves only RNA-polymerases and DNA: it implies that the transcription of an operon mechanically enhances the transcription of adjacent operons. In support of a primary role of this regulation by facilitated co-transcription, we show that the transcription en bloc of successive operons as a result of transcriptional read-through is strongly and specifically enhanced in synteny segments. Finally, our analysis indicates that facilitated co-transcription may be evolutionary primitive and may apply beyond bacteria. PMID:27195891

  11. Co-expression of mitosis-regulating genes contributes to malignant progression and prognosis in oligodendrogliomas.

    PubMed

    Liu, Yanwei; Hu, Huimin; Zhang, Chuanbao; Wang, Haoyuan; Zhang, Wenlong; Wang, Zheng; Li, Mingyang; Zhang, Wei; Zhou, Dabiao; Jiang, Tao

    2015-11-10

    The clinical prognosis of patients with glioma is determined by tumor grades, but tumors of different subtypes with equal malignancy grade usually have different prognosis that is largely determined by genetic abnormalities. Oligodendrogliomas (ODs) are the second most common type of gliomas. In this study, integrative analyses found that distribution of TCGA transcriptomic subtypes was associated with grade progression in ODs. To identify critical gene(s) associated with tumor grades and TCGA subtypes, we analyzed 34 normal brain tissue (NBT), 146 WHO grade II and 130 grade III ODs by microarray and RNA sequencing, and identified a co-expression network of six genes (AURKA, NDC80, CENPK, KIAA0101, TIMELESS and MELK) that was associated with tumor grades and TCGA subtypes as well as Ki-67 expression. Validation of the six genes was performed by qPCR in additional 28 ODs. Importantly, these genes also were validated in four high-grade recurrent gliomas and the initial lower-grade gliomas resected from the same patients. Finally, the RNA data on two genes with the highest discrimination potential (AURKA and NDC80) and Ki-67 were validated on an independent cohort (5 NBTs and 86 ODs) by immunohistochemistry. Knockdown of AURKA and NDC80 by siRNAs suppressed Ki-67 expression and proliferation of gliomas cells. Survival analysis showed that high expression of the six genes corporately indicated a poor survival outcome. Correlation and protein interaction analysis provided further evidence for this co-expression network. These data suggest that the co-expression of the six mitosis-regulating genes was associated with malignant progression and prognosis in ODs. PMID:26468983

  12. Co-expression of mitosis-regulating genes contributes to malignant progression and prognosis in oligodendrogliomas

    PubMed Central

    Liu, Yanwei; Hu, Huimin; Zhang, Chuanbao; Wang, Haoyuan; Zhang, Wenlong; Wang, Zheng; Li, Mingyang; Zhang, Wei; Zhou, Dabiao; Jiang, Tao

    2015-01-01

    The clinical prognosis of patients with glioma is determined by tumor grades, but tumors of different subtypes with equal malignancy grade usually have different prognosis that is largely determined by genetic abnormalities. Oligodendrogliomas (ODs) are the second most common type of gliomas. In this study, integrative analyses found that distribution of TCGA transcriptomic subtypes was associated with grade progression in ODs. To identify critical gene(s) associated with tumor grades and TCGA subtypes, we analyzed 34 normal brain tissue (NBT), 146 WHO grade II and 130 grade III ODs by microarray and RNA sequencing, and identified a co-expression network of six genes (AURKA, NDC80,CENPK, KIAA0101, TIMELESS and MELK) that was associated with tumor grades and TCGA subtypes as well as Ki-67 expression. Validation of the six genes was performed by qPCR in additional 28 ODs. Importantly, these genes also were validated in four high-grade recurrent gliomas and the initial lower-grade gliomas resected from the same patients. Finally, the RNA data on two genes with the highest discrimination potential (AURKA and NDC80) and Ki-67 were validated on an independent cohort (5 NBTs and 86 ODs) by immunohistochemistry. Knockdown of AURKA and NDC80 by siRNAs suppressed Ki-67 expression and proliferation of gliomas cells. Survival analysis showed that high expression of the six genes corporately indicated a poor survival outcome. Correlation and protein interaction analysis provided further evidence for this co-expression network. These data suggest that the co-expression of the six mitosis-regulating genes was associated with malignant progression and prognosis in ODs. PMID:26468983

  13. Liver Facts

    MedlinePlus

    ... Home / Before The Transplant / Organ Facts / Liver Organ Facts Heart Lung Heart/Lung Kidney Pancreas Kidney/Pancreas Liver ... Receiving "the call" About the Operation Heart Lung Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Liver Facts How the Liver Works The liver is one ...

  14. Novel structural co-expression analysis linking the NPM1-associated ribosomal biogenesis network to chronic myelogenous leukemia

    PubMed Central

    Chan, Lawrence WC; Lin, Xihong; Yung, Godwin; Lui, Thomas; Chiu, Ya Ming; Wang, Fengfeng; Tsui, Nancy BY; Cho, William CS; Yip, SP; Siu, Parco M.; Wong, SC Cesar; Yung, Benjamin YM

    2015-01-01

    Co-expression analysis reveals useful dysregulation patterns of gene cooperativeness for understanding cancer biology and identifying new targets for treatment. We developed a structural strategy to identify co-expressed gene networks that are important for chronic myelogenous leukemia (CML). This strategy compared the distributions of expressional correlations between CML and normal states, and it identified a data-driven threshold to classify strongly co-expressed networks that had the best coherence with CML. Using this strategy, we found a transcriptome-wide reduction of co-expression connectivity in CML, reflecting potentially loosened molecular regulation. Conversely, when we focused on nucleophosmin 1 (NPM1) associated networks, NPM1 established more co-expression linkages with BCR-ABL pathways and ribosomal protein networks in CML than normal. This finding implicates a new role of NPM1 in conveying tumorigenic signals from the BCR-ABL oncoprotein to ribosome biogenesis, affecting cellular growth. Transcription factors may be regulators of the differential co-expression patterns between CML and normal. PMID:26205693

  15. Tissue-specific Co-expression of Long Non-coding and Coding RNAs Associated with Breast Cancer

    PubMed Central

    Wu, Wenting; Wagner, Erin K.; Hao, Yangyang; Rao, Xi; Dai, Hongji; Han, Jiali; Chen, Jinhui; Storniolo, Anna Maria V.; Liu, Yunlong; He, Chunyan

    2016-01-01

    Inference of the biological roles of lncRNAs in breast cancer development remains a challenge. Here, we analyzed RNA-seq data in tumor and normal breast tissue samples from 18 breast cancer patients and 18 healthy controls and constructed a functional lncRNA-mRNA co-expression network. We revealed two distinctive co-expression patterns associated with breast cancer, reflecting different underlying regulatory mechanisms: (1) 516 pairs of lncRNA-mRNAs have differential co-expression pattern, in which the correlation between lncRNA and mRNA expression differs in tumor and normal breast tissue; (2) 291 pairs have dose-response co-expression pattern, in which the correlation is similar, but the expression level of lncRNA or mRNA differs in the two tissue types. We further validated our findings in TCGA dataset and annotated lncRNAs using TANRIC. One novel lncRNA, AC145110.1 on 8p12, was found differentially co-expressed with 127 mRNAs (including TOX4 and MAEL) in tumor and normal breast tissue and also highly correlated with breast cancer clinical outcomes. Functional enrichment and pathway analyses identified distinct biological functions for different patterns of co-expression regulations. Our data suggested that lncRNAs might be involved in breast tumorigenesis through the modulation of gene expression in multiple pathologic pathways. PMID:27597120

  16. Tissue-specific Co-expression of Long Non-coding and Coding RNAs Associated with Breast Cancer.

    PubMed

    Wu, Wenting; Wagner, Erin K; Hao, Yangyang; Rao, Xi; Dai, Hongji; Han, Jiali; Chen, Jinhui; Storniolo, Anna Maria V; Liu, Yunlong; He, Chunyan

    2016-01-01

    Inference of the biological roles of lncRNAs in breast cancer development remains a challenge. Here, we analyzed RNA-seq data in tumor and normal breast tissue samples from 18 breast cancer patients and 18 healthy controls and constructed a functional lncRNA-mRNA co-expression network. We revealed two distinctive co-expression patterns associated with breast cancer, reflecting different underlying regulatory mechanisms: (1) 516 pairs of lncRNA-mRNAs have differential co-expression pattern, in which the correlation between lncRNA and mRNA expression differs in tumor and normal breast tissue; (2) 291 pairs have dose-response co-expression pattern, in which the correlation is similar, but the expression level of lncRNA or mRNA differs in the two tissue types. We further validated our findings in TCGA dataset and annotated lncRNAs using TANRIC. One novel lncRNA, AC145110.1 on 8p12, was found differentially co-expressed with 127 mRNAs (including TOX4 and MAEL) in tumor and normal breast tissue and also highly correlated with breast cancer clinical outcomes. Functional enrichment and pathway analyses identified distinct biological functions for different patterns of co-expression regulations. Our data suggested that lncRNAs might be involved in breast tumorigenesis through the modulation of gene expression in multiple pathologic pathways. PMID:27597120

  17. Meta-Analysis of Differential Connectivity in Gene Co-Expression Networks in Multiple Sclerosis

    PubMed Central

    Creanza, Teresa Maria; Liguori, Maria; Liuni, Sabino; Nuzziello, Nicoletta; Ancona, Nicola

    2016-01-01

    Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment. PMID:27314336

  18. Meta-Analysis of Differential Connectivity in Gene Co-Expression Networks in Multiple Sclerosis.

    PubMed

    Creanza, Teresa Maria; Liguori, Maria; Liuni, Sabino; Nuzziello, Nicoletta; Ancona, Nicola

    2016-01-01

    Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment. PMID:27314336

  19. Opsin co-expression in Limulus photoreceptors: differential regulation by light and a circadian clock.

    PubMed

    Katti, C; Kempler, K; Porter, M L; Legg, A; Gonzalez, R; Garcia-Rivera, E; Dugger, D; Battelle, B-A

    2010-08-01

    A long-standing concept in vision science has held that a single photoreceptor expresses a single type of opsin, the protein component of visual pigment. However, the number of examples in the literature of photoreceptors from vertebrates and invertebrates that break this rule is increasing. Here, we describe a newly discovered Limulus opsin, Limulus opsin5, which is significantly different from previously characterized Limulus opsins, opsins1 and 2. We show that opsin5 is co-expressed with opsins1 and 2 in Limulus lateral and ventral eye photoreceptors and provide the first evidence that the expression of co-expressed opsins can be differentially regulated. We show that the relative levels of opsin5 and opsin1 and 2 in the rhabdom change with a diurnal rhythm and that their relative levels are also influenced by the animal's central circadian clock. An analysis of the sequence of opsin5 suggests it is sensitive to visible light (400-700 nm) but that its spectral properties may be different from that of opsins1 and 2. Changes in the relative levels of these opsins may underlie some of the dramatic day-night changes in Limulus photoreceptor function and may produce a diurnal change in their spectral sensitivity. PMID:20639420

  20. AuPairWise: A Method to Estimate RNA-Seq Replicability through Co-expression.

    PubMed

    Ballouz, Sara; Gillis, Jesse

    2016-04-01

    In addition to detecting novel transcripts and higher dynamic range, a principal claim for RNA-sequencing has been greater replicability, typically measured in sample-sample correlations of gene expression levels. Through a re-analysis of ENCODE data, we show that replicability of transcript abundances will provide misleading estimates of the replicability of conditional variation in transcript abundances (i.e., most expression experiments). Heuristics which implicitly address this problem have emerged in quality control measures to obtain 'good' differential expression results. However, these methods involve strict filters such as discarding low expressing genes or using technical replicates to remove discordant transcripts, and are costly or simply ad hoc. As an alternative, we model gene-level replicability of differential activity using co-expressing genes. We find that sets of housekeeping interactions provide a sensitive means of estimating the replicability of expression changes, where the co-expressing pair can be regarded as pseudo-replicates of one another. We model the effects of noise that perturbs a gene's expression within its usual distribution of values and show that perturbing expression by only 5% within that range is readily detectable (AUROC~0.73). We have made our method available as a set of easily implemented R scripts. PMID:27082953

  1. A co-expression modules based gene selection for cancer recognition.

    PubMed

    Lu, Xinguo; Deng, Yong; Huang, Lei; Feng, Bingtao; Liao, Bo

    2014-12-01

    Gene expression profiles are used to recognize patient samples for cancer diagnosis and therapy. Gene selection is crucial to high recognition performance. In usual gene selection methods the genes are considered as independent individuals and the correlation among genes is not used efficiently. In this description, a co-expression modules based gene selection method for cancer recognition is proposed. First, in the cancer dataset a weighted correlation network is constructed according to the correlation between each pair of genes, different modules from this network are identified and the significant modules are selected for following exploration. Second, based on these informative modules information gain is applied to selecting the feature genes for cancer recognition. Then using LOOCV, the experiments with different classification algorithms are conducted and the results show that the proposed method makes better classification accuracy than traditional gene selection methods. At last, via gene ontology enrichment analysis the biological significance of the co-expressed genes in specific modules was verified. PMID:24440175

  2. Construction and application of a co-expression network in Mycobacterium tuberculosis.

    PubMed

    Jiang, Jun; Sun, Xian; Wu, Wei; Li, Li; Wu, Hai; Zhang, Lu; Yu, Guohua; Li, Yao

    2016-01-01

    Because of its high pathogenicity and infectivity, tuberculosis is a serious threat to human health. Some information about the functions of the genes in Mycobacterium tuberculosis genome was currently available, but it was not enough to explore transcriptional regulatory mechanisms. Here, we applied the WGCNA (Weighted Gene Correlation Network Analysis) algorithm to mine pooled microarray datasets for the M. tuberculosis H37Rv strain. We constructed a co-expression network that was subdivided into 78 co-expression gene modules. The different response to two kinds of vitro models (a constant 0.2% oxygen hypoxia model and a Wayne model) were explained based on these modules. We identified potential transcription factors based on high Pearson's correlation coefficients between the modules and genes. Three modules that may be associated with hypoxic stimulation were identified, and their potential transcription factors were predicted. In the validation experiment, we determined the expression levels of genes in the modules under hypoxic condition and under overexpression of potential transcription factors (Rv0081, furA (Rv1909c), Rv0324, Rv3334, and Rv3833). The experimental results showed that the three identified modules related to hypoxia and that the overexpression of transcription factors could significantly change the expression levels of genes in the corresponding modules. PMID:27328747

  3. A contribution to the study of plant development evolution based on gene co-expression networks

    PubMed Central

    Romero-Campero, Francisco J.; Lucas-Reina, Eva; Said, Fatima E.; Romero, José M.; Valverde, Federico

    2013-01-01

    Phototrophic eukaryotes are among the most successful organisms on Earth due to their unparalleled efficiency at capturing light energy and fixing carbon dioxide to produce organic molecules. A conserved and efficient network of light-dependent regulatory modules could be at the bases of this success. This regulatory system conferred early advantages to phototrophic eukaryotes that allowed for specialization, complex developmental processes and modern plant characteristics. We have studied light-dependent gene regulatory modules from algae to plants employing integrative-omics approaches based on gene co-expression networks. Our study reveals some remarkably conserved ways in which eukaryotic phototrophs deal with day length and light signaling. Here we describe how a family of Arabidopsis transcription factors involved in photoperiod response has evolved from a single algal gene according to the innovation, amplification and divergence theory of gene evolution by duplication. These modifications of the gene co-expression networks from the ancient unicellular green algae Chlamydomonas reinhardtii to the modern brassica Arabidopsis thaliana may hint on the evolution and specialization of plants and other organisms. PMID:23935602

  4. Co-expression networks in generation of induced pluripotent stem cells.

    PubMed

    Paul, Sharan; Pflieger, Lance; Dansithong, Warunee; Figueroa, Karla P; Gao, Fuying; Coppola, Giovanni; Pulst, Stefan M

    2016-01-01

    We developed an adenoviral vector, in which Yamanaka's four reprogramming factors (RFs) were controlled by individual CMV promoters in a single cassette (Ad-SOcMK). This permitted coordinated expression of RFs (SOX2, OCT3/4, c-MYC and KLF4) in a cell for a transient period of time, synchronizing the reprogramming process with the majority of transduced cells assuming induced pluripotent stem cell (iPSC)-like characteristics as early as three days post-transduction. These reprogrammed cells resembled human embryonic stem cells (ESCs) with regard to morphology, biomarker expression, and could be differentiated into cells of the germ layers in vitro and in vivo. These iPSC-like cells, however, failed to expand into larger iPSC colonies. The short and synchronized reprogramming process allowed us to study global transcription changes within short time intervals. Weighted gene co-expression network analysis (WGCNA) identified sixteen large gene co-expression modules, each including members of gene ontology categories involved in cell differentiation and development. In particular, the brown module contained a significant number of ESC marker genes, whereas the turquoise module contained cell-cycle-related genes that were downregulated in contrast to upregulation in human ESCs. Strong coordinated expression of all four RFs via adenoviral transduction may constrain stochastic processes and lead to silencing of genes important for cellular proliferation. PMID:26892236

  5. Construction and application of a co-expression network in Mycobacterium tuberculosis

    PubMed Central

    Jiang, Jun; Sun, Xian; Wu, Wei; Li, Li; Wu, Hai; Zhang, Lu; Yu, Guohua; Li, Yao

    2016-01-01

    Because of its high pathogenicity and infectivity, tuberculosis is a serious threat to human health. Some information about the functions of the genes in Mycobacterium tuberculosis genome was currently available, but it was not enough to explore transcriptional regulatory mechanisms. Here, we applied the WGCNA (Weighted Gene Correlation Network Analysis) algorithm to mine pooled microarray datasets for the M. tuberculosis H37Rv strain. We constructed a co-expression network that was subdivided into 78 co-expression gene modules. The different response to two kinds of vitro models (a constant 0.2% oxygen hypoxia model and a Wayne model) were explained based on these modules. We identified potential transcription factors based on high Pearson’s correlation coefficients between the modules and genes. Three modules that may be associated with hypoxic stimulation were identified, and their potential transcription factors were predicted. In the validation experiment, we determined the expression levels of genes in the modules under hypoxic condition and under overexpression of potential transcription factors (Rv0081, furA (Rv1909c), Rv0324, Rv3334, and Rv3833). The experimental results showed that the three identified modules related to hypoxia and that the overexpression of transcription factors could significantly change the expression levels of genes in the corresponding modules. PMID:27328747

  6. Polarizing the Neuron through Sustained Co-expression of Alternatively Spliced Isoforms.

    PubMed

    Yap, Karen; Xiao, Yixin; Friedman, Brad A; Je, H Shawn; Makeyev, Eugene V

    2016-05-10

    Alternative splicing (AS) is an important source of proteome diversity in eukaryotes. However, how this affects protein repertoires at a single-cell level remains an open question. Here, we show that many 3'-terminal exons are persistently co-expressed with their alternatives in mammalian neurons. In an important example of this scenario, cell polarity gene Cdc42, a combination of polypyrimidine tract-binding, protein-dependent, and constitutive splicing mechanisms ensures a halfway switch from the general (E7) to the neuron-specific (E6) alternative 3'-terminal exon during neuronal differentiation. Perturbing the nearly equimolar E6/E7 ratio in neurons results in defects in both axonal and dendritic compartments and suggests that Cdc42E7 is involved in axonogenesis, whereas Cdc42E6 is required for normal development of dendritic spines. Thus, co-expression of a precise blend of functionally distinct splice isoforms rather than a complete switch from one isoform to another underlies proper structural and functional polarization of neurons. PMID:27134173

  7. AuPairWise: A Method to Estimate RNA-Seq Replicability through Co-expression

    PubMed Central

    Ballouz, Sara; Gillis, Jesse

    2016-01-01

    In addition to detecting novel transcripts and higher dynamic range, a principal claim for RNA-sequencing has been greater replicability, typically measured in sample-sample correlations of gene expression levels. Through a re-analysis of ENCODE data, we show that replicability of transcript abundances will provide misleading estimates of the replicability of conditional variation in transcript abundances (i.e., most expression experiments). Heuristics which implicitly address this problem have emerged in quality control measures to obtain ‘good’ differential expression results. However, these methods involve strict filters such as discarding low expressing genes or using technical replicates to remove discordant transcripts, and are costly or simply ad hoc. As an alternative, we model gene-level replicability of differential activity using co-expressing genes. We find that sets of housekeeping interactions provide a sensitive means of estimating the replicability of expression changes, where the co-expressing pair can be regarded as pseudo-replicates of one another. We model the effects of noise that perturbs a gene’s expression within its usual distribution of values and show that perturbing expression by only 5% within that range is readily detectable (AUROC~0.73). We have made our method available as a set of easily implemented R scripts. PMID:27082953

  8. Sharing and Specificity of Co-expression Networks across 35 Human Tissues

    PubMed Central

    Pierson, Emma; Koller, Daphne; Battle, Alexis; Mostafavi, Sara

    2015-01-01

    To understand the regulation of tissue-specific gene expression, the GTEx Consortium generated RNA-seq expression data for more than thirty distinct human tissues. This data provides an opportunity for deriving shared and tissue specific gene regulatory networks on the basis of co-expression between genes. However, a small number of samples are available for a majority of the tissues, and therefore statistical inference of networks in this setting is highly underpowered. To address this problem, we infer tissue-specific gene co-expression networks for 35 tissues in the GTEx dataset using a novel algorithm, GNAT, that uses a hierarchy of tissues to share data between related tissues. We show that this transfer learning approach increases the accuracy with which networks are learned. Analysis of these networks reveals that tissue-specific transcription factors are hubs that preferentially connect to genes with tissue specific functions. Additionally, we observe that genes with tissue-specific functions lie at the peripheries of our networks. We identify numerous modules enriched for Gene Ontology functions, and show that modules conserved across tissues are especially likely to have functions common to all tissues, while modules that are upregulated in a particular tissue are often instrumental to tissue-specific function. Finally, we provide a web tool, available at mostafavilab.stat.ubc.ca/GNAT, which allows exploration of gene function and regulation in a tissue-specific manner. PMID:25970446

  9. Co-expression networks in generation of induced pluripotent stem cells

    PubMed Central

    Paul, Sharan; Pflieger, Lance; Dansithong, Warunee; Figueroa, Karla P.; Gao, Fuying; Coppola, Giovanni; Pulst, Stefan M.

    2016-01-01

    ABSTRACT We developed an adenoviral vector, in which Yamanaka's four reprogramming factors (RFs) were controlled by individual CMV promoters in a single cassette (Ad-SOcMK). This permitted coordinated expression of RFs (SOX2, OCT3/4, c-MYC and KLF4) in a cell for a transient period of time, synchronizing the reprogramming process with the majority of transduced cells assuming induced pluripotent stem cell (iPSC)-like characteristics as early as three days post-transduction. These reprogrammed cells resembled human embryonic stem cells (ESCs) with regard to morphology, biomarker expression, and could be differentiated into cells of the germ layers in vitro and in vivo. These iPSC-like cells, however, failed to expand into larger iPSC colonies. The short and synchronized reprogramming process allowed us to study global transcription changes within short time intervals. Weighted gene co-expression network analysis (WGCNA) identified sixteen large gene co-expression modules, each including members of gene ontology categories involved in cell differentiation and development. In particular, the brown module contained a significant number of ESC marker genes, whereas the turquoise module contained cell-cycle-related genes that were downregulated in contrast to upregulation in human ESCs. Strong coordinated expression of all four RFs via adenoviral transduction may constrain stochastic processes and lead to silencing of genes important for cellular proliferation. PMID:26892236

  10. Multi-tissue analysis of co-expression networks by higher-order generalized singular value decomposition identifies functionally coherent transcriptional modules.

    PubMed

    Xiao, Xiaolin; Moreno-Moral, Aida; Rotival, Maxime; Bottolo, Leonardo; Petretto, Enrico

    2014-01-01

    Recent high-throughput efforts such as ENCODE have generated a large body of genome-scale transcriptional data in multiple conditions (e.g., cell-types and disease states). Leveraging these data is especially important for network-based approaches to human disease, for instance to identify coherent transcriptional modules (subnetworks) that can inform functional disease mechanisms and pathological pathways. Yet, genome-scale network analysis across conditions is significantly hampered by the paucity of robust and computationally-efficient methods. Building on the Higher-Order Generalized Singular Value Decomposition, we introduce a new algorithmic approach for efficient, parameter-free and reproducible identification of network-modules simultaneously across multiple conditions. Our method can accommodate weighted (and unweighted) networks of any size and can similarly use co-expression or raw gene expression input data, without hinging upon the definition and stability of the correlation used to assess gene co-expression. In simulation studies, we demonstrated distinctive advantages of our method over existing methods, which was able to recover accurately both common and condition-specific network-modules without entailing ad-hoc input parameters as required by other approaches. We applied our method to genome-scale and multi-tissue transcriptomic datasets from rats (microarray-based) and humans (mRNA-sequencing-based) and identified several common and tissue-specific subnetworks with functional significance, which were not detected by other methods. In humans we recapitulated the crosstalk between cell-cycle progression and cell-extracellular matrix interactions processes in ventricular zones during neocortex expansion and further, we uncovered pathways related to development of later cognitive functions in the cortical plate of the developing brain which were previously unappreciated. Analyses of seven rat tissues identified a multi-tissue subnetwork of co-expressed

  11. Multi-tissue Analysis of Co-expression Networks by Higher-Order Generalized Singular Value Decomposition Identifies Functionally Coherent Transcriptional Modules

    PubMed Central

    Bottolo, Leonardo; Petretto, Enrico

    2014-01-01

    Recent high-throughput efforts such as ENCODE have generated a large body of genome-scale transcriptional data in multiple conditions (e.g., cell-types and disease states). Leveraging these data is especially important for network-based approaches to human disease, for instance to identify coherent transcriptional modules (subnetworks) that can inform functional disease mechanisms and pathological pathways. Yet, genome-scale network analysis across conditions is significantly hampered by the paucity of robust and computationally-efficient methods. Building on the Higher-Order Generalized Singular Value Decomposition, we introduce a new algorithmic approach for efficient, parameter-free and reproducible identification of network-modules simultaneously across multiple conditions. Our method can accommodate weighted (and unweighted) networks of any size and can similarly use co-expression or raw gene expression input data, without hinging upon the definition and stability of the correlation used to assess gene co-expression. In simulation studies, we demonstrated distinctive advantages of our method over existing methods, which was able to recover accurately both common and condition-specific network-modules without entailing ad-hoc input parameters as required by other approaches. We applied our method to genome-scale and multi-tissue transcriptomic datasets from rats (microarray-based) and humans (mRNA-sequencing-based) and identified several common and tissue-specific subnetworks with functional significance, which were not detected by other methods. In humans we recapitulated the crosstalk between cell-cycle progression and cell-extracellular matrix interactions processes in ventricular zones during neocortex expansion and further, we uncovered pathways related to development of later cognitive functions in the cortical plate of the developing brain which were previously unappreciated. Analyses of seven rat tissues identified a multi-tissue subnetwork of co-expressed

  12. Liver Wellness

    MedlinePlus

    ... to liver wellness. • There are more than 100 liver diseases. • Liver disease is one of the top 10 causes of ... out of every 10 Americans is affected by liver disease. • Some liver diseases such as hepatitis A, hepatitis ...

  13. Identification of Common Regulators of Genes in Co-Expression Networks Affecting Muscle and Meat Properties

    PubMed Central

    Ponsuksili, Siriluck; Siengdee, Puntita; Du, Yang; Trakooljul, Nares; Murani, Eduard; Schwerin, Manfred; Wimmers, Klaus

    2015-01-01

    Understanding the genetic contributions behind skeletal muscle composition and metabolism is of great interest in medicine and agriculture. Attempts to dissect these complex traits combine genome-wide genotyping, expression data analyses and network analyses. Weighted gene co-expression network analysis (WGCNA) groups genes into modules based on patterns of co-expression, which can be linked to phenotypes by correlation analysis of trait values and the module eigengenes, i.e. the first principal component of a given module. Network hub genes and regulators of the genes in the modules are likely to play an important role in the emergence of respective traits. In order to detect common regulators of genes in modules showing association with meat quality traits, we identified eQTL for each of these genes, including the highly connected hub genes. Additionally, the module eigengene values were used for association analyses in order to derive a joint eQTL for the respective module. Thereby major sites of orchestrated regulation of genes within trait-associated modules were detected as hotspots of eQTL of many genes of a module and of its eigengene. These sites harbor likely common regulators of genes in the modules. We exemplarily showed the consistent impact of candidate common regulators on the expression of members of respective modules by RNAi knockdown experiments. In fact, Cxcr7 was identified and validated as a regulator of genes in a module, which is involved in the function of defense response in muscle cells. Zfp36l2 was confirmed as a regulator of genes of a module related to cell death or apoptosis pathways. The integration of eQTL in module networks enabled to interpret the differentially-regulated genes from a systems perspective. By integrating genome-wide genomic and transcriptomic data, employing co-expression and eQTL analyses, the study revealed likely regulators that are involved in the fine-tuning and synchronization of genes with trait

  14. Identification of key genes for laryngeal squamous cell carcinoma using weighted co-expression network analysis

    PubMed Central

    LI, XIAO-TIAN

    2016-01-01

    Laryngeal squamous cell carcinoma (LSCC) is the most common malignant tumor in the head and neck, and can seriously affect the daily life of patients. To study the mechanisms of LSCC, the microarray of GSE51958 was analyzed in the present study. GSE51958 was downloaded from Gene Expression Omnibus, and included a collection of LSCC tissue samples and matched adjacent non-cancerous tissue samples from 10 patients. Differentially-expressed genes (DEGs) were identified using limma package. Next, a weighted co-expression network was constructed for the DEGs by WGCNA package in R. Modules of the weighted co-expression network were obtained through constructing a hierarchical clustering tree using the hybrid dynamic shear tree method. Using the clusterProfiler package, the potential functions of DEGs in the modules correlated with LSCC were predicted by pathway enrichment analysis. In total, 959 DEGs were screened from the LSCC samples compared with the adjacent non-cancerous samples, including 553 upregulated and 406 downregulated genes. The appointed black, brown, gray, pink and yellow modules were screened for the DEGs in the weighted co-expression network. For the DEGs in the brown and yellow modules, the enriched pathways were cytokine-cytokine receptor interaction and metabolic pathways, respectively. The DEGs in the pink module were involved in the majority of pathways. With high connectivity degrees in the pink module, TPX2, microtubule-associated (TPX2; degree, 25), minichromosome maintenance complex component 2 (MCM2; degree, 25), ubiquitin-like with PHD and ring finger domains 1 (UHRF1; degree, 22), cyclin-dependent kinase 2 (CDK2; degree, 20) and protein regulator of cytokinesis 1 (PRC1; degree, 20) may be involved in LSCC. Overall, In conclusion, from the integrated bioinformatics analysis of genes that may be associated with LSCC, 959 DEGs were obtained from LSCC samples compared with adjacent non-cancerous samples, and TPX2, MCM2, UHRF1, CDK2 and PRC1 were

  15. Identification of common regulators of genes in co-expression networks affecting muscle and meat properties.

    PubMed

    Ponsuksili, Siriluck; Siengdee, Puntita; Du, Yang; Trakooljul, Nares; Murani, Eduard; Schwerin, Manfred; Wimmers, Klaus

    2015-01-01

    Understanding the genetic contributions behind skeletal muscle composition and metabolism is of great interest in medicine and agriculture. Attempts to dissect these complex traits combine genome-wide genotyping, expression data analyses and network analyses. Weighted gene co-expression network analysis (WGCNA) groups genes into modules based on patterns of co-expression, which can be linked to phenotypes by correlation analysis of trait values and the module eigengenes, i.e. the first principal component of a given module. Network hub genes and regulators of the genes in the modules are likely to play an important role in the emergence of respective traits. In order to detect common regulators of genes in modules showing association with meat quality traits, we identified eQTL for each of these genes, including the highly connected hub genes. Additionally, the module eigengene values were used for association analyses in order to derive a joint eQTL for the respective module. Thereby major sites of orchestrated regulation of genes within trait-associated modules were detected as hotspots of eQTL of many genes of a module and of its eigengene. These sites harbor likely common regulators of genes in the modules. We exemplarily showed the consistent impact of candidate common regulators on the expression of members of respective modules by RNAi knockdown experiments. In fact, Cxcr7 was identified and validated as a regulator of genes in a module, which is involved in the function of defense response in muscle cells. Zfp36l2 was confirmed as a regulator of genes of a module related to cell death or apoptosis pathways. The integration of eQTL in module networks enabled to interpret the differentially-regulated genes from a systems perspective. By integrating genome-wide genomic and transcriptomic data, employing co-expression and eQTL analyses, the study revealed likely regulators that are involved in the fine-tuning and synchronization of genes with trait

  16. Co-Expression of GRK2 Reveals a Novel Conformational State of the µ-Opioid Receptor

    PubMed Central

    Nickolls, Sarah A.; Humphreys, Sian; Clark, Mellissa; McMurray, Gordon

    2013-01-01

    Agonists at the µ-opioid receptor are known to produce potent analgesic responses in the clinical setting, therefore, an increased understanding of the molecular interactions of ligands at this receptor could lead to improved analgesics. As historically morphine has been shown to be a poor recruiter of β-arrestin in recombinant cell systems and this can be overcome by the co-expression of GRK2, we investigated the effects of GRK2 co-expression, in a recombinant µ-opioid receptor cell line, on ligand affinity and intrinsic activity in both β-arrestin recruitment and [35S]GTPγS binding assays. We also investigated the effect of receptor depletion in the β-arrestin assay. GRK2 co-expression increased both agonist Emax and potency in the β-arrestin assay. The increase in agonist potency could not be reversed using receptor depletion, supporting that the effects were due to a novel receptor conformation not system amplification. We also observed a small but significant effect on agonist KL values. Potency values in the [35S]GTPγS assay were unchanged; however, inverse agonist activity became evident with GRK2 co-expression. We conclude that this is direct evidence that the µ-opioid receptor is an allosteric protein and the co-expression of signalling molecules elicits changes in its conformation and thus ligand affinity. This has implications when describing how ligands interact with the receptor and how efficacy is determined. PMID:24376730

  17. Protein-protein interaction and gene co-expression maps of ARFs and Aux/IAAs in Arabidopsis

    PubMed Central

    Piya, Sarbottam; Shrestha, Sandesh K.; Binder, Brad; Stewart, C. Neal; Hewezi, Tarek

    2014-01-01

    The phytohormone auxin regulates nearly all aspects of plant growth and development. Based on the current model in Arabidopsis thaliana, Auxin/indole-3-acetic acid (Aux/IAA) proteins repress auxin-inducible genes by inhibiting auxin response transcription factors (ARFs). Experimental evidence suggests that heterodimerization between Aux/IAA and ARF proteins are related to their unique biological functions. The objective of this study was to generate the Aux/IAA-ARF protein-protein interaction map using full length sequences and locate the interacting protein pairs to specific gene co-expression networks in order to define tissue-specific responses of the Aux/IAA-ARF interactome. Pairwise interactions between 19 ARFs and 29 Aux/IAAs resulted in the identification of 213 specific interactions of which 79 interactions were previously unknown. The incorporation of co-expression profiles with protein-protein interaction data revealed a strong correlation of gene co-expression for 70% of the ARF-Aux/IAA interacting pairs in at least one tissue/organ, indicative of the biological significance of these interactions. Importantly, ARF4-8 and 19, which were found to interact with almost all Aux-Aux/IAA showed broad co-expression relationships with Aux/IAA genes, thus, formed the central hubs of the co-expression network. Our analyses provide new insights into the biological significance of ARF-Aux/IAA associations in the morphogenesis and development of various plant tissues and organs. PMID:25566309

  18. Computational gene expression profiling under salt stress reveals patterns of co-expression.

    PubMed

    Sanchita; Sharma, Ashok

    2016-03-01

    Plants respond differently to environmental conditions. Among various abiotic stresses, salt stress is a condition where excess salt in soil causes inhibition of plant growth. To understand the response of plants to the stress conditions, identification of the responsible genes is required. Clustering is a data mining technique used to group the genes with similar expression. The genes of a cluster show similar expression and function. We applied clustering algorithms on gene expression data of Solanum tuberosum showing differential expression in Capsicum annuum under salt stress. The clusters, which were common in multiple algorithms were taken further for analysis. Principal component analysis (PCA) further validated the findings of other cluster algorithms by visualizing their clusters in three-dimensional space. Functional annotation results revealed that most of the genes were involved in stress related responses. Our findings suggest that these algorithms may be helpful in the prediction of the function of co-expressed genes. PMID:26981411

  19. Co-expression of Endoxylanase and Endoglucanase in Scheffersomyces stipitis and Its Application in Ethanol Production.

    PubMed

    Puseenam, Aekkachai; Tanapongpipat, Sutipa; Roongsawang, Niran

    2015-12-01

    Scheffersomyces stipitis strain BCC15191 is considered as a biotechnologically valuable yeast for its ability to ferment glucose and xylose, the main sugar components in plant biomass, to ethanol. However, the wild strain lacks of endogenous cellulases and hemicellulases that limited biomass utilization. In order to improve biomass degrading ability of S. stipitis BCC15191, new integrative plasmids harboring constitutive TEF1 promoter and codon-optimized zeocin or hygromycin antibiotic resistance genes were developed. Aspergillus niger endoxylanase and Aspergillus aculeatus endoglucanase activities were demonstrated in transformant cells expressing codon-optimized genes. S. stipitis co-expressing endoxylanase and endoglucanase was able to grow in medium containing xylan and β-glucan as carbon sources and directly produced ethanol with yields of 2.7 g/L. It could also use pretreated corncob as a carbon source for ethanol production. These results suggested that recombinant S. stipilis is possible for consolidated bioprocessing of biomass. PMID:26378014

  20. Co-expression network analysis of Down's syndrome based on microarray data

    PubMed Central

    Zhao, Jianping; Zhang, Zhengguo; Ren, Shumin; Zong, Yanan; Kong, Xiangdong

    2016-01-01

    Down's syndrome (DS) is a type of chromosome disease. The present study aimed to explore the underlying molecular mechanisms of DS. GSE5390 microarray data downloaded from the gene expression omnibus database was used to identify differentially expressed genes (DEGs) in DS. Pathway enrichment analysis of the DEGs was performed, followed by co-expression network construction. Significant differential modules were mined by mutual information, followed by functional analysis. The accuracy of sample classification for the significant differential modules of DEGs was evaluated by leave-one-out cross-validation. A total of 997 DEGs, including 638 upregulated and 359 downregulated genes, were identified. Upregulated DEGs were enriched in 15 pathways, such as cell adhesion molecules, whereas downregulated DEGs were enriched in maturity onset diabetes of the young. Three significant differential modules with the highest discriminative scores (mutual information>0.35) were selected from a co-expression network. The classification accuracy of GSE16677 expression profile samples was 54.55% and 72.73% when characterized by 12 DEGs and 3 significant differential modules, respectively. Genes in significant differential modules were significantly enriched in 5 functions, including the endoplasmic reticulum (P=0.018) and regulation of apoptosis (P=0.061). The identified DEGs, in particular the 12 DEGs in the significant differential modules, such as B-cell lymphoma 2-associated transcription factor 1, heat shock protein 90 kDa beta member 1, UBX domain-containing protein 2 and transmembrane protein 50B, may serve important roles in the pathogenesis of DS. PMID:27588071

  1. Gene co-expression networks shed light into diseases of brain iron accumulation

    PubMed Central

    Bettencourt, Conceição; Forabosco, Paola; Wiethoff, Sarah; Heidari, Moones; Johnstone, Daniel M.; Botía, Juan A.; Collingwood, Joanna F.; Hardy, John; Milward, Elizabeth A.; Ryten, Mina; Houlden, Henry

    2016-01-01

    Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach. We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model. We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading. We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention. PMID:26707700

  2. Energy transfer between fusion biliproteins co-expressed with phycobiliprotein in Escherichia coli.

    PubMed

    Ma, Qiong; Zhou, Nan; Zhou, Ming

    2016-10-01

    In cyanobacteria, phycobiliproteins (PBS) show excellent energy transfer among the chromophores absorbing over most of the visible. The energy transfers are used to study phycobilisome assembly and bioimaging. Using All4261GAF2(C81L) as energy donor, ApcE(1-240/Δ87-130) as energy acceptor, we co-expressed fusion protein ApcE(1-240/Δ87-130)::All4261GAF2(C81L) with phycobiliprotein in Escherichia Coli and studied the energy transfer between two protein domains. With N-terminal His6 tag, ApcE(1-240/Δ87-130)::All4261GAF2(C81L) cannot be purified by nickel-affinity column. We added six histidines in the C-terminal of ApcE(1-240/Δ87-130)::All4261GAF2(C81L) and co-expressed it with phycobiliprotein. ApcE(1-240/Δ87-130)::PCB-All4261GAF2(C81L)His6 was purified successfully and only singly chromophorylated at All4261GAF2(C81L)His6 domain. The singly chromophorylate ApcE(1-240/Δ87-130)::PCB-All4261GAF2(C81L)His6 was incubated with fresh PCB and the doubly chromophorylated PCB-ApcE(1-240/Δ87-130)::PCB-All4261GAF2(C81L)His6 was obtained. The double chromophored fusion protein absorbed light in the range of 615-660 nm, and fluoresced only at 668 nm. Photochemistry analysis showed that excitation energy transfer from the short-wavelength absorbing at All4261GAF2(C81L) domain was achieved successfully to the long-wavelength absorbing at the ApcE(1-240/Δ87-130) domain. PMID:27260968

  3. Gene co-expression networks shed light into diseases of brain iron accumulation.

    PubMed

    Bettencourt, Conceição; Forabosco, Paola; Wiethoff, Sarah; Heidari, Moones; Johnstone, Daniel M; Botía, Juan A; Collingwood, Joanna F; Hardy, John; Milward, Elizabeth A; Ryten, Mina; Houlden, Henry

    2016-03-01

    Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach. We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model. We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading. We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention. PMID:26707700

  4. CD90 and CD24 Co-Expression Is Associated with Pancreatic Intraepithelial Neoplasias

    PubMed Central

    Pei, Xiucong; Zhu, Jianhui; Yang, Rui; Tan, Zhijing; An, Mingrui; Shi, Jiaqi; Lubman, David M.

    2016-01-01

    Thy-1 (CD90) has been shown to be a potential marker for several different types of cancer. However, reports on CD90 expression in pancreatic intraepithelial neoplasia (PanIN) lesions are still limited where PanINs are the most important precursor lesion of pancreatic ductal adenocarcinoma (PDAC). Herein, we investigate candidate markers for PanIN lesions by examining the distribution and trend of CD90 and CD24 expression as well as their co-expression in various stages of PanINs. Thirty cases of PanINs, which were confirmed histopathologically and clinically, were used to evaluate protein expression of CD90 and CD24 by immunofluoresence double staining. CD90 was found to be mainly expressed in stroma around lesion ducts while not observed in acini and islets in PanINs. CD90 also showed increased expression in PanIN III compared to PanIN III. CD24 was mainly present in the cytoplasm and membrane of pancreatic ductal epithelia, especially in the apical epithelium of the duct. CD24 had higher expression in PanIN III compared with PanIN IIIIII or PanIN III. CD90 was expressed around CD24 sites, but there was little overlap between cells that expressed each of these proteins. A correlation analysis showed that these two proteins have a moderate relationship with PanIN stages respectively. These results suggest that co-expression of CD90 and CD24 may have an important role in the development and progression of PanINs, which is also conducive to early detection and treatment of PDAC. PMID:27332878

  5. Differential co-expression analysis of rheumatoid arthritis with microarray data.

    PubMed

    Wang, Kunpeng; Zhao, Liqiang; Liu, Xuefeng; Hao, Zhenyong; Zhou, Yong; Yang, Chuandong; Li, Hongqiang

    2014-11-01

    The aim of the present study was to investigate the underlying molecular mechanisms of rheumatoid arthritis (RA) using microarray expression profiles from osteoarthritis and RA patients, to improve diagnosis and treatment strategies for the condition. The gene expression profile of GSE27390 was downloaded from Gene Expression Omnibus, including 19 samples from patients with RA (n=9) or osteoarthritis (n=10). Firstly, the differentially expressed genes (DEGs) were obtained with the thresholds of |logFC|>1.0 and P<0.05, using the t‑test method in LIMMA package. Then, differentially co-expressed genes (DCGs) and differentially co-expressed links (DCLs) were screened with q<0.25 by the differential coexpression analysis and differential regulation analysis of gene expression microarray data package. Secondly, pathway enrichment analysis for DCGs was performed by the Database for Annotation, Visualization and Integrated Discovery and the DCLs associated with RA were selected by comparing the obtained DCLs with known transcription factor (TF)-targets in the TRANSFAC database. Finally, the obtained TFs were mapped to the known TF-targets to construct the network using cytoscape software. A total of 1755 DEGs, 457 DCGs and 101988 DCLs were achieved and there were 20 TFs in the obtained six TF-target relations (STAT3-TNF, PBX1‑PLAU, SOCS3-STAT3, GATA1-ETS2, ETS1-ICAM4 and CEBPE‑GATA1) and 457 DCGs. A number of TF-target relations in the constructed network were not within DCLs when the TF and target gene were DCGs. The identified TFs may have an important role in the pathogenesis of RA and have the potential to be used as biomarkers for the development of novel diagnostic and therapeutic strategies for RA. PMID:25118911

  6. The Structure of a Gene Co-Expression Network Reveals Biological Functions Underlying eQTLs

    PubMed Central

    Villa-Vialaneix, Nathalie; Liaubet, Laurence; Laurent, Thibault; Cherel, Pierre; Gamot, Adrien; SanCristobal, Magali

    2013-01-01

    What are the commonalities between genes, whose expression level is partially controlled by eQTL, especially with regard to biological functions? Moreover, how are these genes related to a phenotype of interest? These issues are particularly difficult to address when the genome annotation is incomplete, as is the case for mammalian species. Moreover, the direct link between gene expression and a phenotype of interest may be weak, and thus difficult to handle. In this framework, the use of a co-expression network has proven useful: it is a robust approach for modeling a complex system of genetic regulations, and to infer knowledge for yet unknown genes. In this article, a case study was conducted with a mammalian species. It showed that the use of a co-expression network based on partial correlation, combined with a relevant clustering of nodes, leads to an enrichment of biological functions of around 83%. Moreover, the use of a spatial statistics approach allowed us to superimpose additional information related to a phenotype; this lead to highlighting specific genes or gene clusters that are related to the network structure and the phenotype. Three main results are worth noting: first, key genes were highlighted as a potential focus for forthcoming biological experiments; second, a set of biological functions, which support a list of genes under partial eQTL control, was set up by an overview of the global structure of the gene expression network; third, pH was found correlated with gene clusters, and then with related biological functions, as a result of a spatial analysis of the network topology. PMID:23577081

  7. The structure of a gene co-expression network reveals biological functions underlying eQTLs.

    PubMed

    Villa-Vialaneix, Nathalie; Liaubet, Laurence; Laurent, Thibault; Cherel, Pierre; Gamot, Adrien; SanCristobal, Magali

    2013-01-01

    What are the commonalities between genes, whose expression level is partially controlled by eQTL, especially with regard to biological functions? Moreover, how are these genes related to a phenotype of interest? These issues are particularly difficult to address when the genome annotation is incomplete, as is the case for mammalian species. Moreover, the direct link between gene expression and a phenotype of interest may be weak, and thus difficult to handle. In this framework, the use of a co-expression network has proven useful: it is a robust approach for modeling a complex system of genetic regulations, and to infer knowledge for yet unknown genes. In this article, a case study was conducted with a mammalian species. It showed that the use of a co-expression network based on partial correlation, combined with a relevant clustering of nodes, leads to an enrichment of biological functions of around 83%. Moreover, the use of a spatial statistics approach allowed us to superimpose additional information related to a phenotype; this lead to highlighting specific genes or gene clusters that are related to the network structure and the phenotype. Three main results are worth noting: first, key genes were highlighted as a potential focus for forthcoming biological experiments; second, a set of biological functions, which support a list of genes under partial eQTL control, was set up by an overview of the global structure of the gene expression network; third, pH was found correlated with gene clusters, and then with related biological functions, as a result of a spatial analysis of the network topology. PMID:23577081

  8. Liver Transplant

    MedlinePlus

    ... You Can Use April May Calendar Liver Lowdown Mar 2014 Calendar of Events In The News Academic ... 2016 Calendar Jan Feb 2016 recipe Liver Lowdown Mar/Apr 2016 Liver Lowdown August 2016 Know Your ...

  9. Liver Diseases

    MedlinePlus

    ... remove poisons. There are many kinds of liver diseases. Viruses cause some of them, like hepatitis A, ... the skin, can be one sign of liver disease. Cancer can affect the liver. You could also ...

  10. Liver disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000205.htm Liver disease To use the sharing features on this page, please enable JavaScript. The term "liver disease" applies to many conditions that stop the liver ...

  11. Liver biopsy

    MedlinePlus

    Biopsy - liver; Percutaneous biopsy ... the biopsy needle to be inserted into the liver. This is often done by using ultrasound. The ... the chance of damage to the lung or liver. The needle is removed quickly. Pressure will be ...

  12. Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo

    PubMed Central

    Ren, Xin; Liu, Hao; Zhang, Mingjie; Wang, Mengjun; Ma, Shiyin

    2016-01-01

    Hypopharyngeal cancer is a distinct type of malignant head and neck tumor, which exhibits low sensitivity to anti-cancer drugs. The importance of developing methods for reducing chemotherapy resistance, and improving and enhancing prognosis has previously been emphasized and is considered a challenge for effective clinical treatment of hypopharyngeal cancer. The current study investigated the effects of co-expression of inhibitor of growth protein 4 (ING4) and P53, a tumor suppressor gene, on chemosensitivity to cisplatin in human hypopharyngeal cancer xenografts in vivo, and the potential molecular mechanisms involved. A tumor model was established by injecting athymic nude mice with FADU human hypopharyngeal cancer cells. Five days after intratumoral and peritumoral injections of an empty adenoviral vector (Ad), Ad-ING4-P53, cisplatin, or a combination of Ad-ING4-P53 and cisplatin (Ad-ING4-P53 + cisplatin) every other day for 5 days, the mice were euthanized and their tumors, livers, and kidneys were removed. The tumor weights were used to calculate the inhibition rate, and the expression levels of ING4 and P53 were detected by reverse transcription-polymerase chain reaction. Additionally, apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunohistochemistry determined the levels ING4, P53, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) protein expression. The results demonstrated increased expression of ING4 and P53 in the Ad-ING4-P53 groups compared with PBS and Ad groups, indicating successful introduction of the genes into the tumor cells. Notably, the Ad-ING4-P53 + cisplatin group exhibited a higher inhibition rate compared with the four other groups. The results of immunohistochemistry analysis demonstrated that Bax expression was increased and Bcl-2 was decreased in the Ad-ING4-P53 + cisplatin group. This suggested that the enhanced cisplatin chemosensitivity with Ad-ING4-P53 gene therapy

  13. Discovery of core biotic stress responsive genes in Arabidopsis by weighted gene co-expression network analysis.

    PubMed

    Amrine, Katherine C H; Blanco-Ulate, Barbara; Cantu, Dario

    2015-01-01

    Intricate signal networks and transcriptional regulators translate the recognition of pathogens into defense responses. In this study, we carried out a gene co-expression analysis of all currently publicly available microarray data, which were generated in experiments that studied the interaction of the model plant Arabidopsis thaliana with microbial pathogens. This work was conducted to identify (i) modules of functionally related co-expressed genes that are differentially expressed in response to multiple biotic stresses, and (ii) hub genes that may function as core regulators of disease responses. Using Weighted Gene Co-expression Network Analysis (WGCNA) we constructed an undirected network leveraging a rich curated expression dataset comprising 272 microarrays that involved microbial infections of Arabidopsis plants with a wide array of fungal and bacterial pathogens with biotrophic, hemibiotrophic, and necrotrophic lifestyles. WGCNA produced a network with scale-free and small-world properties composed of 205 distinct clusters of co-expressed genes. Modules of functionally related co-expressed genes that are differentially regulated in response to multiple pathogens were identified by integrating differential gene expression testing with functional enrichment analyses of gene ontology terms, known disease associated genes, transcriptional regulators, and cis-regulatory elements. The significance of functional enrichments was validated by comparisons with randomly generated networks. Network topology was then analyzed to identify intra- and inter-modular gene hubs. Based on high connectivity, and centrality in meta-modules that are clearly enriched in defense responses, we propose a list of 66 target genes for reverse genetic experiments to further dissect the Arabidopsis immune system. Our results show that statistical-based data trimming prior to network analysis allows the integration of expression datasets generated by different groups, under different

  14. Discovery of Core Biotic Stress Responsive Genes in Arabidopsis by Weighted Gene Co-Expression Network Analysis

    PubMed Central

    Amrine, Katherine C. H.; Blanco-Ulate, Barbara; Cantu, Dario

    2015-01-01

    Intricate signal networks and transcriptional regulators translate the recognition of pathogens into defense responses. In this study, we carried out a gene co-expression analysis of all currently publicly available microarray data, which were generated in experiments that studied the interaction of the model plant Arabidopsis thaliana with microbial pathogens. This work was conducted to identify (i) modules of functionally related co-expressed genes that are differentially expressed in response to multiple biotic stresses, and (ii) hub genes that may function as core regulators of disease responses. Using Weighted Gene Co-expression Network Analysis (WGCNA) we constructed an undirected network leveraging a rich curated expression dataset comprising 272 microarrays that involved microbial infections of Arabidopsis plants with a wide array of fungal and bacterial pathogens with biotrophic, hemibiotrophic, and necrotrophic lifestyles. WGCNA produced a network with scale-free and small-world properties composed of 205 distinct clusters of co-expressed genes. Modules of functionally related co-expressed genes that are differentially regulated in response to multiple pathogens were identified by integrating differential gene expression testing with functional enrichment analyses of gene ontology terms, known disease associated genes, transcriptional regulators, and cis-regulatory elements. The significance of functional enrichments was validated by comparisons with randomly generated networks. Network topology was then analyzed to identify intra- and inter-modular gene hubs. Based on high connectivity, and centrality in meta-modules that are clearly enriched in defense responses, we propose a list of 66 target genes for reverse genetic experiments to further dissect the Arabidopsis immune system. Our results show that statistical-based data trimming prior to network analysis allows the integration of expression datasets generated by different groups, under different

  15. ComPlEx: conservation and divergence of co-expression networks in A. thaliana, Populus and O. sativa

    PubMed Central

    2014-01-01

    Background Divergence in gene regulation has emerged as a key mechanism underlying species differentiation. Comparative analysis of co-expression networks across species can reveal conservation and divergence in the regulation of genes. Results We inferred co-expression networks of A. thaliana, Populus spp. and O. sativa using state-of-the-art methods based on mutual information and context likelihood of relatedness, and conducted a comprehensive comparison of these networks across a range of co-expression thresholds. In addition to quantifying gene-gene link and network neighbourhood conservation, we also applied recent advancements in network analysis to do cross-species comparisons of network properties such as scale free characteristics and gene centrality as well as network motifs. We found that in all species the networks emerged as scale free only above a certain co-expression threshold, and that the high-centrality genes upholding this organization tended to be conserved. Network motifs, in particular the feed-forward loop, were found to be significantly enriched in specific functional subnetworks but where much less conserved across species than gene centrality. Although individual gene-gene co-expression had massively diverged, up to ~80% of the genes still had a significantly conserved network neighbourhood. For genes with multiple predicted orthologs, about half had one ortholog with conserved regulation and another ortholog with diverged or non-conserved regulation. Furthermore, the most sequence similar ortholog was not the one with the most conserved gene regulation in over half of the cases. Conclusions We have provided a comprehensive analysis of gene regulation evolution in plants and built a web tool for Comparative analysis of Plant co-Expression networks (ComPlEx, http://complex.plantgenie.org/). The tool can be particularly useful for identifying the ortholog with the most conserved regulation among several sequence-similar alternatives and

  16. Inter-species comparisons of carcinogenicity.

    PubMed Central

    Purchase, I. F.

    1980-01-01

    The carcinogenicity of 250 chemicals in 2 species, usually the rat and the mouse, was obtained from the published literature through 3 independent sources. Of the 250 compounds listed, 38% were non-carcinogenic in both rats and mice, and 44% were carcinogenic in both species. A total of 43 compounds had different results in the two species, 21 (8%) being carcinogenic in mice only, 17 (7%) in rats only and 5 (2%) having differing results from other species. A comparison of the major target organs affected by chemicals carcinogenic in both species revealed that 64% of the chemicals studied produced cancer at the same site. This comparison of carcinogenic activity in 2 species suggests that extrapolation from results in a single-animal study to man may be subject to substantial errors. PMID:7387835

  17. Co-expression of non-selective cation channels of the transient receptor potential canonical family in central aminergic neurones.

    PubMed

    Sergeeva, Olga A; Korotkova, Tatiana M; Scherer, Annette; Brown, Ritchie E; Haas, Helmut L

    2003-06-01

    The mammalian transient receptor potential canonical (TRPC) group of channels is a family of Ca2+-permeable cation channels that are activated following receptor-mediated stimulation of different isoforms of phospholipase C. In vitro TRPC proteins can form hetero- or homo-oligomeric channels. We performed single-cell RT-PCR analysis to reveal the co-expression of seven TRPC channels in identified rat aminergic neurones. All serotonergic neurones of the dorsal raphe (DR), the majority of histaminergic (tuberomamillary nucleus; TMN) and dopaminergic cells of the ventral tegmental area (VTA), as well as some GABAergic neurones from the VTA, expressed at least one variant of TRPC channels. No TRPC channel expression was found in the locus coeruleus. In raphe neurones TRPC6 and TRPC5 mRNAs occurred most frequently. In VTA and TMN co-expression of TRPC4 with TRPC5 and TRPC6 with TRPC7 was not found in individual neurones (in contrast to the whole-brain regions). Their co-expression in non-neuronal cells could not be excluded. The neonatal TRPC3 subunit was rarely seen. In DR, but not in the other nuclei studied, the expression of orexin receptors correlated with the expression of TRPC channels. We conclude that several TRPC channel populations exist in individual neurones and that their subunit co-expression pattern is region and cell-type specific. PMID:12787073

  18. Modeling the effects of HER/ErbB1-3 co-expression on receptor dimerization and biological response

    SciTech Connect

    Shankaran, Harish; Wiley, H. S.; Resat, Haluk

    2006-06-01

    The human epidermal growth factor receptor (HER/ErbB) system comprises the epidermal growth factor receptor (EGFR/HER1) and three other homologues viz. HER2-4. This receptor system plays a critical role in cell proliferation and differentiation and receptor over-expression can be associated with poor prognosis in cancers of the epithelium. Here, we examine the effect of co-expressing varying levels of HER1-3 on the receptor dimerization patterns using a detailed kinetic model for ErbB heterodimerization and trafficking. Our results indicate that co-expression of EGFR with HER2 or HER3 biases signaling to the cell surface and retards signal down-regulation. In addition, simultaneous co-expression of HER1-3 leads to preferential formation of HER2-HER3 heterodimers, which are known to be potent inducers of cell growth and transformation. Analysis of the parameter dependencies in the model reveals that measurements of HER3 phosphorylation and HER2 internalization ratio may prove to be especially useful for the estimation of critical model parameters. Further, we examined the effect of receptor dimerization patterns on cell phenotype using a simple phenomenological model. Results indicate that co-expression of EGFR with HER2 and HER3 at low to moderate levels may enable cells to match the phenotype of a high HER2 expresser.

  19. Co-expression as a convenient method for the production and purification of core histones in bacteria.

    PubMed

    Anderson, Megan; Huh, Joon H; Ngo, Thien; Lee, Alice; Hernandez, Genaro; Pang, Joy; Perkins, Jennifer; Dutnall, Robert N

    2010-08-01

    Co-expression offers an important strategy for producing multiprotein complexes for biochemical and biophysical studies. We have found that co-expression of histones H2A and H2B (from yeast, chicken or Drosophila) leads to production of soluble heterodimeric H2AH2B complexes. Drosophila histones H3 and H4 can also be produced as a soluble (H3H4)(2) heterotetrameric complex if they are co-expressed with the histone chaperone Asf1. The soluble H2AH2B and (H3H4)(2) can be purified by simple chromatographic techniques and have similar properties to endogenous histones. Our methods should facilitate histone production for studies of chromatin structure and regulatory proteins that interact with histones. We describe a simple strategy for constructing co-expression plasmids, based on the T7 RNA polymerase system, which is applicable to other systems. It offers several advantages for quickly creating plasmids to express two or more proteins and for testing different combinations of proteins for optimal complex production, solubility or activity. PMID:20347990

  20. Novel role of ZmaNAC36 in co-expression of starch synthetic genes in maize endosperm.

    PubMed

    Zhang, Junjie; Chen, Jiang; Yi, Qiang; Hu, Yufeng; Liu, Hanmei; Liu, Yinghong; Huang, Yubi

    2014-02-01

    Starch is an essential commodity that is widely used as food, feed, fuel and in industry. However, its mechanism of synthesis is not fully understood, especially in terms of the expression and regulation of the starch synthetic genes. It was reported that the starch synthetic genes were co-expressed during maize endosperm development; however, the mechanism of the co-expression was not reported. In this paper, the ZmaNAC36 gene was amplified by homology-based cloning, and its expression vector was constructed for transient expression. The nuclear localization, transcriptional activation and target sites of the ZmaNAC36 protein were identified. The expression profile of ZmaNAC36 showed that it was strongly expressed in the maize endosperm and was co-expressed with most of the starch synthetic genes. Moreover, the expressions of many starch synthesis genes in the endosperm were upregulated when ZmaNAC36 was transiently overexpressed. All our results indicated that NAC36 might be a transcription factor and play a potential role in the co-expression of starch synthetic genes in the maize endosperm. PMID:24235061

  1. Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.

    PubMed

    Mahfouz, Ahmed; Ziats, Mark N; Rennert, Owen M; Lelieveldt, Boudewijn P F; Reinders, Marcel J T

    2015-12-01

    Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD. We analyzed the co-expression relationships of 455 genes previously implicated in autism using the BrainSpan human transcriptome database, across 16 anatomical brain regions spanning prenatal life through adulthood. We discovered modules of ASD candidate genes with biologically relevant temporal co-expression dynamics, which were enriched for functional ontologies related to synaptogenesis, apoptosis, and GABA-ergic neurons. Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination. Hub genes central to these ASD-enriched modules were further identified, and their functions supported these ontological findings. Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function. PMID:26399424

  2. Genetic architecture of wood properties based on association analysis and co-expression networks in white spruce.

    PubMed

    Lamara, Mebarek; Raherison, Elie; Lenz, Patrick; Beaulieu, Jean; Bousquet, Jean; MacKay, John

    2016-04-01

    Association studies are widely utilized to analyze complex traits but their ability to disclose genetic architectures is often limited by statistical constraints, and functional insights are usually minimal in nonmodel organisms like forest trees. We developed an approach to integrate association mapping results with co-expression networks. We tested single nucleotide polymorphisms (SNPs) in 2652 candidate genes for statistical associations with wood density, stiffness, microfibril angle and ring width in a population of 1694 white spruce trees (Picea glauca). Associations mapping identified 229-292 genes per wood trait using a statistical significance level of P < 0.05 to maximize discovery. Over-representation of genes associated for nearly all traits was found in a xylem preferential co-expression group developed in independent experiments. A xylem co-expression network was reconstructed with 180 wood associated genes and several known MYB and NAC regulators were identified as network hubs. The network revealed a link between the gene PgNAC8, wood stiffness and microfibril angle, as well as considerable within-season variation for both genetic control of wood traits and gene expression. Trait associations were distributed throughout the network suggesting complex interactions and pleiotropic effects. Our findings indicate that integration of association mapping and co-expression networks enhances our understanding of complex wood traits. PMID:26619072

  3. Co-expression of cystatin inhibitors OCI and OCII in transgenic potato plants alters Colorado potato beetle development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oryzacystatins I and II (OCI and OCII) show potential for controlling pests that utilize cysteine proteinases for protein digestion. To strengthen individual inhibitory range and achieve an additive effect in the overall efficiency of these proteins against pests, both cystatin genes were co-express...

  4. G-NEST: A gene neighborhood scoring tool to identify co-conserved, co-expressed genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In previous studies, gene neighborhoods--spatial clusters of co-expressed genes in the genome--have been defined using arbitrary rules such as requiring adjacency, a minimum number of genes, a fixed window size, or a minimum expression level. In the current study, we developed a Gene Neighborhood Sc...

  5. In vivo modification of tyrosine residues in recombinant mussel adhesive protein by tyrosinase co-expression in Escherichia coli

    PubMed Central

    2012-01-01

    Background In nature, mussel adhesive proteins (MAPs) show remarkable adhesive properties, biocompatibility, and biodegradability. Thus, they have been considered promising adhesive biomaterials for various biomedical and industrial applications. However, limited production of natural MAPs has hampered their practical applications. Recombinant production in bacterial cells could be one alternative to obtain useable amounts of MAPs, although additional post-translational modification of tyrosine residues into 3,4-dihydroxyphenyl-alanine (Dopa) and Dopaquinone is required. The superior properties of MAPs are mainly attributed to the introduction of quinone-derived intermolecular cross-links. To solve this problem, we utilized a co-expression strategy of recombinant MAP and tyrosinase in Escherichia coli to successfully modify tyrosine residues in vivo. Results A recombinant hybrid MAP, fp-151, was used as a target for in vivo modification, and a dual vector system of pET and pACYC-Duet provided co-expression of fp-151 and tyrosinase. As a result, fp-151 was over-expressed and mainly obtained from the soluble fraction in the co-expression system. Without tyrosinase co-expression, fp-151 was over-expressed in an insoluble form in inclusion bodies. The modification of tyrosine residues in the soluble-expressed fp-151 was clearly observed from nitroblue tetrazolium staining and liquid-chromatography-mass/mass spectrometry analyses. The purified, in vivo modified, fp-151 from the co-expression system showed approximately 4-fold higher bulk-scale adhesive strength compared to in vitro tyrosinase-treated fp-151. Conclusion Here, we reported a co-expression system to obtain in vivo modified MAP; additional in vitro tyrosinase modification was not needed to obtain adhesive properties and the in vivo modified MAP showed superior adhesive strength compared to in vitro modified protein. It is expected that this co-expression strategy will accelerate the use of functional MAPs in

  6. Co-expression analysis of differentially expressed genes in hepatitis C virus-induced hepatocellular carcinoma.

    PubMed

    Song, Qingfeng; Zhao, Chang; Ou, Shengqiu; Meng, Zhibin; Kang, Ping; Fan, Liwei; Qi, Feng; Ma, Yilong

    2015-01-01

    The aim of the current study was to investigate the molecular mechanisms underlying hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) using the expression profiles of HCV-infected Huh7 cells at different time points. The differentially expressed genes (DEGs) were identified with the Samr package in R software once the data were normalized. Functional and pathway enrichment analysis of the identified DEGs was also performed. Subsequently, MCODE in Cytoscape software was applied to conduct module analysis of the constructed co-expression networks. A total of 1,100 DEGs were identified between the HCV-infected and control samples at 12, 18, 24 and 48 h post-infection. DEGs at 24 and 48 h were involved in the same signaling pathways and biological processes, including sterol biosynthetic processes and tRNA amino-acylation. There were 22 time series genes which were clustered into 3 expression patterns, and the demarcation point of the 2 expression patterns that 401 overlapping DEGs at 24 and 48 h clustered into was 24 h post-infection. tRNA synthesis-related biological processes emerged at 24 and 48 h. Replication and assembly of HCV in HCV-infected Huh7 cells occurred mainly at 24 h post-infection. In view of this, the screened time series genes have the potential to become candidate target molecules for monitoring, diagnosing and treating HCV-induced HCC. PMID:25339452

  7. Midbrain catecholaminergic neurons co-express α-synuclein and tau in progressive supranuclear palsy

    PubMed Central

    Erro Aguirre, María Elena; Zelaya, María Victoria; Sánchez Ruiz de Gordoa, Javier; Tuñón, María Teresa; Lanciego, José Luis

    2015-01-01

    Objective: To analyze the frequency and distribution of α-synuclein deposits in progressive supranuclear palsy (PSP). Methods: The brains of 25 cases of pathologically confirmed PSP were evaluated with immunohistochemistry for α-synuclein and tau. Multiple immunofluorescent stains were applied to analyze the expression of tau and α-synuclein aggregates in catecholaminergic neurons. Patients’ clinical symptoms were retrospectively recorded. Results: Deposits α-synuclein in the form of typical Lewy bodies (LBs) were only found in two PSP cases (8%) that fulfilled the clinical subtype of PSP known as Richardson’s syndrome (RS). LBs were present in the locus ceruleus (LC), substantia nigra pars compacta (SNc), basal forebrain, amygdala and cingulated cortex in a distribution mimicking that of Parkinson’s disease (PD). Triple-immunolabeling revealed co-expression of α-synuclein and tau proteins in some tyrosine hydroxilase (TH)-positive neurons of the LC and SNc. Conclusions: There is no apparent clinical correlation between the presence of LBs in PSP. Tau protein co-aggregate with α-synuclein in catecholaminergic neurons of PSP brains suggesting a synergistic interaction between the two proteins. This is in keeping with the current view of neurodegenerative disorders as “misfolded protein diseases”. PMID:25814937

  8. [Construction of recombinant baculovirus co-expressing M1 and HA of influenza A virus].

    PubMed

    Xu, Peng-Wei; Guo, Jian-Qiang; Yao, Li-Hong; Chen, Ai-Jun; Liu, Xiao-Yu; Zeng, Xian-Yin; Zhang, Zhi-Qing

    2012-05-01

    The M1 and HA genes of H1N1 influenza virus were amplified and then cloned into the pFastBac dual donor plasmid. The recombinant pFastBac Dual-M1-HA was identified by restriction enzyme digestion. After the pFastBacdual-M1-HA was transformed into the baculovirus shuttle plasmid (bacmid) in DH10Bac competent cells, the colonies were identified by antibiotics and blue-white selection. The rBac-mid-M1-HA was verified by PCR and transfected into S f9 cells to produce recombinant baculovirus (rBac-M1-HA). Gene insertion of rBac-M1-HA was verified and the expression of M1 and HA genes was analyzed by IFA and Western-blot, demonstrating M1 and HA were co-expressed successfully. This study provides the foundation for researching the formation mechanism of influenza VLP and developing new influenza vaccines. PMID:22764525

  9. Co-expression analysis of differentially expressed genes in hepatitis C virus-induced hepatocellular carcinoma

    PubMed Central

    SONG, QINGFENG; ZHAO, CHANG; OU, SHENGQIU; MENG, ZHIBIN; KANG, PING; FAN, LIWEI; QI, FENG; MA, YILONG

    2015-01-01

    The aim of the current study was to investigate the molecular mechanisms underlying hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) using the expression profiles of HCV-infected Huh7 cells at different time points. The differentially expressed genes (DEGs) were identified with the Samr package in R software once the data were normalized. Functional and pathway enrichment analysis of the identified DEGs was also performed. Subsequently, MCODE in Cytoscape software was applied to conduct module analysis of the constructed co-expression networks. A total of 1,100 DEGs were identified between the HCV-infected and control samples at 12, 18, 24 and 48 h post-infection. DEGs at 24 and 48 h were involved in the same signaling pathways and biological processes, including sterol biosynthetic processes and tRNA amino-acylation. There were 22 time series genes which were clustered into 3 expression patterns, and the demarcation point of the 2 expression patterns that 401 overlapping DEGs at 24 and 48 h clustered into was 24 h post-infection. tRNA synthesis-related biological processes emerged at 24 and 48 h. Replication and assembly of HCV in HCV-infected Huh7 cells occurred mainly at 24 h post-infection. In view of this, the screened time series genes have the potential to become candidate target molecules for monitoring, diagnosing and treating HCV-induced HCC. PMID:25339452

  10. Microarray and Co-expression Network Analysis of Genes Associated with Acute Doxorubicin Cardiomyopathy in Mice.

    PubMed

    Wei, Sheng-Nan; Zhao, Wen-Jie; Zeng, Xiang-Jun; Kang, Yu-Ming; Du, Jie; Li, Hui-Hua

    2015-10-01

    Clinical use of doxorubicin (DOX) in cancer therapy is limited by its dose-dependent cardiotoxicity. But molecular mechanisms underlying this phenomenon have not been well defined. This study was to investigate the effect of DOX on the changes of global genomics in hearts. Acute cardiotoxicity was induced by giving C57BL/6J mice a single intraperitoneal injection of DOX (15 mg/kg). Cardiac function and apoptosis were monitored using echocardiography and TUNEL assay at days 1, 3 and 5. Myocardial glucose and ATP levels were measured. Microarray assays were used to screen gene expression profiles in the hearts at day 5, and the results were confirmed with qPCR analysis. DOX administration caused decreased cardiac function, increased cardiomyocyte apoptosis and decreased glucose and ATP levels. Microarrays showed 747 up-regulated genes and 438 down-regulated genes involved in seven main functional categories. Among them, metabolic pathway was the most affected by DOX. Several key genes, including 2,3-bisphosphoglycerate mutase (Bpgm), hexokinase 2, pyruvate dehydrogenase kinase, isoenzyme 4 and fructose-2,6-bisphosphate 2-phosphatase, are closely related to glucose metabolism. Gene co-expression networks suggested the core role of Bpgm in DOX cardiomyopathy. These results obtained in mice were further confirmed in cultured cardiomyocytes. In conclusion, genes involved in glucose metabolism, especially Bpgm, may play a central role in the pathogenesis of DOX-induced cardiotoxicity. PMID:25575753

  11. Analysis of the dynamic co-expression network of heart regeneration in the zebrafish.

    PubMed

    Rodius, Sophie; Androsova, Ganna; Götz, Lou; Liechti, Robin; Crespo, Isaac; Merz, Susanne; Nazarov, Petr V; de Klein, Niek; Jeanty, Céline; González-Rosa, Juan M; Muller, Arnaud; Bernardin, Francois; Niclou, Simone P; Vallar, Laurent; Mercader, Nadia; Ibberson, Mark; Xenarios, Ioannis; Azuaje, Francisco

    2016-01-01

    The zebrafish has the capacity to regenerate its heart after severe injury. While the function of a few genes during this process has been studied, we are far from fully understanding how genes interact to coordinate heart regeneration. To enable systematic insights into this phenomenon, we generated and integrated a dynamic co-expression network of heart regeneration in the zebrafish and linked systems-level properties to the underlying molecular events. Across multiple post-injury time points, the network displays topological attributes of biological relevance. We show that regeneration steps are mediated by modules of transcriptionally coordinated genes, and by genes acting as network hubs. We also established direct associations between hubs and validated drivers of heart regeneration with murine and human orthologs. The resulting models and interactive analysis tools are available at http://infused.vital-it.ch. Using a worked example, we demonstrate the usefulness of this unique open resource for hypothesis generation and in silico screening for genes involved in heart regeneration. PMID:27241320

  12. Ligand Similarity Complements Sequence, Physical Interaction, and Co-Expression for Gene Function Prediction

    PubMed Central

    Shoichet, Brian K.; Gillis, Jesse

    2016-01-01

    The expansion of protein-ligand annotation databases has enabled large-scale networking of proteins by ligand similarity. These ligand-based protein networks, which implicitly predict the ability of neighboring proteins to bind related ligands, may complement biologically-oriented gene networks, which are used to predict functional or disease relevance. To quantify the degree to which such ligand-based protein associations might complement functional genomic associations, including sequence similarity, physical protein-protein interactions, co-expression, and disease gene annotations, we calculated a network based on the Similarity Ensemble Approach (SEA: sea.docking.org), where protein neighbors reflect the similarity of their ligands. We also measured the similarity with functional genomic networks over a common set of 1,131 genes, and found that the networks had only small overlaps, which were significant only due to the large scale of the data. Consistent with the view that the networks contain different information, combining them substantially improved Molecular Function prediction within GO (from AUROC~0.63–0.75 for the individual data modalities to AUROC~0.8 in the aggregate). We investigated the boost in guilt-by-association gene function prediction when the networks are combined and describe underlying properties that can be further exploited. PMID:27467773

  13. Co-expression of RNA–protein complexes in Escherichia coli and applications to RNA biology

    PubMed Central

    Ponchon, Luc; Catala, Marjorie; Seijo, Bili; El Khouri, Marguerite; Dardel, Frédéric; Nonin-Lecomte, Sylvie; Tisné, Carine

    2013-01-01

    RNA has emerged as a major player in many cellular processes. Understanding these processes at the molecular level requires homogeneous RNA samples for structural, biochemical and pharmacological studies. We previously devised a generic approach that allows efficient in vivo expression of recombinant RNA in Escherichia coli. In this work, we have extended this method to RNA/protein co-expression. We have engineered several plasmids that allow overexpression of RNA–protein complexes in E. coli. We have investigated the potential of these tools in many applications, including the production of nuclease-sensitive RNAs encapsulated in viral protein pseudo-particles, the co-production of non-coding RNAs with chaperone proteins, the incorporation of a post-transcriptional RNA modification by co-production with the appropriate modifying enzyme and finally the production and purification of an RNA–His-tagged protein complex by nickel affinity chromatography. We show that this last application easily provides pure material for crystallographic studies. The new tools we report will pave the way to large-scale structural and molecular investigations of RNA function and interactions with proteins. PMID:23804766

  14. Understanding developmental and adaptive cues in pine through metabolite profiling and co-expression network analysis

    PubMed Central

    Cañas, Rafael A.; Canales, Javier; Muñoz-Hernández, Carmen; Granados, Jose M.; Ávila, Concepción; García-Martín, María L.; Cánovas, Francisco M.

    2015-01-01

    Conifers include long-lived evergreen trees of great economic and ecological importance, including pines and spruces. During their long lives conifers must respond to seasonal environmental changes, adapt to unpredictable environmental stresses, and co-ordinate their adaptive adjustments with internal developmental programmes. To gain insights into these responses, we examined metabolite and transcriptomic profiles of needles from naturally growing 25-year-old maritime pine (Pinus pinaster L. Aiton) trees over a year. The effect of environmental parameters such as temperature and rain on needle development were studied. Our results show that seasonal changes in the metabolite profiles were mainly affected by the needles’ age and acclimation for winter, but changes in transcript profiles were mainly dependent on climatic factors. The relative abundance of most transcripts correlated well with temperature, particularly for genes involved in photosynthesis or winter acclimation. Gene network analysis revealed relationships between 14 co-expressed gene modules and development and adaptation to environmental stimuli. Novel Myb transcription factors were identified as candidate regulators during needle development. Our systems-based analysis provides integrated data of the seasonal regulation of maritime pine growth, opening new perspectives for understanding the complex regulatory mechanisms underlying conifers’ adaptive responses. Taken together, our results suggest that the environment regulates the transcriptome for fine tuning of the metabolome during development. PMID:25873654

  15. Genetic Network Inference: From Co-Expression Clustering to Reverse Engineering

    NASA Technical Reports Server (NTRS)

    Dhaeseleer, Patrik; Liang, Shoudan; Somogyi, Roland

    2000-01-01

    Advances in molecular biological, analytical, and computational technologies are enabling us to systematically investigate the complex molecular processes underlying biological systems. In particular, using high-throughput gene expression assays, we are able to measure the output of the gene regulatory network. We aim here to review datamining and modeling approaches for conceptualizing and unraveling the functional relationships implicit in these datasets. Clustering of co-expression profiles allows us to infer shared regulatory inputs and functional pathways. We discuss various aspects of clustering, ranging from distance measures to clustering algorithms and multiple-duster memberships. More advanced analysis aims to infer causal connections between genes directly, i.e., who is regulating whom and how. We discuss several approaches to the problem of reverse engineering of genetic networks, from discrete Boolean networks, to continuous linear and non-linear models. We conclude that the combination of predictive modeling with systematic experimental verification will be required to gain a deeper insight into living organisms, therapeutic targeting, and bioengineering.

  16. Analysis of the dynamic co-expression network of heart regeneration in the zebrafish

    PubMed Central

    Rodius, Sophie; Androsova, Ganna; Götz, Lou; Liechti, Robin; Crespo, Isaac; Merz, Susanne; Nazarov, Petr V.; de Klein, Niek; Jeanty, Céline; González-Rosa, Juan M.; Muller, Arnaud; Bernardin, Francois; Niclou, Simone P.; Vallar, Laurent; Mercader, Nadia; Ibberson, Mark; Xenarios, Ioannis; Azuaje, Francisco

    2016-01-01

    The zebrafish has the capacity to regenerate its heart after severe injury. While the function of a few genes during this process has been studied, we are far from fully understanding how genes interact to coordinate heart regeneration. To enable systematic insights into this phenomenon, we generated and integrated a dynamic co-expression network of heart regeneration in the zebrafish and linked systems-level properties to the underlying molecular events. Across multiple post-injury time points, the network displays topological attributes of biological relevance. We show that regeneration steps are mediated by modules of transcriptionally coordinated genes, and by genes acting as network hubs. We also established direct associations between hubs and validated drivers of heart regeneration with murine and human orthologs. The resulting models and interactive analysis tools are available at http://infused.vital-it.ch. Using a worked example, we demonstrate the usefulness of this unique open resource for hypothesis generation and in silico screening for genes involved in heart regeneration. PMID:27241320

  17. Integrated gene co-expression network analysis in the growth phase of Mycobacterium tuberculosis reveals new potential drug targets.

    PubMed

    Puniya, Bhanwar Lal; Kulshreshtha, Deepika; Verma, Srikant Prasad; Kumar, Sanjiv; Ramachandran, Srinivasan

    2013-11-01

    We have carried out weighted gene co-expression network analysis of Mycobacterium tuberculosis to gain insights into gene expression architecture during log phase growth. The differentially expressed genes between at least one pair of 11 different M. tuberculosis strains as source of biological variability were used for co-expression network analysis. This data included genes with highest coefficient of variation in expression. Five distinct modules were identified using topological overlap based clustering. All the modules together showed significant enrichment in biological processes: fatty acid biosynthesis, cell membrane, intracellular membrane bound organelle, DNA replication, Quinone biosynthesis, cell shape and peptidoglycan biosynthesis, ribosome and structural constituents of ribosome and transposition. We then extracted the co-expressed connections which were supported either by transcriptional regulatory network or STRING database or high edge weight of topological overlap. The genes trpC, nadC, pitA, Rv3404c, atpA, pknA, Rv0996, purB, Rv2106 and Rv0796 emerged as top hub genes. After overlaying this network on the iNJ661 metabolic network, the reactions catalyzed by 15 highly connected metabolic genes were knocked down in silico and evaluated by Flux Balance Analysis. The results showed that in 12 out of 15 cases, in 11 more than 50% of reactions catalyzed by genes connected through co-expressed connections also had altered fluxes. The modules 'Turquoise', 'Blue' and 'Red' also showed enrichment in essential genes. We could map 152 of the previously known or proposed drug targets in these modules and identified 15 new potential drug targets based on their high degree of co-expressed connections and strong correlation with module eigengenes. PMID:24056838

  18. Co-expression of glutathione S-transferase with methionine aminopeptidase: a system of producing enriched N-terminal processed proteins in Escherichia coli.

    PubMed Central

    Hwang, D D; Liu, L F; Kuan, I C; Lin, L Y; Tam, T C; Tam, M F

    1999-01-01

    We describe here an Escherichia coli expression system that produces recombinant proteins enriched in the N-terminal processed form, by using glutathione S-transferase cGSTM1-1 and rGSTT1-1 as models, where c and r refer to chick and rat respectively. Approximately 90% of the cGSTM1-1 or rGSTT1-1 overexpressed in E. coli under the control of a phoA promoter retained the initiator methionine residue that was absent from the mature isoenzymes isolated from tissues. The amount of initiator methionine was decreased to 40% of the expressed cGSTM1-1 when the isoenzyme was co-expressed with an exogenous methionine aminopeptidase gene under the control of a separate phoA promoter. The recombinant proteins expressed were mainly methionine aminopeptidase. The yield of cGSTM1-1 was decreased to 10% of that expressed in the absence of the exogenous methionine aminopeptidase gene. By replacing the phoA with its natural promoter, the expression of methionine aminopeptidase decreased drastically. The yield of the co-expressed cGSTM1-1 was approx. 60% of that in the absence of the exogenous methionine aminopeptidase gene; approx. 65% of the initiator methionine residues were removed from the enzyme. Under similar conditions, N-terminal processing was observed in approx. 70% of the recombinant rGSTT1-1 expressed. By increasing the concentration of phosphate in the growth medium, the amount of initiator methionine on cGSTM1-1 was decreased to 14% of the overexpressed isoenzymes, whereas no further improvement could be observed for rGSTT1-1. The initiator methionine residue does not affect the enzymic activities of either cGSTM1-1 or rGSTT1-1. However, the epoxidase activity and the 4-nitrobenzyl chloride-conjugating activity of the purified recombinant rGSTT1-1 are markedly higher that those reported recently for the same isoenzyme isolated from rat livers. PMID:10024508

  19. Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells

    PubMed Central

    Mason, Mike J; Fan, Guoping; Plath, Kathrin; Zhou, Qing; Horvath, Steve

    2009-01-01

    Background Recent work has revealed that a core group of transcription factors (TFs) regulates the key characteristics of embryonic stem (ES) cells: pluripotency and self-renewal. Current efforts focus on identifying genes that play important roles in maintaining pluripotency and self-renewal in ES cells and aim to understand the interactions among these genes. To that end, we investigated the use of unsigned and signed network analysis to identify pluripotency and differentiation related genes. Results We show that signed networks provide a better systems level understanding of the regulatory mechanisms of ES cells than unsigned networks, using two independent murine ES cell expression data sets. Specifically, using signed weighted gene co-expression network analysis (WGCNA), we found a pluripotency module and a differentiation module, which are not identified in unsigned networks. We confirmed the importance of these modules by incorporating genome-wide TF binding data for key ES cell regulators. Interestingly, we find that the pluripotency module is enriched with genes related to DNA damage repair and mitochondrial function in addition to transcriptional regulation. Using a connectivity measure of module membership, we not only identify known regulators of ES cells but also show that Mrpl15, Msh6, Nrf1, Nup133, Ppif, Rbpj, Sh3gl2, and Zfp39, among other genes, have important roles in maintaining ES cell pluripotency and self-renewal. We also report highly significant relationships between module membership and epigenetic modifications (histone modifications and promoter CpG methylation status), which are known to play a role in controlling gene expression during ES cell self-renewal and differentiation. Conclusion Our systems biologic re-analysis of gene expression, transcription factor binding, epigenetic and gene ontology data provides a novel integrative view of ES cell biology. PMID:19619308

  20. Co-expression of three opsins in cone photoreceptors of the salamander, Ambystoma tigrinum

    PubMed Central

    Isayama, Tomoki; Chen, Ying; Kono, Masahiro; Fabre, Eduard; Slavsky, Michael; DeGrip, Willem J.; Ma, Jian-Xing; Crouch, Rosalie K.; Makino, Clint L.

    2014-01-01

    Whereas more than one type of visual opsin is present in the retina of most vertebrates, it was thought that each type of photoreceptor expressed only one opsin. However, evidence has accumulated that some photoreceptors contain more than one opsin, in many cases as a result of a developmental transition from the expression of one opsin to another. The salamander UV-sensitive (UV) cone is particularly notable because it contains three opsins (Makino and Dodd, 1996; J Gen Physiol 108:27–34). Two opsin types are expressed at levels more than a hundred times lower than that of the primary opsin. Here, immunohistochemical experiments identified the primary component as a UV cone opsin and the two minor components as the short wavelength-sensitive (S) and long wavelength-sensitive (L) cone opsins. Based on single cell recordings of 156 photoreceptors, the presence of three components in UV cones of hatchlings and terrestrial adults ruled out a developmental transition. There was no evidence for multiple opsin types within rods or S cones. But immunohistochemistry and partial bleaching in conjunction with single cell recording revealed that both single and double L cones contained low levels of short wavelength-sensitive pigments in addition to the main L visual pigment. These results raise the possibility that co-expression of multiple opsins in other vertebrates was overlooked because a minor component absorbing at short wavelengths was masked by the main visual pigment or because the expression level of a component absorbing at long wavelengths was exceedingly low. PMID:24374736

  1. Co-expression network analysis reveals transcription factors associated to cell wall biosynthesis in sugarcane.

    PubMed

    Ferreira, Savio Siqueira; Hotta, Carlos Takeshi; Poelking, Viviane Guzzo de Carli; Leite, Debora Chaves Coelho; Buckeridge, Marcos Silveira; Loureiro, Marcelo Ehlers; Barbosa, Marcio Henrique Pereira; Carneiro, Monalisa Sampaio; Souza, Glaucia Mendes

    2016-05-01

    Sugarcane is a hybrid of Saccharum officinarum and Saccharum spontaneum, with minor contributions from other species in Saccharum and other genera. Understanding the molecular basis of cell wall metabolism in sugarcane may allow for rational changes in fiber quality and content when designing new energy crops. This work describes a comparative expression profiling of sugarcane ancestral genotypes: S. officinarum, S. spontaneum and S. robustum and a commercial hybrid: RB867515, linking gene expression to phenotypes to identify genes for sugarcane improvement. Oligoarray experiments of leaves, immature and intermediate internodes, detected 12,621 sense and 995 antisense transcripts. Amino acid metabolism was particularly evident among pathways showing natural antisense transcripts expression. For all tissues sampled, expression analysis revealed 831, 674 and 648 differentially expressed genes in S. officinarum, S. robustum and S. spontaneum, respectively, using RB867515 as reference. Expression of sugar transporters might explain sucrose differences among genotypes, but an unexpected differential expression of histones were also identified between high and low Brix° genotypes. Lignin biosynthetic genes and bioenergetics-related genes were up-regulated in the high lignin genotype, suggesting that these genes are important for S. spontaneum to allocate carbon to lignin, while S. officinarum allocates it to sucrose storage. Co-expression network analysis identified 18 transcription factors possibly related to cell wall biosynthesis while in silico analysis detected cis-elements involved in cell wall biosynthesis in their promoters. Our results provide information to elucidate regulatory networks underlying traits of interest that will allow the improvement of sugarcane for biofuel and chemicals production. PMID:26820137

  2. Liver transplant

    MedlinePlus

    ... series References Keefe EB. Hepatic failure and liver transplantation. In: Goldman L, Schafer AI, eds. Goldman's Cecil ... 2011:chap 157. Martin P, Rosen HR. Liver transplantation. In: Feldman M, Friedman LS, Brandt LJ, eds. ...

  3. Liver spots

    MedlinePlus

    Sun-induced skin changes - liver spots; Senile or solar lentigines; Skin spots - aging; Age spots ... Liver spots are changes in skin color that occur in older skin. The coloring may be due to aging, exposure to the sun ...

  4. Liver biopsy

    MedlinePlus

    ... Test is Performed The biopsy helps diagnose many liver diseases . The procedure also helps assess the stage (early, advanced) of liver disease. This is especially important in hepatitis C infection. ...

  5. Liver Diseases

    MedlinePlus

    Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. There are many kinds of liver diseases. Viruses cause some of them, like hepatitis ...

  6. Liver Biopsy

    MedlinePlus

    ... Organizations ​​ (PDF, 341 KB)​​​​. Alternate Language URL Español Liver Biopsy Page Content On this page: What is ... Points to Remember Clinical Trials What is a liver biopsy? A liver biopsy is a procedure that ...

  7. Liver Biopsy

    MedlinePlus

    ... PDF, 341 KB)​​​​. Alternate Language URL Español Liver Biopsy Page Content On this page: What is a ... to Remember Clinical Trials What is a liver biopsy? A liver biopsy is a procedure that involves ...

  8. Recursive Indirect-Paths Modularity (RIP-M) for Detecting Community Structure in RNA-Seq Co-expression Networks.

    PubMed

    Rahmani, Bahareh; Zimmermann, Michael T; Grill, Diane E; Kennedy, Richard B; Oberg, Ann L; White, Bill C; Poland, Gregory A; McKinney, Brett A

    2016-01-01

    Clusters of genes in co-expression networks are commonly used as functional units for gene set enrichment detection and increasingly as features (attribute construction) for statistical inference and sample classification. One of the practical challenges of clustering for these purposes is to identify an optimal partition of the network where the individual clusters are neither too large, prohibiting interpretation, nor too small, precluding general inference. Newman Modularity is a spectral clustering algorithm that automatically finds the number of clusters, but for many biological networks the cluster sizes are suboptimal. In this work, we generalize Newman Modularity to incorporate information from indirect paths in RNA-Seq co-expression networks. We implement a merge-and-split algorithm that allows the user to constrain the range of cluster sizes: large enough to capture genes in relevant pathways, yet small enough to resolve distinct functions. We investigate the properties of our recursive indirect-pathways modularity (RIP-M) and compare it with other clustering methods using simulated co-expression networks and RNA-seq data from an influenza vaccine response study. RIP-M had higher cluster assignment accuracy than Newman Modularity for finding clusters in simulated co-expression networks for all scenarios, and RIP-M had comparable accuracy to Weighted Gene Correlation Network Analysis (WGCNA). RIP-M was more accurate than WGCNA for modest hard thresholds and comparable for high, while WGCNA was slightly more accurate for soft thresholds. In the vaccine study data, RIP-M and WGCNA enriched for a comparable number of immunologically relevant pathways. PMID:27242890

  9. Recursive Indirect-Paths Modularity (RIP-M) for Detecting Community Structure in RNA-Seq Co-expression Networks

    PubMed Central

    Rahmani, Bahareh; Zimmermann, Michael T.; Grill, Diane E.; Kennedy, Richard B.; Oberg, Ann L.; White, Bill C.; Poland, Gregory A.; McKinney, Brett A.

    2016-01-01

    Clusters of genes in co-expression networks are commonly used as functional units for gene set enrichment detection and increasingly as features (attribute construction) for statistical inference and sample classification. One of the practical challenges of clustering for these purposes is to identify an optimal partition of the network where the individual clusters are neither too large, prohibiting interpretation, nor too small, precluding general inference. Newman Modularity is a spectral clustering algorithm that automatically finds the number of clusters, but for many biological networks the cluster sizes are suboptimal. In this work, we generalize Newman Modularity to incorporate information from indirect paths in RNA-Seq co-expression networks. We implement a merge-and-split algorithm that allows the user to constrain the range of cluster sizes: large enough to capture genes in relevant pathways, yet small enough to resolve distinct functions. We investigate the properties of our recursive indirect-pathways modularity (RIP-M) and compare it with other clustering methods using simulated co-expression networks and RNA-seq data from an influenza vaccine response study. RIP-M had higher cluster assignment accuracy than Newman Modularity for finding clusters in simulated co-expression networks for all scenarios, and RIP-M had comparable accuracy to Weighted Gene Correlation Network Analysis (WGCNA). RIP-M was more accurate than WGCNA for modest hard thresholds and comparable for high, while WGCNA was slightly more accurate for soft thresholds. In the vaccine study data, RIP-M and WGCNA enriched for a comparable number of immunologically relevant pathways. PMID:27242890

  10. Enhancement of soluble expression of codon-optimized Thermomicrobium roseum sarcosine oxidase in Escherichia coli via chaperone co-expression.

    PubMed

    Tong, Yanjun; Feng, Shoushuai; Xin, Yu; Yang, Hailin; Zhang, Ling; Wang, Wu; Chen, Wei

    2016-01-20

    The codon-optimized sarcosine oxidase from Thermomicrobium roseum (TrSOX) was successfully expressed in Escherichia coli and its soluble expression was significantly enhanced via the co-expression of chaperones. With the assistance of whole-genome analysis of T. roseum DSM 5159, the sox gene was predicated and its sequence was optimized based on the codon bias of E. coli. The TrSOX gene was successfully constructed in the pET28a plasmid. After induction with IPTG for 8h, SDS-PAGE analysis of crude enzyme solutions showed a significant 43 kDa protein band, indicating SOX was successfully expressed in E. coli. However, the dark band corresponding to the intracellular insoluble fraction indicated that most of TrSOX enzyme existed in the inactive form in "inclusion bodies" owing to the "hot spots" of TrSOX. Furthermore, the co-expression of five different combinations of chaperones indicated that the soluble expression of TrSOX was greatly improved by the co-expression of molecular chaperones GroES-GroEL and DnaK-DnaJ-GrpE-GroES-GroEL. Additionally, the analysis of intramolecular forces indicated that the hydrophobic amino acids, hydrogen bonds, and ionic bonds were favorable for enhancing the interaction and stability of TrSOX secondary structure. This study provides a novel strategy for enhancing the soluble expression of TrSOX in E. coli. PMID:26626227

  11. A set of ligation-independent expression vectors for co-expression of proteins in Escherichia coli.

    PubMed

    Chanda, Pranab K; Edris, Wade A; Kennedy, Jeffrey D

    2006-05-01

    A set of ligation-independent expression vectors system has been developed for co-expression of proteins in Escherichia coli. These vectors contain a strong T7 promoter, different drug resistant genes, and an origin of DNA replication from a different incompatibility group, allowing combinations of these plasmids to be stably maintained together. In addition, these plasmids also contain the lacI gene, a transcriptional terminator, and a 3' polyhistidine (6x His) affinity tag (H6) for easy purification of target proteins. All of these vectors contain an identical transportable cassette flanked by suitable restriction enzyme cleavage sites for easy cloning and shuttling among different vectors. This cassette incorporates a ligation-independent cloning (LIC) site for LIC manipulations, an optimal ribosome binding site for efficient protein translation, and a 6x His affinity tag for protein purification Therefore, any E. coli expression vector of choice can be easily converted to LIC type expression vectors by shuttling the cassette using the restriction enzyme cleavage sites at the ends. We have demonstrated the expression capabilities of these vectors by co-expressing three bacterial (dsbA, dsbG, and Trx) and also two other mammalian proteins (KChIP1 and Kv4.3). We further show that co-expressed KChIP1/Kv4.3 forms soluble protein complexes that can be purified for further studies. PMID:16325426

  12. A co-expression network analysis reveals lncRNA abnormalities in peripheral blood in early-onset schizophrenia.

    PubMed

    Ren, Yan; Cui, Yuehua; Li, Xinrong; Wang, Binhong; Na, Long; Shi, Junyan; Wang, Liang; Qiu, Lixia; Zhang, Kerang; Liu, Guifen; Xu, Yong

    2015-12-01

    Long non-coding RNAs (lncRNAs) are emerging as important regulators of gene expression and disease processes especially in neuropsychiatric disorders. To explore the potential regulatory roles of lncRNAs in schizophrenia, we performed an integrated co-expression network analysis on lncRNA and mRNA microarray profiles generated from the peripheral blood samples in 19 drug-naïve first-episode early-onset schizophrenia (EOS) patients and 18 demographically matched typically developing controls (TDCs). Using weighted gene co-expression network analysis (WGCNA), we showed that the lncRNAs were organized into co-expressed modules, and two lncRNA modules were associated with EOS. The mRNA networks were constructed and three disease-associated modules were identified. Gene Ontology (GO) analysis indicated that the mRNAs were highly enriched for mitochondrion and related biological processes. Moreover, our results revealed a significant correlation between lncRNAs and mRNAs using the canonical correlation analysis (CCA). Our results suggest that the convergent lncRNA alteration may be involved in the etiologies of EOS, and mitochondrial dysfunction participates in the pathological process of the disease. Our findings may shed light on the pathogenesis of schizophrenia and facilitate future diagnosis and therapeutic strategies. PMID:25967042

  13. Co-expression of Triosephosphate Isomerase, Fructose-1, 6-bisphosphate Aldolase and Fructose-1, 6-bisphosphatase in E.coli.

    PubMed

    Tang, Gong-Li; Yang, Chun-Song; Bao, Jian-Shao; Wang, Yan-Fang; Chen, Hai-Bao; Shi, Ding-Ji; Liu, Feng-Long

    2001-01-01

    To establish a way to control or to decrease the daily increasing concentration of atmospheric CO(2), metabolically engineering Cyanobacteria was taken for the improvement of its efficiency of photosynthetic CO(2) fixation. As a preliminary stage of this study, three genes coding for three important Calvin cycle enzymes, i.e. triosephosphate isomerase (TPI), fructose-1, 6-bisphosphate aldolase(FBP aldolase),and fructose-1, 6-bisphosphatase(FBPase), respectively, have been cloned into one plasmid, pTrcFAT, which is controlled by promoter trc. Successful co-transcriptional expression of these three genes resulted inhigh yields of these enzymes under the induction of 0.25 mmol/L IPTG. Bioassay showed that the expressed enzymes from one liter of culture could directly catalyze DHAP conversion into 700 &mgr;mol of fructose-6-phosphate (F-6-P) per one minute. Furthermore, in order to introduce the three genes co-expression system into Cyanobacteria, a shuttle plasmid between E.coli and Cyanobacteria was constructed using plasmid pTrcFAT and a shuttle vector pDC-8, forming ashuttle plasmid pDCFAT-2 containing a dimer of the three genes co-expression operator. Successful co-expression in E.coli of pDCFAT-2 with higher full activity has been obtained. This shuttle was used to transform of Cyanobacteria Synechococcus sp. PCC 7942, and a few positive colonies were obtained. PMID:12053203

  14. [Construction of recombinant adenovirus co-expressing M1 and HA genes of influenza virus type A].

    PubMed

    Guo, Jian-Qiang; Yao, Li-Hong; Chen, Ai-Jun; Xu, Yi; Jia, Run-Qing; Bo, Hong; Dong, Jie; Zhou, Jian-Fang; Shu, Yue-Long; Zhang, Zhi-Qing

    2009-03-01

    Based on the human H5N1 influenza virus strain A/Anhui/1/2005, recombinant adenovirus co-expressing M1 and HA genes of H5N1 influenza virus was constructed using an internal ribosome entry site (IRES) sequence to link the two genes. The M1 and HA genes of H5N1 influenza virus were amplified by PCR and subcloned into pStar vector separately. Then the M1-IRES-HA fragment was amplified and subcloned into pShuttle-CMV vector, the shuttle plasmid was then linearized and transformed into BJ5183 bacteria which contained backbone vector pAd-Easy. The recombinant vector pAd-Easy was packaged in 293 cells to get recombinant adenovirus Ad-M1/HA. CPE was observed after 293 cells were transfected by Ad-M1/HA. The co-expression of M1 and HA genes was confirmed by Western-blot and IFA (immunofluorescence assay). The IRES containing recombinant adenovirus allowed functional co-expression of M1 and HA genes and provided the foundation for developing new influenza vaccines with adenoviral vector. PMID:19678564

  15. The novel neuropeptide phoenixin is highly co-expressed with nesfatin-1 in the rat hypothalamus, an immunohistochemical study.

    PubMed

    Pałasz, Artur; Rojczyk, Ewa; Bogus, Katarzyna; Worthington, John J; Wiaderkiewicz, Ryszard

    2015-04-10

    The hypothalamus regulates a number of autonomic functions essential for homeostasis; therefore, investigations concerning hypothalamic neuropeptides and their functions and distribution are of great importance in contemporary neuroscience. Recently, novel regulatory factors expressed in the hypothalamus have been discovered, of which nesfatin-1 and phoenixin (PNX), show intriguing similarities in their brain distributions. There are currently few studies characterizing PNX expression, so it is imperative to accurately trace its localization, with particular attention to the hypothalamic nuclei and nesfatin-1 co-expression. Using fluorescence and classical immunohistochemical stainings on adult rat brain, we visualized the potential co-expression of nesfatin-1 and PNX immunoreactive cells. We have demonstrated a distinct PNX-immunoreactivity in 21-32% of cells in the arcuate nucleus, paraventricular nucleus, ventromedial and lateral hypothalamus. Nesfatin-1 expression reached 45-68% of all neurons in the same sites, while co-expression was strikingly seen in the vast majority (70-86%) of PNX-immunoreactive neurons in the rat hypothalamic nuclei. Our results demonstrate for the first time, a wide distribution of PNX in the hypothalamus which could implicate a potential functional relationship with nesfatin-1, possibly in the regulation of the hypothalamic-pituitary-gonadal axis or other autonomic functions, which require further study. PMID:25736948

  16. In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach

    SciTech Connect

    Motwani, Hitesh V. Törnqvist, Margareta

    2014-12-15

    1,3-Butadiene (BD) is a rodent and human carcinogen. In the cancer tests, mice have been much more susceptible than rats with regard to BD-induced carcinogenicity. The species-differences are dependent on metabolic formation/disappearance of the genotoxic BD epoxy-metabolites that lead to variations in the respective in vivo doses, i.e. “area under the concentration-time curve” (AUC). Differences in AUC of the most gentoxic BD epoxy-metabolite, diepoxybutane (DEB), are considered important with regard to cancer susceptibility. The present work describes: the application of cob(I)alamin for accurate measurements of in vitro enzyme kinetic parameters associated with BD epoxy-metabolites in human, mouse and rat; the use of published data on hemoglobin (Hb) adduct levels of BD epoxides from BD exposure studies on the three species to calculate the corresponding AUCs in blood; and a parallelogram approach for extrapolation of AUC of DEB based on the in vitro metabolism studies and adduct data from in vivo measurements. The predicted value of AUC of DEB for humans from the parallelogram approach was 0.078 nM · h for 1 ppm · h of BD exposure compared to 0.023 nM · h/ppm · h as calculated from Hb adduct levels observed in occupational exposure. The corresponding values in nM · h/ppm · h were for mice 41 vs. 38 and for rats 1.26 vs. 1.37 from the parallelogram approach vs. experimental exposures, respectively, showing a good agreement. This quantitative inter-species extrapolation approach will be further explored for the clarification of metabolic rates/pharmacokinetics and the AUC of other genotoxic electrophilic compounds/metabolites, and has a potential to reduce and refine animal experiments. - Highlights: • In vitro metabolism to in vivo dose extrapolation of butadiene metabolites was proposed. • A parallelogram approach was introduced to estimate dose (AUC) in humans and rodents. • AUC of diepoxybutane predicted in humans was 0.078 nM h/ppm h

  17. Liver transplantation☆

    PubMed Central

    Rossi, M.; Mennini, G.; Lai, Q.; Ginanni Corradini, S.; Drudi, F.M.; Pugliese, F.; Berloco, P.B.

    2007-01-01

    Orthotopic liver transplantation (OLT) involves the substitution of a diseased native liver with a normal liver (or part of one) taken from a deceased or living donor. Considered an experimental procedure through the 1980s, OLT is now regarded as the treatment of choice for a number of otherwise irreversible forms of acute and chronic liver disease. The first human liver transplantation was performed in the United States in 1963 by Prof. T.E. Starzl of the University of Colorado. The first OLT to be performed in Italy was done in 1982 by Prof. R. Cortesini. The procedure was successfully performed at the Policlinico Umberto I of the University of Rome (La Sapienza). The paper reports the indications for liver transplantation, donor selection and organ allocation in our experience, surgical technique, immunosuppression, complications and results of liver transplantation in our center. PMID:23396075

  18. Construction of a compatible Gateway-based co-expression vector set for expressing multiprotein complexes in E. coli.

    PubMed

    Salim, Loubna; Feger, Claire; Busso, Didier

    2016-11-01

    We report the construction of a versatile Gateway-based co-expression vector set for producing multiprotein complexes in Escherichia coli. The set consists of two groups of three vectors (pCoGW and pCo0GW), each having a specific antibiotic resistance gene, a compatible origin of replication and allowing cloning of up to two genes, each under control of its own T7 promoter. To validate the set, 33 (co-)expression plasmids encoding fluorescent protein (GFP, DsRed and ECFP) have been generated. Protein expression levels were quantified and (co-)expression visualized by fluorescent microscopy. The results illustrate the applicability of these vectors in co-expression studies. PMID:27558914

  19. Whole genome co-expression analysis of soybean cytochrome P450 genes identifies nodulation-specific P450 monooxygenases

    PubMed Central

    2010-01-01

    Background Cytochrome P450 monooxygenases (P450s) catalyze oxidation of various substrates using oxygen and NAD(P)H. Plant P450s are involved in the biosynthesis of primary and secondary metabolites performing diverse biological functions. The recent availability of the soybean genome sequence allows us to identify and analyze soybean putative P450s at a genome scale. Co-expression analysis using an available soybean microarray and Illumina sequencing data provides clues for functional annotation of these enzymes. This approach is based on the assumption that genes that have similar expression patterns across a set of conditions may have a functional relationship. Results We have identified a total number of 332 full-length P450 genes and 378 pseudogenes from the soybean genome. From the full-length sequences, 195 genes belong to A-type, which could be further divided into 20 families. The remaining 137 genes belong to non-A type P450s and are classified into 28 families. A total of 178 probe sets were found to correspond to P450 genes on the Affymetrix soybean array. Out of these probe sets, 108 represented single genes. Using the 28 publicly available microarray libraries that contain organ-specific information, some tissue-specific P450s were identified. Similarly, stress responsive soybean P450s were retrieved from 99 microarray soybean libraries. We also utilized Illumina transcriptome sequencing technology to analyze the expressions of all 332 soybean P450 genes. This dataset contains total RNAs isolated from nodules, roots, root tips, leaves, flowers, green pods, apical meristem, mock-inoculated and Bradyrhizobium japonicum-infected root hair cells. The tissue-specific expression patterns of these P450 genes were analyzed and the expression of a representative set of genes were confirmed by qRT-PCR. We performed the co-expression analysis on many of the 108 P450 genes on the Affymetrix arrays. First we confirmed that CYP93C5 (an isoflavone synthase gene) is

  20. Over-producing soluble protein complex and validating protein-protein interaction through a new bacterial co-expression system.

    PubMed

    Zeng, Jumei; Zhang, Lei; Li, Yuqing; Wang, Yi; Wang, Mingchao; Duan, Xin; He, Zheng-Guo

    2010-01-01

    Many proteins exert their functions through a protein complex and protein-protein interactions. However, the study of these types of interactions is complicated when dealing with toxic or hydrophobic proteins. It is difficult to use the popular Escherichia coli host for their expression, as these proteins in all likelihood require a critical partner protein to ensure their proper folding and stability. In the present study, we have developed a novel co-expression vector, pHEX, which is compatible with, and thus can be partnered with, many commercially available E. coli vectors, such as pET, pGEX and pMAL. The pHEX contains the p15A origin of replication and a T7 promoter, which can over-produce a His-tagged recombinant protein. The new co-expression system was demonstrated to efficiently co-produce and co-purify heterodimeric protein complexes, for example PE25/PPE41 (Rv2430c/Rv2431c) and ESAT6/CFP10 (Rv3874/Rv3875), from the human pathogen Mycobacterium tuberculosis H37Rv. Furthermore, the system was also effectively used to characterize protein-protein interactions through convenient affinity tags. Using an in vivo pull-down assay, for the first time we have confirmed the presence of three pairs of PE/PPE-related novel protein interactions in this pathogen. In summary, a convenient and efficient co-expression vector system has been successfully developed. The new system should be applicable to any protein complex or any protein-protein interaction of interest in a wide range of biological organisms. PMID:19747546

  1. Liver spots

    MedlinePlus

    Sun-induced skin changes - liver spots; Senile or solar lentigines; Skin spots - aging; Age spots ... Liver spots are changes in skin color that occur in older skin. The coloring may be due to aging, exposure to the sun or other sources of ...

  2. Improved production of biohydrogen in light-powered Escherichia coli by co-expression of proteorhodopsin and heterologous hydrogenase

    PubMed Central

    2012-01-01

    Background Solar energy is the ultimate energy source on the Earth. The conversion of solar energy into fuels and energy sources can be an ideal solution to address energy problems. The recent discovery of proteorhodopsin in uncultured marine γ-proteobacteria has made it possible to construct recombinant Escherichia coli with the function of light-driven proton pumps. Protons that translocate across membranes by proteorhodopsin generate a proton motive force for ATP synthesis by ATPase. Excess protons can also be substrates for hydrogen (H2) production by hydrogenase in the periplasmic space. In the present work, we investigated the effect of the co-expression of proteorhodopsin and hydrogenase on H2 production yield under light conditions. Results Recombinant E. coli BL21(DE3) co-expressing proteorhodopsin and [NiFe]-hydrogenase from Hydrogenovibrio marinus produced ~1.3-fold more H2 in the presence of exogenous retinal than in the absence of retinal under light conditions (70 μmole photon/(m2·s)). We also observed the synergistic effect of proteorhodopsin with endogenous retinal on H2 production (~1.3-fold more) with a dual plasmid system compared to the strain with a single plasmid for the sole expression of hydrogenase. The increase of light intensity from 70 to 130 μmole photon/(m2·s) led to an increase (~1.8-fold) in H2 production from 287.3 to 525.7 mL H2/L-culture in the culture of recombinant E. coli co-expressing hydrogenase and proteorhodopsin in conjunction with endogenous retinal. The conversion efficiency of light energy to H2 achieved in this study was ~3.4%. Conclusion Here, we report for the first time the potential application of proteorhodopsin for the production of biohydrogen, a promising alternative fuel. We showed that H2 production was enhanced by the co-expression of proteorhodopsin and [NiFe]-hydrogenase in recombinant E. coli BL21(DE3) in a light intensity-dependent manner. These results demonstrate that E. coli can be applied as

  3. Gene co-expression network analysis in Rhodobacter capsulatus and application to comparative expression analysis of Rhodobacter sphaeroides

    SciTech Connect

    Pena-Castillo, Lourdes; Mercer, Ryan; Gurinovich, Anastasia; Callister, Stephen J.; Wright, Aaron T.; Westbye, Alexander; Beatty, J. T.; Lang, Andrew S.

    2014-08-28

    The genus Rhodobacter contains purple nonsulfur bacteria found mostly in freshwater environments. Representative strains of two Rhodobacter species, R. capsulatus and R. sphaeroides, have had their genomes fully sequenced and both have been the subject of transcriptional profiling studies. Gene co-expression networks can be used to identify modules of genes with similar expression profiles. Functional analysis of gene modules can then associate co-expressed genes with biological pathways, and network statistics can determine the degree of module preservation in related networks. In this paper, we constructed an R. capsulatus gene co-expression network, performed functional analysis of identified gene modules, and investigated preservation of these modules in R. capsulatus proteomics data and in R. sphaeroides transcriptomics data. Results: The analysis identified 40 gene co-expression modules in R. capsulatus. Investigation of the module gene contents and expression profiles revealed patterns that were validated based on previous studies supporting the biological relevance of these modules. We identified two R. capsulatus gene modules preserved in the protein abundance data. We also identified several gene modules preserved between both Rhodobacter species, which indicate that these cellular processes are conserved between the species and are candidates for functional information transfer between species. Many gene modules were non-preserved, providing insight into processes that differentiate the two species. In addition, using Local Network Similarity (LNS), a recently proposed metric for expression divergence, we assessed the expression conservation of between-species pairs of orthologs, and within-species gene-protein expression profiles. Conclusions: Our analyses provide new sources of information for functional annotation in R. capsulatus because uncharacterized genes in modules are now connected with groups of genes that constitute a joint functional

  4. Liver bioengineering

    PubMed Central

    Caralt, Mireia; Velasco, Enrique; Lanas, Angel; Baptista, Pedro M

    2014-01-01

    Liver bioengineering has been a field of intense research and popular excitement in the past decades. It experiences great interest since the introduction of whole liver acellular scaffolds generated by perfusion decellularization1–3. Nevertheless, the different strategies developed so far have failed to generate hepatic tissue in vitro bioequivalent to native liver tissue. Even notable novel strategies that rely on iPSC-derived liver progenitor cells potential to self-organize in association with endothelial cells in hepatic organoids are lacking critical components of the native tissue (e.g., bile ducts, functional vascular network, hepatic microarchitecture, etc)4. Hence, it is vital to understand the strengths and short comes of our current strategies in this quest to re-create liver organogenesis in vitro. To shed some light into these issues, this review describes the different actors that play crucial roles in liver organogenesis and highlights the steps still missing to successfully generate whole livers and hepatic organoids in vitro for multiple applications. PMID:25102189

  5. Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity.

    PubMed

    Gu, Yang-Zhuo; Fan, Chuan-Wen; Lu, Ran; Shao, Bin; Sang, Ya-Xiong; Huang, Qiao-Rong; Li, Xue; Meng, Wen-Tong; Mo, Xian-Ming; Wei, Yu-Quan

    2016-01-01

    Genetic modification of whole-cell cancer vaccines to augment their efficacies has a history of over two and a half decades. Various genes and gene combinations, targeting different aspects of immune responses have been tested in pursuit of potent adjuvant effects. Here we show that co-expression of two cytokine members of the common cytokine receptor γ-chain family, IL-21 and IL-7, in whole-cell cancer vaccines boosts antitumor immunity in a CD4(+) and CD8(+) T cell-dependent fashion. It also generates effective immune memory. The vaccine-elicited short-term effects positively correlated with enhanced infiltration of CD4(+) and CD8(+) effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8(+) effector memory T cells. Preliminary data suggested that the vaccine exhibited good safety profile in murine models. Taken together, the combination of IL-21 and IL-7 possesses potent adjuvant efficacy in whole-cell vaccines. This finding warrants future development of IL-21 and IL-7 co-expressing whole-cell cancer vaccines and their relevant combinatorial regimens. PMID:27571893

  6. [Enhancement of Coprinus cinereus peroxidase in Pichia pastoris by co-expression chaperone PDI and Ero1].

    PubMed

    Chen, Fei; Hu, Meirong; Jiang, Xianzhang; Tao, Yong; Huang, Jianzhong

    2015-12-01

    The 1,095 bp gene encoding peroxidase from Coprinus cinereus was synthesized and integrated into the genome of Pichia pastoris with a highly inducible alcohol oxidase. The recombinant CiP (rCiP) fused with the a-mating factor per-pro leader sequence derived from Saccharomyces cerevisiae was secreted into the culture medium and identified as the target protein by mass spectrometry, confirming that a C. cinereus peroxidase (CiP) was successfully expressed in P. pastoris. The endoplasmic reticulum oxidoreductase 1 (Ero1) and protein disulfide isomerase (PDI) were co-expressed with rCiP separately and simultaneously. Compared with the wild type, overexpression of PDI and Erol-PDI increaseed Cip activity in 2.43 and 2.6 fold and their activity reached 316 U/mL and 340 U/mL respectively. The strains co-expressed with Erol-PDI was used to high density fermentation, and their activity reached 3,379 U/mL, which was higher than previously reported of 1,200 U/mL. PMID:27093831

  7. Engineering production of functional scFv antibody in E. coli by co-expressing the molecule chaperone Skp.

    PubMed

    Wang, Rongzhi; Xiang, Shuangshuang; Feng, Youjun; Srinivas, Swaminath; Zhang, Yonghui; Lin, Mingshen; Wang, Shihua

    2013-01-01

    Single-chain variable fragment (scFv) is a class of engineered antibodies generated by the fusion of the heavy (VH) and light chains (VL) of immunoglobulins through a short polypeptide linker. ScFv play a critical role in therapy and diagnosis of human diseases, and may in fact also be developed into a potential diagnostic and/or therapeutic agent. However, the fact that current scFv antibodies have poor stability, low solubility, and affinity, seriously limits their diagnostic and clinical implication. Here we have developed four different expression vectors, and evaluated their abilities to express a soluble scFv protein. The solubility and binding activity of the purified proteins were determined using both SDS-PAGE and ELISA. Amongst the four purified proteins, the Skp co-expressed scFv showed the highest solubility, and the binding activity to antigen TLH was 3-4 fold higher than the other three purified scFv. In fact, this scFv is specific for TLH and does not cross-react with other TLH-associated proteins and could be used to detect TLH directly in real samples. These results suggest that the pACYC-Duet-skp co-expression vector might be a useful tool for the production of soluble and functional scFv antibody. PMID:24224158

  8. Development of a single-replicon miniBYV vector for co-expression of heterologous proteins.

    PubMed

    Prokhnevsky, Alex; Mamedov, Tarlan; Leffet, Brett; Rahimova, Rahila; Ghosh, Ananya; Mett, Vadim; Yusibov, Vidadi

    2015-02-01

    In planta production of recombinant proteins, including vaccine antigens and monoclonal antibodies, continues gaining acceptance. With the broadening range of target proteins, the need for vectors with higher performance is increasing. Here, we have developed a single-replicon vector based on beet yellows virus (BYV) that enables co-delivery of two target genes into the same host cell, resulting in transient expression of each target. This BYV vector maintained genetic stability during systemic spread throughout the host plant, Nicotiana benthamiana. Furthermore, we have engineered a miniBYV vector carrying the sequences encoding heavy and light chains of a monoclonal antibody (mAb) against protective antigen (PA) of Bacillius anthracis, and achieved the expression of the full-length functional anti-PA mAb at ~300 mg/kg of fresh leaf tissue. To demonstrate co-expression and functionality of two independent proteins, we cloned the sequences of the Pfs48/45 protein of Plasmodium falciparum and endoglycosidase F (PNGase F) from Flavobacterium meningosepticum into the miniBYV vector under the control of two subgenomic RNA promoters. Agroinfiltration of N. benthamiana with this miniBYV vector resulted in accumulation of biologically active Pfs48/45 that was devoid of N-linked glycosylation and had correct conformation and epitope display. Overall, our findings demonstrate that the new BYV-based vector is capable of co-expressing two functionally active recombinant proteins within the same host cell. PMID:25280556

  9. Identification of candidate genes in Populus cell wall biosynthesis using text-mining, co-expression network and comparative genomics

    SciTech Connect

    Yang, Xiaohan; Ye, Chuyu; Bisaria, Anjali; Tuskan, Gerald A; Kalluri, Udaya C

    2011-01-01

    Populus is an important bioenergy crop for bioethanol production. A greater understanding of cell wall biosynthesis processes is critical in reducing biomass recalcitrance, a major hindrance in efficient generation of ethanol from lignocellulosic biomass. Here, we report the identification of candidate cell wall biosynthesis genes through the development and application of a novel bioinformatics pipeline. As a first step, via text-mining of PubMed publications, we obtained 121 Arabidopsis genes that had the experimental evidences supporting their involvement in cell wall biosynthesis or remodeling. The 121 genes were then used as bait genes to query an Arabidopsis co-expression database and additional genes were identified as neighbors of the bait genes in the network, increasing the number of genes to 548. The 548 Arabidopsis genes were then used to re-query the Arabidopsis co-expression database and re-construct a network that captured additional network neighbors, expanding to a total of 694 genes. The 694 Arabidopsis genes were computationally divided into 22 clusters. Queries of the Populus genome using the Arabidopsis genes revealed 817 Populus orthologs. Functional analysis of gene ontology and tissue-specific gene expression indicated that these Arabidopsis and Populus genes are high likelihood candidates for functional genomics in relation to cell wall biosynthesis.

  10. Paramyxovirus mediated cell fusion requires co-expression of both the fusion and hemagglutinin-neuraminidase glycoproteins.

    PubMed

    Heminway, B R; Yu, Y; Galinski, M S

    1994-01-01

    Syncytia formation in either CV-1 or HeLa T4+ cells required recombinant expression of both fusion (F) and hemagglutinin-neuraminidase (HN) glycoproteins from the human parainfluenza virus type 3 (HPIV3), human parainfluenza virus type 2 (HPIV2), and simian virus 5 (SV5). In this system, recombinant T7 transcription vectors (pT7-5 or pGEM) containing F or HN, were transfected individually or in combination into cells previously infected with a recombinant vaccinia virus expressing T7 RNA polymerase (vTF7-3). While both proteins were processed and expressed at the cell surface, syncytia formation occurred only when both glycoproteins were co-expressed. The function of HN in the fusion process could not be replaced using lectins or by co-expression of heterologous F and HN proteins. Further, cell fusion was not observed when experiments were performed using individually expressed F and HN proteins in adjacent cells. The data presented in this report support the notion that a specific interaction between both paramyxoviral glycoproteins is required for the formation of syncytia in tissue culture monolayers. PMID:8165862

  11. Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function

    PubMed Central

    Aprile-Garcia, Fernando; Metzger, Michael W.; Paez-Pereda, Marcelo; Stadler, Herbert; Acuña, Matías; Liberman, Ana C.; Senin, Sergio A.; Gerez, Juan; Hoijman, Esteban; Refojo, Damian; Mitkovski, Mišo; Panhuysen, Markus; Stühmer, Walter; Holsboer, Florian; Deussing, Jan M.; Arzt, Eduardo

    2016-01-01

    The P2X7 receptor is a member of the P2X family of ligand-gated ion channels. A single-nucleotide polymorphism leading to a glutamine (Gln) by arginine (Arg) substitution at codon 460 of the purinergic P2X7 receptor (P2X7R) has been associated with mood disorders. No change in function (loss or gain) has been described for this SNP so far. Here we show that although the P2X7R-Gln460Arg variant per se is not compromised in its function, co-expression of wild-type P2X7R with P2X7R-Gln460Arg impairs receptor function with respect to calcium influx, channel currents and intracellular signaling in vitro. Moreover, co-immunoprecipitation and FRET studies show that the P2X7R-Gln460Arg variant physically interacts with P2X7R-WT. Specific silencing of either the normal or polymorphic variant rescues the heterozygous loss of function phenotype and restores normal function. The described loss of function due to co-expression, unique for mutations in the P2RX7 gene so far, explains the mechanism by which the P2X7R-Gln460Arg variant affects the normal function of the channel and may represent a mechanism of action for other mutations. PMID:26986975

  12. Quantitative proteomics reveals the novel co-expression signatures in early brain development for prognosis of glioblastoma multiforme

    PubMed Central

    Yu, Xuexin; Feng, Lin; Liu, Dianming; Zhang, Lianfeng; Wu, Bo; Jiang, Wei; Han, Zujing; Cheng, Shujun

    2016-01-01

    Although several researches have explored the similarity across development and tumorigenesis in cellular behavior and underlying molecular mechanisms, not many have investigated the developmental characteristics at proteomic level and further extended to cancer clinical outcome. In this study, we used iTRAQ to quantify the protein expression changes during macaque rhesus brain development from fetuses at gestation 70 days to after born 5 years. Then, we performed weighted gene co-expression network analysis (WGCNA) on protein expression data of brain development to identify co-expressed modules that highly expressed on distinct development stages, including early stage, middle stage and late stage. Moreover, we used the univariate cox regression model to evaluate the prognostic potentials of these genes in two independent glioblastoma multiforme (GBM) datasets. The results showed that the modules highly expressed on early stage contained more reproducible prognostic genes, including ILF2, CCT7, CCT4, RPL10A, MSN, PRPS1, TFRC and APEX1. These genes were not only associated with clinical outcome, but also tended to influence chemoresponse. These signatures identified from embryonic brain development might contribute to precise prediction of GBM prognosis and identification of novel drug targets in GBM therapies. Thus, the development could become a viable reference model for researching cancers, including identifying novel prognostic markers and promoting new therapies. PMID:26895104

  13. Gene Co-Expression Network Analysis for Identifying Modules and Functionally Enriched Pathways in Type 1 Diabetes.

    PubMed

    Riquelme Medina, Ignacio; Lubovac-Pilav, Zelmina

    2016-01-01

    Type 1 diabetes (T1D) is a complex disease, caused by the autoimmune destruction of the insulin producing pancreatic beta cells, resulting in the body's inability to produce insulin. While great efforts have been put into understanding the genetic and environmental factors that contribute to the etiology of the disease, the exact molecular mechanisms are still largely unknown. T1D is a heterogeneous disease, and previous research in this field is mainly focused on the analysis of single genes, or using traditional gene expression profiling, which generally does not reveal the functional context of a gene associated with a complex disorder. However, network-based analysis does take into account the interactions between the diabetes specific genes or proteins and contributes to new knowledge about disease modules, which in turn can be used for identification of potential new biomarkers for T1D. In this study, we analyzed public microarray data of T1D patients and healthy controls by applying a systems biology approach that combines network-based Weighted Gene Co-Expression Network Analysis (WGCNA) with functional enrichment analysis. Novel co-expression gene network modules associated with T1D were elucidated, which in turn provided a basis for the identification of potential pathways and biomarker genes that may be involved in development of T1D. PMID:27257970

  14. Quantitative proteomics reveals the novel co-expression signatures in early brain development for prognosis of glioblastoma multiforme.

    PubMed

    Yu, Xuexin; Feng, Lin; Liu, Dianming; Zhang, Lianfeng; Wu, Bo; Jiang, Wei; Han, Zujing; Cheng, Shujun

    2016-03-22

    Although several researches have explored the similarity across development and tumorigenesis in cellular behavior and underlying molecular mechanisms, not many have investigated the developmental characteristics at proteomic level and further extended to cancer clinical outcome. In this study, we used iTRAQ to quantify the protein expression changes during macaque rhesus brain development from fetuses at gestation 70 days to after born 5 years. Then, we performed weighted gene co-expression network analysis (WGCNA) on protein expression data of brain development to identify co-expressed modules that highly expressed on distinct development stages, including early stage, middle stage and late stage. Moreover, we used the univariate cox regression model to evaluate the prognostic potentials of these genes in two independent glioblastoma multiforme (GBM) datasets. The results showed that the modules highly expressed on early stage contained more reproducible prognostic genes, including ILF2, CCT7, CCT4, RPL10A, MSN, PRPS1, TFRC and APEX1. These genes were not only associated with clinical outcome, but also tended to influence chemoresponse. These signatures identified from embryonic brain development might contribute to precise prediction of GBM prognosis and identification of novel drug targets in GBM therapies. Thus, the development could become a viable reference model for researching cancers, including identifying novel prognostic markers and promoting new therapies. PMID:26895104

  15. Integration of Metabolic Modeling with Gene Co-expression Reveals Transcriptionally Programmed Reactions Explaining Robustness in Mycobacterium tuberculosis

    PubMed Central

    Puniya, Bhanwar Lal; Kulshreshtha, Deepika; Mittal, Inna; Mobeen, Ahmed; Ramachandran, Srinivasan

    2016-01-01

    Robustness of metabolic networks is accomplished by gene regulation, modularity, re-routing of metabolites and plasticity. Here, we probed robustness against perturbations of biochemical reactions of M. tuberculosis in the form of predicting compensatory trends. In order to investigate the transcriptional programming of genes associated with correlated fluxes, we integrated with gene co-expression network. Knock down of the reactions NADH2r and ATPS responsible for producing the hub metabolites, and Central carbon metabolism had the highest proportion of their associated genes under transcriptional co-expression with genes of their flux correlated reactions. Reciprocal gene expression correlations were observed among compensatory routes, fresh activation of alternative routes and in the multi-copy genes of Cysteine synthase and of Phosphate transporter. Knock down of 46 reactions caused the activation of Isocitrate lyase or Malate synthase or both reactions, which are central to the persistent state of M. tuberculosis. A total of 30 new freshly activated routes including Cytochrome c oxidase, Lactate dehydrogenase, and Glycine cleavage system were predicted, which could be responsible for switching into dormant or persistent state. Thus, our integrated approach of exploring transcriptional programming of flux correlated reactions has the potential to unravel features of system architecture conferring robustness. PMID:27000948

  16. MCT1 modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4

    PubMed Central

    Hong, Candice Sun; Graham, Nicholas A.; Gu, Wen; Camacho, Carolina Espindola; Mah, Vei; Maresh, Erin L.; Alavi, Mohammed; Bagryanova, Lora; Krotee, Pascal A. L.; Gardner, Brian K.; Behbahan, Iman Saramipoor; Horvath, Steve; Chia, David; Mellinghoff, Ingo K.; Hurvitz, Sara A.; Dubinett, Steven M.; Critchlow, Susan E.; Kurdistani, Siavash K.; Goodglick, Lee; Braas, Daniel; Graeber, Thomas G.; Christofk, Heather R.

    2016-01-01

    SUMMARY Monocarboxylate Transporter 1 (MCT1) inhibition is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show MCT1 inhibition impairs proliferation of glycolytic breast cancer cells co-expressing MCT1 and MCT4 via disruption of pyruvate rather than lactate export. MCT1 expression is elevated in glycolytic breast tumors, and high MCT1 expression predicts poor prognosis in breast and lung cancer patients. Acute MCT1 inhibition reduces pyruvate export but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that co-express MCT1 and MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors further supporting their use as anti-cancer therapeutics. PMID:26876179

  17. Gene Co-Expression Network Analysis for Identifying Modules and Functionally Enriched Pathways in Type 1 Diabetes

    PubMed Central

    Riquelme Medina, Ignacio; Lubovac-Pilav, Zelmina

    2016-01-01

    Type 1 diabetes (T1D) is a complex disease, caused by the autoimmune destruction of the insulin producing pancreatic beta cells, resulting in the body’s inability to produce insulin. While great efforts have been put into understanding the genetic and environmental factors that contribute to the etiology of the disease, the exact molecular mechanisms are still largely unknown. T1D is a heterogeneous disease, and previous research in this field is mainly focused on the analysis of single genes, or using traditional gene expression profiling, which generally does not reveal the functional context of a gene associated with a complex disorder. However, network-based analysis does take into account the interactions between the diabetes specific genes or proteins and contributes to new knowledge about disease modules, which in turn can be used for identification of potential new biomarkers for T1D. In this study, we analyzed public microarray data of T1D patients and healthy controls by applying a systems biology approach that combines network-based Weighted Gene Co-Expression Network Analysis (WGCNA) with functional enrichment analysis. Novel co-expression gene network modules associated with T1D were elucidated, which in turn provided a basis for the identification of potential pathways and biomarker genes that may be involved in development of T1D. PMID:27257970

  18. Integration of Metabolic Modeling with Gene Co-expression Reveals Transcriptionally Programmed Reactions Explaining Robustness in Mycobacterium tuberculosis.

    PubMed

    Puniya, Bhanwar Lal; Kulshreshtha, Deepika; Mittal, Inna; Mobeen, Ahmed; Ramachandran, Srinivasan

    2016-01-01

    Robustness of metabolic networks is accomplished by gene regulation, modularity, re-routing of metabolites and plasticity. Here, we probed robustness against perturbations of biochemical reactions of M. tuberculosis in the form of predicting compensatory trends. In order to investigate the transcriptional programming of genes associated with correlated fluxes, we integrated with gene co-expression network. Knock down of the reactions NADH2r and ATPS responsible for producing the hub metabolites, and Central carbon metabolism had the highest proportion of their associated genes under transcriptional co-expression with genes of their flux correlated reactions. Reciprocal gene expression correlations were observed among compensatory routes, fresh activation of alternative routes and in the multi-copy genes of Cysteine synthase and of Phosphate transporter. Knock down of 46 reactions caused the activation of Isocitrate lyase or Malate synthase or both reactions, which are central to the persistent state of M. tuberculosis. A total of 30 new freshly activated routes including Cytochrome c oxidase, Lactate dehydrogenase, and Glycine cleavage system were predicted, which could be responsible for switching into dormant or persistent state. Thus, our integrated approach of exploring transcriptional programming of flux correlated reactions has the potential to unravel features of system architecture conferring robustness. PMID:27000948

  19. Enhanced production of shikimic acid using a multi-gene co-expression system in Escherichia coli.

    PubMed

    Liu, Xiang-Lei; Lin, Jun; Hu, Hai-Feng; Zhou, Bin; Zhu, Bao-Quan

    2016-04-01

    Shikimic acid (SA) is the key synthetic material for the chemical synthesis of Oseltamivir, which is prescribed as the front-line treatment for serious cases of influenza. Multi-gene expression vector can be used for expressing the plurality of the genes in one plasmid, so it is widely applied to increase the yield of metabolites. In the present study, on the basis of a shikimate kinase genetic defect strain Escherichia coli BL21 (ΔaroL/aroK, DE3), the key enzyme genes aroG, aroB, tktA and aroE of SA pathway were co-expressed and compared systematically by constructing a series of multi-gene expression vectors. The results showed that different gene co-expression combinations (two, three or four genes) or gene orders had different effects on the production of SA. SA production of the recombinant BL21-GBAE reached to 886.38 mg·L(-1), which was 17-fold (P < 0.05) of the parent strain BL21 (ΔaroL/aroK, DE3). PMID:27114316

  20. Increased co-expression of genes harboring the damaging de novo mutations in Chinese schizophrenic patients during prenatal development

    PubMed Central

    Wang, Qiang; Li, Miaoxin; Yang, Zhenxing; Hu, Xun; Wu, Hei-Man; Ni, Peiyan; Ren, Hongyan; Deng, Wei; Li, Mingli; Ma, Xiaohong; Guo, Wanjun; Zhao, Liansheng; Wang, Yingcheng; Xiang, Bo; Lei, Wei; Sham, Pak C; Li, Tao

    2015-01-01

    Schizophrenia is a heritable, heterogeneous common psychiatric disorder. In this study, we evaluated the hypothesis that de novo variants (DNVs) contribute to the pathogenesis of schizophrenia. We performed exome sequencing in Chinese patients (N = 45) with schizophrenia and their unaffected parents (N = 90). Forty genes were found to contain DNVs. These genes had enriched transcriptional co-expression profile in prenatal frontal cortex (Bonferroni corrected p < 9.1 × 10−3), and in prenatal temporal and parietal regions (Bonferroni corrected p < 0.03). Also, four prenatal anatomical subregions (VCF, MFC, OFC and ITC) have shown significant enrichment of connectedness in co-expression networks. Moreover, four genes (LRP1, MACF1, DICER1 and ABCA2) harboring the damaging de novo mutations are strongly prioritized as susceptibility genes by multiple evidences. Our findings in Chinese schizophrenic patients indicate the pathogenic role of DNVs, supporting the hypothesis that schizophrenia is a neurodevelopmental disease. PMID:26666178

  1. Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity

    PubMed Central

    Gu, Yang-Zhuo; Fan, Chuan-Wen; Lu, Ran; Shao, Bin; Sang, Ya-Xiong; Huang, Qiao-Rong; Li, Xue; Meng, Wen-Tong; Mo, Xian-Ming; Wei, Yu-Quan

    2016-01-01

    Genetic modification of whole-cell cancer vaccines to augment their efficacies has a history of over two and a half decades. Various genes and gene combinations, targeting different aspects of immune responses have been tested in pursuit of potent adjuvant effects. Here we show that co-expression of two cytokine members of the common cytokine receptor γ-chain family, IL-21 and IL-7, in whole-cell cancer vaccines boosts antitumor immunity in a CD4+ and CD8+ T cell-dependent fashion. It also generates effective immune memory. The vaccine-elicited short-term effects positively correlated with enhanced infiltration of CD4+ and CD8+ effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8+ effector memory T cells. Preliminary data suggested that the vaccine exhibited good safety profile in murine models. Taken together, the combination of IL-21 and IL-7 possesses potent adjuvant efficacy in whole-cell vaccines. This finding warrants future development of IL-21 and IL-7 co-expressing whole-cell cancer vaccines and their relevant combinatorial regimens. PMID:27571893

  2. Liver Regeneration

    PubMed Central

    Michalopoulos, George K.

    2009-01-01

    Liver regeneration after partial hepatectomy is a very complex and well-orchestrated phenomenon. It is carried out by the participation of all mature liver cell types. The process is associated with signaling cascades involving growth factors, cytokines, matrix remodeling, and several feedbacks of stimulation and inhibition of growth related signals. Liver manages to restore any lost mass and adjust its size to that of the organism, while at the same time providing full support for body homeostasis during the entire regenerative process. In situations when hepatocytes or biliary cells are blocked from regeneration, these cell types can function as facultative stem cells for each other. PMID:17559071

  3. What Is Liver Cancer?

    MedlinePlus

    ... Topic Key statistics about liver cancer What is liver cancer? Cancer starts when cells in the body ... structure and function of the liver. About the liver The liver is the largest internal organ. It ...

  4. Benign Liver Tumors

    MedlinePlus

    ... Search: Your Liver Liver Health and Wellness Recipes Liver Disease Information Patients & Families Caregiver's FAQ Become an Organ ... 2013 Liver Awareness Month Personal Story - David Roncori Liver Disease - The Big Picture 13 Ways to a Healthy ...

  5. Liver Panel

    MedlinePlus

    ... liver; the best test for detecting hepatitis Alkaline phosphatase (ALP) – an enzyme related to the bile ducts ... only moderately elevated or close to normal. Alkaline phosphatase (ALP) ALP may be significantly increased with obstructed ...

  6. Liver cirrhosis.

    PubMed Central

    Williams, E. J.; Iredale, J. P.

    1998-01-01

    Liver fibrosis and its related complications continue to represent a significant worldwide healthcare burden. Over the past decade there has been considerable improvement in our understanding of the cellular mechanisms and pathophysiology underlying hepatic fibrosis. This greater insight into the relevant basic sciences may lead to the development of novel treatment strategies designed to block the fibrogenic cascade or even enhance matrix degradation. In addition, there have been significant advances in the management of the complications of cirrhosis, with specific treatments now available for some conditions. Perhaps most notably, liver transplantation is now a highly successful treatment for end-stage liver disease and should be considered in all patients with chronic liver disease. PMID:9683971

  7. Liver transplant

    MedlinePlus

    Risks for any anesthesia are: Problems breathing Reactions to medications Risks for any surgery are: Bleeding Heart attack or stroke Infection Liver transplant surgery and management after surgery carry major risks. There is ...

  8. [Liver intervention].

    PubMed

    Oi, H

    2000-12-01

    Interventional radiology is now widely performed for the treatment of liver tumors, because surgery is sometimes limited by poor liver function. Transcatheter arterial chemoembolization(TACE) is an effective therapy for hepatocellular carcinoma. Lipiodol TACE shows a strong antitumor effect because of the overflow of excess iodized oil into the portal veins, and segmental TACE is recommended to avoid deteriorating liver function. Selective CT arteriography is performed in order to decide on the treatment area, and TACE under CT guidance leads to effective results in terms of dense accumulation of the chemotherapeutic drug in the individual tumors that are affected by the ischemic state and anticancer drugs. Percutaneous microwave or radiofrequency coagulation therapy is adequate for a few of the hypovascular tumors. Excessive coagulation through the needle tract is indispensable in these therapies, and precisely designed puncture is necessary to minimize damage to the liver parenchyma. Selective chemotherapy to the tumor-bearing organ is the first step in a number of liver tumors. Continuous intra-arterial infusion chemotherapy is performed for multiple liver metastases. The reservoir implantation technique is percutaneously achieved via the left subclavian artery under ultrasound guidance, without the exposure of an artery in the incision method, which can induce thrombus formation. PMID:11197832

  9. Nucleoside transporters and liver cell growth.

    PubMed

    Pastor-Anglada, M; Felipe, A; Casado, F J; del Santo, B; Mata, J F; Valdés, R

    1998-01-01

    Liver parenchymal cells show a wide variety of plasma membrane transporters that are tightly regulated by endocrine and nutritional factors. This review summarizes work performed in our laboratory on these transport systems, particularly nucleoside transporters, which are up-regulated in physiological situations associated with liver cell growth. Rat hepatocytes show a Na+-dependent nucleoside transport activity that is stimulated by pancreatic hormones. Indeed, this biological activity appears to be the result of the co-expression of at least two isoforms of nucleoside carriers, CNT1 and CNT2 (also called SPNT). These two transporters are up-regulated during the early phase of liver growth after partial hepatectomy, although to different extents, suggesting differential regulation of the two isoforms. The recent generation of isoform-specific antibodies allowed us to demonstrate that carrier expression may also have complex post-transcriptional regulation on the basis of the lack of correspondence between mRNA and protein levels. The analysis of nucleoside transport systems in hepatoma cells and the comparison with those in hepatocytes has also provided evidence that the differentiation status of liver parenchymal cells may determine the pattern of nucleoside transporters expressed. PMID:10353710

  10. Protein Co-Expression Analysis as a Strategy to Complement a Standard Quantitative Proteomics Approach: Case of a Glioblastoma Multiforme Study

    PubMed Central

    Deighton, Ruth F.

    2016-01-01

    Although correlation network studies from co-expression analysis are increasingly popular, they are rarely applied to proteomics datasets. Protein co-expression analysis provides a complementary view of underlying trends, which can be overlooked by conventional data analysis. The core of the present study is based on Weighted Gene Co-expression Network Analysis applied to a glioblastoma multiforme proteomic dataset. Using this method, we have identified three main modules which are associated with three different membrane associated groups; mitochondrial, endoplasmic reticulum, and a vesicle fraction. The three networks based on protein co-expression were assessed against a publicly available database (STRING) and show a statistically significant overlap. Each of the three main modules were de-clustered into smaller networks using different strategies based on the identification of highly connected networks, hierarchical clustering and enrichment of Gene Ontology functional terms. Most of the highly connected proteins found in the endoplasmic reticulum module were associated with redox activity while a core of the unfolded protein response was identified in addition to proteins involved in oxidative stress pathways. The proteins composing the electron transfer chain were found differently affected with proteins from mitochondrial Complex I being more down-regulated than proteins from Complex III. Finally, the two pyruvate kinases isoforms show major differences in their co-expressed protein networks suggesting roles in different cellular locations. PMID:27571357

  11. Transcription factor-pathway co-expression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma

    PubMed Central

    Wang, Xujun; Yan, Zhenyu; Fulciniti, Mariateresa; Li, Yingxiang; Gkotzamanidou, Maria; Amin, Samir B; Shah, Parantu K; Zhang, Yong

    2014-01-01

    Multiple myeloma is a hematological cancer of plasma B-cells and remains incurable. Two major subtypes of myeloma, hyperdiploid (HMM) and non-hyperdiploid myeloma (NHMM), have distinct chromosomal alterations and different survival outcomes. Transcription factors (TrFs) have been implicated in myeloma oncogenesis but their dysregulation in myeloma subtypes are less studied. Here we develop a TrF-pathway co-expression analysis to identify altered co-expression between two sample types. We apply the method to the two myeloma subtypes and the cell cycle arrest pathway, which is significantly differentially expressed between the two subtypes. We find that TrFs MYC, NF-κB and HOXA9 have significantly lower co-expression with cell cycle arrest in HMM, co-occurring with their over-activation in HMM. In contrast, TrFs ESR1, SP1 and E2F1 have significantly lower co-expression with cell cycle arrest in NHMM. SP1 ChIP targets are enriched by cell cycle arrest genes. These results motivate a cooperation model of ESR1 and SP1 in regulating cell cycle arrest, and a hypothesis that their over-activation in NHMM disrupts proper regulation of cell cycle arrest. Co-targeting ESR1 and SP1 shows a synergistic effect on inhibiting myeloma proliferation in NHMM cell lines. Therefore, studying TrF-pathway co-expression dysregulation in human cancers facilitates forming novel hypotheses towards clinical utility. PMID:23925045

  12. Protein Co-Expression Analysis as a Strategy to Complement a Standard Quantitative Proteomics Approach: Case of a Glioblastoma Multiforme Study.

    PubMed

    Kanonidis, Evangelos I; Roy, Marcia M; Deighton, Ruth F; Le Bihan, Thierry

    2016-01-01

    Although correlation network studies from co-expression analysis are increasingly popular, they are rarely applied to proteomics datasets. Protein co-expression analysis provides a complementary view of underlying trends, which can be overlooked by conventional data analysis. The core of the present study is based on Weighted Gene Co-expression Network Analysis applied to a glioblastoma multiforme proteomic dataset. Using this method, we have identified three main modules which are associated with three different membrane associated groups; mitochondrial, endoplasmic reticulum, and a vesicle fraction. The three networks based on protein co-expression were assessed against a publicly available database (STRING) and show a statistically significant overlap. Each of the three main modules were de-clustered into smaller networks using different strategies based on the identification of highly connected networks, hierarchical clustering and enrichment of Gene Ontology functional terms. Most of the highly connected proteins found in the endoplasmic reticulum module were associated with redox activity while a core of the unfolded protein response was identified in addition to proteins involved in oxidative stress pathways. The proteins composing the electron transfer chain were found differently affected with proteins from mitochondrial Complex I being more down-regulated than proteins from Complex III. Finally, the two pyruvate kinases isoforms show major differences in their co-expressed protein networks suggesting roles in different cellular locations. PMID:27571357

  13. Use of transcriptomics and co-expression networks to analyze the interconnections between nitrogen assimilation and photorespiratory metabolism

    PubMed Central

    Pérez-Delgado, Carmen M.; Moyano, Tomás C.; García-Calderón, Margarita; Canales, Javier; Gutiérrez, Rodrigo A.; Márquez, Antonio J.; Betti, Marco

    2016-01-01

    Nitrogen is one of the most important nutrients for plants and, in natural soils, its availability is often a major limiting factor for plant growth. Here we examine the effect of different forms of nitrogen nutrition and of photorespiration on gene expression in the model legume Lotus japonicus with the aim of identifying regulatory candidate genes co-ordinating primary nitrogen assimilation and photorespiration. The transcriptomic changes produced by the use of different nitrogen sources in leaves of L. japonicus plants combined with the transcriptomic changes produced in the same tissue by different photorespiratory conditions were examined. The results obtained provide novel information on the possible role of plastidic glutamine synthetase in the response to different nitrogen sources and in the C/N balance of L. japonicus plants. The use of gene co-expression networks establishes a clear relationship between photorespiration and primary nitrogen assimilation and identifies possible transcription factors connected to the genes of both routes. PMID:27117340

  14. Use of transcriptomics and co-expression networks to analyze the interconnections between nitrogen assimilation and photorespiratory metabolism.

    PubMed

    Pérez-Delgado, Carmen M; Moyano, Tomás C; García-Calderón, Margarita; Canales, Javier; Gutiérrez, Rodrigo A; Márquez, Antonio J; Betti, Marco

    2016-05-01

    Nitrogen is one of the most important nutrients for plants and, in natural soils, its availability is often a major limiting factor for plant growth. Here we examine the effect of different forms of nitrogen nutrition and of photorespiration on gene expression in the model legume Lotus japonicus with the aim of identifying regulatory candidate genes co-ordinating primary nitrogen assimilation and photorespiration. The transcriptomic changes produced by the use of different nitrogen sources in leaves of L. japonicus plants combined with the transcriptomic changes produced in the same tissue by different photorespiratory conditions were examined. The results obtained provide novel information on the possible role of plastidic glutamine synthetase in the response to different nitrogen sources and in the C/N balance of L. japonicus plants. The use of gene co-expression networks establishes a clear relationship between photorespiration and primary nitrogen assimilation and identifies possible transcription factors connected to the genes of both routes. PMID:27117340

  15. Co-expression of ferrochelatase allows for complete heme incorporation into recombinant proteins produced in E. coli

    PubMed Central

    Sudhamsu, Jawahar; Kabir, Mariam; Airola, Michael V.; Patel, Bhumit A.; Yeh, Syun-Ru; Rousseau, Dennis L.; Crane, Brian R.

    2010-01-01

    Over-expression of heme binding proteins in E. coli often results in sub-optimal heme incorporation and the amount of heme-bound protein produced usually varies with the protein of interest. Complete heme incorporation is important for biochemical characterization, spectroscopy, structural studies, and for the production of homogeneous commercial proteins with high activity. We have determined that recombinant proteins expressed in E. coli often contain less than a full complement of heme because they rather are partially incorporated with free-base porphyrin. Porphyrin-incorporated proteins have similar spectral characteristics as the desired heme-loaded targets, and thus are difficult to detect, even in purified samples. We present a straightforward and inexpensive solution to this problem that involves the co-expression of native ferrochelatase with the protein of interest. The method is shown to be effective for proteins that contain either Cys- or His- ligated hemes. PMID:20303407

  16. Assessing the Biological Significance of Gene Expression Signatures and Co-Expression Modules by Studying Their Network Properties

    PubMed Central

    Minguez, Pablo; Dopazo, Joaquin

    2011-01-01

    Microarray experiments have been extensively used to define signatures, which are sets of genes that can be considered markers of experimental conditions (typically diseases). Paradoxically, in spite of the apparent functional role that might be attributed to such gene sets, signatures do not seem to be reproducible across experiments. Given the close relationship between function and protein interaction, network properties can be used to study to what extent signatures are composed of genes whose resulting proteins show a considerable level of interaction (and consequently a putative common functional role). We have analysed 618 signatures and 507 modules of co-expression in cancer looking for significant values of four main protein-protein interaction (PPI) network parameters: connection degree, cluster coefficient, betweenness and number of components. A total of 3904 gene ontology (GO) modules, 146 KEGG pathways, and 263 Biocarta pathways have been used as functional modules of reference. Co-expression modules found in microarray experiments display a high level of connectivity, similar to the one shown by conventional modules based on functional definitions (GO, KEGG and Biocarta). A general observation for all the classes studied is that the networks formed by the modules improve their topological parameters when an external protein is allowed to be introduced within the paths (up to the 70% of GO modules show network parameters beyond the random expectation). This fact suggests that functional definitions are incomplete and some genes might still be missing. Conversely, signatures are clearly not capturing the altered functions in the corresponding studies. This is probably because the way in which the genes have been selected in the signatures is too conservative. These results suggest that gene selection methods which take into account relationships among genes should be superior to methods that assume independence among genes outside their functional

  17. Construction of individual, fused, and co-expressed proteins of endoglucanase and β-glucosidase for hydrolyzing sugarcane bagasse.

    PubMed

    Kurniasih, Sari Dewi; Alfi, Almasul; Natalia, Dessy; Radjasa, Ocky Karna; Nurachman, Zeily

    2014-01-01

    At least a combination of endoglucanase (EglII) and β-glucosidase (BglZ) is required for hydrolyzing crystalline cellulose. To understand the catalytic efficiency of combination enzymes for converting biomass to sugars, EglII and BglZ were constructed in the form of individual, fused as well as co-expression proteins, and their activities for hydrolyzing sugarcane bagasse were evaluated. The genes, eglII isolated from Bacillus amyloliquefaciens PSM3.1 earlier and bglZ from B. amyloliquefaciens ABBD, were expressed extracellularly in Bacillus megaterium MS941. EglII exhibited both exoglucanase and endoglucanase activities, and BglZ belonging to the glycoside hydrolase 1 family (GH 1) showed β-glucosidase activity. A combination of EglII and BglZ showed activity on substrates Avicel, CMC and sugarcane bagasse. Specifically for hydrolyzing sugarcane bagasse, fused protein (fus-EglII+BglZ), co-expression protein (coex-BglZ+EglII), and mixed-individual protein (mix-EglII+BglZ) produced cellobiose as the main product, along with a small amount of glucose. The amount of reducing sugars released from the hydrolyzing bleached sugarcane bagasse (BSB) using fus-EglII+BglZ and mix-EglII+BglZ was 2.7- and 4.2-fold higher, respectively, than steamed sugarcane bagasse (SSB), indicating the synergetic enzymes worked better on treated sugarcane bagasse. Compared with fus-EglII+BglZ and mix-EglII+BglZ, coex-BglZ+EglII released more mol reducing sugars from SSB, indicating the enzymes were potential for biomass conversion. Additionally, coex-BglZ+EglII acted on BSB 2.5-fold faster than fus-EglII+BglZ. Thus, coex-bglZ+eglII expression system was the best choice to produce enzymes for hydrolyzing sugarcane baggase. PMID:24598011

  18. Co-Expression of TWIST1 and ZEB2 in Oral Squamous Cell Carcinoma Is Associated with Poor Survival

    PubMed Central

    Kong, Yink Heay; Syed Zanaruddin, Sharifah Nurain; Lau, Shin Hin; Ramanathan, Anand; Kallarakkal, Thomas George; Vincent-Chong, Vui King; Wan Mustafa, Wan Mahadzir; Abraham, Mannil Thomas; Abdul Rahman, Zainal Ariff; Zain, Rosnah Binti; Cheong, Sok Ching

    2015-01-01

    Oral squamous cell carcinoma (OSCC) is an aggressive disease accounting for more than 260,000 cancer cases diagnosed and 128,000 deaths worldwide. A large majority of cancer deaths result from cancers that have metastasized beyond the primary tumor. The relationship between genetic changes and clinical outcome can reflect the biological events that promote cancer’s aggressive behavior, and these can serve as molecular markers for improved patient management and survival. To this end, epithelial-mesenchymal transition (EMT) is a major process that promotes tumor invasion and metastasis, making EMT-related proteins attractive diagnostic biomarkers and therapeutic targets. In this study, we used immunohistochemistry to study the expression of a panel of transcription factors (TWIST1, SNAI1/2, ZEB1 and ZEB2) and other genes intimately related to EMT (CDH1 and LAMC2) at the invasive tumor front of OSCC tissues. The association between the expression of these proteins and clinico-pathological parameters were examined with Pearson Chi-square and correlation with survival was analyzed using Kaplan Meier analysis. Our results demonstrate that there was a significant differential expression of CDH1, LAMC2, SNAI1/2 and TWIST1 between OSCC and normal oral mucosa (NOM). Specifically, CDH1 loss was significantly associated with Broder’s grading, while diffused LAMC2 was similarly associated with non-cohesive pattern of invasion. Notably, co-expression of TWIST1 and ZEB2 in OSCC was significantly associated with poorer overall survival, particularly in patients without detectable lymph node metastasis. This study demonstrates that EMT-related proteins are differentially expressed in OSCC and that the co-expression of TWIST1 and ZEB2 could be of clinical value in identifying patients with poor survival for appropriate patient management. PMID:26214683

  19. Improved 1, 2, 4-butanetriol production from an engineered Escherichia coli by co-expression of different chaperone proteins.

    PubMed

    Lu, Xinyao; He, Shuying; Zong, Hong; Song, Jian; Chen, Wen; Zhuge, Bin

    2016-09-01

    1, 2, 4-Butanetriol (BT) is a high-value non-natural chemical and has important applications in polymers, medical production and military industry. In the constructed BT biosynthesis pathway from xylose in Escherichia coli, the xylose dehydrogenase (Xdh) and the benzoylformate decarboxylase (MdlC) are heterologous enzymes and the activity of MdlC is the key limiting factor for BT production. In this study, six chaperone protein systems were introduced into the engineered E. coli harboring the recombinant BT pathway. The chaperone GroES-GroEL was beneficial to Xdh activity but had a negative effect on MdlC activity and BT titer. The plasmid pTf16 containing the tig gene (trigger factor) was beneficial to Xdh and MdlC activities and improved the BT titer from 0.42 to 0.56 g/l from 20 g/l xylose. However, co-expression of trigger factor and GroES-GroEL simultaneously reduced the activity of MdlC and had no effect on the BT production. The plasmid pKJE7 harboring dnaK-dnaJ-grpE showed significant negative effects on these enzyme activities and cell growth, leading to completely restrained the BT production. Similarly, co-expression of DnaKJ-GrpPE and GroES-GroEL simultaneously reduced Xdh and MdlC activities and decreased the BT titer by 45.2 %. The BT production of the engineered E. coli harboring pTf16 was further improved to the highest level at 1.01 g/l under pH control (pH 7). This work showed the potential application of chaperone proteins in microorganism engineering to get high production of target compounds as an effective and valuable tool. PMID:27430516

  20. Gene Co-Expression Network Analysis Provides Novel Insights into Myostatin Regulation at Three Different Mouse Developmental Timepoints

    PubMed Central

    Yang, Xuerong; Koltes, James E.; Park, Carissa A.; Chen, Daiwen; Reecy, James M.

    2015-01-01

    Myostatin (Mstn) knockout mice exhibit large increases in skeletal muscle mass. However, relatively few of the genes that mediate or modify MSTN effects are known. In this study, we performed co-expression network analysis using whole transcriptome microarray data from MSTN-null and wild-type mice to identify genes involved in important biological processes and pathways related to skeletal muscle and adipose development. Genes differentially expressed between wild-type and MSTN-null mice were further analyzed for shared DNA motifs using DREME. Differentially expressed genes were identified at 13.5 d.p.c. during primary myogenesis and at d35 during postnatal muscle development, but not at 17.5 d.p.c. during secondary myogenesis. In total, 283 and 2034 genes were differentially expressed at 13.5 d.p.c. and d35, respectively. Over-represented transcription factor binding sites in differentially expressed genes included SMAD3, SP1, ZFP187, and PLAGL1. The use of regulatory (RIF) and phenotypic (PIF) impact factor and differential hubbing co-expression analyses identified both known and potentially novel regulators of skeletal muscle growth, including Apobec2, Atp2a2, and Mmp13 at d35 and Sox2, Tmsb4x, and Vdac1 at 13.5 d.p.c. Among the genes with the highest PIF scores were many fiber type specifying genes. The use of RIF, PIF, and differential hubbing analyses identified both known and potentially novel regulators of muscle development. These results provide new details of how MSTN may mediate transcriptional regulation as well as insight into novel regulators of MSTN signal transduction that merit further study regarding their physiological roles in muscle and adipose development. PMID:25695797

  1. Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma.

    PubMed

    Skoda, Jan; Hermanova, Marketa; Loja, Tomas; Nemec, Pavel; Neradil, Jakub; Karasek, Petr; Veselska, Renata

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its dismal prognosis is often attributed to the presence of cancer stem cells (CSCs) that have been identified in PDAC using various markers. However, the co-expression of all of these markers has not yet been evaluated. Furthermore, studies that compare the expression levels of CSC markers in PDAC tumor samples and in cell lines derived directly from those tumors are lacking. Here, we analyzed the expression of putative CSC markers-CD24, CD44, epithelial cell adhesion molecule (EpCAM), CD133, and nestin-by immunofluorescence, flow cytometry and quantitative PCR in 3 PDAC-derived cell lines and by immunohistochemistry in 3 corresponding tumor samples. We showed high expression of the examined CSC markers among all of the cell lines and tumor samples, with the exception of CD24 and CD44, which were enriched under in vitro conditions compared with tumor tissues. The proportions of cells positive for the remaining markers were comparable to those detected in the corresponding tumors. Co-expression analysis using flow cytometry revealed that CD24+/CD44+/EpCAM+/CD133+ cells represented a significant population of the cells (range, 43 to 72%) among the cell lines. The highest proportion of CD24+/CD44+/EpCAM+/CD133+ cells was detected in the cell line derived from the tumor of a patient with the shortest survival. Using gene expression profiling, we further identified the specific pro-tumorigenic expression profile of this cell line compared with the profiles of the other two cell lines. Together, CD24+/CD44+/EpCAM+/CD133+ cells are present in PDAC cell lines derived from primary tumors, and their increased proportion corresponds with a pro-tumorigenic gene expression profile. PMID:27414409

  2. MGMT enrichment and second gene co-expression in hematopoietic progenitor cells using separate or dual-gene lentiviral vectors.

    PubMed

    Roth, Justin C; Alberti, Michael O; Ismail, Mourad; Lingas, Karen T; Reese, Jane S; Gerson, Stanton L

    2015-01-22

    The DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT) allows efficient in vivo enrichment of transduced hematopoietic stem cells (HSC). Thus, linking this selection strategy to therapeutic gene expression offers the potential to reconstitute diseased hematopoietic tissue with gene-corrected cells. However, different dual-gene expression vector strategies are limited by poor expression of one or both transgenes. To evaluate different co-expression strategies in the context of MGMT-mediated HSC enrichment, we compared selection and expression efficacies in cells cotransduced with separate single-gene MGMT and GFP lentivectors to those obtained with dual-gene vectors employing either encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) or foot and mouth disease virus (FMDV) 2A elements for co-expression strategies. Each strategy was evaluated in vitro and in vivo using equivalent multiplicities of infection (MOI) to transduce 5-fluorouracil (5-FU) or Lin(-)Sca-1(+)c-kit(+) (LSK)-enriched murine bone marrow cells (BMCs). The highest dual-gene expression (MGMT(+)GFP(+)) percentages were obtained with the FMDV-2A dual-gene vector, but half of the resulting gene products existed as fusion proteins. Following selection, dual-gene expression percentages in single-gene vector cotransduced and dual-gene vector transduced populations were similar. Equivalent MGMT expression levels were obtained with each strategy, but GFP expression levels derived from the IRES dual-gene vector were significantly lower. In mice, vector-insertion averages were similar among cells enriched after dual-gene vectors and those cotransduced with single-gene vectors. These data demonstrate the limitations and advantages of each strategy in the context of MGMT-mediated selection, and may provide insights into vector design with respect to a particular therapeutic gene or hematologic defect. PMID:25479595

  3. Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma

    PubMed Central

    Skoda, Jan; Hermanova, Marketa; Loja, Tomas; Nemec, Pavel; Neradil, Jakub; Karasek, Petr; Veselska, Renata

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its dismal prognosis is often attributed to the presence of cancer stem cells (CSCs) that have been identified in PDAC using various markers. However, the co-expression of all of these markers has not yet been evaluated. Furthermore, studies that compare the expression levels of CSC markers in PDAC tumor samples and in cell lines derived directly from those tumors are lacking. Here, we analyzed the expression of putative CSC markers—CD24, CD44, epithelial cell adhesion molecule (EpCAM), CD133, and nestin—by immunofluorescence, flow cytometry and quantitative PCR in 3 PDAC-derived cell lines and by immunohistochemistry in 3 corresponding tumor samples. We showed high expression of the examined CSC markers among all of the cell lines and tumor samples, with the exception of CD24 and CD44, which were enriched under in vitro conditions compared with tumor tissues. The proportions of cells positive for the remaining markers were comparable to those detected in the corresponding tumors. Co-expression analysis using flow cytometry revealed that CD24+/CD44+/EpCAM+/CD133+ cells represented a significant population of the cells (range, 43 to 72%) among the cell lines. The highest proportion of CD24+/CD44+/EpCAM+/CD133+ cells was detected in the cell line derived from the tumor of a patient with the shortest survival. Using gene expression profiling, we further identified the specific pro-tumorigenic expression profile of this cell line compared with the profiles of the other two cell lines. Together, CD24+/CD44+/EpCAM+/CD133+ cells are present in PDAC cell lines derived from primary tumors, and their increased proportion corresponds with a pro-tumorigenic gene expression profile. PMID:27414409

  4. City block distance and rough-fuzzy clustering for identification of co-expressed microRNAs.

    PubMed

    Paul, Sushmita; Maji, Pradipta

    2014-06-01

    The microRNAs or miRNAs are short, endogenous RNAs having ability to regulate mRNA expression at the post-transcriptional level. Various studies have revealed that miRNAs tend to cluster on chromosomes. The members of a cluster that are in close proximity on chromosomes are highly likely to be processed as co-transcribed units. Therefore, a large proportion of miRNAs are co-expressed. Expression profiling of miRNAs generates a huge volume of data. Complicated networks of miRNA-mRNA interaction increase the challenges of comprehending and interpreting the resulting mass of data. In this regard, this paper presents a clustering algorithm in order to extract meaningful information from miRNA expression data. It judiciously integrates the merits of rough sets, fuzzy sets, the c-means algorithm, and the normalized range-normalized city block distance to discover co-expressed miRNA clusters. While the membership functions of fuzzy sets enable efficient handling of overlapping partitions in a noisy environment, the concept of lower and upper approximations of rough sets deals with uncertainty, vagueness, and incompleteness in cluster definition. The city block distance is used to compute the membership functions of fuzzy sets and to find initial partition of a data set, and therefore helps to handle minute differences between two miRNA expression profiles. The effectiveness of the proposed approach, along with a comparison with other related methods, is demonstrated for several miRNA expression data sets using different cluster validity indices. Moreover, the gene ontology is used to analyze the functional consistency and biological significance of generated miRNA clusters. PMID:24682049

  5. Origin of Co-Expression Patterns in E.coli and S.cerevisiae Emerging from Reverse Engineering Algorithms

    PubMed Central

    Zampieri, Mattia; Soranzo, Nicola; Bianchini, Daniele; Altafini, Claudio

    2008-01-01

    Background The concept of reverse engineering a gene network, i.e., of inferring a genome-wide graph of putative gene-gene interactions from compendia of high throughput microarray data has been extensively used in the last few years to deduce/integrate/validate various types of “physical” networks of interactions among genes or gene products. Results This paper gives a comprehensive overview of which of these networks emerge significantly when reverse engineering large collections of gene expression data for two model organisms, E.coli and S.cerevisiae, without any prior information. For the first organism the pattern of co-expression is shown to reflect in fine detail both the operonal structure of the DNA and the regulatory effects exerted by the gene products when co-participating in a protein complex. For the second organism we find that direct transcriptional control (e.g., transcription factor–binding site interactions) has little statistical significance in comparison to the other regulatory mechanisms (such as co-sharing a protein complex, co-localization on a metabolic pathway or compartment), which are however resolved at a lower level of detail than in E.coli. Conclusion The gene co-expression patterns deduced from compendia of profiling experiments tend to unveil functional categories that are mainly associated to stable bindings rather than transient interactions. The inference power of this systematic analysis is substantially reduced when passing from E.coli to S.cerevisiae. This extensive analysis provides a way to describe the different complexity between the two organisms and discusses the critical limitations affecting this type of methodologies. PMID:18714358

  6. Cell-free Co-expression of Functional Membrane Proteins and Apolipoprotein, Forming Soluble Nanolipoprotein Particles*S⃞

    PubMed Central

    Cappuccio, Jenny A.; Blanchette, Craig D.; Sulchek, Todd A.; Arroyo, Erin S.; Kralj, Joel M.; Hinz, Angela K.; Kuhn, Edward A.; Chromy, Brett A.; Segelke, Brent W.; Rothschild, Kenneth J.; Fletcher, Julia E.; Katzen, Federico; Peterson, Todd C.; Kudlicki, Wieslaw A.; Bench, Graham; Hoeprich, Paul D.; Coleman, Matthew A.

    2008-01-01

    Here we demonstrate rapid production of solubilized and functional membrane protein by simultaneous cell-free expression of an apolipoprotein and a membrane protein in the presence of lipids, leading to the self-assembly of membrane protein-containing nanolipoprotein particles (NLPs). NLPs have shown great promise as a biotechnology platform for solubilizing and characterizing membrane proteins. However, current approaches are limited because they require extensive efforts to express, purify, and solubilize the membrane protein prior to insertion into NLPs. By the simple addition of a few constituents to cell-free extracts, we can produce membrane proteins in NLPs with considerably less effort. For this approach an integral membrane protein and an apolipoprotein scaffold are encoded by two DNA plasmids introduced into cell-free extracts along with lipids. For this study reported here we used plasmids encoding the bacteriorhodopsin (bR) membrane apoprotein and scaffold protein Δ1–49 apolipoprotein A-I fragment (Δ49A1). Cell free co-expression of the proteins encoded by these plasmids, in the presence of the cofactor all-trans-retinal and dimyristoylphosphatidylcholine, resulted in production of functional bR as demonstrated by a 5-nm shift in the absorption spectra upon light adaptation and characteristic time-resolved FT infrared difference spectra for the bR → M transition. Importantly the functional bR was solubilized in discoidal bR·NLPs as determined by atomic force microscopy. A survey study of other membrane proteins co-expressed with Δ49A1 scaffold protein also showed significantly increased solubility of all of the membrane proteins, indicating that this approach may provide a general method for expressing membrane proteins enabling further studies. PMID:18603642

  7. Liver cancer - hepatocellular carcinoma

    MedlinePlus

    Primary liver cell carcinoma; Tumor - liver; Cancer - liver; Hepatoma ... Hepatocellular carcinoma accounts for most liver cancers. This type of cancer occurs more often in men than women. It is usually diagnosed in people age 50 or older. Hepatocellular ...

  8. Liver cancer - hepatocellular carcinoma

    MedlinePlus

    Primary liver cell carcinoma; Tumor - liver; Cancer - liver; Hepatoma ... Hepatocellular carcinoma accounts for most liver cancers. This type of cancer occurs more often in men than women. It is usually diagnosed in people age 50 or older. ...

  9. Liver disease - resources

    MedlinePlus

    Resources - liver disease ... The following organizations are good resources for information on liver disease : American Liver Foundation -- www.liverfoundation.org Children's Liver Association for Support Services -- www.classkids.org Hepatitis ...

  10. Tests for Liver Cancer

    MedlinePlus

    ... cancer Next Topic Liver cancer stages Tests for liver cancer If you have some of the signs ... cancer has come back (recurred). Other blood tests Liver function tests (LFTs): Because liver cancer often develops ...

  11. Liver transplant - series (image)

    MedlinePlus

    The liver is in the right upper abdomen. The liver serves many functions, including the detoxification of substances delivered ... A liver transplant may be recommended for: liver damage due to alcoholism (Alcoholic cirrhosis) primary biliary cirrhosis long-term ( ...

  12. Mouse white adipocytes and 3T3-L1 cells display an anomalous pattern of carnitine palmitoyltransferase (CPT) I isoform expression during differentiation. Inter-tissue and inter-species expression of CPT I and CPT II enzymes.

    PubMed Central

    Brown, N F; Hill, J K; Esser, V; Kirkland, J L; Corkey, B E; Foster, D W; McGarry, J D

    1997-01-01

    The outer mitochondrial membrane enzyme carnitine palmitoyltransferase I (CPT I) represents the initial and regulated step in the beta-oxidation of fatty acids. It exists in at least two isoforms, denoted L (liver) and M (muscle) types, with very different kinetic properties and sensitivities to malonyl-CoA. Here we have examined the relative expression of the CPT I isoforms in two different models of adipocyte differentiation and in a number of rat tissues. Adipocytes from mice, hamsters and humans were also evaluated. Primary monolayer cultures of undifferentiated rat preadipocytes expressed solely L-CPT I, but significant levels of M-CPT I emerged after only 3 days of differentiation in vitro; in the mature cell M-CPT I predominated. In sharp contrast, the murine 3T3-L1 preadipocyte expressed essentially exclusively L-CPT I, both in the undifferentiated state and throughout the differentiation process in vitro. This was also true of the mature mouse white fat cell. Fully developed adipocytes from the hamster and human behaved similarly to those of the rat. Thus the mouse white fat cell differs fundamentally from those of the other species examined in terms of tis choice of a key regulatory enzyme in fatty acid metabolism. In contrast, brown adipose tissue from all three rodents displayed the same isoform profiles, each expressing overwhelmingly M-CPT I. Northern blot analysis of other rat tissues established L-CPT I as the dominant isoform not only in liver but also in kidney, lung, ovary, spleen, brain, intestine and pancreatic islets. In addition to its primacy in skeletal muscle, heart and fat, M-CPT I was also found to dominate the testis. The same inter-tissue isoform pattern (with the exception of white fat) was found in the mouse. Taken together, the data bring to light an intriguing divergence between white adipocytes of the mouse and other mammalian species. They also raise a cautionary note that should be considered in the choice of animal model used

  13. Autodisplay for the co-expression of lipase and foldase on the surface of E. coli: washing with designer bugs

    PubMed Central

    2014-01-01

    Background Lipases including the lipase from Burkholderia cepacia are in a main focus in biotechnology research since many years because of their manifold possibilities for application in industrial processes. The application of Burkholderia cepacia lipase for these processes appears complicated because of the need for support by a chaperone, the lipase specific foldase. Purification and reconstitution protocols therefore interfere with an economic implementation of such enzymes in industry. Autodisplay is a convenient method to express a variety of passenger proteins on the surface of E. coli. This method makes subsequent purification steps to obtain the protein of interest unnecessary. If enzymes are used as passengers, the corresponding cells can simply be applied as whole cell biocatalysts. Furthermore, enzymes surface displayed in this manner often acquire stabilization by anchoring within the outer membrane of E. coli. Results The lipase and its chaperone foldase from B. cepacia were co-expressed on the surface of E. coli via autodisplay. The whole cell biocatalyst obtained thereby exhibited an enzymatic activity of 2.73 mU mL-1 towards the substrate p-nitrophenyl palmitate when applied in an OD578 =1. Outer membrane fractions prepared from the same culture volume showed a lipase activity of 4.01 mU mL-1. The lipase-whole cell biocatalyst as well as outer membrane preparations thereof were used in a standardized laundry test, usually adopted to determine the power of washing agents. In this test, the lipase whole cell biocatalyst and the membrane preparation derived thereof exhibited the same lipolytic activity as the purified lipase from B. cepacia and a lipase preparation which is already applied in commercial washing agents. Conclusions Co-expression of both the lipase and its chaperone foldase on the surface of E. coli yields a lipid degrading whole cell biocatalyst. Therefore the chaperone supported folding process, absolutely required for the lipolytic

  14. Serotonin-2C and -2A Receptor Co-expression on Cells in the Rat Medial Prefrontal Cortex

    PubMed Central

    Nocjar, Christine; Alex, Katherine D; Sonneborn, Alex; Abbas, Atheir I; Roth, Bryan L; Pehek, Elizabeth A

    2015-01-01

    Neural function within the medial prefrontal cortex (mPFC) regulates normal cognition, attention and impulse control, implicating neuroregulatory abnormalities within this region in mental dysfunction related to schizophrenia, depression and drug abuse. Both serotonin -2A (5-HT2A) and -2C (5-HT2C) receptors are known to be important in neuropsychiatric drug action and are distributed throughout the mPFC. However, their interactive role in serotonergic cortical regulation is poorly understood. While the main signal transduction mechanism for both receptors is stimulation of phosphoinositide production, they can have opposite effects downstream. 5-HT2A versus 5-HT2C receptor activation oppositely regulates behavior and can oppositely affect neurochemical release within the mPFC. These distinct receptor effects could be caused by their differential cellular distribution within the cortex and/or other areas. It is known that both receptors are located on GABAergic and pyramidal cells within the mPFC, but it is not clear whether they are expressed on the same or different cells. The present work employed immunofluorescence with confocal microscopy to examine this in layers V-VI of the prelimbic mPFC. The majority of GABA cells in the deep prelimbic mPFC expressed 5-HT2C receptor immunoreactivity. Furthermore, most cells expressing 5-HT2C receptor immunoreactivity notably co-expressed 5-HT2A receptors. However, 27% of 5-HT2C receptor immunoreactive cells were not GABAergic, indicating that a population of prelimbic pyramidal projection cells could express the 5-HT2C receptor. Indeed, some cells with 5-HT2C and 5-HT2A receptor co-labeling had a pyramidal shape and were expressed in the typical layered fashion of pyramidal cells. This indirectly demonstrates that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells. Thus a

  15. ATTED-II: a database of co-expressed genes and cis elements for identifying co-regulated gene groups in Arabidopsis

    PubMed Central

    Obayashi, Takeshi; Kinoshita, Kengo; Nakai, Kenta; Shibaoka, Masayuki; Hayashi, Shinpei; Saeki, Motoshi; Shibata, Daisuke; Saito, Kazuki; Ohta, Hiroyuki

    2007-01-01

    Publicly available database of co-expressed gene sets would be a valuable tool for a wide variety of experimental designs, including targeting of genes for functional identification or for regulatory investigation. Here, we report the construction of an Arabidopsis thaliana trans-factor and cis-element prediction database (ATTED-II) that provides co-regulated gene relationships based on co-expressed genes deduced from microarray data and the predicted cis elements. ATTED-II () includes the following features: (i) lists and networks of co-expressed genes calculated from 58 publicly available experimental series, which are composed of 1388 GeneChip data in A.thaliana; (ii) prediction of cis-regulatory elements in the 200 bp region upstream of the transcription start site to predict co-regulated genes amongst the co-expressed genes; and (iii) visual representation of expression patterns for individual genes. ATTED-II can thus help researchers to clarify the function and regulation of particular genes and gene networks. PMID:17130150

  16. Correlated mRNAs and miRNAs from co-expression and regulatory networks affect porcine muscle and finally meat properties

    PubMed Central

    2013-01-01

    Background Physiological processes aiding the conversion of muscle to meat involve many genes associated with muscle structure and metabolic processes. MicroRNAs regulate networks of genes to orchestrate cellular functions, in turn regulating phenotypes. Results We applied weighted gene co-expression network analysis to identify co-expression modules that correlated to meat quality phenotypes and were highly enriched for genes involved in glucose metabolism, response to wounding, mitochondrial ribosome, mitochondrion, and extracellular matrix. Negative correlation of miRNA with mRNA and target prediction were used to select transcripts out of the modules of trait-associated mRNAs to further identify those genes that are correlated with post mortem traits. Conclusions Porcine muscle co-expression transcript networks that correlated to post mortem traits were identified. The integration of miRNA and mRNA expression analyses, as well as network analysis, enabled us to interpret the differentially-regulated genes from a systems perspective. Linking co-expression networks of transcripts and hierarchically organized pairs of miRNAs and mRNAs to meat properties yields new insight into several biological pathways underlying phenotype differences. These pathways may also be diagnostic for many myopathies, which are accompanied by deficient nutrient and oxygen supply of muscle fibers. PMID:23915301

  17. Differential Co-Expression between α-Synuclein and IFN-γ Signaling Genes across Development and in Parkinson’s Disease

    PubMed Central

    Liscovitch, Noa; French, Leon

    2014-01-01

    Expression patterns of the alpha-synuclein gene (SNCA) were studied across anatomy, development, and disease to better characterize its role in the brain. In this postmortem study, negative spatial co-expression between SNCA and 73 interferon-γ (IFN-γ) signaling genes was observed across many brain regions. Recent animal studies have demonstrated that IFN-γ induces loss of dopamine neurons and nigrostriatal degeneration. This opposing pattern between SNCA and IFN-γ signaling genes increases with age (rho = −0.78). In contrast, a meta-analysis of four microarray experiments representing 126 substantia nigra samples reveals a switch to positive co-expression in Parkinson’s disease (p<0.005). Use of genome-wide testing demonstrates this relationship is specific to SNCA (p<0.002). This change in co-expression suggests an immunomodulatory role of SNCA that may provide insight into neurodegeneration. Genes showing similar co-expression patterns have been previously linked to Alzheimer’s (ANK1) and Parkinson’s disease (UBE2E2, PCMT1, HPRT1 and RIT2). PMID:25493648

  18. Visual Display and Co-Expressivity as Students Strive for Intersubjectivity in a Spatial Reasoning Task. WCER Working Paper No. 2005-10

    ERIC Educational Resources Information Center

    Nathan, Mitchell J.; Eilam, Billie

    2005-01-01

    This paper explores the role of co-expressivity of drawing, speech, and gesture as sixth graders strive for intersubjectivity in their attempts to communicate solutions of a spatial reasoning task. Several obstacles to intersubjectivity are documented, particularly conflicts between a literal and geometric interpretation, limits of students'…

  19. Co-Expression of Bmi-1 and Podoplanin Predicts Overall Survival in Patients With Squamous Cell Carcinoma of the Head and Neck Treated With Radio(chemo)therapy

    SciTech Connect

    Vormittag, Laurenz; Thurnher, Dietmar; Geleff, Silvana; Pammer, Johannes; Heiduschka, Gregor; Brunner, Markus; Grasl, Matthaeus Ch.; Erovic, Boban M.

    2009-03-01

    Purpose: This study was conducted to determine the expression of Bmi-1 and podoplanin in healthy oral mucosa and in untreated tumor tissues samples of patients with squamous cell carcinomas of the head and neck. All patients were treated by primary radio(chemo)therapy. Methods and Materials: The expression of Bmi-1 and podoplanin was immunohistochemically evaluated in 12 normal oral mucosa and 63 tumor specimens and correlated with patients' clinical data. Results: In healthy mucosa expression of Bmi-1 and podoplanin was restricted to the basal cell layer. Expression of both proteins was found in 79% and 86% of our tumor samples, respectively. In 17 and 8 samples, Bmi-1 and podoplanin were co-expressed at the invasive border or diffuse in the bulk of the tumor, respectively. Univariate analysis showed that the co-expression of Bmi-1 and podoplanin correlated to decreased overall survival (p = 0.044). Moreover, multivariate testing identified high expression of podoplanin (p = 0.044), co-expression of Bmi-1 and podoplanin (p = 0.007) and lack of response to therapy (p < 0.0001) as predictors of shortened overall survival in patients treated with primary radio(chemo)therapy. Conclusions: Bmi-1 and podoplanin are expressed at the invasive front of squamous cell carcinomas of the head and neck. Co-expression of Bmi-1 and podoplanin predicts significantly overall survival of patients treated with primary radio(chemo)therapy.

  20. Long-term safety and stability of angiogenesis induced by balanced single-vector co-expression of PDGF-BB and VEGF164 in skeletal muscle

    PubMed Central

    Gianni-Barrera, Roberto; Burger, Maximilian; Wolff, Thomas; Heberer, Michael; Schaefer, Dirk J.; Gürke, Lorenz; Mujagic, Edin; Banfi, Andrea

    2016-01-01

    Therapeutic angiogenesis by growth factor delivery is an attractive treatment strategy for ischemic diseases, yet clinical efficacy has been elusive. The angiogenic master regulator VEGF-A can induce aberrant angiogenesis if expressed above a threshold level. Since VEGF remains localized in the matrix around expressing cells, homogeneous dose distribution in target tissues is required, which is challenging. We found that co-expression of the pericyte-recruiting factor PDGF-BB at a fixed ratio with VEGF from a single bicistronic vector ensured normal angiogenesis despite heterogeneous high VEGF levels. Taking advantage of a highly controlled gene delivery platform, based on monoclonal populations of transduced myoblasts, in which every cell stably produces the same amount of each factor, here we rigorously investigated a) the dose-dependent effects, and b) the long-term safety and stability of VEGF and PDGF-BB co-expression in skeletal muscle. PDGF-BB co-expression did not affect the normal angiogenesis by low and medium VEGF doses, but specifically prevented vascular tumors by high VEGF, yielding instead normal and mature capillary networks, accompanied by robust arteriole formation. Induced angiogenesis persisted unchanged up to 4 months, while no tumors appeared. Therefore, PDGF-BB co-expression is an attractive strategy to improve safety and efficacy of therapeutic angiogenesis by VEGF gene delivery. PMID:26882992

  1. Co-expression of xerophyte Zygophyllum xanthoxylum ZxNHX and ZxVP1-1 confers enhanced salinity tolerance in chimeric sugar beet (Beta vulgaris L.).

    PubMed

    Wu, Guo-Qiang; Feng, Rui-Jun; Wang, Suo-Min; Wang, Chun-Mei; Bao, Ai-Ke; Wei, Li; Yuan, Hui-Jun

    2015-01-01

    Salinity is one of the major abiotic stresses that limit the growth and productivity of sugar beet (Beta vulgaris L.). To improve sugar beet's salinity tolerance, the ZxNHX and ZxVP1-1 genes encoding tonoplast Na(+)/H(+) antiporter and H(+)-PPase from xerophyte Zygophyllum xanthoxylum were co-expressed by Agrobacterium tumefaciens-mediated transformation. It is showed here that co-expression of ZxNHX and ZxVP1-1 confers enhanced salinity tolerance to the transformed sugar beet plants compared with the wild-type (WT) plants. The chimeric plants grew well in the presence of high salinity (400 mM NaCl), whereas WT plants displayed chlorosis and died within 8 days. Compared to WT plants, the chimeric plants co-expressing ZxNHX and ZxVP1-1 accumulated more proline, Na(+) and K(+) in their leaves and petioles when exposed to high salinity, which caused lower solute potential, retained more water and thus subjected to lesser cell membrane damage. Interestingly, the chimeric plants accumulated higher sucrose, glucose and fructose contents in their storage roots than WT plants in the absence or presence of high salinity. Our results suggested that co-expression of ZxNHX and ZxVP1-1 improved the osmoregulatory capacity in chimeric sugar beet through increased compartmentalization of ions into the vacuoles by enhancing the activity of proton pumps and thus mitigated Na(+)-toxicity for plants. PMID:26284097

  2. Co-expression of perforin and granzyme B genes induces apoptosis and inhibits the tumorigenicity of laryngeal cancer cell line Hep-2

    PubMed Central

    Li, Xiu-Ying; Li, Zhi; An, Gui-Jie; Liu, Sha; Lai, Yan-Dong

    2014-01-01

    Granzyme B and perforin, two of the most important components, have shown anticancer properties in various cancers, but their effects in laryngeal cancer remain unexplored. Here we decided to examine the effects of Granzyme B and perforin in Hep-2 cells and clarify the role of perforin and granzyme B in the tumorigenicity of laryngeal cancer cell line. Hep-2 cells were transfected with pVAX1-PIG co-expression vector (comprising perforin and granzyme B genes), and then the growth and apoptosis of these Hep-2 cells were evaluated. The tumorigenicity of Hep-2 cell line co-expressing perforin and granzyme B genes was tested in BALB/c nu/nu mice. We found that the co-expression of perforin and granzyme B genes could obviously inhibit cell focus formation and induce cell apoptosis in Hep-2 cells. Furthermore, after subcutaneous injection of Hep-2 cells transfected with pVAX1-PIG, an extensive delay in tumor growth was observed in BALB/c-nu/nu mice. Moreover, our studies demonstrated that the anticancer activity of perforin and granzyme B was sustainable in vivo as tumor development by inducing cell apoptosis. Taken together, our data indicate that the co-expression of perforin and granzyme B genes exhibits anticancer potential, and hopefully provide potential therapeutic applications in laryngeal cancer. PMID:24696715

  3. Co-expression networks revealed potential core lncRNAs in the triple-negative breast cancer.

    PubMed

    Yang, Fan; Liu, Ye-Huan; Dong, Si-Yang; Yao, Zhi-Han; Lv, Lin; Ma, Rui-Min; Dai, Xuan-Xuan; Wang, Jiao; Zhang, Xiao-Hua; Wang, Ou-Chen

    2016-10-15

    Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with unfavorable outcome. It is urgent to explore novel biomarkers and potential therapeutic targets in this malignancy. Increasing knowledge of long noncoding RNAs (lncRNAs) significantly deepens our understanding of cancer biology. Here, we sequenced eight paired TNBC tumor tissues and non-cancerous tissues, and validated significantly differentially expressed lncRNAs. Gene ontology (GO) and pathway analysis were used to investigate the function of differentially expressed mRNAs. Further, potential core lncRNAs in TNBC were identified by co-expression networks. Kaplan-Meier analysis also indicated that breast cancer patients with lower expression level of rhabdomyosarcoma 2 associated transcript (RMST), one of the potential core lncRNAs, had worse overall survival. To the best of our knowledge, it was the first report that RMST was involved in breast cancer. Our research provided a rich resource to the research community for further investigating lncRNAs functions and identifying lncRNAs with diagnostic and therapeutic potentials in TNBC. PMID:27380926

  4. Co-expression of protein tyrosine kinases EGFR-2 and PDGFRβ with protein tyrosine phosphatase 1B in Pichia pastoris.

    PubMed

    Tu, Pham Ngoc; Wang, Yamin; Cai, Menghao; Zhou, Xiangshan; Zhang, Yuanxing

    2014-02-28

    The regulation of protein tyrosine phosphorylation is mediated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) and is essential for cellular homeostasis. Coexpression of PTKs with PTPs in Pichia pastoris was used to facilitate the expression of active PTKs by neutralizing their apparent toxicity to cells. In this study, the gene encoding phosphatase PTP1B with or without a blue fluorescent protein or peroxisomal targeting signal 1 was cloned into the expression vector pAG32 to produce four vectors. These vectors were subsequently transformed into P. pastoris GS115. The tyrosine kinases EGFR-2 and PDGFRβ were expressed from vector pPIC3.5K and were fused with a His-tag and green fluorescent protein at the N-terminus. The two plasmids were transformed into P. pastoris with or without PTP1B, resulting in 10 strains. The EGFR-2 and PDGFRβ fusion proteins were purified by Ni(2+) affinity chromatography. In the recombinant P. pastoris, the PTKs co-expressed with PTP1B exhibited higher kinase catalytic activity than did those expressing the PTKs alone. The highest activities were achieved by targeting the PTKs and PTP1B into peroxisomes. Therefore, the EGFR-2 and PDGFRβ fusion proteins expressed in P. pastoris may be attractive drug screening targets for anticancer therapeutics. PMID:24248091

  5. A genome-wide cis-regulatory element discovery method based on promoter sequences and gene co-expression networks

    PubMed Central

    2013-01-01

    Background Deciphering cis-regulatory networks has become an attractive yet challenging task. This paper presents a simple method for cis-regulatory network discovery which aims to avoid some of the common problems of previous approaches. Results Using promoter sequences and gene expression profiles as input, rather than clustering the genes by the expression data, our method utilizes co-expression neighborhood information for each individual gene, thereby overcoming the disadvantages of current clustering based models which may miss specific information for individual genes. In addition, rather than using a motif database as an input, it implements a simple motif count table for each enumerated k-mer for each gene promoter sequence. Thus, it can be used for species where previous knowledge of cis-regulatory motifs is unknown and has the potential to discover new transcription factor binding sites. Applications on Saccharomyces cerevisiae and Arabidopsis have shown that our method has a good prediction accuracy and outperforms a phylogenetic footprinting approach. Furthermore, the top ranked gene-motif regulatory clusters are evidently functionally co-regulated, and the regulatory relationships between the motifs and the enriched biological functions can often be confirmed by literature. Conclusions Since this method is simple and gene-specific, it can be readily utilized for insufficiently studied species or flexibly used as an additional step or data source for previous transcription regulatory networks discovery models. PMID:23368633

  6. Co-expression of Dorsal and Rel2 Negatively Regulates Antimicrobial Peptide Expression in the Tobacco Hornworm Manduca sexta

    PubMed Central

    Zhong, Xue; Rao, Xiang-Jun; Yi, Hui-Yu; Lin, Xin-Yu; Huang, Xiao-Hong; Yu, Xiao-Qiang

    2016-01-01

    Nuclear factor κB (NF-κB) plays an essential role in regulation of innate immunity. In mammals, NF-κB factors can form homodimers and heterodimers to activate gene expression. In insects, three NF-κB factors, Dorsal, Dif and Relish, have been identified to activate antimicrobial peptide (AMP) gene expression. However, it is not clear whether Dorsal (or Dif) and Relish can form heterodimers. Here we report the identification and functional analysis of a Dorsal homologue (MsDorsal) and two Relish short isoforms (MsRel2A and MsRel2B) from the tobacco hornworm, Manduca sexta. Both MsRel2A and MsRel2B contain only a Rel homology domain (RHD) and lack the ankyrin-repeat inhibitory domain. Overexpression of the RHD domains of MsDorsal and MsRel2 in Drosophila melanogaster S2 and Spodoptera frugiperda Sf9 cells can activate AMP gene promoters from M. sexta and D. melanogaster. We for the first time confirmed the interaction between MsDorsal-RHD and MsRel2-RHD, and suggesting that Dorsal and Rel2 may form heterodimers. More importantly, co-expression of MsDorsal-RHD with MsRel2-RHD suppressed activation of several M. sexta AMP gene promoters. Our results suggest that the short MsRel2 isoforms may form heterodimers with MsDorsal as a novel mechanism to prevent over-activation of antimicrobial peptides. PMID:26847920

  7. In planta production of the highly potent resveratrol analogue pterostilbene via stilbene synthase and O-methyltransferase co-expression

    SciTech Connect

    Rimando A. M.; Liu C.; Pan, Z.; Polashock, J. J.; Dayan, F. E., Mizuno, C. S.; Snook, M. E.; Baerson, S. R.

    2012-04-01

    Resveratrol and related stilbenes are thought to play important roles in defence responses in several plant species and have also generated considerable interest as nutraceuticals owing to their diverse health-promoting properties. Pterostilbene, a 3,5-dimethylether derivative of resveratrol, possesses properties similar to its parent compound and, additionally, exhibits significantly higher fungicidal activity in vitro and superior pharmacokinetic properties in vivo. Recombinant enzyme studies carried out using a previously characterized O-methyltransferase sequence from Sorghum bicolor (SbOMT3) demonstrated its ability to catalyse the A ring-specific 3,5-bis-O-methylation of resveratrol, yielding pterostilbene. A binary vector was constructed for the constitutive co-expression of SbOMT3 with a stilbene synthase sequence from peanut (AhSTS3) and used for the generation of stably transformed tobacco and Arabidopsis plants, resulting in the accumulation of pterostilbene in both species. A reduced floral pigmentation phenotype observed in multiple tobacco transformants was further investigated by reversed-phase HPLC analysis, revealing substantial decreases in both dihydroquercetin-derived flavonoids and phenylpropanoid-conjugated polyamines in pterostilbene-producing SbOMT3/AhSTS3 events. These results demonstrate the potential utility of this strategy for the generation of pterostilbene-producing crops and also underscore the need for the development of additional approaches for minimizing concomitant reductions in key phenylpropanoid-derived metabolites.

  8. Co-Expression of Two Subtypes of Melatonin Receptor on Rat M1-Type Intrinsically Photosensitive Retinal Ganglion Cells

    PubMed Central

    Sheng, Wen-Long; Chen, Wei-Yi; Yang, Xiong-Li; Zhong, Yong-Mei; Weng, Shi-Jun

    2015-01-01

    Intrinsically photosensitive retinal ganglion cells (ipRGCs) are involved in circadian and other non-image forming visual responses. An open question is whether the activity of these neurons may also be under the regulation mediated by the neurohormone melatonin. In the present work, by double-staining immunohistochemical technique, we studied the expression of MT1 and MT2, two known subtypes of mammalian melatonin receptors, in rat ipRGCs. A single subset of retinal ganglion cells labeled by the specific antibody against melanopsin exhibited the morphology typical of M1-type ipRGCs. Immunoreactivity for both MT1 and MT2 receptors was clearly seen in the cytoplasm of all labeled ipRGCs, indicating that these two receptors were co-expressed in each of these neurons. Furthermore, labeling for both the receptors were found in neonatal M1 cells as early as the day of birth. It is therefore highly plausible that retinal melatonin may directly modulate the activity of ipRGCs, thus regulating non-image forming visual functions. PMID:25714375

  9. Identification of hub genes of pneumocyte senescence induced by thoracic irradiation using weighted gene co-expression network analysis

    PubMed Central

    XING, YONGHUA; ZHANG, JUNLING; LU, LU; LI, DEGUAN; WANG, YUEYING; HUANG, SONG; LI, CHENGCHENG; ZHANG, ZHUBO; LI, JIANGUO; MENG, AIMIN

    2016-01-01

    Irradiation commonly causes pneumocyte senescence, which may lead to severe fatal lung injury characterized by pulmonary dysfunction and respiratory failure. However, the molecular mechanism underlying the induction of pneumocyte senescence by irradiation remains to be elucidated. In the present study, weighted gene co-expression network analysis (WGCNA) was used to screen for differentially expressed genes, and to identify the hub genes and gene modules, which may be critical for senescence. A total of 2,916 differentially expressed genes were identified between the senescence and non-senescence groups following thoracic irradiation. In total, 10 gene modules associated with cell senescence were detected, and six hub genes were identified, including B-cell scaffold protein with ankyrin repeats 1, translocase of outer mitochondrial membrane 70 homolog A, actin filament-associated protein 1, Cd84, Nuf2 and nuclear factor erythroid 2. These genes were markedly associated with cell proliferation, cell division and cell cycle arrest. The results of the present study demonstrated that WGCNA of microarray data may provide further insight into the molecular mechanism underlying pneumocyte senescence. PMID:26572216

  10. Enhancement of succinate production by metabolically engineered Escherichia coli with co-expression of nicotinic acid phosphoribosyltransferase and pyruvate carboxylase.

    PubMed

    Ma, Jiangfeng; Gou, Dongmei; Liang, Liya; Liu, Rongming; Chen, Xu; Zhang, Changqing; Zhang, Jiuhua; Chen, Kequan; Jiang, Min

    2013-08-01

    Escherichia coli BA002, in which the ldhA and pflB genes are deleted, cannot utilize glucose anaerobically due to the inability to regenerate NAD(+). To restore glucose utilization, overexpression of nicotinic acid phosphoribosyltransferase (NAPRTase) encoded by the pncB gene, a rate-limiting enzyme of NAD(H) synthesis pathway, resulted in a significant increase in cell mass and succinate production under anaerobic conditions. However, a high concentration of pyruvate accumulated. Thus, co-expression of NAPRTase and the heterologous pyruvate carboxylase (PYC) of Lactococcus lactis subsp. cremoris NZ9000 in recombinant E. coli BA016 was investigated. The total concentration of NAD(H) was 9.8-fold higher in BA016 than in BA002, and the NADH/NAD(+) ratio decreased from 0.60 to 0.04. Under anaerobic conditions, BA016 consumed 17.50 g l(-1) glucose and produced 14.08 g l(-1) succinate with a small quantity of pyruvate. Furthermore, when the reducing agent dithiothreitol or reduced carbon source sorbitol was added, the cell growth and carbon source consumption rate of BA016 was reasonably enhanced and succinate productivity increased. PMID:23740313

  11. Methyl green and nitrotetrazolium blue chloride co-expression in colon tissue: A hyperspectral microscopic imaging analysis

    NASA Astrophysics Data System (ADS)

    Li, Qingli; Liu, Hongying; Wang, Yiting; Sun, Zhen; Guo, Fangmin; Zhu, Jianzhong

    2014-12-01

    Histological observation of dual-stained colon sections is usually performed by visual observation under a light microscope, or by viewing on a computer screen with the assistance of image processing software in both research and clinical settings. These traditional methods are usually not sufficient to reliably differentiate spatially overlapping chromogens generated by different dyes. Hyperspectral microscopic imaging technology offers a solution for these constraints as the hyperspectral microscopic images contain information that allows differentiation between spatially co-located chromogens with similar but different spectra. In this paper, a hyperspectral microscopic imaging (HMI) system is used to identify methyl green and nitrotetrazolium blue chloride in dual-stained colon sections. Hyperspectral microscopic images are captured and the normalized score algorithm is proposed to identify the stains and generate the co-expression results. Experimental results show that the proposed normalized score algorithm can generate more accurate co-localization results than the spectral angle mapper algorithm. The hyperspectral microscopic imaging technology can enhance the visualization of dual-stained colon sections, improve the contrast and legibility of each stain using their spectral signatures, which is helpful for pathologist performing histological analyses.

  12. Co-expression of G2-EPSPS and glyphosate acetyltransferase GAT genes conferring high tolerance to glyphosate in soybean

    PubMed Central

    Guo, Bingfu; Guo, Yong; Hong, Huilong; Jin, Longguo; Zhang, Lijuan; Chang, Ru-Zhen; Lu, Wei; Lin, Min; Qiu, Li-Juan

    2015-01-01

    Glyphosate is a widely used non-selective herbicide with broad spectrum of weed control around the world. At present, most of the commercial glyphosate tolerant soybeans utilize glyphosate tolerant gene CP4-EPSPS or glyphosate acetyltransferase gene GAT separately. In this study, both glyphosate tolerant gene G2-EPSPS and glyphosate degraded gene GAT were co-transferred into soybean and transgenic plants showed high tolerance to glyphosate. Molecular analysis including PCR, Sothern blot, qRT-PCR, and Western blot revealed that target genes have been integrated into genome and expressed effectively at both mRNA and protein levels. Furthermore, the glyphosate tolerance analysis showed that no typical symptom was observed when compared with a glyphosate tolerant line HJ06-698 derived from GR1 transgenic soybean even at fourfold labeled rate of Roundup. Chlorophyll and shikimic acid content analysis of transgenic plant also revealed that these two indexes were not significantly altered after glyphosate application. These results indicated that co-expression of G2-EPSPS and GAT conferred high tolerance to the herbicide glyphosate in soybean. Therefore, combination of tolerant and degraded genes provides a new strategy for developing glyphosate tolerant transgenic crops. PMID:26528311

  13. Enhancement of heavy metal accumulation by tissue specific co-expression of iaaM and ACC deaminase genes in plants.

    PubMed

    Zhang, Yong; Zhao, Lihong; Wang, Yao; Yang, Baoyu; Chen, Shiyun

    2008-06-01

    1-Aminocyclopropane deaminase (ACC) and tryptophan monooxygenase are two enzymes involved in plant senescence-inhibiting and growth-promoting regulation, respectively. In this study, two binary vectors were constructed in which the Agrobacterium iaaM gene was under the transcriptional control of a xylem-specific glycine-rich protein promoter alone, or co-expressed with the bacterial ACC deaminase gene, which was driven by the constitutive CaMV 35S promoter. Transgenic petunia shoots co-expressing both genes were able to root on medium supplemented with 7.5 mg l(-1) CoCl2. When T1 transgenic tobacco plants were grown in sand supplemented with Cu2+ and Co2+, tissue specific co-expression of both iaaM and ACC deaminase genes showed faster growth with larger biomass with a more extensive root system, and accumulated a greater amount of heavy metals than the empty vector control plants. When T1 transgenic tobacco plants were grown in soil watered with different concentrations of CuSO4, xylem specific expression of the iaaM gene caused the accumulation of more Cu2+ than the empty vector control at lower CuSO4 concentrations, but showed severe toxic symptoms at concentration of 100 mg l(-1) CuSO4. T1 transgenic plants co-expressing both genes accumulated more heavy metals into the plant shoots and can tolerate CuSO4 at 150 mg l(-1). In addition, plants co-expressing these two genes can grow well in a complex contaminated soil containing both inorganic and organic pollutants, while the growth of the control plants was greatly inhibited. PMID:18471863

  14. Pharmacological rescue of hERG currents carried out by G604S and wide type hERG co-expression.

    PubMed

    Huo, Jianhua; Zhang, Aifeng; Guo, Xueyan; Qiang, Hua; Liu, Ping; Bai, Ling; Ma, Aiqun

    2016-09-01

    Mutations in human ether-a-go-go-related gene (hERG) can lead to type 2 long-QT syndrome (LQT2). The authors previously identified the hERG mutation G604S results in a loss of function and obviously decreased current amplitude and impaired channel protein trafficking when co-expressed with WT-hERG. The present study further investigates the biological and electrophysiological consequences of pharmacologic chaperones in HEK293 cells expressing G604S-hERG or co-expressing G604S-hERG and WT-hERG. It was found that a low temperature (27°C), thapsigargin, NS1643 and E-4031 fail to rescue the G604S mutation. Interestingly, only E-4031 treatment resulted in a significant increase in hERG currents in cells co-expressing G604S-hERG and WT-hERG, correspondingly more mature protein band at 155 kDa by Western blotting and an increased membrane staining by confocal microscopy. In addition, E-4031 treatment shifted the steady-state half maximal activation voltage (V1/2 ) of the inactivation curve by +8 mV in cells co-expressing G604S-hERG and WT-hERG. The present experimental results suggest that a G604S mutation is resistant to pharmacological rescue. E-4031 treatment resulted in a significant increase in hERG currents by promoting the hERG channel processing and trafficking in cells co-expressing G604S-hERG and WT-hERG. PMID:27199074

  15. The murine VpreB1 and VpreB2 genes both encode a protein of the surrogate light chain and are co-expressed during B cell development.

    PubMed

    Dul, J L; Argon, Y; Winkler, T; ten Boekel, E; Melchers, F; Mårtensson, I L

    1996-04-01

    The surrogate light chain is composed of two polypeptides, VpreB and lambda 5. In the mouse there are two VpreB genes which are 99% identical within the coding regions. Extensive restriction enzyme mapping and sequencing of these two genes showed that only the coding region and immediate 5' and 3' flanking sequences exhibited such high homology. More distal sequences have diverged considerably. The region 5' of the respective gene directed transcription of a reporter gene in a pre-B cell line, indicating that it contained promoter, and perhaps enhancer function. The VpreB2 gene is functional, as it directed the production in COS cells of a 16-kDa protein that assembled with lambda 5 and was recognized by a VpreB-specific monoclonal antibody. Using transfected COS cells expressing either VpreB1 or VpreB2, a PCR assay was developed to examine the steady state level of transcripts from each gene. When this assay was applied to a number of cell lines representing early stages of B cell differentiation, co-expression of the two genes was observed in every case. VpreB1 and VpreB2 were co-expressed in the fetal liver of CB17 mice, where peak expression of each gene occurred at days 16-17 of gestation. Similarly, adult bone marrow from several strains of mice expressed both genes. In sorted bone marrow cells expression of both VpreB genes was detected in pro-B/pre-BI and large pre-BII cells, while the RNA steady state levels were at least 100-fold lower in small pre-BII and immature/mature B cells. Finally, single-cell reverse transcriptase-polymerase chain reaction on such sorted bone marrow cells detected VpreB1 and VpreB2 expression in at least 30% of all pro-B/pre-BI cells and large Ig heavy chain, surrogate light chain (pre-B receptor) expressing pre-BII cells. These results demonstrate that the control of expression of the two VpreB genes overlaps during development. They suggest that both VpreB1 and VpreB2 polypeptides can assemble with lambda 5 and mu to form pre

  16. Transcriptional networks implicated in human nonalcoholic fatty liver disease.

    PubMed

    Ye, Hua; Liu, Wei

    2015-10-01

    The transcriptome of nonalcoholic fatty liver disease (NAFLD) was investigated in several studies. However, the implications of transcriptional networks in progressive NAFLD are not clear and mechanisms inducing transition from nonalcoholic simple fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) are still elusive. The aims of this study were to (1) construct networks for progressive NAFLD, (2) identify hub genes and functional modules in these networks and (3) infer potential linkages among hub genes, transcription factors and microRNAs (miRNA) for NAFLD progression. A systems biology approach by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA) was utilized to dissect transcriptional profiles in 19 normal, 10 NAFL and 16 NASH patients. Based on this framework, 3 modules related to chromosome organization, proteasomal ubiquitin-dependent protein degradation and immune response were identified in NASH network. Furthermore, 9 modules of co-expressed genes associated with NAFL/NASH transition were found. Further characterization of these modules defined 13 highly connected hub genes in NAFLD progression network. Interestingly, 11 significantly changed miRNAs were predicted to target 10 of the 13 hub genes. Characterization of modules and hub genes that may be regulated by miRNAs could facilitate the identification of candidate genes and pathways responsible for NAFL/NASH transition and lead to a better understanding of NAFLD pathogenesis. The identified modules and hub genes may point to potential targets for therapeutic interventions. PMID:25851235

  17. Gamma-Retroviral Vector Design for the Co-Expression of Artificial microRNAs and Therapeutic Proteins

    PubMed Central

    Park, Tristen S.; Zhang, Ling; Zheng, Zhili; Morgan, Richard A.

    2014-01-01

    To generate γ-retroviral vectors for stable conjoint expression of artificial microRNAs (amiR) and therapeutic genes in primary human lymphocytes, and to identify the design parameters that are key for successful vector generation. Gamma-retroviral vectors were designed to co-express both amiRs and a linked reporter gene, truncated CD34 (tCD34). Artificial miRs based on microRNAs miR-16, miR-142, miR-146b, miR-150, miR155, and miR-223 were inserted into sites within the intron of the vector and tested for tCD34 expression by flow cytometry (FACS). Different constructs were assembled with amiRs targeted to knockdown expression of suppressor of cytokine signaling 1 (SOCS1) or programmed cell death 1 (PDCD1, PD-1). Three of the six amiRs maintained tCD34 expression. Expansion of primary human T cells transduced with these amiR vectors, as well as transgene expression, were equivalent to control engineered T cells over a 40-day period. Knockdown of SOCS1 RNA and PD-1 expression by FACS was shown to vary between constructs, dependent on either the specific short interfering RNA sequence used in the amiR, or the microRNA backbone and location in the vector intron. Gamma-retroviral vectors that both efficiently knockdown endogenous gene expression and maintain linked transgene production can be produced, but empirical vector evaluations were best suited for optimal construct analysis. PMID:25019196

  18. Co-expression of phosphoenolpyruvate carboxykinase and nicotinic acid phosphoribosyltransferase for succinate production in engineered Escherichia coli.

    PubMed

    Jiang, Min; Chen, Xu; Liang, Liya; Liu, Rongming; Wan, Qing; Wu, Mingke; Zhang, Hanwen; Ma, Jiangfeng; Chen, Kequan; Ouyang, Pingkai

    2014-03-01

    Succinate is not the dominant fermentation product from xylose in wild-type Escherichia coli K12. E. coli BA 203 is a lactate dehydrogenase (ldhA), pyruvate formate lyase (pflB), and phosphoenolpyruvate (PEP)-carboxylase (ppc) deletion strain. To increase succinate accumulation and reduce byproduct formation, engineered E. coli BA204, in which ATP-forming PEP-carboxykinase (PEPCK) is overexpressed in BA203, was constructed and produced 2.17-fold higher succinate yield. To further improve the biomass and the consumption rate of xylose, nicotinic acid phosphoribosyltransferase (NAPRTase), a rate limiting enzyme in the synthesis of NAD(H), was also overexpressed. Thus, co-expression of PEPCK and NAPRTase in recombinant E. coli BA209 was investigated. In BA209, the pck gene and the pncB gene each have a trc promoter, hence, both genes are well expressed. During a 72-h anaerobic fermentation in sealed bottles, the total concentration of NAD(H) in BA209 was 1.25-fold higher than that in BA204, and the NADH/NAD+ ratio decreased from 0.28 to 0.11. During the exclusively anaerobic fermentation in a 3-L bioreactor, BA209 consumed 17.1 g L⁻¹ xylose and produced 15.5 g L⁻¹ succinate. Furthermore, anaerobic fermentation of corn stalk hydrolysate contained 30.1 g L⁻¹ xylose, 2.1 g L⁻¹ glucose and 1.5 g L⁻¹ arabinose, it produced a final succinate concentration of 17.2 g L⁻¹ with a yield of 0.94 g g⁻¹ total sugars. PMID:24564896

  19. Mining Temporal Protein Complex Based on the Dynamic PIN Weighted with Connected Affinity and Gene Co-Expression

    PubMed Central

    Shen, Xianjun; Jiang, Xingpeng; He, Tingting; Hu, Xiaohua; Yang, Jincai

    2016-01-01

    The identification of temporal protein complexes would make great contribution to our knowledge of the dynamic organization characteristics in protein interaction networks (PINs). Recent studies have focused on integrating gene expression data into static PIN to construct dynamic PIN which reveals the dynamic evolutionary procedure of protein interactions, but they fail in practice for recognizing the active time points of proteins with low or high expression levels. We construct a Time-Evolving PIN (TEPIN) with a novel method called Deviation Degree, which is designed to identify the active time points of proteins based on the deviation degree of their own expression values. Owing to the differences between protein interactions, moreover, we weight TEPIN with connected affinity and gene co-expression to quantify the degree of these interactions. To validate the efficiencies of our methods, ClusterONE, CAMSE and MCL algorithms are applied on the TEPIN, DPIN (a dynamic PIN constructed with state-of-the-art three-sigma method) and SPIN (the original static PIN) to detect temporal protein complexes. Each algorithm on our TEPIN outperforms that on other networks in terms of match degree, sensitivity, specificity, F-measure and function enrichment etc. In conclusion, our Deviation Degree method successfully eliminates the disadvantages which exist in the previous state-of-the-art dynamic PIN construction methods. Moreover, the biological nature of protein interactions can be well described in our weighted network. Weighted TEPIN is a useful approach for detecting temporal protein complexes and revealing the dynamic protein assembly process for cellular organization. PMID:27100396

  20. Progression of Liver Disease

    MedlinePlus

    ... You Can Use April May Calendar Liver Lowdown Mar 2014 Calendar of Events In The News Academic ... 2016 Calendar Jan Feb 2016 recipe Liver Lowdown Mar/Apr 2016 Liver Lowdown August 2016 Know Your ...

  1. Liver Function Tests

    MedlinePlus

    ... herbal supplements you are taking. What are normal ranges for liver function tests? Normal ranges for liver function tests can vary by age, ... other factors. Laboratory test results usually provide normal ranges for each liver function test with your results. ...

  2. Liver Function Tests

    MedlinePlus

    ... food, store energy, and remove poisons. Liver function tests are blood tests that check to see how well your liver ... hepatitis and cirrhosis. You may have liver function tests as part of a regular checkup. Or you ...

  3. Pyogenic liver abscess

    MedlinePlus

    Liver abscess; Bacterial liver abscess ... There are many potential causes of liver abscesses, including: Abdominal infection, such as appendicitis , diverticulitis , or a perforated bowel Infection in the blood Infection of the bile draining tubes ...

  4. Diet and Your Liver

    MedlinePlus

    ... scarring of your liver (cirrhosis). For people with liver disease, even a small amount of alcohol can make ... time. Eating an unhealthy diet can lead to liver disease. For example, a person who eats a lot ...

  5. The evaluative value of Sema3C and MFN2 co-expression detected by immunohistochemistry for prognosis in hepatocellular carcinoma patients after hepatectomy

    PubMed Central

    Feng, Xu; Zhu, Kelei; Liu, Jinghua; Chen, Jiang; Tang, Jiacheng; Liang, Yuelong; Jin, Renan; Liang, Xiao; Cai, Xiujun

    2016-01-01

    Background The ability to evaluate the prognosis of hepatocellular carcinoma (HCC) following hepatectomy using biological markers is of great importance. Materials and methods In this study, we collected samples from 54 patients with HCC after hepatectomy. Immunohistochemistry was used to detect the expression of Sema3C and MFN2 in the HCC samples. Results Immunohistochemistry results showed that Sema3C and MFN2 co-expression was significantly associated with tumor size. In addition, a significant association between high Sema3C and low MFN2 levels and shorter overall survival was noted, when Sema3C and MFN2 co-expression was analyzed. Conclusion The results suggest that the correlative expression level of Sema3C and MFN2 has a strong value in the prognosis of patients with HCC following hepatectomy. PMID:27313467

  6. Co-expression of NCED and ALO improves vitamin C level and tolerance to drought and chilling in transgenic tobacco and stylo plants.

    PubMed

    Bao, Gegen; Zhuo, Chunliu; Qian, Chunmei; Xiao, Ting; Guo, Zhenfei; Lu, Shaoyun

    2016-01-01

    Abscisic acid (ABA) regulates plant adaptive responses to various environmental stresses, while L-ascorbic acid (AsA) that is also named vitamin C is an important antioxidant and involves in plant stress tolerance and the immune system in domestic animals. Transgenic tobacco (Nicotiana tabacum L.) and stylo [Stylosanthes guianensis (Aublet) Swartz], a forage legume, plants co-expressing stylo 9-cis-epoxycarotenoid dioxygenase (SgNCED1) and yeast D-arabinono-1,4-lactone oxidase (ALO) genes were generated in this study, and tolerance to drought and chilling was analysed in comparison with transgenic tobacco overexpressing SgNCED1 or ALO and the wild-type plants. Compared to the SgNCED1 or ALO transgenic plants, in which only ABA or AsA levels were increased, both ABA and AsA levels were increased in transgenic tobacco and stylo plants co-expressing SgNCED1 and ALO genes. Compared to the wild type, an enhanced drought tolerance was observed in SgNCED1 transgenic tobacco plants with induced expression of drought-responsive genes, but not in ALO plants, while an enhanced chilling tolerance was observed in ALO transgenic tobaccos with induced expression of cold-responsive genes, but not in SgNCED1 plants. Co-expression of SgNCED1 and ALO genes resulted in elevated tolerance to both drought and chilling in transgenic tobacco and stylo plants with induced expression of both drought and cold-responsive genes. Our result suggests that co-expression of SgNCED1 and ALO genes is an effective way for use in forage plant improvement for increased tolerance to drought and chilling and nutrition quality. PMID:25865630

  7. Cis-Natural Antisense Transcripts Are Mainly Co-expressed with Their Sense Transcripts and Primarily Related to Energy Metabolic Pathways during Muscle Development

    PubMed Central

    Zhao, Yunxia; Hou, Ye; Zhao, Changzhi; Liu, Fei; Luan, Yu; Jing, Lu; Li, Xinyun; Zhu, Mengjin; Zhao, Shuhong

    2016-01-01

    Cis-natural antisense transcripts (cis-NATs) are a new class of RNAs identified in various species. However, the biological functions of cis-NATs are largely unknown. In this study, we investigated the transcriptional characteristics and functions of cis-NATs in the muscle tissue of lean Landrace and indigenous fatty Lantang pigs. In total, 3,306 cis-NATs of 2,469 annotated genes were identified in the muscle tissue of pigs. More than 1,300 cis-NATs correlated with their sense genes at the transcriptional level, and approximately 80% of them were co-expressed in the two breeds. Furthermore, over 1,200 differentially expressed cis-NATs were identified during muscle development. Function annotation showed that the cis-NATs participated in muscle development mainly by co-expressing with genes involved in energy metabolic pathways, including citrate cycle (TCA cycle), glycolysis or gluconeogenesis, mitochondrial activation and so on. Moreover, these cis-NATs and their sense genes abruptly increased at the transition from the late fetal stages to the early postnatal stages and then decreased along with muscle development. In conclusion, the cis-NATs in the muscle tissue of pigs were identified and determined to be mainly co-expressed with their sense genes. The co-expressed cis-NATs and their sense gene were primarily related to energy metabolic pathways during muscle development in pigs. Our results offered novel evidence on the roles of cis-NATs during the muscle development of pigs. PMID:27489504

  8. Cis-Natural Antisense Transcripts Are Mainly Co-expressed with Their Sense Transcripts and Primarily Related to Energy Metabolic Pathways during Muscle Development.

    PubMed

    Zhao, Yunxia; Hou, Ye; Zhao, Changzhi; Liu, Fei; Luan, Yu; Jing, Lu; Li, Xinyun; Zhu, Mengjin; Zhao, Shuhong

    2016-01-01

    Cis-natural antisense transcripts (cis-NATs) are a new class of RNAs identified in various species. However, the biological functions of cis-NATs are largely unknown. In this study, we investigated the transcriptional characteristics and functions of cis-NATs in the muscle tissue of lean Landrace and indigenous fatty Lantang pigs. In total, 3,306 cis-NATs of 2,469 annotated genes were identified in the muscle tissue of pigs. More than 1,300 cis-NATs correlated with their sense genes at the transcriptional level, and approximately 80% of them were co-expressed in the two breeds. Furthermore, over 1,200 differentially expressed cis-NATs were identified during muscle development. Function annotation showed that the cis-NATs participated in muscle development mainly by co-expressing with genes involved in energy metabolic pathways, including citrate cycle (TCA cycle), glycolysis or gluconeogenesis, mitochondrial activation and so on. Moreover, these cis-NATs and their sense genes abruptly increased at the transition from the late fetal stages to the early postnatal stages and then decreased along with muscle development. In conclusion, the cis-NATs in the muscle tissue of pigs were identified and determined to be mainly co-expressed with their sense genes. The co-expressed cis-NATs and their sense gene were primarily related to energy metabolic pathways during muscle development in pigs. Our results offered novel evidence on the roles of cis-NATs during the muscle development of pigs. PMID:27489504

  9. Co-expression of xerophyte Zygophyllum xanthoxylum ZxNHX and ZxVP1-1 confers enhanced salinity tolerance in chimeric sugar beet (Beta vulgaris L.)

    PubMed Central

    Wu, Guo-Qiang; Feng, Rui-Jun; Wang, Suo-Min; Wang, Chun-Mei; Bao, Ai-Ke; Wei, Li; Yuan, Hui-Jun

    2015-01-01

    Salinity is one of the major abiotic stresses that limit the growth and productivity of sugar beet (Beta vulgaris L.). To improve sugar beet’s salinity tolerance, the ZxNHX and ZxVP1-1 genes encoding tonoplast Na+/H+ antiporter and H+-PPase from xerophyte Zygophyllum xanthoxylum were co-expressed by Agrobacterium tumefaciens-mediated transformation. It is showed here that co-expression of ZxNHX and ZxVP1-1 confers enhanced salinity tolerance to the transformed sugar beet plants compared with the wild-type (WT) plants. The chimeric plants grew well in the presence of high salinity (400 mM NaCl), whereas WT plants displayed chlorosis and died within 8 days. Compared to WT plants, the chimeric plants co-expressing ZxNHX and ZxVP1-1 accumulated more proline, Na+ and K+ in their leaves and petioles when exposed to high salinity, which caused lower solute potential, retained more water and thus subjected to lesser cell membrane damage. Interestingly, the chimeric plants accumulated higher sucrose, glucose and fructose contents in their storage roots than WT plants in the absence or presence of high salinity. Our results suggested that co-expression of ZxNHX and ZxVP1-1 improved the osmoregulatory capacity in chimeric sugar beet through increased compartmentalization of ions into the vacuoles by enhancing the activity of proton pumps and thus mitigated Na+-toxicity for plants. PMID:26284097

  10. Efficient multicistronic co-expression of hNIS and hTPO in prostate cancer cells for nonthyroidal tumor radioiodine therapy.

    PubMed

    Li, Guoquan; Xiang, Lei; Yang, Weidong; Wang, Zhe; Wang, Jing; Chen, Kai

    2012-01-01

    Radioiodine therapy has proven to be a safe and effective approach in the treatment of differentiated thyroid cancer. Similar treatment strategies have been exploited in nonthyroidal malignancies by transfecting hNIS gene into tumor cells or xenografts. However, rapid radioiodine efflux is often observed after radioiodine uptake, limiting the overall antitumor effects. In this study, we aimed at constructing multicistronic co-expression of hNIS and hTPO genes in tumor cells to enhance the radioiodine uptake and prolong the radioiodine retention. Driven by the cytomegalovirus promoter, hNIS and hTPO were simultaneously inserted into the expression cassette of adenoviral vector. An Ad5 viral vector (Ad-CMV-hTPO-T2A-hNIS) was assembled as a gene therapy vehicle by Gateway technology and 2A method. The co-expression of hNIS and hTPO genes was confirmed by a double-label immunofluorescence assay. The radioiodine ((125)I) uptake and efflux effects induced by co-expression of hNIS and hTPO genes were determined in transfected and non-transfected PC-3 cells. Significantly higher uptake (6.58 ± 0.56 fold, at 1 h post-incubation) and prolonged retention (5.47 ± 0.36 fold, at 1 h of cell efflux) of radioiodine ((125)I) were observed in hNIS and hTPO co-expressed PC-3 cells as compared to non-transfected PC-3 cells. We concluded that the new virus vector displayed favorable radioiodine uptake and retention properties in hNIS-hTPO transfected PC-3 cells. Our study will provide valuable information on improving the efficacy of hNIS-hTPO co-mediated radioiodine gene therapy. PMID:23145364

  11. Metabolic liver disease.

    PubMed

    McKiernan, Pat

    2012-06-01

    Diagnosis of metabolic liver disease requires a high level of diagnostic suspicion. Diet is usually the primary treatment for metabolic liver disease. Where indicated, liver transplantation provides lifelong functional correction of liver-based metabolic defects. Liver cell therapy warrants further study for the future treatment of metabolic liver disease. All families should receive genetic advice and pre-emptive management of future affected siblings. PMID:22521124

  12. Unique Responses are Observed in Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and TRPV1) Co-Expressing Cells

    PubMed Central

    Sadofsky, Laura R.; Sreekrishna, Koti T.; Lin, Yakang; Schinaman, Renee; Gorka, Kate; Mantri, Yogita; Haught, John Christian; Huggins, Thomas G.; Isfort, Robert J.; Bascom, Charles C.; Morice, Alyn H.

    2014-01-01

    Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are implicated in modulation of cough and nociception. In vivo, TRPA1 and TRPV1 are often co-expressed in neurons and TRPA1V1 hetero-tetramer formation is noted in cells co-transfected with the respective expression plasmids. In order to understand the impact of TRP receptor interaction on activity, we created stable cell lines expressing the TRPA1, TRPV1 and co-expressing the TRPA1 and TRPV1 (TRPA1V1) receptors. Among the 600 compounds screened against these receptors, we observed a number of compounds that activated the TRPA1, TRPV1 and TRPA1V1 receptors; compounds that activated TRPA1 and TRPA1V1; compounds that activated TRPV1 and TRPA1V1; compounds in which TRPA1V1 response was modulated by either TRPA1 or TRPV1; and compounds that activated only TRPV1 or TRPA1 or TRPA1V1; and one compound that activated TRPA1 and TRPV1, but not TRPA1V1. These results suggest that co-expression of TRPA1 and TRPV1 receptors imparts unique activation profiles different from that of cells expressing only TRPA1 or TRPV1. PMID:24921186

  13. Co-expression of chaperones from P. furiosus enhanced the soluble expression of the recombinant hyperthermophilic α-amylase in E. coli.

    PubMed

    Peng, Shuaiying; Chu, Zhongmei; Lu, Jianfeng; Li, Dongxiao; Wang, Yonghong; Yang, Shengli; Zhang, Yi

    2016-05-01

    The extracellular α-amylase from the hyperthermophilic archaeum Pyrococcus furiosus (PFA) is extremely thermostable and of an industrial importance and interest. PFA aggregates and accumulates as insoluble inclusion bodies when expressed as a heterologous protein at a high level in Escherichia coli. In the present study, we investigated the roles of chaperones from P. furiosus in the soluble expression of recombinant PFA in E. coli. The results indicate that co-expression of PFA with the molecular chaperone prefoldin alone significantly increased the soluble expression of PFA. Although, co-expression of other main chaperone components from P. furiosus, such as the small heat shock protein (sHSP) or chaperonin (HSP60), was also able to improve the soluble expression of PFA to a certain extent. Co-expression of chaperonin or sHSP in addition to prefoldin did not further increase the soluble expression of PFA. This finding emphasizes the biotechnological potentials of the molecular chaperone prefoldin from P. furiosus, which may facilitate the production of recombinant PFA. PMID:26862080

  14. Significant enhancement of methionol production by co-expression of the aminotransferase gene ARO8 and the decarboxylase gene ARO10 in Saccharomyces cerevisiae.

    PubMed

    Yin, Sheng; Lang, Tiandan; Xiao, Xiao; Liu, Li; Sun, Baoguo; Wang, Chengtao

    2015-03-01

    Methionol is an important volatile sulfur flavor compound, which can be produced via the Ehrlich pathway in Saccharomyces cerevisiae. Aminotransferase and decarboxylase are essential enzymes catalyzing methionol biosynthesis. In this work, two aminotransferase genes ARO8 and ARO9 and one decarboxylase gene ARO10 were introduced into S. cerevisiae S288c, respectively, via an expression vector. Over-expression of ARO8 resulted in higher aminotransferase activity than that of ARO9. And the cellular decarboxylase activity was remarkably increased by over-expression of ARO10. A co-expression vector carrying both ARO8 and ARO10 was further constructed to generate the recombinant strain S810. Shaking flask experiments showed that the methionol yield from S810 reached 1.27 g L(-1), which was increased by 51.8 and 68.8% compared to that from the wild-type strain and the control strain harboring the empty vector. The fed-batch fermentation by strain S810 produced 3.24 g L(-1) of methionol after 72 h of cultivation in a bioreactor. These results demonstrated that co-expression of ARO8 and ARO10 significantly boosted the methionol production. It is the first time that more than 3.0 g L(-1) of methionol produced by genetically engineered yeast strain was reported by co-expression of the aminotransferase and decarboxylase via the Ehrlich pathway. PMID:25743068

  15. Co-expression of D-glucose isomerase and D-psicose 3-epimerase: development of an efficient one-step production of D-psicose.

    PubMed

    Men, Yan; Zhu, Yueming; Zeng, Yan; Izumori, Ken; Sun, Yuanxia; Ma, Yanhe

    2014-10-01

    D-Psicose has been attracting attention in recent years because of its alimentary activities and is used as an ingredient in a range of foods and dietary supplements. To develop a one-step enzymatic process of D-psicose production, thermoactive D-glucose isomerase and the D-psicose 3-epimerase obtained from Bacillus sp. and Ruminococcus sp., respectively, were successfully co-expressed in Escherichia coli BL21 strain. The substrate of one-step enzymatic process was D-glucose. The co-expression system exhibited maximum activity at 65 °C and pH 7.0. Mg(2+) could enhance the output of D-psicose by 2.32 fold to 1.6 g/L from 10 g/L of D-glucose. When using high-fructose corn syrup (HFCS) as substrate, 135 g/L D-psicose was produced under optimum conditions. The mass ratio of D-glucose, D-fructose, and D-psicose was almost 3.0:2.7:1.0, when the reaction reached equilibrium after an 8h incubation time. This co-expression system approaching to produce D-psicose has potential application in food and beverage products, especially softdrinks. PMID:25152409

  16. Keratitis-Ichthyosis-Deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43

    PubMed Central

    García, Isaac E.; Maripillán, Jaime; Jara, Oscar; Ceriani, Ricardo; Palacios-Muñoz, Angelina; Ramachandran, Jayalakshimi; Olivero, Pablo; Pérez-Acle, Tomás; González, Carlos; Sáez, Juan C.; Contreras, Jorge E.; Martínez, Agustín D.

    2015-01-01

    Mutations in Cx26 gene are found in most cases of human genetic deafness. Some mutations produce syndromic deafness associated with skin disorders, like Keratitis Ichthyosis Deafness syndrome (KID). Because in the human skin Cx26 is co-expressed with other connexins, like Cx43 and Cx30, and since KID syndrome is inherited as autosomal dominant condition, it is possible that KID mutations change the way Cx26 interacts with other co-expressed connexins. Indeed, some Cx26 syndromic mutations showed gap junction dominant negative effect when co-expressed with wild type connexins, including Cx26 and Cx43. The nature of these interactions and the consequences on hemichannels and gap junction channels functions remain unknown. In this study we demonstrate that syndromic mutations at the N-terminus segment of Cx26, change connexin oligomerization compatibility, allowing aberrant interactions with Cx43. Strikingly, heteromeric oligomer formed by Cx43/Cx26 (syndromic mutants) show exacerbated hemichannel activity, but nonfunctional gap junction channels; this also occurs for those Cx26 KID mutants that do not show functional homomeric hemichannels. Heterologous expression of these hyperactive heteromeric hemichannels increases cell membrane permeability, favoring ATP release and Ca2+ overload. The functional paradox produced by oligomerization of Cx43 and Cx26 KID mutants could underlie the severe syndromic phenotype in human skin. PMID:25625422

  17. Amebic liver abscess

    MedlinePlus

    Hepatic amebiasis; Extraintestinal amebiasis; Abscess - amebic liver ... Amebic liver abscess is caused by Entamoeba histolytica. This parasite causes amebiasis , an intestinal infection that is also called ...

  18. High level accumulation of soluble diphtheria toxin mutant (CRM197) with co-expression of chaperones in recombinant Escherichia coli.

    PubMed

    Mahamad, Pornpimol; Boonchird, Chuenchit; Panbangred, Watanalai

    2016-07-01

    CRM197 is the diphtheria toxin mutant used in many conjugate vaccines. A fusion CRM197 (fCRM197) containing all the tags conferred by the pET32a vector was produced as a soluble protein in Escherichia coli co-expressing several chaperone proteins in conjunction with low temperature cultivation. Trigger factor (Tf) enhanced formation of soluble fCRM197 (150.69 ± 8.95 μg/mL) to a greater degree than other chaperones when fCRM197 expression was induced at 25 °C for 12 h. However, prolonged cultivation resulted in a progressive reduction of fCRM197 accumulation. In contrast, at 15 °C cells, with or without Tf, fCRM197 accumulated to the highest level at 48 h (153.70 ± 13.14 μg/mL and 150.07 ± 8.13 μg/mL, respectively). Transmission electron microscopy (TEM) demonstrated that the formation of inclusion protein as well as cell lysis was reduced in cultures grown at 15 °C. Cell viability was substantially reduced in cells expressing Tf, compared to cultures without Tf, when fCRM197 was induced at 25 °C. The viability of Tf-expressing cells was enhanced when cultured at 15 °C. Both purified fCRM197 and CRM197 efficiently digested lambda DNA (λDNA) at 37 °C (92.78 and 97.45 %, respectively). Digestion efficiency of fCRM197 and CRM197 was reduced at 25 °C (80.80 and 62.73 %, respectively) and at 15 °C (7.34 and 24.79 %, respectively). These results demonstrating nuclease activity, enhanced cell lysis, and reduced cell viability are consistent with the finding of lower fCRM197 yield when cultivation and induction times were prolonged at 25 °C. The present work provides a procedure for the high-level production of soluble fCRM197 using E. coli as a heterologous host. PMID:27020286

  19. Alcohol-Related Liver Disease

    MedlinePlus

    ... to run events. Please support us. Donate | Volunteer Alcohol-Related Liver Disease Discussion on Inspire Support Community ... Liver > Liver Disease Information > Alcohol-Related Liver Disease Alcohol-Related Liver Disease Explore this section to learn ...

  20. Alcoholic Liver Disease and Liver Transplantation.

    PubMed

    Gallegos-Orozco, Juan F; Charlton, Michael R

    2016-08-01

    Excessive alcohol use is a common health care problem worldwide and is associated with significant morbidity and mortality. Alcoholic liver disease represents the second most frequent indication for liver transplantation in North America and Europe. The pretransplant evaluation of patients with alcoholic liver disease should aim at identifying those at high risk for posttransplant relapse of alcohol use disorder, as return to excessive drinking can be deleterious to graft and patient survival. Carefully selected patients with alcoholic liver disease, including those with severe alcoholic hepatitis, will have similar short-term and long-term outcomes when compared with other indications for liver transplantation. PMID:27373614

  1. Role of liver progenitors in liver regeneration

    PubMed Central

    Best, Jan; Manka, Paul; Syn, Wing-Kin; Dollé, Laurent; van Grunsven, Leo A.

    2015-01-01

    During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs. PMID:25713804

  2. Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes

    PubMed Central

    Sutherland, Jeffrey J.; Jolly, Robert A.; Goldstein, Keith M.; Stevens, James L.

    2016-01-01

    The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), human primary hepatocytes (HPH) from TG, and mouse liver / HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance. PMID:27028627

  3. Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes.

    PubMed

    Sutherland, Jeffrey J; Jolly, Robert A; Goldstein, Keith M; Stevens, James L

    2016-03-01

    The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), human primary hepatocytes (HPH) from TG, and mouse liver/HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance. PMID:27028627

  4. Engineering Liver

    PubMed Central

    Griffith, Linda G.; Wells, Alan; Stolz, Donna Beer

    2014-01-01

    Interest in “engineering liver” arises from multiple communities: therapeutic replacement; mechanistic models of human processes; and drug safety and efficacy studies. An explosion of micro- and nano-fabrication, biomaterials, microfluidic, and other technologies potentially afford unprecedented opportunity to create microphysiological models of human liver, but engineering design principles for how to deploy these tools effectively towards specific applications, including how to define the essential constraints of any given application (including available sources of cells, acceptable cost, and user-friendliness) are still emerging. Arguably less appreciated is the parallel growth in computational systems biology approaches towards these same problems – particularly, in parsing complex disease processes from clinical material, building models of response networks, and in how to interpret the growing compendium of data on drug efficacy and toxicology in patient populations. Here, we provide insight into how the complementary paths of “engineering liver” – experimental and computational – are beginning to interplay towards greater illumination of human disease states and technologies for drug development. PMID:24668880

  5. Liver xenotransplantation.

    PubMed

    Marino, I R; Tzakis, A G; Fung, J J; Todo, S; Doyle, H R; Manez, R; Starzl, T E

    1993-10-01

    During the past 30 years orthotopic liver transplantation has become a highly successful form of surgical treatments. The significant advances achieved in this field have led to an increased demand for organs and created a wide gap between organ availability and organ supply. A wider availability of organs for transplantation would allow an expansions rather than a contraction of the indications for transplantation, and, at the same time a relaxation of the patient selection criteria. All these facts clearly justify the renewed interest observed in the last decade in xenotransplantation. The original concept of xenografting, meaning the transplantation of cells, tissues, or organs between different species, is so ancient that it is easily recognizable in Greek and Roman mythology. The centaur Chiron, the teacher of Esculapius, and the Chimera are legendary examples of discordant xenogeneic creatures. However, it is only during this century that scientists have been able to bring this idea into the clinical arena. The early efforts were prompted by the shortage of humans organs at a time when there were few alternatives for treating end-stage organ failure. PMID:25951555

  6. Liver disease in menopause

    PubMed Central

    Brady, Carla W

    2015-01-01

    There are numerous physiologic and biochemical changes in menopause that can affect the function of the liver and mediate the development of liver disease. Menopause represents a state of growing estrogen deficiency, and this loss of estrogen in the setting of physiologic aging increases the likelihood of mitochondrial dysfunction, cellular senescence, declining immune responses to injury, and disarray in the balance between antioxidant formation and oxidative stress. The sum effect of these changes can contribute to increased susceptibility to development of significant liver pathology, particularly nonalcoholic fatty liver disease and hepatocellular carcinoma, as well as accelerated progression of fibrosis in liver diseases, as has been particularly demonstrated in hepatitis C virus liver disease. Recognition of the unique nature of these mediating factors should raise suspicion for liver disease in perimenopausal and menopausal women and offer an opportunity for implementation of aggressive treatment measures so as to avoid progression of liver disease to cirrhosis, liver cancer and liver failure. PMID:26167064

  7. Liver fibrosis markers in alcoholic liver disease

    PubMed Central

    Chrostek, Lech; Panasiuk, Anatol

    2014-01-01

    Alcohol is one of the main factors of liver damage. The evaluation of the degree of liver fibrosis is of great value for therapeutic decision making in patients with alcoholic liver disease (ALD). Staging of liver fibrosis is essential to define prognosis and management of the disease. Liver biopsy is a gold standard as it has high sensitivity and specificity in fibrosis diagnostics. Taking into account the limitations of liver biopsy, there is an exigency to introduce non-invasive serum markers for fibrosis that would be able to replace liver biopsy. Ideal serum markers should be specific for the liver, easy to perform and independent to inflammation and fibrosis in other organs. Serum markers of hepatic fibrosis are divided into direct and indirect. Indirect markers reflect alterations in hepatic function, direct markers reflect extracellular matrix turnover. These markers should correlate with dynamic changes in fibrogenesis and fibrosis resolution. The assessment of the degree of liver fibrosis in alcoholic liver disease has diagnostic and prognostic implications, therefore noninvasive assessment of fibrosis remains important. There are only a few studies evaluating the diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with ALD. Several noninvasive laboratory tests have been used to assess liver fibrosis in patients with alcoholic liver disease, including the hyaluronic acid, FibroTest, FibrometerA, Hepascore, Forns and APRI indexes, FIB4, an algorithm combining Prothrombin index (PI), α-2 macroglobulin and hyaluronic acid. Among these tests, Fibrotest, FibrometerA and Hepascore demonstrated excellent diagnostic accuracy in identifying advanced fibrosis and cirrhosis, and additionally, Fibrotest was independently associated with survival. Therefore, the use of biomarkers may reduce the need for liver biopsy and permit an earlier treatment of alcoholic patients. PMID:25009372

  8. Characteristics of Schistosoma japonicum infection induced IFN-γ and IL-4 co-expressing plasticity Th cells.

    PubMed

    Chen, Dianhui; Xie, Hongyan; Cha, Hefei; Qu, Jiale; Wang, Mei; Li, Lu; Yu, Sifei; Wu, Changyou; Tang, Xiaoping; Huang, Jun

    2016-09-01

    Schistosoma japonicum infection can induce granulomatous inflammation and cause tissue damage in the mouse liver. The cytokine secretion profile of T helper (Th) cells depends on both the nature of the activating stimulus and the local microenvironment (e.g. cytokines and other soluble factors). In the present study, we found an accumulation of large numbers of IFN-γ(+)  IL-4(+)  CD4(+) T cells in mouse livers. This IFN-γ(+)  IL-4(+) cell population increased from 0·68 ± 0·57% in uninfected mice to 7·05 ± 3·0% by week 4 following infection and to 9·6 ± 5·28% by week 6, before decreasing to 6·3 ± 5·9% by week 8 in CD4 T cells. Moreover, IFN-γ(+)  IL-4(+) Th cells were also found in mouse spleen and mesenteric lymph nodes 6 weeks after infection. The majority of the IFN-γ(+)  IL-4(+) Th cells were thought to be related to a state of immune activation, and some were memory T cells. Moreover, we found that these S. japonicum infection-induced IFN-γ(+)  IL-4(+) cells could express interleukin-2 (IL-2), IL-9, IL-17 and high IL-10 levels at 6 weeks after S. japonicum infection. Taken together, our data suggest the existence of a population of IFN-γ(+)  IL-4(+) plasticity effector/memory Th cells following S. japonicum infection in C57BL/6 mice. PMID:27242265

  9. Transient Co-Expression of Post-Transcriptional Gene Silencing Suppressors for Increased in Planta Expression of a Recombinant Anthrax Receptor Fusion Protein

    PubMed Central

    Arzola, Lucas; Chen, Junxing; Rattanaporn, Kittipong; Maclean, James M.; McDonald, Karen A.

    2011-01-01

    Potential epidemics of infectious diseases and the constant threat of bioterrorism demand rapid, scalable, and cost-efficient manufacturing of therapeutic proteins. Molecular farming of tobacco plants provides an alternative for the recombinant production of therapeutics. We have developed a transient production platform that uses Agrobacterium infiltration of Nicotiana benthamiana plants to express a novel anthrax receptor decoy protein (immunoadhesin), CMG2-Fc. This chimeric fusion protein, designed to protect against the deadly anthrax toxins, is composed of the von Willebrand factor A (VWA) domain of human capillary morphogenesis 2 (CMG2), an effective anthrax toxin receptor, and the Fc region of human immunoglobulin G (IgG). We evaluated, in N. benthamiana intact plants and detached leaves, the expression of CMG2-Fc under the control of the constitutive CaMV 35S promoter, and the co-expression of CMG2-Fc with nine different viral suppressors of post-transcriptional gene silencing (PTGS): p1, p10, p19, p21, p24, p25, p38, 2b, and HCPro. Overall, transient CMG2-Fc expression was higher on intact plants than detached leaves. Maximum expression was observed with p1 co-expression at 3.5 days post-infiltration (DPI), with a level of 0.56 g CMG2-Fc per kg of leaf fresh weight and 1.5% of the total soluble protein, a ten-fold increase in expression when compared to absence of suppression. Co-expression with the p25 PTGS suppressor also significantly increased the CMG2-Fc expression level after just 3.5 DPI. PMID:21954339

  10. Co-Expression of Anti-Rotavirus Proteins (Llama VHH Antibody Fragments) in Lactobacillus: Development and Functionality of Vectors Containing Two Expression Cassettes in Tandem

    PubMed Central

    Günaydın, Gökçe; Álvarez, Beatriz; Lin, Yin; Hammarström, Lennart; Marcotte, Harold

    2014-01-01

    Rotavirus is an important pediatric pathogen, causing severe diarrhea and being associated with a high mortality rate causing approximately 500 000 deaths annually worldwide. Even though some vaccines are currently available, their efficacy is lower in the developing world, as compared to developed countries. Therefore, alternative or complementary treatment options are needed in the developing countries where the disease burden is the largest. The effect of Lactobacillus in promoting health and its use as a vehicle for delivery of protein and antibody fragments was previously shown. In this study, we have developed co-expression vectors enabling Lactobacillus paracasei BL23 to produce two VHH fragments against rotavirus (referred to as anti-rotavirus proteins 1 and 3, ARP1 and ARP3) as secreted and/or surface displayed products. ARP1 and ARP3 fragments were successfully co-expressed as shown by Western blot and flow cytometry. In addition, engineered Lactobacillus produced VHH antibody fragments were shown to bind to a broad range of rotavirus serotypes (including the human rotavirus strains 69M, Va70, F45, DS1, Wa and ST3 and simian rotavirus strains including RRV and SA11), by flow cytometry and ELISA. Hereby, we have demonstrated for the first time that when RRV was captured by one VHH displayed on the surface of co-expressor Lactobacillus, targeting other epitope was possible with another VHH secreted from the same bacterium. Therefore, Lactobacillus producing two VHH antibody fragments may potentially serve as treatment against rotavirus with a reduced risk of development of escape mutants. This co-expression and delivery platform can also be used for delivery of VHH fragments against a variety of mucosal pathogens or production of other therapeutic molecules. PMID:24781086

  11. An expression quantitative trait loci-guided co-expression analysis for constructing regulatory network using a rice recombinant inbred line population.

    PubMed

    Wang, Jia; Yu, Huihui; Weng, Xiaoyu; Xie, Weibo; Xu, Caiguo; Li, Xianghua; Xiao, Jinghua; Zhang, Qifa

    2014-03-01

    The ability to reveal the regulatory architecture of genes at the whole-genome level by constructing a regulatory network is critical for understanding the biological processes and developmental programmes of organisms. Here, we conducted an eQTL-guided function-related co-expression analysis to identify the putative regulators and construct gene regulatory network. We performed an eQTL analysis of 210 recombinant inbred lines (RILs) derived from a cross between two indica rice lines, Zhenshan 97 and Minghui 63, the parents of an elite hybrid, using data obtained by hybridizing RNA samples of flag leaves at the heading stage with Affymetrix whole-genome arrays. Making use of an ultrahigh-density single-nucleotide polymorphism bin map constructed by population sequencing, 13 647 eQTLs for 10 725 e-traits were detected, comprising 5079 cis-eQTLs (37.2%) and 8568 trans-eQTLs (62.8%). The analysis revealed 138 trans-eQTLs hotspots, each of which apparently regulates the expression variations of many genes. Co-expression analysis of functionally related genes within the framework of regulator-target relationships outlined by the eQTLs led to the identification of putative regulators in the system. The usefulness of the strategy was demonstrated with the genes known to be involved in flowering. We also applied this strategy to the analysis of QTLs for yield traits, which also suggested likely candidate genes. eQTL-guided co-expression analysis may provide a promising solution for outlining a framework for the complex regulatory network of an organism. PMID:24420573

  12. Biomarkers for liver fibrosis

    SciTech Connect

    Jacobs, Jon M.; Burnum-Johnson, Kristin E.; Baker, Erin M.; Smith, Richard D.; Gritsenko, Marina A.; Orton, Daniel

    2015-09-15

    Methods and systems for diagnosing or prognosing liver fibrosis in a subject are provided. In some examples, such methods and systems can include detecting liver fibrosis-related molecules in a sample obtained from the subject, comparing expression of the molecules in the sample to controls representing expression values expected in a subject who does not have liver fibrosis or who has non-progressing fibrosis, and diagnosing or prognosing liver fibrosis in the subject when differential expression of the molecules between the sample and the controls is detected. Kits for the diagnosis or prognosis of liver fibrosis in a subject are also provided which include reagents for detecting liver fibrosis related molecules.

  13. Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

    PubMed

    Eising, Else; Huisman, Sjoerd M H; Mahfouz, Ahmed; Vijfhuizen, Lisanne S; Anttila, Verneri; Winsvold, Bendik S; Kurth, Tobias; Ikram, M Arfan; Freilinger, Tobias; Kaprio, Jaakko; Boomsma, Dorret I; van Duijn, Cornelia M; Järvelin, Marjo-Riitta R; Zwart, John-Anker; Quaye, Lydia; Strachan, David P; Kubisch, Christian; Dichgans, Martin; Davey Smith, George; Stefansson, Kari; Palotie, Aarno; Chasman, Daniel I; Ferrari, Michel D; Terwindt, Gisela M; de Vries, Boukje; Nyholt, Dale R; Lelieveldt, Boudewijn P F; van den Maagdenberg, Arn M J M; Reinders, Marcel J T

    2016-04-01

    Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology. PMID:26899160

  14. Genome-Wide Expression of Transcriptomes and Their Co-Expression Pattern in Subtropical Maize (Zea mays L.) under Waterlogging Stress

    PubMed Central

    Thirunavukkarasu, Nepolean; Hossain, Firoz; Mohan, Sweta; Shiriga, Kaliyugam; Mittal, Swati; Sharma, Rinku; Singh, Rita Kumari; Gupta, Hari Shankar

    2013-01-01

    Waterlogging causes extensive damage to maize crops in tropical and subtropical regions. The identification of tolerance genes and their interactions at the molecular level will be helpful to engineer tolerant genotypes. A whole-genome transcriptome assay revealed the specific role of genes in response to waterlogging stress in susceptible and tolerant genotypes. Genes involved in the synthesis of ethylene and auxin, cell wall metabolism, activation of G-proteins and formation of aerenchyma and adventitious roots, were upregulated in the tolerant genotype. Many transcription factors, particularly ERFs, MYB, HSPs, MAPK, and LOB-domain protein were involved in regulation of these traits. Genes responsible for scavenging of ROS generated under stress were expressed along with those involved in carbohydrate metabolism. The physical locations of 21 genes expressed in the tolerant genotype were found to correspond with the marker intervals of known QTLs responsible for development of adaptive traits. Among the candidate genes, most showed synteny with genes of sorghum and foxtail millet. Co-expression analysis of 528 microarray samples including 16 samples from the present study generated seven functional modules each in the two genotypes, with differing characteristics. In the tolerant genotype, stress genes were co-expressed along with peroxidase and fermentation pathway genes. PMID:23936429

  15. Enhancement of antibody fragment secretion into the Escherichia coli periplasm by co-expression with the peptidyl prolyl isomerase, FkpA, in the cytoplasm.

    PubMed

    Levy, Raphael; Ahluwalia, Kiran; Bohmann, David J; Giang, Hoa M; Schwimmer, Lauren J; Issafras, Hassan; Reddy, Nithin B; Chan, Chung; Horwitz, Arnold H; Takeuchi, Toshihiko

    2013-08-30

    Improper protein folding or aggregation can frequently be responsible for low expression and poor functional activity of antibody fragments secreted into the Escherichia coli periplasm. Expression issues also can affect selection of antibody candidates from phage libraries, since antibody fragments displayed on phage also are secreted into the E. coli periplasm. To improve secretion of properly folded antibody fragments into the periplasm, we have developed a novel approach that involves co-expressing the antibody fragments with the peptidyl prolyl cis-trans isomerase, FkpA, lacking its signal sequence (cytFkpA) which consequently is expressed in the E. coli cytosol. Cytoplasmic expression of cytFkpA improved secretion of functional Fab fragments into the periplasm, exceeding even the benefits from co-expressing Fab fragments with native, FkpA localized in the periplasm. In addition, panning and subsequent screening of large Fab and scFv naïve phage libraries in the presence of cytFkpA significantly increased the number of unique clones selected, as well as their functional expression levels and diversity. PMID:23624043

  16. Neutralization of Bacterial YoeBSpn Toxicity and Enhanced Plant Growth in Arabidopsis thaliana via Co-Expression of the Toxin-Antitoxin Genes

    PubMed Central

    Abu Bakar, Fauziah; Yeo, Chew Chieng; Harikrishna, Jennifer Ann

    2016-01-01

    Bacterial toxin-antitoxin (TA) systems have various cellular functions, including as part of the general stress response. The genome of the Gram-positive human pathogen Streptococcus pneumoniae harbors several putative TA systems, including yefM-yoeBSpn, which is one of four systems that had been demonstrated to be biologically functional. Overexpression of the yoeBSpn toxin gene resulted in cell stasis and eventually cell death in its native host, as well as in Escherichia coli. Our previous work showed that induced expression of a yoeBSpn toxin-Green Fluorescent Protein (GFP) fusion gene apparently triggered apoptosis and was lethal in the model plant, Arabidopsis thaliana. In this study, we investigated the effects of co-expression of the yefMSpn antitoxin and yoeBSpn toxin-GFP fusion in transgenic A. thaliana. When co-expressed in Arabidopsis, the YefMSpn antitoxin was found to neutralize the toxicity of YoeBSpn-GFP. Interestingly, the inducible expression of both yefMSpn antitoxin and yoeBSpn toxin-GFP fusion in transgenic hybrid Arabidopsis resulted in larger rosette leaves and taller plants with a higher number of inflorescence stems and increased silique production. To our knowledge, this is the first demonstration of a prokaryotic antitoxin neutralizing its cognate toxin in plant cells. PMID:27104531

  17. Neutralization of Bacterial YoeBSpn Toxicity and Enhanced Plant Growth in Arabidopsis thaliana via Co-Expression of the Toxin-Antitoxin Genes.

    PubMed

    Abu Bakar, Fauziah; Yeo, Chew Chieng; Harikrishna, Jennifer Ann

    2016-01-01

    Bacterial toxin-antitoxin (TA) systems have various cellular functions, including as part of the general stress response. The genome of the Gram-positive human pathogen Streptococcus pneumoniae harbors several putative TA systems, including yefM-yoeBSpn, which is one of four systems that had been demonstrated to be biologically functional. Overexpression of the yoeBSpn toxin gene resulted in cell stasis and eventually cell death in its native host, as well as in Escherichia coli. Our previous work showed that induced expression of a yoeBSpn toxin-Green Fluorescent Protein (GFP) fusion gene apparently triggered apoptosis and was lethal in the model plant, Arabidopsis thaliana. In this study, we investigated the effects of co-expression of the yefMSpn antitoxin and yoeBSpn toxin-GFP fusion in transgenic A. thaliana. When co-expressed in Arabidopsis, the YefMSpn antitoxin was found to neutralize the toxicity of YoeBSpn-GFP. Interestingly, the inducible expression of both yefMSpn antitoxin and yoeBSpn toxin-GFP fusion in transgenic hybrid Arabidopsis resulted in larger rosette leaves and taller plants with a higher number of inflorescence stems and increased silique production. To our knowledge, this is the first demonstration of a prokaryotic antitoxin neutralizing its cognate toxin in plant cells. PMID:27104531

  18. Discovering gene re-ranking efficiency and conserved gene-gene relationships derived from gene co-expression network analysis on breast cancer data

    PubMed Central

    Bourdakou, Marilena M.; Athanasiadis, Emmanouil I.; Spyrou, George M.

    2016-01-01

    Systemic approaches are essential in the discovery of disease-specific genes, offering a different perspective and new tools on the analysis of several types of molecular relationships, such as gene co-expression or protein-protein interactions. However, due to lack of experimental information, this analysis is not fully applicable. The aim of this study is to reveal the multi-potent contribution of statistical network inference methods in highlighting significant genes and interactions. We have investigated the ability of statistical co-expression networks to highlight and prioritize genes for breast cancer subtypes and stages in terms of: (i) classification efficiency, (ii) gene network pattern conservation, (iii) indication of involved molecular mechanisms and (iv) systems level momentum to drug repurposing pipelines. We have found that statistical network inference methods are advantageous in gene prioritization, are capable to contribute to meaningful network signature discovery, give insights regarding the disease-related mechanisms and boost drug discovery pipelines from a systems point of view. PMID:26892392

  19. Enhancement of lipase r27RCL production in Pichia pastoris by regulating gene dosage and co-expression with chaperone protein disulfide isomerase.

    PubMed

    Sha, Chong; Yu, Xiao-Wei; Lin, Nai-Xin; Zhang, Meng; Xu, Yan

    2013-12-10

    Pichia pastoris has been successfully used in the production of many secreted and intracellular recombinant proteins, but there is still a large room of improvement for this expression system. Two factors drastically influence the lipase r27RCL production from Rhizopus chinensis CCTCC M201021, which are gene dosage and protein folding in the endoplasmic reticulum (ER). Regarding the effect of gene dosage, the enzyme activity for recombinant strain with three copies lipase gene was 1.95-fold higher than that for recombinant strain with only one copy lipase gene. In addition, the lipase production was further improved by co-expression with chaperone PDI involved in the disulfide bond formation in the ER. Overall, the maximum enzyme activity reached 355U/mL by the recombinant strain with one copy chaperone gene PDI plus five copies lipase gene proRCL in shaking flasks, which was 2.74-fold higher than that for the control strain with only one copy lipase gene. Overall, co-expression with PDI vastly increased the capacity for processing proteins of ER in P. pastoris. PMID:24315648

  20. Co-Expression of Monodehydroascorbate Reductase and Dehydroascorbate Reductase from Brassica rapa Effectively Confers Tolerance to Freezing-Induced Oxidative Stress

    PubMed Central

    Shin, Sun-Young; Kim, Myung-Hee; Kim, Yul-Ho; Park, Hyang-Mi; Yoon, Ho-Sung

    2013-01-01

    Plants are exposed to various environmental stresses and have therefore developed antioxidant enzymes and molecules to protect their cellular components against toxicity derived from reactive oxygen species (ROS). Ascorbate is a very important antioxidant molecule in plants, and monodehydroascorbate reductase (MDHAR; EC 1.6.5.4) and dehydroascorbate reductase (DHAR; EC 1.8.5.1) are essential to regeneration of ascorbate for maintenance of ROS scavenging ability. The MDHAR and DHAR genes from Brassica rapa were cloned, transgenic plants overexpressing either BrMDHAR and BrDHAR were established, and then, each transgenic plant was hybridized to examine the effects of co-expression of both genes conferring tolerance to freezing. Transgenic plants co-overexpressing BrMDHAR and BrDHAR showed activated expression of relative antioxidant enzymes, and enhanced levels of glutathione and phenolics under freezing condition. Then, these alteration caused by co-expression led to alleviated redox status and lipid peroxidation and consequently conferred improved tolerance against severe freezing stress compared to transgenic plants overexpressing single gene. The results of this study suggested that although each expression of BrMDHAR or BrDHAR was available to according tolerance to freezing, the simultaneous expression of two genes generated synergistic effects conferring improved tolerance more effectively even severe freezing. PMID:24170089

  1. Inhibition of 3' modification of small RNAs in virus-infected plants require spatial and temporal co-expression of small RNAs and viral silencing-suppressor proteins.

    PubMed

    Lózsa, Rita; Csorba, Tibor; Lakatos, Lóránt; Burgyán, József

    2008-07-01

    Plant viruses are inducers and targets of RNA silencing. Viruses counteract with RNA silencing by expressing silencing-suppressor proteins. Many of the identified proteins bind siRNAs, which prevents assembly of silencing effector complexes, and also interfere with their 3' methylation, which protects them against degradation. Here, we investigated the 3' modification of silencing-related small RNAs in Nicotiana benthamiana plants infected with viruses expressing RNA silencing suppressors, the p19 protein of Carnation Italian ringspot virus (CIRV) and HC-Pro of Tobacco etch virus (TEV). We found that CIRV had only a slight effect on viral siRNA 3' modification, but TEV significantly inhibited the 3' modification of si/miRNAs. We also found that p19 and HC-Pro were able to bind both 3' modified and non-modified small RNAs in vivo. The findings suggest that the 3' modification of viral siRNAs occurs in the cytoplasm, though miRNA 3' modification likely takes place in the nucleus as well. Both silencing suppressors inhibited the 3' modification of si/miRNAs when they and small RNAs were transiently co-expressed, suggesting that the inhibition of si/miRNA 3' modification requires spatial and temporal co-expression. Finally, our data revealed that a HEN1-like methyltransferase might account for the small RNA modification at the their 3'-terminal nucleotide in N. benthamiana. PMID:18539609

  2. Co-expression of interleukin 12 enhances antitumor effects of a novel chimeric promoter-mediated suicide gene therapy in an immunocompetent mouse model

    SciTech Connect

    Xu, Yu; Liu, Zhengchun; Kong, Haiyan; Sun, Wenjie; Liao, Zhengkai; Zhou, Fuxiang; Xie, Conghua; and others

    2011-09-09

    Highlights: {yields} A novel chimeric promoter consisting of CArG element and hTERT promoter was developed. {yields} The promoter was characterized with radiation-inducibility and tumor-specificity. {yields} Suicide gene system driven by the promoter showed remarkable cytotoxicity in vitro. {yields} Co-expression of IL12 enhanced the promoter mediated suicide gene therapy in vivo. -- Abstract: The human telomerase reverse transcriptase (hTERT) promoter has been widely used in target gene therapy of cancer. However, low transcriptional activity limited its clinical application. Here, we designed a novel dual radiation-inducible and tumor-specific promoter system consisting of CArG elements and the hTERT promoter, resulting in increased expression of reporter genes after gamma-irradiation. Therapeutic and side effects of adenovirus-mediated horseradish peroxidase (HRP)/indole-3-acetic (IAA) system downstream of the chimeric promoter were evaluated in mice bearing Lewis lung carcinoma, combining with or without adenovirus-mediated interleukin 12 (IL12) gene driven by the cytomegalovirus promoter. The combination treatment showed more effective suppression of tumor growth than those with single agent alone, being associated with pronounced intratumoral T-lymphocyte infiltration and minor side effects. Our results suggest that the combination treatment with HRP/IAA system driven by the novel chimeric promoter and the co-expression of IL12 might be an effective and safe target gene therapy strategy of cancer.

  3. Mini-P-gp and P-gp Co-Expression in Brown Trout Erythrocytes: A Prospective Blood Biomarker of Aquatic Pollution

    PubMed Central

    Valton, Emeline; Amblard, Christian; Desmolles, François; Combourieu, Bruno; Penault-Llorca, Frédérique; Bamdad, Mahchid

    2015-01-01

    In aquatic organisms, such as fish, blood is continually exposed to aquatic contaminants. Multidrug Resistance (MDR) proteins are ubiquitous detoxification membrane pumps, which recognize various xenobiotics. Moreover, their expression is induced by a large class of drugs and pollutants. We have highlighted the co-expression of a mini P-gp of 75 kDa and a P-gp of 140 kDa in the primary culture of brown trout erythrocytes and in the erythrocytes of wild brown trout collected from three rivers in the Auvergne region of France. In vitro experiments showed that benzo[a]pyrene, a highly toxic pollutant model, induced the co-expression of mini-P-gp and P-gp in trout erythrocytes in a dose-dependent manner and relay type response. Similarly, in the erythrocytes of wild brown trout collected from rivers contaminated by a mixture of PAH and other multi-residues of pesticides, mini-P-gp and P-gp were able to modulate their expression, according to the nature of the pollutants. The differential and complementary responses of mini-P-gp and P-gp in trout erythrocytes suggest the existence in blood cells of a real protective network against xenobiotics/drugs. This property could be exploited to develop a blood biomarker of river pollution. PMID:26854141

  4. Sulfation of the FLAG epitope is affected by co-expression of G protein-coupled receptors in a mammalian cell model.

    PubMed

    Hunter, Morag Rose; Grimsey, Natasha Lillia; Glass, Michelle

    2016-01-01

    G protein-coupled receptors (GPCRs) are important therapeutic targets and therefore extensively studied. Like most transmembrane proteins, there has been considerable difficulty in developing reliable specific antibodies for them. To overcome this, epitope tags are often used to facilitate antibody recognition in studies on fundamental receptor signalling and trafficking. In our study of cannabinoid CB1/dopamine D2 interactions we sought to generate HEK293 cells expressing FLAG-tagged D2 for use in antibody-based assays of GPCR localisation and trafficking activity, however observed that stable FLAG-hD2 expression was particularly challenging to maintain. In contrast, when expressed in cell lines expressing hCB1 robust and stable FLAG-hD2 expression was observed. We hypothesised that co-expression of CB1 might stabilise surface FLAG-hD2 expression, and therefore investigated this further. Here, we describe the observation that co-expression of either cannabinoid CB1 or CB2 receptors in HEK293 decreases the sulfation of a FLAG epitope appended at the N-terminus of the dopamine D2 receptor. Sulfation alters epitope recognition by some anti-FLAG antibodies, leading to the detection of fewer receptors, even though expression is maintained. This demonstrates that cannabinoid receptor expression modifies posttranslational processing of the FLAG-hD2 receptor, and importantly, has wider implications for the utilisation and interpretation of receptor studies involving epitope tags. PMID:27273047

  5. Sulfation of the FLAG epitope is affected by co-expression of G protein-coupled receptors in a mammalian cell model

    PubMed Central

    Hunter, Morag Rose; Grimsey, Natasha Lillia; Glass, Michelle

    2016-01-01

    G protein-coupled receptors (GPCRs) are important therapeutic targets and therefore extensively studied. Like most transmembrane proteins, there has been considerable difficulty in developing reliable specific antibodies for them. To overcome this, epitope tags are often used to facilitate antibody recognition in studies on fundamental receptor signalling and trafficking. In our study of cannabinoid CB1/dopamine D2 interactions we sought to generate HEK293 cells expressing FLAG-tagged D2 for use in antibody-based assays of GPCR localisation and trafficking activity, however observed that stable FLAG-hD2 expression was particularly challenging to maintain. In contrast, when expressed in cell lines expressing hCB1 robust and stable FLAG-hD2 expression was observed. We hypothesised that co-expression of CB1 might stabilise surface FLAG-hD2 expression, and therefore investigated this further. Here, we describe the observation that co-expression of either cannabinoid CB1 or CB2 receptors in HEK293 decreases the sulfation of a FLAG epitope appended at the N-terminus of the dopamine D2 receptor. Sulfation alters epitope recognition by some anti-FLAG antibodies, leading to the detection of fewer receptors, even though expression is maintained. This demonstrates that cannabinoid receptor expression modifies posttranslational processing of the FLAG-hD2 receptor, and importantly, has wider implications for the utilisation and interpretation of receptor studies involving epitope tags. PMID:27273047

  6. Cod Liver Oil

    MedlinePlus

    ... Talk with your health provider.Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs)Cod liver oil might slow blood clotting. Taking cod liver oil along with medications that ...

  7. Liver (Hepatocellular) Cancer Prevention

    MedlinePlus

    ... Liver cancer is not common in the United States. Liver cancer is the fourth most common cancer and the third leading cause of cancer death in the world. In the United States, men, especially Chinese American men, have an increased ...

  8. Fatty liver - nonalcoholic

    MedlinePlus

    ... American Gastroenterological Association. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and ...

  9. Alcoholic liver disease

    MedlinePlus

    ... blood count (CBC) Liver biopsy Liver function tests Coagulation studies Tests to rule out other diseases include: ... over-the-counter medicines. MEDICINES FROM YOUR DOCTOR "Water pills" (diuretics) to get rid of fluid build- ...

  10. Liver transplant - series (image)

    MedlinePlus

    Liver failure causes many problems, including malnutrition, problems with blood clotting, bleeding form the gastrointestinal tract, and jaundice. Frequently, patients who undergo liver transplantation are quite ill, and require ...

  11. Antioxidants in liver health

    PubMed Central

    Casas-Grajales, Sael; Muriel, Pablo

    2015-01-01

    Liver diseases are a worldwide medical problem because the liver is the principal detoxifying organ and maintains metabolic homeostasis. The liver metabolizes various compounds that produce free radicals (FR). However, antioxidants scavenge FR and maintain the oxidative/antioxidative balance in the liver. When the liver oxidative/antioxidative balance is disrupted, the state is termed oxidative stress. Oxidative stress leads to deleterious processes in the liver and produces liver diseases. Therefore, restoring antioxidants is essential to maintain homeostasis. One method of restoring antioxidants is to consume natural compounds with antioxidant capacity. The objective of this review is to provide information pertaining to various antioxidants found in food that have demonstrated utility in improving liver diseases. PMID:26261734

  12. Diet - liver disease

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/002441.htm Diet - liver disease To use the sharing features on this page, please enable JavaScript. Some people with liver disease must eat a special diet. This diet helps ...

  13. Autoimmune liver disease panel

    MedlinePlus

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cirrhosis. This group of tests helps your health care provider diagnose ...

  14. Alcoholic liver disease

    MedlinePlus

    Liver disease due to alcohol; Cirrhosis or hepatitis - alcoholic; Laennec's cirrhosis ... Alcoholic liver disease occurs after years of heavy drinking. Over time, scarring and cirrhosis can occur. Cirrhosis is the ...

  15. Liver angioscintigraphy: clinical applications.

    PubMed

    Dragoteanu, Mircea; Cotul, Sabin O; Pîgleşan, Cecilia; Tamaş, Stefan

    2004-03-01

    Liver angioscintigraphy (LAS) is a radio-isotope method for the investigation of liver perfusion and its alteration in various hepatic diseases. It measures the arterial and portal venous fractions of total liver blood flow. The percentage of liver blood flow supplied by hepatic artery is estimated mathematically by the hepatic perfusion index (HPI), normally between 25 % and 40 %. The decrease of portal blood flow in liver cirrhosis is compensated ("buffer" mechanisms) by increased arterial supply, with higher HPI value. For a patient with chronic liver disease, HPI over 50% suggests arterialization of hepatic perfusion, guiding the diagnose to liver cirrhosis. Splenic curve is completing the diagnostic information of the hepatic curve. Corroborated with per rectal scintigraphy and liver SPECT, LAS offers a good hemodynamic staging of chronic inflammatory liver diseases. Malignant tumors (primitive or metastases) increase the arterial supply of the liver and decrease the portal flow, HPI being over 50% (currently 65 % - 90 %). Benign tumors do not change portal/arterial liver blood flow ratio. SPECT or non-scintigraphic morphological investigations increase the diagnostic value of LAS for primitive liver tumors. Liver cancer occurring on cirrhosis is a limitative factor for LAS. Hepatic metastases increase the arterial perfusion (and HPI value) very quickly, before their size allows morphologic imaging diagnosis. LAS is therefore an early method to diagnose liver metastases being especially used in colorectal cancer. Other clinical applications of LAS are: follow up of liver toxicity of drugs, evaluation of portal vein permeability, post surgery follow up of the liver tumor patients. PMID:15054528

  16. Cell Therapies for Liver Diseases

    PubMed Central

    Yu, Yue; Fisher, James E.; Lillegard, Joseph B.; Rodysill, Brian; Amiot, Bruce; Nyberg, Scott L.

    2011-01-01

    Cell therapies, which include bioartificial liver support and hepatocyte transplantation, have emerged as potential treatments for a variety of liver diseases. Acute liver failure (ALF), acute-on-chronic liver failure, and inherited metabolic liver diseases are examples of liver diseases that have been successfully treated with cell therapies at centers around the world. Cell therapies also have the potential for wide application in other liver diseases, including non-inherited liver diseases and liver cancer, and in improving the success of liver transplantation. Here we briefly summarize current concepts of cell therapy for liver diseases. PMID:22140063

  17. Liver Transplantation for Alcoholic Liver Disease.

    PubMed

    Addolorato, Giovanni; Bataller, Ramón; Burra, Patrizia; DiMartini, Andrea; Graziadei, Ivo; Lucey, Michael R; Mathurin, Philippe; OʼGrady, John; Pageaux, Georges; Berenguer, Marina

    2016-05-01

    Alcohol-related liver disease is the second most frequent indication for liver transplantation (LT), yet as many as 90% to 95% of patients with alcohol-related end-stage liver disease are never formally evaluated for LT. Furthermore, despite its significance as a cause of chronic liver disease and indication for LT, it has received little attention in recent years for several reasons, including the good posttransplant short-term results, and the lack of specific "drugs" used for this disease. A writing group, endorsed by the International Liver Transplant Society, was convened to write guidelines on Liver Transplantation for Alcoholic Liver Disease to summarize current knowledge and provide answers to controversial and delicate ethical as well as clinical problems. We report here a short version of the guidelines (long version available at www.ilts.org) with the final recommendations graded for level of evidence. The writing group membership is expected to remain active for 5 years, reviewing the guideline annually, and updating the online version when appropriate. PMID:26985744

  18. Acute liver failure and liver transplantation.

    PubMed

    Akamatsu, Nobuhisa; Sugawara, Yasuhiko; Kokudo, Norihiro

    2013-08-01

    Acute liver failure (ALF) is defined by the presence of coagulopathy (International Normalized Ratio ≥ 1.5) and hepatic encephalopathy due to severe liver damage in patients without pre-existing liver disease. Although the mortality due to ALF without liver transplantation is over 80%, the survival rates of patients have considerably improved with the advent of liver transplantation, up to 60% to 90% in the last two decades. Recent large studies in Western countries reported 1, 5, and 10-year patient survival rates after liver transplantation for ALF of approximately 80%, 70%, and 65%, respectively. Living donor liver transplantation (LDLT), which has mainly evolved in Asian countries where organ availability from deceased donors is extremely scarce, has also improved the survival rate of ALF patients in these regions. According to recent reports, the overall survival rate of adult ALF patients who underwent LDLT ranges from 60% to 90%. Although there is still controversy regarding the graft type, optimal graft volume, and ethical issues, LDLT has become an established treatment option for ALF in areas where the use of deceased donor organs is severely restricted. PMID:25343108

  19. Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo.

    PubMed

    Ren, Xin; Liu, Hao; Zhang, Mingjie; Wang, Mengjun; Ma, Shiyin

    2016-09-01

    Hypopharyngeal cancer is a distinct type of malignant head and neck tumor, which exhibits low sensitivity to anti-cancer drugs. The importance of developing methods for reducing chemotherapy resistance, and improving and enhancing prognosis has previously been emphasized and is considered a challenge for effective clinical treatment of hypopharyngeal cancer. The current study investigated the effects of co‑expression of inhibitor of growth protein 4 (ING4) and P53, a tumor suppressor gene, on chemosensitivity to cisplatin in human hypopharyngeal cancer xenografts in vivo, and the potential molecular mechanisms involved. A tumor model was established by injecting athymic nude mice with FADU human hypopharyngeal cancer cells. Five days after intratumoral and peritumoral injections of an empty adenoviral vector (Ad), Ad‑ING4‑P53, cisplatin, or a combination of Ad‑ING4‑P53 and cisplatin (Ad‑ING4‑P53 + cisplatin) every other day for 5 days, the mice were euthanized and their tumors, livers, and kidneys were removed. The tumor weights were used to calculate the inhibition rate, and the expression levels of ING4 and P53 were detected by reverse transcription‑polymerase chain reaction. Additionally, apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunohistochemistry determined the levels ING4, P53, B‑cell lymphoma‑2 (Bcl‑2) and Bcl‑2 associated X protein (Bax) protein expression. The results demonstrated increased expression of ING4 and P53 in the Ad‑ING4‑P53 groups compared with PBS and Ad groups, indicating successful introduction of the genes into the tumor cells. Notably, the Ad‑ING4‑P53 + cisplatin group exhibited a higher inhibition rate compared with the four other groups. The results of immunohistochemistry analysis demonstrated that Bax expression was increased and Bcl‑2 was decreased in the Ad‑ING4‑P53 + cisplatin group. This suggested that the enhanced

  20. A moth pheromone brewery: production of (Z)-11-hexadecenol by heterologous co-expression of two biosynthetic genes from a noctuid moth in a yeast cell factory

    PubMed Central

    2013-01-01

    Background Moths (Lepidoptera) are highly dependent on chemical communication to find a mate. Compared to conventional unselective insecticides, synthetic pheromones have successfully served to lure male moths as a specific and environmentally friendly way to control important pest species. However, the chemical synthesis and purification of the sex pheromone components in large amounts is a difficult and costly task. The repertoire of enzymes involved in moth pheromone biosynthesis in insecta can be seen as a library of specific catalysts that can be used to facilitate the synthesis of a particular chemical component. In this study, we present a novel approach to effectively aid in the preparation of semi-synthetic pheromone components using an engineered vector co-expressing two key biosynthetic enzymes in a simple yeast cell factory. Results We first identified and functionally characterized a ∆11 Fatty-Acyl Desaturase and a Fatty-Acyl Reductase from the Turnip moth, Agrotis segetum. The ∆11-desaturase produced predominantly Z11-16:acyl, a common pheromone component precursor, from the abundant yeast palmitic acid and the FAR transformed a series of saturated and unsaturated fatty acids into their corresponding alcohols which may serve as pheromone components in many moth species. Secondly, when we co-expressed the genes in the Brewer’s yeast Saccharomyces cerevisiae, a set of long-chain fatty acids and alcohols that are not naturally occurring in yeast were produced from inherent yeast fatty acids, and the presence of (Z)-11-hexadecenol (Z11-16:OH), demonstrated that both heterologous enzymes were active in concert. A 100 ml batch yeast culture produced on average 19.5 μg Z11-16:OH. Finally, we demonstrated that oxidized extracts from the yeast cells containing (Z)-11-hexadecenal and other aldehyde pheromone compounds elicited specific electrophysiological activity from male antennae of the Tobacco budworm, Heliothis virescens, supporting the idea that

  1. FXR and liver carcinogenesis

    PubMed Central

    Huang, Xiong-fei; Zhao, Wei-yu; Huang, Wen-dong

    2015-01-01

    Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer. PMID:25500874

  2. Coffee and Liver Disease.

    PubMed

    Wadhawan, Manav; Anand, Anil C

    2016-03-01

    Coffee is the most popular beverage in the world. Consumption of coffee has been shown to benefit health in general, and liver health in particular. This article reviews the effects of coffee intake on development and progression of liver disease due to various causes. We also describe the putative mechanisms by which coffee exerts the protective effect. The clinical evidence of benefit of coffee consumption in Hepatitis B and C, as well as nonalcoholic fatty liver disease and alcoholic liver disease, has also been presented. Coffee consumption is associated with improvement in liver enzymes (ALT, AST, and GGTP), especially in individuals with risk for liver disease. Coffee intake more than 2 cups per day in patients with preexisting liver disease has been shown to be associated with lower incidence of fibrosis and cirrhosis, lower hepatocellular carcinoma rates, as well as decreased mortality. PMID:27194895

  3. [Tumours and liver transplants].

    PubMed

    Mejzlík, Vladimír; Husová, Libuše; Kuman, Milan; Štěpánková, Soňa; Ondrášek, Jiří; Němec, Petr

    2015-01-01

    Liver transplantation as a curative treatment method can be used for selected primary liver tumours, in particular for hepatocellular carcinoma and rather rare semi-malignant tumours such as epithelioid hemangioendothelioma, further for infiltration of liver by metastatic neuroendocrine tumours (provided that metastases are only located in the liver and the primary tumour was removed) and for benign tumours (hemangiomas and adenomas) with oppression symptoms and size progression. Cholangiocarcinoma is not indicated for liver transplantation at the CKTCH Brno. In recent years liver transplants for hepatocellular carcinoma have increased and hepatocellular carcinoma has also been more frequently found ex post, in the explanted livers. Liver transplantation is indicated in selected patients with a good chance of long-term survival after liver transplantation (a generally accepted limit is 5 year survival of 50 % after transplantation). By 20 March 2015 there were liver transplants carried out on 38 patients - in 25 of them was hepatocellular carcinoma diagnosed before transplantation and in 13 it was found in the liver explants. 5 year survival following transplantation is reached by 53 % of this cohort. 32 % patients suffered from chronic hepatitis C. The longest surviving (32 years) patient at CKTCH Brno had liver transplanted for a big fibrolamellar hepatocellular carcinoma, which points to the prognostic significance of tumour histology: the criterion only considered in some indication schemes for practical reasons. Benign liver tumours (adenomatosis, cystadenoma, hemangioma with oppression symptoms) are rather rare indications and the transplantation results are favourable. 4 patients underwent transplantation for infiltration of liver by carcinoid, tumour recurrence occurred in one. PMID:26375706

  4. Engineering of Saccharomyces cerevisiae to utilize xylan as a sole carbohydrate source by co-expression of an endoxylanase, xylosidase and a bacterial xylose isomerase.

    PubMed

    Mert, Marlin John; la Grange, Daniël Coenrad; Rose, Shaunita Hellouise; van Zyl, Willem Heber

    2016-04-01

    Xylan represents a major component of lignocellulosic biomass, and its utilization by Saccharomyces cerevisiae is crucial for the cost effective production of ethanol from plant biomass. A recombinant xylan-degrading and xylose-assimilating Saccharomyces cerevisiae strain was engineered by co-expression of the xylanase (xyn2) of Trichoderma reesei, the xylosidase (xlnD) of Aspergillus niger, the Scheffersomyces stipitis xylulose kinase (xyl3) together with the codon-optimized xylose isomerase (xylA) from Bacteroides thetaiotaomicron. Under aerobic conditions, the recombinant strain displayed a complete respiratory mode, resulting in higher yeast biomass production and consequently higher enzyme production during growth on xylose as carbohydrate source. Under oxygen limitation, the strain produced ethanol from xylose at a maximum theoretical yield of ~90 %. This study is one of only a few that demonstrates the construction of a S. cerevisiae strain capable of growth on xylan as sole carbohydrate source by means of recombinant enzymes. PMID:26749525

  5. Microcystin accumulation in liver and muscle of tilapia in two large Brazilian hydroelectric reservoirs.

    PubMed

    Deblois, Charles P; Aranda-Rodriguez, Rocio; Giani, Alessandra; Bird, David F

    2008-03-01

    The objective of this study was to measure levels of the toxin microcystin in different tissues of fish known to feed on cyanobacteria during toxic bloom events. Wild Nile and redbreast tilapia (Oreochromis niloticus and Tilapia rendalli) were sampled from the catch of artisanal fishermen at eutrophic stations of Funil and Furnas reservoirs in southeastern Brazil. Phytoplankton communities in the two reservoirs were quite different taxonomically, but not dissimilar in microcystin content (200 microg g dry weight (DW) seston(-1) at Funil, 800 microg gDW seston(-1) at Furnas). All of the 27 fish sampled contained microcystin, ranging from 0.8 to 32.1 microg g liver(-1) and from 0.9 to 12.0 ng g muscle(-1). Most microcystin variants found in seston were also found in fish liver. T. rendalli had the lowest concentration in both tissues when compared to O. niloticus. In both reservoirs, one of every four fish sampled, always O. niloticus, had a level of microcystins beyond the World Health Organization tolerable daily intake (8 ng g tissue(-1)) and represented a risk for consumers. It is possible that closer study of inter-species variability in toxin burden in cyanobacteria-impacted water bodies will permit the development of guidelines for fish consumption that will better protect public health. PMID:18067935

  6. Mining the bladder cancer-associated genes by an integrated strategy for the construction and analysis of differential co-expression networks

    PubMed Central

    2015-01-01

    Background Bladder cancer is the most common malignant tumor of the urinary system and it is a heterogeneous disease with both superficial and invasive growth. However, its aetiological agent is still unclear. And it is indispensable to find key genes or modules causing the bladder cancer. Based on gene expression microarray datasets, constructing differential co-expression networks (DCNs) is an important method to investigate diseases and there have been some relevant good tools such as R package 'WGCNA', 'DCGL'. Results Employing an integrated strategy, 36 up-regulated differentially expressed genes (DEGs) and 356 down-regulated DEGs were selected and main functions of those DEGs are cellular physiological precess(24 up-regulated DEGs; 167 down-regulated DEGs) and cellular metabolism (19 up-regulated DEGs; 104 down-regulated DEGs). The up-regulated DEGs are mainly involved in the the pathways related to "metabolism". By comparing two DCNs between the normal and cancer states, we found some great changes in hub genes and topological structure, which suggest that the modules of two different DCNs change a lot. Especially, we screened some hub genes of a differential subnetwork between the normal and the cancer states and then do bioinformatics analysis for them. Conclusions Through constructing and analyzing two differential co-expression networks at different states using the screened DEGs, we found some hub genes associated with the bladder cancer. The results of the bioinformatics analysis for those hub genes will support the biological experiments and the further treatment of the bladder cancer. PMID:25707808

  7. Yeast gene CMR1/YDL156W is consistently co-expressed with genes participating in DNA-metabolic processes in a variety of stringent clustering experiments

    PubMed Central

    Abu-Jamous, Basel; Fa, Rui; Roberts, David J.; Nandi, Asoke K.

    2013-01-01

    The binarization of consensus partition matrices (Bi-CoPaM) method has, among its unique features, the ability to perform ensemble clustering over the same set of genes from multiple microarray datasets by using various clustering methods in order to generate tunable tight clusters. Therefore, we have used the Bi-CoPaM method to the most synchronized 500 cell-cycle-regulated yeast genes from different microarray datasets to produce four tight, specific and exclusive clusters of co-expressed genes. We found 19 genes formed the tightest of the four clusters and this included the gene CMR1/YDL156W, which was an uncharacterized gene at the time of our investigations. Two very recent proteomic and biochemical studies have independently revealed many facets of CMR1 protein, although the precise functions of the protein remain to be elucidated. Our computational results complement these biological results and add more evidence to their recent findings of CMR1 as potentially participating in many of the DNA-metabolism processes such as replication, repair and transcription. Interestingly, our results demonstrate the close co-expressions of CMR1 and the replication protein A (RPA), the cohesion complex and the DNA polymerases α, δ and ɛ, as well as suggest functional relationships between CMR1 and the respective proteins. In addition, the analysis provides further substantial evidence that the expression of the CMR1 gene could be regulated by the MBF complex. In summary, the application of a novel analytic technique in large biological datasets has provided supporting evidence for a gene of previously unknown function, further hypotheses to test, and a more general demonstration of the value of sophisticated methods to explore new large datasets now so readily generated in biological experiments. PMID:23349438

  8. Co-expression of the protease furin in Nicotiana benthamiana leads to efficient processing of latent transforming growth factor-β1 into a biologically active protein.

    PubMed

    Wilbers, Ruud H P; Westerhof, Lotte B; van Raaij, Debbie R; van Adrichem, Marloes; Prakasa, Andreas D; Lozano-Torres, Jose L; Bakker, Jaap; Smant, Geert; Schots, Arjen

    2016-08-01

    Transforming growth factor beta (TGF-β) is a signalling molecule that plays a key role in developmental and immunological processes in mammals. Three TGF-β isoforms exist in humans, and each isoform has unique therapeutic potential. Plants offer a platform for the production of recombinant proteins, which is cheap and easy to scale up and has a low risk of contamination with human pathogens. TGF-β3 has been produced in plants before using a chloroplast expression system. However, this strategy requires chemical refolding to obtain a biologically active protein. In this study, we investigated the possibility to transiently express active human TGF-β1 in Nicotiana benthamiana plants. We successfully expressed mature TGF-β1 in the absence of the latency-associated peptide (LAP) using different strategies, but the obtained proteins were inactive. Upon expression of LAP-TGF-β1, we were able to show that processing of the latent complex by a furin-like protease does not occur in planta. The use of a chitinase signal peptide enhanced the expression and secretion of LAP-TGF-β1, and co-expression of human furin enabled the proteolytic processing of latent TGF-β1. Engineering the plant post-translational machinery by co-expressing human furin also enhanced the accumulation of biologically active TGF-β1. This engineering step is quite remarkable, as furin requires multiple processing steps and correct localization within the secretory pathway to become active. Our data demonstrate that plants can be a suitable platform for the production of complex proteins that rely on specific proteolytic processing. PMID:26834022

  9. [Construction and expression of a eukaryotic vector co-expressing immunodominant antigens of CFP10, ESAT6, Ag85A and Ag85B of Mycobacterium tuberculosis].

    PubMed

    Li, Wu; Deng, Guangcun; Liu, Xiaoming; Wang, Yujiong

    2014-02-01

    CFP10, ESAT6, Antigen 85A (Ag85A) and antigen 85B (Ag85B) are the key immunodominant antigens of Mycobacterium tuberculosis. In order to construct a eukaryotic vector able to co-express the four genes in one vector, we amplified the target gene fragments encoding the CFP10, ESAT6, Ag85A and Ag85B antigens and inserted them into the multicloning site of the shuttle plasmid vector pcDNA3.1 (+), of which the CFP10 and ESAT6 encoding genes were in frame fused with a linker encoding (Gly4Ser)3 residue, before the fused gene was inserted downstream of CMV promoter with a bovine growth hormone poly A(BGH pA) sequence at the 3'-end; Ag85A and Ag85B encoding genes were fused with a separation of internal ribosome entry site (IRES) sequence before the fused gene cassette was inserted downstream of RSV promoter with a BGH pA sequence at the 3'-end. The final plasmid containing all four genes was confirmed by sequence analysis and designated as pcDNA-CFP10-ESAT6-Ag85A-Ag85B (pcDNA-CEAB). In order to verify the ability of this construct to express target proteins, we then transfected the recombinant plasmid into Human embryonic kidney (HEK) 293T cells and harvested the cell lysates, and the cell lysates were then separated by SDS-PAGE and subjected to Western blot analysis 48 h after transfection. All four of the target proteins were detected in the cell lysates against the respective specific antibodies, suggesting that we have successfully constructed a eukaryotic vector co-expressing the four immunodominant antigens of Mycobacterium tuberculosis, which lay a foundation for the further study of the immunogenicity and protective activity of the four antigens. PMID:24941747

  10. [Liver and drug metabolism].

    PubMed

    Mikheeva, O M

    2011-01-01

    Liver metabolism aims to change the biological activity of drugs to make them water-soluble to be excreted with bile and urine. The degree of metabolism depends on fermentative capacity for each drag (P450 fermentative system is localized in microsomal fraction of hepatocyte). Metabolism ability also changes under the influence of other substances. Liver diseases lead up to decrease of drug clirens and to increase the semi-excretion time because of reduction of liver metabolism. Therefore the drags usually undergoing intensive liver metabolism necessitate a high risk of overdose when liver diseases present. On the other hand no risk of overdose exist when drags with low liver metabolism are used. PMID:21560652

  11. Liver transplantation in India.

    PubMed

    Narasimhan, Gomathy; Kota, Venugopal; Rela, Mohamed

    2016-07-01

    Liver transplantation as an established form of treatment for end-stage liver disease has gained acceptance in India over the last 10 years. Liver transplantation in India has unique features that have contributed to the growth of both deceased donor and living donor transplantations of which living donor currently dominates the picture. Living donor contributes to 80% and deceased donor to 20% of the liver transplants currently performed in India. The majority of these transplants are performed within the private sector with public sector hospitals lagging behind significantly. This article gives an overview of the evolution of liver transplantation in India and the potential future challenges. Liver Transplantation 22 1019-1024 2016 AASLD. PMID:27082718

  12. Tolerance Induction in Liver.

    PubMed

    Karimi, M H; Geramizadeh, B; Malek-Hosseini, S A

    2015-01-01

    Liver is an exclusive anatomical and immunological organ that displays a considerable tolerance effect. Liver allograft acceptance is shown to occur spontaneously within different species. Although in human transplant patients tolerance is rarely seen, the severity level and cellular mechanisms of transplant rejection vary. Non-paranchymal liver cells, including Kupffer cells, liver sinusoidal endothelial cells, hepatic stellate cells, and resident dendritic cells may participate in liver tolerogenicity. The mentioned cells secret anti-inflammatory cytokines such as TGF-β and IL-10 and express negative co-stimulatory molecules like PD-L1 to mediate immunosuppression. Other mechanisms such as microchimerism, soluble major histocompatibility complex and regulatory T cells may take part in tolerance induction. Understanding the mechanisms involved in liver transplant rejection/tolerance helps us to improve therapeutic options to induce hepatic tolerance. PMID:26082828

  13. Robotic liver surgery

    PubMed Central

    Leung, Universe

    2014-01-01

    Robotic surgery is an evolving technology that has been successfully applied to a number of surgical specialties, but its use in liver surgery has so far been limited. In this review article we discuss the challenges of minimally invasive liver surgery, the pros and cons of robotics, the evolution of medical robots, and the potentials in applying this technology to liver surgery. The current data in the literature are also presented. PMID:25392840

  14. Statins and the Liver.

    PubMed

    Herrick, Cynthia; Bahrainy, Samira; Gill, Edward A

    2016-03-01

    Lipid lowering, particularly with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins"), reduces the risk of cardiovascular disease. Patients with chronic liver disease present challenges to the use of lipid medications. In the case of most liver disorders, the concern has been one of safety. There is evidence that most lipid-lowering medications can be used safely in many situations, although large outcomes trials are lacking. This review examines lipid physiology and cardiovascular risk in specific liver diseases and reviews the evidence for lipid lowering and the use of statins in chronic liver disease. PMID:26893001

  15. Human Liver Progenitor Cells for Liver Repair

    PubMed Central

    Lombard, Catherine A.; Prigent, Julie; Sokal, Etienne M.

    2013-01-01

    Because of their high proliferative capacity, resistance to cryopreservation, and ability to differentiate into hepatocyte-like cells, stem and progenitor cells have recently emerged as attractive cell sources for liver cell therapy, a technique used as an alternative to orthotopic liver transplantation in the treatment of various hepatic ailments ranging from metabolic disorders to end-stage liver disease. Although stem and progenitor cells have been isolated from various tissues, obtaining them from the liver could be an advantage for the treatment of hepatic disorders. However, the techniques available to isolate these stem/progenitor cells are numerous and give rise to cell populations with different morphological and functional characteristics. In addition, there is currently no established consensus on the tests that need to be performed to ensure the quality and safety of these cells when used clinically. The purpose of this review is to describe the different types of liver stem/progenitor cells currently reported in the literature, discuss their suitability and limitations in terms of clinical applications, and examine how the culture and transplantation techniques can potentially be improved to achieve a better clinical outcome. PMID:26858860

  16. Liver transplantation for polycystic liver disease.

    PubMed

    Pirenne, J; Aerts, R; Yoong, K; Gunson, B; Koshiba, T; Fourneau, I; Mayer, D; Buckels, J; Mirza, D; Roskams, T; Elias, E; Nevens, F; Fevery, J; McMaster, P

    2001-03-01

    Polycystic liver disease (PLD) may provoke massive hepatomegaly and severe physical and social handicaps. Data on orthotopic liver transplantation (OLT) for PLD are rare and conflicting. Conservative surgery (resection or fenestration) is indicated for large single cysts, but its value for small diffuse cysts is questionable. In addition, conservative surgery is not devoid of morbidity and mortality. OLT offers the prospect of a fully curative treatment, but controversy remains because those patients usually have preserved liver function. Thus, we reviewed our experience with OLT for PLD. Sixteen adult women underwent OLT for small diffuse PLD between 1990 and 1999. Mean age was 45 years (range, 34 to 56 years). Fourteen patients had combined liver and kidney cystic disease, but only 1 patient required combined liver and kidney transplantation, whereas 13 patients underwent OLT alone. Two patients had isolated PLD. Indications for transplantation were massive hepatomegaly causing physical handicaps (n = 16), social handicaps (n = 16), malnutrition (n = 4), and cholestasis and/or portal hypertension (n = 5). OLT caused no technical difficulty in 15 of 16 patients (surgery duration, 6.8 hours; range, 5 to 8 hours), with blood transfusions of 7.9 units (range, 0 to 22 units). One patient who underwent attempted liver-mass reduction pre-OLT died of bleeding and pulmonary emboli. Native liver weight was 10 to 20 kg. Posttransplantation immunosuppression consisted of cyclosporine or FK506, azathioprine, and steroids (discontinued at 3 months). Morbidity included biliary stricture (2 patients), revision for bleeding and hepatitis (1 patient), pneumothorax and subphrenic collection (1 patient), and tracheostomy (1 patient). One patient died of lung cancer 6 years posttransplantation. Both patient and graft survival rates are 87.5% (follow-up, 3 months to 9 years). Of 15 patients who underwent OLT alone, only 1 patient needed a kidney transplant 4 years after OLT. Kidney

  17. Nonalcoholic Fatty Liver Disease and Liver Transplantation.

    PubMed

    Pham, Tuan; Dick, Travis B; Charlton, Michael R

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is prevalent in the general population and a growing indication for liver transplant. Longer wait times and challenges with pretransplant survivorship are expected, underscoring the need for improved management of attendant comorbidities. Recognition with potential modification of obesity, sarcopenia, chronic kidney disease, and cardiovascular disease in patients with NAFLD may have important implications in the pretransplant and posttransplant periods. Although patients with NAFLD have generally favorable postoperative outcomes, they are at risk for developing recurrent disease in their allograft, driving the need for pharmacotherapies and dietary innovations appropriate for use in the posttransplant period. PMID:27063277

  18. The impact of high co-expression of Sp1 and HIF1α on prognosis of patients with hepatocellular cancer

    PubMed Central

    LIU, LIANG; JI, PING; QU, NING; PU, WEI-LIN; JIANG, DAO-WEN; LIU, WEI-YAN; LI, YA-QI; SHI, RONG-LIANG

    2016-01-01

    Transcription factor specificity protein 1 (Sp1) and hypoxia-inducible factor 1α (HIF1α) serve vital roles in tumor growth and metastasis. The present study aimed to evaluate the impact of co-expression of Sp1 and HIF1α on the prognosis of patients with hepatocellular cancer (HCC) using The Cancer Genome Atlas (TCGA) database and to validate the association between the expression levels of Sp1/HIF1α in HCC specimens and patient survival using immunohistochemical analysis. A total of 214 eligible patients with HCC from TCGA database were collected for the study. The expression profile of Sp1 and HIF1α were obtained from the TCGA RNAseq database. Clinicopathological characteristics, including age, height, weight, gender, race, ethnicity, family cancer history, serum α-fetoprotein (AFP), surgical procedures and TNM stage were collected. The Cox proportional hazards regression model and Kaplan-Meier curves were used to assess the relative factors. Receiver operating characteristic (ROC) curves for cancer-specific survival (CSS) prediction were plotted to compare the prediction ability of expression of Sp1 and HIF1α and their co-expression. The location and expression of Sp1 and HIF1α in the HCC tissues were detected by immunohistochemistry (IHC) to verify the association between these two genes and CSS. The results demonstrated that the expressions of Sp1 and HIF1α were significantly increased in the succumbed group (P=0.001), compared with the surviving group. The CSS rates were 60.1% at 3 years (1,067 days), 35.8% at 5 years (1,823 days) and 9.5% at 10 years (3,528 days). Multivariate Cox regression analysis demonstrated that only the high expression levels of Sp1 and HIF1α (≥2×103) were independent predictors for cancer mortality, with P=0.001 and P=0.029, respectively. The area under the curve for the ROC was found to be higher using the combination testing for two genes (0.751) in predicting cancer mortality, compared to a single gene (0.632 for Sp1

  19. About the Operation: Liver Transplant

    MedlinePlus

    ... Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Liver Transplant There are two very different surgical approaches to liver transplantation: the orthotopic and the heterotopic approach, both of ...

  20. About the Operation: Liver Transplant

    MedlinePlus

    ... Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Liver Transplant There are two very different surgical approaches to liver transplantation: the orthotopic and the heterotopic approach, both ...

  1. Liver Cell Culture Devices

    PubMed Central

    Andria, B.; Bracco, A.; Cirino, G.; Chamuleau, R. A. F. M.

    2010-01-01

    In the last 15 years many different liver cell culture devices, consisting of functional liver cells and artificial materials, have been developed. They have been devised for numerous different applications, such as temporary organ replacement (a bridge to liver transplantation or native liver regeneration) and as in vitro screening systems in the early stages of the drug development process, like assessing hepatotoxicity, hepatic drug metabolism, and induction/inhibition studies. Relevant literature is summarized about artificial human liver cell culture systems by scrutinizing PubMed from 2003 to 2009. Existing devices are divided in 2D configurations (e.g., static monolayer, sandwich, perfused cells, and flat plate) and 3D configurations (e.g., liver slices, spheroids, and different types of bioreactors). The essential features of an ideal liver cell culture system are discussed: different types of scaffolds, oxygenation systems, extracellular matrixes (natural and artificial), cocultures with nonparenchymal cells, and the role of shear stress problems. Finally, miniaturization and high-throughput systems are discussed. All these factors contribute in their own way to the viability and functionality of liver cells in culture. Depending on the aim for which they are designed, several good systems are available for predicting hepatotoxicity and hepatic metabolism within the general population. To predict hepatotoxicity in individual cases genomic analysis might be essential as well. PMID:26998397

  2. Nutrition and liver diseases.

    PubMed

    Teran, J C

    1999-08-01

    Malnutrition and micronutrient deficiencies are common in patients with liver diseases. The pathogenesis of protein-energy malnutrition in cirrhosis involves many factors, including poor oral intake, malabsorption, and metabolic abnormalities similar to stress. Encephalopathy may complicate cirrhosis but is usually not caused by diet. Protein restriction is only necessary in rare patients with refractory encephalopathy. The use of branched-chain amino-acid solutions is not supported by the literature. Chronic liver diseases without cirrhosis are not usually associated with protein-energy malnutrition, but vitamin and mineral deficiencies are common, especially with significant cholestasis. Fatty liver may result from excessive triglyceride uptake and production by the liver or by a secretory defect. Therapy for fatty liver depends on its cause. Chronic total parenteral nutrition may induce fatty liver and inflammation especially in patients with short-bowel syndrome. Deficiency of choline in parenteral nutrition has been proposed as the mechanism for liver disease. Acute liver diseases such as fulminant hepatic failure or alcoholic hepatitis are considered hypercatabolic diseases and thus require prompt nutritional intervention with a high-calorie enteral or parenteral formula. In fulminant hepatic failure, low-protein, fluid-restricted formulas are recommended. PMID:10980970

  3. Bmi1 Is Required for Hepatic Progenitor Cell Expansion and Liver Tumor Development

    PubMed Central

    Wang, Chunmei; Tao, Junyan; Ho, Coral; Jiang, Lijie; Gui, Bing; Huang, Shiang; Evert, Matthias; Calvisi, Diego F.; Chen, Xin

    2012-01-01

    Bmi1 is a polycomb group transcriptional repressor and it has been implicated in regulating self-renewal and proliferation of many types of stem or progenitor cells. In addition, Bmi1 has been shown to function as an oncogene in multiple tumor types. In this study, we investigated the functional significance of Bmi1 in regulating hepatic oval cells, the major type of bipotential progenitor cells in adult liver, as well as the role of Bmi1 during hepatocarcinogenesis using Bmi1 knockout mice. We found that loss of Bmi1 significantly restricted chemically induced oval cell expansion in the mouse liver. Concomitant deletion of Ink4a/Arf in Bmi1 deficient mice completely rescued the oval cell expansion phenotype. Furthermore, ablation of Bmi1 delayed hepatocarcinogenesis induced by AKT and Ras co-expression. This antineoplastic effect was accompanied by the loss of hepatic oval cell marker expression in the liver tumor samples. In summary, our data demonstrated that Bmi1 is required for hepatic oval cell expansion via deregulating the Ink4a/Arf locus in mice. Our study also provides the evidence, for the first time, that Bmi1 expression is required for liver cancer development in vivo, thus representing a promising target for innovative treatments against human liver cancer. PMID:23029524

  4. ESR1 Is Co-Expressed with Closely Adjacent Uncharacterised Genes Spanning a Breast Cancer Susceptibility Locus at 6q25.1

    PubMed Central

    Dunbier, Anita K.; Anderson, Helen; Ghazoui, Zara; Lopez-Knowles, Elena; Pancholi, Sunil; Ribas, Ricardo; Drury, Suzanne; Sidhu, Kally; Leary, Alexandra; Martin, Lesley-Ann; Dowsett, Mitch

    2011-01-01

    Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast cancer risk. Our investigation of factors associated with the level of expression of ESR1 in ER+ve tumours has revealed unexpected associations between genes in this region and ESR1 expression that are important to consider in studies of the genetic causes of breast cancer risk. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with an aromatase (oestrogen synthase) inhibitor was analyzed on Illumina 48K microarrays. Multiple-testing corrected Spearman correlation revealed that three previously uncharacterized open reading frames (ORFs) located immediately upstream of ESR1, C6ORF96, C6ORF97, and C6ORF211 were highly correlated with ESR1 (Rs = 0.67, 0.64, and 0.55 respectively, FDR<1×10−7). Publicly available datasets confirmed this relationship in other groups of ER+ve tumours. DNA copy number changes did not account for the correlations. The correlations were maintained in cultured cells. An ERα antagonist did not affect the ORFs' expression or their correlation with ESR1, suggesting their transcriptional co-activation is not directly mediated by ERα. siRNA inhibition of C6ORF211 suppressed proliferation in MCF7 cells, and C6ORF211 positively correlated with a proliferation metagene in tumours. In contrast, C6ORF97 expression correlated negatively with the metagene and predicted for improved disease-free survival in a tamoxifen-treated published dataset, independently of ESR1. Our observations suggest that some of the biological effects previously attributed to ER could be mediated and/or modified by these co-expressed genes. The co-expression and function of these genes may be important influences

  5. Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence.

    PubMed

    Mamdani, Mohammed; Williamson, Vernell; McMichael, Gowon O; Blevins, Tana; Aliev, Fazil; Adkins, Amy; Hack, Laura; Bigdeli, Tim; van der Vaart, Andrew D; Web, Bradley Todd; Bacanu, Silviu-Alin; Kalsi, Gursharan; Kendler, Kenneth S; Miles, Michael F; Dick, Danielle; Riley, Brien P; Dumur, Catherine; Vladimirov, Vladimir I

    2015-01-01

    Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD. PMID:26381263

  6. The Co-Expression Pattern of Odorant Binding Proteins and Olfactory Receptors Identify Distinct Trichoid Sensilla on the Antenna of the Malaria Mosquito Anopheles gambiae

    PubMed Central

    Schultze, Anna; Pregitzer, Pablo; Walter, Marika F.; Woods, Daniel F.; Marinotti, Osvaldo; Breer, Heinz; Krieger, Jürgen

    2013-01-01

    The initial steps of odorant recognition in the insect olfactory system involve odorant binding proteins (OBPs) and odorant receptors (ORs). While large families of OBPs have been identified in the malaria vector A. gambiae, little is known about their expression pattern in the numerous sensory hairs of the female antenna. We applied whole mount fluorescence in Situ hybridization (WM-FISH) and fluorescence immunohistochemistry (WM-FIHC) to investigate the sensilla co-expression of eight A. gambiae OBPs (AgOBPs), most notably AgOBP1 and AgOBP4, which all have abundant transcripts in female antenna. WM-FISH analysis of female antennae using AgOBP-specific probes revealed marked differences in the number of cells expressing each various AgOBPs. Testing combinations of AgOBP probes in two-color WM-FISH resulted in distinct cellular labeling patterns, indicating a combinatorial expression of AgOBPs and revealing distinct AgOBP requirements for various functional sensilla types. WM-FIHC with antisera to AgOBP1 and AgOBP4 confirmed expression of the respective proteins by support cells and demonstrated a location of OBPs within sensilla trichodea. Based on the finding that AgOBP1 and AgOBP4 as well as the receptor type AgOR2 are involved in the recognition of indole, experiments were performed to explore if the AgOBP-types and AgOR2 are co-expressed in distinct olfactory sensilla. Applying two-color WM-FISH with AgOBP-specific probes and probes specific for AgOR2 revealed a close association of support cells bearing transcripts for AgOBP1 and AgOBP4 and neurons with a transcript for the receptor AgOR2. Moreover, combined WM-FISH/-FIHC approaches using an AgOR2-specific riboprobe and AgOBP-specific antisera revealed the expression of the “ligand-matched” AgOBP1, AgOBP4 and AgOR2 to single trichoid hairs. This result substantiates the notion that a specific response to indole is mediated by an interplay of the proteins. PMID:23861970

  7. CorSig: A General Framework for Estimating Statistical Significance of Correlation and Its Application to Gene Co-Expression Analysis

    PubMed Central

    Wang, Hong-Qiang; Tsai, Chung-Jui

    2013-01-01

    With the rapid increase of omics data, correlation analysis has become an indispensable tool for inferring meaningful associations from a large number of observations. Pearson correlation coefficient (PCC) and its variants are widely used for such purposes. However, it remains challenging to test whether an observed association is reliable both statistically and biologically. We present here a new method, CorSig, for statistical inference of correlation significance. CorSig is based on a biology-informed null hypothesis, i.e., testing whether the true PCC (ρ) between two variables is statistically larger than a user-specified PCC cutoff (τ), as opposed to the simple null hypothesis of ρ = 0 in existing methods, i.e., testing whether an association can be declared without a threshold. CorSig incorporates Fisher's Z transformation of the observed PCC (r), which facilitates use of standard techniques for p-value computation and multiple testing corrections. We compared CorSig against two methods: one uses a minimum PCC cutoff while the other (Zhu's procedure) controls correlation strength and statistical significance in two discrete steps. CorSig consistently outperformed these methods in various simulation data scenarios by balancing between false positives and false negatives. When tested on real-world Populus microarray data, CorSig effectively identified co-expressed genes in the flavonoid pathway, and discriminated between closely related gene family members for their differential association with flavonoid and lignin pathways. The p-values obtained by CorSig can be used as a stand-alone parameter for stratification of co-expressed genes according to their correlation strength in lieu of an arbitrary cutoff. CorSig requires one single tunable parameter, and can be readily extended to other correlation measures. Thus, CorSig should be useful for a wide range of applications, particularly for network analysis of high-dimensional genomic data. Software

  8. Co-expression of laminin β3 and γ2 chains and epigenetic inactivation of laminin α3 chain in gastric cancer.

    PubMed

    Ii, Masanori; Yamamoto, Hiroyuki; Taniguchi, Hiroaki; Adachi, Yasushi; Nakazawa, Mayumi; Ohashi, Hirokazu; Tanuma, Tokuma; Sukawa, Yasutaka; Suzuki, Hiromu; Sasaki, Shigeru; Imai, Kohzoh; Shinomura, Yasuhisa

    2011-09-01

    Laminin-332 (LM-332, formerly termed laminin-5) is a heterotrimeric glycoprotein that regulates cell adhesion and migration. Molecular alterations of LM-332 are involved in cancer progression. The aim of this study was to clarify alterations of LM-332 in gastric carcinoma. The expression of LM-332 subunits in 10 gastric carcinoma cell lines was investigated by RT-PCR, Western blotting, and immuno-cytochemical/immunofluorescent analyses. The promoter methylation status of LM-332-encoding genes (LAMA3, LAMB3 and LAMC2) was analyzed by methylation-specific PCR (MSP). The relationship between cell migration and LM-332 expression was assessed by the scratch assay. The expression of LM-332 was analyzed immunohistochemically in 90 gastric cancer tissues. Co-expression of laminin β3 and γ2 chains was often observed in gastric carcinoma cell lines at mRNA and protein levels. In contrast, there was no expression of laminin α3 at either the mRNA or protein levels. Extra-cellular secretion of laminin β3 and γ2 chains was found in 2 of the 10 cell lines. The LAMA3 gene was transcriptionally silenced by methylation of the promoter CpG islands in all of the cell lines, while the LAMB3 and LAMC2 genes were silenced in several cell lines. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), restored expression of the LM-332-encoding genes. Methylation frequency of LAMA3 was higher than those of the LAMB2 and LAMC2 genes in gastric cancer tissues. Migration distances were significantly correlated with cytoplasmic laminin γ2 chain expression. Immunohistochemistry showed frequent co-expression of laminin β3 and γ2 chains in gastric carcinoma cells, which was significantly correlated with depth of invasion and advanced tumor stage. The results suggest that the laminin β3 and γ2 chains accumulate intracellularly and play a role in gastric cancer progression, while epigenetic silencing of the laminin α3 chain may lead to inability to synthesize the basement

  9. Human CD4+CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells

    PubMed Central

    Schuler, P J; Saze, Z; Hong, C-S; Muller, L; Gillespie, D G; Cheng, D; Harasymczuk, M; Mandapathil, M; Lang, S; Jackson, E K; Whiteside, T L

    2014-01-01

    While murine CD4+CD39+ regulatory T cells (Treg) co-express CD73 and hydrolyze exogenous (e) adenosine triphosphate (ATP) to immunosuppressive adenosine (ADO), surface co-expression of CD73 on human circulating CD4+CD39+ Treg is rare. Therefore, the ability of human Treg to produce and utilize ADO for suppression remains unclear. Using mass spectrometry, we measured nucleoside production by subsets of human CD4+CD39+ and CD4+CD39(–)CD73+ T cells or CD19+ B cells isolated from blood of 30 volunteers and 14 cancer patients. CD39 and CD73 expression was evaluated by flow cytometry, Western blots, confocal microscopy or reverse transcription–polymerase chain reaction (RT–PCR). Circulating CD4+CD39+ Treg which hydrolyzed eATP to 5′-AMP contained few intracytoplasmic granules and had low CD73 mRNA levels. Only ∼1% of these Treg were CD39+CD73+. In contrast, CD4+CD39negCD73+ T cells contained numerous CD73+ granules in the cytoplasm and strongly expressed surface CD73. In vitro-generated Treg (Tr1) and most B cells were CD39+CD73+. All these CD73+ T cell subsets and B cells hydrolyzed 5′-AMP to ADO. Exosomes isolated from plasma of normal control (NC) or cancer patients carried enzymatically active CD39 and CD73+ and, when supplied with eATP, hydrolyzed it to ADO. Only CD4+CD39+ Treg co-incubated with CD4+CD73+ T cells, B cells or CD39+CD73+ exosomes produced ADO. Thus, contact with membrane-tethered CD73 was sufficient for ADO production by CD4+CD39+ Treg. In microenvironments containing CD4+CD73+ T cells, B cells or CD39+CD73+ exosomes, CD73 is readily available to CD4+CD39+CD73neg Treg for the production of immunosuppressive ADO. PMID:24749746

  10. Demethionylation of Pro-1 variants of 4-oxalocrotonate tautomerase in Escherichia coli by co-expression with an engineered methionine aminopeptidase

    PubMed Central

    Baas, Bert-Jan; Zandvoort, Ellen; Wasiel, Anna A.; Poelarends, Gerrit J.

    2014-01-01

    4-Oxalocrotonate tautomerase (4-OT) catalyzes the enol-keto tautomerization of 2-hydroxymuconate, utilizing its N-terminal proline (Pro-1) as general base catalyst. Substituting Pro-1 with bulky or charged residues will result in poor or no post-translational removal of the translation-initiating methionine by the methionine aminopeptidase (MetAP) of the Escherichiacoli expression host. Here, we set out to investigate whether co-expression with previously engineered aminopeptidase MetAP-∗TG can be used to produce the P1S, P1H and P1Q variants of 4-OT in a demethionylated form. The P1S variant, which carries a small residue at the penultimate position (the first position after the initiating methionine), was found to be fully processed by wild-type MetAP. The P1S variant has low-level 2-hydroxymuconate tautomerase and promiscuous oxaloacetate decarboxylase activity. The P1Q and P1H variants of 4-OT, which carry bulky residues at the penultimate position, could only be obtained in a demethionylated form (a minor fraction of the purified protein is still composed of methionylated enzyme) by co-expression with MetAP-∗TG. Interestingly, the Gln-1 residue of the demethionylated P1Q variant undergoes intramolecular cyclization to form pyroglutamate (pE), yielding variant P1pE. Whereas the P1H/M1P2H mixture has low-level tautomerase activity, the P1pE/M1P2Q mixture has robust tautomerase activity. The substitution of Pro-1 by Gln, followed by removal of the initiating Met and cyclization of Gln-1 to form pE, is a unique way to obtain a structural analogue of proline on the N-terminus of 4-OT. This opens up new possibilities to study the importance of Pro-1 in recently discovered C–C bond-forming activities of this highly promiscuous tautomerase. PMID:25161874

  11. Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence

    PubMed Central

    Blevins, Tana; Aliev, Fazil; Adkins, Amy; Hack, Laura; Bigdeli, Tim; D. van der Vaart, Andrew; Web, Bradley Todd; Bacanu, Silviu-Alin; Kalsi, Gursharan; Kendler, Kenneth S.; Miles, Michael F.; Dick, Danielle; Riley, Brien P.; Dumur, Catherine; Vladimirov, Vladimir I.

    2015-01-01

    Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD. PMID:26381263

  12. Use of the Foot-and-Mouth Disease Virus 2A Peptide Co-Expression System to Study Intracellular Protein Trafficking in Arabidopsis

    PubMed Central

    Ötvös, Krisztina; Samuelsson, Göran; Bakó, László

    2012-01-01

    Background A tool for stoichiometric co-expression of effector and target proteins to study intracellular protein trafficking processes has been provided by the so called 2A peptide technology. In this system, the 16–20 amino acid 2A peptide from RNA viruses allows synthesis of multiple gene products from single transcripts. However, so far the use of the 2A technology in plant systems has been limited. Methodology/Principal Findings The aim of this work was to assess the suitability of the 2A peptide technology to study the effects exerted by dominant mutant forms of three small GTPase proteins, RABD2a, SAR1, and ARF1 on intracellular protein trafficking in plant cells. Special emphasis was given to CAH1 protein from Arabidopsis, which is trafficking to the chloroplast via a poorly characterized endoplasmic reticulum-to-Golgi pathway. Dominant negative mutants for these GTPases were co-expressed with fluorescent marker proteins as polyproteins separated by a 20 residue self-cleaving 2A peptide. Cleavage efficiency analysis of the generated polyproteins showed that functionality of the 2A peptide was influenced by several factors. This enabled us to design constructs with greatly increased cleavage efficiency compared to previous studies. The dominant negative GTPase variants resulting from cleavage of these 2A peptide constructs were found to be stable and active, and were successfully used to study the inhibitory effect on trafficking of the N-glycosylated CAH1 protein through the endomembrane system. Conclusions/Significance We demonstrate that the 2A peptide is a suitable tool when studying plant intracellular protein trafficking and that transient protoplast and in planta expression of mutant forms of SAR1 and RABD2a disrupts CAH1 trafficking. Similarly, expression of dominant ARF1 mutants also caused inhibition of CAH1 trafficking to a different extent. These results indicate that early trafficking of the plastid glycoprotein CAH1 depends on canonical

  13. Co-expression of Dsb proteins enables soluble expression of a single-chain variable fragment (scFv) against human type 1 insulin-like growth factor receptor (IGF-1R) in E. coli.

    PubMed

    Sun, Xue-Wen; Wang, Xiao-Hua; Yao, Yan-Bing

    2014-12-01

    Type 1 insulin-like growth factor receptor (IGF-1R) is a promising therapeutic target for cancer treatment. A single-chain variable fragment (scFv) against human IGF-1R forms inclusion body when expressed in periplasmic space of E. coli routinely. Here, we described that co-expression of appropriate disulfide bonds (Dsb) proteins known to catalyze the formation and isomerization of Dsb can markedly recover the soluble expression of target scFv in E. coli. A 50 % recovery in solubility of the scFv was observed upon co-expression of DsbC alone, and a maximum solubility (80 %) was obtained when DsbA and DsbC were co-expressed in combination. Furthermore, the soluble scFv present full antigen-binding activity with IGF-1R, suggesting its correct folding. This study also suggested that the selection of Dsb proteins should be tested case-by-case if the approach of co-expression of Dsb system is adopted to address the problem of insoluble expression of proteins carrying Dsb. PMID:25256416

  14. [Liver diseases in the elderly].

    PubMed

    Bruguera, Miguel

    2014-11-01

    Liver diseases in the elderly have aroused less interest than diseases of other organs, since the liver plays a limited role in aging. There are no specific liver diseases of old age, but age-related anatomical and functional modifications of the liver cause changes in the frequency and clinical behavior of some liver diseases compared with those in younger patients. This review discusses the most important features of liver function in the healthy elderly population, as well as the features of the most prevalent liver diseases in this age group, especially the diagnostic approach to the most common liver problems in the elderly: asymptomatic elevation of serum transaminases and jaundice. PMID:24951302

  15. Co-Expression and Co-Localization of Cartilage Glycoproteins CHI3L1 and Lubricin in Osteoarthritic Cartilage: Morphological, Immunohistochemical and Gene Expression Profiles.

    PubMed

    Szychlinska, Marta Anna; Trovato, Francesca Maria; Di Rosa, Michelino; Malaguarnera, Lucia; Puzzo, Lidia; Leonardi, Rosy; Castrogiovanni, Paola; Musumeci, Giuseppe

    2016-01-01

    Osteoarthritis is the most common human arthritis characterized by degeneration of articular cartilage. Several studies reported that levels of human cartilage glycoprotein chitinase 3-like-1 (CHI3L1) are known as a potential marker for the activation of chondrocytes and the progression of Osteoarthritis (OA), whereas lubricin appears to be chondroprotective. The aim of this study was to investigate the co-expression and co-localization of CHI3L1 and lubricin in normal and osteoarthritic rat articular cartilage to correlate their modified expression to a specific grade of OA. Samples of normal and osteoarthritic rat articular cartilage were analyzed by the Kellgren-Lawrence OA severity scores, the Kraus' modified Mankin score and the Histopathology Osteoarthritis Research Society International (OARSI) system for histomorphometric evaluations, and through CHI3L1 and lubricin gene expression, immunohistochemistry and double immuno-staining analysis. The immunoexpression and the mRNA levels of lubricin increased in normal cartilage and decreased in OA cartilage (normal vs. OA, p < 0.01). By contrast, the immunoexpression and the mRNA levels of CHI3L1 increased in OA cartilage and decreased in normal cartilage (normal vs. OA, p < 0.01). Our findings are consistent with reports suggesting that these two glycoproteins are functionally associated with the development of OA and in particular with grade 2/3 of OA, suggesting that in the future they could be helpful to stage the severity and progression of the disease. PMID:26978347

  16. Use of the growing environment as a source of variation to identify the quantitative trait transcripts and modules of co-expressed genes that determine chlorogenic acid accumulation

    PubMed Central

    JOËT, THIERRY; SALMONA, JORDI; LAFFARGUE, ANDRÉINA; DESCROIX, FRÉDÉRIC; DUSSERT, STÉPHANE

    2010-01-01

    Developing Coffea arabica seeds accumulate large amounts of chlorogenic acids (CGAs) as a storage form of phenylpropanoid derivatives, making coffee a valuable model to investigate the metabolism of these widespread plant phenolics. However, developmental and environmental regulations of CGA metabolism are poorly understood. In the present work, the expression of selected phenylpropanoid genes, together with CGA isomer profiles, was monitored throughout seed development across a wide set of contrasted natural environments. Although CGA metabolism was controlled by major developmental factors, the mean temperature during seed development had a direct impact on the time-window of CGA biosynthesis, as well as on final CGA isomer composition through subtle transcriptional regulations. We provide evidence that the variability induced by the environment is a useful tool to test whether CGA accumulation is quantitatively modulated at the transcriptional level, hence enabling detection of rate-limiting transcriptional steps [quantitative trait transcripts (QTTs)] for CGA biosynthesis. Variations induced by the environment also enabled a better description of the phenylpropanoid gene transcriptional network throughout seed development, as well as the detection of three temporally distinct modules of quantitatively co-expressed genes. Finally, analysis of metabolite-to-metabolite relationships revealed new biochemical characteristics of the isomerization steps that remain uncharacterized at the gene level. PMID:20199615

  17. T-cell acute lymphoblastic leukemia with co-expression of CD56, CD34, CD117 and CD33: A case with poor prognosis

    PubMed Central

    Eren, Rafet; Aslan, Ceyda; Yokuş, Osman; Doğu, Mehmet Hilmi; Suyani, Elif

    2016-01-01

    T-cell acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy, accounting for ~25% of all adult cases of ALL. We herein report a case of T-cell ALL exhibiting aberrant CD34, CD56, CD33 and CD117 expression in addition to T-cell markers, which did not respond to induction treatment. A 55-year-old woman was admitted to our hospital with a sore throat unresponsive to medication for 1 month. The laboratory examination revealed pancytopenia and the peripheral blood smear examination revealed blast cells. On flow cytometric analysis, the blast cells were found to be positive for cytoplasmic CD3, CD2, CD5, CD7, CD34, CD56, CD33 and CD117, and negative for myeloperoxidase, CD13, CD11b, CD15, CD19, CD79a, CD22 and CD10. The patient was diagnosed with T-cell ALL according to the 2008 World Health Organisation classification. The patient did not respond to Hyper-cyclophosphamide, vincristine, adriamycin and dexamethasone (CVAD) course A treatment and succumbed to the disease during Hyper-CVAD course B treatment. To the best of our knowledge, this is the first report of aberrant co-expression of the natural killer cell marker CD56, myeloid cell markers CD117 and CD33 and stem cell marker CD34 in a patient with T-cell ALL. This appears to be associated with an unfavorable outcome, despite the use of intensive chemotherapy.

  18. Efficient Production of Hydroxylated Human-Like Collagen Via the Co-Expression of Three Key Genes in Escherichia coli Origami (DE3).

    PubMed

    Tang, Yunping; Yang, Xiuliang; Hang, Baojian; Li, Jiangtao; Huang, Lei; Huang, Feng; Xu, Zhinan

    2016-04-01

    Mature collagen is abundant in human bodies and very valuable for a range of industrial and medical applications. The biosynthesis of mature collagen requires post-translational modifications to increase the stability of collagen triple helix structure. By co-expressing the human-like collagen (HLC) gene with human prolyl 4-hydroxylase (P4H) and D-arabinono-1, 4-lactone oxidase (ALO) in Escherichia coli, we have constructed a prokaryotic expression system to produce the hydroxylated HLC. Then, five different media, as well as the induction conditions were investigated with regard to the soluble expression of such protein. The results indicated that the highest soluble expression level of target HLC obtained in shaking flasks was 49.55 ± 0.36 mg/L, when recombinant cells were grew in MBL medium and induced by 0.1 mM IPTG at the middle stage of exponential growth phase. By adopting the glucose feeding strategy, the expression level of target HLC can be improved up to 260 mg/L in a 10 L bench-top fermentor. Further, HPLC analyses revealed that more than 10 % of proline residues in purified HLC were successfully hydroxylated. The present work has provided a solid base for the large-scale production of hydroxylated HLC in E. coli. PMID:26712247

  19. A Gene Co-Expression Network in Whole Blood of Schizophrenia Patients Is Independent of Antipsychotic-Use and Enriched for Brain-Expressed Genes

    PubMed Central

    de Jong, Simone; Boks, Marco P. M.; Fuller, Tova F.; Strengman, Eric; Janson, Esther; de Kovel, Carolien G. F.; Ori, Anil P. S.; Vi, Nancy; Mulder, Flip; Blom, Jan Dirk; Glenthøj, Birte; Schubart, Chris D.; Cahn, Wiepke; Kahn, René S.; Horvath, Steve; Ophoff, Roel A.

    2012-01-01

    Despite large-scale genome-wide association studies (GWAS), the underlying genes for schizophrenia are largely unknown. Additional approaches are therefore required to identify the genetic background of this disorder. Here we report findings from a large gene expression study in peripheral blood of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co-expression modules associated with schizophrenia. Several of these disease related modules are likely to reflect expression changes due to antipsychotic medication. However, two of the disease modules could be replicated in an independent second data set involving antipsychotic-free patients and controls. One of these robustly defined disease modules is significantly enriched with brain-expressed genes and with genetic variants that were implicated in a GWAS study, which could imply a causal role in schizophrenia etiology. The most highly connected intramodular hub gene in this module (ABCF1), is located in, and regulated by the major histocompatibility (MHC) complex, which is intriguing in light of the fact that common allelic variants from the MHC region have been implicated in schizophrenia. This suggests that the MHC increases schizophrenia susceptibility via altered gene expression of regulatory genes in this network. PMID:22761806

  20. A bioinformatics prediction approach towards analyzing the glycosylation, co-expression and interaction patterns of epithelial membrane antigen (EMA/MUC1)

    NASA Astrophysics Data System (ADS)

    Kalra, Rajkumar S.; Wadhwa, Renu

    2015-02-01

    Epithelial membrane antigen (EMA or MUC1) is a heavily glycosylated, type I transmembrane glycoprotein commonly expressed by epithelial cells of duct organs. It has been shown to be aberrantly glycosylated in several diseases including cancer. Protein sequence based annotation and analysis of glycosylation profile of glycoproteins by robust computational and comprehensive algorithms provides possible insights to the mechanism(s) of anomalous glycosylation. In present report, by using a number of bioinformatics applications we studied EMA/MUC1 and explored its trans-membrane structural domain sequence that is widely subjected to glycosylation. Exploration of different extracellular motifs led to prediction of N and O-linked glycosylation target sites. Based on the putative O-linked target sites, glycosylated moieties and pathways were envisaged. Furthermore, Protein network analysis demonstrated physical interaction of EMA with a number of proteins and confirmed its functional involvement in cell growth and proliferation pathways. Gene Ontology analysis suggested an involvement of EMA in a number of functions including signal transduction, protein binding, processing & transport along with glycosylation. Thus, present study explored potential of bioinformatics prediction approach in analyzing glycosylation, co-expression and interaction patterns of EMA/MUC1 glycoprotein.

  1. AAV1 mediated co-expression of formylglycine-generating enzyme and arylsulfatase a efficiently corrects sulfatide storage in a mouse model of metachromatic leukodystrophy.

    PubMed

    Kurai, Toshiyuki; Hisayasu, Sanae; Kitagawa, Ryo; Migita, Makoto; Suzuki, Hidenori; Hirai, Yukihiko; Shimada, Takashi

    2007-01-01

    Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by a deficiency of arylsulfatase A (ASA) and is characterized by deposition of sulfatide in all organs, particularly the nervous system. Recently, formylglycine-generating enzyme (FGE) was found to be essential for activation of sulfatases. This study examined the utility of FGE co-expression in AAV type 1 vector (AAV1)-mediated gene therapy of ASA knockout (MLD) mice. AAV1-ASA alone or AAV1-ASA and AAV1-FGE were co-injected into a single site of the hippocampus. Enzyme assay and immunohistochemical analysis showed that ASA was detected not only in the injected hemisphere but also in the non-injected hemisphere by 7 months after injection. Level of ASA activity and extent of ASA distribution were significantly enhanced by co-introduction of AAV1-FGE. Marked reductions in sulfatide levels were observed throughout the entire brain. The unexpectedly widespread distribution of ASA may be due to a combination of diffusion in extracellular spaces, transport through axons, and circulation in cerebrospinal fluid. The rotarod test revealed improvement of neurological functions. These results demonstrate that direct injection of AAV1 vectors expressing ASA and FGE represents a highly promising approach with significant implications for the development of clinical protocols for MLD gene therapy. PMID:17164773

  2. Understanding the progression of atherosclerosis through gene profiling and co-expression network analysis in Apob(tm2Sgy)Ldlr(tm1Her) double knockout mice.

    PubMed

    Deshpande, Vrushali; Sharma, Ankit; Mukhopadhyay, Rupak; Thota, Lakshmi Narasimha Rao; Ghatge, Madankumar; Vangala, Rajani Kanth; Kakkar, Vijay V; Mundkur, Lakshmi

    2016-06-01

    The objective of the study was to gain molecular insights into the progression of atherosclerosis in Apob(tm2Sgy)Ldlr(tm1Her) mice, using transcriptome profiles. Weighted gene co network analysis (WGCNA) and time course analysis using limma were used to study disease progression from 0 to 20weeks. Five co-expression modules were identified by WGCNA using the expression values of 2153 genes. Genes associated with autophagy, endoplasmic reticulum stress, inflammation and lipid metabolism were differentially expressed at early stages of atherosclerosis. Time course analysis highlighted activation of inflammatory gene signaling at 4weeks, cell proliferation and calcification at 8weeks, amyloid like structures and oxidative stress at 14weeks and enhanced production of inflammatory cytokines at 20weeks. Our results suggest that maximum gene perturbations occur during early atherosclerosis which could be the danger signals associated with subclinical disease. Understanding these genes and associated pathways can help in improvement of diagnostic and therapeutic targets for atherosclerosis. PMID:27133569

  3. Co-Expression Analysis of Fetal Weight-Related Genes in Ovine Skeletal Muscle during Mid and Late Fetal Development Stages

    PubMed Central

    Xu, Lingyang; Zhao, Fuping; Ren, Hangxing; Li, Li; Lu, Jian; Liu, Jiasen; Zhang, Shifang; Liu, George E.; Song, Jiuzhou; Zhang, Li; Wei, Caihong; Du, Lixin

    2014-01-01

    Background: Muscle development and lipid metabolism play important roles during fetal development stages. The commercial Texel sheep are more muscular than the indigenous Ujumqin sheep. Results: We performed serial transcriptomics assays and systems biology analyses to investigate the dynamics of gene expression changes associated with fetal longissimus muscles during different fetal stages in two sheep breeds. Totally, we identified 1472 differentially expressed genes during various fetal stages using time-series expression analysis. A systems biology approach, weighted gene co-expression network analysis (WGCNA), was used to detect modules of correlated genes among these 1472 genes. Dramatically different gene modules were identified in four merged datasets, corresponding to the mid fetal stage in Texel and Ujumqin sheep, the late fetal stage in Texel and Ujumqin sheep, respectively. We further detected gene modules significantly correlated with fetal weight, and constructed networks and pathways using genes with high significances. In these gene modules, we identified genes like TADA3, LMNB1, TGF-β3, EEF1A2, FGFR1, MYOZ1, and FBP2 correlated with fetal weight. Conclusion: Our study revealed the complex network characteristics involved in muscle development and lipid metabolism during fetal development stages. Diverse patterns of the network connections observed between breeds and fetal stages could involve some hub genes, which play central roles in fetal development, correlating with fetal weight. Our findings could provide potential valuable biomarkers for selection of body weight-related traits in sheep and other livestock. PMID:25285036

  4. Co-Expression and Co-Localization of Cartilage Glycoproteins CHI3L1 and Lubricin in Osteoarthritic Cartilage: Morphological, Immunohistochemical and Gene Expression Profiles

    PubMed Central

    Szychlinska, Marta Anna; Trovato, Francesca Maria; Di Rosa, Michelino; Malaguarnera, Lucia; Puzzo, Lidia; Leonardi, Rosy; Castrogiovanni, Paola; Musumeci, Giuseppe

    2016-01-01

    Osteoarthritis is the most common human arthritis characterized by degeneration of articular cartilage. Several studies reported that levels of human cartilage glycoprotein chitinase 3-like-1 (CHI3L1) are known as a potential marker for the activation of chondrocytes and the progression of Osteoarthritis (OA), whereas lubricin appears to be chondroprotective. The aim of this study was to investigate the co-expression and co-localization of CHI3L1 and lubricin in normal and osteoarthritic rat articular cartilage to correlate their modified expression to a specific grade of OA. Samples of normal and osteoarthritic rat articular cartilage were analyzed by the Kellgren–Lawrence OA severity scores, the Kraus’ modified Mankin score and the Histopathology Osteoarthritis Research Society International (OARSI) system for histomorphometric evaluations, and through CHI3L1 and lubricin gene expression, immunohistochemistry and double immuno-staining analysis. The immunoexpression and the mRNA levels of lubricin increased in normal cartilage and decreased in OA cartilage (normal vs. OA, p < 0.01). By contrast, the immunoexpression and the mRNA levels of CHI3L1 increased in OA cartilage and decreased in normal cartilage (normal vs. OA, p < 0.01). Our findings are consistent with reports suggesting that these two glycoproteins are functionally associated with the development of OA and in particular with grade 2/3 of OA, suggesting that in the future they could be helpful to stage the severity and progression of the disease. PMID:26978347

  5. Lignin, mitochondrial family, and photorespiratory transporter classification as case studies in using co-expression, co-response, and protein locations to aid in identifying transport functions

    PubMed Central

    Tohge, Takayuki; Fernie, Alisdair R.

    2014-01-01

    Whole genome sequencing and the relative ease of transcript profiling have facilitated the collection and data warehousing of immense quantities of expression data. However, a substantial proportion of genes are not yet functionally annotated a problem which is particularly acute for transport proteins. In Arabidopsis, for example, only a minor fraction of the estimated 700 intracellular transporters have been identified at the molecular genetic level. Furthermore it is only within the last couple of years that critical genes such as those encoding the final transport step required for the long distance transport of sucrose and the first transporter of the core photorespiratory pathway have been identified. Here we will describe how transcriptional coordination between genes of known function and non-annotated genes allows the identification of putative transporters on the premise that such co-expressed genes tend to be functionally related. We will additionally extend this to include the expansion of this approach to include phenotypic information from other levels of cellular organization such as proteomic and metabolomic data and provide case studies wherein this approach has successfully been used to fill knowledge gaps in important metabolic pathways and physiological processes. PMID:24672529

  6. Co-expression of mouse TMEM63A, TMEM63B and TMEM63C confers hyperosmolarity activated ion currents in HEK293 cells.

    PubMed

    Zhao, Xin; Yan, Xiaojuan; Liu, Yuanhu; Zhang, Ping; Ni, Xin

    2016-06-01

    Osmoreception is essential for systemic osmoregulation, a process to stabilize the tonicity and volume of the extracellular fluid through regulating the ingestive behaviour, sympathetic outflow and renal function. The sensation of osmotic changes by osmoreceptor neurons is mediated by ion channels that detect the change of osmolarity in extracellular fluid. However, the molecular identity of these channels remains mysterious. AtCSC1and OSCA1,two closely related paralogues from Arabidopsis, have been demonstrated to form hyperosmolarity activated ion channels, which makes their mammalian orthologues-the members of TMEM63 proteins, possible candidates for osmoreceptor transduction channel. To test this possibility, we cloned the cDNAs of all the three members of the mouse TMEM63 family, TMEM63A, TMEM63B and TMEM63C from the mRNA from mouse brain. When all of the three subtypes of TMEM63 proteins were co-expressed in HEK293 cells, we recorded membrane currents evoked by hypertonic stimulation in these cells. However, the cells expressing the combinations of any two subtypes of TMEM63 proteins could not exhibit any hyperosmolarity evoked currents. Thus, all the three members of TMEM63 proteins are required to constitute a hyperosmolarity activated ion channel. We propose that the TMEM63 proteins may serve as an osmolarity sensitive ion channel for the osmoreception. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27045885

  7. Co-expression of Foxa.a, Foxd and Fgf9/16/20 defines a transient mesendoderm regulatory state in ascidian embryos

    PubMed Central

    Hudson, Clare; Sirour, Cathy; Yasuo, Hitoyoshi

    2016-01-01

    In many bilaterian embryos, nuclear β-catenin (nβ-catenin) promotes mesendoderm over ectoderm lineages. Although this is likely to represent an evolutionary ancient developmental process, the regulatory architecture of nβ-catenin-induced mesendoderm remains elusive in the majority of animals. Here, we show that, in ascidian embryos, three nβ-catenin transcriptional targets, Foxa.a, Foxd and Fgf9/16/20, are each required for the correct initiation of both the mesoderm and endoderm gene regulatory networks. Conversely, these three factors are sufficient, in combination, to produce a mesendoderm ground state that can be further programmed into mesoderm or endoderm lineages. Importantly, we show that the combinatorial activity of these three factors is sufficient to reprogramme developing ectoderm cells to mesendoderm. We conclude that in ascidian embryos, the transient mesendoderm regulatory state is defined by co-expression of Foxa.a, Foxd and Fgf9/16/20. DOI: http://dx.doi.org/10.7554/eLife.14692.001 PMID:27351101

  8. A cotton BURP domain protein interacts with α-expansin and their co-expression promotes plant growth and fruit production.

    PubMed

    Xu, Bing; Gou, Jin-Ying; Li, Fu-Guang; Shangguan, Xiao-Xia; Zhao, Bo; Yang, Chang-Qing; Wang, Ling-Jian; Yuan, Sheng; Liu, Chang-Jun; Chen, Xiao-Ya

    2013-05-01

    Plant growth requires cell wall extension. The cotton AtRD22-Like 1 gene GhRDL1, predominately expressed in elongating fiber cells, encodes a BURP domain-containing protein. Here, we show that GhRDL1 is localized in cell wall and interacts with GhEXPA1, an α-expansin functioning in wall loosening. Transgenic cotton overexpressing GhRDL1 showed an increase in fiber length and seed mass, and an enlargement of endopleura cells of ovules. Expression of either GhRDL1 or GhEXPA1 alone in Arabidopsis led to a substantial increase in seed size; interestingly, their co-expression resulted in the increased number of siliques, the nearly doubled seed mass, and the enhanced biomass production. Cotton plants overexpressing GhRDL1 and GhEXPA1 proteins produced strikingly more fruits (bolls), leading to up to 40% higher fiber yield per plant without adverse effects on fiber quality and vegetative growth. We demonstrate that engineering cell wall protein partners has a great potential in promoting plant growth and crop yield. PMID:23041940

  9. Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein

    PubMed Central

    Parra, Marcela; Liu, Xia; Derrick, Steven C.; Yang, Amy; Molina-Cruz, Alvaro; Barillas-Mury, Carolina; Zheng, Hong; Thao Pham, Phuong; Sedegah, Martha; Belmonte, Arnel; Litilit, Dianne D.; Waldmann, Thomas A.; Kumar, Sanjai; Morris, Sheldon L.; Perera, Liyanage P.

    2015-01-01

    Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)–based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies. PMID:26505634

  10. Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein.

    PubMed

    Parra, Marcela; Liu, Xia; Derrick, Steven C; Yang, Amy; Molina-Cruz, Alvaro; Barillas-Mury, Carolina; Zheng, Hong; Thao Pham, Phuong; Sedegah, Martha; Belmonte, Arnel; Litilit, Dianne D; Waldmann, Thomas A; Kumar, Sanjai; Morris, Sheldon L; Perera, Liyanage P

    2015-01-01

    Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies. PMID:26505634

  11. Discriminative gene co-expression network analysis uncovers novel modules involved in the formation of phosphate deficiency-induced root hairs in Arabidopsis.

    PubMed

    Salazar-Henao, Jorge E; Lin, Wen-Dar; Schmidt, Wolfgang

    2016-01-01

    Cell fate and differentiation in the Arabidopsis root epidermis are genetically defined but remain plastic to environmental signals such as limited availability of inorganic phosphate (Pi). Root hairs of Pi-deficient plants are more frequent and longer than those of plants grown under Pi-replete conditions. To dissect genes involved in Pi deficiency-induced root hair morphogenesis, we constructed a co-expression network of Pi-responsive genes against a customized database that was assembled from experiments in which differentially expressed genes that encode proteins with validated functions in root hair development were over-represented. To further filter out less relevant genes, we combined this procedure with a search for common cis-regulatory elements in the promoters of the selected genes. In addition to well-described players and processes such as auxin signalling and modifications of primary cell walls, we discovered several novel aspects in the biology of root hairs induced by Pi deficiency, including cell cycle control, putative plastid-to-nucleus signalling, pathogen defence, reprogramming of cell wall-related carbohydrate metabolism, and chromatin remodelling. This approach allows the discovery of novel of aspects of a biological process from transcriptional profiles with high sensitivity and accuracy. PMID:27220366

  12. [Effect of co-expression of nicotinic acid phosphoribosyl transferase and pyruvate carboxylase on succinic acid production in Escherichia coli BA002].

    PubMed

    Cao, Weijia; Gou, Dongmei; Liang, Liya; Liu, Rongming; Chen, Kequan; Ma, Jiangfeng; Jiang, Min

    2013-12-01

    Escherichia coli BA002, in which the ldhA and pflB genes are deleted, cannot utilize glucose anaerobically due to the inability to regenerate NAD+. To restore glucose utilization, overexpression of nicotinic acid phosphoribosyltransferase (NAPRTase) encoded by the pncB gene, a rate-limiting enzyme of NAD(H) synthesis pathway, resulted in a significant increase in cell mass and succinate production under anaerobic conditions. However, a high concentration of pyruvate was accumulated. Thus, co-expression of NAPRTase and the heterologous pyruvate carboxylase (PYC) of Lactococcus lactis subsp. cremoris NZ9000 in recombinant E. coli BA016 was investigated. Results in 3 L fermentor showed that OD600 is 4.64 and BA016 consumed 35.00 g/L glucose and produced 25.09 g/L succinate after 112 h under anaerobic conditions. Overexpression of pncB and pyc in BA016, the accumulation of pyruvic acid was further decreased, and the formation of succinic acid was further increased. PMID:24660633

  13. Discriminative gene co-expression network analysis uncovers novel modules involved in the formation of phosphate deficiency-induced root hairs in Arabidopsis

    PubMed Central

    Salazar-Henao, Jorge E.; Lin, Wen-Dar; Schmidt, Wolfgang

    2016-01-01

    Cell fate and differentiation in the Arabidopsis root epidermis are genetically defined but remain plastic to environmental signals such as limited availability of inorganic phosphate (Pi). Root hairs of Pi-deficient plants are more frequent and longer than those of plants grown under Pi-replete conditions. To dissect genes involved in Pi deficiency-induced root hair morphogenesis, we constructed a co-expression network of Pi-responsive genes against a customized database that was assembled from experiments in which differentially expressed genes that encode proteins with validated functions in root hair development were over-represented. To further filter out less relevant genes, we combined this procedure with a search for common cis-regulatory elements in the promoters of the selected genes. In addition to well-described players and processes such as auxin signalling and modifications of primary cell walls, we discovered several novel aspects in the biology of root hairs induced by Pi deficiency, including cell cycle control, putative plastid-to-nucleus signalling, pathogen defence, reprogramming of cell wall-related carbohydrate metabolism, and chromatin remodelling. This approach allows the discovery of novel of aspects of a biological process from transcriptional profiles with high sensitivity and accuracy. PMID:27220366

  14. New vectors for co-expression of proteins : structure of bacillus subtilis ScoAB obtained by high-throughput protocols.

    SciTech Connect

    Stols, L.; Zhou, M.; Eschenfeldt, W. H.; Millard, C. S.; Abdullah, J.; Collart, F. R.; Kim, Y.; Donnelly, M. I.; Biosciences Division

    2007-06-01

    The Bacillus subtilis genes scoA and scoB encode subunits of the heteromeric enzyme ScoAB, a putative succinyl-CoA:acetoacetate coenzyme A transferase. High-throughput, ligation-independent cloning (LIC) vectors used extensively for production and purification of single proteins were modified to allow simultaneous expression of interacting proteins and selective purification of functional complexes. Transfer of the LIC region of vector pMCSG7 into commercial vectors with alternative, compatible origins of replication allowed introduction of standard LIC PCR products into the vectors by uniform protocols. Replacement of the His-tag encoding region of pMCSG7 with a sequence encoding the S-tag enabled selective purification of interacting proteins based on the His-tag associated with one member of the complex. When expressed separately and mixed, the ScoAB subunits failed to interact productively; no transferase activity was detected, and S-tagged ScoB failed to co-purify with His-tagged ScoA. Co-expression, in contrast, generated active transferase that catalyzed the predicted reaction. The ScoAB complex was purified by standard high-throughput metal-ion affinity chromatography procedures, crystallized robotically, and its structure was determined by molecular replacement.

  15. Gene Co-Expression Analysis Inferring the Crosstalk of Ethylene and Gibberellin in Modulating the Transcriptional Acclimation of Cassava Root Growth in Different Seasons

    PubMed Central

    Saithong, Treenut; Saerue, Samorn; Kalapanulak, Saowalak; Sojikul, Punchapat; Narangajavana, Jarunya; Bhumiratana, Sakarindr

    2015-01-01

    Cassava is a crop of hope for the 21st century. Great advantages of cassava over other crops are not only the capacity of carbohydrates, but it is also an easily grown crop with fast development. As a plant which is highly tolerant to a poor environment, cassava has been believed to own an effective acclimation process, an intelligent mechanism behind its survival and sustainability in a wide range of climates. Herein, we aimed to investigate the transcriptional regulation underlying the adaptive development of a cassava root to different seasonal cultivation climates. Gene co-expression analysis suggests that AP2-EREBP transcription factor (ERF1) orthologue (D142) played a pivotal role in regulating the cellular response to exposing to wet and dry seasons. The ERF shows crosstalk with gibberellin, via ent-Kaurene synthase (D106), in the transcriptional regulatory network that was proposed to modulate the downstream regulatory system through a distinct signaling mechanism. While sulfur assimilation is likely to be a signaling regulation for dry crop growth response, calmodulin-binding protein is responsible for regulation in the wet crop. With our initiative study, we hope that our findings will pave the way towards sustainability of cassava production under various kinds of stress considering the future global climate change. PMID:26366737

  16. Co-expression of a modified maize ribosome-inactivating protein and a rice basic chitinase gene in transgenic rice plants confers enhanced resistance to sheath blight.

    PubMed

    Kim, Ju-Kon; Jang, In-Cheol; Wu, Ray; Zuo, Wei-Neng; Boston, Rebecca S; Lee, Yong-Hwan; Ahn, Il-Pyung; Nahm, Baek Hie

    2003-08-01

    Chitinases, beta-1,3-glucanases, and ribosome-inactivating proteins are reported to have antifungal activity in plants. With the aim of producing fungus-resistant transgenic plants, we co-expressed a modified maize ribosome-inactivating protein gene, MOD1, and a rice basic chitinase gene, RCH10, in transgenic rice plants. A construct containing MOD1 and RCH10 under the control of the rice rbcS and Act1 promoters, respectively, was co-transformed with a plasmid containing the herbicide-resistance gene bar as a selection marker into rice by particle bombardment. Several transformants analyzed by genomic Southern-blot hybridization demonstrated integration of multiple copies of the foreign gene into rice chromosomes. Immunoblot experiments showed that MOD1 formed approximately 0.5% of the total soluble protein in transgenic leaves. RCH10 expression was examined using the native polyacrylamide-overlay gel method, and high RCH10 activity was observed in leaf tissues where endogenous RCH10 is not expressed. R1 plants were analyzed in a similar way, and the Southern-blot patterns and levels of transgene expression remained the same as in the parental line. Analysis of the response of R2 plants to three fungal pathogens of rice, Rhizoctonia solani, Bipolaris oryzae, and Magnaporthe grisea, indicated statistically significant symptom reduction only in the case of R. solani (sheath blight). The increased resistance co-segregated with herbicide tolerance, reflecting a correlation between the resistance phenotype and transgene expression. PMID:12885168

  17. Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren's syndrome: a pilot study.

    PubMed

    Alunno, A; Carubbi, F; Bistoni, O; Caterbi, S; Bartoloni, E; Di Benedetto, P; Cipriani, P; Giacomelli, R; Gerli, R

    2016-06-01

    Compelling evidence suggests that interleukin (IL)-17 and IL-17-producing cells play a pivotal role in the pathogenesis of primary Sjögren's syndrome (pSS). We investigated phenotypical and functional effects of the anti-CD20 antibody rituximab (RTX) on circulating and glandular IL-17-producing T cells in pSS. RTX is able to deplete glandular IL-17(+) CD3(+) CD4(-) CD8(-) double-negative (DN) and CD4(+) Th17 cells as well as circulating IL-17(+) DN T cells. A fraction of glandular and circulating IL-17(+) DN cells and CD4(+) T helper type 17 (Th17) cells co-expresses CD20 on the cell surface explaining, at least in part, such depletive capacity of RTX. The exposure to RTX does not rescue the in-vitro corticosteroid resistance of IL-17(+) DN T cells. Our results support further the therapeutic role in pSS of RTX that, despite its B cell specificity, appears able to also hamper IL-17-producing T cells in this disease. PMID:26814615

  18. A bioinformatics prediction approach towards analyzing the glycosylation, co-expression and interaction patterns of epithelial membrane antigen (EMA/MUC1)

    SciTech Connect

    Kalra, Rajkumar S. Wadhwa, Renu

    2015-02-27

    Epithelial membrane antigen (EMA or MUC1) is a heavily glycosylated, type I transmembrane glycoprotein commonly expressed by epithelial cells of duct organs. It has been shown to be aberrantly glycosylated in several diseases including cancer. Protein sequence based annotation and analysis of glycosylation profile of glycoproteins by robust computational and comprehensive algorithms provides possible insights to the mechanism(s) of anomalous glycosylation. In present report, by using a number of bioinformatics applications we studied EMA/MUC1 and explored its trans-membrane structural domain sequence that is widely subjected to glycosylation. Exploration of different extracellular motifs led to prediction of N and O-linked glycosylation target sites. Based on the putative O-linked target sites, glycosylated moieties and pathways were envisaged. Furthermore, Protein network analysis demonstrated physical interaction of EMA with a number of proteins and confirmed its functional involvement in cell growth and proliferation pathways. Gene Ontology analysis suggested an involvement of EMA in a number of functions including signal transduction, protein binding, processing and transport along with glycosylation. Thus, present study explored potential of bioinformatics prediction approach in analyzing glycosylation, co-expression and interaction patterns of EMA/MUC1 glycoprotein.

  19. Proteoglycans in liver cancer.

    PubMed

    Baghy, Kornélia; Tátrai, Péter; Regős, Eszter; Kovalszky, Ilona

    2016-01-01

    Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain, such as a heparan, dermatan, chondroitin, or keratan sulfate, covalently attached to the protein core. These molecules are categorized based on their structure, localization, and function, and can be found in the extracellular matrix, on the cell surface, and in the cytoplasm. Cell-surface heparan sulfate proteoglycans, such as syndecans, are the primary type present in healthy liver tissue. However, deterioration of the liver results in overproduction of other proteoglycan types. The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer. A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans. The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels. This article details and discusses the roles of syndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan, asporin, fibromodulin, lumican, and versican in liver function. Specifically, glypicans, agrin, and versican play significant roles in the development of liver cancer. Conversely, the presence of decorin could potentially provide protective effects. PMID:26755884

  20. Pathogenesis of liver cirrhosis

    PubMed Central

    Zhou, Wen-Ce; Zhang, Quan-Bao; Qiao, Liang

    2014-01-01

    Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions. PMID:24966602

  1. Proteoglycans in liver cancer

    PubMed Central

    Baghy, Kornélia; Tátrai, Péter; Regős, Eszter; Kovalszky, Ilona

    2016-01-01

    Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain, such as a heparan, dermatan, chondroitin, or keratan sulfate, covalently attached to the protein core. These molecules are categorized based on their structure, localization, and function, and can be found in the extracellular matrix, on the cell surface, and in the cytoplasm. Cell-surface heparan sulfate proteoglycans, such as syndecans, are the primary type present in healthy liver tissue. However, deterioration of the liver results in overproduction of other proteoglycan types. The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer. A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans. The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels. This article details and discusses the roles of syndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan, asporin, fibromodulin, lumican, and versican in liver function. Specifically, glypicans, agrin, and versican play significant roles in the development of liver cancer. Conversely, the presence of decorin could potentially provide protective effects. PMID:26755884

  2. Capecitabine-related liver lesions: sinusoidal dilatation mimicking liver metastasis.

    PubMed

    Groom, Katherine; Penna, Marta; Arul, Dhili; Steward, Michael; Leonard, Pauline; Wilson, Jonathan

    2016-06-01

    A 30-year-old lady treated with capecitabine for primary colon adenocarcinoma developed liver lesions suspicious for metastasis. Liver biopsies showed sinusoidal dilatation thought to be secondary to capecitabine. This case highlights the importance of differentiating between benign and malignant liver lesions during cancer surveillance preventing unnecessary liver resections for benign disease. PMID:27398193

  3. Infections in Liver Disease.

    PubMed

    Nanchal, Rahul S; Ahmad, Shahryar

    2016-07-01

    Infectious complications are common occurrences in end-stage liver disease (ESLD). Frequent infections precipitate decompensation of liver disease leading to acute or chronic liver failure, organ dysfunction, de-listing from transplant, and major morbidity and mortality. The spectrum of microorganisms has shifted with the emergence of multidrug-resistant strains, which has major implications for both therapy and prophylaxis. Cirrhosis is often associated with an underlying noninfectious systemic inflammatory state that makes diagnosis of infections particularly challenging. Adequate resuscitation and timely administration of appropriate antibiotics are pivotal to improved outcomes from infections in ESLD. PMID:27339680

  4. Imaging of liver cancer

    PubMed Central

    Ariff, Ben; Lloyd, Claire R; Khan, Sameer; Shariff, Mohamed; Thillainayagam, Andrew V; Bansi, Devinder S; Khan, Shahid A; Taylor-Robinson, Simon D; Lim, Adrian KP

    2009-01-01

    Improvements in imaging technology allow exploitation of the dual blood supply of the liver to aid in the identification and characterisation of both malignant and benign liver lesions. Imaging techniques available include contrast enhanced ultrasound, computed tomography and magnetic resonance imaging. This review discusses the application of several imaging techniques in the diagnosis and staging of both hepatocellular carcinoma and cholangiocarcinoma and outlines certain characteristics of benign liver lesions. The advantages of each imaging technique are highlighted, while underscoring the potential pitfalls and limitations of each imaging modality. PMID:19294758

  5. Pasteurella multocida liver abscess.

    PubMed

    Cortez, J C; Shapiro, M; Awe, R J

    1986-08-01

    A previously healthy 61-year-old woman was seen with an abnormal chest roentgenogram and a 3-week history of fever, chills, malaise, and right upper quadrant pain. Blood cultures revealed Pasteurella multocida sensitive to penicillin. Liver spleen radioisotope scan and CT scan revealed space occupying lesions in the right lobe of the liver. The patient was a gardener with no pets or animal exposure. This case illustrates P. multocida septicemia and a liver abscess in a patient without animal exposure. In addition, the possibility of soil as another reservoir of infection is raised. PMID:3487981

  6. Alcohol induced liver disease.

    PubMed Central

    Fleming, K A; McGee, J O

    1984-01-01

    Alcohol induces a variety of changes in the liver: fatty change, hepatitis, fibrosis, and cirrhosis. The histopathological appearances of these conditions are discussed, with special attention to differential diagnosis. Many forms of alcoholic liver disease are associated with Mallory body formation and fibrosis. Mallory bodies are formed, at least in part, from intermediate filaments. Associated changes in intermediate filament organisation in alcoholic liver disease also occur. Their significance in the pathogenesis of hepatocyte death may be related to abnormalities in messenger RNA function. The mechanisms underlying hepatic fibrogenesis are also discussed. Images PMID:6086722

  7. Managing alcoholic liver disease

    PubMed Central

    2015-01-01

    Alcoholic liver disease continues to be a significant cause of liver-related morbidity and mortality throughout the world. A number of diagnostic and prognostic models have been developed in the management of this condition, although specific roles for liver biopsy still remain particularly in the setting of alcoholic hepatitis. Despite a large number of recent treatment trials, the ideal pharmacotherapy approach remains undefined. Most essential is the supportive care and focus on abstinence and nutrition. Owing in part to a great deal of attention from governmental funding sources, a number of new treatment approaches are undergoing rigorous evaluation, hopefully providing future treatment options in this very severe condition. PMID:26523266

  8. Liver Transplantation for Cholestatic Liver Diseases in Adults.

    PubMed

    Khungar, Vandana; Goldberg, David Seth

    2016-02-01

    Liver transplantation (LT) is an established lifesaving therapy for patients with cholestatic liver diseases, including primary cholestatic diseases, namely primary sclerosing cholangitis and primary biliary cirrhosis, as well as secondary forms of cholestatic liver disease, including those with cholestatic complications of LT needing a retransplant. Patients with cholestatic liver diseases can be transplanted for complications of end-stage liver disease or for disease-specific symptoms before the onset of end-stage liver disease. These patients should be regularly assessed. Patient survival after LT for cholestatic liver diseases is generally better than for other indications. PMID:26593299

  9. Liver Transplantation for Alcohol-Related Liver Disease.

    PubMed

    Choudhary, Narendra S; Kumar, Naveen; Saigal, Sanjiv; Rai, Rahul; Saraf, Neeraj; Soin, Arvinder S

    2016-03-01

    Alcoholic liver disease (ALD) is a common indication for liver transplantation. It is a much debated indication for deceased donor liver transplantation due to organ shortage and potential of alcohol relapse after liver transplantation. A six-month abstinence before liver transplantation is required at most centers to decrease chances of alcohol relapse after liver transplantation. However, this rule is not relevant for patients with severe alcoholic hepatitis or severely decompensated patients who are unlikely to survive till 6 months. Long-term care of these patients after liver transplantation includes assessment of relapse, smoking, and surveillance of de novo malignancies. Current review discusses role of abstinence, factors affecting alcohol relapse, liver transplantation for alcoholic hepatitis, role of living donor liver transplantation, and long-term care of ALD patients who undergo liver transplantation. PMID:27194896

  10. Pregnancy after liver transplantation.

    PubMed

    Ramirez, Carlo B; Doria, Cataldo

    2014-11-01

    Women constitute >30% of patients undergoing liver transplantation (orthotopic liver transplantation, OLT) and about 8% are of reproductive age, and 5% are pediatric females who will mostly survive into adulthood and will consider pregnancy. Although pregnancy in OLT recipients is associated with an increased incidence of hypertension, preeclampsia, anemia, preterm deliveries, and cesarean section, acute rejection and liver allograft loss do not appear to be increased and pregnancy-related maternal death is uncommon. The incidence of structural malformations in the newborn of liver transplant recipients is reported to be 4.4%, which is similar to the rate of 3-5% in the US general population. Patients are advised to defer conception for at least 1-2 years after OLT, while maintaining effective contraception. Pregnancy after OLT usually results in a favorable maternal and neonatal outcome when there is coordinated pre- and perinatal care by a multidisciplinary team composed of obstetric-gynecologists, and a transplant team. PMID:25257968

  11. Research Areas: Liver Disease

    MedlinePlus

    ... 900 drugs and supplements.​​ Recent discoveries from NIDDK research include: New medication shows promise against liver fibrosis ... linked to biliary atresia in newborn animals Support Research NIDDK invests in basic, clinical and translational research ...

  12. Fusobacterium Liver Abscess

    PubMed Central

    Buelow, Ben D.; Lambert, Joelle M.; Gill, Ryan M.

    2013-01-01

    Fusobacterium is well characterized as an oropharyngeal pathogen that may induce a septic thrombophlebitis by direct extension of abscess into an adjacent neck vessel (Lemierre's syndrome); its potential for visceral abscess formation, however, remains under-recognized. A 65-year-old man with a recent history of multiple rim-enhancing liver lesions presented to the emergency room with fever and abdominal pain. Based on interval increase in the size of the lesions, abscess was suspected. A liver biopsy was performed, and although no organism could be identified on routine microscopy, Warthin-Starry stain revealed Gram-negative bacilli consistent with an anaerobic Fusobacterium species as the underlying etiology of liver abscess formation. Subsequent anaerobic culture results confirmed the diagnosis. This case highlights the importance of consideration for Fusobacterium infection in the setting of liver abscess if anaerobic organisms have not yet been excluded on initial culture evaluation. PMID:24348321

  13. Fusobacterium liver abscess.

    PubMed

    Buelow, Ben D; Lambert, Joelle M; Gill, Ryan M

    2013-01-01

    Fusobacterium is well characterized as an oropharyngeal pathogen that may induce a septic thrombophlebitis by direct extension of abscess into an adjacent neck vessel (Lemierre's syndrome); its potential for visceral abscess formation, however, remains under-recognized. A 65-year-old man with a recent history of multiple rim-enhancing liver lesions presented to the emergency room with fever and abdominal pain. Based on interval increase in the size of the lesions, abscess was suspected. A liver biopsy was performed, and although no organism could be identified on routine microscopy, Warthin-Starry stain revealed Gram-negative bacilli consistent with an anaerobic Fusobacterium species as the underlying etiology of liver abscess formation. Subsequent anaerobic culture results confirmed the diagnosis. This case highlights the importance of consideration for Fusobacterium infection in the setting of liver abscess if anaerobic organisms have not yet been excluded on initial culture evaluation. PMID:24348321

  14. Liver (Hepatocellular) Cancer Screening

    MedlinePlus

    ... United States than in other parts of the world. Liver cancer is uncommon in the United States, ... is the fourth most common cancer in the world. In the United States, men, especially Chinese American ...

  15. Liver Transplant: Nutrition

    MedlinePlus

    ... VHA Forms & Publications Quality & Safety Quality of Care Ethics VA/DOD Clinical Practice Guidelines Hospital Quality Data ... decreases the strain on your liver and other organs, and will make your recovery from surgery easier. ...

  16. [Diabetes in liver cirrhosis].

    PubMed

    García-Compeán, Diego; Jáquez-Quintana, Joel O; González-González, José A; Lavalle-González, Fernando J; Villarreal-Pérez, Jesús Z; Maldonado-Garza, Hector J

    2013-01-01

    The prevalence of overt diabetes mellitus (DM) in liver cirrhosis is about 30%. However, DM or impaired glucose tolerance can be observed in 90% after an oral glucose tolerance test in patients with normal fasting plasma glucose. Type 2 DM may produce cirrhosis, whereas DM may be a complication of cirrhosis. The latter is known as «hepatogenous diabetes». Overt and subclinical DM is associated with liver complications and death in cirrhotic patients. Treating diabetes is difficult in cirrhotic patients because of the metabolic impairments due to liver disease and because the most appropriate pharmacologic treatment has not been defined. It is also unknown if glycemic control with hypoglycemic agents has any impact on the course of the liver disease. PMID:23628170

  17. Pediatric liver transplantation

    PubMed Central

    Spada, Marco; Riva, Silvia; Maggiore, Giuseppe; Cintorino, Davide; Gridelli, Bruno

    2009-01-01

    In previous decades, pediatric liver transplantation has become a state-of-the-art operation with excellent success and limited mortality. Graft and patient survival have continued to improve as a result of improvements in medical, surgical and anesthetic management, organ availability, immunosuppression, and identification and treatment of postoperative complications. The utilization of split-liver grafts and living-related donors has provided more organs for pediatric patients. Newer immunosuppression regimens, including induction therapy, have had a significant impact on graft and patient survival. Future developments of pediatric liver transplantation will deal with long-term follow-up, with prevention of immunosuppression-related complications and promotion of as normal growth as possible. This review describes the state-of-the-art in pediatric liver transplantation. PMID:19222089

  18. Cod Liver Oil

    MedlinePlus

    ... cod liver oil on their skin to speed wound healing. When taken in appropriate doses by mouth, cod ... young children. Heart disease. Systemic lupus erythematosus (SLE). Wound healing. Glaucoma. Other conditions. More evidence is needed to ...

  19. Hepatic (Liver) Function Panel

    MedlinePlus

    ... AST). This enzyme, which plays a role in processing proteins, is found in the liver, heart, muscles, ... doctor. © 1995- The Nemours Foundation. All rights reserved. Images provided by The Nemours Foundation, iStock, Getty Images, ...

  20. Amebic liver abscess

    MedlinePlus

    ... sanitation exist. Africa, Latin America, Southeast Asia, and India have significant health problems from this disease. Risk ... are the usual treatment for liver abscess. A drug such as paromomycin or diloxanide must also be ...

  1. Analgesia after liver transplantation

    PubMed Central

    Milan, Zoka

    2015-01-01

    This article addresses postoperative analgesia in patients with end-stage liver disease who have undergone liver transplantation (LT). Postoperative analgesia determines how patients perceive LT. Although important, this topic is underrepresented in the current literature. With an increased frequency of fast tracking in LT, efficient intra- and postoperative analgesia are undergoing changes. We herein review the current literature, compare the benefits and disadvantages of the therapeutic options, and make recommendations based on the current literature and clinical experience. PMID:26413222

  2. Classification of Liver Trauma

    PubMed Central

    Rizoli, Sandro B.; Brenneman, Frederick D.; Hanna, Sherif S.; Kahnamoui, Kamyar

    1996-01-01

    The classification of liver injuries is important for clinical practice, clinical research and quality assurance activities. The Organ Injury Scaling (OIS) Committee of the American Association for the Surgery of Trauma proposed the OIS for liver trauma in 1989. The purpose ofthe present study was to apply this scale to a cohort ofliver trauma patients managed at a single Canadian trauma centre from January 1987 to June 1992.170 study patients were identified and reviewed. The mean age was 30, with 69% male and a mean ISS of 33.90% had a blunt mechanism ofinjury. The 170 patients were categorized into the 60IS grades ofliver injury. The number of units of blood transfused, the magnitude of the operative treatment required, the liver-related complications and the liver-related mortality correlated well with the OIS grade. The OIS grade was unable to predict the need for laparotomy or the length of stay in hospital. We conclude that the OIS is a useful, practical and important tool for the categorization of liver injuries, and it may prove to be the universally accepted classification scheme in liver trauma. PMID:8809585

  3. Liver transplantation in Ireland.

    PubMed

    Iqbal, Masood; Elrayah, Elgaily A; Traynor, Oscar; McCormick, P Aiden

    2016-07-01

    The Irish National Liver Transplant program commenced in 1993 in St. Vincent's University Hospital in Dublin. It is an adult-only program and is the only liver transplant program in Ireland. Pediatric recipients are referred to King's College Hospital in the United Kingdom. To date, almost 1000 adult liver transplants have been performed. Current 1-year patient survival is 93%, and 5-year survival is 79%. The program is fully funded by the government health service. There is a close collaboration with the United Kingdom Organ Donation and Transplant Directorate, and there is an arrangement for organ sharing for super-urgent transplants. Traditionally, organ donation rates have been high in Ireland. However, demand for liver transplant has increased over the past 20 years, and waiting lists are now lengthening. Deceased cardiac death donation is now being considered, but there are no plans for living related donor liver transplant. Donor coordinators have recently been appointed to the major hospitals in Ireland, and it is hoped that this initiative will lead to an increase in organ donation rates. Liver Transplantation 22 1014-1018 2016 AASLD. PMID:27065358

  4. Fortuitously discovered liver lesions

    PubMed Central

    Dietrich, Christoph F; Sharma, Malay; Gibson, Robert N; Schreiber-Dietrich, Dagmar; Jenssen, Christian

    2013-01-01

    The fortuitously discovered liver lesion is a common problem. Consensus might be expected in terms of its work-up, and yet there is none. This stems in part from the fact that there is no preventive campaign involving the early detection of liver tumors other than for patients with known liver cirrhosis and oncological patients. The work-up (detection and differential diagnosis) of liver tumors comprises theoretical considerations, history, physical examination, laboratory tests, standard ultrasound, Doppler ultrasound techniques, contrast-enhanced ultrasound (CEUS), computed tomography and magnetic resonance imaging, as well as image-guided biopsy. CEUS techniques have proved to be the most pertinent method; these techniques became part of the clinical routine about 10 years ago in Europe and Asia and are used for a variety of indications in daily clinical practice. CEUS is in many cases the first and also decisive technical intervention for detecting and characterizing liver tumors. This development is reflected in many CEUS guidelines, e.g., in the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines 2004, 2008 and 2012 as well as the recently published World Federation for Ultrasound in Medicine and Biology-EFSUMB guidelines 2012. This article sets out considerations for making a structured work-up of incidental liver tumors feasible. PMID:23745019

  5. Identification of Identical Transcript Changes in Liver and Whole Blood during Acetaminophen Toxicity

    PubMed Central

    Zhang, Liwen; Bushel, Pierre R.; Chou, Jeff; Zhou, Tong; Watkins, Paul B.

    2012-01-01

    The ability to identify mechanisms underlying drug-induced liver injury (DILI) in man has been hampered by the difficulty in obtaining liver tissue from patients. It has recently been proposed that whole blood toxicogenomics may provide a non-invasive means for mechanistic studies of human DILI. However, it remains unclear to what extent changes in whole blood transcriptome mirror those in liver mechanistically linked to hepatotoxicity. To address this question, we applied the program Extracting Patterns and Identifying co-expressed Genes (EPIG) to publically available toxicogenomic data obtained from rats treated with both toxic and subtoxic doses of acetaminophen (APAP). In a training set of animals, we identified genes (760 at 6 h and 185 at 24 h post dose) with similar patterns of expression in blood and liver during APAP-induced hepatotoxicity. The pathways represented in the coordinately regulated genes largely involved mitochondrial and immune functions. The identified expression signatures were then evaluated in a separate set of animals for discernment of APAP exposure level or APAP-induced hepatotoxicity. At 6 h, the gene sets from liver and blood had equally sufficient classification of APAP exposure levels. At 24 h when toxicity was evident, the gene sets did not perform well in evaluating APAP exposure doses, but provided accurate classification of dose-independent liver injury that was evaluated by serum ALT elevation in the blood. Only 38 genes were common to both the 6 and 24-h gene sets, but these genes had the same capability as the parent gene sets to discern the exposure level and degree of liver injury. Some of the parallel transcript changes reflect pathways that are relevant to APAP hepatotoxicity, including mitochondria and immune functions. However, the extent to which these changes reflect similar mechanisms of action in both tissues remains to be determined. PMID:22973295

  6. The Liver in Critical Illness.

    PubMed

    Damm, Tessa W; Kramer, David J

    2016-07-01

    Caring for critically ill patients with acute and/or chronic liver dysfunction poses a unique challenge. Proper resuscitation and early consideration for transfer to liver transplant centers have resulted in improved outcomes. Liver support devices and cellular models have not yet shown mortality benefit, but they hold promise in the critical care of patients with liver disease. This article reviews pertinent anatomic and physiologic considerations of the liver in critical illness, followed by a selective review of associated organ dysfunction. PMID:27339681

  7. Autoimmune liver disease, autoimmunity and liver transplantation.

    PubMed

    Carbone, Marco; Neuberger, James M

    2014-01-01

    Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major autoimmune liver diseases (AILD). PBC, PSC, and AIH are all complex disorders in that they result from the effects of multiple genes in combination with as yet unidentified environmental factors. Recent genome-wide association studies have identified numerous risk loci for PBC and PSC that host genes involved in innate or acquired immune responses. These loci may provide a clue as to the immune-based pathogenesis of AILD. Moreover, many significant risk loci for PBC and PSC are also risk loci for other autoimmune disorders, such type I diabetes, multiple sclerosis and rheumatoid arthritis, suggesting a shared genetic basis and possibly similar molecular pathways for diverse autoimmune conditions. There is no curative treatment for all three disorders, and a significant number of patients eventually progress to end-stage liver disease requiring liver transplantation (LT). LT in this context has a favourable overall outcome with current patient and graft survival exceeding 80% at 5years. Indications are as for other chronic liver disease although recent data suggest that while lethargy improves after transplantation, the effect is modest and variable so lethargy alone is not an indication. In contrast, pruritus rapidly responds. Cholangiocarcinoma, except under rigorous selection criteria, excludes LT because of the high risk of recurrence. All three conditions may recur after transplantation and are associated with a greater risk of both acute cellular and chronic ductopenic rejection. It is possible that a crosstalk between alloimmune and autoimmune response perpetuate each other. An immunological response toward self- or allo-antigens is well recognised after LT in patients transplanted for non-autoimmune indications and sometimes termed "de novo autoimmune hepatitis". Whether this is part of the spectrum of rejection or an autoimmune

  8. Enzymatic synthesis of 2'-deoxyuridine by whole cell catalyst co-expressing uridine phosphorylase and thymidine phosphorylase through auto-induction system.

    PubMed

    Xiong, Shuli; Wang, Yingbin; Wang, Xi; Wang, Jie; Li, Jie; Zhang, Guiyou; Zhang, Rongqing; Xie, Liping; Wang, Hongzhong

    2014-12-01

    Genes encoding uridine phosphorylase (UP) and thymidine phosphorylase (TP) from Escherichia coli K12 were cloned and recombined respectively into plasmids pET-21a(+) and pET-28a(+). The recombinant plasmids BL21/pET21a-UP and BL21/pET28a-TP were co-transformed into E. coli BL21(DE3) to construct highly effective BTU strain (BL21/pET28a-TP, pET21a-UP) overexpressing both of UP and TP. BTU was cultivated in ZYM-Fe-5052 medium for 10 h and used as catalyst to synthesize 2'-deoxyuridine (dUR). It was found to increase the productivity of dUR by 8-9 fold when compared to wild E. coli K12 and E. coli BL21(DE3) strains. A series of experiments were carried out to find out the optimal conditions for synthesis of dUR. At 50°C, with 0.25‰ dry wt./v to catalyze the reaction of 2:1 β-thymidine: uracil (60 mM β-thymidine, 30 mM uracil), the conversion rate of dUR would reach 61.6% at 1 h, which was much higher than the rates obtained by BTU strain cultured in LB medium and induced by IPTG. This result proved co-expression and auto-induction were efficient methods in enhancing the expression quantity and activity of nucleoside phosphorylases, and they also had significant implications for large-scale industrial production of dUR and synthesis of other nucleoside derivatives. PMID:24910260

  9. A Specific and Essential Role for Na,K-ATPase α3 in Neurons Co-expressing α1 and α3*

    PubMed Central

    Azarias, Guillaume; Kruusmägi, Markus; Connor, Siobhan; Akkuratov, Evgeny E.; Liu, Xiao-Li; Lyons, David; Brismar, Hjalmar; Broberger, Christian; Aperia, Anita

    2013-01-01

    Most neurons co-express two catalytic isoforms of Na,K-ATPase, the ubiquitous α1, and the more selectively expressed α3. Although neurological syndromes are associated with α3 mutations, the specific role of this isoform is not completely understood. Here, we used electrophysiological and Na+ imaging techniques to study the role of α3 in central nervous system neurons expressing both isoforms. Under basal conditions, selective inhibition of α3 using a low concentration of the cardiac glycoside, ouabain, resulted in a modest increase in intracellular Na+ concentration ([Na+]i) accompanied by membrane potential depolarization. When neurons were challenged with a large rapid increase in [Na+]i, similar to what could be expected following suprathreshold neuronal activity, selective inhibition of α3 almost completely abolished the capacity to restore [Na+]i in soma and dendrite. Recordings of Na,K-ATPase specific current supported the notion that when [Na+]i is elevated in the neuron, α3 is the predominant isoform responsible for rapid extrusion of Na+. Low concentrations of ouabain were also found to disrupt cortical network oscillations, providing further support for the importance of α3 function in the central nervous system. The α isoforms express a well conserved protein kinase A consensus site, which is structurally associated with an Na+ binding site. Following activation of protein kinase A, both the α3-dependent current and restoration of dendritic [Na+]i were significantly attenuated, indicating that α3 is a target for phosphorylation and may participate in short term regulation of neuronal function. PMID:23195960

  10. CD8+ T Cell Fate and Function Influenced by Antigen-Specific Virus-Like Nanoparticles Co-Expressing Membrane Tethered IL-2

    PubMed Central

    Wojta-Stremayr, Daniela; Neunkirchner, Alina; Srinivasan, Bharani; Trapin, Doris; Schmetterer, Klaus G.; Pickl, Winfried F.

    2015-01-01

    A variety of adjuvants fostering humoral immunity are known as of today. However, there is a lack of adjuvants or adjuvant strategies, which directly target T cellular effector functions and memory. We here determined whether systemically toxic cytokines such as IL-2 can be restricted to the site of antigen presentation and used as ‘natural adjuvants’. Therefore, we devised antigen-presenting virus-like nanoparticles (VNP) co-expressing IL-2 attached to different membrane-anchors and assessed their potency to modulate CD8+ T cell responses in vitro and in vivo. Efficient targeting of IL-2 to lipid rafts and ultimately VNP was achieved by fusing IL-2 at its C-terminus to a minimal glycosylphosphatidylinositol (GPI)-anchor acceptor sequence. To identify optimal membrane-anchor dimensions we inserted one (1Ig), two (2Ig) or four (4Ig) immunoglobulin(Ig)-like domains of CD16b between IL-2 and the minimal GPI-anchor acceptor sequence of CD16b (GPI). We found that the 2IgGPI version was superior to all other evaluated IL-2 variants (IL-2v) in terms of its i) degree of targeting to lipid rafts and to the VNP surface, ii) biological activity, iii) co-stimulation of cognate T cells in the absence of bystander activation and iv) potency to induce differentiation and acquisition of CD8+ T cell effector functions in vitro and in vivo. In contrast, the GPI version rather favored memory precursor cell formation. These results exemplify novel beneficial features of membrane-bound IL-2, which in addition to its mere T cell stimulatory capacity include the induction of differential effector and memory functions in CD8+ T lymphocytes. PMID:25946103

  11. Co-expression of neuronal intermediate filaments, peripherin and α-internexin in human well-differentiated endocrine neoplasms (carcinoid tumors) of the appendix.

    PubMed

    Ishida, Mitsuaki; Kushima, Ryoji; Brevet, Marie; Chatelain, Denis; Okabe, Hidetoshi

    2008-01-01

    The rectum and appendix are the two major sites of well-differentiated endocrine neoplasms (carcinoid tumors) in the lower gastrointestinal tract. Previously, we reported the consistent expression of peripherin in rectal well-differentiated endocrine neoplasms without metastases. However, its expression has not as yet been examined in appendiceal well-differentiated endocrine neoplasms. The aim of our present study was to clarify whether peripherin, a type III neuronal intermediate filament, and α-internexin, a type IV neuronal intermediate filament, are expressed in appendiceal well-differentiated endocrine neoplasms. Other endocrine markers were also examined and compared with the findings from the rectal well-differentiated endocrine neoplasms. The analyses were carried out by immunohistochemical methods using 12 formalin-fixed and paraffin-embedded appendiceal well-differentiated endocrine neoplasms. In all the neoplasms examined, diffuse immunoreactivity of peripherin was observed. In addition, immunoreactivity of α-internexin, which was frequently co-expressed with peripherin, was found in all appendiceal cases. Chromogranin A and neural cell adhesion molecule expression was found in all appendiceal tumors, and serotonin was also frequently expressed (83%, 10/12 cases). Incidences of the expression of these three markers were much higher in the appendiceal than in the rectal cases. Peripherin expression is a common feature of appendiceal and rectal well-differentiated endocrine neoplasms, but the manner of neural marker expression is different depending on the site of origin. It is uncertain whether the expression of peripherin and/or α-internexin is present in the well-differentiated endocrine neoplasms of other organs; further analysis is required to clarify this issue. PMID:21479396

  12. Co-expression of Ubiquitin gene and capsid protein gene enhances the potency of DNA immunization of PCV2 in mice

    PubMed Central

    2011-01-01

    A recombinant plasmid that co-expressed ubiquitin and porcine circovirus type 2 (PCV2) virus capsid protein (Cap), denoted as pc-Ub-Cap, and a plasmid encoding PCV2 virus Cap alone, denoted as pc-Cap, were transfected into 293T cells. Indirect immunofluorescence (IIF) and confocal microscopy were performed to measure the cellular expression of Cap. Three groups of mice were then vaccinated once every three weeks for a total of three doses with pc-Ub-Cap, pc-Cap or the empty vector pCAGGS, followed by challenging all mice intraperitoneally with 0.5 mL 106.5 TCID50/mL PCV2. To characterize the protective immune response against PCV2 infection in mice, assays of antibody titer (including different IgG isotypes), flow cytometric analysis (FCM), lymphocyte proliferation, cytokine production and viremia were evaluated. The results showed that pc-Ub-Cap and pc-Cap were efficiently expressed in 293T cells. However, pc-Ub-Cap-vaccinated animals had a significantly higher level of Cap-specific antibody and induced a stronger Th1 type cellular immune response than did pc-Cap-vaccinated animals, suggesting that ubiquitin conjugation improved both the cellular and humoral immune responses. Additionally, viral replication in blood was lower in the pc-Ub-Cap-vaccinated group than in the pc-Cap and empty vector groups, suggesting that the protective immunity induced by pc-Ub-Cap is superior to that induced by pc-Cap. PMID:21624113

  13. A fiber-modified adenovirus co-expressing HSV-TK and Coli.NTR enhances antitumor activities in breast cancer cells

    PubMed Central

    Zhan, Yang; Yu, Bin; Wang, Zhen; Zhang, Yu; Zhang, Hai-Hong; Wu, Hao; Feng, Xiao; Geng, Ran-Shen; Kong, Wei; Yu, Xiang-Hui

    2014-01-01

    Breast cancers especially in late and metastatic stages remain refractory to treatment despite advances in surgical techniques and chemotherapy. Suicide gene therapy based on adenoviral technology will be promising strategies for such advanced diseases. We previously showed that co-expression of herpes simplex virus thymidine kinase (HSV-TK) and Escherichia coli nitroreductase (Coli.NTR) by an hTERT-driven adenovirus vector resulted in additive anti-tumor effects in breast cancer cells in vitro and in vivo. As many tumor tissue and cancer cells express low level of coxsackie-adenovirus receptor (CAR), which is the functional receptor for the fiber protein of human adenovirus serotype 5 (Ad5), novel Ad5 vectors containing genetically modifi ed fiber are attractive vehicles for achieving targeted gene transfer and improving suicide gene expression in these cancer cells. In the present study, we first built a simplified Ad5 vector platform for fiber modification and quick detection for gene transfer. Then a fiber-modified adenovirus vector containing an RGD motif in the HI loop of the fiber knob was constructed. After recombined with HSV-TK and Coli.NTR gene, this fiber-modified Ad5 vector (Ad-RGD-hT-TK/NTR) was compared with that of our previously constructed Ad5 vector (Ad-hT-TK/NTR) for its therapeutic effects in human breast cancer cell lines. The anti-tumor activity of Ad-RGD-hT-TK/NTR was significantly enhanced compared with Ad-hT-TK/NTR both in vitro and in vivo. This new vector platform provided a robust and simplified approach for capsid modification, and the fiber-modified Ad5 with double suicide genes under the control of hTERT promoter would be a useful gene therapy strategy for breast cancer. PMID:25031704

  14. “Related to ABA-Insensitive3(ABI3)/Viviparous1 and AtABI5 transcription factor co-expression in cotton enhances drought stress adaptation”

    PubMed Central

    Mittal, Amandeep; Gampala, Srinivas S. L.; Ritchie, Glen L.; Payton, Paxton; Burke, John J.; Rock, Christopher D.

    2014-01-01

    Drought tolerance is an important trait being pursued by the agbiotech industry. Abscisic acid (ABA) is a stress hormone that mediates a multitude of processes in growth and development, water use efficiency (WUE), and gene expression during seed development and in response to environmental stresses. Arabidopsis B3-domain transcription factor Related to ABA-Insensitive3 (ABI3)/Viviparous1 (namely, AtRAV2) and basic leucine zipper (bZIPs) AtABI5 or AtABF3 transactivated ABA- inducible promoter: GUS reporter expression in a maize mesophyll protoplast transient assay and showed synergies in reporter transactivation when co-expressed. Transgenic cotton (Gossypium hirsutum) expressing AtRAV1/2 and/or AtABI5 showed resistance to imposed drought stress under field and greenhouse conditions and exhibited improved photosynthetic and WUEs associated with absorption through larger root system and greater leaf area. We observed synergy for root biomass accumulation in the greenhouse, intrinsic WUE in the field, and drought tolerance in stacked AtRAV and AtABI5 double-transgenic cotton. We assessed AtABI5 and AtRAV1/2 involvement in drought stress adaptations though reactive oxygen species scavenging and osmotic adjustment by marker gene expression in cotton. Deficit irrigation-grown AtRAV1/2 and AtABI5 transgenics had “less stressed” molecular and physiological phenotypes under drought, likely due to improved photoassimilation and root and shoot sink strengths and enhanced expression of endogenous GhRAV and genes for antioxidant and osmolyte biosynthesis. Over-expression of bZIP and RAV TFs could impact sustainable cotton agriculture and potentially other crops under limited irrigation conditions. PMID:24483851

  15. Osteogenic differentiation of adipose-derived stem cells and calvarial defect repair using baculovirus-mediated co-expression of BMP-2 and miR-148b.

    PubMed

    Liao, Ya-Hsin; Chang, Yu-Han; Sung, Li-Yu; Li, Kuei-Chang; Yeh, Chia-Lin; Yen, Tzu-Chen; Hwang, Shiaw-Min; Lin, Kun-Ju; Hu, Yu-Chen

    2014-06-01

    Repair of large calvarial bony defect remains a challenge for orthopedic surgeons. Since microRNAs (miRNAs) modulate the osteogenesis of osteoprogenitor cells, we aimed to engineer human adipose-derived stem cells (hASCs), a promising cell source for bone engineering, with miRNA-expressing baculovirus vectors. We constructed 4 baculoviruses each expressing 1 human miRNA (miR-26a, miR-29b, miR-148b, miR-196a) and verified that the miRNA-expressing baculovirus vectors augmented hASCs osteogenesis. Among these 4 miRNAs, miR-148b and miR-196a exerted more potent osteoinductive effects than miR-26a and miR-29b. Furthermore, we unveiled that co-transduction of hASCs with miR-148b-expressing and bone morphogenetic protein 2 (BMP-2)-expressing baculovirus vectors enhanced and prolonged BMP-2 expression, and synergistically promoted the in vitro osteogenic differentiation of hASCs. Implantation of the hASCs co-expressing BMP-2/miR-148b into critical-size (4 mm in diameter) calvarial bone defects in nude mice accelerated and potentiated the bone healing and remodeling, filling ≈94% of defect area and ≈89% of defect volume with native calvaria-like flat bone in 12 weeks, as judged from micro computed tomography, histology and immunohistochemical staining. Altogether, this study confirmed the feasibility of combining miRNA and growth factor expression for synergistic stimulation of in vitro osteogenesis and in vivo calvarial bone healing. PMID:24674465

  16. A novel subunit vaccine co-expressing GM-CSF and PCV2b Cap protein enhances protective immunity against porcine circovirus type 2 in piglets.

    PubMed

    Zhang, Huawei; Qian, Ping; Peng, Bo; Shi, Lin; Chen, Huanchun; Li, Xiangmin

    2015-05-15

    Porcine circovirus type 2 (PCV2) causes porcine circovirus-associated disease. Capsid (Cap) protein of PCV2 is the principal immunogenic protein that induces neutralizing antibodies and protective immunity. GM-CSF is an immune adjuvant that enhances responses to vaccines. In this study, recombinant baculoviruses Ac-Cap and Ac-Cap-GM-CSF expressing the Cap protein alone and co-expressing the Cap protein and porcine GM-CSF, respectively, were constructed successfully. The target proteins were analyzed by western blotting and IFA. Further, these proteins were confirmed by electron microscopy, which showed that Cap proteins could self-assemble into virus-like particles having diameters of 17-25nm. Animal experiments showed that pigs immunized with Cap-GM-CSF subunit vaccine showed significantly higher levels of PCV2-specific antibodies and neutralizing antibodies than pigs immunized with the Cap subunit vaccine and a commercial vaccine (Ingelvac CircoFLEX; P<0.05). After PCV2 wild strain challenged, Pigs receiving the Cap-GM-CSF subunit vaccine showed significantly higher average daily weight gain after wild-type PCV2 challenge than pigs receiving the other three vaccines (P<0.05). None of PCV2 DNA was detected in all immunized animals, except control animals immunized with phosphate-buffered saline. These results indicated that GM-CSF was a powerful immunoadjuvant for PCV2 subunit vaccines because it enhanced humoral immune response and improved immune protection against PCV2 infection in pigs. Thus, the novel Cap-GM-CSF subunit vaccine has the potential to be used as an effective and safe vaccine candidate against PCV2 infection. PMID:25863115

  17. Arabidopsis PECTIN METHYLESTERASE17 is co-expressed with and processed by SBT3.5, a subtilisin-like serine protease

    PubMed Central

    Sénéchal, Fabien; Graff, Lucile; Surcouf, Ogier; Marcelo, Paulo; Rayon, Catherine; Bouton, Sophie; Mareck, Alain; Mouille, Gregory; Stintzi, Annick; Höfte, Herman; Lerouge, Patrice; Schaller, Andreas; Pelloux, Jérôme

    2014-01-01

    Background and Aims In Arabidopsis thaliana, the degree of methylesterification (DM) of homogalacturonans (HGs), the main pectic constituent of the cell wall, can be modified by pectin methylesterases (PMEs). In all organisms, two types of protein structure have been reported for PMEs: group 1 and group 2. In group 2 PMEs, the active part (PME domain, Pfam01095) is preceded by an N-terminal extension (PRO part), which shows similarities to PME inhibitors (PMEI domain, Pfam04043). This PRO part mediates retention of unprocessed group 2 PMEs in the Golgi apparatus, thus regulating PME activity through a post-translational mechanism. This study investigated the roles of a subtilisin-type serine protease (SBT) in the processing of a PME isoform. Methods Using a combination of functional genomics, biochemistry and proteomic approaches, the role of a specific SBT in the processing of a group 2 PME was assessed together with its consequences for plant development. Key Results A group 2 PME, AtPME17 (At2g45220), was identified, which was highly co-expressed, both spatially and temporally, with AtSBT3.5 (At1g32940), a subtilisin-type serine protease (subtilase, SBT), during root development. PME activity was modified in roots of knockout mutants for both proteins with consequent effects on root growth. This suggested a role for SBT3.5 in the processing of PME17 in planta. Using transient expression in Nicotiana benthamiana, it was indeed shown that SBT3.5 can process PME17 at a specific single processing motif, releasing a mature isoform in the apoplasm. Conclusions By revealing the potential role of SBT3.5 in the processing of PME17, this study brings new evidence of the complexity of the regulation of PMEs in plants, and highlights the need for identifying specific PME–SBT pairs. PMID:24665109

  18. Development of recombinant cell line co-expressing mutated Nav1.5, Kir2.1, and hERG for the safety assay of drug candidates.

    PubMed

    Fujii, Masato; Ohya, Susumu; Yamamura, Hisao; Imaizumi, Yuji

    2012-07-01

    To provide a high-throughput screening method for human ether-a-go-go-gene-related gene (hERG) K(+) channel inhibition, a new recombinant cell line, in which single action potential (AP)-induced cell death was produced by gene transfection. Mutated human cardiac Na(+) channel Nav1.5 (IFM/Q3), which shows extremely slow inactivation, and wild-type inward rectifier K(+) channel, Kir2.1, were stably co-expressed in HEK293 cells (IFM/Q3+Kir2.1). In IFM/Q3+Kir2.1, application of single electrical stimulation (ES) elicited a long AP lasting more than 30 s and led cells to die by more than 70%, whereas HEK293 co-transfected with wild-type Nav1.5 and Kir2.1 fully survived. The additional expression of hERG K(+) channels in IFM/Q3+Kir2.1 shortened the duration of evoked AP and thereby markedly reduced the cell death. The treatment of the cells with hERG channel inhibitors such as nifekalant, E-4031, cisapride, terfenadine, and verapamil, recovered the prolonged AP and dose-dependently facilitated cell death upon ES. The EC(50) values to induce the cell death were 3 µM, 19 nM, 17 nM, 74 nM, and 3 µM, respectively, whereas 10 µM nifedipine did not induce cell death. Results indicate the high utility of this cell system for hERG K(+) channel safety assay. PMID:22498908

  19. Pathways of Lipid Metabolism in Marine Algae, Co-Expression Network, Bottlenecks and Candidate Genes for Enhanced Production of EPA and DHA in Species of Chromista

    PubMed Central

    Mühlroth, Alice; Li, Keshuai; Røkke, Gunvor; Winge, Per; Olsen, Yngvar; Hohmann-Marriott, Martin F.; Vadstein, Olav; Bones, Atle M.

    2013-01-01

    The importance of n-3 long chain polyunsaturated fatty acids (LC-PUFAs) for human health has received more focus the last decades, and the global consumption of n-3 LC-PUFA has increased. Seafood, the natural n-3 LC-PUFA source, is harvested beyond a sustainable capacity, and it is therefore imperative to develop alternative n-3 LC-PUFA sources for both eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Genera of algae such as Nannochloropsis, Schizochytrium, Isochrysis and Phaedactylum within the kingdom Chromista have received attention due to their ability to produce n-3 LC-PUFAs. Knowledge of LC-PUFA synthesis and its regulation in algae at the molecular level is fragmentary and represents a bottleneck for attempts to enhance the n-3 LC-PUFA levels for industrial production. In the present review, Phaeodactylum tricornutum has been used to exemplify the synthesis and compartmentalization of n-3 LC-PUFAs. Based on recent transcriptome data a co-expression network of 106 genes involved in lipid metabolism has been created. Together with recent molecular biological and metabolic studies, a model pathway for n-3 LC-PUFA synthesis in P. tricornutum has been proposed, and is compared to industrialized species of Chromista. Limitations of the n-3 LC-PUFA synthesis by enzymes such as thioesterases, elongases, acyl-CoA synthetases and acyltransferases are discussed and metabolic bottlenecks are hypothesized such as the supply of the acetyl-CoA and NADPH. A future industrialization will depend on optimization of chemical compositions and increased biomass production, which can be achieved by exploitation of the physiological potential, by selective breeding and by genetic engineering. PMID:24284429

  20. Co-expression of the transcription factors CEH-14 and TTX-1 regulates AFD neuron-specific genes gcy-8 and gcy-18 in C. elegans.

    PubMed

    Kagoshima, Hiroshi; Kohara, Yuji

    2015-03-15

    A wide variety of cells are generated by the expression of characteristic sets of genes, primarily those regulated by cell-specific transcription. To elucidate the mechanism regulating cell-specific gene expression in a highly specialized cell, AFD thermosensory neuron in Caenorhabditis elegans, we analyzed the promoter sequences of guanylyl cyclase genes, gcy-8 and gcy-18, exclusively expressed in AFD. In this study, we showed that AFD-specific expression of gcy-8 and gcy-18 requires the co-expression of homeodomain proteins, CEH-14/LHX3 and TTX-1/OTX1. We observed that mutation of ttx-1 or ceh-14 caused a reduction in the expression of gcy-8 and gcy-18 and that the expression was completely lost in double mutants. This synergy effect was also observed with other AFD marker genes, such as ntc-1, nlp-21and cng-3. Electrophoretic mobility shift assays revealed direct interaction of CEH-14 and TTX-1 proteins with gcy-8 and gcy-18 promoters in vitro. The binding sites of CEH-14 and TTX-1 proteins were confirmed to be essential for AFD-specific expression of gcy-8 and gcy-18 in vivo. We also demonstrated that forced expression of CEH-14 and TTX-1 in AWB chemosensory neurons induced ectopic expression of gcy-8 and gcy-18 reporters in this neuron. Finally, we showed that the regulation of gcy-8 and gcy-18 expression by ceh-14 and ttx-1 is evolutionally conserved in five Caenorhabditis species. Taken together, ceh-14 and ttx-1 expression determines the fate of AFD as terminal selector genes at the final step of cell specification. PMID:25614239

  1. Pathways of lipid metabolism in marine algae, co-expression network, bottlenecks and candidate genes for enhanced production of EPA and DHA in species of Chromista.

    PubMed

    Mühlroth, Alice; Li, Keshuai; Røkke, Gunvor; Winge, Per; Olsen, Yngvar; Hohmann-Marriott, Martin F; Vadstein, Olav; Bones, Atle M

    2013-11-01

    The importance of n-3 long chain polyunsaturated fatty acids (LC-PUFAs) for human health has received more focus the last decades, and the global consumption of n-3 LC-PUFA has increased. Seafood, the natural n-3 LC-PUFA source, is harvested beyond a sustainable capacity, and it is therefore imperative to develop alternative n-3 LC-PUFA sources for both eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Genera of algae such as Nannochloropsis, Schizochytrium, Isochrysis and Phaedactylum within the kingdom Chromista have received attention due to their ability to produce n-3 LC-PUFAs. Knowledge of LC-PUFA synthesis and its regulation in algae at the molecular level is fragmentary and represents a bottleneck for attempts to enhance the n-3 LC-PUFA levels for industrial production. In the present review, Phaeodactylum tricornutum has been used to exemplify the synthesis and compartmentalization of n-3 LC-PUFAs. Based on recent transcriptome data a co-expression network of 106 genes involved in lipid metabolism has been created. Together with recent molecular biological and metabolic studies, a model pathway for n-3 LC-PUFA synthesis in P. tricornutum has been proposed, and is compared to industrialized species of Chromista. Limitations of the n-3 LC-PUFA synthesis by enzymes such as thioesterases, elongases, acyl-CoA synthetases and acyltransferases are discussed and metabolic bottlenecks are hypothesized such as the supply of the acetyl-CoA and NADPH. A future industrialization will depend on optimization of chemical compositions and increased biomass production, which can be achieved by exploitation of the physiological potential, by selective breeding and by genetic engineering. PMID:24284429

  2. Localization and distribution of neurons that co-express xeroderma pigmentosum-A and epidermal growth factor receptor within Rosenthal's canal.

    PubMed

    Guthrie, O'neil W

    2015-10-01

    Xeroderma pigmentosum-A (XPA) is a C4-type zinc-finger scaffolding protein that regulates the removal of bulky-helix distorting DNA damage products from the genome. Phosphorylation of serine residues within the XPA protein is associated with improved protection of genomic DNA and cell death resistance. Therefore, kinase signaling is one important mechanism for regulating the protective function of XPA. Previous experiments have shown that spiral ganglion neurons (SGNs) may mobilize XPA as a general stress response to chemical and physical ototoxicants. Therapeutic optimization of XPA via kinase signaling could serve as a means to improve DNA repair capacity within neurons following injury. The kinase signaling activity of the epidermal growth factor receptor (EGFR) has been shown in tumor cell lines to increase the repair of DNA damage products that are primarily repaired by XPA. Such observations suggest that EGFR may regulate the protective function of XPA. However, it is not known whether SGNs in particular or neurons in general could co-express XPA and EGFR. In the current study gene and protein expression of XPA and EGFR were determined from cochlear homogenates. Immunofluorescence assays were then employed to localize neurons expressing both EGFR and XPA within the ganglion. This work was then confirmed with double-immunohistochemistry. Rosenthal's canal served as the reference space in these experiments and design-based stereology was employed in first-order stereology quantification of immunoreactive neurons. The results confirmed that a population of SGNs that constitutively express XPA may also express the EGFR. These results provide the basis for future experiments designed to therapeutically manipulate the EGFR in order to regulate XPA activity and restore gene function in neurons following DNA damage. PMID:26493720

  3. THEMES OF LIVER TRANSPLANTATION

    PubMed Central

    Starzl, Thomas E.; Fung, John J.

    2010-01-01

    Liver transplantation was the product of 5 interlocking themes. These began in 1958-59 with canine studies of then theoretical hepatotrophic molecules in portal venous blood (Theme I) and with the contemporaneous parallel development of liver and multivisceral transplant models (Theme II). Further Theme I investigations showed that insulin was the principal, although not the only, portal hepatotrophic factor. In addition to resolving long-standing controversies about the pathophysiology of portacaval shunt, the hepatotrophic studies blazed new trails in the regulation of liver size, function, and regeneration. They also targeted inborn metabolic errors (e.g. familial hyperlipoproteinemia) whose palliation by portal diversion presaged definitive correction with liver replacement. Clinical use of the Theme II transplant models depended on multiple drug immunosuppression (Theme III, Immunology), guided by an empirical algorithm of pattern recognition and therapeutic response. Successful liver replacement was first accomplished in 1967 with azathioprine, prednisone, and ALG. With this regimen, the world’s longest surviving liver recipient is now 40 years postoperative. Incremental improvements in survival outcome occurred (Theme IV) when azathioprine was replaced by cyclosporine (1979) which was replaced in turn by tacrolimus (1989). However, the biologic meaning of alloengraftment remained enigmatic until multilineage donor leukocyte microchimerism was discovered in 1992 in long surviving organ recipients. Seminal mechanisms were then identified (clonal exhaustion-deletion and immune ignorance) that linked organ engraftment and the acquired tolerance of bone marrow transplantation and eventually clarified the relationship of transplantation immunology to the immunology of infections, neoplasms, and autoimmune disorders. With this insight, better strategies of immunosuppression have evolved. As liver and other kinds of organ transplantation became accepted as

  4. Themes of liver transplantation.

    PubMed

    Starzl, Thomas E; Fung, John J

    2010-06-01

    Liver transplantation was the product of five interlocking themes. These began in 1958-1959 with canine studies of then theoretical hepatotrophic molecules in portal venous blood (Theme I) and with the contemporaneous parallel development of liver and multivisceral transplant models (Theme II). Further Theme I investigations showed that insulin was the principal, although not the only, portal hepatotrophic factor. In addition to resolving long-standing controversies about the pathophysiology of portacaval shunt, the hepatotrophic studies blazed new trails in the regulation of liver size, function, and regeneration. They also targeted inborn metabolic errors (e.g., familial hyperlipoproteinemia) whose palliation by portal diversion presaged definitive correction with liver replacement. Clinical use of the Theme II transplant models depended on multiple drug immunosuppression (Theme III, Immunology), guided by an empirical algorithm of pattern recognition and therapeutic response. Successful liver replacement was first accomplished in 1967 with azathioprine, prednisone, and antilymphoid globulin. With this regimen, the world's longest surviving liver recipient is now 40 years postoperative. Incremental improvements in survival outcome occurred (Theme IV) when azathioprine was replaced by cyclosporine (1979), which was replaced in turn by tacrolimus (1989). However, the biologic meaning of alloengraftment remained enigmatic until multilineage donor leukocyte microchimerism was discovered in 1992 in long-surviving organ recipients. Seminal mechanisms were then identified (clonal exhaustion-deletion and immune ignorance) that linked organ engraftment and the acquired tolerance of bone marrow transplantation and eventually clarified the relationship of transplantation immunology to the immunology of infections, neoplasms, and autoimmune disorders. With this insight, better strategies of immunosuppression have evolved. As liver and other kinds of organ transplantation

  5. Liver transplantation in acute-on-chronic liver failure: lessons learnt from acute liver failure setting.

    PubMed

    Reddy, Mettu Srinivas; Rajalingam, Rajesh; Rela, Mohamed

    2015-10-01

    Acute-on-chronic liver failure is a clinical entity with high risk of mortality. These patients can have severe liver dysfunction complicated with multiple organ failure. Liver transplantation is the definitive treatment for these patients. Literature regarding management of acute liver failure with special emphasis on liver transplantation was reviewed. Lessons learnt from the management of patients with acute liver failure which could be extrapolated to the management of patients with acute-on-chronic liver failure are discussed. Significant improvement in outcomes of acute liver failure has been reported across the world. Several aspects in transplantation for acute liver failure were found to be relevant to the management of acute-on-chronic liver failure. These include defining criteria to identify patients needing early liver transplantation, prioritizing patients with acute liver failure on the waiting list, defining when to abandon transplantation in acute liver failure, emphasis on graft quality and the need for a multi-disciplinary approach to manage multiple organ dysfunction. Useful lessons can be learnt from the progress made in the management of acute liver failure and these can be extrapolated to the management of patients with acute-on-chronic liver failure. PMID:25788191

  6. Gut microbiota and liver diseases

    PubMed Central

    Minemura, Masami; Shimizu, Yukihiro

    2015-01-01

    Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases. PMID:25684933

  7. ILT4 drives B7-H3 expression via PI3K/AKT/mTOR signalling and ILT4/B7-H3 co-expression correlates with poor prognosis in non-small cell lung cancer.

    PubMed

    Zhang, Pei; Yu, Shuwen; Li, Hongyu; Liu, Chuanyong; Li, Juan; Lin, Wenli; Gao, Aiqin; Wang, Linlin; Gao, Wei; Sun, Yuping

    2015-08-01

    Immunoglobulin-like transcript (ILT) 4 is critical for the inhibitory function of certain immune cells. We previously demonstrated that ILT4 is over-expressed in human non-small cell lung cancer (NSCLC) cells and is involved in tumour evasion via an unknown mechanism. In this report, we demonstrate that ILT4 increases the expression of the co-inhibitory molecule B7-H3 through PI3K/AKT/mTOR signalling. In primary human NSCLC tissues, a significant positive relationship is observed between ILT4 and B7-H3 expression. ILT4/B7-H3 co-expression is significantly associated with a reduction in T infiltrating lymphoid cells and lower overall survival. In summary, ILT4 increases B7-H3 expression and ILT4/B7-H3 co-expression may be involved in NSCLC progression. PMID:26149216

  8. Imaging in pediatric liver transplantation.

    PubMed

    Monti, L; Soglia, G; Tomà, P

    2016-05-01

    Liver transplantation has become an established curative treatment in adult patients with acute or chronic end-stage liver diseases. In pediatric cases the number of cadaveric donor livers is not sufficient and to overcome the shortage of appropriate-sized whole liver grafts, technical variants of liver transplantation have been practiced. Reduced-size cadaveric and split cadaveric allografts have become an important therapeutic option, expanding the availability of size-appropriate organs for pediatric recipients with terminal liver disease. The number of pediatric deaths awaiting liver transplantation has been reduced by the introduction of living-related liver transplantation, developed to overcome the shortage of suitable grafts for children. It is important for radiologists to know that children have distinct imaging of liver transplantation that distinguish them from adults. A multidisciplinary pediatric liver transplantation team should be skilled in pediatric conditions and in associated processes, risks and complications. Radiologists should know the common pediatric liver diseases that lead to liver transplantation, the anastomotic techniques and the expected postoperative imaging findings. The aim of this study is to illustrate the role of non-invasive imaging such us ultrasonography, color Doppler ultrasonography, multidetector computed tomography and magnetic resonance imaging in the evaluation of pediatric liver transplantation and in potential liver donors. PMID:26909515

  9. HCV in liver transplantation.

    PubMed

    Germani, Giacomo; Tsochatzis, Emmanuel; Papastergiou, Vasilios; Burroughs, Andrew K

    2013-01-01

    HCV-related cirrhosis represents the leading indication for liver transplantation in the Western countries. HCV reinfection after liver transplantation occurs in virtually all patients transplanted for HCV-related liver disease Histological evidence of chronic HCV infection develops in 50 to 90 % of patients by 12 months after liver transplantation, and cirrhosis occurs in about 20 % of patients within 5 years after transplant. Several studies have evaluated host, viral, and transplant-related factors that might be associated with the severity of HCV recurrence. Among host factors, immunosuppression is one of the major factors that accounts for accelerated HCV recurrence and it has been an area of extensive research and controversy. Donor age, steatosis, and immunogenetic factors are also relevant in determining the outcome in patients transplanted for HCV-related cirrhosis. A major step to prevent complications of HCV recurrence related to the rapid fibrosis is the posttransplant antiviral treatment. Two strategies have been tried: pre-emptive or other strategies as soon as possible after liver transplantation or elective therapy once there is histological evidence of recurrent hepatitis C. Retransplantation due to graft failure from recurrent hepatitis C is rarely an option in the era of organ shortage as it is associated with poor outcome, but many case needs to be considered early in the evolution of disease. New antivirals may change the outcome dramatically of patients transplanted for HCV cirrhosis. PMID:22829333

  10. Anesthesia for liver transplantation.

    PubMed

    Dalal, Aparna

    2016-01-01

    Patients with end stage liver disease (ESLD) have complex problems such as cirrhotic cardiomyopathy, coronary artery disease, hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), hepatic encephalopathy, intracranial hypertension, (ICP), left ventricular outflow tract obstruction (LVOTO), high Model of end liver disease (MELD) scores, hyponatremia, and coagulopathies. The anesthesia management for liver transplantation can be very complex, dynamic and challenging. Anesthesia agents affect hepatic blood flow and anesthetic drug distribution, metabolism and elimination maybe altered in end stage liver disease. Other non-anesthetic agents such as nitric oxide, epoprosterenol, THAM, hypertonic saline, fibrinogen concentrates, fresh frozen plasma, platelets, packed red blood cells, recombinant plasminogen activator, calcium chloride, epinephrine etc. may play a vital role in the perioperative management of these patients. Intraoperative hemostasis and coagulation management can be very arduous as these patients may bleed or be at risk for thrombosis. Monitoring modalities such as Thromboelastography (TEG), Transcranial Doppler (TCD), Transesophageal Echocardiography (TEE), Bispectral Index (BIS) and Optic Nerve Sheath Diameter (ONSD) ultrasound play a significant role in various circumstances. Surgical techniques include complete or partial occlusion of the inferior vena cava (IVC) with or without use of venovenous bypass (VVBP) or portocaval shunts. Post reperfusion syndrome (PRS) is a crucial event in this procedure, where patients may experience arrhythmia and/or cardiac arrest. Anesthetic handling of this phase has been recapitulated in detail. Provision of anesthesia services to the living liver transplant donor and pain management has been outlined. PMID:26118926

  11. Angiogenesis and liver fibrosis

    PubMed Central

    Elpek, Gülsüm Özlem

    2015-01-01

    Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases (CLDs) that are characterized by inflammation and progressive fibrosis. Because anti-angiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical and experimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis. PMID:25848465

  12. Exosomes in liver pathology.

    PubMed

    Sato, Keisaku; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco

    2016-07-01

    Exosomes are small (∼100nm) membrane-bound extracellular vesicles released by various types of cells into biological fluids. They contain proteins, mRNAs and miRNAs as cargo. Different cell types can take up exosomes by endocytosis and the cargo contained within them can be transferred horizontally to these recipient cells. Exosomal proteins and miRNAs can be functional and regulate physiological cell events modifying the microenvironment in target cells, a key event of liver pathology. Exosome-mediated cell-cell communication can alter tumor growth, cell migration, antiviral infection and hepatocyte regeneration, indicating that exosomes have great potential for development as diagnostic or therapeutic tools. Analyses of circulating total or exosomal miRNAs have identified a large number of candidate miRNAs that are regulated in liver diseases, and the diagnostic testing using single or multiple miRNAs shows good sensitivity and specificity. Some candidate miRNAs have been identified to play an important role in various liver disorders. This review summarizes recent findings on the role of extracellular vesicles in liver diseases and their diagnostic and therapeutic potential, mainly focusing on exosomes but also includes microvesicles in liver pathology. PMID:26988731

  13. Stereoscopic liver surface reconstruction

    PubMed Central

    Karwan, Adam; Rudnicki, Jerzy; Wróblewski, Tadeusz

    2012-01-01

    The paper presents a practical approach to measuring liver motion, both respiratory and laparoscopic, with a tool guided in the operating room. The presented method is based on standard operating room equipment, i.e. rigid laparoscopic cameras and a single incision laparoscopic surgery trocar. The triangulation algorithm is used and stereo correspondence points are marked manually by two independent experts. To calibrate the cameras two perpendicular chessboards, a pinhole camera model and a Tsai algorithm are used. The data set consists of twelve real liver surgery video sequences: ten open surgery and two laparoscopic, gathered from different patients. The setup equipment and methodology are presented. The proposed evaluation method based on both calibration points of the chessboard reconstruction and measurements made by the Polaris Vicra tracking system are used as a reference system. In the analysis stage we focused on two specific goals, measuring respiration and laparoscopic tool guided liver motions. We have presented separate examples for left and right liver lobes. It is possible to reconstruct liver motion using the SILS trocar. Our approach was made without additional position or movement sensors. Diffusion of cameras and laser for distance measurement seems to be less practical for in vivo laparoscopic data, but we do not exclude exploring such sensors in further research. PMID:23256023

  14. Kidney Injury in Liver Disease.

    PubMed

    Regner, Kevin R; Singbartl, Kai

    2016-07-01

    Acute kidney injury (AKI) occurs frequently in patients with liver disease and increases morbidity and mortality. Hepatorenal syndrome is a common cause of AKI in patients with decompensated cirrhosis and is due to alterations in systemic and renal hemodynamics. Serum creatinine-based estimation of kidney function is a key component of the Model for End-stage Liver Disease score in liver transplant candidates. Continuous renal replacement therapy is used in critically ill patients with liver failure and AKI. Simultaneous liver-kidney transplantation (SLK) may be required in patients with liver failure and prolonged AKI. Identification of appropriate candidates for SLK remains controversial. PMID:27339675

  15. Liver involvement in systemic infection

    PubMed Central

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2014-01-01

    The liver is often involved in systemic infections, resulting in various types of abnormal liver function test results. In particular, hyperbilirubinemia in the range of 2-10 mg/dL is often seen in patients with sepsis, and several mechanisms for this phenomenon have been proposed. In this review, we summarize how the liver is involved in various systemic infections that are not considered to be primarily hepatotropic. In most patients with systemic infections, treatment for the invading microbes is enough to normalize the liver function tests. However, some patients may show severe liver injury or fulminant hepatic failure, requiring intensive treatment of the liver. PMID:25276279

  16. Liver disease in the adolescent.

    PubMed

    Mavis, Alisha M; Alonso, Estella M

    2015-02-01

    This article discusses common liver diseases in the adolescent. Briefly reviewed is the evaluation of the adolescent with new-onset liver enzyme elevation. Then the article discusses common liver diseases, such as nonalcoholic fatty liver disease, hepatitis, metabolic disease, biliary atresia, cystic fibrosis, and inherited disorders of cholestasis. Finally, a management approach to the adolescent with liver disease is outlined, noting the challenges that must be addressed to effectively care for not only liver disease in the adolescent but also the patient as a whole. PMID:25454303

  17. Immunobiology of liver xenotransplantation

    PubMed Central

    Ekser, Burcin; Burlak, Christopher; Waldman, Joshua P; Lutz, Andrew J; Paris, Leela L; Veroux, Massimiliano; Robson, Simon C; Rees, Michael A; Ayares, David; Gridelli, Bruno; Tector, A Joseph; Cooper, David KC

    2013-01-01

    Pigs are currently the preferred species for future organ xenotransplantation. With advances in the development of genetically modified pigs, clinical xenotransplantation is becoming closer to reality. In preclinical studies (pig-to-nonhuman primate), the xenotransplantation of livers from pigs transgenic for human CD55 or from α1,3-galactosyltransferase gene-knockout pigs+/− transgenic for human CD46, is associated with survival of approximately 7–9 days. Although hepatic function, including coagulation, has proved to be satisfactory, the immediate development of thrombocytopenia is very limiting for pig liver xenotransplantation even as a ‘bridge’ to allotransplantation. Current studies are directed to understand the immunobiology of platelet activation, aggregation and phagocytosis, in particular the interaction between platelets and liver sinusoidal endothelial cells, hepatocytes and Kupffer cells, toward identifying interventions that may enable clinical application. PMID:23078060

  18. Alcoholic liver disease: Treatment

    PubMed Central

    Suk, Ki Tae; Kim, Moon Young; Baik, Soon Koo

    2014-01-01

    The excess consumption of alcohol is associated with alcoholic liver diseases (ALD). ALD is a major healthcare problem, personal and social burden, and significant reason for economic loss worldwide. The ALD spectrum includes alcoholic fatty liver, alcoholic hepatitis, cirrhosis, and the development of hepatocellular carcinoma. The diagnosis of ALD is based on a combination of clinical features, including a history of significant alcohol intake, evidence of liver disease, and laboratory findings. Abstinence is the most important treatment for ALD and the treatment plan varies according to the stage of the disease. Various treatments including abstinence, nutritional therapy, pharmacological therapy, psychotherapy, and surgery are currently available. For severe alcoholic hepatitis, corticosteroid or pentoxifylline are recommended based on the guidelines. In addition, new therapeutic targets are being under investigation. PMID:25278689

  19. Liver transplantation in Germany.

    PubMed

    Tacke, Frank; Kroy, Daniela C; Barreiros, Ana Paula; Neumann, Ulf P

    2016-08-01

    Liver transplantation (LT) is a well-accepted procedure for end-stage liver disease in Germany. In 2015, 1489 patients were admitted to the waiting list (including 1308 new admissions), with the leading etiologies being fibrosis and cirrhosis (n = 349), alcoholic liver disease (n = 302), and hepatobiliary malignancies (n = 220). Organ allocation in Germany is regulated within the Eurotransplant system based on urgency as expressed by the Model for End-Stage Liver Disease score. In 2015, only 894 LTs (n = 48 from living donors) were performed at 23 German transplant centers, reflecting a shortage of organs. Several factors may contribute to the low number of organ donations. The German transplant legislation only accepts donation after brain death (not cardiac death), whereas advances in neurosurgery and a more frequently requested "palliative care" approach render fewer patients suitable as potential donors. The legislation further requires the active consent of the donor or first-degree relatives before donation. Ongoing debates within the German transplant field address the optimal management of patients with alcoholic liver cirrhosis, hepatocellular carcinoma (HCC), and cholangiocarcinoma and measures to increase living donor transplantations. As a result of irregularities at mainly 4 German transplant centers that were exposed in 2012, guiding principles updated by the German authorities have since implemented strict rules (including internal and external auditing, the 8-eyes principle, mandatory repeated testing for alcohol consumption) to prohibit any manipulations in organ allocation. In conclusion, we will summarize important aspects on the management of LT in Germany, discuss legal and organizational aspects, and highlight challenges mainly related to the relative lack of organ donations, increasing numbers of extended criteria donors, and the peculiarities of the recipient patients. Liver Transplantation 22 1136-1142 2016 AASLD. PMID:27082951

  20. Neoplasms of the liver

    SciTech Connect

    Okuda, K.; Ishak, K.G.

    1987-01-01

    Primary Liver Cancer is perhaps the most prevalent malignancy in the world, particularly in South East Asia and Africa. After the discovery of hepatitis B virus as a cause of chronic liver disease often terminating cirrhosis and hepatocellular carcinoma, and, more recently, the integration of viral DNA into host chromosomal DNA, the progress made in this field has been remarkable. This book contains 35 chapters and covers all topical aspects, such as oncogenes, epidemiology, carcinogenic role of hepatitis viruses, histopathology, new imaging techniques and new treatment modalities that include ultrasound-guided intratumor injections of ethanol and targeting chemotherapy.

  1. Obesity and liver transplantation

    PubMed Central

    Ayloo, Subhashini; Armstrong, John; Hurton, Scott; Molinari, Michele

    2015-01-01

    The percentage of overweight and obese patients (OPs) waiting for a liver transplant continues to increase. Despite the significant advances occurred in bariatric medicine, obesity is still considered a relative contraindication to liver transplantation (LT). The main aim of this review is to appraise the literature on the outcomes of OPs undergoing LT, treatments that might reduce their weight before, during or after surgery, and discuss some of the controversies and limitations of the current knowledge with the intent of highlighting areas where future research is needed. PMID:26421262

  2. Liver and chorion cytochemistry.

    PubMed

    Roels, F; De Prest, B; De Pestel, G

    1995-01-01

    Microscopic visualization of peroxisomes in chorionic villus cytotrophoblast and in biopsy and autopsy samples of liver and kidney, the presence of enlarged liver macrophages containing lipid droplets insoluble in acetone and n-hexane as well as polarizing inclusions formed by stacks of trilamellar sheets are of diagnostic value in peroxisomal disorders. Methods are presented for evaluating these structures by light microscopy; trilamellar inclusions are only detected by electron microscopy. Macrophage features are preserved in archival paraffin blocks. In adrenal cortex, insoluble lipid, polarizing inclusions and trilamellar structures should be looked for. The stains are easily reproducible, and all reagents are commercially available. PMID:9053549

  3. Eosinophilic Liver Infiltration

    PubMed Central

    Figueroa Rivera, Ivonne; Toro, Doris H.; Gutierrez, Jose; Acosta, Eduardo

    2015-01-01

    Eosinophilic liver infiltration is a commonly encountered focal eosinophil-related inflammation with or without necrosis, which can be seen on computed tomography (CT) in the presence of peripheral eosinophilia. Although this entity has a relatively benign course, it is related to numerable conditions for which diagnosis may be challenging and requires substantial diagnostic work-up for proper management and care of the underlying disease. We report a case of a 60-year-old man who presented with a 1-week history of right upper quadrant abdominal pain with multiple ill-defined liver hypodensities associated with significant eosinophilia. PMID:26504883

  4. Construction of a bivalent DNA vaccine co-expressing S genes of transmissible gastroenteritis virus and porcine epidemic diarrhea virus delivered by attenuated Salmonella typhimurium.

    PubMed

    Zhang, Yudi; Zhang, Xiaohui; Liao, Xiaodan; Huang, Xiaobo; Cao, Sanjie; Wen, Xintian; Wen, Yiping; Wu, Rui; Liu, Wumei

    2016-06-01

    Porcine transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) can cause severe diarrhea in newborn piglets and led to significant economic losses. The S proteins are the main structural proteins of PEDV and TGEV capable of inducing neutralizing antibodies in vivo. In this study, a DNA vaccine SL7207 (pVAXD-PS1-TS) co-expressing S proteins of TGEV and PEDV delivered by attenuated Salmonella typhimurium was constructed and its immunogenicity in piglets was investigated. Twenty-day-old piglets were orally immunized with SL7207 (pVAXD-PS1-TS) at a dosage of 1.6 × 10(11) CFU per piglet and then booster immunized with 2.0 × 10(11) CFU after 2 weeks. Humoral immune responses, as reflected by virus neutralizing antibodies and specific IgG and sIgA, and cellular immune responses, as reflected by IFN-γ, IL-4, and lymphocyte proliferation, were evaluated. SL7207 (pVAXD-PS1-TS) simultaneously elicited immune responses against TGEV and PEDV after oral immunization. The immune levels started to increase at 2 weeks after immunization and increased to levels statistically significantly different than controls at 4 weeks post-immunization, peaking at 6 weeks and declined at 8 weeks. The humoral, mucosal, and cellular immune responses induced by SL7207 (pAXD-PS1-TS) were significantly higher than those of the PBS and SL7207 (pVAXD) (p < 0.01). In particular, the levels of IFN-γ and IL-4 were higher than those induced by the single-gene vaccine SL7207 (pVAXD-PS1) (p < 0.05). These results demonstrated that SL7207 (pVAXD-PS1-TS) possess the immunological functions of the two S proteins of TGEV and PEDV, indicating that SL7207 (pVAXD-PS1-TS) is a candidate oral vaccine for TGE and PED. PMID:26980672

  5. A Genome-Wide Association Study for Culm Cellulose Content in Barley Reveals Candidate Genes Co-Expressed with Members of the CELLULOSE SYNTHASE A Gene Family

    PubMed Central

    Houston, Kelly; Burton, Rachel A.; Sznajder, Beata; Rafalski, Antoni J.; Dhugga, Kanwarpal S.; Mather, Diane E.; Taylor, Jillian; Steffenson, Brian J.; Waugh, Robbie; Fincher, Geoffrey B.

    2015-01-01

    Cellulose is a fundamentally important component of cell walls of higher plants. It provides a scaffold that allows the development and growth of the plant to occur in an ordered fashion. Cellulose also provides mechanical strength, which is crucial for both normal development and to enable the plant to withstand both abiotic and biotic stresses. We quantified the cellulose concentration in the culm of 288 two – rowed and 288 six – rowed spring type barley accessions that were part of the USDA funded barley Coordinated Agricultural Project (CAP) program in the USA. When the population structure of these accessions was analysed we identified six distinct populations, four of which we considered to be comprised of a sufficient number of accessions to be suitable for genome-wide association studies (GWAS). These lines had been genotyped with 3072 SNPs so we combined the trait and genetic data to carry out GWAS. The analysis allowed us to identify regions of the genome containing significant associations between molecular markers and cellulose concentration data, including one region cross-validated in multiple populations. To identify candidate genes we assembled the gene content of these regions and used these to query a comprehensive RNA-seq based gene expression atlas. This provided us with gene annotations and associated expression data across multiple tissues, which allowed us to formulate a supported list of candidate genes that regulate cellulose biosynthesis. Several regions identified by our analysis contain genes that are co-expressed with CELLULOSE SYNTHASE A (HvCesA) across a range of tissues and developmental stages. These genes are involved in both primary and secondary cell wall development. In addition, genes that have been previously linked with cellulose synthesis by biochemical methods, such as HvCOBRA, a gene of unknown function, were also associated with cellulose levels in the association panel. Our analyses provide new insights into the

  6. Exposure to depleted uranium does not alter the co-expression of HER-2/neu and p53 in breast cancer patients

    PubMed Central

    2011-01-01

    Background Amongst the extensive literature on immunohistochemical profile of breast cancer, very little is found on populations exposed to a potential risk factor such as depleted uranium. This study looked at the immunohistochemical expression of HER-2/neu (c-erbB2) and p53 in different histological types of breast cancer found in the middle Euphrates region of Iraq, where the population has been exposed to high levels of depleted uranium. Findings The present investigation was performed over a period starting from September 2008 to April 2009. Formalin-fixed, paraffin-embedded blocks from 70 patients with breast cancer (62 ductal and 8 lobular carcinoma) were included in this study. A group of 25 patients with fibroadenoma was included as a comparative group, and 20 samples of normal breast tissue sections were used as controls. Labeled streptavidin-biotin (LSAB+) complex method was employed for immunohistochemical detection of HER-2/neu and p53. The detection rate of HER-2/neu and p53 immunohistochemical expression were 47.14% and 35.71% respectively in malignant tumors; expression was negative in the comparative and control groups (p < 0.05). HER-2/neu immunostaining was significantly associated with histological type, tumor size, nodal involvement, and recurrence of breast carcinoma (p < 0.05), p53 immunostaining was significantly associated with tumor size, nodal involvement and recurrence of breast cancer (p < 0.05). There was greater immunoexpression of HER-2/neu in breast cancer in this population, compared with findings in other populations. Both biomarkers were positively correlated with each other. Furthermore, all the cases that co-expressed both HER-2/neu and p53 showed the most unfavorable biopathological profile. Conclusion P53 and HER-2/neu over-expression play an important role in pathogenesis of breast carcinoma. The findings indicate that in regions exposed to high levels of depleted uranium, although p53 and HER-2/neu overexpression are both

  7. The Virtual Liver: Modeling Chemical-Induced Liver Toxicity

    EPA Science Inventory

    The US EPA Virtual Liver (v-Liver) project is aimed at modeling chemical-induced processes in hepatotoxicity and simulating their dose-dependent perturbations. The v-Liver embodies an emerging field of research in computational tissue modeling that integrates molecular and cellul...

  8. Interventional Treatments for Liver Disease

    MedlinePlus

    ... Search Patient information Membership Directory (SIR login) Interventional Radiology Interventional Treatments for Liver Disease There are a ... liver that can be treated with nonsurgical, interventional radiology techniques. Portal Hypertension Seen most frequently in patients ...

  9. Plants Consumption and Liver Health

    PubMed Central

    Guan, Yong-Song; He, Qing

    2015-01-01

    The liver is a very important organ with a lot of functions for the host to survive. Dietary components are essential for and can be beneficial or detrimental to the healthy or diseased liver. Plants food is an essential part of the human diet and comprises various compounds which are closely related to liver health. Selected food plants can provide nutritional and medicinal support for liver disease. At the present, the knowledge of the effects of plants on the liver is still incomplete. The most urgent task at the present time is to find the best dietary and medicinal plants for liver health in an endless list of candidates. This review article updates the knowledge about the effects of plants consumption on the health of the liver, putting particular emphasis on the potential beneficial and harmful impact of dietary and medicinal plants on liver function. PMID:26221179

  10. CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism

    PubMed Central

    Wilhelm, Annika; Aldridge, Victoria; Haldar, Debashis; Naylor, Amy J; Weston, Christopher J; Hedegaard, Ditte; Garg, Abhilok; Fear, Janine; Reynolds, Gary M; Croft, Adam P; Henderson, Neil C; Buckley, Christopher D; Newsome, Philip N

    2016-01-01

    Introduction CD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix. Objective To determine the role of CD248 in the development of liver fibrosis in the rodent and human setting. Design CD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248−/− and wild-type controls with carbon tetrachloride (CCl4) treatment. Results Expression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248−/− mice compared with wild-type mice after CCl4 treatment. Isolated HSC from wild-type and CD248−/− mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248−/− HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248−/− HSC was confirmed by significantly reduced c-fos expression in CD248−/− HSC compared with wild-type HSC. Conclusions Our data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury. PMID:26078290

  11. Coffee and liver health.

    PubMed

    Morisco, Filomena; Lembo, Vincenzo; Mazzone, Giovanna; Camera, Silvia; Caporaso, Nicola

    2014-01-01

    Coffee is one of the most widely used beverages in the world. It includes a wide array of components that can have potential implications for health. Several epidemiological studies associate coffee consumption with a reduced incidence of various chronic diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases. Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma. The mechanisms of action through which it exerts its beneficial effects are not fully understood. Experimental studies show that coffee consumption reduces fat accumulation and collagen deposition in the liver and promotes antioxidant capacity through an increase in glutathione as well as modulation of the gene and protein expression of several inflammatory mediators. Animal and in vitro studies indicate that cafestol and kahweol, 2 diterpens, can operate by modulating multiple enzymes involved in the detoxification process of carcinogens causing hepatocellular carcinoma. It is unclear whether the benefits are significant enough to "treat" patients with chronic liver disease. While we await clarification, moderate daily unsweetened coffee use is a reasonable adjuvant to therapy for these patients. PMID:25291138

  12. Solitary liver nodules.

    PubMed

    Fisher, A W; Curry, B; Jacques, J

    1975-05-17

    There has been confusion in the literature over the nomenclature of solitary liver nodules. Several such lesions have recently been reported in patients taking oral contraceptives. Similarities exist between these cases that suggest they may be examples of focal nodular hyperplasia. Here three further cases are presented. The criteria for making the diagnosis and its importance are discussed. PMID:165001

  13. The EPA Liver Project

    EPA Science Inventory

    The v-Liver is part of a broader EPA effort on Virtual Tissues (VT) aimed at reducing the magnitude and spectrum of animal testing by integrative in silico and in vitro models, which recapitulate the properties of intact organs. The other VT projects include the Virtual Embryo (...

  14. Ton That Tung's livers.

    PubMed

    Helling, Thomas S; Azoulay, Daniel

    2014-06-01

    Born in the early 20th century, the Vietnamese surgeon Ton That Tung received his medical education in French colonial Indochina at the fledgling l'Ecole de Médecine de Hanoi, the first indigenous medical school in Southeast Asia. The benefactor of a postgraduate position at the medical school, Ton That Tung subsequently obtained his surgical training at the Phù Doãn Hospital in Hanoi and concurrently developed a passion for the study of liver anatomy, pathology, and surgery. His contributions to an understanding of liver anatomy based on meticulous dissection of autopsy specimens antedated and rivaled later work by the famous Western anatomists Couinaud, Healey, Schroy, and others. Ton That Tung's contributions, however, were overshadowed by the intense national struggles of the Vietnamese to establish independent rule and self-governance from the French and by eventual alignment with eastern bloc Communist countries, thus isolating much of his work behind the "Iron Curtain" until well after the end of the Cold War. Nevertheless, Ton That Tung remains a pioneer in liver anatomy and liver surgery. His commitment to surgical science and, more importantly, to the Vietnamese people stands as a tribute to the tireless pursuit of his ideals. PMID:24335785

  15. Glycosylation and Liver Cancer

    PubMed Central

    Mehta, Anand; Herrera, Harmin; Block, Timothy

    2015-01-01

    Liver cancer is the 5th most common cancer, but the 2nd leading cause of cancer death, in the world, with more than 700,000 fatalities annually. The major etiology of liver cancer is infection with an hepatotropic virus such as hepatitis B virus (HBV) or hepatitis C virus infection (HCV). While chronic viral infection remains the main cause of liver disease and risk of HCC, rates of non –viral associated HCC are occurring at an alarmingly increasing rate. Like many cancers, survival rates are closely associated with time of detection. If HCC is caught early, survival rates can be as high as 50%. Regrettably, most cases of HCC are caught late where survival rates can be as low as 2–7%. Thus, there has been great interest in discovering serum biomarkers that could be used to identify those with HCC. To this end, many groups have examined the N-linked glycans to identify changes that occur with HCC. As the liver secretes the vast majority of proteins into the serum, this has often been a starting point for study. In serum, alterations in core fucosylation, outer-arm fucosylation, increased sialylation and glycan branching have been observed in patients with HCC. Similar findings have been found directly in HCC tissue suggesting that these glycan changes may play a role in tumor formation and development. PMID:25727150

  16. [Dietotherapy children with liver diseases].

    PubMed

    Pavlovskaia, E V; Strokova, T V; Topil'skaia, N V; Isakova, V A

    2009-01-01

    In children with liver diseases disorders of the nutritional status appear more quickly and delay normal growth and development. Administration of the nutritional support based on nosological and syndromal approaches lets provide optimal conditions for normalization of the liver functions, improves efficiency of therapy and prognosis of the disease. The article contents modern recommendations on the organization of nutrition in children with different liver diseases, correction of metabolic disorders during complications of liver pathology. PMID:20120964

  17. Liver transplantation in Spain.

    PubMed

    de la Rosa, Gloria; Fondevila, Constantino; Navasa, Miquel

    2016-09-01

    Liver transplantation (LT) activity started in Spain in 1984 and has exceeded 23,700 interventions, with more than 1000 transplants performed yearly. Every hospital needs official authorization to perform a LT, which implies the obligation to register all patients on the national waiting list. The Spanish National Transplant Organization (ONT) provides essential support for organ procurement, allocation, and management of the waiting list at a national level. Liver allocation is center-oriented as all available organs are referred to the ONT for the whole country. The allocation rules for LT are made according to disease severity after consensus among professionals from every transplant center and ratified by representatives of the regional health authorities. Authorization and location/distribution of transplant centers are regulated by the country (Spain) and by the different regions according to the Real Decreto 1723/2012. For a total population of 47,850,795 inhabitants, there are 24 centers for LT for adults (1 team/2 million people) and 5 for LT for children (1 team/9.5 million people). Nonbiliary cirrhosis, particularly alcohol- and hepatitis C virus-related cirrhosis (60%), and tumors, mainly hepatocellular carcinoma (19%), are the most common indications for LT in Spain. Unusual causes of LT include metabolic diseases like Wilson's disease, familial amyloid polyneuropathy and hyperoxaluria type I, polycystic kidney and liver disease, and some tumors (epithelioid hemangioendothelioma and neuroendocrine tumors). Important efforts are now being undertaken to improve the quality and transplantability of extended criteria livers, in particular those arising from DCD, which represent the greatest opportunity to expand the donor pool. These efforts have to be addressed to adapt the organ preservation procedures, be it through the application of regional perfusion in situ or the use of machine perfusion preservation ex situ. Liver Transplantation 22 1259-1264 2016

  18. Nonalcoholic fatty liver disease.

    PubMed

    Brunt, Elizabeth M; Wong, Vincent W-S; Nobili, Valerio; Day, Christopher P; Sookoian, Silvia; Maher, Jacquelyn J; Bugianesi, Elisabetta; Sirlin, Claude B; Neuschwander-Tetri, Brent A; Rinella, Mary E

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring. PMID:27188459

  19. Alcoholic liver disease: The gut microbiome and liver crosstalk

    PubMed Central

    Hartmann, Phillipp; Seebauer, Caroline T.; Schnabl, Bernd

    2015-01-01

    Alcoholic liver disease is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with alcoholic liver disease have increased intestinal permeability and elevated systemic levels of gut-derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier or preventing cellular responses to microbial products protect from experimental alcoholic liver disease. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of alcoholic liver disease. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship and consequences for alcoholic liver disease. We also discuss how the liver affects the intestinal microbiota. PMID:25872593

  20. Hedgehog Signaling in the Liver

    PubMed Central

    Omenetti, Alessia; Choi, Steve; Michelotti, Gregory; Diehl, Anna Mae

    2010-01-01

    Reactivation of Hedgehog (Hh), a morphogenic signaling pathway that controls progenitor cell fate and tissue construction during embryogenesis occurs during many types of liver injury in adult. The net effects of activating the Hedgehog pathway include expansion of liver progenitor populations to promote liver regeneration, but also hepatic accumulation of inflammatory cells, liver fibrogenesis, and vascular remodeling. All of these latter responses are known to be involved in the pathogenesis of cirrhosis. In addition, Hh signaling may play a role in primary liver cancers, such as cholangiocarcinoma and hepatocellular carcinoma. Study of Hedgehog signaling in liver cells is in its infancy. Additional research in this area is justified given growing experimental and clinical data supporting a role for the pathway in regulating outcomes of liver injury. PMID:21093090

  1. Endoderm specification and liver development.

    PubMed

    Goessling, W; Stainier, D Y

    2016-01-01

    The endoderm is the innermost embryonic germ layer, and in zebrafish, it gives rise to the lining of the gut, the gills, liver, pancreas, gallbladder, and derivatives of the pharyngeal pouch. These organs form the gastrointestinal tract and are involved with the absorption, delivery, and metabolism of nutrients. The liver has a central role in regulating these processes because it controls carbohydrate and lipid metabolism, protein synthesis, and breakdown of endogenous and xenobiotic products. Liver dysfunction frequently leads to significant morbidity and mortality; however, in most settings of organ injury, the liver exhibits remarkable regenerative capacity. In this chapter, we review the principal mechanisms of endoderm and liver formation and provide protocols to assess liver formation and liver regeneration. PMID:27312502

  2. Lipids changes in liver cancer*

    PubMed Central

    Jiang, Jing-ting; Xu, Ning; Zhang, Xiao-ying; Wu, Chang-ping

    2007-01-01

    Liver is one of the most important organs in energy metabolism. Most plasma apolipoproteins and endogenous lipids and lipoproteins are synthesized in the liver. It depends on the integrity of liver cellular function, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs, these processes are impaired and the plasma lipid and lipoprotein patterns may be changed. Liver cancer is the fifth common malignant tumor worldwide, and is closely related to the infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV and HCV infections are quite common in China and other Southeast Asian countries. In addition, liver cancer is often followed by a procession of chronic hepatitis or cirrhosis, so that hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo. In this review we summarize the clinical significance of lipid and lipoprotein metabolism under liver cancer. PMID:17565510

  3. Liver transplantation for hepatocellular carcinoma

    PubMed Central

    Tanwar, Sudeep; Khan, Shahid A; Grover, Vijay Paul Bob; Gwilt, Catherine; Smith, Belinda; Brown, Ashley

    2009-01-01

    Hepatocellular carcinoma (HCC) is the commonest primary malignancy of the liver. It usually occurs in the setting of chronic liver disease and has a poor prognosis if untreated. Orthotopic liver transplantation (OLT) is a suitable therapeutic option for early, unresectable HCC particularly in the setting of chronic liver disease. Following on from disappointing initial results, the seminal study by Mazzaferro et al in 1996 established OLT as a viable treatment for HCC. In this study, the “Milan criteria” were applied achieving a 4-year survival rate similar to OLT for benign disease. Since then various groups have attempted to expand these criteria whilst maintaining long term survival rates. The technique of living donor liver transplantation has evolved over the past decade, particularly in Asia, and published outcome data is comparable to that of OLT. This article will review the evidence, indications, and the future direction of liver transplantation for liver cancer. PMID:19938188

  4. Probiotics in Pediatric Liver Disease.

    PubMed

    Miloh, Tamir

    2015-01-01

    The gut-liver axis involves complex interaction between the intestinal microbiome and the liver parenchyma. Probiotics are live microorganisms that are used in a variety of diseases. With currently only 2 randomized-controlled studies (one with Lactobacillus GG and the other with VSL #3), data are scarce to support the clinical effect of probiotic use in children with nonalcoholic fatty liver disease. There is evidence that probiotics decrease the risk of necrotizing enterocolitis and thereby reduce the prevalence of total parenteral nutrition-induced chronic liver disease. Probiotics are used with a few reported positive outcomes in patients with cystic fibrosis and familial hypercholesterolemia and may be promising in other liver conditions. Probiotics are generally safe and well tolerated in children, premature infants, and in patients after liver transplantation. Large, prospective, randomized clinical trials are needed to evaluate the benefit of probiotics in children with liver diseases. PMID:26447962

  5. Liver Transplantation in Brazil.

    PubMed

    Bittencourt, Paulo Lisboa; Farias, Alberto Queiroz; Couto, Claudia Alves

    2016-09-01

    Over 1700 liver transplantations (LTs) are performed annually in Brazil. In absolute terms, the country performs more LT surgeries than anywhere else in Latin America and is third worldwide. However, due to its increasing population and inadequate donor organ supply, the country averages 5-10 LTs per million population, far lower than required. There is a marked heterogeneity in organ donation and LT activity throughout the country. Access to LT in the underprivileged North, Midwest, and Northeast regions of Brazil is scarce. Major challenges for the future of LT in Brazil will be to increase organ donation and access to LT. The reduction of those geographical disparities in donation, organ procurement, and LT due to political and financial constraints is of utmost importance. Liver Transplantation 22 1254-1258 2016 AASLD. PMID:27228568

  6. Hypervascular liver lesions.

    PubMed

    Kamaya, Aya; Maturen, Katherine E; Tye, Grace A; Liu, Yueyi I; Parti, Naveen N; Desser, Terry S

    2009-10-01

    Hypervascular hepatocellular lesions include both benign and malignant etiologies. In the benign category, focal nodular hyperplasia and adenoma are typically hypervascular. In addition, some regenerative nodules in cirrhosis may be hypervascular. Malignant hypervascular primary hepatocellular lesions include hepatocellular carcinoma, fibrolamellar carcinoma, and peripheral cholangiocarcinoma. Vascular liver lesions often appear hypervascular because they tend to follow the enhancement of the blood pool; these include hemangiomas, arteriovenous malformations, angiosarcomas, and peliosis. While most gastrointestinal malignancies that metastasize to the liver will appear hypovascular on arterial and portal-venous phase imaging, certain cancers such as metastatic neuroendocrine tumors (including pancreatic neuroendocrine tumors, carcinoid, and gastrointestinal stromal tumors) tend to produce hypervascular metastases due to the greater recruitment of arterial blood supply. Finally, rare hepatic lesions such as glomus tumor and inflammatory pseudotumor may have a hypervascular appearance. PMID:19842564

  7. Comparison of liver microRNA transcriptomes of Tibetan and Yorkshire pigs by deep sequencing.

    PubMed

    Li, Yanyue; Li, Xiaocheng; Sun, Wen-Kui; Cheng, Chi; Chen, Yi-Hui; Zeng, Kai; Chen, Xiaohui; Gu, Yiren; Gao, Rong; Liu, Rui; Lv, Xuebin

    2016-02-15

    MicroRNAs (miRNAs) play an important role in the modulation of various metabolic processes in the liver, yet little is known about the liver microRNAome (miRNAome) of the Tibetan pig. Here we used the Yorkshire pig as a control to analyze the Tibetan pig-specific liver miRNAome, and for preliminary investigation of differentially expressed miRNAs participating in metabolism. A comprehensive analysis of Tibetan and Yorkshire pig liver miRNAomes by small RNA sequencing identified 362 unique miRNAs. Among these, 304 were co-expressed in both libraries, and 10 and 48 miRNAs were specifically expressed. Differential expression analysis of miRNAs, miRNA target prediction and KEGG analysis revealed that differentially expressed miRNAs were associated mainly with the metabolism of glucose, lipid and protein. Six differentially expressed miRNAs (miR-34a, miR-326, miR-1, miR-335, miR-185 and miR-378) participating in the metabolism of glucose and lipid were identified. Additionally, qPCR results revealed that a lower expression of miR-34a in Tibetan pig liver may promote gluconeogenesis by increasing the expression of Sirtuin type 1 (Sirt1); a lower expression of miR-1 in Tibetan pig liver may promote the synthesis and accumulation of lipid by increasing the expression of Liver X receptor α (LXRα); and a lower expression of miR-185 in Tibetan pig liver may promote the uptake of cholesterol from blood and secretion of bile by increasing the expression of the scavenger receptor class B type I (SR-BI). Our results provide new information and understanding of porcine miRNA profiles, which may help explain the regulatory mechanisms of miRNAs in the metabolic functions of Tibetan pig liver, and provide new biomarkers to assist in the development of Tibetan pig breeding characteristics. PMID:26656174

  8. Voriconazole and the liver

    PubMed Central

    Mihăilă, Romeo-Gabriel

    2015-01-01

    Voriconazole is an azole useful for the prophylaxis and the treatment of aspergillosis and other fungal infections in immunosuppressed subjects, as those found in aplasia after aggressive polychemotherapy treatments, after hematopoietic stem cell, liver or lung transplantation. Its administration in therapeutic doses lead to extremely varied serum levels from patient to patient and even to the same patient. The explanations are varied: nonlinear pharmacokinetics, certain patient-related factors, including genetic polymorphisms in the cytochrome P450 2C19 gene, the kidney and liver function, simultaneous administration with other drugs metabolised by the same cytochrome. It is recommended to maintain the serum concentrations of voriconazole between 1.5 and 4 μg/mL. At lower values its efficacy decreases and at higher values the risk of neurological toxicity increases. Even at these concentrations it is not excluded the possible appearance of a variety of toxic effects, including on the liver, manifested by cholestasis, hepatocytolisis, or their combination. It is recommended to monitor the clinical and laboratory evolution of all patients treated with voriconazole, and of the serum levels of the drug of those who belong to risk groups, even if there is still no consensus on this issue, given the lack of correlation between the serum level and the occurrence of adverse effects in many patients. PMID:26207164

  9. Tropical liver abscess.

    PubMed Central

    Yeoh, K. G.; Yap, I.; Wong, S. T.; Wee, A.; Guan, R.; Kang, J. Y.

    1997-01-01

    Forty-one consecutive cases of liver abscesses seen at the National University Hospital, Singapore from 1988 to 1994 were reviewed. Twenty-seven cases (65%) were pyogenic, six (15%) amoebic, two (5%) tuberculous and six (15%) indeterminate. The predominance of pyogenic abscesses is in marked contrast to previous studies from the region a decade ago in which amoebic abscesses were the commonest type. The commonest pathogen causing pyogenic abscess was Klebsiella pneumoniae. Two cases were due to Mycobacterium tuberculosis, and this organism needs to be actively looked for in smears and cultures of aspirated material. As the majority of organisms isolated were resistant to ampicillin, empirical antibiotic treatment for suspected pyogenic abscess should include gentamicin or a cephalosporin. Percutaneous needle aspiration of the abscess was performed for 85% of pyogenic abscesses and surgery was necessary in only two cases because of complications. We found that percutaneous aspiration of liver abscess is helpful to confirm the diagnosis, provides a better bacteriological culture yield, gives a good outcome, and may uncover clinically unsuspected conditions like malignancy and tuberculoma which may mimic the presentation of liver abscesses. We recommend routine cytological examination of aspirated abscess material as well as stains and cultures for acid-fast bacilli. PMID:9122104

  10. In vivo formation of unstable heterokaryons after liver damage and hematopoietic stem cell/progenitor transplantation.

    PubMed

    Kashofer, Karl; Siapati, Elena K; Bonnet, Dominique

    2006-04-01

    Following reports of lineage plasticity in human hematopoietic stem cells (HSCs), we investigated the potential of human cord blood HSC-enriched cells to create hepatocytes in hosts after inducing liver damage. Carbon tetrachloride induces severe liver damage and subsequent repair via mitosis of resident hepatocytes. It additionally leads to a threefold increase in homing of human mononuclear cells to bone marrow and liver and subsequently to a substantial enhancement of bone marrow engraftment. Eight weeks after liver damage and infusion of an enhanced green fluorescent protein (eGFP) lentivirus-transduced human HSC-enriched cell population, we observed eGFP-positive cells with clear hepatocyte morphology in the livers of animals. These eGFP-positive cells co-expressed human albumin, and reverse-transcription polymerase chain reaction (PCR) analysis demonstrated the presence of human albumin and alpha-anti-trypsin mRNA. However, two antibodies against human mitochondria and human nuclei failed to mark eGFP-positive hepatocyte-like cells but did give clear staining of donor-derived hematopoietic cells. Subsequent fluorescent in situ hybridization (FISH) analysis revealed the presence of mouse Y chromosome in eGFP-positive hepatocyte-like cells. To resolve this discrepancy, we performed single-cell PCR analysis of microdissected eGFP-positive hepatocyte-like cells and found that they contained mostly mouse and little human genomic material. FISH analysis highlighting the centromeres of all human chromosomes revealed only few human chromosomes in these cells. From these results, we conclude that similar to their murine counterparts, human hematopoietic cells have the potential to fuse with resident host hepatocytes. Because no selective pressure is applied to retain the human genomic material, it is gradually lost over time, leading to a variable phenotype of the chimeric cells and making their detection difficult. PMID:16282440

  11. Living donor liver transplantation in polycystic liver disease.

    PubMed

    Mekeel, Kristin L; Moss, Adyr A; Reddy, Kunam S; Douglas, David D; Vargas, Hugo E; Carey, Elizabeth J; Byrne, Thomas J; Harrison, M E; Rakela, Jorge; Mulligan, David C

    2008-05-01

    In the current Model for End-Stage Liver Disease system, patients with polycystic liver disease (PCLD) who have a poor quality of life secondary to their massive hepatomegaly are no longer competitive for a deceased donor liver transplant if their liver function is well preserved. Traditionally, a caval resection has been advocated in these patients because of the difficulty of the hepatectomy with hepatomegaly, which makes living donation impossible. This series looks at 3 patients who underwent a caval sparing hepatectomy and subsequent living donor liver transplantation (LDLT) for PCLD. Graft and patient survival was 100%, and there were few complications in either donors or recipients. LDLT is an ideal option for patients with PCLD and preserved liver function but poor quality of life. PMID:18433036

  12. Transplantable liver production plan: "Yamaton"--liver project, Japan.

    PubMed

    Hata, Toshiyuki; Uemoto, Shinji; Kobayashi, Eiji

    2013-10-01

    Organ grafts developed in the xenogeneic pig scaffold are expected to resolve most issues of donor safety and ethical concerns about living-donor liver transplantation in Japan. We have been working on so-called "Yamaton" projects to develop transplantable organs using genetically engineered pigs. Our goal is to produce chimeric livers with human parenchyma in such pigs. The Yamaton-Liver project demonstrated the proof of concept by showing that rat-mouse chimeric livers could develop in mice and be successfully transplanted into syngeneic or allogeneic rats. Under conventional immunosuppression, the transplanted livers showed long-term function and protection against rejection. Because chimeric liver grafts have xenogeneic components, additional strategies, such as humanization of pig genes, induction of hematopoietic chimeras in donors, and replacement of pig endothelial cells with human ones, might be required in clinical use. Our projects still need to overcome various hurdles but can bring huge benefits to patients in the future. PMID:23896578

  13. [Liver replacement therapy. Reliable indications in acute liver failure].

    PubMed

    Rifai, K; Ott, M; Bahr, M M; Schneider, A; Manns, M P

    2003-12-01

    Extracorporeal liver support devices aim at improving the therapeutical options for liver failure. Numerous artificial and bioartificial devices have been tested to reduce the high mortality of this dynamic disease. In particular, the detoxification function of the liver should be upheld, by means of a number of different procedures, either until liver function is restored or until transplantation. Both purely artificial, machine-based procedures including different forms of dialysis and hemoadsorption as well as bioartificial procedures based on hepatocytes are being tested, as are different types of extracorporeal liver perfusion. This paper provides an overview of the different methods and devices and their clinical evidence in order to give a recommendation for the handling of the expensive devices. There is no current indication for the application of liver support devices outside of clinical studies at specialised centres. PMID:14689190

  14. Identification and comparative oridonin metabolism in different species liver microsomes by using UPLC-Triple-TOF-MS/MS and PCA.

    PubMed

    Ma, Yinghua; Xie, Weiwei; Tian, Tingting; Jin, Yiran; Xu, Huijun; Zhang, Kerong; Du, Yingfeng

    2016-10-15

    Oridonin (ORI) is an active natural ent-kaurene diterpenoid ingredient with notable anti-cancer and anti-inflammation activities. Currently, a strategy was developed to identify metabolites and to assess the metabolic profiles of ORI in vitro using ultra-high-performance liquid chromatography-Triple/time-of-flight mass spectrometry (UPLC-Triple-TOF-MS/MS). Meanwhile, the metabolism differences of ORI in the liver microsomes of four different species were investigated using a principal component analysis (PCA) based on the metabolite absolute peak area values as the variables. Based on the proposed methods, 27 metabolites were structurally characterized. The results indicate that ORI is universally metabolized in vitro, and the metabolic pathway mainly includes dehydration, hydroxylation, di-hydroxylation, hydrogenation, decarboxylation, and ketone formation. Overall, there are obvious inter-species differences in types and amounts of ORI metabolites in the four species. These results will provide basic data for future pharmacological and toxicological studies of ORI and for other ent-kauranes diterpenoids. Meanwhile, studying the ORI metabolic differences helps to select the proper animal model for further pharmacology and toxicological assessment. PMID:27503750

  15. Liver transplantation in acute liver failure: A challenging scenario

    PubMed Central

    Mendizabal, Manuel; Silva, Marcelo Oscar

    2016-01-01

    Acute liver failure is a critical medical condition defined as rapid development of hepatic dysfunction associated with encephalopathy. The prognosis in these patients is highly variable and depends on the etiology, interval between jaundice and encephalopathy, age, and the degree of coagulopathy. Determining the prognosis for this population is vital. Unfortunately, prognostic models with both high sensitivity and specificity for prediction of death have not been developed. Liver transplantation has dramatically improved survival in patients with acute liver failure. Still, 25% to 45% of patients will survive with medical treatment. The identification of patients who will eventually require liver transplantation should be carefully addressed through the combination of current prognostic models and continuous medical assessment. The concerns of inaccurate selection for transplantation are significant, exposing the recipient to a complex surgery and lifelong immunosuppression. In this challenging scenario, where organ shortage remains one of the main problems, alternatives to conventional orthotopic liver transplantation, such as living-donor liver transplantation, auxiliary liver transplant, and ABO-incompatible grafts, should be explored. Although overall outcomes after liver transplantation for acute liver failure are improving, they are not yet comparable to elective transplantation. PMID:26819519

  16. Liver transplantation in acute liver failure: A challenging scenario.

    PubMed

    Mendizabal, Manuel; Silva, Marcelo Oscar

    2016-01-28

    Acute liver failure is a critical medical condition defined as rapid development of hepatic dysfunction associated with encephalopathy. The prognosis in these patients is highly variable and depends on the etiology, interval between jaundice and encephalopathy, age, and the degree of coagulopathy. Determining the prognosis for this population is vital. Unfortunately, prognostic models with both high sensitivity and specificity for prediction of death have not been developed. Liver transplantation has dramatically improved survival in patients with acute liver failure. Still, 25% to 45% of patients will survive with medical treatment. The identification of patients who will eventually require liver transplantation should be carefully addressed through the combination of current prognostic models and continuous medical assessment. The concerns of inaccurate selection for transplantation are significant, exposing the recipient to a complex surgery and lifelong immunosuppression. In this challenging scenario, where organ shortage remains one of the main problems, alternatives to conventional orthotopic liver transplantation, such as living-donor liver transplantation, auxiliary liver transplant, and ABO-incompatible grafts, should be explored. Although overall outcomes after liver transplantation for acute liver failure are improving, they are not yet comparable to elective transplantation. PMID:26819519

  17. Role of liver progenitors in acute liver injury

    PubMed Central

    Best, Jan; Dollé, Laurent; Manka, Paul; Coombes, Jason; van Grunsven, Leo A.; Syn, Wing-Kin

    2013-01-01

    Acute liver failure (ALF) results from the acute and rapid loss of hepatocyte function and frequently exhibits a fulminant course, characterized by high mortality in the absence of immediate state-of-the-art intensive care and/or emergency liver transplantation (ELT). The role of hepatocyte-mediated liver regeneration during acute and chronic liver injury has been extensively investigated, and recent studies suggest that hepatocytes are not exclusively responsible for the regeneration of the injured liver during fulminant liver injury. Liver progenitor cells (LPC) (or resident liver stem cells) are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. This review aims to provide an overview of the role of the LPC population during ALF, and the role of putative cytokines, growth factors, mitogens, and hormones in the LPC response. We will highlight the potential interaction among cellular compartments during ALF, and discuss the possible prognostic value of the LPC response on ALF outcomes. PMID:24133449

  18. MEK1 signaling promotes self-renewal and tumorigenicity of liver cancer stem cells via maintaining SIRT1 protein stabilization

    PubMed Central

    Cheng, Jiamin; Liu, Chungang; Liu, Limei; Chen, Xuejiao; Shan, Juanjuan; Shen, Junjie; Zhu, Wei; Qian, Cheng

    2016-01-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. This high mortality has been commonly attributed to the presence of residual cancer stem cells (CSCs). Meanwhile, MEK1 signaling is regarded as a key molecular in HCC maintenance and development. However, nobody has figured out the particular mechanisms that how MEK1 signaling regulates liver CSCs self-renewal. In this study, we show that inhibition or depletion of MEK1 can significantly decrease liver CSCs self-renewal and tumor growth both in vitro and vivo conditions. Furthermore, we demonstrate that MEK1 signaling promotes liver CSCs self-renewal and tumorigenicity by maintaining SIRT1 level. Mechanistically, MEK1 signaling keeps SIRT1 protein stabilization through activating SIRT1 ubiquitination, which inhibits proteasomal degradation. Clinical analysis shows that patients co-expression of MEK1 and SIRT1 are associated with poor survival. Our finding indicates that MEK1-SIRT1 can act as a novel diagnostic biomarker and inhibition of MEK1 may be a viable therapeutic option for targeting liver CSCs treatment. PMID:26967560

  19. Experimental models of liver fibrosis.

    PubMed

    Crespo Yanguas, Sara; Cogliati, Bruno; Willebrords, Joost; Maes, Michaël; Colle, Isabelle; van den Bossche, Bert; de Oliveira, Claudia Pinto Marques Souza; Andraus, Wellington; Alves, Venâncio Avancini; Leclercq, Isabelle; Vinken, Mathieu

    2016-05-01

    Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research. PMID:26047667

  20. Experimental models of liver fibrosis

    PubMed Central

    Willebrords, Joost; Maes, Michaël; Colle, Isabelle; van den Bossche, Bert; de Oliveira, Claudia Pinto Marques Souza; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Leclercq, Isabelle; Vinken, Mathieu

    2015-01-01

    Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research. PMID:26047667

  1. Pregnancy-related liver disorders.

    PubMed

    Goel, Ashish; Jamwal, Kapil D; Ramachandran, Anup; Balasubramanian, Kunissery A; Eapen, Chundamannil E

    2014-06-01

    Pregnancy-related liver disorders accounted for 8% of all maternal deaths at our center from 1999 to 2011. Of the three pregnancy-related liver disorders (acute fatty liver of pregnancy (AFLP), HELLP (Hemolysis, elevated liver enzymes, low platelets) syndrome and pre-eclamptic liver dysfunction, which can lead to adverse maternal and fetal outcome, AFLP is most typically under - diagnosed. Risk of maternal death can be minimised by timely recognition and early/aggressive multi-specialty management of these conditions. Urgent termination of pregnancy remains the cornerstone of therapy for some of these life threatening disorders, but recent advancements in our understanding help us in better overall management of these patients. This review focuses on various aspects of pregnancy-related liver disorders. PMID:25755551

  2. Focal lesions in normal liver.

    PubMed

    Semelka, Richard C; Martin, Diego R; Balci, N Cem

    2005-10-01

    A variety of lesions occur in the normal liver. This review will describe the most common benign, malignant, and infectious lesions. Illustration will be made of the magnetic resonance imaging (MRI) appearance of the most common of these. Due to the high accuracy for liver lesion detection and characterization, and the intrinsic safety of the modality, MR should be considered the primary imaging tool to investigate liver diseases. PMID:16174062

  3. Radiation-Associated Liver Injury

    SciTech Connect

    Pan, Charlie C.; Kavanagh, Brian D.; Dawson, Laura A.; Li, X. Allen; Das, Shiva K.; Miften, Moyed; Ten Haken, Randall K.

    2010-03-01

    The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver.

  4. Colorectal Liver Metastases

    PubMed Central

    Haddad, Ashraf J.; Bani Hani, Murad; Pawlik, Timothy M.; Cunningham, Steven C.

    2011-01-01

    The diagnosis and management of CRLM is complex and requires a multidisciplinary team approach for optimal outcomes. Over the past several decades, the 5-year survival following resection of CRLM has increased and the criteria for resection have broadened substantially. Even patients with multiple, bilateral CRLM, previously thought unresectable, may now be candidates for resection. Two-stage hepatectomy, repeat curative-intent hepatectomy, and even selected resection of extrahepatic metastases have further increased the number of patients who may be treated with curative intent. Multiple liver-directed therapies exist to treat unresectable, incurable patients with adequate survival benefit and morbidity rates. PMID:22312501

  5. Inhibition of 3′ modification of small RNAs in virus-infected plants require spatial and temporal co-expression of small RNAs and viral silencing-suppressor proteins

    PubMed Central

    Lózsa, Rita; Csorba, Tibor; Burgyán, József

    2008-01-01

    Plant viruses are inducers and targets of RNA silencing. Viruses counteract with RNA silencing by expressing silencing-suppressor proteins. Many of the identified proteins bind siRNAs, which prevents assembly of silencing effector complexes, and also interfere with their 3′ methylation, which protects them against degradation. Here, we investigated the 3′ modification of silencing-related small RNAs in Nicotiana benthamiana plants infected with viruses expressing RNA silencing suppressors, the p19 protein of Carnation Italian ringspot virus (CIRV) and HC-Pro of Tobacco etch virus (TEV). We found that CIRV had only a slight effect on viral siRNA 3′ modification, but TEV significantly inhibited the 3′ modification of si/miRNAs. We also found that p19 and HC-Pro were able to bind both 3′ modified and non-modified small RNAs in vivo. The findings suggest that the 3′ modification of viral siRNAs occurs in the cytoplasm, though miRNA 3′ modification likely takes place in the nucleus as well. Both silencing suppressors inhibited the 3′ modification of si/miRNAs when they and small RNAs were transiently co-expressed, suggesting that the inhibition of si/miRNA 3′ modification requires spatial and temporal co-expression. Finally, our data revealed that a HEN1-like methyltransferase might account for the small RNA modification at the their 3′-terminal nucleotide in N. benthamiana. PMID:18539609

  6. Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD.

    PubMed

    Williams, Jared R; Trias, Emiliano; Beilby, Pamela R; Lopez, Nathan I; Labut, Edwin M; Bradford, C Samuel; Roberts, Blaine R; McAllum, Erin J; Crouch, Peter J; Rhoads, Timothy W; Pereira, Cliff; Son, Marjatta; Elliott, Jeffrey L; Franco, Maria Clara; Estévez, Alvaro G; Barbeito, Luis; Beckman, Joseph S

    2016-05-01

    Over-expression of mutant copper, zinc superoxide dismutase (SOD) in mice induces ALS and has become the most widely used model of neurodegeneration. However, no pharmaceutical agent in 20 years has extended lifespan by more than a few weeks. The Copper-Chaperone-for-SOD (CCS) protein completes the maturation of SOD by inserting copper, but paradoxically human CCS causes mice co-expressing mutant SOD to die within two weeks of birth. Hypothesizing that co-expression of CCS created copper deficiency in spinal cord, we treated these pups with the PET-imaging agent CuATSM, which is known to deliver copper into the CNS within minutes. CuATSM prevented the early mortality of CCSxSOD mice, while markedly increasing Cu, Zn SOD protein in their ventral spinal cord. Remarkably, continued treatment with CuATSM extended the survival of these mice by an average of 18 months. When CuATSM treatment was stopped, these mice developed ALS-related symptoms and died within 3 months. Restoring CuATSM treatment could rescue these mice after they became symptomatic, providing a means to start and stop disease progression. All ALS patients also express human CCS, raising the hope that familial SOD ALS patients could respond to CuATSM treatment similarly to the CCSxSOD mice. PMID:26826269

  7. KaPPA-View4: a metabolic pathway database for representation and analysis of correlation networks of gene co-expression and metabolite co-accumulation and omics data.

    PubMed

    Sakurai, Nozomu; Ara, Takeshi; Ogata, Yoshiyuki; Sano, Ryosuke; Ohno, Takashi; Sugiyama, Kenjiro; Hiruta, Atsushi; Yamazaki, Kiyoshi; Yano, Kentaro; Aoki, Koh; Aharoni, Asaph; Hamada, Kazuki; Yokoyama, Koji; Kawamura, Shingo; Otsuka, Hirofumi; Tokimatsu, Toshiaki; Kanehisa, Minoru; Suzuki, Hideyuki; Saito, Kazuki; Shibata, Daisuke

    2011-01-01

    Correlations of gene-to-gene co-expression and metabolite-to-metabolite co-accumulation calculated from large amounts of transcriptome and metabolome data are useful for uncovering unknown functions of genes, functional diversities of gene family members and regulatory mechanisms of metabolic pathway flows. Many databases and tools are available to interpret quantitative transcriptome and metabolome data, but there are only limited ones that connect correlation data to biological knowledge and can be utilized to find biological significance of it. We report here a new metabolic pathway database, KaPPA-View4 (http://kpv.kazusa.or.jp/kpv4/), which is able to overlay gene-to-gene and/or metabolite-to-metabolite relationships as curves on a metabolic pathway map, or on a combination of up to four maps. This representation would help to discover, for example, novel functions of a transcription factor that regulates genes on a metabolic pathway. Pathway maps of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and maps generated from their gene classifications are available at KaPPA-View4 KEGG version (http://kpv.kazusa.or.jp/kpv4-kegg/). At present, gene co-expression data from the databases ATTED-II, COXPRESdb, CoP and MiBASE for human, mouse, rat, Arabidopsis, rice, tomato and other plants are available. PMID:21097783

  8. Getting a New Liver: Facts about Liver Transplants

    MedlinePlus

    ... liver does several things: • It helps digest your food. • It clears wastes from your blood. • It makes proteins that help your blood to clot. • It stores the sugars (glycogen) that are used for ... liver also controls the way your body uses food and the way it works with your immune ...

  9. Therapy of Liver Abscesses

    PubMed Central

    Lübbert, Christoph; Wiegand, Johannes; Karlas, Thomas

    2014-01-01

    Summary Background Liver abscess (LA) is an uncommon but potentially life-threatening disease with significant morbidity and mortality. Methods This review comprehensively describes epidemiology, pathogenesis, diagnosis, and treatment of LA, with a strong focus on antimicrobial treatment choices and the impact of multidrug-resistant pathogens. Results In industrialized areas, pyogenic liver abscess (PLA) accounts for over 80% of the cases, whereas Entamoeba histolyticais responsible for up to 10% of the cases, with a higher incidence in tropical areas. Highly virulent strains of Klebsiella pneumoniaehave emerged as a predominant cause of PLA in Asian countries and tend to spread to the USA, Australia, and European countries, therefore requiring special alertness. Most common symptoms of LA are fever, chills, and right upper quadrant abdominal pain, although a broad spectrum of non-specific symptoms may also occur. Conclusion Imaging studies (ultrasound, computed tomography scan) and microbiological findings play a crucial role in the diagnosis of LA. The treatment of choice for PLA is a multimodal approach combining broad-spectrum antibiotics and aspiration or drainage of larger abscess cavities. Amebic LA can be cured by metronidazole therapy without drainage. PMID:26287275

  10. [Liver metastasis: therapeutic strategy].

    PubMed

    Gennari, L; Doci, R; Bignami, P

    1996-01-01

    The liver is one of the most frequent sites of metastatic growth, in particular from digestive malignancies (DM). The first goal is to reduce the incidence of metastases. Adjuvant systemic chemotherapies have been demonstrated to reduce the recurrence rate and to improve survival in Dukes C colon cancer. Fluorouracil is the pivot of adjuvant treatment modulated by Leucovorin or Levamisol. A short postoperative administration of fluorouracil by intraportal route has been tested, but the results are controversial. Adjuvant treatments for different DM are under investigation. When hepatic metastases are clinically evident, therapeutic decisions depend on several factors: site and nature of primary, extent of hepatic and extrahepatic disease, patient characteristics, efficacy of treatments. A staging system should be adopted to allow a rational approach. In selected cases a locoregional treatment can achieve consistent results. Hepatic Intrarterial Chemotherapy (HIAC) for colorectal metastases achieves objective responses in more than 50% of patients. Survival seems positively affected. When feasible, Ro hepatic resection is the most effective treatment, five-year survival rate being about 30% when metastases are from colorectal cancer. Since the liver is the most frequent site of recurrence after resection, repeat resection have been successfully performed. PMID:9214269

  11. Pediatric Liver Transplantation

    PubMed Central

    Dominguez, Rodrigo; Young, Lionel W.; Ledesma-Medina, Jocyline; Cienfuegos, Javier; Gartner, J. Carlton; Bron, Klaus M.; Starzl, Thomas E.

    2010-01-01

    The postoperative diagnostic imaging examinations of 44 children who underwent 59 orthotopic liver transplantations were reviewed. The imaging modalities used for the evaluation of suspected complications include plain roentgenography, ultrasonography (US), computed tomography (CT), nuclear scintigraphy, arteriography, percutaneous and operative cholangiography, and endoscopic retrograde cholangiopancreatography. The main postoperative complications included ischemia, thrombosis (hepatic artery and portal vein), infarction, obstruction or leakage of the biliary anastomosis, hepatic and perihepatic infection, and allograft rejection. US, the most frequently used abdominal imaging modality, was best suited for detection of biliary duct dilatation, fluid collections in or around the transplanted liver, and hepatic arterial, inferior vena caval, and portal vein thrombosis. CT was especially helpful in corroborating findings of infection and in locating abscesses. Technetium 99m sulfur colloid (early- and late-phase imaging) provided a sensitive, although nonspecific, means of assessing allograft vascularization and morphology. Angiography showed vascularity most clearly, and cholangiography was the most useful In the assessment of bile duct patency. A diagnostic imaging algorithm is proposed for evaluation of suspected complications. PMID:3901104

  12. Bioartificial liver support anno 2001.

    PubMed

    Chamuleau, Robert A F M

    2002-12-01

    Despite maximal intensive care, mortality of acute fulminant hepatic failure is high: 60%-75% in several studies. In addition patients with chronic liver insufficiency suffer from a bad quality of life: all patients suffer from fatigue; symptoms of hepatic encephalopathy, jaundice, and itching are often present. Analogous to artificial kidney treatment in patients with renal failure, an artificial liver assist device is needed not only to bridge patients with fulminant hepatic failure to liver transplantation or own liver regeneration, but also to improve the quality of life of patients with chronic liver insufficiency. Several modalities of artificial liver support are under investigation, like plasma exchange, haemodialysis, haemadsorption, albumin dialysis, liver cell transplantation, and the bioartificial liver. Artificial livers based on only supportive detoxification function do not show significant improvement of survival in controlled studies. Bioartificial liver support systems have also the potential to support hepatic synthetic functions. Bioreactors can be charged with freshly isolated or cryopreserved porcine hepatocytes, but also by human hepatoma cell lines. Several uncontrolled studies in humans show safety of such a treatment, even by using porcine cells. Transmission of porcine endogenous retrovirus to recipients has not been found. Furthermore, beneficial effects have been reported on symptoms of hepatic encephalopathy, on the height of intracranial pressure and on hemodynamic parameters. By using porcine cells immunological problems (e.g., serum sickness) can be expected during treatments longer than one week. However, "proof of the pudding" in the sense of improvement of survival is not yet available. The creation of a "liver dialysis unit" in the near future depends mainly on the development of well-differentiated immortalized human hepatocytes. Some progress in this field has already been obtained. PMID:12602524

  13. Recurrence of autoimmune liver diseases after liver transplantation

    PubMed Central

    Faisal, Nabiha; Renner, Eberhard L

    2015-01-01

    Liver transplantation (LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), but not for primary sclerosing cholangitis (PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease (AIH, PBC, PSC) following LT. PMID:26689244

  14. Co-expression of the carbamoyl-phosphate synthase 1 gene and its long non-coding RNA correlates with poor prognosis of patients with intrahepatic cholangiocarcinoma

    PubMed Central

    MA, SEN-LIN; LI, AI-JUN; HU, ZHAO-YANG; SHANG, FU-SHENG; WU, MENG-CHAO

    2015-01-01

    The mechanisms leading to high rates of malignancy and recurrence of human intrahepatic cholangiocarcinoma (ICC) remain unclear. It is difficult to diagnose and assess the prognosis of patients with ICC in the clinic due to the lack of specific biomarkers. In addition, long non-coding RNAs (lncRNAs) have been reported to serve important roles in certain types of tumorigenesis however a role in ICC remains to be reported. The aim of the current study was to screen for genes and lncRNAs that are abnormally expressed in ICC and to investigate their biological and clinicopathological significance in ICC. The global gene and lncRNA expression profiles in ICC were measured using bioinformatics analysis. Carbamoyl-phosphate synthase 1 (CPS1) and its lncRNA CPS1 intronic transcript 1 (CPS1-IT1) were observed to be upregulated in ICC. The expression of CPS1 and CPS1-IT1 was measured in 31 tissue samples from patients with ICC and a number of cell lines. The effects of CPS1 and CPS1-IT1 on the proliferation and apoptosis of the ICC-9810 cell line were measured. In addition, the clinicopathological features and survival rates of patients with ICC with respect to the gene and lncRNA expression status were analyzed. CPS1 and CPS1-IT1 were co-upregulated in ICC tissues compared with non-cancerous tissues. Knockdown of CPS1 andor CPS1-IT1 reduced the proliferation and increased the apoptosis of ICC-9810 cells. Additionally, clinical analysis indicated that CPS1 and CPS1-IT1 were associated with poor liver function and reduced survival rates when the relative expression values were greater than 4 in cancer tissues. The comparisons between the high CPS1 expression group and the low expression group indicated significant differences in international normalized ratio (P=0.048), total protein (P=0.049), indirect bilirubin (P=0.025), alkaline phosphatase (P=0.003) and disease-free survival (P=0.034). In addition, there were differential trends in CA19-9 (P=0.068), globulin (P=0

  15. 25 Ways to Love Your Liver

    MedlinePlus

    ... You Can Use April May Calendar Liver Lowdown Mar 2014 Calendar of Events In The News Academic ... 2016 Calendar Jan Feb 2016 recipe Liver Lowdown Mar/Apr 2016 Liver Lowdown August 2016 Know Your ...

  16. More People Surviving Sudden Liver Failure

    MedlinePlus

    ... Lee, a liver specialist at the University of Texas Southwestern Medical Center at Dallas. Acute liver failure, ... division of digestive and liver diseases, University of Texas Southwestern Medical Center at Dallas; David Bernstein, M. ...

  17. Evaluation of abnormal liver function tests.

    PubMed

    Agrawal, Swastik; Dhiman, Radha K; Limdi, Jimmy K

    2016-04-01

    Incidentally detected abnormality in liver function tests is a common situation encountered by physicians across all disciplines. Many of these patients do not have primary liver disease as most of the commonly performed markers are not specific for the liver and are affected by myriad factors unrelated to liver disease. Also, many of these tests like liver enzyme levels do not measure the function of the liver, but are markers of liver injury, which is broadly of two types: hepatocellular and cholestatic. A combination of a careful history and clinical examination along with interpretation of pattern of liver test abnormalities can often identify type and aetiology of liver disease, allowing for a targeted investigation approach. Severity of liver injury is best assessed by composite scores like the Model for End Stage Liver Disease rather than any single parameter. In this review, we discuss the interpretation of the routinely performed liver tests along with the indications and utility of quantitative tests. PMID:26842972

  18. Loss of brain function - liver disease

    MedlinePlus

    ... of chronic liver damage. Common causes of chronic liver disease in the United States are: Chronic hepatitis B ... hepatitis Bile duct disorders Some medicines Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) Once you have ...

  19. Chronic Liver Disease and Hispanic Americans

    MedlinePlus

    ... Population Profiles > Hispanic/Latino > Chronic Liver Disease Chronic Liver Disease and Hispanic Americans Among the Hispanic/Latino population, chronic liver disease is a leading cause of death. While the ...

  20. Percutaneous Cryoablation for Liver Cancer

    PubMed Central

    Niu, Li-Zhi; Li, Jia-Liang; Xu, Ke-Cheng

    2014-01-01

    Based on the primary tumor site, liver cancer can be divided into two categories: (1) primary liver cancer and (2) metastatic cancer to the liver from a distant primary site. Guided cryoablation via many imaging methods induces iceball formation and tumor necrosisand is an attractive option for treating unresectable hepatocellular carcinoma (HCC) and metastatic liver cancer. There are several advantages to using cryoablation for the treatment of liver cancer: it can be performed percutaneously, intraoperatively, and laparoscopically; iceball formation can be monitored; it has little impact on nearby large blood vessels; and it induces a cryo-immunological response in situ. Clinically, primary research has shown that percutaneous cryoablation of liver cancer is relatively safe and efficient, and it can be combined with other methods, such as radiation therapy, chemotherapy, and immunology, to control disease. Although research is preliminary, cryosurgery is fast becoming an alternative treatment method for HCC or liver tumors. Here, we review the mechanisms of liver tumor cryoablation, cryoablation program selection, clinical efficiency, and complications following treatment. PMID:26355719