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Sample records for profiling uncovers plasmid-induced

  1. In vivo visualization of delta opioid receptors upon physiological activation uncovers a distinct internalization profile.

    PubMed

    Faget, Lauren; Erbs, Eric; Le Merrer, Julie; Scherrer, Gregory; Matifas, Audrey; Benturquia, Nadia; Noble, Florence; Decossas, Marion; Koch, Marc; Kessler, Pascal; Vonesch, Jean-Luc; Schwab, Yannick; Kieffer, Brigitte L; Massotte, Dominique

    2012-05-23

    G-protein-coupled receptors (GPCRs) mediate numerous physiological functions and represent prime therapeutic targets. Receptor trafficking upon agonist stimulation is critical for GPCR function, but examining this process in vivo remains a true challenge. Using knock-in mice expressing functional fluorescent delta opioid receptors under the control of the endogenous promoter, we visualized in vivo internalization of this native GPCR upon physiological stimulation. We developed a paradigm in which animals were made dependent on morphine in a drug-paired context. When re-exposed to this context in a drug-free state, mice showed context-dependent withdrawal signs and activation of the hippocampus. Receptor internalization was transiently detected in a subset of CA1 neurons, uncovering regionally restricted opioid peptide release. Importantly, a pool of surface receptors always remained, which contrasts with the in vivo profile previously established for exogenous drug-induced internalization. Therefore, a distinct response is observed at the receptor level upon a physiological or pharmacological stimulation. Altogether, direct in vivo GPCR visualization enables mapping receptor stimulation promoted by a behavioral challenge and represents a powerful approach to study endogenous GPCR physiology.

  2. In vivo visualization of delta opioid receptors upon physiological activation uncovers a distinct internalization profile

    PubMed Central

    FAGET, Lauren; ERBS, Eric; LE MERRER, Julie; SCHERRER, Gregory; MATIFAS, Audrey; BENTURQUIA, Nadia; NOBLE, Florence; DECOSSAS, Marion; KOCH, Marc; KESSLER, Pascal; VONESCH, Jean-Luc; SCHWAB, Yannick; KIEFFER, Brigitte L.; MASSOTTE, Dominique

    2012-01-01

    G protein-coupled receptors (GPCRs) mediate numerous physiological functions and represent prime therapeutic targets. Receptor trafficking upon agonist stimulation is critical for GPCR function, but examining this process in vivo remains a true challenge. Using knock-in mice expressing functional fluorescent delta opioid receptors under the control of the endogenous promoter, we visualized in vivo internalization of this native GPCR upon physiological stimulation. We developed a paradigm in which animals were made dependent to morphine in a drug-paired context. When re-exposed to this context in a drug-free state, mice showed context-dependent withdrawal signs and activation of the hippocampus. Receptor internalization was transiently detected in a subset of CA1 neurons, uncovering regionally restricted opioid peptide release. Importantly, a pool of surface receptors always remained, which contrasts with the in vivo profile previously established for exogenous drug-induced internalization. Therefore, a distinct response is observed at the receptor level upon a physiological or pharmacological stimulation. Altogether, direct in vivo GPCR visualization enables mapping receptor stimulation promoted by a behavioral challenge, and represents a powerful approach to study endogenous GPCR physiology. PMID:22623675

  3. Developing Guidance Material To Uncover a Mathematics Profile of Adult Participants on a Crane Course.

    ERIC Educational Resources Information Center

    Lindenskov, Lena

    This paper reports on a pilot study in the Danish "Profile in Mathematics" project implemented by the Directorate General for Employment, Placement and Vocational Training and the Ministry of Education. The pilot study develops and tests specific guidance materials to guide participants and teachers through a course for crane workers…

  4. De novo assembly and transcriptome characterization of spruce dwarf mistletoe Arceuthobium sichuanense uncovers gene expression profiling associated with plant development.

    PubMed

    Wang, Yonglin; Li, Xuewu; Zhou, Weifen; Li, Tao; Tian, Chengming

    2016-10-01

    The parasitic flowering plant dwarf mistletoe (Arceuthobium spp., Viscaceae) is one of the most destructive forest pests, posing a major threat to numerous conifer species worldwide. Arceuthobium sichuanense (spruce dwarf mistletoe, SDM) infects Qinghai spruce (Picea crassifolia) and causes severe damage to spruce forests in Northwest China. SDM is a Chinese native parasitic plant and acquires carbohydrates and mineral nutrition from its hosts. However, underlying molecular basis of the physiological development is largely unknown. Investigations of these physiological traits have been hampered by the lack of genomic resources for this species. In this study, to investigate the transcriptomic processes underlying physiological traits and development in SDM, we used RNA from four major tissues (i.e., shoots, flowers, fruits, and seeds) for de novo assembly and to annotate the transcriptome of this species. We uncovered the annotated transcriptome and performed whole genome expression profiling to uncover transcriptional dynamics during physiological development, and we identified key gene categories involved in the process of sexual development. The assembled SDM transcriptome reported in this work contains 331,347 assembled transcripts; 226,687 unigenes were functionally annotated by Gene Ontology analysis. RNA-Seq analysis using this reference transcriptome identified 22,641 differentially expressed genes from shoots, flowers, fruits, and seeds. These genes are enriched in processes including organic substance metabolism, cellular metabolism, biosynthesis, and cellular component. In addition, genes related to transport, transcription, hormone biosynthesis and signaling, carbohydrate metabolism, and photosynthesis were differentially expressed between tissues. This work reveals tissue-specific gene expression patterns and pathways of SDM and implied to a difference between photosynthetic and non-photosynthetic tissues in plants. The data can potentially be used for

  5. Transcriptome Profiling of Wild Arachis from Water-Limited Environments Uncovers Drought Tolerance Candidate Genes.

    PubMed

    Brasileiro, Ana C M; Morgante, Carolina V; Araujo, Ana C G; Leal-Bertioli, Soraya C M; Silva, Amanda K; Martins, Andressa C Q; Vinson, Christina C; Santos, Candice M R; Bonfim, Orzenil; Togawa, Roberto C; Saraiva, Mario A P; Bertioli, David J; Guimaraes, Patricia M

    Peanut (Arachis hypogaea L.) is an important legume cultivated mostly in drought-prone areas where its productivity can be limited by water scarcity. The development of more drought-tolerant varieties is, therefore, a priority for peanut breeding programs worldwide. In contrast to cultivated peanut, wild relatives have a broader genetic diversity and constitute a rich source of resistance/tolerance alleles to biotic and abiotic stresses. The present study takes advantage of this diversity to identify drought-responsive genes by analyzing the expression profile of two wild species, Arachis duranensis and Arachis magna (AA and BB genomes, respectively), in response to progressive water deficit in soil. Data analysis from leaves and roots of A. duranensis (454 sequencing) and A. magna (suppression subtractive hybridization (SSH)) stressed and control complementary DNA (cDNA) libraries revealed several differentially expressed genes in silico, and 44 of them were selected for further validation by quantitative RT-PCR (qRT-PCR). This allowed the identification of drought-responsive candidate genes, such as Expansin, Nitrilase, NAC, and bZIP transcription factors, displaying significant levels of differential expression during stress imposition in both species. This is the first report on identification of differentially expressed genes under drought stress and recovery in wild Arachis species. The generated transcriptome data, besides being a valuable resource for gene discovery, will allow the characterization of new alleles and development of molecular markers associated with drought responses in peanut. These together constitute important tools for the peanut breeding program and also contribute to a better comprehension of gene modulation in response to water deficit and rehydration.

  6. Expression profiles uncover the relationship between erythropoietin and cell proliferation in rat hepatocytes after a partial hepatectomy.

    PubMed

    Zhang, Jihong; Yang, Yajuan; He, Tingting; Liu, Yunqing; Zhou, Yun; Chen, Yongkang; Xu, Cunshuan

    2014-09-01

    Erythropoietin (EPO) has a beneficial effect on hepatic cell proliferation during liver regeneration. However, the underlying mechanism has not yet been elucidated. To uncover the proliferation response of EPO in rat liver regeneration after partial hepatectomy (PH) at the cellular level, hepatocytes (HCs) were isolated using Percoll density gradient centrifugation. The genes of the EPO-mediated signaling pathway and the target genes of the transcription factor (TF) in the pathway were identified in a pathway and TF database search. Their expression profiles were then detected using Rat Genome 230 2.0 Microarray. The results indicated that the EPO-mediated signaling pathway is involved in 19 paths and that 124 genes participate, of which 32 showed significant changes and could be identified as liver regeneration-related genes. In addition, 443 targets regulated by the TFs of the pathway and 60 genes associated with cell proliferation were contained in the array. Subsequently, the synergetic effect of these genes in liver regeneration was analyzed using the E(t) mathematical model based on their expression profiles. The results demonstrated that the E(t) values of paths 3, 8, 12 and 14-17 were significantly strengthened in the progressing phase of liver regeneration through the RAS/MEK/ERK or PI3K/AκT pathways. The synergetic effect of the target genes, in parallel with target-related cell proliferation, was also enhanced 12-72 h after PH, suggesting a potential positive effect of EPO on HC proliferation during rat liver regeneration. These data imply that the EPO receptor may allow EPO to promote HC proliferation through paths 3, 8, 12 and 14-17, mediating the RAS/MEK/ERK and PI3K/AκT pathways in rat liver regeneration after PH.

  7. Inositol Pyrophosphate Profiling of Two HCT116 Cell Lines Uncovers Variation in InsP8 Levels

    PubMed Central

    Gu, Chunfang; Wilson, Miranda S. C.; Jessen, Henning J.; Saiardi, Adolfo; Shears, Stephen B.

    2016-01-01

    The HCT116 cell line, which has a pseudo-diploid karotype, is a popular model in the fields of cancer cell biology, intestinal immunity, and inflammation. In the current study, we describe two batches of diverged HCT116 cells, which we designate as HCT116NIH and HCT116UCL. Using both gel electrophoresis and HPLC, we show that HCT116UCL cells contain 6-fold higher levels of InsP8 than HCT116NIH cells. This observation is significant because InsP8 is one of a group of molecules collectively known as ‘inositol pyrophosphates’ (PP-InsPs)—highly ‘energetic’ and conserved regulators of cellular and organismal metabolism. Variability in the cellular levels of InsP8 within divergent HCT116 cell lines could have impacted the phenotypic data obtained in previous studies. This difference in InsP8 levels is more remarkable for being specific; levels of other inositol phosphates, and notably InsP6 and 5-InsP7, are very similar in both HCT116NIH and HCT116UCL lines. We also developed a new HPLC procedure to record 1-InsP7 levels directly (for the first time in any mammalian cell line); 1-InsP7 comprised <2% of total InsP7 in HCT116NIH and HCT116UCL lines. The elevated levels of InsP8 in the HCT116UCL lines were not due to an increase in expression of the PP-InsP kinases (IP6Ks and PPIP5Ks), nor to a decrease in the capacity to dephosphorylate InsP8. We discuss how the divergent PP-InsP profiles of the newly-designated HCT116NIH and HCT116UCL lines should be considered an important research opportunity: future studies using these two lines may uncover new features that regulate InsP8 turnover, and may also yield new directions for studying InsP8 function. PMID:27788189

  8. Analysis of microRNA and Gene Expression Profiles in Multiple Sclerosis: Integrating Interaction Data to Uncover Regulatory Mechanisms

    PubMed Central

    Freiesleben, Sherry; Hecker, Michael; Zettl, Uwe Klaus; Fuellen, Georg; Taher, Leila

    2016-01-01

    MicroRNAs (miRNAs) have been reported to contribute to the pathophysiology of multiple sclerosis (MS), an inflammatory disorder of the central nervous system. Here, we propose a new consensus-based strategy to analyse and integrate miRNA and gene expression data in MS as well as other publically available data to gain a deeper understanding of the role of miRNAs in MS and to overcome the challenges posed by studies with limited patient sample sizes. We processed and analysed microarray datasets, and compared the expression of genes and miRNAs in the blood of MS patients and controls. We then used our consensus and integration approach to construct two molecular networks dysregulated in MS: a miRNA- and a gene-based network. We identified 18 differentially expressed (DE) miRNAs and 128 DE genes that may contribute to the regulatory alterations behind MS. The miRNAs were linked to immunological and neurological pathways, and we exposed let-7b-5p and miR-345-5p as promising blood-derived disease biomarkers in MS. The results suggest that DE miRNAs are more informative than DE genes in uncovering pathways potentially involved in MS. Our findings provide novel insights into the regulatory mechanisms and networks underlying MS. PMID:27694855

  9. Gene expression profiling in hearts of diabetic mice uncovers a potential role of estrogen-related receptor γ in diabetic cardiomyopathy.

    PubMed

    Lasheras, Jaime; Vilà, Maria; Zamora, Mònica; Riu, Efrén; Pardo, Rosario; Poncelas, Marcos; Cases, Ildefonso; Ruiz-Meana, Marisol; Hernández, Cristina; Feliu, Juan E; Simó, Rafael; García-Dorado, David; Villena, Josep A

    2016-07-15

    Diabetic cardiomyopathy is characterized by an abnormal oxidative metabolism, but the underlying mechanisms remain to be defined. To uncover potential mechanisms involved in the pathophysiology of diabetic cardiomyopathy, we performed a gene expression profiling study in hearts of diabetic db/db mice. Diabetic hearts showed a gene expression pattern characterized by the up-regulation of genes involved in lipid oxidation, together with an abnormal expression of genes related to the cardiac contractile function. A screening for potential regulators of the genes differentially expressed in diabetic mice found that estrogen-related receptor γ (ERRγ) was increased in heart of db/db mice. Overexpression of ERRγ in cultured cardiomyocytes was sufficient to promote the expression of genes involved in lipid oxidation, increase palmitate oxidation and induce cardiomyocyte hypertrophy. Our findings strongly support a role for ERRγ in the metabolic alterations that underlie the development of diabetic cardiomyopathy.

  10. Comprehensive profiling of amino acid response uncovers unique methionine-deprived response dependent on intact creatine biosynthesis.

    PubMed

    Tang, Xiaohu; Keenan, Melissa M; Wu, Jianli; Lin, Chih-An; Dubois, Laura; Thompson, J Will; Freedland, Stephen J; Murphy, Susan K; Chi, Jen-Tsan

    2015-04-01

    Besides being building blocks for protein synthesis, amino acids serve a wide variety of cellular functions, including acting as metabolic intermediates for ATP generation and for redox homeostasis. Upon amino acid deprivation, free uncharged tRNAs trigger GCN2-ATF4 to mediate the well-characterized transcriptional amino acid response (AAR). However, it is not clear whether the deprivation of different individual amino acids triggers identical or distinct AARs. Here, we characterized the global transcriptional response upon deprivation of one amino acid at a time. With the exception of glycine, which was not required for the proliferation of MCF7 cells, we found that the deprivation of most amino acids triggered a shared transcriptional response that included the activation of ATF4, p53 and TXNIP. However, there was also significant heterogeneity among different individual AARs. The most dramatic transcriptional response was triggered by methionine deprivation, which activated an extensive and unique response in different cell types. We uncovered that the specific methionine-deprived transcriptional response required creatine biosynthesis. This dependency on creatine biosynthesis was caused by the consumption of S-Adenosyl-L-methionine (SAM) during creatine biosynthesis that helps to deplete SAM under methionine deprivation and reduces histone methylations. As such, the simultaneous deprivation of methionine and sources of creatine biosynthesis (either arginine or glycine) abolished the reduction of histone methylation and the methionine-specific transcriptional response. Arginine-derived ornithine was also required for the complete induction of the methionine-deprived specific gene response. Collectively, our data identify a previously unknown set of heterogeneous amino acid responses and reveal a distinct methionine-deprived transcriptional response that results from the crosstalk of arginine, glycine and methionine metabolism via arginine

  11. Comprehensive Profiling of Amino Acid Response Uncovers Unique Methionine-Deprived Response Dependent on Intact Creatine Biosynthesis

    PubMed Central

    Tang, Xiaohu; Keenan, Melissa M.; Wu, Jianli; Lin, Chih-An; Dubois, Laura; Thompson, J. Will; Freedland, Stephen J.; Murphy, Susan K.; Chi, Jen-Tsan

    2015-01-01

    Besides being building blocks for protein synthesis, amino acids serve a wide variety of cellular functions, including acting as metabolic intermediates for ATP generation and for redox homeostasis. Upon amino acid deprivation, free uncharged tRNAs trigger GCN2-ATF4 to mediate the well-characterized transcriptional amino acid response (AAR). However, it is not clear whether the deprivation of different individual amino acids triggers identical or distinct AARs. Here, we characterized the global transcriptional response upon deprivation of one amino acid at a time. With the exception of glycine, which was not required for the proliferation of MCF7 cells, we found that the deprivation of most amino acids triggered a shared transcriptional response that included the activation of ATF4, p53 and TXNIP. However, there was also significant heterogeneity among different individual AARs. The most dramatic transcriptional response was triggered by methionine deprivation, which activated an extensive and unique response in different cell types. We uncovered that the specific methionine-deprived transcriptional response required creatine biosynthesis. This dependency on creatine biosynthesis was caused by the consumption of S-Adenosyl-L-methionine (SAM) during creatine biosynthesis that helps to deplete SAM under methionine deprivation and reduces histone methylations. As such, the simultaneous deprivation of methionine and sources of creatine biosynthesis (either arginine or glycine) abolished the reduction of histone methylation and the methionine-specific transcriptional response. Arginine-derived ornithine was also required for the complete induction of the methionine-deprived specific gene response. Collectively, our data identify a previously unknown set of heterogeneous amino acid responses and reveal a distinct methionine-deprived transcriptional response that results from the crosstalk of arginine, glycine and methionine metabolism via arginine

  12. Uncovering Molecular Biomarkers That Correlate Cognitive Decline with the Changes of Hippocampus' Gene Expression Profiles in Alzheimer's Disease

    PubMed Central

    Gómez Ravetti, Martín; Rosso, Osvaldo A.; Berretta, Regina; Moscato, Pablo

    2010-01-01

    Background Alzheimer's disease (AD) is characterized by a neurodegenerative progression that alters cognition. On a phenotypical level, cognition is evaluated by means of the MiniMental State Examination (MMSE) and the post-morten examination of Neurofibrillary Tangle count (NFT) helps to confirm an AD diagnostic. The MMSE evaluates different aspects of cognition including orientation, short-term memory (retention and recall), attention and language. As there is a normal cognitive decline with aging, and death is the final state on which NFT can be counted, the identification of brain gene expression biomarkers from these phenotypical measures has been elusive. Methodology/Principal Findings We have reanalysed a microarray dataset contributed in 2004 by Blalock et al. of 31 samples corresponding to hippocampus gene expression from 22 AD subjects of varying degree of severity and 9 controls. Instead of only relying on correlations of gene expression with the associated MMSE and NFT measures, and by using modern bioinformatics methods based on information theory and combinatorial optimization, we uncovered a 1,372-probe gene expression signature that presents a high-consensus with established markers of progression in AD. The signature reveals alterations in calcium, insulin, phosphatidylinositol and wnt-signalling. Among the most correlated gene probes with AD severity we found those linked to synaptic function, neurofilament bundle assembly and neuronal plasticity. Conclusions/Significance A transcription factors analysis of 1,372-probe signature reveals significant associations with the EGR/KROX family of proteins, MAZ, and E2F1. The gene homologous of EGR1, zif268, Egr-1 or Zenk, together with other members of the EGR family, are consolidating a key role in the neuronal plasticity in the brain. These results indicate a degree of commonality between putative genes involved in AD and prion-induced neurodegenerative processes that warrants further investigation

  13. Transcript profiles uncover temporal and stress-induced changes of metabolic pathways in germinating sugar beet seeds

    PubMed Central

    Pestsova, Elena; Meinhard, Juliane; Menze, Andreas; Fischer, Uwe; Windhövel, Andrea; Westhoff, Peter

    2008-01-01

    Background With a cultivation area of 1.75 Mio ha and sugar yield of 16.7 Mio tons in 2006, sugar beet is a crop of great economic importance in Europe. The productivity of sugar beet is determined significantly by seed vigour and field emergence potential; however, little is known about the molecular mechanisms underlying these traits. Both traits exhibit large variations within sugar beet germplasm that have been difficult to ascribe to either environmental or genetic causes. Among potential targets for trait improvement, an enhancement of stress tolerance is considered because of the high negative influence of environmental stresses on trait parameters. Extending our knowledge of genetic and molecular determinants of sugar beet germination, stress response and adaptation mechanisms would facilitate the detection of new targets for breeding crop with an enhanced field emergence potential. Results To gain insight into the sugar beet germination we initiated an analysis of gene expression in a well emerging sugar beet hybrid showing high germination potential under various environmental conditions. A total of 2,784 ESTs representing 2,251 'unigenes' was generated from dry mature and germinating seeds. Analysis of the temporal expression of these genes during germination under non-stress conditions uncovered drastic transcriptional changes accompanying a shift from quiescent to metabolically active stages of the plant life cycle. Assay of germination under stressful conditions revealed 157 genes showing significantly different expression patterns in response to stress. As deduced from transcriptome data, stress adaptation mechanisms included an alteration in reserve mobilization pathways, an accumulation of the osmoprotectant glycine betaine, late embryogenesis abundant proteins and detoxification enzymes. The observed transcriptional changes are supposed to be regulated by ABA-dependent signal transduction pathway. Conclusion This study provides an important step

  14. Uncovering the Spatial Profile of Contour Integration from Fixational Saccades: Evidence for Widespread Processing in V1.

    PubMed

    Gilad, Ariel; Oz, Roy; Slovin, Hamutal

    2016-10-05

    During contour integration, neuronal populations in the primary visual cortex (V1) enhance their responses to the contour while suppressing their responses to the noisy background. However, the spatial extent and profile of these responses are not fully understood. To investigate this question, 2 monkeys were trained on a contour detection task while we measured population responses in V1 using voltage-sensitive dyes. During stimulus presentation the animals made few fixational saccades, and we used their changing gaze position to image and analyze neuronal responses from large part of the stimulus, encoding multiple contour/background elements. We found that contour enhancement was present over the entire contour-mapped areas. The background suppression increased with distance from the contour, extending into background-mapped areas remotely located from the contour. The spatial profile of enhancement and suppression fitted well with a Gaussian model. These results imply that the divergent cortical responses to contour integration are modulated independently and extend over large areas in V1.

  15. Gene expression profiling of single bovine embryos uncovers significant effects of in vitro maturation, fertilization and culture.

    PubMed

    Smith, Sadie L; Everts, Robin E; Sung, Li-Ying; Du, Fuliang; Page, Raymond L; Henderson, Boyd; Rodriguez-Zas, Sandra L; Nedambale, Tshimangadzo L; Renard, Jean-Paul; Lewin, Harris A; Yang, Xiangzhong; Tian, X Cindy

    2009-01-01

    In vitro production (IVP) has been shown to affect embryonic gene expression and often result in large offspring syndrome (LOS) in cattle and sheep. To dissect the effects of in vitro maturation, fertilization and culture on bovine embryos, we compared the expression profiles of single blastocysts generated by: (1) in vitro maturation, fertilization and culture (IVF); (2) in vivo maturation, fertilization and in vitro culture (IVD); and (3) in vivo maturation, fertilization and development (AI). To conduct expression profiling, total RNA was isolated from individual embryos, linearly amplified and hybridized to a custom bovine cDNA microarray containing approximately 6,300 unique genes. There were 306, 367, and 200 genes differentially expressed between the AI and IVD, IVF and IVD, and AI and IVF comparisons, respectively. Interestingly, 44 differentially expressed genes were identified between the AI embryos and both the IVF and IVD embryos, making these potential candidates for LOS. There were 60 genes differentially expressed between the IVF embryos and the AI and IVD embryos. The Gene Ontology category "RNA processing" was over-represented among the genes that were down-regulated in the IVF embryos, indicating an effect of in vitro oocyte maturation/fertilization on the ability to transcribe maternal RNA stores. A culture effect on the expression of genes involved in translation was also observed by the comparison of AI with IVD embryos.

  16. Proteomic profiling of NCI-60 extracellular vesicles uncovers common protein cargo and cancer type-specific biomarkers

    PubMed Central

    Liu, Xia; Singh, Rakesh K.; Meckes, David G.

    2016-01-01

    Packed with biological information, extracellular vesicles (EVs) offer exciting promise for biomarker discovery and applications in therapeutics and non-invasive diagnostics. Currently, our understanding of EV contents is confined by the limited cells from which vesicles have been characterized utilizing the same enrichment method. Using sixty cell lines from the National Cancer Institute (NCI-60), here we provide the largest proteomic profile of EVs in a single study, identifying 6,071 proteins with 213 common to all isolates. Proteins included established EV markers, and vesicular trafficking proteins such as Rab GTPases and tetraspanins. Differentially-expressed proteins offer potential for cancer diagnosis and prognosis. Network analysis of vesicle quantity and proteomes identified EV components associated with vesicle secretion, including CD81, CD63, syntenin-1, VAMP3, Rab GTPases, and integrins. Integration of vesicle proteomes with whole-cell molecular profiles revealed similarities, suggesting EVs provide a reliable reflection of their progenitor cell content, and are therefore excellent indicators of disease. PMID:27894104

  17. Profiling of Free Fatty Acids Using Stable Isotope Tagging Uncovers a Role for Saturated Fatty Acids in Neuroexocytosis.

    PubMed

    Narayana, Vinod K; Tomatis, Vanesa M; Wang, Tong; Kvaskoff, David; Meunier, Frederic A

    2015-10-20

    The phospholipase-catalyzed release of free fatty acids (FFAs) from phospholipids is implicated in many critical biological processes such as neurotransmission, inflammation, and cancer. However, determining the individual change in FFAs generated during these processes has remained challenging due to the limitations of current methods, and has hampered our understanding of these key mediators. Here, we developed an "iTRAQ"-like method for profiling FFAs by stable isotope tagging (FFAST), based on the differential labeling of the carboxyl group and designed to resolve analytical variance, through a multiplexed assay in cells and subcellular fractions. With nanomolar sensitivity, this method revealed a spectrum of saturated FFAs elicited during stimulation of exocytosis that was identical in neurons and neurosecretory cells. Purified secretory vesicles also generated these FFAs when challenged with cytosol. Our multiplex method will be invaluable to assess the range of FFAs generated in other physiological and pathological settings.

  18. Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma

    PubMed Central

    Shen, Yulei; Huang, Xin; Liu, Yanyan; Wake, Laura; Liu, Cuiling; Deffenbacher, Karen; Lachel, Cynthia M.; Wang, Chao; Rohr, Joseph; Guo, Shuangping; Smith, Lynette M.; Wright, George; Bhagavathi, Sharathkumar; Dybkaer, Karen; Fu, Kai; Greiner, Timothy C.; Vose, Julie M.; Jaffe, Elaine; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Armitage, James O.; Weisenburger, Dennis D.; Staudt, Louis M.; Gascoyne, Randy D.; McKeithan, Timothy W.; Chan, Wing C.

    2015-01-01

    We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)–DLBCL compared with activated B-cell (ABC)–DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the “gold standard” GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. PMID:25498913

  19. Polypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat.

    PubMed

    Drakakis, Georgios; Wafford, Keith A; Brewerton, Suzanne C; Bodkin, Michael J; Evans, David A; Bender, Andreas

    2017-06-16

    In this work, we describe the computational ("in silico") mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side effects for 491 compounds tested in rat, we defined an "optimal" (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles. We demonstrated that predicted bioactivities improved classification performance compared to using only structural information. Moreover, DrugBank molecules were processed via the same pipeline, and compounds in many cases not annotated as sedative-hypnotic (alcaftadine, benzatropine, palonosetron, ecopipam, cyproheptadine, sertindole, and clopenthixol) were prospectively validated in vivo. Alcaftadine, ecopipam cyproheptadine, and clopenthixol were found to promote sleep as predicted, benzatropine showed only a small increase in NREM sleep, whereas sertindole promoted wakefulness. To our knowledge, the sedative-hypnotic effects of alcaftadine and ecopipam have not been previously discussed in the literature. The method described extends previous single-target, single-mode-of-action models and is applicable across disease areas.

  20. Gene expression profiles uncover individual identities of gnathal neuroblasts and serial homologies in the embryonic CNS of Drosophila

    PubMed Central

    Urbach, Rolf; Jussen, David; Technau, Gerhard M.

    2016-01-01

    The numbers and types of progeny cells generated by neural stem cells in the developing CNS are adapted to its region-specific functional requirements. In Drosophila, segmental units of the CNS develop from well-defined patterns of neuroblasts. Here we constructed comprehensive neuroblast maps for the three gnathal head segments. Based on the spatiotemporal pattern of neuroblast formation and the expression profiles of 46 marker genes (41 transcription factors), each neuroblast can be uniquely identified. Compared with the thoracic ground state, neuroblast numbers are progressively reduced in labial, maxillary and mandibular segments due to smaller sizes of neuroectodermal anlagen and, partially, to suppression of neuroblast formation and induction of programmed cell death by the Hox gene Deformed. Neuroblast patterns are further influenced by segmental modifications in dorsoventral and proneural gene expression. With the previously published neuroblast maps and those presented here for the gnathal region, all neuroectodermal neuroblasts building the CNS of the fly (ventral nerve cord and brain, except optic lobes) are now individually identified (in total 2×567 neuroblasts). This allows, for the first time, a comparison of the characteristics of segmental populations of stem cells and to screen for serially homologous neuroblasts throughout the CNS. We show that approximately half of the deutocerebral and all of the tritocerebral (posterior brain) and gnathal neuroblasts, but none of the protocerebral (anterior brain) neuroblasts, display serial homology to neuroblasts in thoracic/abdominal neuromeres. Modifications in the molecular signature of serially homologous neuroblasts are likely to determine the segment-specific characteristics of their lineages. PMID:27095493

  1. Transcriptomic Profiling of Yersinia pseudotuberculosis Reveals Reprogramming of the Crp Regulon by Temperature and Uncovers Crp as a Master Regulator of Small RNAs

    PubMed Central

    Nuss, Aaron M.; Heroven, Ann Kathrin; Waldmann, Barbara; Reinkensmeier, Jan; Jarek, Michael; Beckstette, Michael; Dersch, Petra

    2015-01-01

    One hallmark of pathogenic yersiniae is their ability to rapidly adjust their life-style and pathogenesis upon host entry. In order to capture the range, magnitude and complexity of the underlying gene control mechanisms we used comparative RNA-seq-based transcriptomic profiling of the enteric pathogen Y. pseudotuberculosis under environmental and infection-relevant conditions. We identified 1151 individual transcription start sites, multiple riboswitch-like RNA elements, and a global set of antisense RNAs and previously unrecognized trans-acting RNAs. Taking advantage of these data, we revealed a temperature-induced and growth phase-dependent reprogramming of a large set of catabolic/energy production genes and uncovered the existence of a thermo-regulated ‘acetate switch’, which appear to prime the bacteria for growth in the digestive tract. To elucidate the regulatory architecture linking nutritional status to virulence we also refined the CRP regulon. We identified a massive remodelling of the CRP-controlled network in response to temperature and discovered CRP as a transcriptional master regulator of numerous conserved and newly identified non-coding RNAs which participate in this process. This finding highlights a novel level of complexity of the regulatory network in which the concerted action of transcriptional regulators and multiple non-coding RNAs under control of CRP adjusts the control of Yersinia fitness and virulence to the requirements of their environmental and virulent life-styles. PMID:25816203

  2. People Interview: Cosmic rays uncover universe theories

    NASA Astrophysics Data System (ADS)

    2012-07-01

    INTERVIEW Cosmic rays uncover universe theories David Smith talks to Paula Chadwick about why she is fascinated by cosmic and gamma rays, and how this is the year that their profile is going to be raised

  3. Gene expression profiling following short-term and long-term morphine exposure in mice uncovers genes involved in food intake.

    PubMed

    Anghel, A; Jamieson, C A M; Ren, X; Young, J; Porche, R; Ozigbo, E; Ghods, D E; Lee, M L; Liu, Y; Lutfy, K; Friedman, T C

    2010-05-05

    Addictive drugs including opioids activate signal transduction pathways that regulate gene expression in the brain. However, changes in CNS gene expression following morphine exposure are poorly understood. We determined changes in gene expression following short- and long-term morphine treatment in the hypothalamus and pituitary using genome-wide DNA microarray analysis and confirmed those alterations in gene expression by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. In the hypothalamus, short-term morphine administration up-regulated (at least twofold) 39 genes and down-regulated six genes. Long-term morphine treatment up-regulated 35 genes and down-regulated 51 genes. In the pituitary, short-term morphine administration up-regulated 110 genes and down-regulated 29 genes. Long-term morphine treatment up-regulated 85 genes and down-regulated 37 pituitary genes. Microarray analysis uncovered several genes involved in food intake (neuropeptide Y, agouti-related protein, and cocaine and amphetamine-regulated transcript) whose expression was strongly altered by morphine exposure in either the hypothalamus or pituitary. Subsequent RT-PCR analysis confirmed similar regulation in expression of these genes in the hypothalamus and pituitary. Finally, we found functional correlation between morphine-induced alterations in food intake and regulation of genes involved in this process. Changes in genes related to food intake may uncover new pathways related to some of the physiological effects of opioids. (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. TMA Uncovers Medicare Mistakes.

    PubMed

    Sorrel, Amy Lynn

    2015-07-01

    The Texas Medical Association recently uncovered some major Medicare mistakes that show just why some physicians talk about leaving the federal program. Investigations and advocacy by TMA staff put Medicare on the path to a fix.

  5. Integrative Comparative Analyses of Transcript and Metabolite Profiles from Pepper and Tomato Ripening and Development Stages Uncovers Species-Specific Patterns of Network Regulatory Behavior[W][OA

    PubMed Central

    Osorio, Sonia; Alba, Rob; Nikoloski, Zoran; Kochevenko, Andrej; Fernie, Alisdair R.; Giovannoni, James J.

    2012-01-01

    Integrative comparative analyses of transcript and metabolite levels from climacteric and nonclimacteric fruits can be employed to unravel the similarities and differences of the underlying regulatory processes. To this end, we conducted combined gas chromatography-mass spectrometry and heterologous microarray hybridization assays in tomato (Solanum lycopersicum; climacteric) and pepper (Capsicum chilense; nonclimacteric) fruits across development and ripening. Computational methods from multivariate and network-based analyses successfully revealed the difference between the covariance structures of the integrated data sets. Moreover, our results suggest that both fruits have similar ethylene-mediated signaling components; however, their regulation is different and may reflect altered ethylene sensitivity or regulators other than ethylene in pepper. Genes involved in ethylene biosynthesis were not induced in pepper fruits. Nevertheless, genes downstream of ethylene perception such as cell wall metabolism genes, carotenoid biosynthesis genes, and the never-ripe receptor were clearly induced in pepper as in tomato fruit. While signaling sensitivity or actual signals may differ between climacteric and nonclimacteric fruit, the evidence described here suggests that activation of a common set of ripening genes influences metabolic traits. Also, a coordinate regulation of transcripts and the accumulation of key organic acids, including malate, citrate, dehydroascorbate, and threonate, in pepper fruit were observed. Therefore, the integrated analysis allows us to uncover additional information for the comprehensive understanding of biological events relevant to metabolic regulation during climacteric and nonclimacteric fruit development. PMID:22685169

  6. Multistability: Uncovering hidden attractors

    NASA Astrophysics Data System (ADS)

    Kapitaniak, T.; Leonov, G. A.

    2015-07-01

    This topical issue collects contributions exemplifying the recent scientific progress in understanding the dynamics of multistable systems. The individual papers focus on different questions of present day interest in theory and applications of systems with multiple attractors. The particular attention is paid to uncovering and characterizing hidden attractors. Both theoretical and experimental studies are presented.

  7. Uncovering the Math Curriculum

    ERIC Educational Resources Information Center

    Burns, Marilyn

    2014-01-01

    Teachers often express to Marulyn Burns their worry about the need to "cover the curriculum." In response, she draws on one of her favorite quotes: "You don't want to cover a subject; you want to uncover it." This quote is from "The Having of Wonderful Ideas and Other Essays on Teaching and Learning" by Eleanor…

  8. Uncovering the Math Curriculum

    ERIC Educational Resources Information Center

    Burns, Marilyn

    2014-01-01

    Teachers often express to Marulyn Burns their worry about the need to "cover the curriculum." In response, she draws on one of her favorite quotes: "You don't want to cover a subject; you want to uncover it." This quote is from "The Having of Wonderful Ideas and Other Essays on Teaching and Learning" by Eleanor…

  9. Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling.

    PubMed

    Taskesen, Erdogan; Havermans, Marije; van Lom, Kirsten; Sanders, Mathijs A; van Norden, Yvette; Bindels, Eric; Hoogenboezem, Remco; Reinders, Marcel J T; Figueroa, Maria E; Valk, Peter J M; Löwenberg, Bob; Melnick, Ari; Delwel, Ruud

    2014-05-22

    Mutations in splice factor (SF) genes occur more frequently in myelodysplastic syndromes (MDS) than in acute myeloid leukemias (AML). We sequenced complementary DNA from bone marrow of 47 refractory anemia with excess blasts (RAEB) patients, 29 AML cases with low marrow blast cell count, and 325 other AML patients and determined the presence of SF-hotspot mutations in SF3B1, U2AF35, and SRSF2. SF mutations were found in 10 RAEB, 12 AML cases with low marrow blast cell count, and 25 other AML cases. Our study provides evidence that SF-mutant RAEB and SF-mutant AML are clinically, cytologically, and molecularly highly similar. An integrated analysis of genomewide messenger RNA (mRNA) expression profiling and DNA-methylation profiling data revealed 2 unique patient clusters highly enriched for SF-mutant RAEB/AML. The combined genomewide mRNA expression profiling/DNA-methylation profiling signatures revealed 1 SF-mutant patient cluster with an erythroid signature. The other SF-mutant patient cluster was enriched for NRAS/KRAS mutations and showed an inferior survival. We conclude that SF-mutant RAEB/AML constitutes a related disorder overriding the artificial separation between AML and MDS, and that SF-mutant RAEB/AML is composed of 2 molecularly and clinically distinct subgroups. We conclude that SF-mutant disorders should be considered as myeloid malignancies that transcend the boundaries of AML and MDS.

  10. The SSR-based molecular profile of 1005 grapevine (Vitis vinifera L.) accessions uncovers new synonymy and parentages, and reveals a large admixture amongst varieties of different geographic origin.

    PubMed

    Cipriani, Guido; Spadotto, Alessandro; Jurman, Irena; Di Gaspero, Gabriele; Crespan, Manna; Meneghetti, Stefano; Frare, Enrica; Vignani, Rita; Cresti, Mauro; Morgante, Michele; Pezzotti, Mario; Pe, Enrico; Policriti, Alberto; Testolin, Raffaele

    2010-11-01

    A collection of 1005 grapevine accessions was genotyped at 34 microsatellite loci (SSR) with the aim of analysing genetic diversity and exploring parentages. The comparison of molecular profiles revealed 200 groups of synonymy. The removal of perfect synonyms reduced the database to 745 unique genotypes, on which population genetic parameters were calculated. The analysis of kinship uncovered 74 complete pedigrees, with both parents identified. Many of these parentages were not previously known and are of considerable historical interest, e.g. Chenin blanc (Sauvignon × Traminer rot), Covè (Harslevelu selfed), Incrocio Manzoni 2-14 and 2-15 (Cabernet franc × Prosecco), Lagrein (Schiava gentile × Teroldego), Malvasia nera of Bolzano (Perera × Schiava gentile), Manzoni moscato (Raboso veronese × Moscato d'Amburgo), Moscato violetto (Moscato bianco × Duraguzza), Muscat of Alexandria (Muscat blanc à petit grain × Axina de tres bias) and others. Statistical robustness of unexpected pedigrees was reinforced with the analysis of an additional 7-30 SSRs. Grouping the accessions by profile resulted in a weak correlation with their geographical origin and/or current area of cultivation, revealing a large admixture of local varieties with those most widely cultivated, as a result of ancient commerce and population flow. The SSRs with tri- to penta-nucleotide repeats adopted for the present study showed a great capacity for discriminating amongst accessions, with probabilities of identity by chance as low as 1.45 × 10(-27) and 9.35 × 10(-12) for unrelated and full sib individuals, respectively. A database of allele frequencies and SSR profiles of 32 reference cultivars are provided.

  11. Proteasome Activity Profiling Uncovers Alteration of Catalytic β2 and β5 Subunits of the Stress-Induced Proteasome during Salinity Stress in Tomato Roots

    PubMed Central

    Kovács, Judit; Poór, Péter; Kaschani, Farnusch; Chandrasekar, Balakumaran; Hong, Tram N.; Misas-Villamil, Johana C.; Xin, Bo T.; Kaiser, Markus; Overkleeft, Herman S.; Tari, Irma; van der Hoorn, Renier A. L.

    2017-01-01

    The stress proteasome in the animal kingdom facilitates faster conversion of oxidized proteins during stress conditions by incorporating different catalytic β subunits. Plants deal with similar kind of stresses and also carry multiple paralogous genes encoding for each of the three catalytic β subunits. Here, we investigated the existence of stress proteasomes upon abiotic stress (salt stress) in tomato roots. In contrast to Arabidopsis thaliana, tomato has a simplified proteasome gene set with single genes encoding each β subunit except for two genes encoding β2. Using proteasome activity profiling on tomato roots during salt stress, we discovered a transient modification of the catalytic subunits of the proteasome coinciding with a loss of cell viability. This stress-induced active proteasome disappears at later time points and coincides with the need to degrade oxidized proteins during salt stress. Subunit-selective proteasome probes and MS analysis of fluorescent 2D gels demonstrated that the detected stress-induced proteasome is not caused by an altered composition of subunits in active proteasomes, but involves an increased molecular weight of both labeled β2 and β5 subunits, and an additional acidic pI shift for labeled β5, whilst labeled β1 remains mostly unchanged. Treatment with phosphatase or glycosidases did not affect the migration pattern. This stress-induced proteasome may play an important role in PCD during abiotic stress. PMID:28217134

  12. Peroxisome Proliferator-activated Receptor (PPAR) Gene Profiling Uncovers Insulin-like Growth Factor-1 as a PPARα Target Gene in Cardioprotection*

    PubMed Central

    el Azzouzi, Hamid; Leptidis, Stefanos; Bourajjaj, Meriem; Armand, Anne-Sophie; van der Nagel, Roel; van Bilsen, Marc; Da Costa Martins, Paula A.; De Windt, Leon J.

    2011-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPARα, PPARβ/δ, and PPARγ. Considerable evidence indicates the importance of PPARs in cardiovascular lipid homeostasis and diabetes, yet the isoform-dependent cardiac target genes remain unknown. Here, we constructed murine ventricular clones allowing stable expression of siRNAs to achieve specifically knockdown for each of the PPAR isoforms. By combining gene profiling and computational peroxisome proliferator response element analysis following PPAR isoform activation in normal versus PPAR isoform-deficient cardiomyocyte-like cells, we have, for the first time, determined PPAR isoform-specific endogenous target genes in the heart. Electromobility shift and chromatin immunoprecipitation assays demonstrated the existence of an evolutionary conserved peroxisome proliferator response element consensus-binding site in an insulin-like growth factor-1 (igf-1) enhancer. In line, Wy-14643-mediated PPARα activation in the wild-type mouse heart resulted in up-regulation of igf-1 transcript abundance and provided protection against cardiomyocyte apoptosis following ischemia/reperfusion or biomechanical stress. Taken together, these data confirm igf-1 as an in vivo target of PPARα and the involvement of a PPARα/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions. PMID:21245137

  13. Peroxisome proliferator-activated receptor (PPAR) gene profiling uncovers insulin-like growth factor-1 as a PPARalpha target gene in cardioprotection.

    PubMed

    el Azzouzi, Hamid; Leptidis, Stefanos; Bourajjaj, Meriem; Armand, Anne-Sophie; van der Nagel, Roel; van Bilsen, Marc; Da Costa Martins, Paula A; De Windt, Leon J

    2011-04-22

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPARα, PPARβ/δ, and PPARγ. Considerable evidence indicates the importance of PPARs in cardiovascular lipid homeostasis and diabetes, yet the isoform-dependent cardiac target genes remain unknown. Here, we constructed murine ventricular clones allowing stable expression of siRNAs to achieve specifically knockdown for each of the PPAR isoforms. By combining gene profiling and computational peroxisome proliferator response element analysis following PPAR isoform activation in normal versus PPAR isoform-deficient cardiomyocyte-like cells, we have, for the first time, determined PPAR isoform-specific endogenous target genes in the heart. Electromobility shift and chromatin immunoprecipitation assays demonstrated the existence of an evolutionary conserved peroxisome proliferator response element consensus-binding site in an insulin-like growth factor-1 (igf-1) enhancer. In line, Wy-14643-mediated PPARα activation in the wild-type mouse heart resulted in up-regulation of igf-1 transcript abundance and provided protection against cardiomyocyte apoptosis following ischemia/reperfusion or biomechanical stress. Taken together, these data confirm igf-1 as an in vivo target of PPARα and the involvement of a PPARα/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions.

  14. Proteasome Activity Profiling Uncovers Alteration of Catalytic β2 and β5 Subunits of the Stress-Induced Proteasome during Salinity Stress in Tomato Roots.

    PubMed

    Kovács, Judit; Poór, Péter; Kaschani, Farnusch; Chandrasekar, Balakumaran; Hong, Tram N; Misas-Villamil, Johana C; Xin, Bo T; Kaiser, Markus; Overkleeft, Herman S; Tari, Irma; van der Hoorn, Renier A L

    2017-01-01

    The stress proteasome in the animal kingdom facilitates faster conversion of oxidized proteins during stress conditions by incorporating different catalytic β subunits. Plants deal with similar kind of stresses and also carry multiple paralogous genes encoding for each of the three catalytic β subunits. Here, we investigated the existence of stress proteasomes upon abiotic stress (salt stress) in tomato roots. In contrast to Arabidopsis thaliana, tomato has a simplified proteasome gene set with single genes encoding each β subunit except for two genes encoding β2. Using proteasome activity profiling on tomato roots during salt stress, we discovered a transient modification of the catalytic subunits of the proteasome coinciding with a loss of cell viability. This stress-induced active proteasome disappears at later time points and coincides with the need to degrade oxidized proteins during salt stress. Subunit-selective proteasome probes and MS analysis of fluorescent 2D gels demonstrated that the detected stress-induced proteasome is not caused by an altered composition of subunits in active proteasomes, but involves an increased molecular weight of both labeled β2 and β5 subunits, and an additional acidic pI shift for labeled β5, whilst labeled β1 remains mostly unchanged. Treatment with phosphatase or glycosidases did not affect the migration pattern. This stress-induced proteasome may play an important role in PCD during abiotic stress.

  15. Non-targeted profiling of semi-polar metabolites in Arabidopsis root exudates uncovers a role for coumarin secretion and lignification during the local response to phosphate limitation

    PubMed Central

    Ziegler, Jörg; Schmidt, Stephan; Chutia, Ranju; Müller, Jens; Böttcher, Christoph; Strehmel, Nadine; Scheel, Dierk; Abel, Steffen

    2016-01-01

    Plants have evolved two major strategies to cope with phosphate (Pi) limitation. The systemic response, mainly comprising increased Pi uptake and metabolic adjustments for more efficient Pi use, and the local response, enabling plants to explore Pi-rich soil patches by reorganization of the root system architecture. Unlike previous reports, this study focused on root exudation controlled by the local response to Pi deficiency. To approach this, a hydroponic system separating the local and systemic responses was developed. Arabidopsis thaliana genotypes exhibiting distinct sensitivities to Pi deficiency could be clearly distinguished by their root exudate composition as determined by non-targeted reversed-phase ultraperformance liquid chromatography electrospray ionization quadrupole-time-of-flight mass spectrometry metabolite profiling. Compared with wild-type plants or insensitive low phosphate root 1 and 2 (lpr1 lpr2) double mutant plants, the hypersensitive phosphate deficiency response 2 (pdr2) mutant exhibited a reduced number of differential features in root exudates after Pi starvation, suggesting the involvement of PDR2-encoded P5-type ATPase in root exudation. Identification and analysis of coumarins revealed common and antagonistic regulatory pathways between Pi and Fe deficiency-induced coumarin secretion. The accumulation of oligolignols in root exudates after Pi deficiency was inversely correlated with Pi starvation-induced lignification at the root tips. The strongest oligolignol accumulation in root exudates was observed for the insensitive lpr1 lpr2 double mutant, which was accompanied by the absence of Pi deficiency-induced lignin deposition, suggesting a role of LPR ferroxidases in lignin polymerization during Pi starvation. PMID:26685189

  16. Uncovering the Human Methyltransferasome*

    PubMed Central

    Petrossian, Tanya C.; Clarke, Steven G.

    2011-01-01

    We present a comprehensive analysis of the human methyltransferasome. Primary sequences, predicted secondary structures, and solved crystal structures of known methyltransferases were analyzed by hidden Markov models, Fisher-based statistical matrices, and fold recognition prediction-based threading algorithms to create a model, or profile, of each methyltransferase superfamily. These profiles were used to scan the human proteome database and detect novel methyltransferases. 208 proteins in the human genome are now identified as known or putative methyltransferases, including 38 proteins that were not annotated previously. To date, 30% of these proteins have been linked to disease states. Possible substrates of methylation for all of the SET domain and SPOUT methyltransferases as well as 100 of the 131 seven-β-strand methyltransferases were surmised from sequence similarity clusters based on alignments of the substrate-specific domains. PMID:20930037

  17. Research uncovers 'unacceptable risks'.

    PubMed

    Langford, Melvyn

    2013-06-01

    Dr Melvyn Langford C.Eng, MIMechE, MCIBSE, who worked in the NHS for nearly 40 years, including as an estates and facilities manager at several NHS Trusts, has written several previous HEJ articles on 'systematic failures' in the way maintenance of NHS healthcare buildings has been managed, and on what he claims is a 'fundamental flaw' within the national guidance for backlog maintenance (see HEJ - November 2009, September 2010, and September 2011). Here he outlines the conclusions of a recent three-year research project, which he says strongly suggest that that the service's continuing use of fixed yearly budgets, and a lack of sufficient monitoring, may be resulting in what he dubs 'a catalogue of systematic failures within most organisations that are generating risk profiles that expose patients, visitors, and staff, to unacceptable levels of risk'.

  18. Uncovering Black Womanhood in Engineering

    ERIC Educational Resources Information Center

    Gibson, Sheree L.; Espino, Michelle M.

    2016-01-01

    Despite the growing research that outlines the experiences of Blacks and women undergraduates in engineering, little is known about Black women in this field. The purpose of this qualitative study was to uncover how eight Black undergraduate women in engineering understood their race and gender identities in a culture that can be oppressive to…

  19. Uncovering Black Womanhood in Engineering

    ERIC Educational Resources Information Center

    Gibson, Sheree L.; Espino, Michelle M.

    2016-01-01

    Despite the growing research that outlines the experiences of Blacks and women undergraduates in engineering, little is known about Black women in this field. The purpose of this qualitative study was to uncover how eight Black undergraduate women in engineering understood their race and gender identities in a culture that can be oppressive to…

  20. Profiles.

    ERIC Educational Resources Information Center

    Macintosh, Henry G.

    An introduction to profiles is presented with examples provided to permit an overall appraisal of the potential of profiles, of the principles upon which they might be based, and of the problems that will have to be overcome if their potential is to be realized in practice. The larger scale examples of profiles discussed are the Scottish Pupil…

  1. Profiles.

    ERIC Educational Resources Information Center

    School Arts, 1979

    1979-01-01

    Profiles seven Black, Native American, and Chicano artists and art teachers: Hale A. Woodruff, Allan Houser, Luis Jimenez, Betrand D. Phillips, James E. Pate, I, and Fernando Navarro. This article is part of a theme issue on multicultural art. (SJL)

  2. Profiles.

    ERIC Educational Resources Information Center

    School Arts, 1979

    1979-01-01

    Profiles seven Black, Native American, and Chicano artists and art teachers: Hale A. Woodruff, Allan Houser, Luis Jimenez, Betrand D. Phillips, James E. Pate, I, and Fernando Navarro. This article is part of a theme issue on multicultural art. (SJL)

  3. Computer Hypertextual "Uncovering" in Art Education

    ERIC Educational Resources Information Center

    Taylor, Pamela G.; Carpenter, B. Stephen, II

    2005-01-01

    Teaching for understanding is a traditional goal in education that is enhanced through what curriculum theorists Wiggins and McTighe (1998) called "uncovering." In this article the authors describe the ways that interactive computer technology--hypertext--facilitates this act of "uncovering" as students try out ideas, formulate questions, and…

  4. Uncovering blue diffuse dwarf galaxies

    NASA Astrophysics Data System (ADS)

    James, Bethan L.; Koposov, Sergey; Stark, Daniel P.; Belokurov, Vasily; Pettini, Max; Olszewski, Edward W.

    2015-04-01

    Extremely metal poor (XMP) galaxies are known to be very rare, despite the large numbers of low-mass galaxies predicted by the local galaxy luminosity function. This paper presents a subsample of galaxies that were selected via a morphology-based search on Sloan Digital Sky Survey images with the aim of finding these elusive XMP galaxies. By using the recently discovered XMP galaxy, Leo P, as a guide, we obtained a collection of faint, blue systems, each with isolated H II regions embedded in a diffuse continuum, that have remained optically undetected until now. Here we show the first results from optical spectroscopic follow-up observations of 12 of ˜100 of these blue diffuse dwarf (BDD) galaxies yielded by our search algorithm. Oxygen abundances were obtained via the direct method for eight galaxies, and found to be in the range 7.45 < 12 + log (O/H) < 8.0, with two galaxies being classified as XMPs. All BDDs were found to currently have a young star-forming population (<10 Myr) and relatively high ionization parameters of their H II regions. Despite their low luminosities (-11 ≲ MB ≲ -18) and low surface brightnesses (˜23-25 mag arcsec-2), the galaxies were found to be actively star forming, with current star formation rates between 0.0003 and 0.078 M⊙ yr-1. From our current subsample, BDD galaxies appear to be a population of non-quiescent dwarf irregular galaxies, or the diffuse counterparts to blue compact galaxies and as such may bridge the gap between these two populations. Our search algorithm demonstrates that morphology-based searches are successful in uncovering more diffuse metal-poor star-forming galaxies, which traditional emission-line-based searches overlook.

  5. Uncovering the Hidden Decisions that Shape Curricula

    NASA Astrophysics Data System (ADS)

    Harlow, Danielle Boyd

    2010-10-01

    Developing explanatory models is a central practice to scientific inquiry. When students create and test explanatory models for scientific phenomenon, they develop content knowledge, knowledge of the nature of science, and creative thinking skills. Unfortunately, such instruction rarely occurs in K-12 science. This is, in part, because teachers do not have the opportunity to develop sophisticated understandings of the process of modeling, but also because teaching in this way requires teachers to make real-time instructional decisions that are responsive to students' ideas. This is challenging for teachers, especially because this decision process is often invisible. In this talk, I will highlight the importance of providing opportunities for sophisticated science thinking for our youngest learners and consider how uncovering the decisions that shape physics courses for teachers may benefit their future students.

  6. Uncovering hidden flows in physical networks

    NASA Astrophysics Data System (ADS)

    Wang, Chengwei; Grebogi, Celso; Baptista, Murilo S.

    2017-06-01

    Understanding the interactions among nodes in a complex network is of great importance, since they disclose how these nodes are cooperatively supporting the functioning of the network. Scientists have developed numerous methods to uncover the underlying adjacent physical connectivity based on measurements of functional quantities of the nodes states. Often, the physical connectivity, the adjacency matrix, is available. Yet, little is known about how this adjacent connectivity impacts on the “hidden” flows being exchanged between any two arbitrary nodes, after travelling longer non-adjacent paths. In this letter, we show that hidden physical flows in conservative flow networks, a quantity that is usually inaccessible to measurements, can be determined by the interchange of physical flows between any pair of adjacent nodes. Our approach applies to steady or dynamic state of either linear or non-linear complex networks that can be modelled by conservative flow networks, such as gas supply networks, water supply networks and power grids.

  7. Uncovering the Architecture of Action Semantics

    PubMed Central

    Watson, Christine E.; Buxbaum, Laurel J.

    2014-01-01

    Despite research suggesting that stored sensorimotor information about tool use is a component of the semantic representations of tools, little is known about the action features or organizing principles that underlie this knowledge. We used methods similar to those applied in other semantic domains to examine the “architecture” of action semantic knowledge. In Experiment 1, participants sorted photographs of tools into groups according to the similarity of their associated “use” actions and rated tools on dimensions related to action. The results suggest that the magnitude of arm movement, configuration of the hand, and manner of motion during tool use play a role in determining how tools cluster in action “semantic space”. In Experiment 2, we validated the architecture uncovered in Experiment 1 using an implicit semantic task for which tool use knowledge was not ostensibly relevant (blocked cyclic word-picture matching). Using stimuli from Experiment 1, we found that participants performed more poorly during blocks of trials containing tools used with similar versus unrelated actions, and the amount of semantic interference depended on the magnitude of action similarity among tools. Thus, the degree of featural overlap between tool use actions plays a role in determining the overall semantic similarity of tools. PMID:25045905

  8. Uncovering hidden variation in polyploid wheat

    PubMed Central

    Krasileva, Ksenia V.; Vasquez-Gross, Hans A.; Howell, Tyson; Bailey, Paul; Paraiso, Francine; Clissold, Leah; Simmonds, James; Ramirez-Gonzalez, Ricardo H.; Wang, Xiaodong; Borrill, Philippa; Fosker, Christine; Ayling, Sarah; Phillips, Andrew L.; Uauy, Cristobal

    2017-01-01

    Comprehensive reverse genetic resources, which have been key to understanding gene function in diploid model organisms, are missing in many polyploid crops. Young polyploid species such as wheat, which was domesticated less than 10,000 y ago, have high levels of sequence identity among subgenomes that mask the effects of recessive alleles. Such redundancy reduces the probability of selection of favorable mutations during natural or human selection, but also allows wheat to tolerate high densities of induced mutations. Here we exploited this property to sequence and catalog more than 10 million mutations in the protein-coding regions of 2,735 mutant lines of tetraploid and hexaploid wheat. We detected, on average, 2,705 and 5,351 mutations per tetraploid and hexaploid line, respectively, which resulted in 35–40 mutations per kb in each population. With these mutation densities, we identified an average of 23–24 missense and truncation alleles per gene, with at least one truncation or deleterious missense mutation in more than 90% of the captured wheat genes per population. This public collection of mutant seed stocks and sequence data enables rapid identification of mutations in the different copies of the wheat genes, which can be combined to uncover previously hidden variation. Polyploidy is a central phenomenon in plant evolution, and many crop species have undergone recent genome duplication events. Therefore, the general strategy and methods developed herein can benefit other polyploid crops. PMID:28096351

  9. TGFβ1-induced leucine limitation uncovered by differential ribosome codon reading.

    PubMed

    Loayza-Puch, Fabricio; Rooijers, Koos; Zijlstra, Jelle; Moumbeini, Behzad; Zaal, Esther A; Oude Vrielink, Joachim F; Lopes, Rui; Pineiro Ugalde, Alejandro; Berkers, Celia R; Agami, Reuven

    2017-03-08

    Cancer cells modulate their metabolic networks to support cell proliferation and a higher demand of building blocks. These changes may restrict the availability of certain amino acids for protein synthesis, which can be utilized for cancer therapy. However, little is known about the amino acid demand changes occurring during aggressive and invasive stages of cancer. Recently, we developed diricore, an approach based on ribosome profiling that can uncover amino acid limitations. Here, we applied diricore to a cellular model in which epithelial breast cells respond rapidly to TGFβ1, a cytokine essential for cancer progression and metastasis, and uncovered shortage of leucine. Further analyses indicated that TGFβ1 treatment of human breast epithelial cells reduces the expression of SLC3A2, a subunit of the leucine transporter, which diminishes leucine uptake and inhibits cell proliferation. Thus, we identified a specific amino acid limitation associated with the TGFβ1 response, a vulnerability that might be associated with aggressiveness in cancer.

  10. Uncovering Wolbachia diversity upon artificial host transfer.

    PubMed

    Schneider, Daniela I; Riegler, Markus; Arthofer, Wolfgang; Merçot, Hervé; Stauffer, Christian; Miller, Wolfgang J

    2013-01-01

    The common endosymbiotic Wolbachia bacteria influence arthropod hosts in multiple ways. They are mostly recognized for their manipulations of host reproduction, yet, more recent studies demonstrate that Wolbachia also impact host behavior, metabolic pathways and immunity. Besides their biological and evolutionary roles, Wolbachia are new potential biological control agents for pest and vector management. Importantly, Wolbachia-based control strategies require controlled symbiont transfer between host species and predictable outcomes of novel Wolbachia-host associations. Theoretically, this artificial horizontal transfer could inflict genetic changes within transferred Wolbachia populations. This could be facilitated through de novo mutations in the novel recipient host or changes of haplotype frequencies of polymorphic Wolbachia populations when transferred from donor to recipient hosts. Here we show that Wolbachia resident in the European cherry fruit fly, Rhagoletis cerasi, exhibit ancestral and cryptic sequence polymorphism in three symbiont genes, which are exposed upon microinjection into the new hosts Drosophila simulans and Ceratitis capitata. Our analyses of Wolbachia in microinjected D. simulans over 150 generations after microinjection uncovered infections with multiple Wolbachia strains in trans-infected lines that had previously been typed as single infections. This confirms the persistence of low-titer Wolbachia strains in microinjection experiments that had previously escaped standard detection techniques. Our study demonstrates that infections by multiple Wolbachia strains can shift in prevalence after artificial host transfer driven by either stochastic or selective processes. Trans-infection of Wolbachia can claim fitness costs in new hosts and we speculate that these costs may have driven the shifts of Wolbachia strains that we saw in our model system.

  11. 20. UNCOVERED TEST CELL AT THE STATIC TEST TOWER ON ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    20. UNCOVERED TEST CELL AT THE STATIC TEST TOWER ON THE WEST SIDE WHERE F-1 ENGINE WAS TESTED. - Marshall Space Flight Center, Saturn Propulsion & Structural Test Facility, East Test Area, Huntsville, Madison County, AL

  12. NLM Grantee's "HealthMap" Helps Uncover Measles Vaccination Gap

    MedlinePlus

    ... of NLM NLM Grantee's "HealthMap" Helps Uncover Measles Vaccination Gap Inadequate vaccine coverage is likely a driving ... stop this and future measles outbreaks is through vaccination." The research indicates that vaccine coverage among the ...

  13. η Carinae Baby Homunculus uncovered by ALMA

    SciTech Connect

    Abraham, Zulema; Beaklini, Pedro P. B.; Falceta-Gonçalves, Diego

    2014-08-20

    We report observations of η Carinae obtained with ALMA in the continuum of 100, 230, 280, and 660 GHz in 2012 November, with a resolution that varied from 2.''88 to 0.''45 for the lower and higher frequencies, respectively. The source is not resolved, even at the highest frequency; its spectrum is characteristic of thermal bremsstrahlung of a compact source, but different from the spectrum of optically thin wind. The recombination lines H42α, He42α, H40α, He40α, H50β, H28α, He28α, H21α, and He21α were also detected, and their intensities reveal non-local thermodynamic equilibrium effects. We found that the line profiles could only be fit by an expanding shell of dense and ionized gas, which produces a slow shock in the surroundings of η Carinae. Combined with fittings to the continuum, we were able to constrain the shell size, radius, density, temperature, and velocity. The detection of the He recombination lines is compatible with the high-temperature gas and requires a high-energy ionizing photon flux, which must be provided by the companion star. The mass-loss rate and wind velocity, necessary to explain the formation of the shell, are compatible with an luminous blue variable eruption. The position, velocity, and physical parameters of the shell coincide with those of the Weigelt blobs. The dynamics found for the expanding shell correspond to matter ejected by η Carinae in 1941 in an event similar to that which formed the Little Homunculus; for that reason, we called the new ejecta the 'Baby Homunculus'.

  14. Uncovering the Nutritional Landscape of Food

    PubMed Central

    Kim, Seunghyeon; Sung, Jaeyun; Foo, Mathias; Jin, Yong-Su; Kim, Pan-Jun

    2015-01-01

    Recent progresses in data-driven analysis methods, including network-based approaches, are revolutionizing many classical disciplines. These techniques can also be applied to food and nutrition, which must be studied to design healthy diets. Using nutritional information from over 1,000 raw foods, we systematically evaluated the nutrient composition of each food in regards to satisfying daily nutritional requirements. The nutrient balance of a food was quantified and termed nutritional fitness; this measure was based on the food’s frequency of occurrence in nutritionally adequate food combinations. Nutritional fitness offers a way to prioritize recommendable foods within a global network of foods, in which foods are connected based on the similarities of their nutrient compositions. We identified a number of key nutrients, such as choline and α-linolenic acid, whose levels in foods can critically affect the nutritional fitness of the foods. Analogously, pairs of nutrients can have the same effect. In fact, two nutrients can synergistically affect the nutritional fitness, although the individual nutrients alone may not have an impact. This result, involving the tendency among nutrients to exhibit correlations in their abundances across foods, implies a hidden layer of complexity when exploring for foods whose balance of nutrients within pairs holistically helps meet nutritional requirements. Interestingly, foods with high nutritional fitness successfully maintain this nutrient balance. This effect expands our scope to a diverse repertoire of nutrient-nutrient correlations, which are integrated under a common network framework that yields unexpected yet coherent associations between nutrients. Our nutrient-profiling approach combined with a network-based analysis provides a more unbiased, global view of the relationships between foods and nutrients, and can be extended towards nutritional policies, food marketing, and personalized nutrition. PMID:25768022

  15. Uncovering the nutritional landscape of food.

    PubMed

    Kim, Seunghyeon; Sung, Jaeyun; Foo, Mathias; Jin, Yong-Su; Kim, Pan-Jun

    2015-01-01

    Recent progresses in data-driven analysis methods, including network-based approaches, are revolutionizing many classical disciplines. These techniques can also be applied to food and nutrition, which must be studied to design healthy diets. Using nutritional information from over 1,000 raw foods, we systematically evaluated the nutrient composition of each food in regards to satisfying daily nutritional requirements. The nutrient balance of a food was quantified and termed nutritional fitness; this measure was based on the food's frequency of occurrence in nutritionally adequate food combinations. Nutritional fitness offers a way to prioritize recommendable foods within a global network of foods, in which foods are connected based on the similarities of their nutrient compositions. We identified a number of key nutrients, such as choline and α-linolenic acid, whose levels in foods can critically affect the nutritional fitness of the foods. Analogously, pairs of nutrients can have the same effect. In fact, two nutrients can synergistically affect the nutritional fitness, although the individual nutrients alone may not have an impact. This result, involving the tendency among nutrients to exhibit correlations in their abundances across foods, implies a hidden layer of complexity when exploring for foods whose balance of nutrients within pairs holistically helps meet nutritional requirements. Interestingly, foods with high nutritional fitness successfully maintain this nutrient balance. This effect expands our scope to a diverse repertoire of nutrient-nutrient correlations, which are integrated under a common network framework that yields unexpected yet coherent associations between nutrients. Our nutrient-profiling approach combined with a network-based analysis provides a more unbiased, global view of the relationships between foods and nutrients, and can be extended towards nutritional policies, food marketing, and personalized nutrition.

  16. UNCOVERING THE NUCLEUS CANDIDATE FOR NGC 253

    SciTech Connect

    Günthardt, G. I.; Camperi, J. A.; Agüero, M. P.; Díaz, R. J.; Gomez, P. L.; Schirmer, M.; Bosch, G. E-mail: camperi@oac.uncor.edu E-mail: rdiaz@gemini.edu E-mail: mschirmer@gemini.edu

    2015-11-15

    NGC 253 is the nearest spiral galaxy with a nuclear starburst that becomes the best candidate for studying the relationship between starburst and active galactic nucleus activity. However, this central region is veiled by large amounts of dust, and it has been so far unclear which is the true dynamical nucleus to the point that there is no strong evidence that the galaxy harbors a supermassive black hole co-evolving with the starburst as was supposed earlier. Near-infrared (NIR) spectroscopy, especially NIR emission line analysis, could be advantageous in shedding light on the true nucleus identity. Using Flamingos-2 at Gemini South we have taken deep K-band spectra along the major axis of the central structure and through the brightest infrared source. In this work, we present evidence showing that the brightest NIR and mid-infrared source in the central region, already known as radio source TH7 and so far considered just a large stellar supercluster, in fact presents various symptoms of a genuine galactic nucleus. Therefore, it should be considered a valid nucleus candidate. Mentioning some distinctive aspects, it is the most massive compact infrared object in the central region, located at 2.″0 of the symmetry center of the galactic bar, as measured in the K-band emission. Moreover, our data indicate that this object is surrounded by a large circumnuclear stellar disk and it is also located at the rotation center of the large molecular gas disk of NGC 253. Furthermore, a kinematic residual appears in the H{sub 2} rotation curve with a sinusoidal shape consistent with an outflow centered in the candidate nucleus position. The maximum outflow velocity is located about 14 pc from TH7, which is consistent with the radius of a shell detected around the nucleus candidate, observed at 18.3 μm (Qa) and 12.8 μm ([Ne ii]) with T-ReCS. Also, the Brγ emission line profile shows a pronounced blueshift and this emission line also has the highest equivalent width at this

  17. Uncovering the Nucleus Candidate for NGC 253

    NASA Astrophysics Data System (ADS)

    Günthardt, G. I.; Agüero, M. P.; Camperi, J. A.; Díaz, R. J.; Gomez, P. L.; Bosch, G.; Schirmer, M.

    2015-11-01

    NGC 253 is the nearest spiral galaxy with a nuclear starburst that becomes the best candidate for studying the relationship between starburst and active galactic nucleus activity. However, this central region is veiled by large amounts of dust, and it has been so far unclear which is the true dynamical nucleus to the point that there is no strong evidence that the galaxy harbors a supermassive black hole co-evolving with the starburst as was supposed earlier. Near-infrared (NIR) spectroscopy, especially NIR emission line analysis, could be advantageous in shedding light on the true nucleus identity. Using Flamingos-2 at Gemini South we have taken deep K-band spectra along the major axis of the central structure and through the brightest infrared source. In this work, we present evidence showing that the brightest NIR and mid-infrared source in the central region, already known as radio source TH7 and so far considered just a large stellar supercluster, in fact presents various symptoms of a genuine galactic nucleus. Therefore, it should be considered a valid nucleus candidate. Mentioning some distinctive aspects, it is the most massive compact infrared object in the central region, located at 2.″0 of the symmetry center of the galactic bar, as measured in the K-band emission. Moreover, our data indicate that this object is surrounded by a large circumnuclear stellar disk and it is also located at the rotation center of the large molecular gas disk of NGC 253. Furthermore, a kinematic residual appears in the H2 rotation curve with a sinusoidal shape consistent with an outflow centered in the candidate nucleus position. The maximum outflow velocity is located about 14 pc from TH7, which is consistent with the radius of a shell detected around the nucleus candidate, observed at 18.3 μm (Qa) and 12.8 μm ([Ne ii]) with T-ReCS. Also, the Brγ emission line profile shows a pronounced blueshift and this emission line also has the highest equivalent width at this

  18. Weaving Social Foundations through Dance Pedagogy: A Pedagogy of Uncovering

    ERIC Educational Resources Information Center

    Barr, Sherrie; Risner, Doug

    2014-01-01

    Today's dance educators enter classrooms populated by increasingly diverse students in which teachers' pedagogical knowledge necessitates heightened understandings of race, ethnicity, social class, gender, and sexuality. Uncovering taken-for-granted assumptions, dominant stereotypes, and educational structures that reproduce social…

  19. Weaving Social Foundations through Dance Pedagogy: A Pedagogy of Uncovering

    ERIC Educational Resources Information Center

    Barr, Sherrie; Risner, Doug

    2014-01-01

    Today's dance educators enter classrooms populated by increasingly diverse students in which teachers' pedagogical knowledge necessitates heightened understandings of race, ethnicity, social class, gender, and sexuality. Uncovering taken-for-granted assumptions, dominant stereotypes, and educational structures that reproduce social…

  20. Uncovering introductory astronomy students' conceptual modules of lunar phases

    NASA Astrophysics Data System (ADS)

    Lindell, Rebecca; Traxler, Adrienne

    2017-01-01

    Brewe, Bruun and Bearden developed Module Analysis of Multiple Choice Responses (MAMCR) methodology for using network analysis to uncover the underlying conceptual modules of student performance on multiple-choice assessments. The Lunar Phases Concept Inventory (LPCI) assesses students understanding of lunar phases across 8 separate dimensions of understanding based on the results of a detailed qualitative phenomenology of college students' understanding of lunar phases. Unlike many concept inventories, the LPCI has multiple items for each dimension of understanding and each response corresponds to either the scientifically correct answer or to an alternative idea uncovered from the qualitative investigation. In this study, we have combined MAMCR with the database of nearly 2000 LPCI pre-test results. We will report on the preliminary different conceptual modules of lunar phases and the relationship of these modules to previous qualitative research.

  1. Malignant Gastroduodenal Obstruction: Treatment with Self-Expanding Uncovered Wallstent

    SciTech Connect

    Gutzeit, Andreas Binkert, Christoph A.; Schoch, Eric; Sautter, Thomas; Jost, Res; Zollikofer, Christoph L.

    2009-01-15

    Purpose: To retrospectively evaluate the clinical effectiveness of a self-expanding uncovered Wallstent in patients with malignant gastroduodenal obstruction. Materials and Methods: Under combined endoscopic and fluoroscopic guidance, 29 patients with a malignant gastroduodenal stenosis were treated with a self-expanding uncovered metallic Wallstent. A dysphagia score was assessed before and after the intervention to measure the success of this palliative therapy. The dysphagia score ranged between grade 0 to grade 4: grade 0 = able to tolerate solid food, grade 1 = able to tolerate soft food, grade 2 = able to tolerate thick liquids, grade 3 = able to tolerate water or clear fluids, and grade 4 = unable to tolerate anything perorally. Stent patency and patients survival rates were calculated. Results: The insertion of the gastroduodenal stent was technically successful in 28 patients (96.5%). After stenting, 25 patients (86.2%) showed clinical improvement by at least one score point. During follow-up, 22 (78.5%) of 28 patients showed no stent occlusion until death and did not have to undergo any further intervention. In six patients (20.6%), all of whom were treated with secondary stent insertions, occlusion with tumor ingrowth and/or overgrowth was observed after the intervention. The median period of primary stent patency in our study was 240 days. Conclusion: Placement of an uncovered Wallstent is clinically effective in patients with malignant gastroduodenal obstruction. Stent placement is associated with high technical success, good palliation effect, and high durability of stent function.

  2. Partially uncovered Cheatham platinum-covered stent to treat complex aortic coarctation associated with aortic wall aneurysm.

    PubMed

    Butera, Gianfranco; Piazza, Luciane

    2015-04-01

    Percutaneous treatment of aortic coarctation is a widely used option. Covered stents have increased the profile of efficacy and safety of this procedure. Here we report on a 32-year-old woman with significant aortic recoarctation associated with aortic wall aneurysm and close proximity of both lesions to the origin of both the subclavian arteries. It was decided to manually and partially uncover the proximal part of the stent to have a hybrid stent that could act as a bare stent at the level of the origin of the subclavian arteries and as a covered stent at the level of the aneurysm.

  3. Litter box preference in domestic cats: covered versus uncovered.

    PubMed

    Grigg, Emma K; Pick, Lindsay; Nibblett, Belle

    2013-04-01

    Feline inappropriate elimination (periuria and/or perichezia) remains a very common behavioral complaint of cat owners. Treatment recommendations often include improving the attractiveness of the litter boxes available to the cat. One frequent recommendation is to avoid covered litter boxes, although this has not previously been tested experimentally. The goal of this study was to assess whether, all else being equal, cats preferentially used uncovered litter boxes over covered litter boxes. Twenty-eight cats were enrolled in the study and offered the choice of a covered or uncovered box. Waste was scooped daily from each box, and the weight of waste in the different box styles was compared and evaluated using paired t-tests and χ(2) analyses. Overall, there was no significant difference between use of the two box styles. Eight individual cats did exhibit a preference (four for covered, four for uncovered), but individual preference results are not evenly distributed, with more cats than expected showing no preference between litter box types. We postulate that, if boxes are kept sufficiently clean (ie, once daily minimum cleaning), most cats will not show a preference for either box type. The observation that a minority of cats in the study exhibited a preference supports the recommendation of providing individual cats with a 'cafeteria' of litter box styles, including a covered box, to determine whether such a preference exists. These findings add to existing literature on the topic of feline inappropriate elimination and provide additional information for clinicians recommending treatment options for cats exhibiting this behavior.

  4. Uncovering Overlap Community Structure in Complex Networks Using Particle Competition

    NASA Astrophysics Data System (ADS)

    Breve, Fabricio; Zhao, Liang; Quiles, Marcos

    Identification and classification of overlap nodes in communities is an important topic in data mining. In this paper, a new clustering method to uncover overlap nodes in complex networks is proposed. It is based on particles walking and competing with each other, using random-deterministic movement. The new community detection algorithm can output not only hard labels, but also continuous-valued output (soft labels), which corresponds to the levels of membership from the nodes to each of the communities. Computer simulations were performed with synthetic and real data and good results were achieved.

  5. High levels of cryptic species diversity uncovered in Amazonian frogs

    PubMed Central

    Funk, W. Chris; Caminer, Marcel; Ron, Santiago R.

    2012-01-01

    One of the greatest challenges for biodiversity conservation is the poor understanding of species diversity. Molecular methods have dramatically improved our ability to uncover cryptic species, but the magnitude of cryptic diversity remains unknown, particularly in diverse tropical regions such as the Amazon Basin. Uncovering cryptic diversity in amphibians is particularly pressing because amphibians are going extinct globally at an alarming rate. Here, we use an integrative analysis of two independent Amazonian frog clades, Engystomops toadlets and Hypsiboas treefrogs, to test whether species richness is underestimated and, if so, by how much. We sampled intensively in six countries with a focus in Ecuador (Engystomops: 252 individuals from 36 localities; Hypsiboas: 208 individuals from 65 localities) and combined mitochondrial DNA, nuclear DNA, morphological, and bioacoustic data to detect cryptic species. We found that in both clades, species richness was severely underestimated, with more undescribed species than described species. In Engystomops, the two currently recognized species are actually five to seven species (a 150–250% increase in species richness); in Hypsiboas, two recognized species represent six to nine species (a 200–350% increase). Our results suggest that Amazonian frog biodiversity is much more severely underestimated than previously thought. PMID:22130600

  6. Metabolism of human insulin after subcutaneous administration: A possible means to uncover insulin misuse.

    PubMed

    Thomas, Andreas; Brinkkötter, Paul; Schänzer, Wilhelm; Thevis, Mario

    2015-10-15

    The misuse of insulin for performance enhancement in sport or as toxic agent has frequently been reported in the past. In contrast to synthetic insulin analogues, the administration of recombinant human insulin is hardly recognized by mass spectrometry. The present study was designed to uncover the misuse of recombinant human insulin for doping control purposes as well as for forensic applications. It is hypothesized that an altered metabolite profile of circulating insulin prevails after subcutaneous administration due to exposure of insulin to epidermal proteases. In vitro experiments with skin tissue lysates (S9 fraction and microsomes), different biological fluids (urine, serum, plasma) and recombinant human insulin were performed and the deriving metabolites were characterized by liquid chromatography coupled to high resolution mass spectrometry (HRMS). Afterwards, authentic blood samples of patients suffering from diabetes mellitus and a control group of healthy humans were analysed. Therefore, a method using protein precipitation, ultrafiltration and antibody-coated magnetic beads for purification with subsequent separation by nano-scale liquid chromatography coupled a Q Exactive mass spectrometer was applied. Several metabolites of insulin with C-terminally truncated sequences of the B-chain (and A-chain in minor extent) were identified within this study. Here, the DesB30 human insulin represents the major metabolite in all experiments. This metabolite is frequently found in urine samples due to degradation processes and, thus, disqualifies this matrix for the intended purposes. In contrast, blood samples do commonly not contain DesB30 insulin, which was corroborated by data obtained from the control group. In post-administration blood samples, minute but distinct amounts (approx. 50 pg mL(-1)) of DesB30 insulin were found and suggest the use of this analyte as potential marker for subcutaneous human insulin administration, supporting the attempts to

  7. Uncovering Beat Deafness: Detecting Rhythm Disorders with Synchronized Finger Tapping and Perceptual Timing Tasks

    PubMed Central

    Dalla Bella, Simone; Sowiński, Jakub

    2015-01-01

    A set of behavioral tasks for assessing perceptual and sensorimotor timing abilities in the general population (i.e., non-musicians) is presented here with the goal of uncovering rhythm disorders, such as beat deafness. Beat deafness is characterized by poor performance in perceiving durations in auditory rhythmic patterns or poor synchronization of movement with auditory rhythms (e.g., with musical beats). These tasks include the synchronization of finger tapping to the beat of simple and complex auditory stimuli and the detection of rhythmic irregularities (anisochrony detection task) embedded in the same stimuli. These tests, which are easy to administer, include an assessment of both perceptual and sensorimotor timing abilities under different conditions (e.g., beat rates and types of auditory material) and are based on the same auditory stimuli, ranging from a simple metronome to a complex musical excerpt. The analysis of synchronized tapping data is performed with circular statistics, which provide reliable measures of synchronization accuracy (e.g., the difference between the timing of the taps and the timing of the pacing stimuli) and consistency. Circular statistics on tapping data are particularly well-suited for detecting individual differences in the general population. Synchronized tapping and anisochrony detection are sensitive measures for identifying profiles of rhythm disorders and have been used with success to uncover cases of poor synchronization with spared perceptual timing. This systematic assessment of perceptual and sensorimotor timing can be extended to populations of patients with brain damage, neurodegenerative diseases (e.g., Parkinson’s disease), and developmental disorders (e.g., Attention Deficit Hyperactivity Disorder). PMID:25867797

  8. Assessment of Pain When Uncovering Implants with Er:YAG Laser or Scalpel for Second Stage Surgery.

    PubMed

    Matys, Jacek; Dominiak, Marzena

    2016-01-01

    Different methods aimed at decreasing pain during some soft tissue procedures in dentistry are still under research. Modern devices as lasers could be a method to reduce the pain and duration of second stage implant surgery. To assess the pain and the impression quality when uncovering implants with a laser and with a scalpel. The analysis included 60 implants (Dentium SuperLine, Suwon, Korea) in 30 patients (23 women and 7 men) aged 25-69. In the experimental group, 30 implants were uncovered by means of an Er:YAG laser (LiteTouch®, Syneron Dental, Yokneam, Israel) with the following fixed operation parameters: 300 mJ, 18 Hz, water cooling at 40%, energy density per pulse: 38.21 J/cm2, tip size: 1.0 × 17 mm, distance: 2 mm, tip angle set at 70°, no anesthesia. As a control, 30 implants were uncovered using a scalpel and topical application of 20% benzocaine. An 11-point numeric pain rating scale (NRS-11) was used to evaluate the pain level. A 3-point prosthetic impression scale (PIS) designed by the authors was used to assess the quality of the impression of the implant emergence profile. The mean value of pain assessed on the NRS-11 for the Er:YAG laser and scalpel were 2.6 and 6, respectively. The mean value of pain for the laser and scalpel at a supracrestal height of periimplant soft tissue (SHPST) ≤ 3 mm were 1.8 and 4.7 respectively, and for SHPST > 3 mm the values were 3.3 and 7.4, respectively. The implant emergence profile impression showed satisfactory or ideal quality in 26 cases. The use of Er:YAG laser reduces pain and allows minor surgical procedures to be carried out without anesthesia. The impression quality is satisfactory for the preparation of prosthetic reconstructions.

  9. Phylostratigraphic profiles in zebrafish uncover chordate origins of the vertebrate brain.

    PubMed

    Šestak, Martin Sebastijan; Domazet-Lošo, Tomislav

    2015-02-01

    An elaborated tripartite brain is considered one of the important innovations of vertebrates. Other extant chordate groups have a more basic brain organization. For instance, cephalochordates possess a relatively simple brain possibly homologous to the vertebrate forebrain and hindbrain, whereas tunicates display the tripartite organization, but without the specialized brain centers. The difference in anatomical complexity is even more pronounced if one compares chordates with other deuterostomes that have only a diffuse nerve net or alternatively a rather simple central nervous system. To gain a new perspective on the evolutionary roots of the complex vertebrate brain, we made here a phylostratigraphic analysis of gene expression patterns in the developing zebrafish (Danio rerio). The recovered adaptive landscape revealed three important periods in the evolutionary history of the zebrafish brain. The oldest period corresponds to preadaptive events in the first metazoans and the emergence of the nervous system at the metazoan-eumetazoan transition. The origin of chordates marks the next phase, where we found the overall strongest adaptive imprint in almost all analyzed brain regions. This finding supports the idea that the vertebrate brain evolved independently of the brains within the protostome lineage. Finally, at the origin of vertebrates we detected a pronounced signal coming from the dorsal telencephalon, in agreement with classical theories that consider this part of the cerebrum a genuine vertebrate innovation. Taken together, these results reveal a stepwise adaptive history of the vertebrate brain where most of its extant organization was already present in the chordate ancestor. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  10. Ameloblastoma RNA profiling uncovers a distinct non-coding RNA signature

    PubMed Central

    Davanian, Haleh; Balasiddaiah, Anangi; Heymann, Robert; Sundström, Magnus; Redenström, Poppy; Silfverberg, Mikael; Brodin, David; Sällberg, Matti; Lindskog, Sven; Weiner, Carina Kruger; Chen, Margaret

    2017-01-01

    Ameloblastoma of the jaws remains the top difficult to treat odontogenic tumour and has a high recurrence rate. New evidence suggests that non-coding RNAs (ncRNAs) play a critical role in tumourgenesis and prognosis of cancer. However, ameloblastoma ncRNA expression data is lacking. Here we present the first report of ameloblastoma ncRNA signatures. A total of 95 ameloblastoma cases and a global array transcriptome technology covering > 285.000 full-length transcripts were used in this two-step analysis. The analysis first identified in a test cohort 31 upregulated ameloblastoma-associated ncRNAs accompanied by signalling pathways of cancer, spliceosome, mRNA surveillance and Wnt. Further validation in an independent cohort points out the long non-coding (lncRNAs) and small nucleolar RNA (snoRNAs): LINC340, SNORD116-25, SNORA11, SNORA21, SNORA47 and SNORA65 as a distinct ncRNA signature of ameloblastoma. Importantly, the presence of these ncRNAs was independent of BRAF-V600E and SMO-L412F mutations, histology type or tumour location, but was positively correlated with the tumour size. Taken together, this study shows a systematic investigation of ncRNA expression of ameloblastoma, and illuminates new diagnostic and therapeutic targets for this invasive odontogenic tumour. PMID:27965463

  11. Phylostratigraphic Profiles in Zebrafish Uncover Chordate Origins of the Vertebrate Brain

    PubMed Central

    Šestak, Martin Sebastijan; Domazet-Lošo, Tomislav

    2015-01-01

    An elaborated tripartite brain is considered one of the important innovations of vertebrates. Other extant chordate groups have a more basic brain organization. For instance, cephalochordates possess a relatively simple brain possibly homologous to the vertebrate forebrain and hindbrain, whereas tunicates display the tripartite organization, but without the specialized brain centers. The difference in anatomical complexity is even more pronounced if one compares chordates with other deuterostomes that have only a diffuse nerve net or alternatively a rather simple central nervous system. To gain a new perspective on the evolutionary roots of the complex vertebrate brain, we made here a phylostratigraphic analysis of gene expression patterns in the developing zebrafish (Danio rerio). The recovered adaptive landscape revealed three important periods in the evolutionary history of the zebrafish brain. The oldest period corresponds to preadaptive events in the first metazoans and the emergence of the nervous system at the metazoan–eumetazoan transition. The origin of chordates marks the next phase, where we found the overall strongest adaptive imprint in almost all analyzed brain regions. This finding supports the idea that the vertebrate brain evolved independently of the brains within the protostome lineage. Finally, at the origin of vertebrates we detected a pronounced signal coming from the dorsal telencephalon, in agreement with classical theories that consider this part of the cerebrum a genuine vertebrate innovation. Taken together, these results reveal a stepwise adaptive history of the vertebrate brain where most of its extant organization was already present in the chordate ancestor. PMID:25415965

  12. Transcriptional profiles uncover Aspergillus flavus-induced resistance in maize kernels

    USDA-ARS?s Scientific Manuscript database

    Aflatoxin contamination caused by the opportunistic pathogen A. flavus is a major concern in maize production prior to harvest and during storage, and also a concern in many other crops, such as peanuts, cottonseed, tree nuts, and rice. Although a number of resistant maize lines with low aflatoxin c...

  13. Computational biology approach to uncover hepatitis C virus helicase operation

    PubMed Central

    Flechsig, Holger

    2014-01-01

    Hepatitis C virus (HCV) helicase is a molecular motor that splits nucleic acid duplex structures during viral replication, therefore representing a promising target for antiviral treatment. Hence, a detailed understanding of the mechanism by which it operates would facilitate the development of efficient drug-assisted therapies aiming to inhibit helicase activity. Despite extensive investigations performed in the past, a thorough understanding of the activity of this important protein was lacking since the underlying internal conformational motions could not be resolved. Here we review investigations that have been previously performed by us for HCV helicase. Using methods of structure-based computational modelling it became possible to follow entire operation cycles of this motor protein in structurally resolved simulations and uncover the mechanism by which it moves along the nucleic acid and accomplishes strand separation. We also discuss observations from that study in the light of recent experimental studies that confirm our findings. PMID:24707123

  14. Uncovering community structures with initialized Bayesian nonnegative matrix factorization.

    PubMed

    Tang, Xianchao; Xu, Tao; Feng, Xia; Yang, Guoqing

    2014-01-01

    Uncovering community structures is important for understanding networks. Currently, several nonnegative matrix factorization algorithms have been proposed for discovering community structure in complex networks. However, these algorithms exhibit some drawbacks, such as unstable results and inefficient running times. In view of the problems, a novel approach that utilizes an initialized Bayesian nonnegative matrix factorization model for determining community membership is proposed. First, based on singular value decomposition, we obtain simple initialized matrix factorizations from approximate decompositions of the complex network's adjacency matrix. Then, within a few iterations, the final matrix factorizations are achieved by the Bayesian nonnegative matrix factorization method with the initialized matrix factorizations. Thus, the network's community structure can be determined by judging the classification of nodes with a final matrix factor. Experimental results show that the proposed method is highly accurate and offers competitive performance to that of the state-of-the-art methods even though it is not designed for the purpose of modularity maximization.

  15. Uncovering transportation networks from traffic flux by compressed sensing

    NASA Astrophysics Data System (ADS)

    Tang, Si-Qi; Shen, Zhesi; Wang, Wen-Xu; Di, Zengru

    2015-08-01

    Transportation and communication networks are ubiquitous in nature and society. Uncovering the underlying topology as well as link weights, is fundamental to understanding traffic dynamics and designing effective control strategies to facilitate transmission efficiency. We develop a general method for reconstructing transportation networks from detectable traffic flux data using the aid of a compressed sensing algorithm. Our approach enables full reconstruction of network topology and link weights for both directed and undirected networks from relatively small amounts of data compared to the network size. The limited data requirement and certain resistance to noise allows our method to achieve real-time network reconstruction. We substantiate the effectiveness of our method through systematic numerical tests with respect to several different network structures and transmission strategies. We expect our approach to be widely applicable in a variety of transportation and communication systems.

  16. Pleiotropy, apparent stabilizing selection and uncovering fitness optima.

    PubMed

    McGuigan, Katrina; Rowe, Locke; Blows, Mark W

    2011-01-01

    Evolutionary theory has emphasized that the evolution of single traits cannot be understood in isolation when pleiotropy is present. Widespread pleiotropy causes the appearance of stabilizing selection on metric traits owing to joint effects with fitness, and results in the genetic variation being concentrated in relatively few combinations of the measured traits. In this review, we show how trait combinations with high levels of genetic variation can be used to uncover fitness optima that are defined by apparent stabilizing selection. Defining fitness optima in this way could provide one avenue by which researchers can overcome the problem posed by measuring the myriad of traits that must influence fitness, or by measuring total fitness itself.

  17. Uncovering Listeria monocytogenes hypervirulence by harnessing its biodiversity

    PubMed Central

    Charlier, Caroline; Touchon, Marie; Chenal-Francisque, Viviane; Leclercq, Alexandre; Criscuolo, Alexis; Gaultier, Charlotte; Roussel, Sophie; Brisabois, Anne; Disson, Olivier; Rocha, Eduardo P. C.; Brisse, Sylvain; Lecuit, Marc

    2016-01-01

    Microbial pathogenesis studies are typically performed with reference strains, thereby overlooking microbial intra-species virulence heterogeneity. Here we integrated human epidemiological and clinical data with bacterial population genomics to harness the biodiversity of the model foodborne pathogen Listeria monocytogenes and decipher the basis of its neural and placental tropisms. Taking advantage of the clonal structure of this bacterial species, we identify clones epidemiologically associated with either food or human central nervous system (CNS) and maternal-neonatal (MN) listeriosis. The latter are also most prevalent in patients without immunosuppressive comorbidities. Strikingly, CNS and MN clones are hypervirulent in a humanized mouse model of listeriosis. By integrating epidemiological data and comparative genomics, we uncovered multiple novel putative virulence factors and demonstrated experimentally the contribution of the first gene cluster mediating Listeria monocytogenes neural and placental tropisms. This study illustrates the exceptional power of harnessing microbial biodiversity to identify clinically relevant microbial virulence attributes. PMID:26829754

  18. Computational biology approach to uncover hepatitis C virus helicase operation.

    PubMed

    Flechsig, Holger

    2014-04-07

    Hepatitis C virus (HCV) helicase is a molecular motor that splits nucleic acid duplex structures during viral replication, therefore representing a promising target for antiviral treatment. Hence, a detailed understanding of the mechanism by which it operates would facilitate the development of efficient drug-assisted therapies aiming to inhibit helicase activity. Despite extensive investigations performed in the past, a thorough understanding of the activity of this important protein was lacking since the underlying internal conformational motions could not be resolved. Here we review investigations that have been previously performed by us for HCV helicase. Using methods of structure-based computational modelling it became possible to follow entire operation cycles of this motor protein in structurally resolved simulations and uncover the mechanism by which it moves along the nucleic acid and accomplishes strand separation. We also discuss observations from that study in the light of recent experimental studies that confirm our findings.

  19. SpotLight Proteomics: uncovering the hidden blood proteome improves diagnostic power of proteomics

    PubMed Central

    Lundström, Susanna L.; Zhang, Bo; Rutishauser, Dorothea; Aarsland, Dag; Zubarev, Roman A.

    2017-01-01

    The human blood proteome is frequently assessed by protein abundance profiling using a combination of liquid chromatography and tandem mass spectrometry (LC-MS/MS). In traditional sequence database search, many good-quality MS/MS data remain unassigned. Here we uncover the hidden part of the blood proteome via novel SpotLight approach. This method combines de novo MS/MS sequencing of enriched antibodies and co-extracted proteins with subsequent label-free quantification of new and known peptides in both enriched and unfractionated samples. In a pilot study on differentiating early stages of Alzheimer’s disease (AD) from Dementia with Lewy Bodies (DLB), on peptide level the hidden proteome contributed almost as much information to patient stratification as the apparent proteome. Intriguingly, many of the new peptide sequences are attributable to antibody variable regions, and are potentially indicative of disease etiology. When the hidden and apparent proteomes are combined, the accuracy of differentiating AD (n = 97) and DLB (n = 47) increased from ≈85% to ≈95%. The low added burden of SpotLight proteome analysis makes it attractive for use in clinical settings. PMID:28167817

  20. Uncover disease genes by maximizing information flow in the phenome–interactome network

    PubMed Central

    Chen, Yong; Jiang, Tao; Jiang, Rui

    2011-01-01

    Motivation: Pinpointing genes that underlie human inherited diseases among candidate genes in susceptibility genetic regions is the primary step towards the understanding of pathogenesis of diseases. Although several probabilistic models have been proposed to prioritize candidate genes using phenotype similarities and protein–protein interactions, no combinatorial approaches have been proposed in the literature. Results: We propose the first combinatorial approach for prioritizing candidate genes. We first construct a phenome–interactome network by integrating the given phenotype similarity profile, protein–protein interaction network and associations between diseases and genes. Then, we introduce a computational method called MAXIF to maximize the information flow in this network for uncovering genes that underlie diseases. We demonstrate the effectiveness of this method in prioritizing candidate genes through a series of cross-validation experiments, and we show the possibility of using this method to identify diseases with which a query gene may be associated. We demonstrate the competitive performance of our method through a comparison with two existing state-of-the-art methods, and we analyze the robustness of our method with respect to the parameters involved. As an example application, we apply our method to predict driver genes in 50 copy number aberration regions of melanoma. Our method is not only able to identify several driver genes that have been reported in the literature, it also shed some new biological insights on the understanding of the modular property and transcriptional regulation scheme of these driver genes. Contact: ruijiang@tsinghua.edu.cn PMID:21685067

  1. Gene Expression Deconvolution for Uncovering Molecular Signatures in Response to Therapy in Juvenile Idiopathic Arthritis

    PubMed Central

    Rosenberg, Alan M.; Yeung, Rae S. M.; Morris, Quaid

    2016-01-01

    Gene expression-based signatures help identify pathways relevant to diseases and treatments, but are challenging to construct when there is a diversity of disease mechanisms and treatments in patients with complex diseases. To overcome this challenge, we present a new application of an in silico gene expression deconvolution method, ISOpure-S1, and apply it to identify a common gene expression signature corresponding to response to treatment in 33 juvenile idiopathic arthritis (JIA) patients. Using pre- and post-treatment gene expression profiles only, we found a gene expression signature that significantly correlated with a reduction in the number of joints with active arthritis, a measure of clinical outcome (Spearman rho = 0.44, p = 0.040, Bonferroni correction). This signature may be associated with a decrease in T-cells, monocytes, neutrophils and platelets. The products of most differentially expressed genes include known biomarkers for JIA such as major histocompatibility complexes and interleukins, as well as novel biomarkers including α-defensins. This method is readily applicable to expression datasets of other complex diseases to uncover shared mechanistic patterns in heterogeneous samples. PMID:27244050

  2. NuBBEDB: an updated database to uncover chemical and biological information from Brazilian biodiversity.

    PubMed

    Pilon, Alan C; Valli, Marilia; Dametto, Alessandra C; Pinto, Meri Emili F; Freire, Rafael T; Castro-Gamboa, Ian; Andricopulo, Adriano D; Bolzani, Vanderlan S

    2017-08-03

    The intrinsic value of biodiversity extends beyond species diversity, genetic heritage, ecosystem variability and ecological services, such as climate regulation, water quality, nutrient cycling and the provision of reproductive habitats it is also an inexhaustible source of molecules and products beneficial to human well-being. To uncover the chemistry of Brazilian natural products, the Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products Database (NuBBEDB) was created as the first natural product library from Brazilian biodiversity. Since its launch in 2013, the NuBBEDB has proven to be an important resource for new drug design and dereplication studies. Consequently, continuous efforts have been made to expand its contents and include a greater diversity of natural sources to establish it as a comprehensive compendium of available biogeochemical information about Brazilian biodiversity. The content in the NuBBEDB is freely accessible online (https://nubbe.iq.unesp.br/portal/nubbedb.html) and provides validated multidisciplinary information, chemical descriptors, species sources, geographic locations, spectroscopic data (NMR) and pharmacological properties. Herein, we report the latest advancements concerning the interface, content and functionality of the NuBBEDB. We also present a preliminary study on the current profile of the compounds present in Brazilian territory.

  3. Uncover disease genes by maximizing information flow in the phenome-interactome network.

    PubMed

    Chen, Yong; Jiang, Tao; Jiang, Rui

    2011-07-01

    Pinpointing genes that underlie human inherited diseases among candidate genes in susceptibility genetic regions is the primary step towards the understanding of pathogenesis of diseases. Although several probabilistic models have been proposed to prioritize candidate genes using phenotype similarities and protein-protein interactions, no combinatorial approaches have been proposed in the literature. We propose the first combinatorial approach for prioritizing candidate genes. We first construct a phenome-interactome network by integrating the given phenotype similarity profile, protein-protein interaction network and associations between diseases and genes. Then, we introduce a computational method called MAXIF to maximize the information flow in this network for uncovering genes that underlie diseases. We demonstrate the effectiveness of this method in prioritizing candidate genes through a series of cross-validation experiments, and we show the possibility of using this method to identify diseases with which a query gene may be associated. We demonstrate the competitive performance of our method through a comparison with two existing state-of-the-art methods, and we analyze the robustness of our method with respect to the parameters involved. As an example application, we apply our method to predict driver genes in 50 copy number aberration regions of melanoma. Our method is not only able to identify several driver genes that have been reported in the literature, it also shed some new biological insights on the understanding of the modular property and transcriptional regulation scheme of these driver genes. ruijiang@tsinghua.edu.cn.

  4. 77 FR 30501 - Uncovered Innerspring Units From the People's Republic of China: Initiation of Anticircumvention...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-23

    ... petition also included imports of uncovered innerspring units from South Africa and the Socialist Republic of Vietnam. See Uncovered Innerspring Units From the People's Republic of China, South Africa, and... Innerspring Units From South Africa and Vietnam, USITC Pub. 4051, Inv. Nos. 731-TA-1141-1142 at I-11...

  5. 77 FR 12227 - Long Term 2 Enhanced Surface Water Treatment Rule: Uncovered Finished Water Reservoirs; Public...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-29

    ... AGENCY 40 CFR Parts 141 and 142 Long Term 2 Enhanced Surface Water Treatment Rule: Uncovered Finished Water Reservoirs; Public Meeting AGENCY: Environmental Protection Agency (EPA). ACTION: Notice of public..., concerning information that may inform the regulatory review of the uncovered finished water reservoir...

  6. Uncovering patterns of technology use in consumer health informatics.

    PubMed

    Hung, Man; Conrad, Jillian; Hon, Shirley D; Cheng, Christine; Franklin, Jeremy D; Tang, Philip

    2013-11-01

    Internet usage and accessibility has grown at a staggering rate, influencing technology use for healthcare purposes. The amount of health information technology (Health IT) available through the Internet is immeasurable and growing daily. Health IT is now seen as a fundamental aspect of patient care as it stimulates patient engagement and encourages personal health management. It is increasingly important to understand consumer health IT patterns including who is using specific technologies, how technologies are accessed, factors associated with use, and perceived benefits. To fully uncover consumer patterns it is imperative to recognize common barriers and which groups they disproportionately affect. Finally, exploring future demand and predictions will expose significant opportunities for health IT. The most frequently used health information technologies by consumers are gathering information online, mobile health (mHealth) technologies, and personal health records (PHRs). Gathering health information online is the favored pathway for healthcare consumers as it is used by more consumers and more frequently than any other technology. In regard to mHealth technologies, minority Americans, compared with White Americans utilize social media, mobile Internet, and mobile applications more frequently. Consumers believe PHRs are the most beneficial health IT. PHR usage is increasing rapidly due to PHR integration with provider health systems and health insurance plans. Key issues that have to be explicitly addressed in health IT are privacy and security concerns, health literacy, unawareness, and usability. Privacy and security concerns are rated the number one reason for the slow rate of health IT adoption.

  7. Uncovering patterns of technology use in consumer health informatics

    PubMed Central

    Hung, Man; Conrad, Jillian; Hon, Shirley D.; Cheng, Christine; Franklin, Jeremy D.; Tang, Philip

    2014-01-01

    Internet usage and accessibility has grown at a staggering rate, influencing technology use for healthcare purposes. The amount of health information technology (Health IT) available through the Internet is immeasurable and growing daily. Health IT is now seen as a fundamental aspect of patient care as it stimulates patient engagement and encourages personal health management. It is increasingly important to understand consumer health IT patterns including who is using specific technologies, how technologies are accessed, factors associated with use, and perceived benefits. To fully uncover consumer patterns it is imperative to recognize common barriers and which groups they disproportionately affect. Finally, exploring future demand and predictions will expose significant opportunities for health IT. The most frequently used health information technologies by consumers are gathering information online, mobile health (mHealth) technologies, and personal health records (PHRs). Gathering health information online is the favored pathway for healthcare consumers as it is used by more consumers and more frequently than any other technology. In regard to mHealth technologies, minority Americans, compared with White Americans utilize social media, mobile Internet, and mobile applications more frequently. Consumers believe PHRs are the most beneficial health IT. PHR usage is increasing rapidly due to PHR integration with provider health systems and health insurance plans. Key issues that have to be explicitly addressed in health IT are privacy and security concerns, health literacy, unawareness, and usability. Privacy and security concerns are rated the number one reason for the slow rate of health IT adoption. PMID:24904713

  8. Uncovering the mechanism(s) of deep brain stimulation

    NASA Astrophysics Data System (ADS)

    Gang, Li; Chao, Yu; Ling, Lin; C-Y Lu, Stephen

    2005-01-01

    Deep brain stimulators, often called `pacemakers for the brain', are implantable devices which continuously deliver impulse stimulation to specific targeted nuclei of deep brain structure, namely deep brain stimulation (DBS). To date, deep brain stimulation (DBS) is the most effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia). In addition, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been put forward. Although DBS has been effective in the treatment of movement disorders and is rapidly being explored for the treatment of other neurologic disorders, the scientific understanding of its mechanisms of action remains unclear and continues to be debated in the scientific community. Optimization of DBS technology for present and future therapeutic applications will depend on identification of the therapeutic mechanism(s) of action. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS.

  9. Uncovering Community Structures with Initialized Bayesian Nonnegative Matrix Factorization

    PubMed Central

    Tang, Xianchao; Xu, Tao; Feng, Xia; Yang, Guoqing

    2014-01-01

    Uncovering community structures is important for understanding networks. Currently, several nonnegative matrix factorization algorithms have been proposed for discovering community structure in complex networks. However, these algorithms exhibit some drawbacks, such as unstable results and inefficient running times. In view of the problems, a novel approach that utilizes an initialized Bayesian nonnegative matrix factorization model for determining community membership is proposed. First, based on singular value decomposition, we obtain simple initialized matrix factorizations from approximate decompositions of the complex network’s adjacency matrix. Then, within a few iterations, the final matrix factorizations are achieved by the Bayesian nonnegative matrix factorization method with the initialized matrix factorizations. Thus, the network’s community structure can be determined by judging the classification of nodes with a final matrix factor. Experimental results show that the proposed method is highly accurate and offers competitive performance to that of the state-of-the-art methods even though it is not designed for the purpose of modularity maximization. PMID:25268494

  10. Charting the Vasculome: Uncovering the Principles of Vascular Organization

    NASA Astrophysics Data System (ADS)

    Oppenheim, Jacob; Magnasco, Marcelo

    2014-03-01

    The efficient distribution of resources in any system requires a carefully designed architecture that is both space filling and efficient. While the principles of such networks are beginning to be uncovered in plants, they remain poorly elucidated in the case of higher animals. We have developed a high-throughput, easily implemented method of mapping vascular networks in mammalian tissue. By combining high resolution, rapid fluorescence blockface imaging with serial sectioning, we are able to map the vasculature of the rat liver at a resolution of 10 microns, revealing the structure above the level of the capillaries, constituting the largest vascular dataset yet assembled. We have developed algorithms for the efficient three-dimensional reconstruction from two-dimensional images, allowing skeletonization and investigation of its geometry and topology. We are able to calculate the scaling properties of these networks as well as the frequency of loops at each level. Using sophisticated topological tools, we are beginning to elucidate the principles of their organization. Ultimately, a greater understanding of vasculature is necessary for the success of efforts in synthetic and regenerative biology along with the better understanding of the growth and development of cancers.

  11. Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms

    PubMed Central

    Nyström, Alexander; Thriene, Kerstin; Mittapalli, Venugopal; Kern, Johannes S; Kiritsi, Dimitra; Dengjel, Jörn; Bruckner-Tuderman, Leena

    2015-01-01

    Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)—a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence-based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF-β activity is elevated in injured RDEB skin, we targeted TGF-β activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan- vs. vehicle-treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF-α and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-β-mediated inflammation, and matrix remodeling. Inhibition of TGF-β activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms. PMID:26194911

  12. Thermoinhibition uncovers a role for strigolactones in Arabidopsis seed germination.

    PubMed

    Toh, Shigeo; Kamiya, Yuji; Kawakami, Naoto; Nambara, Eiji; McCourt, Peter; Tsuchiya, Yuichiro

    2012-01-01

    Strigolactones are host factors that stimulate seed germination of parasitic plant species such as Striga and Orobanche. This hormone is also important in shoot branching architecture and photomorphogenic development. Strigolactone biosynthetic and signaling mutants in model systems, unlike parasitic plants, only show seed germination phenotypes under limited growth condition. To understand the roles of strigolactones in seed germination, it is necessary to develop a tractable experimental system using model plants such as Arabidopsis. Here, we report that thermoinhibition, which involves exposing seeds to high temperatures, uncovers a clear role for strigolactones in promoting Arabidopsis seed germination. Both strigolactone biosynthetic and signaling mutants showed increased sensitivity to seed thermoinhibition. The synthetic strigolactone GR24 rescued germination of thermoinbibited biosynthetic mutant seeds but not a signaling mutant. Hormone analysis revealed that strigolactones alleviate thermoinhibition by modulating levels of the two plant hormones, GA and ABA. We also showed that GR24 was able to counteract secondary dormancy in Arabidopsis ecotype Columbia (Col) and Cape Verde island (Cvi). Systematic hormone analysis of germinating Striga helmonthica seeds suggested a common mechanism between the parasitic and non-parasitic seeds with respect to how hormones regulate germination. Thus, our simple assay system using Arabidopsis thermoinhibition allows comparisons to determine similarities and differences between parasitic plants and model experimental systems for the use of strigolactones.

  13. Uncovering hidden black holes with extragalactic X-ray surveys

    NASA Astrophysics Data System (ADS)

    Hickox, Ryan C.

    2017-08-01

    Despite remarkable progress over the past decades, our picture of black hole evolution has remained incomplete due to the challenges of detecting the mysterious "elusive" AGN that are highly obscured or hidden beneath the light of their host galaxies. I will present recent studies by our group and colleagues that use X-ray and multiwavelength extragalactic surveys (particularly with Chandra, NuSTAR, and WISE) to uncover the full population of AGN. Including these elusive AGN in our picture has helped illustrate that AGN accretion is a surprisingly universal, yet highly stochastic process, and has shown that AGN obscuration is linked to processes in galaxy evolution. I will conclude by forecasting the exciting science in this area that will be enabled by future observatories including the Lynx concept X-ray mission. This work is supported by the National Science Foundation through grant numbers 1515404 and 1554584, and NASA through grant numbers NNX15AP24G, NNX15AU32H, and NNX16AN48G.

  14. Challenging muscle homeostasis uncovers novel chaperone interactions in Caenorhabditis elegans

    PubMed Central

    Frumkin, Anna; Dror, Shiran; Pokrzywa, Wojciech; Bar-Lavan, Yael; Karady, Ido; Hoppe, Thorsten; Ben-Zvi, Anat

    2014-01-01

    Proteome stability is central to cellular function and the lifespan of an organism. This is apparent in muscle cells, where incorrect folding and assembly of the sarcomere contributes to disease and aging. Apart from the myosin-assembly factor UNC-45, the complete network of chaperones involved in assembly and maintenance of muscle tissue is currently unknown. To identify additional factors required for sarcomere quality control, we performed genetic screens based on suppressed or synthetic motility defects in Caenorhabditis elegans. In addition to ethyl methyl sulfonate-based mutagenesis, we employed RNAi-mediated knockdown of candidate chaperones in unc-45 temperature-sensitive mutants and screened for impaired movement at permissive conditions. This approach confirmed the cooperation between UNC-45 and Hsp90. Moreover, the screens identified three novel co-chaperones, CeHop (STI-1), CeAha1 (C01G10.8) and Cep23 (ZC395.10), required for muscle integrity. The specific identification of Hsp90 and Hsp90 co-chaperones highlights the physiological role of Hsp90 in myosin folding. Our work thus provides a clear example of how a combination of mild perturbations to the proteostasis network can uncover specific quality control modules. PMID:25988162

  15. Uncovering space-independent communities in spatial networks

    PubMed Central

    Expert, Paul; Evans, Tim S.; Blondel, Vincent D.; Lambiotte, Renaud

    2011-01-01

    Many complex systems are organized in the form of a network embedded in space. Important examples include the physical Internet infrastucture, road networks, flight connections, brain functional networks, and social networks. The effect of space on network topology has recently come under the spotlight because of the emergence of pervasive technologies based on geolocalization, which constantly fill databases with people’s movements and thus reveal their trajectories and spatial behavior. Extracting patterns and regularities from the resulting massive amount of human mobility data requires the development of appropriate tools for uncovering information in spatially embedded networks. In contrast with most works that tend to apply standard network metrics to any type of network, we argue in this paper for a careful treatment of the constraints imposed by space on network topology. In particular, we focus on the problem of community detection and propose a modularity function adapted to spatial networks. We show that it is possible to factor out the effect of space in order to reveal more clearly hidden structural similarities between the nodes. Methods are tested on a large mobile phone network and computer-generated benchmarks where the effect of space has been incorporated. PMID:21518910

  16. Uncovering disassortativity in large scale-free networks

    NASA Astrophysics Data System (ADS)

    Litvak, Nelly; van der Hofstad, Remco

    2013-02-01

    Mixing patterns in large self-organizing networks, such as the Internet, the World Wide Web, and social and biological networks, are often characterized by degree-degree dependencies between neighboring nodes. In this paper, we propose a new way of measuring degree-degree dependencies. One of the problems with the commonly used assortativity coefficient is that in disassortative networks its magnitude decreases with the network size. We mathematically explain this phenomenon and validate the results on synthetic graphs and real-world network data. As an alternative, we suggest to use rank correlation measures such as Spearman's ρ. Our experiments convincingly show that Spearman's ρ produces consistent values in graphs of different sizes but similar structure, and it is able to reveal strong (positive or negative) dependencies in large graphs. In particular, we discover much stronger negative degree-degree dependencies in Web graphs than was previously thought. Rank correlations allow us to compare the assortativity of networks of different sizes, which is impossible with the assortativity coefficient due to its genuine dependence on the network size. We conclude that rank correlations provide a suitable and informative method for uncovering network mixing patterns.

  17. Uncovering Cryptic Parasitoid Diversity in Horismenus (Chalcidoidea, Eulophidae)

    PubMed Central

    Hansson, Christer; Alvarez, Nadir; Benrey, Betty

    2015-01-01

    Horismenus parasitoids are an abundant and understudied group of eulophid wasps found mainly in the New World. Recent surveys based on morphological analyses in Costa Rica have quadrupled the number of named taxa, with more than 400 species described so far. This recent revision suggests that there is still a vast number of unknown species to be identified. As Horismenus wasps have been widely described as parasitoids of insect pests associated with crop plants, it is of high importance to properly establish the extant diversity of the genus, in order to provide biological control practitioners with an exhaustive catalog of putative control agents. In this study, we first collected Horismenus wasps from wild Phaseolus bean seeds in Central Mexico and Arizona to assess the genetic relatedness of three morphologically distinct species with overlapping host and geographical ranges. Sequence data from two nuclear and two mitochondrial gene regions uncovered three cryptic species within each of the three focal species (i.e., H. missouriensis, H. depressus and H. butcheri). The monophyly of each cryptic group is statistically supported (except in two of them represented by one single tip in which monophyly cannot be tested). The phylogenetic reconstruction is discussed with respect to differences between gene regions as well as likely reasons for the differences in variability between species. PMID:26352700

  18. Uncovering Phosphorylation-Based Specificities through Functional Interaction Networks*

    PubMed Central

    Wagih, Omar; Sugiyama, Naoyuki; Ishihama, Yasushi; Beltrao, Pedro

    2016-01-01

    Protein kinases are an important class of enzymes involved in the phosphorylation of their targets, which regulate key cellular processes and are typically mediated by a specificity for certain residues around the target phospho-acceptor residue. While efforts have been made to identify such specificities, only ∼30% of human kinases have a significant number of known binding sites. We describe a computational method that utilizes functional interaction data and phosphorylation data to predict specificities of kinases. We applied this method to human kinases to predict substrate preferences for 57% of all known kinases and show that we are able to reconstruct well-known specificities. We used an in vitro mass spectrometry approach to validate four understudied kinases and show that predicted models closely resemble true specificities. We show that this method can be applied to different organisms and can be extended to other phospho-recognition domains. Applying this approach to different types of posttranslational modifications (PTMs) and binding domains could uncover specificities of understudied PTM recognition domains and provide significant insight into the mechanisms of signaling networks. PMID:26572964

  19. One-Pot Two-Nanoprobe Assay Uncovers Targeted Glycoprotein Biosignature.

    PubMed

    Dela Rosa, Mira Anne C; Chen, Wei-Chun; Chen, Yi-Ju; Obena, Rofeamor P; Chang, Chih-Hsiang; Capangpangan, Rey Y; Su, Tung-Hung; Chen, Chi-Ling; Chen, Pei-Jer; Chen, Yu-Ju

    2017-04-04

    We report a one-pot two-nanoprobe approach coupled to mass spectrometry for simultaneous quantification and post-translational modification (PTM) profiling of targeted protein in biofluid. Using N-glycoprotein as model, the assay employs two nanoprobes, antibody-conjugated SiO2 nanoparticles and lectin-conjugated magnetic Fe3O4 nanoparticles, to achieve target glycoprotein isolation from biofluid and subsequent glycopeptide enrichment in a single tube. As demonstrated on α-fetoprotein (AFP), a serum biomarker for hepatocellular carcinoma (HCC), the assay has high purification specificity (20 glycopeptides) with 2-fold and 10-fold superior total glycopeptide intensity compared to non-one-pot method (9 glycopeptides) or without enrichment (6 glycopeptides), respectively. By multiple reaction monitoring mass spectrometry (MRM-MS) analysis of the nonglycopeptides, the assay can quantify low abundant AFP expression (0.5 ng) with good correlation with conventional ELISA method (Pearson's r = 0.987). Furthermore, we present the first study revealing AFP glycopeptide signatures of individual HCC patients, comprised of 23 heterogeneous glycoforms of bi- and triantennary, core and terminal fucosylation, and mono- to trisialylation. In addition to 12 novel AFP glycoforms, our quantification result uncovers five abundant glycoforms in HCC, including 3 core-fucosylated (CF) forms. These identified CF forms may be evaluated in future studies as potential targets in a glycopeptide biomarker panel to further improve accuracy of conventional AFP-L3 tests. Through this one-pot assay, a comprehensive target protein profile comprised of protein expression and glycosylation pattern was achieved in simple protocol with high sensitivity, reduced analysis time, and minute starting material. This assay can be extended to other PTM biosignatures by conjugation of other affinity ligands on the nanoprobe.

  20. Uncovering steroidopathy in women with autism: a latent class analysis

    PubMed Central

    2014-01-01

    Background Prenatal exposure to increased androgens has been implicated in both polycystic ovary syndrome (PCOS) and autism spectrum conditions (ASC), suggesting that PCOS may be increased among women with ASC. One study suggested elevated steroidopathic symptoms (‘steroidopathy’) in women with ASC. As the symptoms are not independent, we conducted a latent class analysis (LCA). The objectives of the current study are: (1) to test if these findings replicate in a larger sample; and (2) to use LCA to uncover affected clusters of women with ASC. Methods We tested two groups of women, screened using the Autism Spectrum Quotient - Group 1: n = 415 women with ASC (mean age 36.39 ± 11.98 years); and Group 2: n = 415 controls (mean age 39.96 ± 11.92 years). All participants completed the Testosterone-related Medical Questionnaire online. A multiple-group LCA was used to identify differences in latent class structure between women with ASC and controls. Results There were significant differences in frequency of steroid-related conditions and symptoms between women with ASC and controls. A two-class semi-constrained model best fit the data. Based on response patterns, we identified the classes as ‘Typical’ and ‘Steroidopathic’. The prevalence of the ‘Steroidopathic’ class was significantly increased within the ASC group (ΔG2 = 15, df =1, P = 0.0001). In particular, we confirmed higher frequencies of epilepsy, amenorrhea, dysmenorrhea, severe acne, gender dysphoria, and transsexualism, and differences in sexual preference in women with ASC. Conclusions Women with ASC are at increased risk for symptoms and conditions linked to steroids. LCA revealed this steroidopathy despite the apparent underdiagnosis of PCOS. PMID:24717046

  1. 17 CFR 39.35 - Default rules and procedures for uncovered credit losses or liquidity shortfalls (recovery) for...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... for uncovered credit losses or liquidity shortfalls (recovery) for systemically important derivatives... for uncovered credit losses or liquidity shortfalls (recovery) for systemically important derivatives... stress event, so that the systemically important derivatives clearing organization or subpart...

  2. Uncovering patterns of consumers' interest for beer: A case study with craft beers.

    PubMed

    Donadini, Gianluca; Porretta, Sebastiano

    2017-01-01

    To uncover patterns of consumer interest in craft beers, the authors explored the quality perception of craft beers in a panel of industrial mass-marketed beer drinkers (n=150) and examined the differences in interest for this beer segment between men and women. The authors adopted a conjoint rating experiment in which the respondents were given forty-nine beer profiles to evaluate and were asked to score the degree of interest in each profile on a 9-point scale. Each profile was described on eight attributes (type of brewery, brewing technology, characterizing raw materials, brewhouse equipment, location of the brewery, type of container, retail price, where to buy) varied at different levels. Results showed that Italian consumers placed greatest importance on type of container (30.49%) and on brewing technology (17.64%). Characterizing raw materials (13.44%) and type of brewery (12.64) rank 3 and 4 and were placed in the same band some way below brewing technology. Retail price (9.87%) and where to buy (8.73%) were of far less importance. The least importance of all was attached to brewhouse equipment (4.44%) and to location of the brewery (2.75%). As far as utility values are concerned, the factor level glass bottle+crown cap and the factor level microfiltration are the utilities that most increased the interest of consumers. They were followed by the factor level local grains, stainless steel keg and monastery. In contrast, the factor level PET Keg, aluminum can and large scale corporate brewery showed the greatest negative impact on interest. Men and women shared similar patterns of interest. However, men placed more importance than women on retail price, location of the brewery and where to buy. Women attached more importance than men on type of container, brewing technology and type of brewer. These findings are relevant to understanding consumers'behavior in the beer market and to translating consumer needs, wants and expectations into manufacturing

  3. Applying metabolomics to uncover novel biology in ARDS.

    PubMed

    Rogers, Angela J; Matthay, Michael A

    2014-06-01

    A better understanding of the pathogenesis and the resolution of the acute respiratory distress syndrome (ARDS) is needed. Although some progress has been made with the use of protein biomarkers and candidate gene studies in understanding the pathobiology of ARDS, we propose that new studies that measure the chemical breakdown products of cellular metabolism (metabolomics) may provide new insights into ARDS, in part because metabolomics targets a later point in the genomics cascade than is possible with studies of DNA, RNA, and protein biomarkers. Technological advances have made large-scale metabolomic profiling increasingly feasible. Metabolomic approaches have already achieved novel insights in nonpulmonary diseases such as diabetes mellitus and malignancy, as well as in sepsis, a major risk factor for developing ARDS. Metabolomic profiling is a promising approach to identify novel pathways in both patients at risk for developing ARDS as well as in the early phase of established ARDS.

  4. 40 CFR 141.714 - Requirements for uncovered finished water storage facilities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... water storage facilities. 141.714 Section 141.714 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS Enhanced... water storage facilities. (a) Systems using uncovered finished water storage facilities must comply with...

  5. 40 CFR 141.714 - Requirements for uncovered finished water storage facilities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... water storage facilities. 141.714 Section 141.714 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS Enhanced... water storage facilities. (a) Systems using uncovered finished water storage facilities must comply with...

  6. 40 CFR 141.714 - Requirements for uncovered finished water storage facilities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... water storage facilities. 141.714 Section 141.714 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS Enhanced... water storage facilities. (a) Systems using uncovered finished water storage facilities must comply with...

  7. 40 CFR 141.714 - Requirements for uncovered finished water storage facilities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... water storage facilities. 141.714 Section 141.714 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS Enhanced... water storage facilities. (a) Systems using uncovered finished water storage facilities must comply with...

  8. 40 CFR 141.714 - Requirements for uncovered finished water storage facilities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... water storage facilities. 141.714 Section 141.714 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS Enhanced... water storage facilities. (a) Systems using uncovered finished water storage facilities must comply with...

  9. ChiNet uncovers rewired rewired transcription subnetworks in tolerant yeast for advanced biofuels conversion

    USDA-ARS?s Scientific Manuscript database

    Conventional differential gene expression analysis is insufficient to dissect altered gene interactions for adapted transcription regulatory networks that impact downstream molecular responses. Here we present comparative chi-square network analysis (ChiNet), a computational method, to uncover rewir...

  10. 75 FR 69055 - Uncovered Innerspring Units From the People's Republic of China: Preliminary Results of First...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-10

    ... innersprings are individual coils covered by a ``pocket'' or ``sock'' of a nonwoven synthetic material or woven material and then glued together in a linear fashion. Uncovered innersprings are classified under...

  11. 77 FR 21961 - Uncovered Innerspring Units From the People's Republic of China: Final Results and Final...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-12

    ... synthetic material or woven material and then glued together in a linear fashion. Uncovered innersprings are... this segment of the proceeding. Timely written notification of the return/destruction of APO materials...

  12. 76 FR 4290 - Uncovered Innerspring Units From the People's Republic of China: Final Results of First...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... synthetic material or woven material and then glued together in a linear fashion. Uncovered innersprings are... materials or conversion to judicial protective order is hereby requested. Failure to comply with the...

  13. Uncovering Suitable Reference Proteins for Expression Studies in Human Adipose Tissue with Relevance to Obesity

    PubMed Central

    Pérez-Pérez, Rafael; López, Juan A.; García-Santos, Eva; Camafeita, Emilio; Gómez-Serrano, María; Ortega-Delgado, Francisco J.; Ricart, Wifredo; Fernández-Real, José M.; Peral, Belén

    2012-01-01

    Background Protein expression studies based on the two major intra-abdominal human fat depots, the subcutaneous and the omental fat, can shed light into the mechanisms involved in obesity and its co-morbidities. Here we address, for the first time, the identification and validation of reference proteins for data standardization, which are essential for accurate comparison of protein levels in expression studies based on fat from obese and non-obese individuals. Methodology and Findings To uncover adipose tissue proteins equally expressed either in omental and subcutaneous fat depots (study 1) or in omental fat from non-obese and obese individuals (study 2), we have reanalyzed our previously published data based on two-dimensional fluorescence difference gel electrophoresis. Twenty-four proteins (12 in study 1 and 12 in study 2) with similar expression levels in all conditions tested were selected and identified by mass spectrometry. Immunoblotting analysis was used to confirm in adipose tissue the expression pattern of the potential reference proteins and three proteins were validated: PARK7, ENOA and FAA. Western Blot analysis was also used to test customary loading control proteins. ENOA, PARK7 and the customary loading control protein Beta-actin showed steady expression profiles in fat from non-obese and obese individuals, whilst FAA maintained steady expression levels across paired omental and subcutaneous fat samples. Conclusions ENOA, PARK7 and Beta-actin are proper reference standards in obesity studies based on omental fat, whilst FAA is the best loading control for the comparative analysis of omental and subcutaneous adipose tissues either in obese and non-obese subjects. Neither customary loading control proteins GAPDH and TBB5 nor CALX are adequate standards in differential expression studies on adipose tissue. The use of the proposed reference proteins will facilitate the adequate analysis of proteins differentially expressed in the context of obesity

  14. Uncovering phenotypes of poor-pitch singing: the Sung Performance Battery (SPB)

    PubMed Central

    Berkowska, Magdalena; Dalla Bella, Simone

    2013-01-01

    Singing is as natural as speaking for humans. Increasing evidence shows that the layman can carry a tune (e.g., when asked to sing a well-known song or to imitate single pitches, intervals and short melodies). Yet, important individual differences exist in the general population with regard to singing proficiency. Some individuals are particularly inaccurate or imprecise in producing or imitating pitch information (poor-pitch singers), thus showing a variety of singing phenotypes. Unfortunately, so far there is not a standard set of tasks for assessing singing proficiency in the general population, allowing to uncover and characterize individual profiles of poor-pitch singing. Different tasks and analysis methods are typically used in various experiments, making the comparison of the results across studies arduous. To fill this gap we propose here a new tool for assessing singing proficiency (the Sung Performance Battery, SPB). The SPB starts from the assessment of participants' vocal range followed by five tasks: (1) single-pitch matching, (2) pitch-interval matching, (3) novel-melody matching, (4) singing from memory of familiar melodies (with lyrics and on a syllable), and (5) singing of familiar melodies (with lyrics and on a syllable) at a slow tempo indicated by a metronome. Data analysis via acoustical methods provides objective measures of pitch accuracy and precision in terms of absolute and relative pitch. The SPB has been tested in a group of 50 occasional singers. The results indicate that the battery is useful for characterizing proficient singing and for detecting cases of inaccurate and/or imprecise singing. PMID:24151475

  15. Tumour-specific proline vulnerability uncovered by differential ribosome codon reading.

    PubMed

    Loayza-Puch, Fabricio; Rooijers, Koos; Buil, Levi C M; Zijlstra, Jelle; Oude Vrielink, Joachim F; Lopes, Rui; Ugalde, Alejandro Pineiro; van Breugel, Pieter; Hofland, Ingrid; Wesseling, Jelle; van Tellingen, Olaf; Bex, Axel; Agami, Reuven

    2016-02-25

    Tumour growth and metabolic adaptation may restrict the availability of certain amino acids for protein synthesis. It has recently been shown that certain types of cancer cells depend on glycine, glutamine, leucine and serine metabolism to proliferate and survive. In addition, successful therapies using L-asparaginase-induced asparagine deprivation have been developed for acute lymphoblastic leukaemia. However, a tailored detection system for measuring restrictive amino acids in each tumour is currently not available. Here we harness ribosome profiling for sensing restrictive amino acids, and develop diricore, a procedure for differential ribosome measurements of codon reading. We first demonstrate the functionality and constraints of diricore using metabolic inhibitors and nutrient deprivation assays. Notably, treatment with L-asparaginase elicited both specific diricore signals at asparagine codons and high levels of asparagine synthetase (ASNS). We then applied diricore to kidney cancer and discover signals indicating restrictive proline. As for asparagine, this observation was linked to high levels of PYCR1, a key enzyme in proline production, suggesting a compensatory mechanism allowing tumour expansion. Indeed, PYCR1 is induced by shortage of proline precursors, and its suppression attenuated kidney cancer cell proliferation when proline was limiting. High PYCR1 is frequently observed in invasive breast carcinoma. In an in vivo model system of this tumour, we also uncover signals indicating restrictive proline. We further show that CRISPR-mediated knockout of PYCR1 impedes tumorigenic growth in this system. Thus, diricore has the potential to reveal unknown amino acid deficiencies, vulnerabilities that can be used to target key metabolic pathways for cancer treatment.

  16. Deepest Image of Exploded Star Uncovers Bipolar Jets

    NASA Astrophysics Data System (ADS)

    2004-08-01

    A spectacular new image of Cassiopeia A from NASA's Chandra X-ray Observatory released today has nearly 200 times more data than the "First Light" Chandra image of this object made five years ago. The new image reveals clues that the initial explosion caused by the collapse of a massive star was far more complicated than suspected. Chandra Broadband Image of Cassiopeia A Chandra Broadband Image of Cassiopeia A "Although this young supernova remnant has been intensely studied for years, this deep observation is the most detailed ever made of the remains of an exploded star," said Martin Laming of the Naval Research Laboratory in Washington, D.C. Laming is part of a team of scientists led by Una Hwang of the Goddard Space Flight Center in Greenbelt, Maryland. "It is a gold mine of data that astronomers will be panning through for years to come." The one-million-second (about 11.5-day) observation of Cassiopeia A uncovered two large, opposed jet-like structures that extend to about 10 light years from the center of the remnant. Clouds of iron that have remained nearly pure for the approximately 340 years since the explosion were also detected. "The presence of the bipolar jets suggests that jets could be more common in relatively normal supernova explosions than supposed by astronomers," said Hwang. A paper by Hwang, Laming and others on the Cassiopeia A observation will appear in an upcoming issue of The Astrophysical Journal Letters. Chandra Enhanced Silicon Image of Cassiopeia A Chandra Enhanced Silicon Image of Cassiopeia A X-ray spectra show that the jets are rich in silicon atoms and relatively poor in iron atoms. In contrast, fingers of almost pure iron gas extend in a direction nearly perpendicular to the jets. This iron was produced in the central, hottest regions of the star. The high silicon and low iron abundances in the jets indicate that massive, matter-dominated jets were not the immediate cause of the explosion, as these should have carried out large

  17. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.

    PubMed

    Pugh, Trevor J; Weeraratne, Shyamal Dilhan; Archer, Tenley C; Pomeranz Krummel, Daniel A; Auclair, Daniel; Bochicchio, James; Carneiro, Mauricio O; Carter, Scott L; Cibulskis, Kristian; Erlich, Rachel L; Greulich, Heidi; Lawrence, Michael S; Lennon, Niall J; McKenna, Aaron; Meldrim, James; Ramos, Alex H; Ross, Michael G; Russ, Carsten; Shefler, Erica; Sivachenko, Andrey; Sogoloff, Brian; Stojanov, Petar; Tamayo, Pablo; Mesirov, Jill P; Amani, Vladimir; Teider, Natalia; Sengupta, Soma; Francois, Jessica Pierre; Northcott, Paul A; Taylor, Michael D; Yu, Furong; Crabtree, Gerald R; Kautzman, Amanda G; Gabriel, Stacey B; Getz, Gad; Jäger, Natalie; Jones, David T W; Lichter, Peter; Pfister, Stefan M; Roberts, Thomas M; Meyerson, Matthew; Pomeroy, Scott L; Cho, Yoon-Jae

    2012-08-02

    Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.

  18. Towards uncovering the roles of switchgrass peroxidases in plant processes

    PubMed Central

    Saathoff, Aaron J.; Donze, Teresa; Palmer, Nathan A.; Bradshaw, Jeff; Heng-Moss, Tiffany; Twigg, Paul; Tobias, Christian M.; Lagrimini, Mark; Sarath, Gautam

    2013-01-01

    Herbaceous perennial plants selected as potential biofuel feedstocks had been understudied at the genomic and functional genomic levels. Recent investments, primarily by the U.S. Department of Energy, have led to the development of a number of molecular resources for bioenergy grasses, such as the partially annotated genome for switchgrass (Panicum virgatum L.), and some related diploid species. In its current version, the switchgrass genome contains 65,878 gene models arising from the A and B genomes of this tetraploid grass. The availability of these gene sequences provides a framework to exploit transcriptomic data obtained from next-generation sequencing platforms to address questions of biological importance. One such question pertains to discovery of genes and proteins important for biotic and abiotic stress responses, and how these components might affect biomass quality and stress response in plants engineered for a specific end purpose. It can be expected that production of switchgrass on marginal lands will expose plants to diverse stresses, including herbivory by insects. Class III plant peroxidases have been implicated in many developmental responses such as lignification and in the adaptive responses of plants to insect feeding. Here, we have analyzed the class III peroxidases encoded by the switchgrass genome, and have mined available transcriptomic datasets to develop a first understanding of the expression profiles of the class III peroxidases in different plant tissues. Lastly, we have identified switchgrass peroxidases that appear to be orthologs of enzymes shown to play key roles in lignification and plant defense responses to hemipterans. PMID:23802005

  19. New incompatibilities uncovered using the Promega DNA IQ™ chemistry.

    PubMed

    Laurin, Nancy; Célestin, Florence; Clark, Meagan; Wilkinson, Della; Yamashita, Brian; Frégeau, Chantal

    2015-12-01

    Over the years, the Promega DNA IQ™ System was proven an effective technology for the production of clean DNA from a wide variety of casework specimens. The capture of DNA using the DNA IQ™ paramagnetic beads, however, was shown to be affected by a few specific chemicals that could be present on exhibits submitted to the laboratory. In this study, various blood and latent fingerprint enhancement reagents/methods, marker pens and adhesive tapes, applied at the crime scene or in the forensic laboratory on casework exhibits or used to collect biological material, were tested for their compatibility with the DNA IQ™ technology. Although no impact on DNA recovery was observed for most reagents, the MAGNA™ Jet Black fingerprint powder and three 3M Scotch(®) adhesive tapes were shown to severely or completely inhibit DNA binding onto the DNA IQ™ beads. The effect of MAGNA™ Jet Black on DNA recovery could be counteracted by separating the magnetic powder from the lysates by centrifugation or filtration, prior to DNA extraction. High quality STR profiles were obtained from samples subjected to MAGNA™ Jet Black suggesting it does not impact DNA integrity. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

  20. Foraminiferal Mn/Ca: Uncovering its Paleoproxy Potential

    NASA Astrophysics Data System (ADS)

    de Baere, B. J.; Klinkhammer, G. P.; Mix, A. C.

    2007-12-01

    College of Oceanic and Atmospheric Sciences, Oregon State University, Ocean Admin Bldg 104, Corvallis, OR 97331, United States of America. The flow-through time-resolved analysis (FT-TRA) technique for foraminiferal proxy work allows for the quantification of pristine biogenic elemental data, such as Mn/Ca, whilst disregarding overgrowth-induced signals. We used this state-of-the-art technique to carry out a core-top survey of the Mn/Ca ratios for surface dwelling foraminifera from across the world's oceans. This study revealed an oceanographically consistent pattern featuring order of magnitude variability, exactly what one would expect from the distribution of dissolved Mn in the mixed layer. Foraminifera at southern hemisphere sites have the lowest Mn/Ca ratios (~ 0.01) while those from the northern hemisphere are distinctly higher (~ 0.2). This pattern is strikingly similar in distribution and scale to variations in the atmospheric iron flux suggesting that foraminiferal Mn/Ca has potential as a paleoproxy for terrestrial input and productivity. The dust-dominated pattern at the surface together with the unique profile of Mn in the water column makes the Mn/Ca ratio of foraminiferal calcite a powerful new paleoproxy.

  1. Uncovering Molecular Bases Underlying Bone Morphogenetic Protein Receptor Inhibitor Selectivity

    PubMed Central

    Alsamarah, Abdelaziz; LaCuran, Alecander E.; Oelschlaeger, Peter; Hao, Jijun; Luo, Yun

    2015-01-01

    Abnormal alteration of bone morphogenetic protein (BMP) signaling is implicated in many types of diseases including cancer and heterotopic ossifications. Hence, small molecules targeting BMP type I receptors (BMPRI) to interrupt BMP signaling are believed to be an effective approach to treat these diseases. However, lack of understanding of the molecular determinants responsible for the binding selectivity of current BMP inhibitors has been a big hindrance to the development of BMP inhibitors for clinical use. To address this issue, we carried out in silico experiments to test whether computational methods can reproduce and explain the high selectivity of a small molecule BMP inhibitor DMH1 on BMPRI kinase ALK2 vs. the closely related TGF-β type I receptor kinase ALK5 and vascular endothelial growth factor receptor type 2 (VEGFR2) tyrosine kinase. We found that, while the rigid docking method used here gave nearly identical binding affinity scores among the three kinases; free energy perturbation coupled with Hamiltonian replica-exchange molecular dynamics (FEP/H-REMD) simulations reproduced the absolute binding free energies in excellent agreement with experimental data. Furthermore, the binding poses identified by FEP/H-REMD led to a quantitative analysis of physical/chemical determinants governing DMH1 selectivity. The current work illustrates that small changes in the binding site residue type (e.g. pre-hinge region in ALK2 vs. ALK5) or side chain orientation (e.g. Tyr219 in caALK2 vs. wtALK2), as well as a subtle structural modification on the ligand (e.g. DMH1 vs. LDN193189) will cause distinct binding profiles and selectivity among BMP inhibitors. Therefore, the current computational approach represents a new way of investigating BMP inhibitors. Our results provide critical information for designing exclusively selective BMP inhibitors for the development of effective pharmacotherapy for diseases caused by aberrant BMP signaling. PMID:26133550

  2. Metabolomics uncovers a link between inositol metabolism and osteosarcoma metastasis

    PubMed Central

    Ren, Ling; Hong, Ellen S.; Mendoza, Arnulfo; Issaq, Sameer; Hoang, Christine Tran; Lizardo, Michael; LeBlanc, Amy; Khanna, Chand

    2017-01-01

    Cancer development and progression are characterized by complex molecular events. The acquisition of these events is primarily believed to result from alterations in gene and protein expression/function. Recent studies have also suggested the role of metabolic alterations, or “metabolic reprogramming,” that may similarly contribute to these events. Indeed, our previous investigations in osteosarcoma (OS) identified metabolic changes uniquely linked to metastasis. Based on those findings, here we sought to build a more detailed understanding of the specific alterations in metabolites or metabolic pathways that may be responsible for the observed metastasis-associated metabolic alterations, suggested by gene expression data. This was pursued using a combination of high-throughput liquid- and gas-chromatography-based mass spectrometry (LC/MS and GC/MS) for a global metabolic profiling/subtraction of four pairs of high/low metastatic OS cell lines. By comparing the identity and level of the metabolites between high/low metastatic cells, several metabolic pathways were identified to be differentially activated, such as arginine, glutathione, inositol and fatty acid metabolic pathways. To further interrogate these results, we investigated the effects of inositol pathway dysregulation, through the exposure of metastatic OS cells to IP6 (inositol hexaphosphate). Although IP6 exposures had modest to minimal effects on cell proliferation, we observed reduced cellular glycolysis, down-regulation of PI3K/Akt signaling and suppression of OS metastatic progression. Collectively these data supported further investigation of metabolic sensitivities as anti-metastatic strategies in a clinical setting as well as investigation of altered metabolomics associated with metastatic progression. PMID:28404949

  3. Uncovering the historic environmental hazards of urban brownfields.

    PubMed

    Litt, Jill S; Burke, Thomas A

    2002-12-01

    In Baltimore, over 1,000 vacant industrial sites persist across its urban landscape, yet little is known about the potential environmental health risks that may undermine future cleanup and redevelopment activities and the health of those in communities near these sites. This study examined the characteristics of urban brownfield properties in southeast Baltimore, Maryland, and screened sites for their potential environmental hazards. In addition, demographic and health data were evaluated to profile the social and health status of those in brownfield communities. The results show that brownfields in southeast Baltimore represent a range of historic operations, including metal smelting, oil refining, warehousing, and transportation, as well as paints, plastics, and metals manufacturing. The screening method identified a range of substances associated with these properties, including heavy metals, chlorinated hydrocarbons, and polycyclic aromatic hydrocarbons, all of which are suspected or recognized toxicants, and many of which are persistent in the environment. Spatially, these sites are concentrated in white, working class neighborhoods in which poverty levels exceed and educational attainment lags behind state and national averages. Moreover, these sites are concentrated in communities in which excess mortality rates due to respiratory disease, cancer, and heart disease exist when compared to the city, state, and national averages. This investigation demonstrated the usefulness of historic archives, real estate records, regulatory files, and national hazard-tracking systems based on standard industrial classification (SIC) to screen brownfield properties for their hazard potential. This analysis provides the foundation for further site monitoring and testing, cleanup and redevelopment priority setting, risk management strategies, and neighborhood planning, and it illustrates the need for increased health surveillance and disease prevention strategies in affected

  4. Lipid Profile

    MedlinePlus

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Lipid Profile Share this page: Was this page helpful? Also ... as: Lipid Panel; Coronary Risk Panel Formal name: Lipid Profile Related tests: Cholesterol ; HDL Cholesterol ; LDL Cholesterol ; Triglycerides ; ...

  5. State Profiles.

    ERIC Educational Resources Information Center

    State-Federal Information Clearinghouse for Exceptional Children, Reston, VA.

    State-by-state public policy profiles are provided by the Council for Exceptional Children's State-Federal Information Clearinghouse. These profiles summarize the present legal base for the delivery of educational services to handicapped children in the United States. Included in each profile is information from various avenues used to establish…

  6. Uncovering Adiponectin Replenishing Property of Sujiaonori Algal Biomaterial in Humans.

    PubMed

    Ngatu, Nlandu Roger; Ikeda, Mitsunori; Watanabe, Hiroyuki; Tanaka, Mamoru; Inoue, Masataka; Kanbara, Sakiko; Nojima, Sayumi

    2017-02-08

    The replenishment of adiponectin-an adipocyte-derived hormone with salutary health effects-has recently been proposed as a new approach to treat hypertension, also ameliorate cardiovascular and metabolic risks. We conducted a prospective placebo-controlled, non-randomized and investigator-blinded dietary intervention study to evaluate the health effects of dietary intake of Sujiaonori (Ulva/Enteromorpha prolifera Müller) algal biomaterial (SBM), especially on adiponectin production, blood pressure (BP), and body mass index (BMI) in human subjects. Participants (N = 32) were divided into two equally sized groups (n = 16 for each group): SBM group (subjects supplemented with 3 g SBM powder twice a day during meal) and the control group (subjects who took 3 g of a supplement made of 70% corn starch powder and 30% spinach twice a day) for four weeks. Two health survey questionnaires (dietary and current health questionnaires) were completed anonymously, saliva sampling was done for adiponectin measurement by ELISA, and blood pressure (BP) and anthropometric parameters were measured at baseline and four weeks later. Student paired t-test was performed to compare baseline and post-intervention data on outcome variables between the two study groups. Results showed a 2.24-fold increase in adiponectin level in SBM group (2.81 and 6.26 ng/mL at baseline and at the end of study, respectively) (p < 0.01); whereas no significant change was observed in controls (3.58 and 3.51 ng/mL, respectively) (p > 0.05). In SBM subjects, an improvement of BP profile was noted with a significant decrease in systolic BP (p < 0.01). A positive correlation was found between SBM supplementation and adiponectin level, whereas an inverse correlation was noted between SBM supplementation and blood pressure, and also BMI. These findings suggest that SBM-increased adiponectin level and improved BP in a sample of Japanese young adults, and has the potential to improve blood pressure in humans.

  7. Uncovering Adiponectin Replenishing Property of Sujiaonori Algal Biomaterial in Humans

    PubMed Central

    Ngatu, Nlandu Roger; Ikeda, Mitsunori; Watanabe, Hiroyuki; Tanaka, Mamoru; Inoue, Masataka; Kanbara, Sakiko; Nojima, Sayumi

    2017-01-01

    The replenishment of adiponectin—an adipocyte-derived hormone with salutary health effects—has recently been proposed as a new approach to treat hypertension, also ameliorate cardiovascular and metabolic risks. We conducted a prospective placebo-controlled, non-randomized and investigator-blinded dietary intervention study to evaluate the health effects of dietary intake of Sujiaonori (Ulva/Enteromorpha prolifera Müller) algal biomaterial (SBM), especially on adiponectin production, blood pressure (BP), and body mass index (BMI) in human subjects. Participants (N = 32) were divided into two equally sized groups (n = 16 for each group): SBM group (subjects supplemented with 3 g SBM powder twice a day during meal) and the control group (subjects who took 3 g of a supplement made of 70% corn starch powder and 30% spinach twice a day) for four weeks. Two health survey questionnaires (dietary and current health questionnaires) were completed anonymously, saliva sampling was done for adiponectin measurement by ELISA, and blood pressure (BP) and anthropometric parameters were measured at baseline and four weeks later. Student paired t-test was performed to compare baseline and post-intervention data on outcome variables between the two study groups. Results showed a 2.24-fold increase in adiponectin level in SBM group (2.81 and 6.26 ng/mL at baseline and at the end of study, respectively) (p < 0.01); whereas no significant change was observed in controls (3.58 and 3.51 ng/mL, respectively) (p > 0.05). In SBM subjects, an improvement of BP profile was noted with a significant decrease in systolic BP (p < 0.01). A positive correlation was found between SBM supplementation and adiponectin level, whereas an inverse correlation was noted between SBM supplementation and blood pressure, and also BMI. These findings suggest that SBM-increased adiponectin level and improved BP in a sample of Japanese young adults, and has the potential to improve blood pressure in humans

  8. Unique small RNA signatures uncovered in the tammar wallaby genome

    PubMed Central

    2012-01-01

    small RNAs are derived largely from centromere-enriched retroelements, including a novel SINE. Conclusions This study encompasses the first analyses of the major classes of small RNAs for the newly completed tammar genome, validates preliminary annotations using deep sequencing and computational approaches, and provides a foundation for future work on tammar-specific as well as conserved, but previously unknown small RNA progenitors and targets identified herein. The characterization of new miRNA target genes and a unique profile for crasiRNAs has allowed for insight into multiple RNA mediated processes in the tammar, including gene regulation, species incompatibilities, centromere and chromosome function. PMID:23075437

  9. Community Mapping in Action: Uncovering Resources and Assets for Young Children and Their Families

    ERIC Educational Resources Information Center

    Ordonez-Jasis, Rosario; Myck-Wayne, Janice

    2012-01-01

    Community mapping is a promising practice that can assist early intervention/early childhood special education (EI/ECSE) professionals uncover the depth and diversity of community needs, resources, and learning opportunities, in the neighborhoods surrounding their schools. Community mapping is an inquiry-based method that situates learning in the…

  10. Using Text Mining to Uncover Students' Technology-Related Problems in Live Video Streaming

    ERIC Educational Resources Information Center

    Abdous, M'hammed; He, Wu

    2011-01-01

    Because of their capacity to sift through large amounts of data, text mining and data mining are enabling higher education institutions to reveal valuable patterns in students' learning behaviours without having to resort to traditional survey methods. In an effort to uncover live video streaming (LVS) students' technology related-problems and to…

  11. Uncovering the Motivating Factors behind Writing in English in en EFL Context

    ERIC Educational Resources Information Center

    Büyükyavuz, Oya; Çakir, Ismail

    2014-01-01

    Writing in a language, whether the target or native, is regarded as a complex activity operating on multiple cognitive levels. This study aimed to uncover the factors which motivate teacher trainees of English to write in English in an EFL context. The study also investigated the differences in the ways teacher trainees are motivated in terms of…

  12. Using Text Mining to Uncover Students' Technology-Related Problems in Live Video Streaming

    ERIC Educational Resources Information Center

    Abdous, M'hammed; He, Wu

    2011-01-01

    Because of their capacity to sift through large amounts of data, text mining and data mining are enabling higher education institutions to reveal valuable patterns in students' learning behaviours without having to resort to traditional survey methods. In an effort to uncover live video streaming (LVS) students' technology related-problems and to…

  13. Uncovering Pre-Service Teacher Beliefs about Young Children: A Photographic Elicitation Methodology

    ERIC Educational Resources Information Center

    Stockall, Nancy; Davis, Sara

    2011-01-01

    This illustrative paper provides an introduction to using mixed qualitative methods of photo-elicitation, face to face interviews and semiotic analysis to uncover pre-service students' beliefs about young children. The researchers share their experience on conducting a study using photo-elicitation and engaging pre-service teachers in a discussion…

  14. Uncovering Influence through Social Network Analysis: The Role of Schools in Education for Sustainable Development

    ERIC Educational Resources Information Center

    Kolleck, Nina

    2016-01-01

    This paper examines the implementation of Education for Sustainable Development (ESD) in Germany and explores the possibilities of Social Network Analysis (SNA) for uncovering influential actors in educational policy innovation processes. From the theoretical perspective, an actor's influence is inferred from its relative position within…

  15. Cross-Species Network Analysis Uncovers Conserved Nitrogen-Regulated Network Modules in Rice1[OPEN

    PubMed Central

    Obertello, Mariana; Shrivastava, Stuti; Katari, Manpreet S.; Coruzzi, Gloria M.

    2015-01-01

    In this study, we used a cross-species network approach to uncover nitrogen (N)-regulated network modules conserved across a model and a crop species. By translating gene network knowledge from the data-rich model Arabidopsis (Arabidopsis thaliana) to a crop, rice (Oryza sativa), we identified evolutionarily conserved N-regulatory modules as targets for translational studies to improve N use efficiency in transgenic plants. To uncover such conserved N-regulatory network modules, we first generated an N-regulatory network based solely on rice transcriptome and gene interaction data. Next, we enhanced the network knowledge in the rice N-regulatory network using transcriptome and gene interaction data from Arabidopsis and new data from Arabidopsis and rice plants exposed to the same N treatment conditions. This cross-species network analysis uncovered a set of N-regulated transcription factors (TFs) predicted to target the same genes and network modules in both species. Supernode analysis of the TFs and their targets in these conserved network modules uncovered genes directly related to N use (e.g. N assimilation) and to other shared biological processes indirectly related to N. This cross-species network approach was validated with members of two TF families in the supernode network, BASIC-LEUCINE ZIPPER TRANSCRIPTION FACTOR1-TGA and HYPERSENSITIVITY TO LOW PI-ELICITED PRIMARY ROOT SHORTENING1 (HRS1)/HRS1 Homolog family, which have recently been experimentally validated to mediate the N response in Arabidopsis. PMID:26045464

  16. 16 CFR 1610.34 - Only uncovered or exposed parts of wearing apparel to be tested.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... procedures set forth in § 1610.6. (b) If the outer layer of plastic film or plastic-coated fabric of a...—Standard for the Flammability of Vinyl Plastic Film. If the outer layer adheres to all or a portion of one... characteristics of the film or coating, the uncovered or exposed layer shall be tested in accordance with...

  17. 16 CFR 1610.34 - Only uncovered or exposed parts of wearing apparel to be tested.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... procedures set forth in § 1610.6. (b) If the outer layer of plastic film or plastic-coated fabric of a...—Standard for the Flammability of Vinyl Plastic Film. If the outer layer adheres to all or a portion of one... characteristics of the film or coating, the uncovered or exposed layer shall be tested in accordance with...

  18. Uncovering the Best Skill Multimap by Constraining the Error Probabilities of the Gain-Loss Model

    ERIC Educational Resources Information Center

    Anselmi, Pasquale; Robusto, Egidio; Stefanutti, Luca

    2012-01-01

    The Gain-Loss model is a probabilistic skill multimap model for assessing learning processes. In practical applications, more than one skill multimap could be plausible, while none corresponds to the true one. The article investigates whether constraining the error probabilities is a way of uncovering the best skill assignment among a number of…

  19. Uncovering Influence through Social Network Analysis: The Role of Schools in Education for Sustainable Development

    ERIC Educational Resources Information Center

    Kolleck, Nina

    2016-01-01

    This paper examines the implementation of Education for Sustainable Development (ESD) in Germany and explores the possibilities of Social Network Analysis (SNA) for uncovering influential actors in educational policy innovation processes. From the theoretical perspective, an actor's influence is inferred from its relative position within…

  20. The Conditions for the Perception of the Covering and Uncovering of a Line

    ERIC Educational Resources Information Center

    Rock, Irvin; Gilchrist, Alan

    1975-01-01

    This paper was concerned with the perceptions that can result from a change in the length of the retinal image of a line. Conditions that lead either to the perception of a line of changing length and the perception of a line of constant length undergoing covering or uncovering by another object were examined. (Author/RK)

  1. Learning "through" Computers: Uncovering Students' Thought Processes while Solving Physics Problems

    ERIC Educational Resources Information Center

    Soong, Benson

    2008-01-01

    This paper presents a study that illustrates how the author and an in service secondary school teacher used basic synchronous computer mediated communications (CMC) technology to help them uncover students' physics preconceptions and thought processes (including their misconceptions and misunderstandings) in a real class setting. In this paper, I…

  2. Archaeology for Kids: Uncovering the Mysteries of Our Past--25 Activities.

    ERIC Educational Resources Information Center

    Panchyk, Richard

    This book provides 25 activities giving children hands-on archeological experience, teaches how archaeologists work, and shows what they have discovered from digging up prehistoric bones between the time when dinosaurs roamed the earth to the uncovering of modern artifacts at a contemporary office building. Ancient civilizations come to life as…

  3. Uncovering the Best Skill Multimap by Constraining the Error Probabilities of the Gain-Loss Model

    ERIC Educational Resources Information Center

    Anselmi, Pasquale; Robusto, Egidio; Stefanutti, Luca

    2012-01-01

    The Gain-Loss model is a probabilistic skill multimap model for assessing learning processes. In practical applications, more than one skill multimap could be plausible, while none corresponds to the true one. The article investigates whether constraining the error probabilities is a way of uncovering the best skill assignment among a number of…

  4. Archaeology for Kids: Uncovering the Mysteries of Our Past--25 Activities.

    ERIC Educational Resources Information Center

    Panchyk, Richard

    This book provides 25 activities giving children hands-on archeological experience, teaches how archaeologists work, and shows what they have discovered from digging up prehistoric bones between the time when dinosaurs roamed the earth to the uncovering of modern artifacts at a contemporary office building. Ancient civilizations come to life as…

  5. Community Mapping in Action: Uncovering Resources and Assets for Young Children and Their Families

    ERIC Educational Resources Information Center

    Ordonez-Jasis, Rosario; Myck-Wayne, Janice

    2012-01-01

    Community mapping is a promising practice that can assist early intervention/early childhood special education (EI/ECSE) professionals uncover the depth and diversity of community needs, resources, and learning opportunities, in the neighborhoods surrounding their schools. Community mapping is an inquiry-based method that situates learning in the…

  6. Uncovering Pre-Service Teacher Beliefs about Young Children: A Photographic Elicitation Methodology

    ERIC Educational Resources Information Center

    Stockall, Nancy; Davis, Sara

    2011-01-01

    This illustrative paper provides an introduction to using mixed qualitative methods of photo-elicitation, face to face interviews and semiotic analysis to uncover pre-service students' beliefs about young children. The researchers share their experience on conducting a study using photo-elicitation and engaging pre-service teachers in a discussion…

  7. Comparison of covered and uncovered self-expandable stents in the treatment of malignant biliary obstruction.

    PubMed

    Flores Carmona, Diana Yamel; Alonso Lárraga, Juan Octavio; Hernández Guerrero, Angélica; Ramírez Solís, Mauro Eduardo

    2016-05-01

    Drainage with metallic stents is the treatment of choice in malignant obstructive jaundice. Technical and clinical success with metallic stents is obtained in over 90% and 80% of cases, respectively. There are self-expandable metallic stents designed to increase permeability. The aim of this study was to describe the results obtained with totally covered self-expandable and uncovered self-expandable metallic stents in the palliative treatment of malignant biliary obstruction. Sixty eight patients with malignant obstructive jaundice secondary to pancreatobiliary or metastatic disease not amenable to surgery were retrospectively included. Two groups were created: group A (covered self-expandable metallic stents) (n = 22) and group B (uncovered self-expandable metallic stents) (n = 46). Serum total bilirubin, direct bilirubin, alkaline phosphatase and gamma glutamyl transferase levels decreased in both groups and no statistically significant difference was detected (p = 0.800, p = 0.190, p = 0.743, p = 0.521). Migration was greater with covered stents but it was not statistically significant either (p = 0.101). Obstruction was greater in the group with uncovered stents but it was not statistically significant either (p = 0.476). There are no differences when using covered self-expandable stents or uncovered self-expandable stents in terms of technical and clinical success or complications in the palliative treatment of malignant obstructive jaundice.

  8. Feminist Approaches to Triangulation: Uncovering Subjugated Knowledge and Fostering Social Change in Mixed Methods Research

    ERIC Educational Resources Information Center

    Hesse-Biber, Sharlene

    2012-01-01

    This article explores the deployment of triangulation in the service of uncovering subjugated knowledge and promoting social change for women and other oppressed groups. Feminist approaches to mixed methods praxis create a tight link between the research problem and the research design. An analysis of selected case studies of feminist praxis…

  9. Uncovering One Trilingual Child's Multi-Literacies Development across Informal and Formal Learning Contexts

    ERIC Educational Resources Information Center

    Kim, Mi Song

    2016-01-01

    Due to globalisation and rapid technological change, today's educators need to help students develop multi-literacy competencies to enable them to function successfully in our culturally and linguistically diverse (CLD) and increasingly connected global and digital society. A qualitative, longitudinal case study attempted to uncover the…

  10. Feminist Approaches to Triangulation: Uncovering Subjugated Knowledge and Fostering Social Change in Mixed Methods Research

    ERIC Educational Resources Information Center

    Hesse-Biber, Sharlene

    2012-01-01

    This article explores the deployment of triangulation in the service of uncovering subjugated knowledge and promoting social change for women and other oppressed groups. Feminist approaches to mixed methods praxis create a tight link between the research problem and the research design. An analysis of selected case studies of feminist praxis…

  11. Thymus cDNA library survey uncovers novel features of immune molecules in Chinese giant salamander Andrias davidianus.

    PubMed

    Zhu, Rong; Chen, Zhong-Yuan; Wang, Jun; Yuan, Jiang-Di; Liao, Xiang-Yong; Gui, Jian-Fang; Zhang, Qi-Ya

    2014-10-01

    A ranavirus-induced thymus cDNA library was constructed from Chinese giant salamander, the largest extant amphibian species. Among the 137 putative immune-related genes derived from this library, these molecules received particular focus: immunoglobulin heavy chains (IgM, IgD, and IgY), IFN-inducible protein 6 (IFI6), and T cell receptor beta chain (TCRβ). Several unusual features were uncovered: IgD displays a structure pattern distinct from those described for other amphibians by having only four constant domains plus a hinge region. A unique IgY form (IgY(ΔFc)), previously undescribed in amphibians, is present in serum. Alternative splicing is observed to generate IgH diversification. IFI6 is newly-identified in amphibians, which occurs in two forms divergent in subcelluar distribution and antiviral activity. TCRβ immunoscope profile follows the typical vertebrate pattern, implying a polyclonal T cell repertoire. Collectively, the pioneering survey of ranavirus-induced thymus cDNA library from Chinese giant salamander reveals immune components and characteristics in this primitive amphibian.

  12. 78 FR 65711 - Uncovered Innerspring Units From China, South Africa, and Vietnam Institution of Five-Year Reviews

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-01

    ... COMMISSION Uncovered Innerspring Units From China, South Africa, and Vietnam Institution of Five-Year Reviews... innerspring units from China, South Africa, and Vietnam would be likely to lead to continuation or recurrence... orders on imports of uncovered innerspring units from South Africa and Vietnam (73 FR 75390 and...

  13. Metabolomic profiling of a modified alcohol liquid diet model for liver injury in the mouse uncovers new markers of disease

    SciTech Connect

    Bradford, Blair U.; O'Connell, Thomas M.; Han, Jun; Kosyk, Oksana; Shymonyak, Svitlana; Ross, Pamela K.; Winnike, Jason; Kono, Hiroshi; Rusyn, Ivan

    2008-10-15

    Metabolomic evaluation of urine and liver was conducted to assess the biochemical changes that occur as a result of alcohol-induced liver injury. Male C57BL/6J mice were fed an isocaloric control- or alcohol-containing liquid diet with 35% of calories from corn oil, 18% protein and 47% carbohydrate/alcohol for up to 36 days ad libitum. Alcohol treatment was initiated at 7 g/kg/day and gradually reached a final dose of 21 g/kg/day. Urine samples were collected at 22, 30 and 36 days and, in additional treatment groups, liver and serum samples were harvested at 28 days. Steatohepatitis was induced in the alcohol-fed group since a 5-fold increase in serum alanine aminotransferase activity, a 6-fold increase in liver injury score (necrosis, inflammation and steatosis) and an increase in lipid peroxidation in liver were observed. Liver and urine samples were analyzed by nuclear magnetic resonance spectroscopy and electrospray infusion/Fourier transform ion cyclotron resonance-mass spectrometry. In livers of alcohol-treated mice the following changes were noted. Hypoxia and glycolysis were activated as evidenced by elevated levels of alanine and lactate. Tyrosine, which is required for L-DOPA and dopamine as well as thyroid hormones, was elevated possibly reflecting alterations of basal metabolism by alcohol. A 4-fold increase in the prostacyclin inhibitor 7,10,13,16-docosatetraenoic acid, a molecule important for regulation of platelet formation and blood clotting, may explain why chronic drinking causes serious bleeding problems. Metabolomic analysis of the urine revealed that alcohol treatment leads to decreased excretion of taurine, a metabolite of glutathione, and an increase in lactate, n-acetylglutamine and n-acetylglycine. Changes in the latter two metabolites suggest an inhibition of the kidney enzyme aminoacylase I and may be useful as markers for alcohol consumption.

  14. Development stage-specific proteomic profiling uncovers small, lineage specific proteins most abundant in the Aspergillus Fumigatus conidial proteome.

    PubMed

    Suh, Moo-Jin; Fedorova, Natalie D; Cagas, Steven E; Hastings, Susan; Fleischmann, Robert D; Peterson, Scott N; Perlin, David S; Nierman, William C; Pieper, Rembert; Momany, Michelle

    2012-04-30

    The pathogenic mold Aspergillus fumigatus is the most frequent infectious cause of death in severely immunocompromised individuals such as leukemia and bone marrow transplant patients. Germination of inhaled conidia (asexual spores) in the host is critical for the initiation of infection, but little is known about the underlying mechanisms of this process. To gain insights into early germination events and facilitate the identification of potential stage-specific biomarkers and vaccine candidates, we have used quantitative shotgun proteomics to elucidate patterns of protein abundance changes during early fungal development. Four different stages were examined: dormant conidia, isotropically expanding conidia, hyphae in which germ tube emergence has just begun, and pre-septation hyphae. To enrich for glycan-linked cell wall proteins we used an alkaline cell extraction method. Shotgun proteomic resulted in the identification of 375 unique gene products with high confidence, with no evidence for enrichment of cell wall-immobilized and secreted proteins. The most interesting discovery was the identification of 52 proteins enriched in dormant conidia including 28 proteins that have never been detected in the A. fumigatus conidial proteome such as signaling protein Pil1, chaperones BipA and calnexin, and transcription factor HapB. Additionally we found many small, Aspergillus specific proteins of unknown function including 17 hypothetical proteins. Thus, the most abundant protein, Grg1 (AFUA_5G14210), was also one of the smallest proteins detected in this study (M.W. 7,367). Among previously characterized proteins were melanin pigment and pseurotin A biosynthesis enzymes, histones H3 and H4.1, and other proteins involved in conidiation and response to oxidative or hypoxic stress. In contrast, expanding conidia, hyphae with early germ tubes, and pre-septation hyphae samples were enriched for proteins responsible for housekeeping functions, particularly translation, respiratory metabolism, amino acid and carbohydrate biosynthesis, and the tricarboxylic acid cycle. The observed temporal expression patterns suggest that the A. fumigatus conidia are dominated by small, lineage-specific proteins. Some of them may play key roles in host-pathogen interactions, signal transduction during conidial germination, or survival in hostile environments.

  15. Transcriptome Profiling of Tomato Uncovers an Involvement of Cytochrome P450s and Peroxidases in Stigma Color Formation.

    PubMed

    Zhang, Yan; Zhao, Guiye; Li, Yushun; Zhang, Jie; Shi, Meijing; Muhammad, Tayeb; Liang, Yan

    2017-01-01

    Stigma is a crucial structure of female reproductive organ in plants. Stigma color is usually regarded as an important trait in variety identification in some species, but the molecular mechanism of stigma color formation remains elusive. Here, we characterized a tomato mutant, yellow stigma (ys), that shows yellow rather than typical green color in the stigma. Analysis of pigment contents revealed that the level of flavonoid naringenin chalcone was increased in the ys stigma, possibly as a result of higher accumulation of p-coumaric acid, suggesting that naringenin chalcone might play a vital role in yellow color control in tomato stigma. To understand the genes and gene networks that regulate tomato stigma color, RNA-sequencing (RNA-Seq) analyses were performed to compare the transcriptomes of stigmas between ys mutant and wild-type (WT). We obtained 507 differentially expressed genes, in which, 84 and 423 genes were significantly up-regulated and down-regulated in the ys mutant, respectively. Two cytochrome P450 genes, SlC3H1 and SlC3H2 which encode p-coumarate 3-hydroxylases, and six peroxidase genes were identified to be dramatically inhibited in the yellow stigma. Further bioinformatic and biochemical analyses implied that the repression of the two SlC3Hs and six PODs may indirectly lead to higher naringenin chalcone level through inhibiting lignin biosynthesis, thereby contributing to yellow coloration in tomato stigma. Thus, our data suggest that two SlC3Hs and six PODs are involved in yellow stigma formation. This study provides valuable information for dissecting the molecular mechanism of stigma color control in tomato. Statement: This study reveals that two cytochrome P450s (SlC3H1 and SlC3H2) and six peroxidases potentially regulate the yellow stigma formation by indirectly enhancing biosynthesis of yellow-colored naringenin chalcone in the stigma of tomato.

  16. Metabolomic profiling of a modified alcohol liquid diet model for liver injury in the mouse uncovers new markers of disease

    PubMed Central

    Bradford, Blair U.; O’Connell, Thomas M.; Han, Jun; Kosyk, Oksana; Shymonyak, Svitlana; Ross, Pamela K.; Winnike, Jason; Kono, Hiroshi; Rusyn, Ivan

    2008-01-01

    Metabolomic evaluation of urine and liver was conducted to assess the biochemical changes that occur as a result of alcohol-induced liver injury. Male C57BL/6J mice were fed an isocaloric control-or alcohol-containing liquid diet with 35% of calories from corn oil, 18% protein and 47% carbohydrate/alcohol for up to 36 days ad libitum. Alcohol treatment was initiated at 7 g/kg/day and gradually reached a final dose of 21 g/kg/day. Urine samples were collected at 22, 30 and 36 days and in additional treatment groups, liver and serum samples were harvested at 28 days. Steatohepatitis was induced in the alcohol-fed group since a 5-fold increase in serum alanine aminotransferase activity, a 6-fold increase in liver injury score (necrosis, inflammation and steatosis) and an increase in lipid peroxidation in liver were observed. Liver and urine samples were analyzed by nuclear magnetic resonance spectroscopy and electrospray infusion/Fourier transform ion cyclotron resonance-mass spectrometry. In livers of alcohol-treated mice the following changes were noted. Hypoxia and glycolysis were activated as evidenced by elevated levels of alanine and lactate. Tyrosine, which is required for L-DOPA and dopamine as well as thyroid hormones, was elevated possibly reflecting alterations of basal metabolism by alcohol. A 4-fold increase in the prostacyclin inhibitor 7,10,13,16-docosatetraenoic acid, a molecule important for regulation of platelet formation and blood clotting, may explain why chronic drinking causes serious bleeding problems. Metabolomic analysis of the urine revealed that alcohol treatment leads to decreased excretion of taurine, a metabolite of glutathione, and an increase in lactate, n-acetylglutamine and n-acetylglycine. Changes in the latter two metabolites suggest an inhibition of the kidney enzyme aminoacylase I and may be useful as markers for alcohol consumption. PMID:18674555

  17. Integrating miRNA and mRNA Expression Profiling Uncovers miRNAs Underlying Fat Deposition in Sheep

    PubMed Central

    Zhou, Guangxian; Wang, Xiaolong; Yuan, Chao; Kang, Danju; Xu, Xiaochun; Zhou, Jiping; Geng, Rongqing; Yang, Yuxin; Yang, Zhaoxia

    2017-01-01

    MicroRNAs (miRNAs) are endogenous, noncoding RNAs that regulate various biological processes including adipogenesis and fat metabolism. Here, we adopted a deep sequencing approach to determine the identity and abundance of miRNAs involved in fat deposition in adipose tissues from fat-tailed (Kazakhstan sheep, KS) and thin-tailed (Tibetan sheep, TS) sheep breeds. By comparing HiSeq data of these two breeds, 539 miRNAs were shared in both breeds, whereas 179 and 97 miRNAs were uniquely expressed in KS and TS, respectively. We also identified 35 miRNAs that are considered to be putative novel miRNAs. The integration of miRNA-mRNA analysis revealed that miRNA-associated targets were mainly involved in the gene ontology (GO) biological processes concerning cellular process and metabolic process, and miRNAs play critical roles in fat deposition through their ability to regulate fundamental pathways. These pathways included the MAPK signaling pathway, FoxO and Wnt signaling pathway, and focal adhesion. Taken together, our results define miRNA expression signatures that may contribute to fat deposition and lipid metabolism in sheep. PMID:28293627

  18. Integrating miRNA and mRNA Expression Profiling Uncovers miRNAs Underlying Fat Deposition in Sheep.

    PubMed

    Zhou, Guangxian; Wang, Xiaolong; Yuan, Chao; Kang, Danju; Xu, Xiaochun; Zhou, Jiping; Geng, Rongqing; Yang, Yuxin; Yang, Zhaoxia; Chen, Yulin

    2017-01-01

    MicroRNAs (miRNAs) are endogenous, noncoding RNAs that regulate various biological processes including adipogenesis and fat metabolism. Here, we adopted a deep sequencing approach to determine the identity and abundance of miRNAs involved in fat deposition in adipose tissues from fat-tailed (Kazakhstan sheep, KS) and thin-tailed (Tibetan sheep, TS) sheep breeds. By comparing HiSeq data of these two breeds, 539 miRNAs were shared in both breeds, whereas 179 and 97 miRNAs were uniquely expressed in KS and TS, respectively. We also identified 35 miRNAs that are considered to be putative novel miRNAs. The integration of miRNA-mRNA analysis revealed that miRNA-associated targets were mainly involved in the gene ontology (GO) biological processes concerning cellular process and metabolic process, and miRNAs play critical roles in fat deposition through their ability to regulate fundamental pathways. These pathways included the MAPK signaling pathway, FoxO and Wnt signaling pathway, and focal adhesion. Taken together, our results define miRNA expression signatures that may contribute to fat deposition and lipid metabolism in sheep.

  19. Complementary Proteomic and Biochemical Analysis of Peptidases in Lobster Gastric Juice Uncovers the Functional Role of Individual Enzymes in Food Digestion.

    PubMed

    Bibo-Verdugo, Betsaida; O'Donoghue, Anthony J; Rojo-Arreola, Liliana; Craik, Charles S; García-Carreño, Fernando

    2016-04-01

    Crustaceans are a diverse group, distributed in widely variable environmental conditions for which they show an equally extensive range of biochemical adaptations. Some digestive enzymes have been studied by purification/characterization approaches. However, global analysis is crucial to understand how digestive enzymes interplay. Here, we present the first proteomic analysis of the digestive fluid from a crustacean (Homarus americanus) and identify glycosidases and peptidases as the most abundant classes of hydrolytic enzymes. The digestion pathway of complex carbohydrates was predicted by comparing the lobster enzymes to similar enzymes from other crustaceans. A novel and unbiased substrate profiling approach was used to uncover the global proteolytic specificity of gastric juice and determine the contribution of cysteine and aspartic acid peptidases. These enzymes were separated by gel electrophoresis and their individual substrate specificities uncovered from the resulting gel bands. This new technique is called zymoMSP. Each cysteine peptidase cleaves a set of unique peptide bonds and the S2 pocket determines their substrate specificity. Finally, affinity chromatography was used to enrich for a digestive cathepsin D1 to compare its substrate specificity and cold-adapted enzymatic properties to mammalian enzymes. We conclude that the H. americanus digestive peptidases may have useful therapeutic applications, due to their cold-adaptation properties and ability to hydrolyze collagen.

  20. Methods in DNA methylation profiling

    PubMed Central

    Zuo, Tao; Tycko, Benjamin; Liu, Ta-Ming; Lin, Huey-Jen L; Huang, Tim H-M

    2010-01-01

    Metastable and somatically heritable patterns of DNA methylation provide an important level of genomic regulation. In this article, we review methods for analyzing these genome-wide epigenetic patterns and offer a perspective on the ever-expanding literature, which we hope will be useful for investigators who are new to this area. The historical aspects that we cover will be helpful in interpreting this literature and we hope that our discussion of the newest analytical methods will stimulate future progress. We emphasize that no single approach can provide a complete view of the overall methylome, and that combinations of several modalities applied to the same sample set will give the clearest picture. Given the unexpected epigenomic patterns and new biological principles, as well as new disease markers, that have been uncovered in recent studies, it is likely that important discoveries will continue to be made using genome-wide DNA methylation profiling. PMID:20526417

  1. Methods in DNA methylation profiling.

    PubMed

    Zuo, Tao; Tycko, Benjamin; Liu, Ta-Ming; Lin, Juey-Jen L; Huang, Tim H-M

    2009-12-01

    Metastable and somatically heritable patterns of DNA methylation provide an important level of genomic regulation. In this article, we review methods for analyzing these genome-wide epigenetic patterns and offer a perspective on the ever-expanding literature, which we hope will be useful for investigators who are new to this area. The historical aspects that we cover will be helpful in interpreting this literature and we hope that our discussion of the newest analytical methods will stimulate future progress. We emphasize that no single approach can provide a complete view of the overall methylome, and that combinations of several modalities applied to the same sample set will give the clearest picture. Given the unexpected epigenomic patterns and new biological principles, as well as new disease markers, that have been uncovered in recent studies, it is likely that important discoveries will continue to be made using genome-wide DNA methylation profiling.

  2. Profiling metabolic networks to study cancer metabolism.

    PubMed

    Hiller, Karsten; Metallo, Christian M

    2013-02-01

    Cancer is a disease of unregulated cell growth and survival, and tumors reprogram biochemical pathways to aid these processes. New capabilities in the computational and bioanalytical characterization of metabolism have now emerged, facilitating the identification of unique metabolic dependencies that arise in specific cancers. By understanding the metabolic phenotype of cancers as a function of their oncogenic profiles, metabolic engineering may be applied to design synthetically lethal therapies for some tumors. This process begins with accurate measurement of metabolic fluxes. Here we review advanced methods of quantifying pathway activity and highlight specific examples where these approaches have uncovered potential opportunities for therapeutic intervention.

  3. Chemical Analysis: An Indispensable Means for Uncovering Severe Cases of Fraud with Cosmetics and Tattoo Inks.

    PubMed

    Hohl, Christopher; Hauri, Urs

    2016-01-01

    Three cases of fraud with commodities containing illegal stealth compounds are presented, which were uncovered by the State Laboratory Basel-City, Switzerland. All three commodities, grapefruit seed extracts, a phytocosmetical skin cream, and tattoo inks, were produced abroad, had forged declarations of ingredients and, in the case of the extracts and the cream, were marketed with far-reaching health claims. While inspections will identify suspicious products and would be able to eliminate health claims to some extent, only chemical analysis can uncover the illegal agents used and give law enforcement bodies the necessary evidence to immediately clamp down on those brands, where the stealth agent presents a serious health hazard to consumers.

  4. The Dialogue of Metastasis-Uncovering Juxtacrine Genetic Cascades with a Toxoplasma Gondii Enzyme

    DTIC Science & Technology

    2008-08-01

    1-0574 TITLE: The Dialogue of Metastasis-Uncovering Juxtacrine Genetic Cascades with a Toxoplasma Gondii Enzyme PRINCIPAL...a Toxoplasma Gondii Enzyme 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Richard A. Steinman, M.D., Ph.D. 5d. PROJECT NUMBER...with the toxoplasma gondii enzyme uracil phosphoribosyl transferase (UPRT) constructed as a fusion protein with a C-terminal fluorescent tag

  5. Biophysical Profile

    MedlinePlus

    ... is Rh positive Worrisome results from other prenatal tests Your health care provider might also recommend a biophysical profile if ... the test and at regular intervals during the test. Your health care provider or a member of your health care ...

  6. Leadership Profiles.

    ERIC Educational Resources Information Center

    Teach, Beverly; And Others

    1994-01-01

    Presents profiles of two leaders in the field of educational media and technology: Carolyn Guss and Mendel Sherman, both retired professors from Indiana University's program in Information Systems Technology. (KRN)

  7. Leadership Profiles.

    ERIC Educational Resources Information Center

    Morgan, Robert M.; And Others

    1992-01-01

    Presents profiles of three leaders in the field of educational media and technology: Robert Mills Gagne, Florida State University; Robert Heinich, Indiana University; and Charles Francis Schuller, University of Georgia. (SLW)

  8. Leadership Profiles.

    ERIC Educational Resources Information Center

    Morgan, Robert M.; And Others

    1992-01-01

    Presents profiles of three leaders in the field of educational media and technology: Robert Mills Gagne, Florida State University; Robert Heinich, Indiana University; and Charles Francis Schuller, University of Georgia. (SLW)

  9. Leadership Profiles.

    ERIC Educational Resources Information Center

    Teach, Beverly; And Others

    1994-01-01

    Presents profiles of two leaders in the field of educational media and technology: Carolyn Guss and Mendel Sherman, both retired professors from Indiana University's program in Information Systems Technology. (KRN)

  10. Magnetization of uncovered and V-covered ultrathin Fe(100) films on V(100)

    SciTech Connect

    Fritzsche, H.; Liu, Y.T.; Hauschild, J.; Maletta, H.

    2004-12-01

    We used polarized neutron reflectometry (PNR) to determine the absolute magnetic moment of uncovered and V-covered Fe films in the thickness range from 0.3 to 5.5 nm. The films were prepared by molecular beam epitaxy on a V(100) buffer layer grown on a MgO(100) crystal. The magnetic moment shows a linear dependence on the Fe film thickness with a reduction (compared to the Fe bulk value) of the magnetic moment equivalent to 0.1 nm bulk Fe for the V-covered films and a reduction equivalent to 0.03 nm bulk Fe for the uncovered Fe films. For the case of the V/Fe/V samples we observe a much smaller reduction of the magnetic moment than reported for experiments on Fe/V multilayers. As theoretical calculations show a strong decrease of the magnetic moment for an interface alloy we conclude that the larger reduction of the magnetization in Fe/V multilayers is due to an increase in interface roughness with increasing film thickness. For the uncovered Fe(100) films we find a much smaller reduction of the magnetic moment than in earlier in situ PNR experiments on V(110)/Fe(110) where we observed a reduction equivalent to 0.4 nm bulk Fe.

  11. Multi-frequency complex network from time series for uncovering oil-water flow structure

    PubMed Central

    Gao, Zhong-Ke; Yang, Yu-Xuan; Fang, Peng-Cheng; Jin, Ning-De; Xia, Cheng-Yi; Hu, Li-Dan

    2015-01-01

    Uncovering complex oil-water flow structure represents a challenge in diverse scientific disciplines. This challenge stimulates us to develop a new distributed conductance sensor for measuring local flow signals at different positions and then propose a novel approach based on multi-frequency complex network to uncover the flow structures from experimental multivariate measurements. In particular, based on the Fast Fourier transform, we demonstrate how to derive multi-frequency complex network from multivariate time series. We construct complex networks at different frequencies and then detect community structures. Our results indicate that the community structures faithfully represent the structural features of oil-water flow patterns. Furthermore, we investigate the network statistic at different frequencies for each derived network and find that the frequency clustering coefficient enables to uncover the evolution of flow patterns and yield deep insights into the formation of flow structures. Current results present a first step towards a network visualization of complex flow patterns from a community structure perspective. PMID:25649900

  12. Endoscopic management of occluded biliary uncovered metal stents: A multicenter experience

    PubMed Central

    Katsinelos, Panagiotis; Beltsis, Athanasios; Chatzimavroudis, Grigoris; Paikos, Dimitris; Paroutoglou, George; Kapetanos, Dimitris; Terzoudis, Sotiris; Lazaraki, Georgia; Pilpilidis, Ioannis; Fasoulas, Kostas; Atmatzidis, Stefanos; Zavos, Christos; Kountouras, Jannis

    2011-01-01

    AIM: To compare diverse endoscopic interventions in the management of occluded uncovered self-expanding metal stents (SEMSs) that had been placed for palliative treatment of unresectable malignant biliary obstruction. METHODS: A retrospective review was undertaken in 4 tertiary endoscopic centers to determine optimal management of different types of occluded SEMSs. The technical success of performed treatment in occluded SEMSs, the patency of the stent, the need for re-intervention and the financial costs of each treatment were analyzed. RESULTS: Fifty four patients were included in the analysis; 21 received Hanaro, 19 Wallstent and 14 Flexus. For the relief of obstruction, a plastic stent was inserted in 24 patients, a second SEMS in 25 and mechanical cleaning was performed in 5 patients. The overall median second patency rates between second SEMSs and plastic stents did not differ (133 d for SEMSs vs 106 d for plastic stents; P = 0.856). Similarly, no difference was found between the overall survival of SEMS and plastic stent groups, and no procedure-related complications occurred. Incremental cost analysis showed that successive plastic stenting was a cost-saving strategy at least in Greece. CONCLUSION: Insertion of uncovered SEMSs or plastic stents is a safe and effective treatment for occluded uncovered SEMSs; insertion of plastic stents appears to be the most cost-effective strategy. PMID:21218089

  13. Endoscopic management of occluded biliary uncovered metal stents: a multicenter experience.

    PubMed

    Katsinelos, Panagiotis; Beltsis, Athanasios; Chatzimavroudis, Grigoris; Paikos, Dimitris; Paroutoglou, George; Kapetanos, Dimitris; Terzoudis, Sotiris; Lazaraki, Georgia; Pilpilidis, Ioannis; Fasoulas, Kostas; Atmatzidis, Stefanos; Zavos, Christos; Kountouras, Jannis

    2011-01-07

    To compare diverse endoscopic interventions in the management of occluded uncovered self-expanding metal stents (SEMSs) that had been placed for palliative treatment of unresectable malignant biliary obstruction. A retrospective review was undertaken in 4 tertiary endoscopic centers to determine optimal management of different types of occluded SEMSs. The technical success of performed treatment in occluded SEMSs, the patency of the stent, the need for re-intervention and the financial costs of each treatment were analyzed. Fifty four patients were included in the analysis; 21 received Hanaro, 19 Wallstent and 14 Flexus. For the relief of obstruction, a plastic stent was inserted in 24 patients, a second SEMS in 25 and mechanical cleaning was performed in 5 patients. The overall median second patency rates between second SEMSs and plastic stents did not differ (133 d for SEMSs vs 106 d for plastic stents; P=0.856). Similarly, no difference was found between the overall survival of SEMS and plastic stent groups, and no procedure-related complications occurred. Incremental cost analysis showed that successive plastic stenting was a cost-saving strategy at least in Greece. Insertion of uncovered SEMSs or plastic stents is a safe and effective treatment for occluded uncovered SEMSs; insertion of plastic stents appears to be the most cost-effective strategy.

  14. Integration of small RNAs, degradome and transcriptome sequencing in hyperaccumulator Sedum alfredii uncovers a complex regulatory network and provides insights into cadmium phytoremediation.

    PubMed

    Han, Xiaojiao; Yin, Hengfu; Song, Xixi; Zhang, Yunxing; Liu, Mingying; Sang, Jiang; Jiang, Jing; Li, Jihong; Zhuo, Renying

    2016-06-01

    The hyperaccumulating ecotype of Sedum alfredii Hance is a cadmium (Cd)/zinc/lead co-hyperaccumulating species of Crassulaceae. It is a promising phytoremediation candidate accumulating substantial heavy metal ions without obvious signs of poisoning. However, few studies have focused on the regulatory roles of miRNAs and their targets in the hyperaccumulating ecotype of S. alfredii. Here, we combined analyses of the transcriptomics, sRNAs and the degradome to generate a comprehensive resource focused on identifying key regulatory miRNA-target circuits under Cd stress. A total of 87 721 unigenes and 356 miRNAs were identified by deep sequencing, and 79 miRNAs were differentially expressed under Cd stress. Furthermore, 754 target genes of 194 miRNAs were validated by degradome sequencing. A gene ontology (GO) enrichment analysis of differential miRNA targets revealed that auxin, redox-related secondary metabolism and metal transport pathways responded to Cd stress. An integrated analysis uncovered 39 pairs of miRNA targets that displayed negatively correlated expression profiles. Ten miRNA-target pairs also exhibited negative correlations according to a real-time quantitative PCR analysis. Moreover, a coexpression regulatory network was constructed based on profiles of differentially expressed genes. Two hub genes, ARF4 (auxin response factor 4) and AAP3 (amino acid permease 3), which might play central roles in the regulation of Cd-responsive genes, were uncovered. These results suggest that comprehensive analyses of the transcriptomics, sRNAs and the degradome provided a useful platform for investigating Cd hyperaccumulation in S. alfredii, and may provide new insights into the genetic engineering of phytoremediation.

  15. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.

    PubMed

    Griffiths, Christopher E M; Reich, Kristian; Lebwohl, Mark; van de Kerkhof, Peter; Paul, Carle; Menter, Alan; Cameron, Gregory S; Erickson, Janelle; Zhang, Lu; Secrest, Roberta J; Ball, Susan; Braun, Daniel K; Osuntokun, Olawale O; Heffernan, Michael P; Nickoloff, Brian J; Papp, Kim

    2015-08-08

    Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177. Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved

  16. Proteomic analysis of propiconazole responses in mouse liver: comparison of genomic and proteomic profiles

    EPA Science Inventory

    We have performed for the first time a comprehensive profiling of changes in protein expression of soluble proteins in livers from mice treated with the mouse liver tumorigen, propiconazole, to uncover the pathways and networks altered by this fungicide. Utilizing twodimensional...

  17. Proteomic Analysis of Propiconazole Responses in Mouse Liver-Comparison of Genomic and Proteomic Profiles

    EPA Science Inventory

    We have performed for the first time a comprehensive profiling of changes in protein expression of soluble proteins in livers from mice treated with the mouse liver tumorigen, propiconazole, to uncover the pathways and networks altered by this commonly used fungicide. Utilizing t...

  18. Proteomic analysis of propiconazole responses in mouse liver: comparison of genomic and proteomic profiles

    EPA Science Inventory

    We have performed for the first time a comprehensive profiling of changes in protein expression of soluble proteins in livers from mice treated with the mouse liver tumorigen, propiconazole, to uncover the pathways and networks altered by this fungicide. Utilizing twodimensional...

  19. Proteomic Analysis of Propiconazole Responses in Mouse Liver-Comparison of Genomic and Proteomic Profiles

    EPA Science Inventory

    We have performed for the first time a comprehensive profiling of changes in protein expression of soluble proteins in livers from mice treated with the mouse liver tumorigen, propiconazole, to uncover the pathways and networks altered by this commonly used fungicide. Utilizing t...

  20. The Profile of Misconceptions among Science Subject Student-Teachers in Primary Schools

    ERIC Educational Resources Information Center

    Subayani, Nataria Wahyuning

    2016-01-01

    Students' different background knowledge determines their quality of conceptions towards a specific subject in college. This research sought to uncover the profile of misconceptions experienced by 48 students of Primary School Teaching Major, studying Science in University of Muhammadiyah Gresik. The educational background of the students in high…

  1. The defect level and ideal thermal conductivity of graphene uncovered by residual thermal reffusivity at the 0 K limit.

    PubMed

    Xie, Yangsu; Xu, Zaoli; Xu, Shen; Cheng, Zhe; Hashemi, Nastaran; Deng, Cheng; Wang, Xinwei

    2015-06-14

    Due to its intriguing thermal and electrical properties, graphene has been widely studied for potential applications in sensor and energy devices. However, the reported value for its thermal conductivity spans from dozens to thousands of W m(-1) K(-1) due to different levels of alternations and defects in graphene samples. In this work, the thermal diffusivity of suspended four-layered graphene foam (GF) is characterized from room temperature (RT) down to 17 K. For the first time, we identify the defect level in graphene by evaluating the inverse of thermal diffusivity (termed "thermal reffusivity": Θ) at the 0 K limit. By using the Debye model of Θ = Θ0 + C× e(-θ/2T) and fitting the Θ-T curve to the point of T = 0 K, we identify the defect level (Θ0) and determine the Debye temperature of graphene. Θ0 is found to be 1878 s m(-2) for the studied GF and 43-112 s m(-2) for three highly crystalline graphite materials. This uncovers a 16-43-fold higher defect level in GF than that in pyrolytic graphite. In GF, the phonon mean free path solely induced by defects and boundary scattering is determined as 166 nm. The Debye temperature of graphene is determined to be 1813 K, which is very close to the average theoretical Debye temperature (1911 K) of the three acoustic phonon modes in graphene. By subtracting the defect effect, we report the ideal thermal diffusivity and conductivity (κideal) of graphene presented in the 3D foam structure in the range of 33-299 K. Detailed physics based on chemical composition and structure analysis are given to explain the κideal-T profile by comparing with those reported for suspended graphene.

  2. Leadership Profiles.

    ERIC Educational Resources Information Center

    Orey, Michael; Moore, David M.; Reeves, Thomas

    2003-01-01

    Contains the following two leadership profiles of individuals who have made significant contributions to the field of instructional technology: "Francis M. Dwyer: Visual Researcher Extraordinaire" (David M. Moore); and "Tribute to John G. Hedberg: Professor of Education, University of Wollongong" (Thomas Reeves). (MES)

  3. Ranking Profiles

    ERIC Educational Resources Information Center

    Van Der Werf, Martin

    2007-01-01

    This article presents the "U.S. News" ranking profiles of four colleges, namely: (1) Smith College; (2) Washington University in St. Louis; (3) Colorado State University at Fort Collins; and (4) Whitman College. Smith College was in the top 10 of the nation's liberal-arts colleges, or just outside it, almost since the "U.S.…

  4. Factors affecting implant mobility at placement and integration of mobile implants at uncovering.

    PubMed

    Orenstein, I H; Tarnow, D P; Morris, H F; Ochi, S

    1998-12-01

    This study examined 1) factors that contributed to implant stability at placement and 2) the likelihood for an implant that was mobile at placement to osseointegrate. Eighty-one (3.1%) of 2,641 implants placed by the Dental Implant Clinical Research Group between 1991 and 1995 were found to be mobile at placement. Seventy-six (93.8%) of the 81 mobile implants were integrated at uncovering compared to 97.5% for the 2,560 immobile implants. Variables that influenced mobility at placement included patient age, implant design and material, anterior-posterior jaw location, bone density, and use of a bone tap. Hydroxyapatite (HA)-coated implants were slightly more likely to be mobile at placement (P = 0.324) than non-hydroxypatite (HA)-coated implants. Of the 54 HA-coated implants that were mobile at placement, all (100%) integrated, while only 17 (81.5%) of the 22 mobile non-HA-coated implants integrated (P = 0.003). Mean electronic mobility testing device values (PTVs) at uncovering for all implants mobile or immobile at placement that integrated were -2.9 and -3.6 respectively. PTVs for HA-coated implants that were mobile (-3.5 PTV) or immobile (-4.0 PTV) at placement differed by 0.5 PTV, whereas non-HA-coated implants exhibited a greater difference of 1.2 PTVs at uncovering. HA-coated implants, regardless of mobility at placement, integrated more frequently and exhibited greater stability than non HA-coated implants.

  5. How is it that microsatellites and random oligonucleotides uncover DNA fingerprint patterns?

    PubMed

    Kashi, Y; Nave, A; Darvasi, A; Gruenbaum, Y; Soller, M; Beckmann, J S

    1994-09-01

    Minisatellites, microsatellites, and short random oligonucleotides all uncover highly polymorphic DNA fingerprint patterns in Southern analysis of genomic DNA that has been digested with a restriction enzyme having a 4-bp specificity. The polymorphic nature of the fragments is attributed to tandem repeat number variation of embedded minisatellite sequences. This explains why DNA fingerprint fragments are uncovered by minisatellite probes, but does not explain how it is that they are also uncovered by microsatellite and random oligonucleotide probes. To clarify this phenomenon, we sequenced a large bovine genomic BamHI restriction fragment hybridizing to the Jeffreys 33.6 minisatellite probe and consisting of small and large Sau3A-resistant subfragments. The large Sau3A subfragment was found to have a complex architecture, consisting of two different minisatellites, flanked and separated by stretches of unique DNA. The three unique sequences were characterized by sequence simplicity, that is, a higher than chance occurrence of tandem or dispersed repetition of simple sequence motifs. This complex repetitive structure explains the absence of Sau3A restriction sites in the large Sau3A subfragment, yet provides this subfragment with the ability to hybridize to a variety of probe sequences. It is proposed that a large class of interspersed tracts sharing this complex yet simplified sequence structure is found in the genome. Each such tract would have a broad ability to hybridize to a variety of probes, yet would exhibit a dearth of restriction sites. For each restriction enzyme having 4-bp specificity, a subclass of such tracts, completely lacking the corresponding restriction sites, will be present. On digestion with the given restriction enzyme, each such tract would form a large fragment.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. RN-to-BSN education: Creating a Context that Uncovers New Possibilities.

    PubMed

    Cangelosi, Pamela R

    2006-05-01

    After 6 years of steady decline in enrollments, RN-to-BSN programs experienced an increase in enrollments from 2002 to 2003. Based on findings from a hermeneutic phenomenological study that examined the connection between faculty and students in RN-to-BSN programs, the theme, "Creating a Context that Uncovers New Possibilities," offered insight into how nurse educators can transform the teaching-learning environment to meet the needs of this valuable group of nursing students. This article describes this interpretive study and suggests strategies nurse educators can use to enhance the educational context and create new possibilities that meet RN-to-BSN students' expectations.

  7. Uncovering beam position monitor noise at the Relativistic Heavy Ion Collider

    NASA Astrophysics Data System (ADS)

    Shen, X.; Lee, S. Y.; Bai, M.

    2015-01-01

    We apply the independent component analysis (ICA) algorithm to uncover intrinsic noise in the beam position monitor (BPM) system. Numerical simulations found that ICA is efficient in the BPM noise estimation. The ICA algorithm is applied to the turn-by-turn data at the Relativistic Heavy Ion Collider. We found the distribution of the BPM noise level, which is consistent with the Johnson-Nyquist thermal noise model. The ICA analysis of turn-by-turn data can be used in neuronetwork feasibility of monitoring a storage ring parasitically.

  8. Computational modeling helps uncover mechanisms related to the progression of emphysema

    PubMed Central

    Suki, Béla; Parameswaran, Harikrishnan

    2014-01-01

    Emphysema is a progressive disease characterized by deterioration of alveolar structure and decline in lung function. While morphometric and molecular biology studies have not fully uncovered the underlying mechanisms, they have produced data to advance computational modeling. In this review, we discuss examples in which modeling has led to novel insight into mechanisms related to disease progression. Finally, we propose a general scheme of multiscale modeling approach that could help unravel the progressive nature of emphysema and provide patient specific mechanisms perhaps suitable for use in treatment therapies. PMID:24904681

  9. Computational modeling helps uncover mechanisms related to the progression of emphysema.

    PubMed

    Suki, Béla; Parameswaran, Harikrishnan

    2014-07-08

    Emphysema is a progressive disease characterized by deterioration of alveolar structure and decline in lung function. While morphometric and molecular biology studies have not fully uncovered the underlying mechanisms, they have produced data to advance computational modeling. In this review, we discuss examples in which modeling has led to novel insight into mechanisms related to disease progression. Finally, we propose a general scheme of multiscale modeling approach that could help unravel the progressive nature of emphysema and provide patient specific mechanisms perhaps suitable for use in treatment therapies.

  10. Macroscopic model for biological fixation and its uncovering idea in Chinese Mongolian traditional osteopathy.

    PubMed

    Zhao, Namula; Li, Xue-en; Wang, Mei; Hu, Da-lai

    2009-08-01

    Splintage external fixation in Chinese Mongolian osteopathy is a biological macroscopic model. In this model, the ideas of self-life "unity of mind and body" and vital natural "correspondence of nature and human" combine the physiological and psychological self-fixation with supplementary external fixation of fracture using small splints. This model implies macroscopic ideas of uncovering fixation and healing: structural stability integrating geometrical "dynamic" stability with mechanical "dynamic" equilibrium and the stability of state integrating statics with dynamics, and osteoblasts with osteoclasts, and psychological stability integrating closed and open systems of human and nature. These ideas indicate a trend of development in modern osteopathy.

  11. Microcephaly-capillary malformation syndrome: Brothers with a homozygous STAMBP mutation, uncovered by exome sequencing.

    PubMed

    Naseer, Muhammad Imran; Sogaty, Sameera; Rasool, Mahmood; Chaudhary, Adeel G; Abutalib, Yousif Ahmed; Walker, Susan; Marshall, Christian R; Merico, Daniele; Carter, Melissa T; Scherer, Stephen W; Al-Qahtani, Mohammad H; Zarrei, Mehdi

    2016-11-01

    We describe two brothers from a consanguineous family of Egyptian ancestry, presenting with microcephaly, apparent global developmental delay, seizures, spasticity, congenital blindness, and multiple cutaneous capillary malformations. Through exome sequencing, we uncovered a homozygous missense variant in STAMBP (p.K303R) in the two siblings, inherited from heterozygous carrier parents. Mutations in STAMBP are known to cause microcephaly-capillary malformation syndrome (MIC-CAP) and the phenotype in this family is consistent with this diagnosis. We compared the findings in the present brothers with those of earlier reported patients. © 2016 Wiley Periodicals, Inc.

  12. Pilot testing model to uncover industrial symbiosis in Brazilian industrial clusters.

    PubMed

    Saraceni, Adriana Valélia; Resende, Luis Mauricio; de Andrade Júnior, Pedro Paulo; Pontes, Joseane

    2017-04-01

    The main objective of this study was to create a pilot model to uncover industrial symbiosis practices in Brazilian industrial clusters. For this purpose, a systematic revision was conducted in journals selected from two categories of the ISI Web of Knowledge: Engineering, Environmental and Engineering, Industrial. After an in-depth revision of literature, results allowed the creation of an analysis structure. A methodology based on fuzzy logic was applied and used to attribute the weights of industrial symbiosis variables. It was thus possible to extract the intensity indicators of the interrelations required to analyse the development level of each correlation between the variables. Determination of variables and their weights initially resulted in a framework for the theory of industrial symbiosis assessments. Research results allowed the creation of a pilot model that could precisely identify the loopholes or development levels in each sphere. Ontology charts for data analysis were also generated. This study contributes to science by presenting the foundations for building an instrument that enables application and compilation of the pilot model, in order to identify opportunity to symbiotic development, which derives from "uncovering" existing symbioses.

  13. Uncovering Sundanese Values by Analyzing Symbolic Meaning of Ménak Priangan Clothing (1800-1942)

    NASA Astrophysics Data System (ADS)

    Karmila, M.; Suciati; Widiaty, I.

    2016-04-01

    This study investigates symbolic meanings found in the Sunda ethnic clothing, particularly the Menak Priangan clothing. This study aims to uncover and document those symbolic meanings found in the Menak Priangan clothing as an effort to develop Sunda cultural artefacts of West Java. This study on Menak Priangan clothing applies ethnography (visual) and aesthetic methods. The visual method is utilized in order to uncover local cultural (Sunda) values found in Menak Priangan clothing visualization, including: design, model, name, and representing colours, which then directed towards local Sundanese aesthetic concepts living within the Priangan community. Furthermore, aesthetic method is used to explore role of aesthetic values in empowering visual cultural values within certain community, particularly Sunda aesthetic values. The study results show that since the 19th century, Sunda ethnic clothing was limited to Priangan Sunda only, while traditional clothing wearing by Priangan people reflects their social strata, consisting of: a. Menak Gede (Menak pangluhurna: mayor), bearing raden title, b. Menak Leutik/Santana (mayor assistant), titles: asep, mas, agus, ujang, (Nyimas for woman), c. Somah/Cacah: ordinary people/lower class. Clothing is a cultural phenomenon within certain culture reflecting such society experiences. For Menak people, clothing and its accessories have important meanings. They wear such traditional clothing and accessories as a symbol of power they have within bureaucratic structure and as a symbol of social status they bear within traditional community structure.

  14. Uncovering signal transduction networks from high-throughput data by integer linear programming.

    PubMed

    Zhao, Xing-Ming; Wang, Rui-Sheng; Chen, Luonan; Aihara, Kazuyuki

    2008-05-01

    Signal transduction is an important process that transmits signals from the outside of a cell to the inside to mediate sophisticated biological responses. Effective computational models to unravel such a process by taking advantage of high-throughput genomic and proteomic data are needed to understand the essential mechanisms underlying the signaling pathways. In this article, we propose a novel method for uncovering signal transduction networks (STNs) by integrating protein interaction with gene expression data. Specifically, we formulate STN identification problem as an integer linear programming (ILP) model, which can be actually solved by a relaxed linear programming algorithm and is flexible for handling various prior information without any restriction on the network structures. The numerical results on yeast MAPK signaling pathways demonstrate that the proposed ILP model is able to uncover STNs or pathways in an efficient and accurate manner. In particular, the prediction results are found to be in high agreement with current biological knowledge and available information in literature. In addition, the proposed model is simple to be interpreted and easy to be implemented even for a large-scale system.

  15. Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

    PubMed Central

    Korpal, Manav; Feala, Jacob; Puyang, Xiaoling; Zou, Jian; Ramos, Alex H.; Wu, Jeremy; Baumeister, Timm; Yu, Lihua; Warmuth, Markus; Zhu, Ping

    2015-01-01

    Although targeted therapies are initially effective, resistance inevitably emerges. Several methods, such as genetic analysis of resistant clinical specimens, have been applied to uncover these resistance mechanisms to facilitate follow-up care. Although these approaches have led to clinically relevant discoveries, difficulties in attaining the relevant patient material or in deconvoluting the genomic data collected from these specimens have severely hampered the path towards a cure. To this end, we here describe a tool for expeditious discovery that may guide improvement in first-line therapies and alternative clinical management strategies. By coupling preclinical in vitro or in vivo drug selection with next-generation sequencing, it is possible to identify genomic structural variations and/or gene expression alterations that may serve as functional drivers of resistance. This approach facilitates the spontaneous emergence of alterations, enhancing the probability that these mechanisms may be observed in the patients. In this protocol we provide guidelines to maximize the potential for uncovering single nucleotide variants that drive resistance using adherent lines. PMID:26710000

  16. Uncovering study abroad: foreignness and its relevance to nurse education and cultural competence.

    PubMed

    Greatrex-White, Sheila

    2008-07-01

    This paper reports some of the findings from a hermeneutic phenomenological research project designed to uncover the nature of the phenomenon 'study abroad' in the context of Nursing Higher Education in the United Kingdom. The research question asked was 'How is study abroad manifest in the experience of nursing students?' Informed by the philosophy of Martin Heidegger, the analysis of 26 study abroad students' diary accounts uncovered six general structures, or ways for study abroad to be, namely; leaving behind, escape, foreigner, self-discovery, learning and risk. The focus here is on the general structure 'foreigner' and the far-reaching implications this can have in terms of understanding how study abroad comes to be. The relationship between study abroad, positive disturbance and the development of students who are able to recognise diversity across different cultures is discussed. It is suggested that if one of the major aims of nurse higher education is the development of culturally competent practitioners, study abroad is deserving of far greater attention than is currently the case.

  17. MPI Profiling

    SciTech Connect

    Han, D K; Jones, T R

    2005-02-11

    The Message Passing Interface (MPI) is the de facto message-passing standard for massively parallel programs. It is often the case that application performance is a crucial factor, especially for solving grand challenge problems. While there have been many studies on the scalability of applications, there have not been many focusing on the specific types of MPI calls being made and their impact on application performance. Using a profiling tool called mpiP, a large spectrum of parallel scientific applications were surveyed and their performance results analyzed.

  18. UnCover on the Web: search hints and applications in library environments.

    PubMed

    Galpern, N F; Albert, K M

    1997-01-01

    Among the huge maze of resources available on the Internet, UnCoverWeb stands out as a valuable tool for medical libraries. This up-to-date, free-access, multidisciplinary database of periodical references is searched through an easy-to-learn graphical user interface that is a welcome improvement over the telnet version. This article reviews the basic and advanced search techniques for UnCoverWeb, as well as providing information on the document delivery functions and table of contents alerting service called Reveal. UnCover's currency is evaluated and compared with other current awareness resources. System deficiencies are discussed, with the conclusion that although UnCoverWeb lacks the sophisticated features of many commercial database search services, it is nonetheless a useful addition to the repertoire of information sources available in a library.

  19. Health Detectives: Uncovering the Mysteries of Disease (LBNL Science at the Theater)

    ScienceCinema

    Bissell, Mina; Canaria, Christie; Celnicker, Susan; Karpen, Gary

    2016-07-12

    In this April 23, 2012 Science at the Theater event, Berkeley Lab scientists discuss how they uncover the mysteries of disease in unlikely places. Speakers and topics include: World-renowned cancer researcher Mina Bissell's pioneering research on the role of the cellular microenvironment in breast cancer has changed the conversation about the disease. How does DNA instability cause disease? To find out, Christie Canaria images neural networks to study disorders such as Huntington's disease. Fruit flies can tell us a lot about ourselves. Susan Celniker explores the fruit fly genome to learn how our genome works. DNA is not destiny. Gary Karpen explores how environmental factors shape genome function and disease through epigenetics.

  20. Treatment of symptomatic coral reef aorta with an uncovered stent graft.

    PubMed

    Bosanquet, D C; Wood, A; Williams, I M

    2015-10-01

    Coral reef aorta is a rare condition characterised by extreme calcific growths affecting the juxta and suprarenal aorta. It can cause symptoms due to visceral ischaemia, lower limb hypoperfusion, and distal embolisation. We present a case of a 61-year-old man with unresponsive hypertension, who was found to have an occluded right renal artery, and an extensive coral reef aorta with a marked pressure gradient across the lesion. Renal hypoperfusion secondary to aortic coral reef aorta was thought to be the cause for his hypertension. Endovascular placement of a balloon expandable uncovered stent resolved his hypertension within one month, with no adverse effects noted at subsequent follow-up. Endovascular treatment of coral reef aorta is technically possible and avoids a major vascular procedure.

  1. Strategies and approaches in plasmidome studies—uncovering plasmid diversity disregarding of linear elements?

    PubMed Central

    Dib, Julián R.; Wagenknecht, Martin; Farías, María E.; Meinhardt, Friedhelm

    2015-01-01

    The term plasmid was originally coined for circular, extrachromosomal genetic elements. Today, plasmids are widely recognized not only as important factors facilitating genome restructuring but also as vehicles for the dissemination of beneficial characters within bacterial communities. Plasmid diversity has been uncovered by means of culture-dependent or -independent approaches, such as endogenous or exogenous plasmid isolation as well as PCR-based detection or transposon-aided capture, respectively. High-throughput-sequencing made possible to cover total plasmid populations in a given environment, i.e., the plasmidome, and allowed to address the quality and significance of self-replicating genetic elements. Since such efforts were and still are rather restricted to circular molecules, here we put equal emphasis on the linear plasmids which—despite their frequent occurrence in a large number of bacteria—are largely neglected in prevalent plasmidome conceptions. PMID:26074886

  2. Strategies and approaches in plasmidome studies-uncovering plasmid diversity disregarding of linear elements?

    PubMed

    Dib, Julián R; Wagenknecht, Martin; Farías, María E; Meinhardt, Friedhelm

    2015-01-01

    The term plasmid was originally coined for circular, extrachromosomal genetic elements. Today, plasmids are widely recognized not only as important factors facilitating genome restructuring but also as vehicles for the dissemination of beneficial characters within bacterial communities. Plasmid diversity has been uncovered by means of culture-dependent or -independent approaches, such as endogenous or exogenous plasmid isolation as well as PCR-based detection or transposon-aided capture, respectively. High-throughput-sequencing made possible to cover total plasmid populations in a given environment, i.e., the plasmidome, and allowed to address the quality and significance of self-replicating genetic elements. Since such efforts were and still are rather restricted to circular molecules, here we put equal emphasis on the linear plasmids which-despite their frequent occurrence in a large number of bacteria-are largely neglected in prevalent plasmidome conceptions.

  3. Health Detectives: Uncovering the Mysteries of Disease (LBNL Science at the Theater)

    SciTech Connect

    Bissell, Mina; Canaria, Christie; Celnicker, Susan; Karpen, Gary

    2012-04-23

    In this April 23, 2012 Science at the Theater event, Berkeley Lab scientists discuss how they uncover the mysteries of disease in unlikely places. Speakers and topics include: World-renowned cancer researcher Mina Bissell's pioneering research on the role of the cellular microenvironment in breast cancer has changed the conversation about the disease. How does DNA instability cause disease? To find out, Christie Canaria images neural networks to study disorders such as Huntington's disease. Fruit flies can tell us a lot about ourselves. Susan Celniker explores the fruit fly genome to learn how our genome works. DNA is not destiny. Gary Karpen explores how environmental factors shape genome function and disease through epigenetics.

  4. Uncovering brain-heart information through advanced signal and image processing.

    PubMed

    Valenza, Gaetano; Toschi, Nicola; Barbieri, Riccardo

    2016-05-13

    Through their dynamical interplay, the brain and the heart ensure fundamental homeostasis and mediate a number of physiological functions as well as their disease-related aberrations. Although a vast number of ad hoc analytical and computational tools have been recently applied to the non-invasive characterization of brain and heart dynamic functioning, little attention has been devoted to combining information to unveil the interactions between these two physiological systems. This theme issue collects contributions from leading experts dealing with the development of advanced analytical and computational tools in the field of biomedical signal and image processing. It includes perspectives on recent advances in 7 T magnetic resonance imaging as well as electroencephalogram, electrocardiogram and cerebrovascular flow processing, with the specific aim of elucidating methods to uncover novel biological and physiological correlates of brain-heart physiology and physiopathology.

  5. Uncovering brain–heart information through advanced signal and image processing

    PubMed Central

    Toschi, Nicola; Barbieri, Riccardo

    2016-01-01

    Through their dynamical interplay, the brain and the heart ensure fundamental homeostasis and mediate a number of physiological functions as well as their disease-related aberrations. Although a vast number of ad hoc analytical and computational tools have been recently applied to the non-invasive characterization of brain and heart dynamic functioning, little attention has been devoted to combining information to unveil the interactions between these two physiological systems. This theme issue collects contributions from leading experts dealing with the development of advanced analytical and computational tools in the field of biomedical signal and image processing. It includes perspectives on recent advances in 7 T magnetic resonance imaging as well as electroencephalogram, electrocardiogram and cerebrovascular flow processing, with the specific aim of elucidating methods to uncover novel biological and physiological correlates of brain–heart physiology and physiopathology. PMID:27044995

  6. Uncovering the Meaning of Home Care Using an Arts-Based and Qualitative Approach.

    PubMed

    Fraser, Kimberly; Archibald, Mandy; Nissen, Catherine

    2014-09-01

    The need for home care is increasing in Canada, yet little is known about the home care experience of clients and their families. Uncovering the meaning of the home care experience is an important step towards developing understanding and public awareness. We explored the experiences of home care using arts-based methods and individual interviews with 11 participants (one client and 10 family caregivers). Participants discussed the numerous ways formal home care and family caregiving affected their lives, how they coped with these effects, their experiences in hospitals or assisted living facilities, and aspects of the home care experience they liked or disliked. Participants agreed that home care facilitated a better quality of life for families and clients, although they acknowledged some challenges with it. The artistic outputs produced by participants facilitated interview dialogue and fostered understanding of key themes within the research team.

  7. Representations of God uncovered in a spirituality group of borderline inpatients.

    PubMed

    Goodman, Geoff; Manierre, Amy

    2008-01-01

    We present aspects of a psychoanalytically-oriented, exploratory spirituality group for nine female psychiatric inpatients diagnosed with borderline personality disorder. Through drawings and group process, the patients uncovered and elaborated on their representations of God. Two patterns of representations were identified: (1) representations of a punitive, judgmental, rigid God that seemed directly to reflect and correspond with parental representations and (2) representations of a depersonified, inanimate, abstract God entailing aspects of idealization that seemed to compensate for parental representations. Interestingly, the second pattern was associated with comorbid narcissistic features in the patients. Those patients who presented punitive God representations were able to begin the process of re-creating these representations toward more benign or benevolent images in the context of this group, while those participants who presented depersonified God representations seemed unable to do so.

  8. Single Cell Oxygen Mapping (SCOM) by Scanning Electrochemical Microscopy Uncovers Heterogeneous Intracellular Oxygen Consumption.

    PubMed

    Santos, Carla Santana; Kowaltowski, Alicia J; Bertotti, Mauro

    2017-09-12

    We developed a highly sensitive oxygen consumption scanning microscopy system using platinized platinum disc microelectrodes. The system is capable of reliably detecting single-cell respiration, responding to classical regulators of mitochondrial oxygen consumption activity as expected. Comparisons with commercial multi-cell oxygen detection systems show that the system has comparable errors (if not smaller), with the advantage of being able to monitor inter and intra-cell heterogeneity in oxygen consumption characteristics. Our results uncover heterogeneous oxygen consumption characteristics between cells and within the same cell´s microenvironments. Single Cell Oxygen Mapping (SCOM) is thus capable of reliably studying mitochondrial oxygen consumption characteristics and heterogeneity at a single-cell level.

  9. Uncovering values-based practice: VBP's implicit commitments to subjectivism and relativism.

    PubMed

    Cassidy, Ben

    2013-06-01

    Despite assertions to the contrary, KWM Fulford's values-based practice is implicitly committed to subjectivism when it comes to reasoning about values. This renders the approach unworkable. The act of merely uncovering underlying values is not enough to effect change and, therefore, resolve problems if we have no way, even in principle, of determining which values are right and which are wrong. Fulford's only departure from subjectivism about value is his commitment to 'framework values', which seems grounded in a version of ethical relativism. I argue that we need to reject both subjectivism and relativism if progress within ethical discussions about practice is to be meaningful and a real possibility. © 2013 John Wiley & Sons Ltd.

  10. Structural features of the lysosomal hydrolase mannose 6-phosphate uncovering enzyme.

    PubMed

    Wei, Yuqiang; Yen, Ten-Yang; Cai, Jian; Trent, John O; Pierce, William M; Young, William W

    2005-02-01

    The uncovering enzyme (UCE) removes N-acetylglucosamine from lysosomal enzymes to uncover the mannose 6-phosphate (Man-6-P) determinant necessary for targeting these enzymes to lysosomes. Failure to create the Man-6-P determinant is one cause of lysosomal storage diseases. Despite its medical importance, little structural information about UCE is available. In this report we have developed a model for the membrane proximal portion of the lumenal domain of UCE based on the structure of the EFG-3 and -4 domains of the extracellular segment of the beta chain of integrin alpha Vbeta 3. In this model the EGF-like domains of UCE (residues 285-345) are predicted to form a rod-shaped stalk region, similar to the stem region in Golgi glycosyltransferases. This stalk causes the proposed catalytic domain (residues 1-277) to be extended away from the Golgi membrane. A portion of the proposed catalytic domain (residues 85-256) resides in Cluster of Orthologous Group (COG) 4632 with four bacterial proteins but is not homologous to any known eukaryotic proteins. Thus, UCE may have evolved from the fusion of a unique catalytic domain with a common EGF-like stalk domain. We have determined by mass spectrometry that the four disulfide bonds of the proposed catalytic domain are located between Cys(2)-Cys(172), Cys(66)-Cys(99), Cys(83)-Cys(274), and Cys(258)-Cys(265). Finally, we determined that four of the six potential N-linked glycosylation sites are glycosylated (Asn 159, Asn 165, Asn 247, and Asn 317) in COS cells.

  11. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective

    PubMed Central

    Surget, Sylvanie; Khoury, Marie P; Bourdon, Jean-Christophe

    2014-01-01

    Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets. PMID:24379683

  12. Uncovering novel 3-hydroxy-4-pyridinone metal ion complexes with potential anti-inflammatory properties.

    PubMed

    Chisté, Renan Campos; Ribeiro, Daniela; Freitas, Marisa; Leite, Andreia; Moniz, Tânia; Rangel, Maria; Fernandes, Eduarda

    2016-02-01

    Ligands of the 3-hydroxy-4-pyridinone (3,4-HPO) type, with one (Hmpp) or two methyl groups (Hdmpp), have been reported to possess biomedical, chemical and analytical applications. In this first screening study aiming to uncover new promising agents to mitigate the oxidative damage highly present in several metabolic disorders, such as diabetes mellitus, we assessed the potential of twelve 3,4-HPO metal ion complexes to modulate oxidative burst in human neutrophils. Metal ion 3,4-HPO complexes of Ni, Fe, V, Co, Cu and Zn were synthesized and tested up to 15μM. Among all the compounds, [Cu(mpp)2] and [Cu(dmpp)2] exhibited the highest scavenging capacity against superoxide radical (O2(-)) (IC50=0.36±0.07 and 0.30±0.06μM, respectively) and against hypochlorous acid (HOCl) (IC50=0.6±0.3 and 0.4±0.1μM, respectively). In the particular case of O2(-), [Fe(mpp)3] and [Fe(dmpp)3] (both at 15μM) presented 35% and 22% of inhibition, respectively, while all the other compounds were neither able to scavenge O2(-) nor stimulate its production. Regarding the scavenging capacity against hydrogen peroxide (H2O2), all the compounds showed low efficiency (from 6-39%). Finally, with exception of [VO(mpp)2] and [VO(dmpp)2], all compounds exhibited scavenging activity against HOCl (39-81%) and the most efficient compounds were Cu(II) and Zn(II) complexes. Thus, these preliminary results uncover promising new metal ion complexes, inhibitors of neutrophil's oxidative burst, with potential anti-inflammatory properties, which may be seen as an useful strategy for further studies in the treatment of a number of diseases where oxidative damage is a serious issue. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Uncovering New Pathogen–Host Protein–Protein Interactions by Pairwise Structure Similarity

    PubMed Central

    Cui, Tao; Li, Weihui; Liu, Lei; Huang, Qiaoyun; He, Zheng-Guo

    2016-01-01

    Pathogens usually evade and manipulate host-immune pathways through pathogen–host protein–protein interactions (PPIs) to avoid being killed by the host immune system. Therefore, uncovering pathogen–host PPIs is critical for determining the mechanisms underlying pathogen infection and survival. In this study, we developed a computational method, which we named pairwise structure similarity (PSS)-PPI, to predict pathogen–host PPIs. First, a high-quality and non-redundant structure–structure interaction (SSI) template library was constructed by exhaustively exploring heteromeric protein complex structures in the PDB database. New interactions were then predicted by searching for PSS with complex structures in the SSI template library. A quantitative score named the PSS score, which integrated structure similarity and residue–residue contact-coverage information, was used to describe the overall similarity of each predicted interaction with the corresponding SSI template. Notably, PSS-PPI yielded experimentally confirmed pathogen–host PPIs of human immunodeficiency virus type 1 (HIV-1) with performance close to that of in vitro high-throughput screening approaches. Finally, a pathogen–host PPI network of human pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, was constructed using PSS-PPI and refined using filtration steps based on cellular localization information. Analysis of the resulting network indicated that secreted proteins of the STPK, ESX-1, and PE/PPE family in M. tuberculosis targeted human proteins involved in immune response and phagocytosis. M. tuberculosis also targeted host factors known to regulate HIV replication. Taken together, our findings provide insights into the survival mechanisms of M. tuberculosis in human hosts, as well as co-infection of tuberculosis and HIV. With the rapid pace of three-dimensional protein structure discovery, the SSI template library we constructed and the PSS-PPI method we devised

  14. Whole-Genome Comparison Uncovers Genomic Mutations between Group B Streptococci Sampled from Infected Newborns and Their Mothers

    PubMed Central

    Almeida, Alexandre; Villain, Adrien; Joubrel, Caroline; Touak, Gérald; Sauvage, Elisabeth; Rosinski-Chupin, Isabelle

    2015-01-01

    ABSTRACT Streptococcus agalactiae (group B Streptococcus or GBS), a commensal of the human gut and genitourinary tract, is a leading cause of neonatal infections, in which vertical transmission from mother to child remains the most frequent route of contamination. Here, we investigated whether the progression of GBS from carriage to disease is associated with genomic adaptation. Whole-genome comparison of 47 GBS samples from 19 mother-child pairs uncovered 21 single nucleotide polymorphisms (SNPs) and seven insertions/deletions. Of the SNPs detected, 16 appear to have been fixed in the population sampled whereas five mutations were found to be polymorphic. In the infant strains, 14 mutations were detected, including two independently fixed variants affecting the covRS locus, which is known to encode a major regulatory system of virulence. A one-nucleotide insertion was also identified in the promoter region of the highly immunogenic surface protein Rib gene. Gene expression analysis after incubation in human blood showed that these mutations influenced the expression of virulence-associated genes. Additional identification of three mutated strains in the mothers' milk raised the possibility of the newborns also being a source of contamination for their mothers. Overall, our work showed that GBS strains in carriage and disease scenarios might undergo adaptive changes following colonization. The types and locations of the mutations found, together with the experimental results showing their phenotypic impact, suggest that those in a context of infection were positively selected during the transition of GBS from commensal to pathogen, contributing to an increased capacity to cause disease. IMPORTANCE Group B Streptococcus (GBS) is a major pathogen responsible for neonatal infections. Considering that its colonization of healthy adults is mostly asymptomatic, the mechanisms behind its switch from a commensal to an invasive state are largely unknown. In this work, we

  15. A randomized trial comparing uncovered and partially covered self-expandable metal stents in the palliation of distal malignant biliary obstruction.

    PubMed

    Telford, Jennifer J; Carr-Locke, David L; Baron, Todd H; Poneros, John M; Bounds, Brenna C; Kelsey, Peter B; Schapiro, Robert H; Huang, Christopher S; Lichtenstein, David R; Jacobson, Brian C; Saltzman, John R; Thompson, Christopher C; Forcione, David G; Gostout, Christopher J; Brugge, William R

    2010-11-01

    The most common complication of uncovered biliary self-expandable metal stents (SEMSs) is tumor ingrowth. The addition of an impenetrable covering may prolong stent patency. To compare stent patency between uncovered and partially covered SEMSs in malignant biliary obstruction. Multicenter randomized trial. Four teaching hospitals. Adults with inoperable distal malignant biliary obstruction. Uncovered or partially covered SEMS insertion. Time to recurrent biliary obstruction, patient survival, serious adverse events, and mechanism of recurrent biliary obstruction. From October 2002 to May 2008, 129 patients were randomized. Recurrent biliary obstruction was observed in 11 of 61 uncovered SEMSs (18%) and 20 of 68 partially covered SEMSs (29%). The median times to recurrent biliary obstruction were 711 days and 357 days for the uncovered and partially covered SEMS groups, respectively (P = .530). Median patient survival was 239 days for the uncovered SEMS and 227 days for the partially covered SEMS groups (P = .997). Serious adverse events occurred in 27 (44%) and 42 (62%) patients in the uncovered and partially covered SEMS groups, respectively (P = .046). None of the uncovered and 8 (12%) of the partially covered SEMSs migrated (P = .0061). Intended sample size was not reached. Allocation to treatment groups was unequal. There was no significant difference in time to recurrent biliary obstruction or patient survival between the partially covered and uncovered SEMS groups. Partially covered SEMSs were associated with more serious adverse events, particularly migration. Copyright © 2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

  16. The ability to cause infection in a pathogenic fungus uncovers a new biological feature of honey bee viruses

    USDA-ARS?s Scientific Manuscript database

    We demonstrated that honey bee viruses, including Deformed Wing Virus (DWV), Black Queen Cell Virus (BQCV) and Isreali Acute Paralysis Virus (IAPV), could infect and replicate in the fungal pathogen Ascosphaera apis, which causes honey bee chalkbrood disease, uncovering a novel biological feature of...

  17. Two Tales of Time: Uncovering the Significance of Sequential Patterns among Contribution Types in Knowledge-Building Discourse

    ERIC Educational Resources Information Center

    Chen, Bodong; Resendes, Monica; Chai, Ching Sing; Hong, Huang-Yao

    2017-01-01

    As collaborative learning is actualized through evolving dialogues, temporality inevitably matters for the analysis of collaborative learning. This study attempts to uncover sequential patterns that distinguish "productive" threads of knowledge-building discourse. A database of Grade 1-6 knowledge-building discourse was first coded for…

  18. Uncovering the Links between Prospective Teachers' Personal Responsibility, Academic Optimism, Hope, and Emotions about Teaching: A Mediation Analysis

    ERIC Educational Resources Information Center

    Eren, Altay

    2014-01-01

    Prospective teachers' sense of personal responsibility has not been examined together with their academic optimism, hope, and emotions about teaching in a single study to date. However, to consider hope, academic optimism, and emotions about teaching together with personal responsibility is important to uncover the factors affecting…

  19. Uncovering the Links between Prospective Teachers' Personal Responsibility, Academic Optimism, Hope, and Emotions about Teaching: A Mediation Analysis

    ERIC Educational Resources Information Center

    Eren, Altay

    2014-01-01

    Prospective teachers' sense of personal responsibility has not been examined together with their academic optimism, hope, and emotions about teaching in a single study to date. However, to consider hope, academic optimism, and emotions about teaching together with personal responsibility is important to uncover the factors affecting…

  20. A Combined Computational and Genetic Approach Uncovers Network Interactions of the Cyanobacterial Circadian Clock.

    PubMed

    Boyd, Joseph S; Cheng, Ryan R; Paddock, Mark L; Sancar, Cigdem; Morcos, Faruck; Golden, Susan S

    2016-09-15

    confirmed known interactions and revealed a core set of subnetworks within the larger HK-RR set. We validated high-scoring candidate proteins via combinatorial genetics, demonstrating that DCA can be utilized to reduce the search space of complex protein networks and to infer undiscovered specific interactions for signaling proteins in vivo Significantly, new interactions that link circadian response to cell division and fitness in a light/dark cycle were uncovered. The combined analysis also uncovered a more basic core clock, illustrating the synergy and applicability of a combined computational and genetic approach for investigating prokaryotic signaling networks. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  1. Uncovering the pKa dependent fluorescence quenching of carbon dots induced by chlorophenols

    NASA Astrophysics Data System (ADS)

    Zhang, Yu; Wang, Yu; Guan, Yafeng; Feng, Liang

    2015-03-01

    Fluorescence quenching induced by targets is always an alluring strategy to elucidate the possible photoluminescence origin of carbon dots. In this study, a new kind of N, S co-doped carbon dots (NSCDs) was synthesized and the fluorescence of NSCDs was surprisingly found to be quenched by chlorophenols (CPs) in a pKa dependent mode. Detailed investigation of this behavior demonstrated that phenolate was the responsible species and N and/or S dopants in NSCDs failed to play a role in the fluorescence quenching. Further evidence uncovered that the quenching was a static one, where a non-fluorescent intermediate was formed between electron-deficient C&z.dbd;O on the CDs surface and the electron-rich phenolic oxygen anion of chlorophenolate via nucleophilic addition. Moreover, one of the main photoluminescence origins of this kind of CDs was derived, namely surface emissive sites mostly attributed to carbonyl groups.Fluorescence quenching induced by targets is always an alluring strategy to elucidate the possible photoluminescence origin of carbon dots. In this study, a new kind of N, S co-doped carbon dots (NSCDs) was synthesized and the fluorescence of NSCDs was surprisingly found to be quenched by chlorophenols (CPs) in a pKa dependent mode. Detailed investigation of this behavior demonstrated that phenolate was the responsible species and N and/or S dopants in NSCDs failed to play a role in the fluorescence quenching. Further evidence uncovered that the quenching was a static one, where a non-fluorescent intermediate was formed between electron-deficient C&z.dbd;O on the CDs surface and the electron-rich phenolic oxygen anion of chlorophenolate via nucleophilic addition. Moreover, one of the main photoluminescence origins of this kind of CDs was derived, namely surface emissive sites mostly attributed to carbonyl groups. Electronic supplementary information (ESI) available: Texts, figures and tables giving partial experimental procedures, detailed characterizations

  2. A Combined Computational and Genetic Approach Uncovers Network Interactions of the Cyanobacterial Circadian Clock

    PubMed Central

    Boyd, Joseph S.; Cheng, Ryan R.; Paddock, Mark L.; Sancar, Cigdem

    2016-01-01

    DCA, independently confirmed known interactions and revealed a core set of subnetworks within the larger HK-RR set. We validated high-scoring candidate proteins via combinatorial genetics, demonstrating that DCA can be utilized to reduce the search space of complex protein networks and to infer undiscovered specific interactions for signaling proteins in vivo. Significantly, new interactions that link circadian response to cell division and fitness in a light/dark cycle were uncovered. The combined analysis also uncovered a more basic core clock, illustrating the synergy and applicability of a combined computational and genetic approach for investigating prokaryotic signaling networks. PMID:27381914

  3. Application of Synthetic Peptide Arrays To Uncover Cyclic Di-GMP Binding Motifs

    PubMed Central

    Düvel, Juliane; Bense, Sarina; Möller, Stefan; Bertinetti, Daniela; Schwede, Frank; Morr, Michael; Eckweiler, Denitsa; Genieser, Hans-Gottfried; Jänsch, Lothar; Herberg, Friedrich W.; Frank, Ronald

    2015-01-01

    ABSTRACT High levels of the universal bacterial second messenger cyclic di-GMP (c-di-GMP) promote the establishment of surface-attached growth in many bacteria. Not only can c-di-GMP bind to nucleic acids and directly control gene expression, but it also binds to a diverse array of proteins of specialized functions and orchestrates their activity. Since its development in the early 1990s, the synthetic peptide array technique has become a powerful tool for high-throughput approaches and was successfully applied to investigate the binding specificity of protein-ligand interactions. In this study, we used peptide arrays to uncover the c-di-GMP binding site of a Pseudomonas aeruginosa protein (PA3740) that was isolated in a chemical proteomics approach. PA3740 was shown to bind c-di-GMP with a high affinity, and peptide arrays uncovered LKKALKKQTNLR to be a putative c-di-GMP binding motif. Most interestingly, different from the previously identified c-di-GMP binding motif of the PilZ domain (RXXXR) or the I site of diguanylate cyclases (RXXD), two leucine residues and a glutamine residue and not the charged amino acids provided the key residues of the binding sequence. Those three amino acids are highly conserved across PA3740 homologs, and their singular exchange to alanine reduced c-di-GMP binding within the full-length protein. IMPORTANCE In many bacterial pathogens the universal bacterial second messenger c-di-GMP governs the switch from the planktonic, motile mode of growth to the sessile, biofilm mode of growth. Bacteria adapt their intracellular c-di-GMP levels to a variety of environmental challenges. Several classes of c-di-GMP binding proteins have been structurally characterized, and diverse c-di-GMP binding domains have been identified. Nevertheless, for several c-di-GMP receptors, the binding motif remains to be determined. Here we show that the use of a synthetic peptide array allowed the identification of a c-di-GMP binding motif of a putative c

  4. Uncovering Molecular Relaxation Processes with Nonlinear Spectroscopies in the Deep UV

    NASA Astrophysics Data System (ADS)

    West, Brantley Andrew

    Conical intersections mediate internal conversion dynamics that compete with even the fastest nuclear motions in molecular systems. Traditional kinetic models do not apply in this regime of commensurate electronic and nuclear motion because the surroundings do not maintain equilibrium throughout the relaxation process. This dissertation focuses on uncovering the physics associated with vibronic interactions at conical intersections. Of particular interest are coherent nuclear motions driven by steep excited state potential energy gradients. Technical advances have only recently made these dynamics accessible in many systems including DNA nucleobases and cyclic polyene molecules. Optical analogues of multidimensional NMR spectroscopies have recently yielded transformative insight in relaxation processes ranging from energy transfer in photosynthesis to bond making and breaking in liquids. Prior to the start of this research, such experiments had only been conducted at infrared and visible wavelengths. Applications in the ultraviolet were motivated by studies of numerous biological systems (e.g., DNA, proteins), but had been challenged by technical issues. The work presented in this dissertation combines pulse generation techniques developed in the optical physics community with spectroscopic techniques largely pioneered by physical chemists to implement two-dimensional ultraviolet spectroscopy (2DUV). This technique is applied at the shortest wavelengths and with the best signal-to-noise ratios reported to date. Sub-picosecond excited state deactivation processes provide photo stability to the DNA double helix. Vibrational energy transfer from the solute to surrounding solvent enables relaxation of the highly non-equilibrium ground state produced by fast internal conversion. In this dissertation, nonlinear spectroscopies carried out at cryogenic temperatures are used to uncover the particular nuclear modes in the solvent that primarily accept vibrational energy from

  5. Combining data mining and machine learning for effective user profiling

    SciTech Connect

    Fawcett, T.; Provost, F.

    1996-12-31

    This paper describes the automatic design of methods for detecting fraudulent behavior. Much of the design is accomplished using a series of machine learning methods. In particular, we combine data mining and constructive induction with more standard machine learning techniques to design methods for detecting fraudulent usage of cellular telephones based on profiling customer behavior. Specifically, we use a rule-learning program to uncover indicators of fraudulent behavior from a large database of cellular calls. These indicators are used to create profilers, which then serve as features to a system that combines evidence from multiple profilers to generate high-confidence alarms. Experiments indicate that this automatic approach performs nearly as well as the best hand-tuned methods for detecting fraud.

  6. DNA Identification of Skeletal Remains from World War II Mass Graves Uncovered in Slovenia

    PubMed Central

    Marjanović, Damir; Durmić-Pašić, Adaleta; Bakal, Narcisa; Haverić, Sanin; Kalamujić, Belma; Kovačević, Lejla; Ramić, Jasmin; Pojskić, Naris; Škaro, Vedrana; Projić, Petar; Bajrović, Kasim; Hadžiselimović, Rifat; Drobnič, Katja; Huffine, Ed; Davoren, Jon; Primorac, Dragan

    2007-01-01

    Aim To present the joint effort of three institutions in the identification of human remains from the World War II found in two mass graves in the area of Škofja Loka, Slovenia. Methods The remains of 27 individuals were found in two small and closely located mass graves. The DNA was isolated from bone and teeth samples using either standard phenol/chloroform alcohol extraction or optimized Qiagen DNA extraction procedure. Some recovered samples required the employment of additional DNA purification methods, such as N-buthanol treatment. QuantifilerTM Human DNA Quantification Kit was used for DNA quantification. PowerPlex 16 kit was used to simultaneously amplify 15 short tandem repeat (STR) loci. Matching probabilities were estimated using the DNA View program. Results Out of all processed samples, 15 remains were fully profiled at all 15 STR loci. The other 12 profiles were partial. The least successful profile included 13 loci. Also, 69 referent samples (buccal swabs) from potential living relatives were collected and profiled. Comparison of victims' profile against referent samples database resulted in 4 strong matches. In addition, 5 other profiles were matched to certain referent samples with lower probability. Conclusion Our results show that more than 6 decades after the end of the World War II, DNA analysis may significantly contribute to the identification of the remains from that period. Additional analysis of Y-STRs and mitochondrial DNA (mtDNA) markers will be performed in the second phase of the identification project. PMID:17696306

  7. Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging

    NASA Astrophysics Data System (ADS)

    Rose, P. B.; Erickson, A. S.; Mayer, M.; Nattress, J.; Jovanovic, I.

    2016-04-01

    Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as “searching for a needle in a haystack” because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method from being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material’s areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications.

  8. Combining Novel Simulation Methods and Nucleation Theory to Uncover the Secrets of Gas Hydrates

    SciTech Connect

    Keyes, Thomas

    2016-04-14

    Conventional computer simulation methods fail for some of the most important problems. With the design and application of innovative algorithms, this project achieved a breakthrough for the case of systems undergoing first-order phase transitions. We gave a complete simulation protocol based upon a well optimized version of our "generalized replica exchange method". The transition of primary interest was gas hydrate formation, a process of significance for climate science and natural gas retrieval. Since hydrates consist of guest molecules in the cages of a water matrix, β ice, the freezing and melting of water was also studied. New information was uncovered about the transition pathways and thermodynamics. Some highlights are 1. the finding that in a very dilute solution without deep supercooling, representative of real-world conditions and very challenging to conventional algorithms, methane can act as a catalyst to drive the formation of large amounts of β ice with empty cages as metastable intermediates, which might be filled by additional methane in a mechanism for hydrate formation, and 2. illumination of the role of metastable cubic ice in water freezing, with determination of the surface tensions of the cubic, hexagonal, and β ices, and the free energy difference of cubic vs hexagonal ice. Work was begun on lipid systems, bilayers and nanoreactors promising for energy-related photoreductions, and targets for future research. Our methods yielded what is arguably the most complete description of the composite lipid/water phases and the transition pathways among them.

  9. Root transcriptome of two contrasting indica rice cultivars uncovers regulators of root development and physiological responses

    PubMed Central

    Singh, Alka; Kumar, Pramod; Gautam, Vibhav; Rengasamy, Balakrishnan; Adhikari, Bijan; Udayakumar, Makarla; Sarkar, Ananda K.

    2016-01-01

    The huge variation in root system architecture (RSA) among different rice (Oryza sativa) cultivars is conferred by their genetic makeup and different growth or climatic conditions. Unlike model plant Arabidopsis, the molecular basis of such variation in RSA is very poorly understood in rice. Cultivars with stable variation are valuable resources for identification of genes involved in RSA and related physiological traits. We have screened for RSA and identified two such indica rice cultivars, IR-64 (OsAS83) and IET-16348 (OsAS84), with stable contrasting RSA. OsAS84 produces robust RSA with more crown roots, lateral roots and root hairs than OsAS83. Using comparative root transcriptome analysis of these cultivars, we identified genes related to root development and different physiological responses like abiotic stress responses, hormone signaling, and nutrient acquisition or transport. The two cultivars differ in their response to salinity/dehydration stresses, phosphate/nitrogen deficiency, and different phytohormones. Differential expression of genes involved in salinity or dehydration response, nitrogen (N) transport, phosphate (Pi) starvation signaling, hormone signaling and root development underlies more resistance of OsAS84 towards abiotic stresses, Pi or N deficiency and its robust RSA. Thus our study uncovers gene-network involved in root development and abiotic stress responses in rice. PMID:28000793

  10. Uncovering the effective interval of resolution parameter across multiple community optimization measures

    NASA Astrophysics Data System (ADS)

    Li, Hui-Jia; Cheng, Qing; Mao, He-Jin; Wang, Huanian; Chen, Junhua

    2017-03-01

    The study of community structure is a primary focus of network analysis, which has attracted a large amount of attention. In this paper, we focus on two famous functions, i.e., the Hamiltonian function H and the modularity density measure D, and intend to uncover the effective thresholds of their corresponding resolution parameter γ without resolution limit problem. Two widely used example networks are employed, including the ring network of lumps as well as the ad hoc network. In these two networks, we use discrete convex analysis to study the interval of resolution parameter of H and D that will not cause the misidentification. By comparison, we find that in both examples, for Hamiltonian function H, the larger the value of resolution parameter γ, the less resolution limit the network suffers; while for modularity density D, the less resolution limit the network suffers when we decrease the value of γ. Our framework is mathematically strict and efficient and can be applied in a lot of scientific fields.

  11. Methods uncovering usability issues in medication-related alerting functions: results from a systematic review.

    PubMed

    Marcilly, Romaric; Vasseur, Francis; Ammenwerth, Elske; Beuscart-Zephir, Marie-Catherine

    2014-01-01

    This paper aims at listing the methods used to evaluate the usability of medication-related alerting functions and at knowing what type of usability issues those methods allow to detect. A sub-analysis of data from this systematic review has been performed. Methods applied in the included papers were collected. Then, included papers were sorted in four types of evaluation: "expert evaluation", "user- testing/simulation", "on site observation" and "impact studies". The types of usability issues (usability flaws, usage problems and negative outcomes) uncovered by those evaluations were analyzed. Results show that a large set of methods are used. The largest proportion of papers uses "on site observation" evaluation. This is the only evaluation type for which every kind of usability flaws, usage problems and outcomes are detected. It is somehow surprising that, in a usability systematic review, most of the papers included use a method that is not often presented as a usability method. Results are discussed about the opportunity to provide usability information collected after the implementation of the technology during their design process, i.e. before their implementation.

  12. Ethnomathematics study: uncovering units of length, area, and volume in Kampung Naga Society

    NASA Astrophysics Data System (ADS)

    Septianawati, T.; Turmudi; Puspita, E.

    2017-02-01

    During this time, mathematics is considered as something neutral and not associated with culture. It can be seen from mathematics learning in the school which adopt many of foreign mathematics learning are considered more advanced (western). In fact, Indonesia is a rich country in cultural diversity. In the cultural activities, there are mathematical ideas that were considered a important thing in the mathematics learning. A study that examines the idea or mathematical practices in a variety of cultural activities are known as ethnomathematics. In Indonesia, there are some ethnic maintain their ancestral traditions, one of them is Kampung Naga. Therefore, this study was conducted in Kampung Naga. This study aims to uncover units of length, area, and volume used by Kampung Naga society. This study used a qualitative approach and ethnography methods. In this research, data collection is done through the principles of ethnography such as observation, interviews, documentation, and field notes. The results of this study are units of length, area, and volume used by Kampung Naga society and its conversion into standard units. This research is expected to give information to the public that mathematics has a relationship with culture and become recommendation to mathematics curriculum in Indonesia.

  13. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

    PubMed

    Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K; Drong, Alexander W; Hayes, James E; Zhao, Jinghua; Pers, Tune H; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Del Greco M, Fabiola; Pasko, Dorota; Renström, Frida; Willems, Sara M; Mahajan, Anubha; Rose, Lynda M; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S; Ju Sung, Yun; Ramos, Yolande F; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J N; Crosslin, David R; Dale, Caroline E; Dastani, Zari; Day, Felix R; Deelen, Joris; Delgado, Graciela E; Demirkan, Ayse; Finucane, Francis M; Ford, Ian; Garcia, Melissa E; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A; Hunter, David J; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S; Jørgensen, Marit E; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P; Myers, Richard H; Männistö, Satu; Nalls, Mike A; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rice, Treva K; Brent Richards, J; Ridker, Paul M; Sattar, Naveed; Savage, David B; Söderberg, Stefan; Timpson, Nicholas J; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I A; Sarzynski, Mark A; Rao, D C; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G; Heliövaara, Markku; Knekt, Paul B; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K; Viikari, Jorma S; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W; van Duijn, Cornelia M; Harris, Tamara B; Bouchard, Claude; Allison, Matthew A; Chasman, Daniel I; Ohlsson, Claes; Lind, Lars; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; Ferrucci, Luigi; Frayling, Timothy M; Pramstaller, Peter P; Borecki, Ingrid B; Waterworth, Dawn M; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B; Eline Slagboom, P; Grallert, Harald; Spector, Tim D; Jukema, J W; Klein, Robert J; Schadt, Erik E; Franks, Paul W; Lindgren, Cecilia M; Leibel, Rudolph L; Loos, Ruth J F

    2016-02-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

  14. Uncovering the structural basis of protein interactions with efficient clustering of 3-D interaction interfaces.

    PubMed

    Aung, Z; Tan, S-H; Ng, S-K; Tan, K-L

    2007-01-01

    The biological mechanisms with which proteins interact with one another are best revealed by studying the structural interfaces between interacting proteins. Protein-protein interfaces can be extracted from 3-D structural data of protein complexes and then clustered to derive biological insights. However, conventional protein interface clustering methods lack computational scalability and statistical support. In this work, we present a new method named "PPiClust" to systematically encode, cluster and analyze similar 3-D interface patterns in protein complexes efficiently. Experimental results showed that our method is effective in discovering visually consistent and statistically significant clusters of interfaces, and at the same time sufficiently time-efficient to be performed on a single computer. The interface clusters are also useful for uncovering the structural basis of protein interactions. Analysis of the resulting interface clusters revealed groups of structurally diverse proteins having similar interface patterns. We also found, in some of the interface clusters, the presence of well-known linear binding motifs which were non-contiguous in the primary sequences. These results suggest that PPiClust can discover not only statistically significant but also biologically significant protein interface clusters from protein complex structural data.

  15. The characteristic blue spectra of accretion disks in quasars as uncovered in the infrared.

    PubMed

    Kishimoto, Makoto; Antonucci, Robert; Blaes, Omer; Lawrence, Andy; Boisson, Catherine; Albrecht, Marcus; Leipski, Christian

    2008-07-24

    Quasars are thought to be powered by supermassive black holes accreting surrounding gas. Central to this picture is a putative accretion disk which is believed to be the source of the majority of the radiative output. It is well known, however, that the most extensively studied disk model-an optically thick disk which is heated locally by the dissipation of gravitational binding energy-is apparently contradicted by observations in a few major respects. In particular, the model predicts a specific blue spectral shape asymptotically from the visible to the near-infrared, but this is not generally seen in the visible wavelength region where the disk spectrum is observable. A crucial difficulty has been that, towards the infrared, the disk spectrum starts to be hidden under strong, hot dust emission from much larger but hitherto unresolved scales, and thus has essentially been impossible to observe. Here we report observations of polarized light interior to the dust-emitting region that enable us to uncover this near-infrared disk spectrum in several quasars. The revealed spectra show that the near-infrared disk spectrum is indeed as blue as predicted. This indicates that, at least for the outer near-infrared-emitting radii, the standard picture of the locally heated disk is approximately correct.

  16. Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging.

    PubMed

    Rose, P B; Erickson, A S; Mayer, M; Nattress, J; Jovanovic, I

    2016-04-18

    Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as "searching for a needle in a haystack" because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method from being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material's areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications.

  17. Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging

    DOE PAGES

    Rose, P. B.; Erickson, A. S.; Mayer, M.; ...

    2016-04-18

    Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as “searching for a needle in a haystack” because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method frommore » being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material’s areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications.« less

  18. Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging

    SciTech Connect

    Rose, P. B.; Erickson, A. S.; Mayer, M.; Nattress, J.; Jovanovic, I.

    2016-04-18

    Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as “searching for a needle in a haystack” because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method from being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material’s areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications.

  19. Uncovering stem-cell heterogeneity in the microniche with label-free microfluidics

    NASA Astrophysics Data System (ADS)

    Sohn, Lydia L.

    2013-03-01

    Better suited for large number of cells from bulk tissue, traditional cell-screening techniques, such as fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS), cannot easily screen stem or progenitor cells from minute populations found in their physiological niches. Furthermore, they rely upon irreversible antibody binding, potentially altering cell properties, including gene expression and regenerative capacity. We have developed a label-free, single-cell analysis microfluidic platform capable of quantifying cell-surface marker expression of functional organ stem cells directly isolated from their micro-anatomical niche. With this platform, we have screened single quiescent muscle stem (satellite) cells derived from single myofibers, and we have uncovered an important heterogeneity in the surface-marker expression of these cells. By sorting the screened cells with our microfluidic device, we have determined what this heterogeneity means in terms of muscle stem-cell functionality. For instance, we show that the levels of beta1-integrin can predict the differentiation capacity of quiescent satellite cells, and in contrast to recent literature, that some CXCR4 + cells are not myogenic. Our results provide the first direct demonstration of a microniche-specific variation in gene expression in stem cells of the same lineage. Overall, our label-free, single-cell analysis and cell-sorting platform could be extended to other systems involving rare-cell subsets. This work was funded by the W. M. Keck Foundation, NIH, and California Institute of Regenerative Medicine

  20. Novel resistance functions uncovered using functional metagenomic investigations of resistance reservoirs

    PubMed Central

    Pehrsson, Erica C.; Forsberg, Kevin J.; Gibson, Molly K.; Ahmadi, Sara; Dantas, Gautam

    2013-01-01

    Rates of infection with antibiotic-resistant bacteria have increased precipitously over the past several decades, with far-reaching healthcare and societal costs. Recent evidence has established a link between antibiotic resistance genes in human pathogens and those found in non-pathogenic, commensal, and environmental organisms, prompting deeper investigation of natural and human-associated reservoirs of antibiotic resistance. Functional metagenomic selections, in which shotgun-cloned DNA fragments are selected for their ability to confer survival to an indicator host, have been increasingly applied to the characterization of many antibiotic resistance reservoirs. These experiments have demonstrated that antibiotic resistance genes are highly diverse and widely distributed, many times bearing little to no similarity to known sequences. Through unbiased selections for survival to antibiotic exposure, functional metagenomics can improve annotations by reducing the discovery of false-positive resistance and by allowing for the identification of previously unrecognizable resistance genes. In this review, we summarize the novel resistance functions uncovered using functional metagenomic investigations of natural and human-impacted resistance reservoirs. Examples of novel antibiotic resistance genes include those highly divergent from known sequences, those for which sequence is entirely unable to predict resistance function, bifunctional resistance genes, and those with unconventional, atypical resistance mechanisms. Overcoming antibiotic resistance in the clinic will require a better understanding of existing resistance reservoirs and the dissemination networks that govern horizontal gene exchange, informing best practices to limit the spread of resistance-conferring genes to human pathogens. PMID:23760651

  1. Discovery of an uncovered region in fibrin clots and its clinical significance

    PubMed Central

    Hisada, Yohei; Yasunaga, Masahiro; Hanaoka, Shingo; Saijou, Shinji; Sugino, Takashi; Tsuji, Atsushi; Saga, Tsuneo; Tsumoto, Kouhei; Manabe, Shino; Kuroda, Jun-ichiro; Kuratsu, Jun-ichi; Matsumura, Yasuhiro

    2013-01-01

    Despite the pathological importance of fibrin clot formation, little is known about the structure of these clots because X-ray and nuclear magnetic resonance (NMR) analyses are not applicable to insoluble proteins. In contrast to previously reported anti-fibrin monoclonal antibodies (mAbs), our anti-fibrin clot mAb (clone 102–10) recognises an uncovered region that is exposed only when a fibrin clot forms. The epitope of the 102–10 mAb was mapped to a hydrophobic region on the Bβ chain that interacted closely with a counterpart region on the γ chain in a soluble state. New anti-Bβ and anti-γ mAbs specific to peptides lining the discovered region appeared to bind exclusively to fibrin clots. Furthermore, the radiolabelled 102–10 mAb selectively accumulated in mouse spontaneous tumours, and immunohistochemistry using this mAb revealed greater fibrin deposition in World Health Organization (WHO) grade 4 glioma than in lower-grade gliomas. Because erosive tumours are apt to cause micro-haemorrhages, even early asymptomatic tumours detected with a radiolabelled 102-10 mAb may be aggressively malignant. PMID:24008368

  2. DNA barcoding uncovers cryptic diversity in 50% of deep-sea Antarctic polychaetes

    PubMed Central

    Wiklund, Helena; Neal, Lenka; Jeffreys, Rachel; Linse, Katrin; Ruhl, Henry; Glover, Adrian G.

    2016-01-01

    The Antarctic marine environment is a diverse ecosystem currently experiencing some of the fastest rates of climatic change. The documentation and management of these changes requires accurate estimates of species diversity. Recently, there has been an increased recognition of the abundance and importance of cryptic species, i.e. those that are morphologically identical but genetically distinct. This article presents the largest genetic investigation into the prevalence of cryptic polychaete species within the deep Antarctic benthos to date. We uncover cryptic diversity in 50% of the 15 morphospecies targeted through the comparison of mitochondrial DNA sequences, as well as 10 previously overlooked morphospecies, increasing the total species richness in the sample by 233%. Our ability to describe universal rules for the detection of cryptic species within polychaetes, or normalization to expected number of species based on genetic data is prevented by taxon-specific differences in phylogenetic outputs and genetic variation between and within potential cryptic species. These data provide the foundation for biogeographic and functional analysis that will provide insight into the drivers of species diversity and its role in ecosystem function. PMID:28018624

  3. Antisocial behaviour and psychopathy: uncovering the externalizing link in the P3 modulation.

    PubMed

    Pasion, Rita; Fernandes, Carina; Pereira, Mariana R; Barbosa, Fernando

    2017-03-22

    In 2009, Gao and Raine's meta-analysis analysed P3 modulation over the antisocial spectrum. However, some questions remained open regarding the P3 modulation patterns across impulsive and violent manifestations of antisocial behaviour, phenotypic components of psychopathy, and P3 components. A systematic review of 36 studies was conducted (N=3514) to extend previous results and to address these unresolved questions. A clear link between decreased P3 amplitude and antisocial behaviour was found. In psychopathy, dimensional approaches become more informative than taxonomic models. Distinct etiological pathways of psychopathy were evidenced in cognitive tasks: impulsive-antisocial psychopathic traits mainly predicted blunted P3 amplitude, while interpersonal-affective psychopathic traits explained enhanced P3 amplitude. Supporting the low fear hypothesis, the interpersonal-affective traits were associated with reduced P3 amplitude in emotional-affective learning tasks. From the accumulated knowledge we propose a framework of P3 amplitude modulation that uncovers the externalizing link between psychopathy and antisocial behaviour. However, the main hypotheses are exploratory and call for more data before stablishing robust conclusions.

  4. DNA barcoding uncovers cryptic diversity in 50% of deep-sea Antarctic polychaetes.

    PubMed

    Brasier, Madeleine J; Wiklund, Helena; Neal, Lenka; Jeffreys, Rachel; Linse, Katrin; Ruhl, Henry; Glover, Adrian G

    2016-11-01

    The Antarctic marine environment is a diverse ecosystem currently experiencing some of the fastest rates of climatic change. The documentation and management of these changes requires accurate estimates of species diversity. Recently, there has been an increased recognition of the abundance and importance of cryptic species, i.e. those that are morphologically identical but genetically distinct. This article presents the largest genetic investigation into the prevalence of cryptic polychaete species within the deep Antarctic benthos to date. We uncover cryptic diversity in 50% of the 15 morphospecies targeted through the comparison of mitochondrial DNA sequences, as well as 10 previously overlooked morphospecies, increasing the total species richness in the sample by 233%. Our ability to describe universal rules for the detection of cryptic species within polychaetes, or normalization to expected number of species based on genetic data is prevented by taxon-specific differences in phylogenetic outputs and genetic variation between and within potential cryptic species. These data provide the foundation for biogeographic and functional analysis that will provide insight into the drivers of species diversity and its role in ecosystem function.

  5. Uncovering a new role for peroxidase enzymes as drivers of angiogenesis.

    PubMed

    Panagopoulos, Vasilios; Zinonos, Irene; Leach, Damien A; Hay, Shelley J; Liapis, Vasilios; Zysk, Aneta; Ingman, Wendy V; DeNichilo, Mark O; Evdokiou, Andreas

    2015-11-01

    Peroxidases are heme-containing enzymes released by activated immune cells at sites of inflammation. To-date their functional role in human health has mainly been limited to providing a mechanism for oxidative defence against invading bacteria and other pathogenic microorganisms. Our laboratory has recently identified a new functional role for peroxidase enzymes in stimulating fibroblast migration and collagen biosynthesis, offering a new insight into the causative association between inflammation and the pro-fibrogenic events that mediate tissue repair and regeneration. Peroxidases are found at elevated levels within and near blood vessels however, their direct involvement in angiogenesis has never been reported. Here we report for the first time that myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are readily internalised by human umbilical vein endothelial cells (HUVEC) where they promote cellular proliferation, migration, invasion, and stimulate angiogenesis both in vitro and in vivo. These pro-angiogenic effects were attenuated using the specific peroxidase inhibitor 4-ABAH, indicating the enzyme's catalytic activity is essential in mediating this response. Mechanistically, we provide evidence that MPO and EPO regulate endothelial FAK, Akt, p38 MAPK, ERK1/2 phosphorylation and stabilisation of HIF-2α, culminating in transcriptional regulation of key angiogenesis pathways. These findings uncover for the first time an important and previously unsuspected role for peroxidases as drivers of angiogenesis, and suggest that peroxidase inhibitors may have therapeutic potential for the treatment of angiogenesis related diseases driven by inflammation.

  6. Structural phylogenomics uncovers the early and concurrent origins of cysteine biosynthesis and iron-sulfur proteins.

    PubMed

    Zhang, Hong-Yu; Qin, Tao; Jiang, Ying-Ying; Caetano-Anollés, Gustavo

    2012-01-01

    Cysteine (Cys) has unique chemical properties of catalysis, metal chelation, and protein stabilization. While Cys biosynthesis is assumed to be very ancient, the actual time of origin of these metabolic pathways remains unknown. Here, we use the molecular clocks of protein folds and fold superfamilies to time the origin of Cys biosynthesis. We find that the tRNA-dependent biosynthetic pathway appeared ~3.5 billion years ago while the tRNA-independent counterpart emerged ~500 million years later. A deep analysis of the origins of Cys biosynthesis in the context of emerging biochemistry uncovers some intriguing features of the planetary environment of early Earth. Results suggest that iron-sulfur (Fe-S) proteins that use cysteinyl sulfur to bind iron atoms were not the first to arise in evolution. Instead, their origin coincides with the appearance of the first Cys biosynthetic pathway. It is therefore likely that Cys did not play an important role in the make up of primordial protein molecules and that Fe-S clusters were not part of active sites at the beginning of biological history.

  7. Uncovering the lived experiences of junior and senior undergraduate female science majors

    NASA Astrophysics Data System (ADS)

    Adornato, Philip

    The following dissertation focuses on a case study that uses critical theory, social learning theory, identity theory, liberal feminine theory, and motivation theory to conduct a narrative describing the lived experience of females and their performance in two highly selective private university, where students can cross-register between school, while majoring in science, technology, engineering and mathematics (STEM). Through the use of narratives, the research attempts to shed additional light on the informal and formal science learning experiences that motivates young females to major in STEM in order to help increase the number of women entering STEM careers and retaining women in STEM majors. In the addition to the narratives, surveys were performed to encompass a larger audience while looking for themes and phenomena which explore what captivates and motivates young females' interests in science and continues to nurture and facilitate their growth throughout high school and college, and propel them into a major in STEM in college. The purpose of this study was to uncover the lived experiences of junior and senior undergraduate female science majors during their formal and informal education, their science motivation to learn science, their science identities, and any experiences in gender inequity they may have encountered. The findings have implications for young women deciding on future careers and majors through early exposure and guidance, understanding and recognizing what gender discrimination, and the positive effects of mentorships.

  8. Uncovering secrets behind low-resistance planing craft hull forms through optimization

    NASA Astrophysics Data System (ADS)

    Mohamad Ayob, Ahmad F.; Ray, Tapabrata; Smith, Warren F.

    2011-11-01

    There has always been significant interest within the naval architectural research community to identify ship hull forms with low resistance. While numerous design optimization frameworks have been proposed over the years to support the activity, very little attention has been paid towards the process of gaining an understanding of 'what makes a good ship design superior?'. Furthermore, there have been limited attempts to identify computationally cheap indicators that can be used to distinguish between good and poor designs. A recent technique named discovery of innovative design principles, which is aimed at understanding the relationship between the design variables, is incorporated in this work. In this article, optimal high-speed planing craft hull forms with minimum calm-water resistance are identified through the use of three state-of-the-art optimization algorithms. Collections of such designs are then used to uncover insights into the underlying relationships between the variables. The importance of such relationships is further analysed to identify computationally cheap performance indicators that can be used in lieu of detailed calm-water resistance calculations. Such indicators are useful at the concept and preliminary design stages, where one needs to sieve efficiently through a number of candidate designs to identify the better ones for further analysis.

  9. Catecholaminergic challenge uncovers distinct Pavlovian and instrumental mechanisms of motivated (in)action

    PubMed Central

    Swart, Jennifer C; Froböse, Monja I; Cook, Jennifer L; Geurts, Dirk EM; Frank, Michael J; Cools, Roshan; den Ouden, Hanneke EM

    2017-01-01

    Catecholamines modulate the impact of motivational cues on action. Such motivational biases have been proposed to reflect cue-based, ‘Pavlovian’ effects. Here, we assess whether motivational biases may also arise from asymmetrical instrumental learning of active and passive responses following reward and punishment outcomes. We present a novel paradigm, allowing us to disentangle the impact of reward and punishment on instrumental learning from Pavlovian response biasing. Computational analyses showed that motivational biases reflect both Pavlovian and instrumental effects: reward and punishment cues promoted generalized (in)action in a Pavlovian manner, whereas outcomes enhanced instrumental (un)learning of chosen actions. These cue- and outcome-based biases were altered independently by the catecholamine enhancer melthylphenidate. Methylphenidate’s effect varied across individuals with a putative proxy of baseline dopamine synthesis capacity, working memory span. Our study uncovers two distinct mechanisms by which motivation impacts behaviour, and helps refine current models of catecholaminergic modulation of motivated action. DOI: http://dx.doi.org/10.7554/eLife.22169.001 PMID:28504638

  10. Uncovering physiologic mechanisms of circadian rhythms and sleep/wake regulation through mathematical modeling.

    PubMed

    Kronauer, Richard E; Gunzelmann, Glenn; Van Dongen, Hans P A; Doyle, Francis J; Klerman, Elizabeth B

    2007-06-01

    Mathematical models of neurobehavioral function are useful both for understanding the underlying physiology and for predicting the effects of rest-activity-work schedules and interventions on neurobehavioral function. In a symposium titled "Modeling Human Neurobehavioral Performance I: Uncovering Physiologic Mechanisms" at the 2006 Society for Industrial and Applied Mathematics/Society for Mathematical Biology (SIAM/SMB) Conference on the Life Sciences, different approaches to modeling the physiology of human circadian rhythms, sleep, and neurobehavioral performance and their usefulness in understanding the underlying physiology were examined. The topics included key elements of the physiology that should be included in mathematical models, a computational model developed within a cognitive architecture that has begun to include the effects of extended wake on information-processing mechanisms that influence neurobehavioral function, how to deal with interindividual differences in the prediction of neurobehavioral function, the applications of systems biology and control theory to the study of circadian rhythms, and comparisons of these methods in approaching the overarching questions of the underlying physiology and mathematical models of circadian rhythms and neurobehavioral function. A unifying theme was that it is important to have strong collaborative ties between experimental investigators and mathematical modelers, both for the design and conduct of experiments and for continued development of the models.

  11. Uncovering system-specific stress signatures in primate teeth with multimodal imaging

    PubMed Central

    Austin, Christine; Smith, Tanya M.; Farahani, Ramin M. Z.; Hinde, Katie; Carter, Elizabeth A.; Lee, Joonsup; Lay, Peter A.; Kennedy, Brendan J.; Sarrafpour, Babak; Wright, Rosalind J.; Wright, Robert O.; Arora, Manish

    2016-01-01

    Early life stress can disrupt development and negatively impact long-term health trajectories. Reconstructing histories of early life exposure to external stressors is hampered by the absence of retrospective time-specific biomarkers. Defects in tooth enamel have been used to reconstruct stress but the methods used are subjective and do not identify the specific biological systems impacted by external stressors. Here we show that external physical and social stressors impart biochemical signatures in primate teeth that can be retrieved to objectively reconstruct the timing of early life developmental disruptions. Using teeth from captive macaques, we uncovered elemental imprints specific to disruptions of skeletal growth, including major disruptions in body weight trajectory and moderate to severe illnesses. Discrete increases in heat shock protein-70 expression in dentine coincided with elemental signatures, confirming that elemental signals were associated with activation of stress-related pathways. To overcome limitations of conventional light-microscopic analysis, we used high resolution Raman microspectral imaging to identify structural and compositional alterations in enamel and dentine that coincided with elemental signatures and with detailed medical and behavioural data. Integrating these objective biochemical markers with temporal mapping of teeth enables the retrospective study of early life developmental disruptions and their ensuing health sequelae. PMID:26727334

  12. Uncovering compounds by synergy of cluster expansion and high-throughput methods.

    PubMed

    Levy, Ohad; Hart, Gus L W; Curtarolo, Stefano

    2010-04-07

    Predicting from first-principles calculations whether mixed metallic elements phase-separate or form ordered structures is a major challenge of current materials research. It can be partially addressed in cases where experiments suggest the underlying lattice is conserved, using cluster expansion (CE) and a variety of exhaustive evaluation or genetic search algorithms. Evolutionary algorithms have been recently introduced to search for stable off-lattice structures at fixed mixture compositions. The general off-lattice problem is still unsolved. We present an integrated approach of CE and high-throughput ab initio calculations (HT) applicable to the full range of compositions in binary systems where the constituent elements or the intermediate ordered structures have different lattice types. The HT method replaces the search algorithms by direct calculation of a moderate number of naturally occurring prototypes representing all crystal systems and guides CE calculations of derivative structures. This synergy achieves the precision of the CE and the guiding strengths of the HT. Its application to poorly characterized binary Hf systems, believed to be phase-separating, defines three classes of alloys where CE and HT complement each other to uncover new ordered structures.

  13. Uncovering buffered pleiotropy: a genome-scale screen for mel-28 genetic interactors in Caenorhabditis elegans.

    PubMed

    Fernandez, Anita G; Mis, Emily K; Lai, Allison; Mauro, Michael; Quental, Angela; Bock, Carly; Piano, Fabio

    2014-01-10

    mel-28 (maternal-effect-lethal-28) encodes a conserved protein required for nuclear envelope function and chromosome segregation in Caenorhabditis elegans. Because mel-28 is a strict maternal-effect lethal gene, its function is required in the early embryo but appears to be dispensable for larval development. We wanted to test the idea that mel-28 has postembryonic roles that are buffered by the contributions of other genes. To find genes that act coordinately with mel-28, we did an RNA interference-based genetic interaction screen using mel-28 and wild-type larvae. We screened 18,364 clones and identified 65 genes that cause sterility in mel-28 but not wild-type worms. Some of these genes encode components of the nuclear pore. In addition we identified genes involved in dynein and dynactin function, vesicle transport, and cell-matrix attachments. By screening mel-28 larvae we have bypassed the requirement for mel-28 in the embryo, uncovering pleiotropic functions for mel-28 later in development that are normally provided by other genes. This work contributes toward revealing the gene networks that underlie cellular processes and reveals roles for a maternal-effect lethal gene later in development.

  14. Uncovering Buffered Pleiotropy: A Genome-Scale Screen for mel-28 Genetic Interactors in Caenorhabditis elegans

    PubMed Central

    Fernandez, Anita G.; Mis, Emily K.; Lai, Allison; Mauro, Michael; Quental, Angela; Bock, Carly; Piano, Fabio

    2013-01-01

    mel-28 (maternal-effect-lethal-28) encodes a conserved protein required for nuclear envelope function and chromosome segregation in Caenorhabditis elegans. Because mel-28 is a strict maternal-effect lethal gene, its function is required in the early embryo but appears to be dispensable for larval development. We wanted to test the idea that mel-28 has postembryonic roles that are buffered by the contributions of other genes. To find genes that act coordinately with mel-28, we did an RNA interference−based genetic interaction screen using mel-28 and wild-type larvae. We screened 18,364 clones and identified 65 genes that cause sterility in mel-28 but not wild-type worms. Some of these genes encode components of the nuclear pore. In addition we identified genes involved in dynein and dynactin function, vesicle transport, and cell-matrix attachments. By screening mel-28 larvae we have bypassed the requirement for mel-28 in the embryo, uncovering pleiotropic functions for mel-28 later in development that are normally provided by other genes. This work contributes toward revealing the gene networks that underlie cellular processes and reveals roles for a maternal-effect lethal gene later in development. PMID:24281427

  15. Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas

    PubMed Central

    Braggio, Esteban; Van Wier, Scott; Ojha, Juhi; McPhail, Ellen; Asmann, Yan W.; Egan, Jan; da Silva, Jackline Ayres; Schiff, David; Lopes, M Beatriz; Decker, Paul A; Valdez, Riccardo; Tibes, Raoul; Eckloff, Bruce; Witzig, Thomas E.; Stewart, A Keith; Fonseca, Rafael; O’Neill, Brian Patrick

    2015-01-01

    Purpose Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental design We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results Biallelic inactivation of TOX and PRKCD were recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. Additionally, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11 and translocations IgH-BCL6. Overall, BCR/TLR/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas. PMID:25991819

  16. Uncovering Special Nuclear Materials by Low-energy Nuclear Reaction Imaging

    PubMed Central

    Rose, P. B.; Erickson, A. S.; Mayer, M.; Nattress, J.; Jovanovic, I.

    2016-01-01

    Weapons-grade uranium and plutonium could be used as nuclear explosives with extreme destructive potential. The problem of their detection, especially in standard cargo containers during transit, has been described as “searching for a needle in a haystack” because of the inherently low rate of spontaneous emission of characteristic penetrating radiation and the ease of its shielding. Currently, the only practical approach for uncovering well-shielded special nuclear materials is by use of active interrogation using an external radiation source. However, the similarity of these materials to shielding and the required radiation doses that may exceed regulatory limits prevent this method from being widely used in practice. We introduce a low-dose active detection technique, referred to as low-energy nuclear reaction imaging, which exploits the physics of interactions of multi-MeV monoenergetic photons and neutrons to simultaneously measure the material’s areal density and effective atomic number, while confirming the presence of fissionable materials by observing the beta-delayed neutron emission. For the first time, we demonstrate identification and imaging of uranium with this novel technique using a simple yet robust source, setting the stage for its wide adoption in security applications. PMID:27087555

  17. Uncovering DELLA-Independent Gibberellin Responses by Characterizing New Tomato procera Mutants.

    PubMed

    Livne, Sivan; Lor, Vai S; Nir, Ido; Eliaz, Natanella; Aharoni, Asaph; Olszewski, Neil E; Eshed, Yuval; Weiss, David

    2015-06-01

    Gibberellin (GA) regulates plant development primarily by triggering the degradation/deactivation of the DELLA proteins. However, it remains unclear whether all GA responses are regulated by DELLAs. Tomato (Solanum lycopersicum) has a single DELLA gene named PROCERA (PRO), and its recessive pro allele exhibits constitutive GA activity but retains responsiveness to external GA. In the loss-of-function mutant pro(ΔGRAS), all examined GA developmental responses were considerably enhanced relative to pro and a defect in seed desiccation tolerance was uncovered. As pro, but not pro(ΔGRAS), elongation was promoted by GA treatment, pro may retain residual DELLA activity. In agreement with homeostatic feedback regulation of the GA biosynthetic pathway, we found that GA20oxidase1 expression was suppressed in pro(ΔGRAS) and was not affected by exogenous GA3. In contrast, expression of GA2oxidase4 was not affected by the elevated GA signaling in pro(ΔGRAS) but was strongly induced by exogenous GA3. Since a similar response was found in Arabidopsis thaliana plants with impaired activity of all five DELLA genes, we suggest that homeostatic GA responses are regulated by both DELLA-dependent and -independent pathways. Transcriptome analysis of GA-treated pro(ΔGRAS) leaves suggests that 5% of all GA-regulated genes in tomato are DELLA independent.

  18. Uncovering the rules for protein–protein interactions from yeast genomic data

    PubMed Central

    Wang, Jin; Li, Chunhe; Wang, Erkang; Wang, Xidi

    2009-01-01

    Identifying protein–protein interactions is crucial for understanding cellular functions. Genomic data provides opportunities and challenges in identifying these interactions. We uncover the rules for predicting protein–protein interactions using a frequent pattern tree (FPT) approach modified to generate a minimum set of rules (mFPT), with rule attributes constructed from the interaction features of the yeast genomic data. The mFPT prediction accuracy is benchmarked against other commonly used methods such as Bayesian networks and logistic regressions under various statistical measures. Our study indicates that mFPT outranks other methods in predicting the protein–protein interactions for the database used. We predict a new protein–protein interaction complex whose biological function is related to premRNA splicing and new protein–protein interactions within existing complexes based on the rules generated. Our method is general and can be used to discover the underlying rules for protein–protein interactions, genomic interactions, structure-function relationships, and other fields of research. PMID:19237561

  19. Newly Uncovered Large-Scale Component of the Northern Jet in R Aqr

    NASA Astrophysics Data System (ADS)

    Montez, Rodolfo; Karovska, Margarita; Nichols, Joy S.; Kashyap, Vinay

    2017-06-01

    R Aqr is a symbiotic system comprised a compact white dwarf and Mira giant star. The interaction of these stars is responsible for the presence of a two-sided jet structure that is seen across the electromagnetic spectrum. X-ray emission from the jet was first discovered in 2000 with an observation by the Chandra X-ray Observatory. Since then follow-up observations have traced the evolution of the X-ray emission from the jet and a central compact source. In X-rays, the NE jet is brighter than the SW jet, but the full extent of the SW jet was larger - before it began fading below the detection threshold. However, we have uncovered evidence for large-scale emission associated with the NE jet that matches the extent of the SW jet. The emission has escaped previous identification because it is near the detection threshold, but it has been present since the first 2000 observation and clearly evolves in subsequent observations. We present our study of the emission from this component of the NE jet, its relationship to multiwavelength observations, and how it impacts our interpretation of the jet-phenomenon in R Aqr.

  20. The work is never ending: uncovering teamwork sustainability using realistic evaluation.

    PubMed

    Frykman, Mandus; von Thiele Schwarz, Ulrica; Muntlin Athlin, Åsa; Hasson, Henna; Mazzocato, Pamela

    2017-03-20

    Purpose The purpose of this paper is to uncover the mechanisms influencing the sustainability of behavior changes following the implementation of teamwork. Design/methodology/approach Realistic evaluation was combined with a framework (DCOM®) based on applied behavior analysis to study the sustainability of behavior changes two and a half years after the initial implementation of teamwork at an emergency department. The DCOM® framework was used to categorize the mechanisms of behavior change interventions (BCIs) into the four categories of direction, competence, opportunity, and motivation. Non-participant observation and interview data were used. Findings The teamwork behaviors were not sustained. A substantial fallback in managerial activities in combination with a complex context contributed to reduced direction, opportunity, and motivation. Reduced direction made staff members unclear about how and why they should work in teams. Deterioration of opportunity was evident from the lack of problem-solving resources resulting in accumulated barriers to teamwork. Motivation in terms of management support and feedback was reduced. Practical implications The implementation of complex organizational changes in complex healthcare contexts requires continuous adaption and managerial activities well beyond the initial implementation period. Originality/value By integrating the DCOM® framework with realistic evaluation, this study responds to the call for theoretically based research on behavioral mechanisms that can explain how BCIs interact with context and how this interaction influences sustainability.

  1. Plant Phenotyping using Probabilistic Topic Models: Uncovering the Hyperspectral Language of Plants.

    PubMed

    Wahabzada, Mirwaes; Mahlein, Anne-Katrin; Bauckhage, Christian; Steiner, Ulrike; Oerke, Erich-Christian; Kersting, Kristian

    2016-03-09

    Modern phenotyping and plant disease detection methods, based on optical sensors and information technology, provide promising approaches to plant research and precision farming. In particular, hyperspectral imaging have been found to reveal physiological and structural characteristics in plants and to allow for tracking physiological dynamics due to environmental effects. In this work, we present an approach to plant phenotyping that integrates non-invasive sensors, computer vision, as well as data mining techniques and allows for monitoring how plants respond to stress. To uncover latent hyperspectral characteristics of diseased plants reliably and in an easy-to-understand way, we "wordify" the hyperspectral images, i.e., we turn the images into a corpus of text documents. Then, we apply probabilistic topic models, a well-established natural language processing technique that identifies content and topics of documents. Based on recent regularized topic models, we demonstrate that one can track automatically the development of three foliar diseases of barley. We also present a visualization of the topics that provides plant scientists an intuitive tool for hyperspectral imaging. In short, our analysis and visualization of characteristic topics found during symptom development and disease progress reveal the hyperspectral language of plant diseases.

  2. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

    PubMed Central

    Kilpeläinen, Tuomas O.; Carli, Jayne F. Martin; Skowronski, Alicja A.; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K.; Drong, Alexander W.; Hayes, James E.; Zhao, Jinghua; Pers, Tune H.; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Greco M, Fabiola Del; Pasko, Dorota; Renström, Frida; Willems, Sara M.; Mahajan, Anubha; Rose, Lynda M.; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E.; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S.; Ju Sung, Yun; Ramos, Yolande F.; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M.; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J. N.; Crosslin, David R.; Dale, Caroline E.; Dastani, Zari; Day, Felix R.; Deelen, Joris; Delgado, Graciela E.; Demirkan, Ayse; Finucane, Francis M.; Ford, Ian; Garcia, Melissa E.; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E.; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A.; Hunter, David J.; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S.; Jørgensen, Marit E.; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A.; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P.; Myers, Richard H.; Männistö, Satu; Nalls, Mike A.; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D.; Rankinen, Tuomo; Rasmussen-Torvik, Laura J.; Rathmann, Wolfgang; Rice, Treva K.; Brent Richards, J; Ridker, Paul M.; Sattar, Naveed; Savage, David B.; Söderberg, Stefan; Timpson, Nicholas J.; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R.; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I. A.; Sarzynski, Mark A.; Rao, D. C.; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G.; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G.; Heliövaara, Markku; Knekt, Paul B.; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K.; Viikari, Jorma S.; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T.; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P.; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W.; van Duijn, Cornelia M.; Harris, Tamara B.; Bouchard, Claude; Allison, Matthew A.; Chasman, Daniel I.; Ohlsson, Claes; Lind, Lars; Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.; Ferrucci, Luigi; Frayling, Timothy M.; Pramstaller, Peter P.; Borecki, Ingrid B.; Waterworth, Dawn M.; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B.; Eline Slagboom, P; Grallert, Harald; Spector, Tim D.; Jukema, J.W.; Klein, Robert J.; Schadt, Erik E; Franks, Paul W.; Lindgren, Cecilia M.; Leibel, Rudolph L.; Loos, Ruth J. F.

    2016-01-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. PMID:26833098

  3. The proteome and phosphoproteome of maize pollen uncovers fertility candidate proteins.

    PubMed

    Chao, Qing; Gao, Zhi-Fang; Wang, Yue-Feng; Li, Zhe; Huang, Xia-He; Wang, Ying-Chun; Mei, Ying-Chang; Zhao, Biligen-Gaowa; Li, Liang; Jiang, Yu-Bo; Wang, Bai-Chen

    2016-06-01

    Maize is unique since it is both monoecious and diclinous (separate male and female flowers on the same plant). We investigated the proteome and phosphoproteome of maize pollen containing modified proteins and here we provide a comprehensive pollen proteome and phosphoproteome which contain 100,990 peptides from 6750 proteins and 5292 phosphorylated sites corresponding to 2257 maize phosphoproteins, respectively. Interestingly, among the total 27 overrepresented phosphosite motifs we identified here, 11 were novel motifs, which suggested different modification mechanisms in plants compared to those of animals. Enrichment analysis of pollen phosphoproteins showed that pathways including DNA synthesis/chromatin structure, regulation of RNA transcription, protein modification, cell organization, signal transduction, cell cycle, vesicle transport, transport of ions and metabolisms, which were involved in pollen development, the following germination and pollen tube growth, were regulated by phosphorylation. In this study, we also found 430 kinases and 105 phosphatases in the maize pollen phosphoproteome, among which calcium dependent protein kinases (CDPKs), leucine rich repeat kinase, SNF1 related protein kinases and MAPK family proteins were heavily enriched and further analyzed. From our research, we also uncovered hundreds of male sterility-associated proteins and phosphoproteins that might influence maize productivity and serve as targets for hybrid maize seed production. At last, a putative complex signaling pathway involving CDPKs, MAPKs, ubiquitin ligases and multiple fertility proteins was constructed. Overall, our data provides new insight for further investigation of protein phosphorylation status in mature maize pollen and construction of maize male sterile mutants in the future.

  4. Phylogenetic Analyses Uncover a Novel Clade of Transferrin in Nonmammalian Vertebrates

    PubMed Central

    Mohd-Adnan, Adura; Gabaldón, Toni

    2013-01-01

    Transferrin is a protein super-family involved in iron transport, a central process in cellular homeostasis. Throughout the evolution of vertebrates, transferrin members have diversified into distinct subfamilies including serotransferrin, ovotransferrin, lactoferrin, melanotransferrin, the inhibitor of carbonic anhydrase, pacifastin, and the major yolk protein in sea urchin. Previous phylogenetic analyses have established the branching order of the diverse transferrin subfamilies but were mostly focused on the transferrin repertoire present in mammals. Here, we conduct a comprehensive phylogenetic analysis of transferrin protein sequences in sequenced vertebrates, placing a special focus on the less-studied nonmammalian vertebrates. Our analyses uncover a novel transferrin clade present across fish, sauropsid, and amphibian genomes but strikingly absent from mammals. Our reconstructed scenario implies that this novel class emerged through a duplication event at the vertebrate ancestor, and that it was subsequently lost in the lineage leading to mammals. We detect footprints of accelerated evolution following the duplication event, which suggest positive selection and early functional divergence of this novel clade. Interestingly, the loss of this novel class of transferrin in mammals coincided with the divergence by duplication of lactoferrin and serotransferrin in this lineage. Altogether, our results provide novel insights on the evolution of iron-binding proteins in the various vertebrate groups. PMID:23258311

  5. A Bayesian nonparametric approach for uncovering rat hippocampal population codes during spatial navigation.

    PubMed

    Linderman, Scott W; Johnson, Matthew J; Wilson, Matthew A; Chen, Zhe

    2016-04-01

    Rodent hippocampal population codes represent important spatial information about the environment during navigation. Computational methods have been developed to uncover the neural representation of spatial topology embedded in rodent hippocampal ensemble spike activity. We extend our previous work and propose a novel Bayesian nonparametric approach to infer rat hippocampal population codes during spatial navigation. To tackle the model selection problem, we leverage a Bayesian nonparametric model. Specifically, we apply a hierarchical Dirichlet process-hidden Markov model (HDP-HMM) using two Bayesian inference methods, one based on Markov chain Monte Carlo (MCMC) and the other based on variational Bayes (VB). The effectiveness of our Bayesian approaches is demonstrated on recordings from a freely behaving rat navigating in an open field environment. The HDP-HMM outperforms the finite-state HMM in both simulated and experimental data. For HPD-HMM, the MCMC-based inference with Hamiltonian Monte Carlo (HMC) hyperparameter sampling is flexible and efficient, and outperforms VB and MCMC approaches with hyperparameters set by empirical Bayes. The Bayesian nonparametric HDP-HMM method can efficiently perform model selection and identify model parameters, which can used for modeling latent-state neuronal population dynamics. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Do weak adapting backgrounds uncover multiple components in the electroretinogram of the horseshoe crab?

    PubMed

    Lucas, J C; Weiner, W W; Ahmed, J

    2003-01-01

    The lateral eye of the horseshoe crab, Limulus polyphemus, has been used as a model system for over a century to study visual and circadian processes. One advantage of this system is the relative simplicity of the retina. The input pathway of the retina consists of photoreceptor cells that are electrically coupled to the dendrite of a second-order cell, which sends action potentials to the brain. Electroretinograms (ERGs) recorded from the lateral eye show a biphasic shape, with a leading negative wave and a later positive peak. The purpose of these experiments was to determine whether adapting backgrounds could be used to uncover multiple adaptation mechanisms within the ERG. To test this idea, ERGs were elicited using variable intensity flashes presented under dark-adapted conditions, as well as in the presence of weak adapting backgrounds. Flashes and backgrounds were generated using green LEDs (lambda max = 525 nm) under software control. ERGs were recorded using a corneal wick electrode placed on the lateral eye of the horseshoe crab. Preliminary results suggest that ERGs recorded in the presence of adapting backgrounds are linearly scaled versions of dark-adapted FRGs. This suggests that there is a single adaptation stage in the Limulus retina. This is in contrast with analogous results from mammals, including mouse, cat and monkey, which show multiple stages of adaptation within their more complex retinas.

  7. A nonparametric Bayesian approach for uncovering rat hippocampal population codes during spatial navigation

    PubMed Central

    Linderman, Scott W.; Johnson, Matthew J.; Wilson, Matthew A.; Chen, Zhe

    2016-01-01

    Background Rodent hippocampal population codes represent important spatial information about the environment during navigation. Computational methods have been developed to uncover the neural representation of spatial topology embedded in rodent hippocampal ensemble spike activity. New method We extend our previous work and propose a novel nonparametric Bayesian approach to infer rat hippocampal population codes during spatial navigation. To tackle the model selection problem, we leverage a nonparametric Bayesian model. Specifically, we apply a hierarchical Dirichlet process-hidden Markov model (HDP-HMM) using two Bayesian inference methods, one based on Markov chain Monte Carlo (MCMC) and the other based on variational Bayes (VB). Results The effectiveness of our Bayesian approaches is demonstrated on recordings from a freely-behaving rat navigating in an open field environment. Comparison with existing methods The HDP-HMM outperforms the finite-state HMM in both simulated and experimental data. For HPD-HMM, the MCMC-based inference with Hamiltonian Monte Carlo (HMC) hyperparameter sampling is flexible and efficient, and outperforms VB and MCMC approaches with hyperparameters set by empirical Bayes. Conclusion The nonparametric Bayesian HDP-HMM method can efficiently perform model selection and identify model parameters, which can used for modeling latent-state neuronal population dynamics. PMID:26854398

  8. Percutaneous Treatment of Malignant Jaundice Due to Extrahepatic Cholangiocarcinoma: Covered Viabil Stent Versus Uncovered Wallstents

    SciTech Connect

    Krokidis, Miltiadis; Fanelli, Fabrizio; Orgera, Gianluigi; Bezzi, Mario; Passariello, Roberto; Hatzidakis, Adam

    2010-02-15

    To compare clinical effectiveness of Viabil-covered stents versus uncovered metallic Wallstents, for palliation of malignant jaundice due to extrahepatic cholangiocarcinoma, 60 patients were enrolled in a prospective and randomized study. In half of the patients a bare Wallstent was used, and in the other half a Viabil biliary stent. Patients were followed up until death. Primary patency, survival, complication rates, and mean cost were calculated in both groups. Stent dysfunction occurred in 9 (30%) patients in the bare stent group after a mean period of 133.1 days and in 4 (13.3%) patients in the covered stent group after a mean of 179.5 days. The incidence of stent dysfunction was significantly lower in the covered stent group (P = 0.046). Tumor ingrowth occurred exclusively in the bare stent group (P = 0.007). Median survival was 180.5 days for the Wallstent and 243.5 days for the Viabil group (P = 0.039). Complications and mean cost were similar in the two groups. Viabil stent-grafts proved to be significantly superior to Wallstents for the palliation of malignant jaundice due to extrahepatic cholangiocarcinoma, with comparable cost and complication rates. Appropriate patient selection should be performed prior to stent placement.

  9. Covered Stents versus Uncovered Stents for Unresectable Malignant Biliary Strictures: A Meta-Analysis.

    PubMed

    Chen, Ming-Yu; Lin, Jia-Wei; Zhu, He-Pan; Zhang, Bin; Jiang, Guang-Yi; Yan, Pei-Jian; Cai, Xiu-Jun

    2016-01-01

    To summarize the covered or uncovered SEMS for treatment of unresectable malignant distal biliary obstruction, comparing the stent patency, patient survival, and incidence of adverse events between the two SEMSs. The meta-analysis search was performed independently by two of the authors, using MEDLINE, EMBASE, OVID, and Cochrane databases on all studies between 2010 and 2015. Pooled effect was calculated using either the fixed or the random effects model. Statistics shows that there is no difference between SEMSs in the hazard ratio for patient survival (HR 1.04; 95% CI, 0.92-1.17; P = 0.55) and stent patency (HR 0.87, 95% CI: 0.58 to 1.30, P = 0.5). However, incidence of adverse events (OR: 0.74, 95% CI: 0.57 to 0.97, P = 0.03) showed significant different results in the covered SEMS, with dysfunctions events (OR: 0.75, 95% CI: 0.56 to 1.00, P = 0.05) playing a more important role than complications (OR: 0.87, 95% CI: 0.58 to 1.30, P = 0.50). Covered SEMS group had lower incidence of adverse events. There is no significant difference in dysfunctions, but covered SEMS trends to be better, with no difference in stent patency, patient survival, and complications.

  10. (TG)n uncovers a sex-specific hybridization pattern in cattle.

    PubMed

    Kashi, Y; Iraqi, F; Tikochinski, Y; Ruzitsky, B; Nave, A; Beckmann, J S; Friedmann, A; Soller, M; Gruenbaum, Y

    1990-05-01

    Screening of a bovine genomic library with the human minisatellite 33.6 probe uncovered a family of clones that, when used to probe Southern blots of bovine genomic DNA digested with the restriction enzyme HaeIII or MboI, revealed sexually dimorphic, but otherwise virtually monomorphic, patterns among the larger DNA fragments to which they hybridized. Characterization of one of these clones revealed that it contains different minisatellite sequences. The sexual dimorphism hybridization pattern observed with this clone was found to be due to multiple copies of two tandemly interspersed repeats: the simple sequence (TG)n and a previously undescribed 29-bp sequence. Both repeats appear to share many genomic loci including autosomal loci. In contrast, Southern analysis of AluI- or HinfI-digested bovine DNA with the (TG)n repeat used as a probe yielded substantial polymorphism. These results show that (i) different minisatellites can be found in a cluster, (ii) both simple and more complex repeated sequences other than the simple quaternary (GATA)n repeat can be sexually dimorphic, and (iii) simple repeats can reveal substantial polymorphism.

  11. Systematic Triple Mutant Analysis Uncovers Functional Connectivity Between Pathways Involved in Chromosome Regulation

    PubMed Central

    Haber, James E.; Braberg, Hannes; Wu, Qiuqin; Alexander, Richard; Haase, Julian; Ryan, Colm; Lipkin-Moore, Zach; Franks-Skiba, Kathleen E.; Johnson, Tasha; Shales, Michael; Lenstra, Tineke L.; Holstege, Frank C. P.; Johnson, Jeffrey R.; Bloom, Kerry; Krogan, Nevan J.

    2013-01-01

    Genetic interactions reveal the functional relationships between pairs of genes. In this study, we describe a method for the systematic generation and quantitation of triple mutants, termed Triple Mutant Analysis (TMA). We have used this approach to interrogate partially redundant pairs of genes in S. cerevisiae, including ASF1 and CAC1, two histone chaperones. After subjecting asf1Δ cac1Δ to TMA, we found that the Swi/Snf Rdh54 protein, compensates for the absence of Asf1 and Cac1. Rdh54 more strongly associates with the chromatin apparatus and the pericentromeric region in the double mutant. Moreover, Asf1 is responsible for the synthetic lethality observed in cac1Δ strains lacking the HIRA-like proteins. A similar TMA was carried out after deleting both CLB5 and CLB6, cyclins that regulate DNA replication, revealing a strong functional connection to chromosome segregation. This approach can reveal functional redundancies that cannot be uncovered using traditional double mutant analyses. PMID:23746449

  12. UNCOVERING THE ORIGINS OF SPIRAL STRUCTURE BY MEASURING RADIAL VARIATION IN PATTERN SPEEDS

    SciTech Connect

    Meidt, Sharon E.; Rand, Richard J.; Merrifield, Michael R.

    2009-09-01

    Current theories of spiral and bar structure predict a variety of pattern speed behaviors, calling for detailed, direct measurement of the radial variation of pattern speeds. Our recently developed Radial Tremaine-Weinberg (TWR) method allows this goal to be achieved for the first time. Here, we present TWR spiral pattern speed estimates for M101, IC 342, NGC 3938, and NGC 3344 in order to investigate whether spiral structure is steady or winding, whether spirals are described by multiple pattern speeds, and the relation between bar and spiral speeds. Where possible, we interpret our pattern speeds estimates according to the resonance radii associated with each (established with the disk angular rotation), and compare these to previous determinations. By analyzing the high-quality H I and CO data cubes available for these galaxies, we show that it is possible to determine directly multiple pattern speeds within these systems, and hence identify the characteristic signatures of the processes that drive the spiral structure. Even this small sample of galaxies reveals a surprisingly complex taxonomy, with the first direct evidence for the presence of resonant coupling of multiple patterns found in some systems, and the measurement of a simple single-pattern speed in others. Overall, this study demonstrates that we are now in a position to uncover more of the apparently complex physics that lies behind spiral structure.

  13. Uncovering Highly-Excited State Mixing in Acetone Using Ultrafast VUV Pulses and Coincidence Imaging Techniques

    DOE PAGES

    Couch, David E.; Kapteyn, Henry C.; Murnane, Margaret M.; ...

    2017-03-17

    Here, understanding the ultrafast dynamics of highly-excited electronic states of small molecules is critical for a better understanding of atmospheric and astrophysical processes, as well as for designing coherent control strategies for manipulating chemical dynamics. In highly excited states, nonadiabatic coupling, electron-electron interactions, and the high density of states govern dynamics. However, these states are computationally and experimentally challenging to access. Fortunately, new sources of ultrafast vacuum ultraviolet pulses, in combination with electron-ion coincidence spectroscopies, provide new tools to unravel the complex electronic landscape. Here we report time-resolved photoelectron-photoion coincidence experiments using 8 eV pump photons to study the highlymore » excited states of acetone. We uncover for the first time direct evidence that the resulting excited state consists of a mixture of both ny → 3p and π → π* character, which decays with a time constant of 330 fs. In the future, this approach can inform models of VUV photochemistry and aid in designing coherent control strategies for manipulating chemical reactions.« less

  14. Plant Phenotyping using Probabilistic Topic Models: Uncovering the Hyperspectral Language of Plants

    PubMed Central

    Wahabzada, Mirwaes; Mahlein, Anne-Katrin; Bauckhage, Christian; Steiner, Ulrike; Oerke, Erich-Christian; Kersting, Kristian

    2016-01-01

    Modern phenotyping and plant disease detection methods, based on optical sensors and information technology, provide promising approaches to plant research and precision farming. In particular, hyperspectral imaging have been found to reveal physiological and structural characteristics in plants and to allow for tracking physiological dynamics due to environmental effects. In this work, we present an approach to plant phenotyping that integrates non-invasive sensors, computer vision, as well as data mining techniques and allows for monitoring how plants respond to stress. To uncover latent hyperspectral characteristics of diseased plants reliably and in an easy-to-understand way, we “wordify” the hyperspectral images, i.e., we turn the images into a corpus of text documents. Then, we apply probabilistic topic models, a well-established natural language processing technique that identifies content and topics of documents. Based on recent regularized topic models, we demonstrate that one can track automatically the development of three foliar diseases of barley. We also present a visualization of the topics that provides plant scientists an intuitive tool for hyperspectral imaging. In short, our analysis and visualization of characteristic topics found during symptom development and disease progress reveal the hyperspectral language of plant diseases. PMID:26957018

  15. CHANG-ES - VIII. Uncovering hidden AGN activity in radio polarization

    NASA Astrophysics Data System (ADS)

    Irwin, Judith A.; Schmidt, Philip; Damas-Segovia, A.; Beck, Rainer; English, Jayanne; Heald, George; Henriksen, Richard N.; Krause, Marita; Li, Jiang-Tao; Rand, Richard J.; Wang, Q. Daniel; Wiegert, Theresa; Kamieneski, Patrick; Paré, Dylan; Sullivan, Kendall

    2017-01-01

    We report on C-band (5-7 GHz) observations of the galaxy, NGC 2992, from the Continuum Halos in Nearby Galaxies - an EVLA Survey (CHANG-ES) sample. This galaxy displays an embedded nuclear double-lobed radio morphology within its spiral disc, as revealed in linearly polarized emission but not in total intensity emission. The radio lobes are kpc-sized, similar to what has been observed in the past for other Seyfert galaxies, and show ordered magnetic fields. NGC 2992 has shown previous evidence for AGN-related activity, but not the linearly polarized radio features that we present here. We draw attention to this galaxy as the first clear example (and prototype) of bipolar radio outflow that is revealed in linearly polarized emission only. Such polarization observations, which are unobscured by dust, provide a new tool for uncovering hidden weak active galactic nucleus (AGN) activity which may otherwise be masked by brighter unpolarized emission within which it is embedded. The radio lobes observed in NGC 2992 are interacting with the surrounding interstellar medium (ISM) and offer new opportunities to investigate the interactions between nuclear outflows and the ISM in nearby galaxies. We also compare the radio emission with a new CHANDRA X-ray image of this galaxy. A new CHANG-ES image of NGC 3079 is also briefly shown as another example as to how much more obvious radio lobes appear in linear polarization as opposed to total intensity.

  16. Systematic triple-mutant analysis uncovers functional connectivity between pathways involved in chromosome regulation.

    PubMed

    Haber, James E; Braberg, Hannes; Wu, Qiuqin; Alexander, Richard; Haase, Julian; Ryan, Colm; Lipkin-Moore, Zach; Franks-Skiba, Kathleen E; Johnson, Tasha; Shales, Michael; Lenstra, Tineke L; Holstege, Frank C P; Johnson, Jeffrey R; Bloom, Kerry; Krogan, Nevan J

    2013-06-27

    Genetic interactions reveal the functional relationships between pairs of genes. In this study, we describe a method for the systematic generation and quantitation of triple mutants, termed triple-mutant analysis (TMA). We have used this approach to interrogate partially redundant pairs of genes in S. cerevisiae, including ASF1 and CAC1, two histone chaperones. After subjecting asf1Δ cac1Δ to TMA, we found that the Swi/Snf Rdh54 protein compensates for the absence of Asf1 and Cac1. Rdh54 more strongly associates with the chromatin apparatus and the pericentromeric region in the double mutant. Moreover, Asf1 is responsible for the synthetic lethality observed in cac1Δ strains lacking the HIRA-like proteins. A similar TMA was carried out after deleting both CLB5 and CLB6, cyclins that regulate DNA replication, revealing a strong functional connection to chromosome segregation. This approach can reveal functional redundancies that cannot be uncovered through traditional double-mutant analyses.

  17. Protein domain structure uncovers the origin of aerobic metabolism and the rise of planetary oxygen.

    PubMed

    Kim, Kyung Mo; Qin, Tao; Jiang, Ying-Ying; Chen, Ling-Ling; Xiong, Min; Caetano-Anollés, Derek; Zhang, Hong-Yu; Caetano-Anollés, Gustavo

    2012-01-11

    The origin and evolution of modern biochemistry remain a mystery despite advances in evolutionary bioinformatics. Here, we use a structural census in nearly 1,000 genomes and a molecular clock of folds to define a timeline of appearance of protein families linked to single-domain enzymes. The timeline sorts out enzymatic recruitment, validates patterns in metabolic history, and reveals that the most ancient reaction of aerobic metabolism involved the synthesis of pyridoxal 5'-phosphate or pyridoxal and appeared 2.9 Gyr ago. The oxygen source for this primordial reaction was probably Mn catalase, which appeared at the same time and could have generated oxygen as a side product of hydrogen peroxide detoxification. Finally, evolutionary analysis of transferred groups and metabolite fragments revealed that oxidized sulfur did not participate in metabolism until the rise of oxygen. The evolutionary patterns we uncover in molecules and chemistries provide strong support for the coevolution of biochemistry and geochemistry. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Systems-level approach to uncovering diffusive states and their transitions from single-particle trajectories

    NASA Astrophysics Data System (ADS)

    Koo, Peter K.; Mochrie, Simon G. J.

    2016-11-01

    The stochastic motions of a diffusing particle contain information concerning the particle's interactions with binding partners and with its local environment. However, an accurate determination of the underlying diffusive properties, beyond normal diffusion, has remained challenging when analyzing particle trajectories on an individual basis. Here, we introduce the maximum-likelihood estimator (MLE) for confined diffusion and fractional Brownian motion. We demonstrate that this MLE yields improved estimation over traditional mean-square displacement analyses. We also introduce a model selection scheme (that we call mleBIC) that classifies individual trajectories to a given diffusion mode. We demonstrate the statistical limitations of classification via mleBIC using simulated data. To overcome these limitations, we introduce a version of perturbation expectation-maximization (pEMv2), which simultaneously analyzes a collection of particle trajectories to uncover the system of interactions that give rise to unique normal and/or non-normal diffusive states within the population. We test and evaluate the performance of pEMv2 on various sets of simulated particle trajectories, which transition among several modes of normal and non-normal diffusion, highlighting the key considerations for employing this analysis methodology.

  19. Uncovering the repertoire of fungal secondary metabolites: From Fleming's laboratory to the International Space Station.

    PubMed

    Boruta, Tomasz

    2017-06-20

    Fungi produce a variety of secondary metabolites (SMs), low-molecular weight compounds associated with many potentially useful biologic activities. The examples of biotechnologically relevant fungal metabolites include penicillin, a β-lactam antibiotic, and lovastatin, a cholesterol-lowering drug. The discovery of pharmaceutical lead compounds within the microbial metabolic pools relies on the selection and biochemical characterization of promising strains. Not all SMs are produced under standard cultivation conditions, hence the uncovering of chemical potential of investigated strains often requires the use of induction strategies to awake the associated biosynthetic genes. Triggering the secondary metabolic pathways can be achieved through the variation of cultivation conditions and growth media composition. The alternative strategy is to use genetic engineering to activate the respective genomic segments, e.g. by the manipulation of regulators or chromatin-modifying enzymes. Recently, whole-genome sequencing of several fungi isolated from the Chernobyl accident area was reported by Singh et al. (Genome Announc 2017; 5:e01602-16). These strains were selected for exposure to microgravity at the International Space Station. Biochemical characterization of fungi cultivated under extreme conditions is likely to provide valuable insights into the adaptation mechanism associated with metabolism and, possibly, a catalog of novel molecules of potential pharmaceutical importance.

  20. Characterizing inactive ribosomes in translational profiling

    PubMed Central

    Liu, Botao; Qian, Shu-Bing

    2016-01-01

    ABSTRACT The broad impact of translational regulation has emerged explosively in the last few years in part due to the technological advance in genome-wide interrogation of gene expression. During mRNA translation, the majority of actively translating ribosomes exist as polysomes in cells with multiple ribosomes loaded on a single transcript. The importance of the monosome, however, has been less appreciated in translational profiling analysis. Here we report that the monosome fraction isolated by sucrose sedimentation contains a large quantity of inactive ribosomes that do not engage on mRNAs to direct translation. We found that the elongation factor eEF2, but not eEF1A, stably resides in these non-translating ribosomes. This unique feature permits direct evaluation of ribosome status under various stress conditions and in the presence of translation inhibitors. Ribosome profiling reveals that the monosome has a similar but not identical pattern of ribosome footprints compared to the polysome. We show that the association of free ribosomal subunits minimally contributes to ribosome occupancy outside of the coding region. Our results not only offer a quantitative method to monitor ribosome availability, but also uncover additional layers of ribosome status needed to be considered in translational profiling analysis. PMID:27335722

  1. Quantitative profiling of initiating ribosomes in vivo.

    PubMed

    Gao, Xiangwei; Wan, Ji; Liu, Botao; Ma, Ming; Shen, Ben; Qian, Shu-Bing

    2015-02-01

    Cells have evolved exquisite mechanisms to fine-tune the rate of protein synthesis in response to stress. Systemic mapping of start-codon positions and precise measurement of the corresponding initiation rate would transform our understanding of translational control. Here we present quantitative translation initiation sequencing (QTI-seq), with which the initiating ribosomes can be profiled in real time at single-nucleotide resolution. Resultant initiation maps not only delineated variations of start-codon selection but also highlighted a dynamic range of initiation rates in response to nutrient starvation. The integrated data set provided unique insights into principles of alternative translation and mechanisms controlling different aspects of translation initiation. With RiboTag mice, QTI-seq permitted tissue-specific profiling of initiating ribosomes in vivo. Liver cell-specific ribosome profiling uncovered a robust translational reprogramming of the proteasome system in fasted mice. Our findings illuminated the prevalence and dynamic nature of translational regulation pivotal to physiological adaptation in vivo.

  2. Simul-seq: combined DNA and RNA sequencing for whole-genome and transcriptome profiling.

    PubMed

    Reuter, Jason A; Spacek, Damek V; Pai, Reetesh K; Snyder, Michael P

    2016-11-01

    Paired DNA and RNA profiling is increasingly employed in genomics research to uncover molecular mechanisms of disease and to explore personal genotype and phenotype correlations. Here, we introduce Simul-seq, a technique for the production of high-quality whole-genome and transcriptome sequencing libraries from small quantities of cells or tissues. We apply the method to laser-capture-microdissected esophageal adenocarcinoma tissue, revealing a highly aneuploid tumor genome with extensive blocks of increased homozygosity and corresponding increases in allele-specific expression. Among this widespread allele-specific expression, we identify germline polymorphisms that are associated with response to cancer therapies. We further leverage this integrative data to uncover expressed mutations in several known cancer genes as well as a recurrent mutation in the motor domain of KIF3B that significantly affects kinesin-microtubule interactions. Simul-seq provides a new streamlined approach for generating comprehensive genome and transcriptome profiles from limited quantities of clinically relevant samples.

  3. Profiling and Racial Profiling: An Interactive Exercise

    ERIC Educational Resources Information Center

    Semple, Philip

    2013-01-01

    Racial Profiling has been recognized as a serious problem that affects many segments of our society and is especially notable in law enforcement. Governments and police services have pronounced that racial profiling is not acceptable and will not be tolerated. They have gone to great lengths in trying to eradicate racial profiling through…

  4. Uncovering dental implants using a new thermo-optically powered (TOP) technology with tissue air-cooling.

    PubMed

    Romanos, Georgios E; Belikov, Andrey V; Skrypnik, Alexei V; Feldchtein, Felix I; Smirnov, Michael Z; Altshuler, Gregory B

    2015-07-01

    Uncovering implants with lasers, while bloodless, has been associated with a risk of implant and bone overheating. The present study evaluated the effect of using a new generation of high-power diode lasers on the temperature of a dental implant and the surrounding tissues using an in vitro model. The implant temperature was measured at three locations using micro thermocouples. Collateral thermal damage of uncovered soft tissues was evaluated using NTBC stain. Implant temperature rise during and collateral thermal soft-tissue damage following implant uncovering with and without tissue air-cooling was studied using both the classic operational mode and the new thermo-optically powered (TOP) technology. For the classic surgical mode using a cork-initiated tip and constant laser power set at 3.4 W, the maximum temperature rise in the coronal and apical parts of the implant was 23.2 ± 4.1°С and 9.5 ± 1.8°С, respectively, while 1.5 ± 0.5 mm of collateral thermal damage of the soft tissue surrounding the implant model occurred. Using the TOP surgical tip with constant laser power reduced implant overheating by 30%; collateral thermal soft-tissue damage was 0.8 ± 0.2 mm. Using the TOP surgical mode with a tip temperature setting of 800°C and air-cooling reduced the implant temperature rise by more than 300%, and only 0.2 ± 0.1 mm of collateral thermal soft-tissue damage occurred, typical for optimized CO2 laser surgery. Furthermore, use of the new generation diode technology (TOP surgical mode) appeared to reduce the time required for implant uncovering by a factor of two, compared to the standard surgical mode. Use of the new generation diode technology (TOP surgical mode) may significantly reduce overheating of dental implants during uncovering and seems to be safer for the adjacent soft and hard tissues. Use of such diode lasers with air-cooling can radically reduce the rise in implant temperatures (by more than three times

  5. Comparative genomics uncovers novel structural and functional features of the heterotrimeric GTPase signaling system

    PubMed Central

    Anantharaman, Vivek; Abhiman, Saraswathi; de Souza, Robson F.; Aravind, L.

    2012-01-01

    Though the heterotrimeric G-proteins signaling system is one of the best studied in eukaryotes, its provenance and its prevalence outside of model eukaryotes remains poorly understood. We utilized the wealth of sequence data from recently sequenced eukaryotic genomes to uncover robust G-protein signaling systems in several poorly studied eukaryotic lineages such as the parabasalids, heteroloboseans and stramenopiles. This indicated that the Gα subunit is likely to have separated from the ARF-like GTPases prior to the last eukaryotic common ancestor. We systematically identified the structure and sequence features associated with this divergence and found that most of the neomorphic positions in Gα form a ring of residues centered on the nucleotide binding site, several of which are likely to be critical for interactions with the RGS domain for its GAP function. We also present evidence that in some of the potentially early branching eukaryotic lineages, like Trichomonas, Gα is likely to function independently of the Gβγ subunits. We were able to identify previously unknown Gγ subunits in Naegleria, suggesting that the trimeric version was already present by the time of the divergence of the heteroloboseans from the remaining eukaryotes. Evolution of Gα subunits is dominated by several independent lineage-specific expansions (LSEs). In most of these cases there are concomitant, independent LSEs of RGS proteins along with an extraordinary diversification of their domain architectures. The diversity of RGS domains from Naegleria in particular, which has the largest complement of Gα and RGS proteins for any eukaryote, provides new insights into RGS function and evolution. We uncovered a new class of soluble ligand receptors of bacterial origin with RGS domains and an extraordinary diversity of membrane-linked, redox-associated, adhesion-dependent and small molecule-induced G-protein signaling networks that evolved in early-branching eukaryotes, independently of

  6. Step selection techniques uncover the environmental predictors of space use patterns in flocks of Amazonian birds

    PubMed Central

    Potts, Jonathan R; Mokross, Karl; Stouffer, Philip C; Lewis, Mark A

    2014-01-01

    Understanding the behavioral decisions behind animal movement and space use patterns is a key challenge for behavioral ecology. Tools to quantify these patterns from movement and animal–habitat interactions are vital for transforming ecology into a predictive science. This is particularly important in environments undergoing rapid anthropogenic changes, such as the Amazon rainforest, where animals face novel landscapes. Insectivorous bird flocks are key elements of avian biodiversity in the Amazonian ecosystem. Therefore, disentangling and quantifying the drivers behind their movement and space use patterns is of great importance for Amazonian conservation. We use a step selection function (SSF) approach to uncover environmental drivers behind movement choices. This is used to construct a mechanistic model, from which we derive predicted utilization distributions (home ranges) of flocks. We show that movement decisions are significantly influenced by canopy height and topography, but depletion and renewal of resources do not appear to affect movement significantly. We quantify the magnitude of these effects and demonstrate that they are helpful for understanding various heterogeneous aspects of space use. We compare our results to recent analytic derivations of space use, demonstrating that the analytic approximation is only accurate when assuming that there is no persistence in the animals' movement. Our model can be translated into other environments or hypothetical scenarios, such as those given by proposed future anthropogenic actions, to make predictions of spatial patterns in bird flocks. Furthermore, our approach is quite general, so could potentially be used to understand the drivers of movement and spatial patterns for a wide variety of animal communities. PMID:25558353

  7. Comparative genomics of Beauveria bassiana: uncovering signatures of virulence against mosquitoes.

    PubMed

    Valero-Jiménez, Claudio A; Faino, Luigi; Spring In't Veld, Daphne; Smit, Sandra; Zwaan, Bas J; van Kan, Jan A L

    2016-12-01

    Entomopathogenic fungi such as Beauveria bassiana are promising biological agents for control of malaria mosquitoes. Indeed, infection with B. bassiana reduces the lifespan of mosquitoes in the laboratory and in the field. Natural isolates of B. bassiana show up to 10-fold differences in virulence between the most and the least virulent isolate. In this study, we sequenced the genomes of five isolates representing the extremes of low/high virulence and three RNA libraries, and applied a genome comparison approach to uncover genetic mechanisms underpinning virulence. A high-quality, near-complete genome assembly was achieved for the highly virulent isolate Bb8028, which was compared to the assemblies of the four other isolates. Whole genome analysis showed a high level of genetic diversity between the five isolates (2.85-16.8 SNPs/kb), which grouped into two distinct phylogenetic clusters. Mating type gene analysis revealed the presence of either the MAT1-1-1 or the MAT1-2-1 gene. Moreover, a putative new MAT gene (MAT1-2-8) was detected in the MAT1-2 locus. Comparative genome analysis revealed that Bb8028 contains 163 genes exclusive for this isolate. These unique genes have a tendency to cluster in the genome and to be often located near the telomeres. Among the genes unique to Bb8028 are a Non-Ribosomal Peptide Synthetase (NRPS) secondary metabolite gene cluster, a polyketide synthase (PKS) gene, and five genes with homology to bacterial toxins. A survey of candidate virulence genes for B. bassiana is presented. Our results indicate several genes and molecular processes that may underpin virulence towards mosquitoes. Thus, the genome sequences of five isolates of B. bassiana provide a better understanding of the natural variation in virulence and will offer a major resource for future research on this important biological control agent.

  8. Uncovering synthetic lethal interactions for therapeutic targets and predictive markers in lung adenocarcinoma

    PubMed Central

    Che, Ting-Fang; Huang, Yi-Syuan; Yeh, Kun-Tu; Shieh, Grace S.; Yang, Pan-Chyr

    2016-01-01

    Two genes are called synthetic lethal (SL) if their simultaneous mutation leads to cell death, but mutation of either individual does not. Targeting SL partners of mutated cancer genes can selectively kill cancer cells, but leave normal cells intact. We present an integrated approach to uncover SL gene pairs as novel therapeutic targets of lung adenocarcinoma (LADC). Of 24 predicted SL pairs, PARP1-TP53 was validated by RNAi knockdown to have synergistic toxicity in H1975 and invasive CL1-5 LADC cells; additionally FEN1-RAD54B, BRCA1-TP53, BRCA2-TP53 and RB1-TP53 were consistent with the literature. While metastasis remains a bottleneck in cancer treatment and inhibitors of PARP1 have been developed, this result may have therapeutic potential for LADC, in which TP53 is commonly mutated. We also demonstrated that silencing PARP1 enhanced the cell death induced by the platinum-based chemotherapy drug carboplatin in lung cancer cells (CL1-5 and H1975). IHC of RAD54B↑, BRCA1↓-RAD54B↑, FEN1(N)↑-RAD54B↑ and PARP1↑-RAD54B↑ were shown to be prognostic markers for 131 Asian LADC patients, and all markers except BRCA1↓-RAD54B↑ were further confirmed by three independent gene expression data sets (a total of 426 patients) including The Cancer Genome Atlas (TCGA) cohort of LADC. Importantly, we identified POLB-TP53 and POLB as predictive markers for the TCGA cohort (230 subjects), independent of age and stage. Thus, POLB and POLB-TP53 may be used to stratify future non-Asian LADC patients for therapeutic strategies. PMID:27655641

  9. Using four-phased unit-based patient safety walkrounds to uncover correctable system flaws.

    PubMed

    Taylor, April M; Chuo, John; Figueroa-Altmann, Ana; DiTaranto, Susan; Shaw, Kathy N

    2013-09-01

    A unit-based Patient Safety Leadership Walkrounds (PSWR) model was deployed in six medical/surgical units at The Children's Hospital of Philadelphia to identify patient safety issues in the clinical microsystem. Specific objectives of PSWR were to (1) provide a forum for frontline staff to freely report and discuss patient safety problems with unit local leaders, (2) improve teamwork and communication within and across units, and (3) develop a supportive environment in which staff and leaders brainstorm on potential solutions. Baseline data collection and discussion with leaders and staff from the pilot units were used to create a standard set of safety tools and questions. Through multiple Plan-Do-Study-Act cycles, safety tools and questions were refined, while the process of walkrounds in each of the six pilot units was customized. Leaders in all six pilot units indicated that PSWR helped them to uncover previously unidentified safety concerns. Top-impact areas included nurse-medical team relationship, work-flow flaws, equipment defects, staff education, and medication safety. The project engaged 149 individuals across all disciplines, including 33 physicians, and entailed 34 PSWR in its first year. Information from these pilot units initiated safety changes that spread across multiple units, with identification of hospital-wide quality and patient safety issues. For participating units, the PSWR process is a situational awareness tool that helps management periodically assess new or unresolved vulnerabilities that may affect safety and care quality on the unit. Unit-based PSWR help identify safety concerns at the microsystem level while improving communication about safety events across units and to hospital leaders in the macrosystem.

  10. Uncovering multiple populations with washington photometry. I. The globular cluster NGC 1851

    SciTech Connect

    Cummings, Jeffrey D.; Geisler, D.; Villanova, S.; Carraro, G.

    2014-08-01

    The analysis of multiple populations (MPs) in globular clusters (GCs) has become a forefront area of research in astronomy. Multiple red giant branches (RGBs), subgiant branches (SGBs), and even main sequences (MSs) have now been observed photometrically in many GCs, while broad abundance distributions of certain elements have been detected spectroscopically in most, if not all, GCs. UV photometry has been crucial in discovering and analyzing these MPs, but the Johnson U and the Stromgren and Sloan u filters that have generally been used are relatively inefficient and very sensitive to reddening and atmospheric extinction. In contrast, the Washington C filter is much broader and redder than these competing UV filters, making it far more efficient at detecting MPs and much less sensitive to reddening and extinction. Here, we investigate the use of the Washington system to uncover MPs using only a 1 m telescope. Our analysis of the well-studied GC NGC 1851 finds that the C filter is both very efficient and effective at detecting its previously discovered MPs in the RGB and SGB. Remarkably, we have also detected an intrinsically broad MS best characterized by two distinct but heavily overlapping populations that cannot be explained by binaries, field stars, or photometric errors. The MS distribution is in very good agreement with that seen on the RGB, with ∼30% of the stars belonging to the second population. There is also evidence for two sequences in the red horizontal branch, but this appears to be unrelated to the MPs in this cluster. Neither of these latter phenomena have been observed previously in this cluster. The redder MS stars are also more centrally concentrated than the blue MS. This is the first time MPs in an MS have been discovered from the ground, and using only a 1 m telescope. The Washington system thus proves to be a very powerful tool for investigating MPs, and holds particular promise for extragalactic objects where photons are limited.

  11. RNA shotgun metagenomic sequencing of northern California (USA) mosquitoes uncovers viruses, bacteria, and fungi

    PubMed Central

    Chandler, James Angus; Liu, Rachel M.; Bennett, Shannon N.

    2015-01-01

    Mosquitoes, most often recognized for the microbial agents of disease they may carry, harbor diverse microbial communities that include viruses, bacteria, and fungi, collectively called the microbiota. The composition of the microbiota can directly and indirectly affect disease transmission through microbial interactions that could be revealed by its characterization in natural populations of mosquitoes. Furthermore, the use of shotgun metagenomic sequencing (SMS) approaches could allow the discovery of unknown members of the microbiota. In this study, we use RNA SMS to characterize the microbiota of seven individual mosquitoes (species include Culex pipiens, Culiseta incidens, and Ochlerotatus sierrensis) collected from a variety of habitats in California, USA. Sequencing was performed on the Illumina HiSeq platform and the resulting sequences were quality-checked and assembled into contigs using the A5 pipeline. Sequences related to single stranded RNA viruses of the Bunyaviridae and Rhabdoviridae were uncovered, along with an unclassified genus of double-stranded RNA viruses. Phylogenetic analysis finds that in all three cases, the closest relatives of the identified viral sequences are other mosquito-associated viruses, suggesting widespread host-group specificity among disparate viral taxa. Interestingly, we identified a Narnavirus of fungi, also reported elsewhere in mosquitoes, that potentially demonstrates a nested host-parasite association between virus, fungi, and mosquito. Sequences related to 8 bacterial families and 13 fungal families were found across the seven samples. Bacillus and Escherichia/Shigella were identified in all samples and Wolbachia was identified in all Cx. pipiens samples, while no single fungal genus was found in more than two samples. This study exemplifies the utility of RNA SMS in the characterization of the natural microbiota of mosquitoes and, in particular, the value of identifying all microbes associated with a specific host

  12. RNA shotgun metagenomic sequencing of northern California (USA) mosquitoes uncovers viruses, bacteria, and fungi.

    PubMed

    Chandler, James Angus; Liu, Rachel M; Bennett, Shannon N

    2015-01-01

    Mosquitoes, most often recognized for the microbial agents of disease they may carry, harbor diverse microbial communities that include viruses, bacteria, and fungi, collectively called the microbiota. The composition of the microbiota can directly and indirectly affect disease transmission through microbial interactions that could be revealed by its characterization in natural populations of mosquitoes. Furthermore, the use of shotgun metagenomic sequencing (SMS) approaches could allow the discovery of unknown members of the microbiota. In this study, we use RNA SMS to characterize the microbiota of seven individual mosquitoes (species include Culex pipiens, Culiseta incidens, and Ochlerotatus sierrensis) collected from a variety of habitats in California, USA. Sequencing was performed on the Illumina HiSeq platform and the resulting sequences were quality-checked and assembled into contigs using the A5 pipeline. Sequences related to single stranded RNA viruses of the Bunyaviridae and Rhabdoviridae were uncovered, along with an unclassified genus of double-stranded RNA viruses. Phylogenetic analysis finds that in all three cases, the closest relatives of the identified viral sequences are other mosquito-associated viruses, suggesting widespread host-group specificity among disparate viral taxa. Interestingly, we identified a Narnavirus of fungi, also reported elsewhere in mosquitoes, that potentially demonstrates a nested host-parasite association between virus, fungi, and mosquito. Sequences related to 8 bacterial families and 13 fungal families were found across the seven samples. Bacillus and Escherichia/Shigella were identified in all samples and Wolbachia was identified in all Cx. pipiens samples, while no single fungal genus was found in more than two samples. This study exemplifies the utility of RNA SMS in the characterization of the natural microbiota of mosquitoes and, in particular, the value of identifying all microbes associated with a specific host.

  13. Step selection techniques uncover the environmental predictors of space use patterns in flocks of Amazonian birds.

    PubMed

    Potts, Jonathan R; Mokross, Karl; Stouffer, Philip C; Lewis, Mark A

    2014-12-01

    Understanding the behavioral decisions behind animal movement and space use patterns is a key challenge for behavioral ecology. Tools to quantify these patterns from movement and animal-habitat interactions are vital for transforming ecology into a predictive science. This is particularly important in environments undergoing rapid anthropogenic changes, such as the Amazon rainforest, where animals face novel landscapes. Insectivorous bird flocks are key elements of avian biodiversity in the Amazonian ecosystem. Therefore, disentangling and quantifying the drivers behind their movement and space use patterns is of great importance for Amazonian conservation. We use a step selection function (SSF) approach to uncover environmental drivers behind movement choices. This is used to construct a mechanistic model, from which we derive predicted utilization distributions (home ranges) of flocks. We show that movement decisions are significantly influenced by canopy height and topography, but depletion and renewal of resources do not appear to affect movement significantly. We quantify the magnitude of these effects and demonstrate that they are helpful for understanding various heterogeneous aspects of space use. We compare our results to recent analytic derivations of space use, demonstrating that the analytic approximation is only accurate when assuming that there is no persistence in the animals' movement. Our model can be translated into other environments or hypothetical scenarios, such as those given by proposed future anthropogenic actions, to make predictions of spatial patterns in bird flocks. Furthermore, our approach is quite general, so could potentially be used to understand the drivers of movement and spatial patterns for a wide variety of animal communities.

  14. Uncovering cyanobacteria ecological networks from long-term monitoring data using Granger causality analysis

    NASA Astrophysics Data System (ADS)

    Nelson, N.; Munoz-Carpena, R.; Kaplan, D. A.; Phlips, E. J.

    2016-12-01

    In many aquatic systems, cyanobacteria form harmful blooms capable of producing toxins, prompting hypoxia, and/or introducing internal nitrogen loads via N2-fixation, among other impacts. Traditionally, system-specific cyanobacteria drivers are determined by performing controlled experiments and bioassays, but these approaches may neglect the influences of confounding factors and over assign importance to only those variables considered within experimental designs. For example, a bioassay may conclude that the cyanobacteria in a particular system are limited by phosphorus, but will not explicitly take into account the role of flow as a control on phosphorus delivery. This study aims to address this analytical gap by identifying environmental controls on cyanobacteria while removing the effects of potentially confounding variables. In the present work, we evaluate a unique long-term (17 year) dataset composed of monthly observations of phytoplankton and zooplankton species abundances, water quality constituents, and hydrologic variables from Lake George, a flow-through lake of the St. Johns River (FL) impacted by cyanobacterial blooms. Using conditional Granger causality analysis, a time series approach that infers causality while removing the effects of confounding variables, data were evaluated to identify biological and physicochemical drivers of cyanobacteria. The analysis was performed for three response variable sets: total cyanobacteria, N2-fixers and non-fixers, and cyanobacteria genera. Results depicted increasing levels of ecological complexity as subdivisions of cyanobacteria became more detailed; whereas causal networks produced from analyses of cyanobacteria genera provided novel insights relevant for management (i.e. nutrients, flow), the total cyanobacteria network only included water temperature as a significant driver. Additionally, the more detailed cyanobacteria subdivisions uncovered that N2-fixation was only evident with the earliest season

  15. Self-Efficacy Beliefs and Mental Time Travel Ability: Uncovering a Hidden Relationship in Educational Settings

    ERIC Educational Resources Information Center

    Eren, Altay

    2009-01-01

    The aim of this study was threefold: first, it was to explore the profiles of student teachers' mental time travel ability; second, it was to examine the relationship between student teachers' mental time travel ability and self-efficacy beliefs; and third, it was to investigate the role of self-efficacy beliefs in relationship between the past…

  16. Self-Efficacy Beliefs and Mental Time Travel Ability: Uncovering a Hidden Relationship in Educational Settings

    ERIC Educational Resources Information Center

    Eren, Altay

    2009-01-01

    The aim of this study was threefold: first, it was to explore the profiles of student teachers' mental time travel ability; second, it was to examine the relationship between student teachers' mental time travel ability and self-efficacy beliefs; and third, it was to investigate the role of self-efficacy beliefs in relationship between the past…

  17. Profiling Instructional Package.

    ERIC Educational Resources Information Center

    Gephart, William J.; Bartos, Bruce B.

    The necessity of evaluating research methodology is discussed, and a profiling approach is proposed. Explanatory statements about the research process, directions for doing the actual profiling of the research report, a research profiling flow chart, a research profile sheet, and two additional graphic aids to understanding are included. The…

  18. Complementation Plasmids, Inducible Gene-Expression Systems, and Reporters for Staphylococci.

    PubMed

    Bertram, Ralph

    2016-01-01

    A cornucopia of methods and molecular tools is available for genetic modification of staphylococci, as shown for at least ten different species to date (Prax et al. Microbiology 159:421-435, 2013). This chapter reviews a number of frequently used vectors for complementation purposes that usually replicate in E. coli and staphylococci and differ in parameters including copy number, mode of replication, and sequence length. Systems for the artificial control of gene expression are described that are modulated by low-molecular-weight effectors such as metal cations, carbohydrates, and antibiotics. Finally, the usefulness of reporter proteins that exhibit enzymatic or autofluorescent characteristics in staphylococci is highlighted.

  19. GFP plasmid-induced defects in Salmonella invasion depend on plasmid architecture, not protein expression.

    PubMed

    Clark, Leann; Martinez-Argudo, Isabel; Humphrey, Tom J; Jepson, Mark A

    2009-02-01

    We have investigated the impact of plasmids and GFP expression on invasion of cultured epithelial cells by Salmonella enterica Typhimurium strain SL1344. The invasiveness of SL1344 carrying plasmids derived from pBR322, encoding promoterless GFP or constitutively expressed rpsM-GFP, was compared under optimal growth conditions with that of SL1344(pBR322), unmodified SL1344 and a strain with chromosome-integrated rpsM-GFP. The strain carrying pBR322 exhibited normal invasion, but the presence of modified plasmids impaired invasiveness, and impairment was exacerbated by plasmid-encoded chloramphenicol resistance (CmR). Using a different antibiotic resistance marker, kanamycin (KmR), did not impair invasiveness. Despite the effect of plasmid-encoded CmR, the strain containing chromosomally encoded GFP, also carrying a CmR gene, was as invasive as the wild-type. To investigate the mechanism by which plasmid carriage decreases invasion, we monitored SPI-1 gene expression using prgH promoter activity as an index of SPI-1 activity. An SL1344 strain with a chromosome-integrated prgH::gfp reporter construct exhibited lower GFP expression during exponential phase when carrying plasmids incorporating CmR or gfp, mirroring invasion data. These data provide evidence that suppression of SPI-1 gene expression is a major factor in the loss of invasiveness associated with plasmid carriage. Our findings also indicate that some plasmids, especially those carrying CmR, should be used with caution, as virulence traits and gene expression may be affected by their presence. Integration of reporter proteins into the bacterial chromosome, however, appears to circumvent the adverse effects observed with plasmids.

  20. A two-plasmid inducible CRISPR/Cas9 genome editing tool for Clostridium acetobutylicum.

    PubMed

    Wasels, François; Jean-Marie, Jennifer; Collas, Florent; López-Contreras, Ana M; Lopes Ferreira, Nicolas

    2017-09-01

    CRISPR/Cas-based genetic engineering has revolutionised molecular biology in both eukaryotes and prokaryotes. Several tools dedicated to the genomic transformation of the Clostridium genus of Gram-positive bacteria have been described in the literature; however, the integration of large DNA fragments still remains relatively limited. In this study, a CRISPR/Cas9 genome editing tool using a two-plasmid strategy was developed for the solventogenic strain Clostridium acetobutylicum ATCC 824. Codon-optimised cas9 from Streptococcus pyogenes was placed under the control of an anhydrotetracycline-inducible promoter on one plasmid, while the gRNA expression cassettes and editing templates were located on a second plasmid. Through the sequential introduction of these vectors into the cell, we achieved highly accurate genome modifications, including nucleotide substitution, gene deletion and cassette insertion up to 3.6kb. To demonstrate its potential, this genome editing tool was used to generate a marker-free mutant of ATCC 824 that produced an isopropanol-butanol-ethanol mixture. Whole-genome sequencing confirmed that no off-target modifications were present in the mutants. Such a tool is a prerequisite for efficient metabolic engineering in this solventogenic strain and provides an alternative editing strategy that might be applicable to other Clostridium strains. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Panoramic view of a superfamily of phosphatases through substrate profiling

    PubMed Central

    Huang, Hua; Pandya, Chetanya; Liu, Chunliang; Al-Obaidi, Nawar F.; Wang, Min; Zheng, Li; Toews Keating, Sarah; Aono, Miyuki; Love, James D.; Evans, Brandon; Seidel, Ronald D.; Hillerich, Brandan S.; Garforth, Scott J.; Almo, Steven C.; Mariano, Patrick S.; Dunaway-Mariano, Debra; Allen, Karen N.; Farelli, Jeremiah D.

    2015-01-01

    Large-scale activity profiling of enzyme superfamilies provides information about cellular functions as well as the intrinsic binding capabilities of conserved folds. Herein, the functional space of the ubiquitous haloalkanoate dehalogenase superfamily (HADSF) was revealed by screening a customized substrate library against >200 enzymes from representative prokaryotic species, enabling inferred annotation of ∼35% of the HADSF. An extremely high level of substrate ambiguity was revealed, with the majority of HADSF enzymes using more than five substrates. Substrate profiling allowed assignment of function to previously unannotated enzymes with known structure, uncovered potential new pathways, and identified iso-functional orthologs from evolutionarily distant taxonomic groups. Intriguingly, the HADSF subfamily having the least structural elaboration of the Rossmann fold catalytic domain was the most specific, consistent with the concept that domain insertions drive the evolution of new functions and that the broad specificity observed in HADSF may be a relic of this process. PMID:25848029

  2. Ribosome profiling and dynamic regulation of translation in mammals.

    PubMed

    Gobet, Cédric; Naef, Felix

    2017-03-28

    Protein synthesis is an energy-demanding cellular process. Consequently, a well-timed, fine-tuned and plastic regulation of translation is needed to adjust and maintain cell states under dynamically changing environments. Genome-wide monitoring of translation was recently facilitated by ribosome profiling, which uncovered key features of translation regulation. In this review, we summarize recent ribosome profiling studies in mammals providing novel insight in dynamic translation regulation, notably related to circadian rhythms, diurnal feeding/fasting cycles, cell cycle progression, stress responses, and tRNA landscapes. In particular, recent results show that regulating translation initiation and elongation represent important mechanisms used in mammalian cells to rapidly modulate protein expression in dynamically changing environments.

  3. Covered versus uncovered self-expandable nitinol stents in the palliative treatment of malignant distal biliary obstruction: results from a randomized, multicenter study.

    PubMed

    Kullman, Eric; Frozanpor, Farshad; Söderlund, Claes; Linder, Stefan; Sandström, Per; Lindhoff-Larsson, Anna; Toth, Ervin; Lindell, Gert; Jonas, Eduard; Freedman, Jacob; Ljungman, Martin; Rudberg, Claes; Ohlin, Bo; Zacharias, Rebecka; Leijonmarck, Carl-Eric; Teder, Kalev; Ringman, Anders; Persson, Gunnar; Gözen, Mehmet; Eriksson, Olle

    2010-11-01

    Covered biliary metal stents have been developed to prevent tumor ingrowth. Previous comparative studies are limited and often include few patients. To compare differences in stent patency, patient survival, and complication rates between covered and uncovered nitinol stents in patients with malignant biliary obstruction. Randomized, multicenter trial conducted between January 2006 and October 2008. Ten sites serving a total catchment area of approximately 2.8 million inhabitants. A total of 400 patients with unresectable distal malignant biliary obstruction. ERCP with insertion of covered or uncovered metal stent. Follow-up conducted monthly for symptoms indicating stent obstruction. Time to stent failure, survival time, and complication rate. The patient survival times were 116 days (interquartile range 242 days) and 174 days (interquartile range 284 days) in the covered and uncovered stent groups, respectively (P = .320). The first quartile stent patency time was 154 days in the covered stent group and 199 days in the uncovered stent group (P = .326). There was no difference in the incidence of pancreatitis or cholecystitis between the 2 groups. Stent migration occurred in 6 patients (3%) in the covered group and in no patients in the uncovered group (P = .030). Randomization was not blinded. There were no significant differences in stent patency time, patient survival time, or complication rates between covered and uncovered nitinol metal stents in the palliative treatment of malignant distal biliary obstruction. However, covered stents migrated significantly more often compared with uncovered stents, and tumor ingrowth was more frequent in uncovered stents. Copyright © 2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

  4. Identification of human remains from the Second World War mass graves uncovered in Bosnia and Herzegovina

    PubMed Central

    Marjanović, Damir; Hadžić Metjahić, Negra; Čakar, Jasmina; Džehverović, Mirela; Dogan, Serkan; Ferić, Elma; Džijan, Snježana; Škaro, Vedrana; Projić, Petar; Madžar, Tomislav; Rod, Eduard; Primorac, Dragan

    2015-01-01

    Aim To present the results obtained in the identification of human remains from World War II found in two mass graves in Ljubuški, Bosnia and Herzegovina. Methods Samples from 10 skeletal remains were collected. Teeth and femoral fragments were collected from 9 skeletons and only a femoral fragment from 1 skeleton. DNA was isolated from bone and teeth samples using an optimized phenol/chloroform DNA extraction procedure. All samples required a pre-extraction decalcification with EDTA and additional post-extraction DNA purification using filter columns. Additionally, DNA from 12 reference samples (buccal swabs from potential living relatives) was extracted using the Qiagen DNA extraction method. QuantifilerTM Human DNA Quantification Kit was used for DNA quantification. PowerPlex ESI kit was used to simultaneously amplify 15 autosomal short tandem repeat (STR) loci, and PowerPlex Y23 was used to amplify 23 Y chromosomal STR loci. Matching probabilities were estimated using a standard statistical approach. Results A total of 10 samples were processed, 9 teeth and 1 femoral fragment. Nine of 10 samples were profiled using autosomal STR loci, which resulted in useful DNA profiles for 9 skeletal remains. A comparison of established victims' profiles against a reference sample database yielded 6 positive identifications. Conclusion DNA analysis may efficiently contribute to the identification of remains even seven decades after the end of the World War II. The significant percentage of positively identified remains (60%), even when the number of the examined possible living relatives was relatively small (only 12), proved the importance of cooperation with the members of the local community, who helped to identify the closest missing persons’ relatives and collect referent samples from them. PMID:26088850

  5. Identification of human remains from the Second World War mass graves uncovered in Bosnia and Herzegovina.

    PubMed

    Marjanović, Damir; Hadžić Metjahić, Negra; Čakar, Jasmina; Džehverović, Mirela; Dogan, Serkan; Ferić, Elma; Džijan, Snježana; Škaro, Vedrana; Projić, Petar; Madžar, Tomislav; Rod, Eduard; Primorac, Dragan

    2015-06-01

    To present the results obtained in the identification of human remains from World War II found in two mass graves in Ljubuški, Bosnia and Herzegovina. Samples from 10 skeletal remains were collected. Teeth and femoral fragments were collected from 9 skeletons and only a femoral fragment from 1 skeleton. DNA was isolated from bone and teeth samples using an optimized phenol/chloroform DNA extraction procedure. All samples required a pre-extraction decalcification with EDTA and additional post-extraction DNA purification using filter columns. Additionally, DNA from 12 reference samples (buccal swabs from potential living relatives) was extracted using the Qiagen DNA extraction method. QuantifilerTM Human DNA Quantification Kit was used for DNA quantification. PowerPlex ESI kit was used to simultaneously amplify 15 autosomal short tandem repeat (STR) loci, and PowerPlex Y23 was used to amplify 23 Y chromosomal STR loci. Matching probabilities were estimated using a standard statistical approach. A total of 10 samples were processed, 9 teeth and 1 femoral fragment. Nine of 10 samples were profiled using autosomal STR loci, which resulted in useful DNA profiles for 9 skeletal remains. A comparison of established victims' profiles against a reference sample database yielded 6 positive identifications. DNA analysis may efficiently contribute to the identification of remains even seven decades after the end of the World War II. The significant percentage of positively identified remains (60%), even when the number of the examined possible living relatives was relatively small (only 12), proved the importance of cooperation with the members of the local community, who helped to identify the closest missing persons' relatives and collect referent samples from them.

  6. Genome-wide methylation and transcriptome analysis in penile carcinoma: uncovering new molecular markers.

    PubMed

    Kuasne, Hellen; Cólus, Ilce Mara de Syllos; Busso, Ariane Fidelis; Hernandez-Vargas, Hector; Barros-Filho, Mateus Camargo; Marchi, Fabio Albuquerque; Scapulatempo-Neto, Cristovam; Faria, Eliney Ferreira; Lopes, Ademar; Guimarães, Gustavo Cardoso; Herceg, Zdenko; Rogatto, Silvia Regina

    2015-01-01

    Despite penile carcinoma (PeCa) being a relatively rare neoplasm, it remains an important public health issue for poor and developing countries. Contrary to most tumors, limited data are available for markers that are capable of assisting in diagnosis, prognosis, and treatment of PeCa. We aimed to identify molecular markers for PeCa by evaluating their epigenomic and transcriptome profiles and comparing them with surrounding non-malignant tissue (SNT) and normal glans (NG). Genome-wide methylation analysis revealed 171 hypermethylated probes in PeCa. Transcriptome profiling presented 2,883 underexpressed and 1,378 overexpressed genes. Integrative analysis revealed a panel of 54 genes with an inverse correlation between methylation and gene expression levels. Distinct methylome and transcriptome patterns were found for human papillomavirus (HPV)-positive (38.6%) and negative tumors. Interestingly, grade 3 tumors showed a distinct methylation profile when compared to grade 1. In addition, univariate analysis revealed that low BDNF methylation was associated with lymph node metastasis and shorter disease-free survival. CpG hypermethylation and gene underexpression were confirmed for a panel of genes, including TWIST1, RSOP2, SOX3, SOX17, PROM1, OTX2, HOXA3, and MEIS1. A unique methylome signature was found for PeCa compared to SNT, with aberrant DNA methylation appearing to modulate the expression of specific genes. This study describes new pathways with the potential to regulate penile carcinogenesis, including stem cell regulatory pathways and markers associated to a worse prognosis. These findings may be instrumental in the discovery and application of new genetic and epigenetic biomarkers in PeCa.

  7. Uncovering new thermal and mechanical behavior at the nanoscale using coherent extreme ultraviolet light

    NASA Astrophysics Data System (ADS)

    Hoogeboom-Pot, Kathleen Marie

    Tremendous recent progress in nanofabrication capabilities has made high-quality single-atomic layers and nanostructures with dimensions well below 50 nm commonplace, enabling unprecedented access to materials at the nanoscale. However, tools and techniques capable of characterizing the properties and function of nanosystems are still quite limited, leaving much of the fundamental physics that dominates material behavior in the deep nano-regime still unknown. Further understanding gained by studying nanoscale materials is critical both to fundamental science and to continued technological development. This thesis applies coherent extreme ultraviolet (EUV) light from tabletop high harmonic generation to study nanoscale systems on their intrinsic length and time scales (nanometers and femtoseconds, and above), specifically following thermal transport and acoustic dynamics. These studies have shown where and how nanostructured material properties can be quite different from their bulk counterparts. This has in turn allowed us to develop new theoretical descriptions to guide further work. By observing heat dissipation from the smallest nanostructure heat sources measured to date (at 20 nm in lateral size), this work uncovers a previously unobserved and unpredicted nanoscale thermal transport regime where both size and spacing of heat sources play a role in determining the heat dissipation effciency. Surprisingly, this shows that nanoscale heat sources can cool more quickly when spaced close together than when far apart. This discovery is significant to the engineering of thermal management in nanoscale systems and devices while also revealing new insight into the fundamental nature of thermal transport. Furthermore, we harness this new regime to demonstrate the first experimental measurement of the differential contributions of phonons with different mean free paths to thermal conductivity, down to mean free paths as short as 14 nm for the first time. The same

  8. No Place to Hide: Missing Primitive Stars Outside Milky Way Uncovered

    NASA Astrophysics Data System (ADS)

    2010-02-01

    After years of successful concealment, the most primitive stars outside our Milky Way galaxy have finally been unmasked. New observations using ESO's Very Large Telescope have been used to solve an important astrophysical puzzle concerning the oldest stars in our galactic neighbourhood - which is crucial for our understanding of the earliest stars in the Universe. "We have, in effect, found a flaw in the forensic methods used until now," says Else Starkenburg, lead author of the paper reporting the study. "Our improved approach allows us to uncover the primitive stars hidden among all the other, more common stars." Primitive stars are thought to have formed from material forged shortly after the Big Bang, 13.7 billion years ago. They typically have less than one thousandth the amount of chemical elements heavier than hydrogen and helium found in the Sun and are called "extremely metal-poor stars" [1]. They belong to one of the first generations of stars in the nearby Universe. Such stars are extremely rare and mainly observed in the Milky Way. Cosmologists think that larger galaxies like the Milky Way formed from the merger of smaller galaxies. Our Milky Way's population of extremely metal-poor or "primitive" stars should already have been present in the dwarf galaxies from which it formed, and similar populations should be present in other dwarf galaxies. "So far, evidence for them has been scarce," says co-author Giuseppina Battaglia. "Large surveys conducted in the last few years kept showing that the most ancient populations of stars in the Milky Way and dwarf galaxies did not match, which was not at all expected from cosmological models." Element abundances are measured from spectra, which provide the chemical fingerprints of stars [2]. The Dwarf galaxies Abundances and Radial-velocities Team [3] used the FLAMES instrument on ESO's Very Large Telescope to measure the spectra of over 2000 individual giant stars in four of our galactic neighbours, the Fornax

  9. Primary School Teachers’ Assessment Profiles in Mathematics Education

    PubMed Central

    Veldhuis, Michiel; van den Heuvel-Panhuizen, Marja

    2014-01-01

    The aim of this study was to contribute to knowledge about classroom assessment by identifying profiles of teachers’ assessment of their students’ understanding of mathematics. For carrying out this study we used data of a nationwide teacher survey (N = 960) in the Netherlands. The data were collected by an online questionnaire. Through exploratory factor analyses the underlying structure of what is measured by this questionnaire was uncovered as consisting of five factors: Goal centeredness of assessment, Authentic nature of assessment, Perceived usefulness of assessment, Diversity of assessment problem format, and Allocated importance of assessing skills and knowledge. By using a latent class analysis four different assessment profiles of teachers were identified: Enthusiastic assessors, Mainstream assessors, Non-enthusiastic assessors, and Alternative assessors. The findings suggest that teachers with particular assessment profiles have qualitatively different assessment practices. The paper concludes with discussing theoretical implications of these assessment profiles and indications these profiles can offer both for designing material for professional development in classroom assessment and for evaluating changes in teachers’ classroom assessment practice. PMID:24466255

  10. Primary school teachers' assessment profiles in mathematics education.

    PubMed

    Veldhuis, Michiel; van den Heuvel-Panhuizen, Marja

    2014-01-01

    The aim of this study was to contribute to knowledge about classroom assessment by identifying profiles of teachers' assessment of their students' understanding of mathematics. For carrying out this study we used data of a nationwide teacher survey (N = 960) in the Netherlands. The data were collected by an online questionnaire. Through exploratory factor analyses the underlying structure of what is measured by this questionnaire was uncovered as consisting of five factors: Goal centeredness of assessment, Authentic nature of assessment, Perceived usefulness of assessment, Diversity of assessment problem format, and Allocated importance of assessing skills and knowledge. By using a latent class analysis four different assessment profiles of teachers were identified: Enthusiastic assessors, Mainstream assessors, Non-enthusiastic assessors, and Alternative assessors. The findings suggest that teachers with particular assessment profiles have qualitatively different assessment practices. The paper concludes with discussing theoretical implications of these assessment profiles and indications these profiles can offer both for designing material for professional development in classroom assessment and for evaluating changes in teachers' classroom assessment practice.

  11. A New Rapid Method for Measuring the Vertical Head Profile.

    PubMed

    Keller, Carl

    2017-03-01

    This study describes a new technique for measuring the head profile in a geologic formation. The technique provides rapid, low cost information on the depth of water-producing zones and aquitards in heterogeneous aquifers, yielding estimates of hydraulic heads in each zone while identifying any potential for cross contamination between zones. The measurements can be performed in a typical borehole in just a few hours. The procedure uses both the continuous transmissivity profile obtained by the installation (eversion) of a flexible borehole liner into an open borehole and the subsequent removal (inversion) of the same liner from the borehole. The method is possible because of the continuous transmissivity profile (T profile described by Keller et al. 2014) obtained by measuring the rate of liner eversion under a constant driving head. The hydraulic heads of producing zones are measured using the reverse head profile (RHP) method (patent no. 9,008,971) based on a stepwise inversion of the borehole liner. As each interval of the borehole is uncovered by inversion of the liner, the head beneath the liner is allowed to equilibrate to a steady-state value. The individual hydraulic heads contributing to each measurement are calculated using the measured transmissivity for each zone. Application of the RHP method to a sedimentary bedrock borehole in New Jersey verified that it reproduced the head distribution obtained the same day in the same borehole instrumented with a multilevel sampling system.

  12. DNA profiles from fingermarks.

    PubMed

    Templeton, Jennifer E L; Linacre, Adrian

    2014-11-01

    Criminal investigations would be considerably improved if DNA profiles could be routinely generated from single fingermarks. Here we report a direct DNA profiling method that was able to generate interpretable profiles from 71% of 170 fingermarks. The data are based on fingermarks from all 5 digits of 34 individuals. DNA was obtained from the fingermarks using a swab moistened with Triton-X, and the fibers were added directly to one of two commercial DNA profiling kits. All profiles were obtained without increasing the number of amplification cycles; therefore, our method is ideally suited for adoption by the forensic science community. We indicate the use of the technique in a criminal case in which a DNA profile was generated from a fingermark on tape that was wrapped around a drug seizure. Our direct DNA profiling approach is rapid and able to generate profiles from touched items when current forensic practices have little chance of success.

  13. GHGRP Industrial Profiles

    EPA Pesticide Factsheets

    EPA's Greenhouse Gas Reporting Program periodically produces detailed profiles of the various industries that report under the program. These profiles contain detailed analyses. This page hosts data highlights for all sectors.

  14. PROFILER: 1D galaxy light profile decomposition

    NASA Astrophysics Data System (ADS)

    Ciambur, Bogdan C.

    2017-05-01

    Written in Python, PROFILER analyzes the radial surface brightness profiles of galaxies. It accurately models a wide range of galaxies and galaxy components, such as elliptical galaxies, the bulges of spiral and lenticular galaxies, nuclear sources, discs, bars, rings, and spiral arms with a variety of parametric functions routinely employed in the field (Sérsic, core-Sérsic, exponential, Gaussian, Moffat and Ferrers). In addition, Profiler can employ the broken exponential model (relevant for disc truncations or antitruncations) and two special cases of the edge-on disc model: namely along the major axis (in the disc plane) and along the minor axis (perpendicular to the disc plane).

  15. Genome-wide profiling of Hfq-binding RNAs uncovers extensive post-transcriptional rewiring of major stress response and symbiotic regulons in Sinorhizobium meliloti.

    PubMed

    Torres-Quesada, Omar; Reinkensmeier, Jan; Schlüter, Jan-Philip; Robledo, Marta; Peregrina, Alexandra; Giegerich, Robert; Toro, Nicolás; Becker, Anke; Jiménez-Zurdo, Jose I

    2014-01-01

    The RNA chaperone Hfq is a global post-transcriptional regulator in bacteria. Here, we used RNAseq to analyze RNA populations from the legume symbiont Sinorhizobium meliloti that were co-immunoprecipitated (CoIP-RNA) with a FLAG-tagged Hfq in five growth/stress conditions. Hfq-bound transcripts (1315) were largely identified in stressed bacteria and derived from small RNAs (sRNAs), both trans-encoded (6.4%) and antisense (asRNAs; 6.3%), and mRNAs (86%). Pull-down with Hfq recovered a small proportion of annotated S. meliloti sRNAs (14% of trans-sRNAs and 2% of asRNAs) suggesting a discrete impact of this protein in sRNA pathways. Nonetheless, Hfq selectively stabilized CoIP-enriched sRNAs, anticipating that these interactions are functionally significant. Transcription of 26 Hfq-bound sRNAs was predicted to occur from promoters recognized by the major stress σ factors σ(E2) or σ(H1/2). Recovery rates of sRNAs in each of the CoIP-RNA libraries suggest a large impact of Hfq-assisted riboregulation in S. meliloti osmoadaptation. Hfq directly targeted 18% of the predicted S. meliloti mRNAs, which encode functionally diverse proteins involved in transport and metabolism, σ(E2)-dependent stress responses, quorum sensing, flagella biosynthesis, ribosome, and membrane assembly or symbiotic nitrogen fixation. Canonical targeting of the 5' regions of two of the ABC transporter mRNAs by the homologous Hfq-binding AbcR1 and AbcR2 sRNAs leading to inhibition of protein synthesis was confirmed in vivo. We therefore provide a comprehensive resource for the systems-level deciphering of hitherto unexplored S. meliloti stress and symbiotic post-transcriptional regulons and the identification of Hfq-dependent sRNA-mRNA regulatory pairs.

  16. Genome-Wide Transcriptional Profiling and Metabolic Analysis Uncover Multiple Molecular Responses of the Grass Species Lolium perenne Under Low-Intensity Xenobiotic Stress

    PubMed Central

    Serra, Anne-Antonella; Couée, Ivan; Heijnen, David; Michon-Coudouel, Sophie; Sulmon, Cécile; Gouesbet, Gwenola

    2015-01-01

    Lolium perenne, which is a major component of pastures, lawns, and grass strips, can be exposed to xenobiotic stresses due to diffuse and residual contaminations of soil. L. perenne was recently shown to undergo metabolic adjustments in response to sub-toxic levels of xenobiotics. To gain insight in such chemical stress responses, a de novo transcriptome analysis was carried out on leaves from plants subjected at the root level to low levels of xenobiotics, glyphosate, tebuconazole, and a combination of the two, leading to no adverse physiological effect. Chemical treatments influenced significantly the relative proportions of functional categories and of transcripts related to carbohydrate processes, to signaling, to protein-kinase cascades, such as Serine/Threonine-protein kinases, to transcriptional regulations, to responses to abiotic or biotic stimuli and to responses to phytohormones. Transcriptomics-based expressions of genes encoding different types of SNF1 (sucrose non-fermenting 1)-related kinases involved in sugar and stress signaling or encoding key metabolic enzymes were in line with specific qRT-PCR analysis or with the important metabolic and regulatory changes revealed by metabolomic analysis. The effects of pesticide treatments on metabolites and gene expression strongly suggest that pesticides at low levels, as single molecule or as mixture, affect cell signaling and functioning even in the absence of major physiological impact. This global analysis of L. perenne therefore highlighted the interactions between molecular regulation of responses to xenobiotics, and also carbohydrate dynamics, energy dysfunction, phytohormones and calcium signaling. PMID:26734031

  17. Genome-Wide Transcriptional Profiling and Metabolic Analysis Uncover Multiple Molecular Responses of the Grass Species Lolium perenne Under Low-Intensity Xenobiotic Stress.

    PubMed

    Serra, Anne-Antonella; Couée, Ivan; Heijnen, David; Michon-Coudouel, Sophie; Sulmon, Cécile; Gouesbet, Gwenola

    2015-01-01

    Lolium perenne, which is a major component of pastures, lawns, and grass strips, can be exposed to xenobiotic stresses due to diffuse and residual contaminations of soil. L. perenne was recently shown to undergo metabolic adjustments in response to sub-toxic levels of xenobiotics. To gain insight in such chemical stress responses, a de novo transcriptome analysis was carried out on leaves from plants subjected at the root level to low levels of xenobiotics, glyphosate, tebuconazole, and a combination of the two, leading to no adverse physiological effect. Chemical treatments influenced significantly the relative proportions of functional categories and of transcripts related to carbohydrate processes, to signaling, to protein-kinase cascades, such as Serine/Threonine-protein kinases, to transcriptional regulations, to responses to abiotic or biotic stimuli and to responses to phytohormones. Transcriptomics-based expressions of genes encoding different types of SNF1 (sucrose non-fermenting 1)-related kinases involved in sugar and stress signaling or encoding key metabolic enzymes were in line with specific qRT-PCR analysis or with the important metabolic and regulatory changes revealed by metabolomic analysis. The effects of pesticide treatments on metabolites and gene expression strongly suggest that pesticides at low levels, as single molecule or as mixture, affect cell signaling and functioning even in the absence of major physiological impact. This global analysis of L. perenne therefore highlighted the interactions between molecular regulation of responses to xenobiotics, and also carbohydrate dynamics, energy dysfunction, phytohormones and calcium signaling.

  18. Genome-wide profiling of Hfq-binding RNAs uncovers extensive post-transcriptional rewiring of major stress response and symbiotic regulons in Sinorhizobium meliloti

    PubMed Central

    Torres-Quesada, Omar; Reinkensmeier, Jan; Schlüter, Jan-Philip; Robledo, Marta; Peregrina, Alexandra; Giegerich, Robert; Toro, Nicolás; Becker, Anke; Jiménez-Zurdo, Jose I

    2014-01-01

    The RNA chaperone Hfq is a global post-transcriptional regulator in bacteria. Here, we used RNAseq to analyze RNA populations from the legume symbiont Sinorhizobium meliloti that were co-immunoprecipitated (CoIP-RNA) with a FLAG-tagged Hfq in five growth/stress conditions. Hfq-bound transcripts (1315) were largely identified in stressed bacteria and derived from small RNAs (sRNAs), both trans-encoded (6.4%) and antisense (asRNAs; 6.3%), and mRNAs (86%). Pull-down with Hfq recovered a small proportion of annotated S. meliloti sRNAs (14% of trans-sRNAs and 2% of asRNAs) suggesting a discrete impact of this protein in sRNA pathways. Nonetheless, Hfq selectively stabilized CoIP-enriched sRNAs, anticipating that these interactions are functionally significant. Transcription of 26 Hfq-bound sRNAs was predicted to occur from promoters recognized by the major stress σ factors σE2 or σH1/2. Recovery rates of sRNAs in each of the CoIP–RNA libraries suggest a large impact of Hfq-assisted riboregulation in S. meliloti osmoadaptation. Hfq directly targeted 18% of the predicted S. meliloti mRNAs, which encode functionally diverse proteins involved in transport and metabolism, σE2-dependent stress responses, quorum sensing, flagella biosynthesis, ribosome, and membrane assembly or symbiotic nitrogen fixation. Canonical targeting of the 5′ regions of two of the ABC transporter mRNAs by the homologous Hfq-binding AbcR1 and AbcR2 sRNAs leading to inhibition of protein synthesis was confirmed in vivo. We therefore provide a comprehensive resource for the systems-level deciphering of hitherto unexplored S. meliloti stress and symbiotic post-transcriptional regulons and the identification of Hfq-dependent sRNA–mRNA regulatory pairs. PMID:24786641

  19. Tumor heterogeneity uncovered by dynamic expression of long noncoding RNA at single-cell resolution.

    PubMed

    Hu, Wangxiong; Wang, Tingzhang; Yang, Yanmei; Zheng, Shu

    2015-12-01

    The expression of long noncoding RNA (lncRNA) is thought to be more cell-type specific than the expression of protein-coding genes. However, the expression profile of individual cells regarding lncRNA remains to be elucidated. Here, we comprehensively investigated the pattern of lncRNA expression across five glioblastoma tumors (414 cells) and two cell lines (GBM6 and GBM8, 127 cells). We found that there were more than 1,000 lncRNAs that varied between any two cells and that there was frequent gain and loss of lncRNA expression during tumor cell proliferation, suggesting a great heterogeneity in lncRNA expression across different single cells in glioblastoma. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Uncovering the deformation mechanisms of origami metamaterials by introducing generic degree-four vertices

    NASA Astrophysics Data System (ADS)

    Fang, Hongbin; Li, Suyi; Ji, Huimin; Wang, K. W.

    2016-10-01

    Origami-based design holds promise for developing new mechanical metamaterials whose overall kinematic and mechanical properties can be programmed using purely geometric criteria. In this article, we demonstrate that the deformation of a generic degree-four vertex (4-vertex) origami cell is a combination of contracting, shearing, bending, and facet-binding. The last three deformation mechanisms are missing in the current rigid-origami metamaterial investigations, which focus mainly on conventional Miura-ori patterns. We show that these mechanisms provide the 4-vertex origami sheets and blocks with new deformation patterns as well as extraordinary kinematical and mechanical properties, including self-locking, tridirectional negative Poisson's ratios, flipping of stiffness profiles, and emerging shearing stiffness. This study reveals that the 4-vertex cells offer a better platform and greater design space for developing origami-based mechanical metamaterials than the conventional Miura-ori cell.

  1. Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification

    PubMed Central

    Lamoliatte, Frédéric; McManus, Francis P.; Maarifi, Ghizlane; Chelbi-Alix, Mounira K.; Thibault, Pierre

    2017-01-01

    Crosstalk between the SUMO and ubiquitin pathways has recently been reported. However, no approach currently exists to determine the interrelationship between these modifications. Here, we report an optimized immunoaffinity method that permits the study of both protein ubiquitylation and SUMOylation from a single sample. This method enables the unprecedented identification of 10,388 SUMO sites in HEK293 cells. The sequential use of SUMO and ubiquitin remnant immunoaffinity purification facilitates the dynamic profiling of SUMOylated and ubiquitylated proteins in HEK293 cells treated with the proteasome inhibitor MG132. Quantitative proteomic analyses reveals crosstalk between substrates that control protein degradation, and highlights co-regulation of SUMOylation and ubiquitylation levels on deubiquitinase enzymes and the SUMOylation of proteasome subunits. The SUMOylation of the proteasome affects its recruitment to promyelocytic leukemia protein (PML) nuclear bodies, and PML lacking the SUMO interacting motif fails to colocalize with SUMOylated proteasome further demonstrating that this motif is required for PML catabolism. PMID:28098164

  2. Transcriptome atlas of eight liver cell types uncovers effects of histidine catabolites on rat liver regeneration.

    PubMed

    Chang, C F; Fan, J Y; Zhang, F C; Ma, J; Xu, C S

    2010-12-01

    Eight liver cell types were isolated using the methods of Percoll density gradient centrifugation and immunomagnetic beads to explore effects of histidine catabolites on rat liver regeneration. Rat Genome 230 2.0 Array was used to detect the expression profiles of genes associated with metabolism of histidine and its catabolites for the above-mentioned eight liver cell types, and bioinformatic and systems biology approaches were employed to analyse the relationship between above genes and rat liver regeneration. The results showed that the urocanic acid (UA) was degraded from histidine in Kupffer cells, acts on Kupffer cells itself and dendritic cells to generate immune suppression by autocrine and paracrine modes. Hepatocytes, biliary epithelia cells, oval cells and dendritic cells can convert histidine to histamine, which can promote sinusoidal endothelial cells proliferation by GsM pathway, and promote the proliferation of hepatocytes and biliary epithelia cells by GqM pathway.

  3. Uncovering the deformation mechanisms of origami metamaterials by introducing generic degree-four vertices.

    PubMed

    Fang, Hongbin; Li, Suyi; Ji, Huimin; Wang, K W

    2016-10-01

    Origami-based design holds promise for developing new mechanical metamaterials whose overall kinematic and mechanical properties can be programmed using purely geometric criteria. In this article, we demonstrate that the deformation of a generic degree-four vertex (4-vertex) origami cell is a combination of contracting, shearing, bending, and facet-binding. The last three deformation mechanisms are missing in the current rigid-origami metamaterial investigations, which focus mainly on conventional Miura-ori patterns. We show that these mechanisms provide the 4-vertex origami sheets and blocks with new deformation patterns as well as extraordinary kinematical and mechanical properties, including self-locking, tridirectional negative Poisson's ratios, flipping of stiffness profiles, and emerging shearing stiffness. This study reveals that the 4-vertex cells offer a better platform and greater design space for developing origami-based mechanical metamaterials than the conventional Miura-ori cell.

  4. A distinctive avian assemblage (Aves: Passeriformes) in Western Darién, Panama is uncovered through a disease surveillance program.

    PubMed

    Miller, Matthew J

    2014-06-01

    Basic knowledge about the distribution of flora and fauna is lacking for most tropical areas. Improving our knowledge of the tropical biota will help address contemporary global problems, including emerging tropical diseases. Less appreciated is the role that applied studies can have in improving our understanding of basic biological patterns and processes in the tropics. Here, I describe a novel avifauna assemblage uncovered in Western Darién province in the Republic of Panama that was uncovered during a vector-borne disease surveillance program. I compared the passerine bird species composition at 16 sites using records from recent ornithological expeditions sponsored by the Smithsonian Tropical Research Institute in Central and Eastern Panama. Based on the results of a Mantel test, geographic distance did not correlate with pairwise distinctiveness of sites. instead, based on an index of distinctiveness modified from the Chao-Jaccard index, most sites were more or less similarly distinctive, with one site, Aruza Abajo, significantly more distinctive than the rest. I found that the distinctiveness of this site was due not only to the presence of several rare and range-restricted taxa, but also to the absence of taxa that are common elsewhere. This finding provides more evidence of high species composition turnover (beta-diversity) in the Panamanian biota, which appears to be driven by a combination of soil and climate differences over narrow distances.

  5. Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C

    PubMed Central

    Xiao, Fei; Fofana, Isabel; Thumann, Christine; Mailly, Laurent; Alles, Roxane; Robinet, Eric; Meyer, Nicolas; Schaeffer, Mickaël; Habersetzer, François; Doffoël, Michel; Leyssen, Pieter; Neyts, Johan; Zeisel, Mirjam B; Baumert, Thomas F

    2015-01-01

    Objective Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy. Design Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection. Results Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice. Conclusions Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens. PMID:24848265

  6. Contribution of the Nurses' Health Studies to Uncovering Risk Factors for Type 2 Diabetes: Diet, Lifestyle, Biomarkers, and Genetics.

    PubMed

    Ley, Sylvia H; Ardisson Korat, Andres V; Sun, Qi; Tobias, Deirdre K; Zhang, Cuilin; Qi, Lu; Willett, Walter C; Manson, JoAnn E; Hu, Frank B

    2016-09-01

    To review the contribution of the Nurses' Health Study (NHS) and the NHS II to addressing hypotheses regarding risk factors for type 2 diabetes. We carried out a narrative review of 1976 to 2016 NHS and NHS II publications. The NHS and NHS II have uncovered important roles in type 2 diabetes for individual nutrients, foods, dietary patterns, and physical activity independent of excess body weight. Up to 90% of type 2 diabetes cases are potentially preventable if individuals follow a healthy diet and lifestyle. The NHS investigations have also identified novel biomarkers for diabetes, including adipokines, inflammatory cytokines, nutrition metabolites, and environmental pollutants, offering new insights into the pathophysiology of the disease. Global collaborative efforts have uncovered many common genetic variants associated with type 2 diabetes and improved our understanding of gene-environment interactions. Continued efforts to identify epigenetic, metagenomic, and metabolomic risk factors for type 2 diabetes have the potential to reveal new pathways and improve prediction and prevention. Over the past several decades, the NHS and NHS II have made major contributions to public health recommendations and strategies designed to reduce the global burden of diabetes.

  7. Contribution of the Nurses’ Health Studies to Uncovering Risk Factors for Type 2 Diabetes: Diet, Lifestyle, Biomarkers, and Genetics

    PubMed Central

    Ley, Sylvia H.; Ardisson Korat, Andres V.; Sun, Qi; Tobias, Deirdre K.; Zhang, Cuilin; Qi, Lu; Willett, Walter C.; Manson, JoAnn E.

    2016-01-01

    Objectives. To review the contribution of the Nurses’ Health Study (NHS) and the NHS II to addressing hypotheses regarding risk factors for type 2 diabetes. Methods. We carried out a narrative review of 1976 to 2016 NHS and NHS II publications. Results. The NHS and NHS II have uncovered important roles in type 2 diabetes for individual nutrients, foods, dietary patterns, and physical activity independent of excess body weight. Up to 90% of type 2 diabetes cases are potentially preventable if individuals follow a healthy diet and lifestyle. The NHS investigations have also identified novel biomarkers for diabetes, including adipokines, inflammatory cytokines, nutrition metabolites, and environmental pollutants, offering new insights into the pathophysiology of the disease. Global collaborative efforts have uncovered many common genetic variants associated with type 2 diabetes and improved our understanding of gene–environment interactions. Continued efforts to identify epigenetic, metagenomic, and metabolomic risk factors for type 2 diabetes have the potential to reveal new pathways and improve prediction and prevention. Conclusions. Over the past several decades, the NHS and NHS II have made major contributions to public health recommendations and strategies designed to reduce the global burden of diabetes. PMID:27459454

  8. Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.

    PubMed

    Lardelli, Rea M; Schaffer, Ashleigh E; Eggens, Veerle R C; Zaki, Maha S; Grainger, Stephanie; Sathe, Shashank; Van Nostrand, Eric L; Schlachetzki, Zinayida; Rosti, Basak; Akizu, Naiara; Scott, Eric; Silhavy, Jennifer L; Heckman, Laura Dean; Rosti, Rasim Ozgur; Dikoglu, Esra; Gregor, Anne; Guemez-Gamboa, Alicia; Musaev, Damir; Mande, Rohit; Widjaja, Ari; Shaw, Tim L; Markmiller, Sebastian; Marin-Valencia, Isaac; Davies, Justin H; de Meirleir, Linda; Kayserili, Hulya; Altunoglu, Umut; Freckmann, Mary Louise; Warwick, Linda; Chitayat, David; Blaser, Susan; Çağlayan, Ahmet Okay; Bilguvar, Kaya; Per, Huseyin; Fagerberg, Christina; Christesen, Henrik T; Kibaek, Maria; Aldinger, Kimberly A; Manchester, David; Matsumoto, Naomichi; Muramatsu, Kazuhiro; Saitsu, Hirotomo; Shiina, Masaaki; Ogata, Kazuhiro; Foulds, Nicola; Dobyns, William B; Chi, Neil C; Traver, David; Spaccini, Luigina; Bova, Stefania Maria; Gabriel, Stacey B; Gunel, Murat; Valente, Enza Maria; Nassogne, Marie-Cecile; Bennett, Eric J; Yeo, Gene W; Baas, Frank; Lykke-Andersen, Jens; Gleeson, Joseph G

    2017-03-01

    Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg(2+)-dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.

  9. Deletion of Cytoplasmic Double-Stranded RNA Sensors Does Not Uncover Viral Small Interfering RNA Production in Human Cells.

    PubMed

    Schuster, Susan; Tholen, Lotte E; Overheul, Gijs J; van Kuppeveld, Frank J M; van Rij, Ronald P

    2017-01-01

    Antiviral immunity in insects and plants is mediated by the RNA interference (RNAi) pathway in which viral long double-stranded RNA (dsRNA) is processed into small interfering RNAs (siRNAs) by Dicer enzymes. Although this pathway is evolutionarily conserved, its involvement in antiviral defense in mammals is the subject of debate. In vertebrates, recognition of viral RNA induces a sophisticated type I interferon (IFN)-based immune response, and it has been proposed that this response masks or inhibits antiviral RNAi. To test this hypothesis, we analyzed viral small RNA production in differentiated cells deficient in the cytoplasmic RNA sensors RIG-I and MDA5. We did not detect 22-nucleotide (nt) viral siRNAs upon infection with three different positive-sense RNA viruses. Our data suggest that the depletion of cytoplasmic RIG-I-like sensors is not sufficient to uncover viral siRNAs in differentiated cells. IMPORTANCE The contribution of the RNA interference (RNAi) pathway in antiviral immunity in vertebrates has been widely debated. It has been proposed that RNAi possesses antiviral activity in mammalian systems but that its antiviral effect is masked by the potent antiviral interferon response in differentiated mammalian cells. In this study, we show that inactivation of the interferon response is not sufficient to uncover antiviral activity of RNAi in human epithelial cells infected with three wild-type positive-sense RNA viruses.

  10. Fusion transcriptome profiling provides insights into alveolar rhabdomyosarcoma.

    PubMed

    Xie, Zhongqiu; Babiceanu, Mihaela; Kumar, Shailesh; Jia, Yuemeng; Qin, Fujun; Barr, Frederic G; Li, Hui

    2016-11-15

    Gene fusions and fusion products were thought to be unique features of neoplasia. However, more and more studies have identified fusion RNAs in normal physiology. Through RNA sequencing of 27 human noncancer tissues, a large number of fusion RNAs were found. By analyzing fusion transcriptome, we observed close clusterings between samples of same or similar tissues, supporting the feasibility of using fusion RNA profiling to reveal connections between biological samples. To put the concept into use, we selected alveolar rhabdomyosarcoma (ARMS), a myogenic pediatric cancer whose exact cell of origin is not clear. PAX3-FOXO1 (paired box gene 3 fused with forkhead box O1) fusion RNA, which is considered a hallmark of ARMS, was recently found during normal muscle cell differentiation. We performed and analyzed RNA sequencing from various time points during myogenesis and uncovered many chimeric fusion RNAs. Interestingly, we found that the fusion RNA profile of RH30, an ARMS cell line, is most similar to the myogenesis time point when PAX3-FOXO1 is expressed. In contrast, full transcriptome clustering analysis failed to uncover this connection. Strikingly, all of the 18 chimeric RNAs in RH30 cells could be detected at the same myogenic time point(s). In addition, the seven chimeric RNAs that follow the exact transient expression pattern as PAX3-FOXO1 are specific to rhabdomyosarcoma cells. Further testing with clinical samples also confirmed their specificity to rhabdomyosarcoma. These results provide further support for the link between at least some ARMSs and the PAX3-FOXO1-expressing myogenic cells and demonstrate that fusion RNA profiling can be used to investigate the etiology of fusion-gene-associated cancers.

  11. RNA sequencing uncovers antisense RNAs and novel small RNAs in Streptococcus pyogenes

    PubMed Central

    Le Rhun, Anaïs; Beer, Yan Yan; Reimegård, Johan; Chylinski, Krzysztof; Charpentier, Emmanuelle

    2016-01-01

    ABSTRACT Streptococcus pyogenes is a human pathogen responsible for a wide spectrum of diseases ranging from mild to life-threatening infections. During the infectious process, the temporal and spatial expression of pathogenicity factors is tightly controlled by a complex network of protein and RNA regulators acting in response to various environmental signals. Here, we focus on the class of small RNA regulators (sRNAs) and present the first complete analysis of sRNA sequencing data in S. pyogenes. In the SF370 clinical isolate (M1 serotype), we identified 197 and 428 putative regulatory RNAs by visual inspection and bioinformatics screening of the sequencing data, respectively. Only 35 from the 197 candidates identified by visual screening were assigned a predicted function (T-boxes, ribosomal protein leaders, characterized riboswitches or sRNAs), indicating how little is known about sRNA regulation in S. pyogenes. By comparing our list of predicted sRNAs with previous S. pyogenes sRNA screens using bioinformatics or microarrays, 92 novel sRNAs were revealed, including antisense RNAs that are for the first time shown to be expressed in this pathogen. We experimentally validated the expression of 30 novel sRNAs and antisense RNAs. We show that the expression profile of 9 sRNAs including 2 predicted regulatory elements is affected by the endoribonucleases RNase III and/or RNase Y, highlighting the critical role of these enzymes in sRNA regulation. PMID:26580233

  12. Integrating Multi-Omics for Uncovering the Architecture of Cross-Talking Pathways in Breast Cancer

    PubMed Central

    Zhao, Hongying; Li, Feng; Hu, Jing; Zhang, Hongyi; Deng, Yulan; Tian, Jiawei; Li, Xia

    2014-01-01

    Cross-talk among abnormal pathways widely occurs in human cancer and generally leads to insensitivity to cancer treatment. Moreover, alterations in the abnormal pathways are not limited to single molecular level. Therefore, we proposed a strategy that integrates a large number of biological sources at multiple levels for systematic identification of cross-talk among risk pathways in cancer by random walk on protein interaction network. We applied the method to multi-Omics breast cancer data from The Cancer Genome Atlas (TCGA), including somatic mutation, DNA copy number, DNA methylation and gene expression profiles. We identified close cross-talk among many known cancer-related pathways with complex change patterns. Furthermore, we identified key genes (linkers) bridging these cross-talks and showed that these genes carried out consistent biological functions with the linked cross-talking pathways. Through identification of leader genes in each pathway, the architecture of cross-talking pathways was built. Notably, we observed that linkers cooperated with leaders to form the fundamentation of cross-talk of pathways which play core roles in deterioration of breast cancer. As an example, we observed that KRAS showed a direct connection to numerous cancer-related pathways, such as MAPK signaling pathway, suggesting that it may be a central communication hub. In summary, we offer an effective way to characterize complex cross-talk among disease pathways, which can be applied to other diseases and provide useful information for the treatment of cancer. PMID:25137136

  13. Joint Spanish-American Research uncovers fracture pattern in northeastern Caribbean

    NASA Astrophysics Data System (ADS)

    Dillon, William P.; Acosta, Juan; Uchupi, Elazar; ten Brink, Uri S.

    A joint Spanish-American geophysical cruise north of the Virgin Islands has delineated the fracture pattern of the North American plate as it is overrun by the northeast corner of the Caribbean plate. Previously known fractures parallel to the plate boundary (approximately east-west) probably result from plate flexure, while newly defined crossing fractures (north-northeast) may be related to extension produced by the compound bend of the North American plate. The direction of the fractures may be modified by preexisting spreading tectonic fabric.The fieldwork took place in May 1997 aboard the Spanish research vessel Hespérides as part of an ongoing effort to study plate interactions and their seismotectonic effects on Puerto Rico and the Virgin Islands. Multichannel seismic-reflection profiles, multibeam bathymetry, and gravity and magnetic data were collected on the cruise. Also examined were reprocessed regional seismic lines, newly relocated earthquake epicenters, and satellite gravity data. The program was planned by scientists from the U.S. Geological Survey (USGS), Instituto Español de Oceanografía (IEO), and the Woods Hole Oceanographic Institution.

  14. Quantitative Proteomics Uncovers Novel Factors Involved in Developmental Differentiation of Trypanosoma brucei

    PubMed Central

    Dejung, Mario; Subota, Ines; Bucerius, Ferdinand; Dindar, Gülcin; Freiwald, Anja; Engstler, Markus; Boshart, Michael; Butter, Falk; Janzen, Christian J.

    2016-01-01

    Developmental differentiation is a universal biological process that allows cells to adapt to different environments to perform specific functions. African trypanosomes progress through a tightly regulated life cycle in order to survive in different host environments when they shuttle between an insect vector and a vertebrate host. Transcriptomics has been useful to gain insight into RNA changes during stage transitions; however, RNA levels are only a moderate proxy for protein abundance in trypanosomes. We quantified 4270 protein groups during stage differentiation from the mammalian-infective to the insect form and provide classification for their expression profiles during development. Our label-free quantitative proteomics study revealed previously unknown components of the differentiation machinery that are involved in essential biological processes such as signaling, posttranslational protein modifications, trafficking and nuclear transport. Furthermore, guided by our proteomic survey, we identified the cause of the previously observed differentiation impairment in the histone methyltransferase DOT1B knock-out strain as it is required for accurate karyokinesis in the first cell division during differentiation. This epigenetic regulator is likely involved in essential chromatin restructuring during developmental differentiation, which might also be important for differentiation in higher eukaryotic cells. Our proteome dataset will serve as a resource for detailed investigations of cell differentiation to shed more light on the molecular mechanisms of this process in trypanosomes and other eukaryotes. PMID:26910529

  15. Transcriptional gene silencing as a tool for uncovering gene function in maize.

    PubMed

    Cigan, A Mark; Unger-Wallace, Erica; Haug-Collet, Kristin

    2005-09-01

    Transcriptional gene silencing has broad applications for studying gene function in planta. In maize, a large number of genes have been identified as tassel-preferred in their expression pattern, both by traditional genetic methods and by recent high-throughput expression profiling platforms. Approaches using RNA suppression may provide a rapid alternative means to identify genes directly related to pollen development in maize. The male fertility gene Ms45 and several anther-expressed genes of unknown function were used to evaluate the efficacy of generating male-sterile plants by transcriptional gene silencing. A high frequency of male-sterile plants was obtained by constitutively expressing inverted repeats (IR) of the Ms45 promoter. These sterile plants lacked MS45 mRNA due to transcriptional inactivity of the target promoter. Moreover, fertility was restored to these promoter IR-containing plants by expressing the Ms45 coding region using heterologous promoters. Transcriptional silencing of other anther-expressed genes also significantly affected male fertility phenotypes and led to increased methylation of the target promoter DNA sequences. These studies provide evidence of disruption of gene activity in monocots by RNA interference constructs directed against either native or transformed promoter regions. This approach not only enables the correlation of monocot anther-expressed genes with functions that are important for reproduction in maize, but may also provide a tool for studying gene function and identifying regulatory components unique to transcriptional gene control.

  16. Comparative genomics uncovers the prolific and distinctive metabolic potential of the cyanobacterial genus Moorea

    PubMed Central

    Leao, Tiago; Castelão, Guilherme; Monroe, Emily A.; Podell, Sheila; Glukhov, Evgenia; Allen, Eric E.; Gerwick, William H.; Gerwick, Lena

    2017-01-01

    Cyanobacteria are major sources of oxygen, nitrogen, and carbon in nature. In addition to the importance of their primary metabolism, some cyanobacteria are prolific producers of unique and bioactive secondary metabolites. Chemical investigations of the cyanobacterial genus Moorea have resulted in the isolation of over 190 compounds in the last two decades. However, preliminary genomic analysis has suggested that genome-guided approaches can enable the discovery of novel compounds from even well-studied Moorea strains, highlighting the importance of obtaining complete genomes. We report a complete genome of a filamentous tropical marine cyanobacterium, Moorea producens PAL, which reveals that about one-fifth of its genome is devoted to production of secondary metabolites, an impressive four times the cyanobacterial average. Moreover, possession of the complete PAL genome has allowed improvement to the assembly of three other Moorea draft genomes. Comparative genomics revealed that they are remarkably similar to one another, despite their differences in geography, morphology, and secondary metabolite profiles. Gene cluster networking highlights that this genus is distinctive among cyanobacteria, not only in the number of secondary metabolite pathways but also in the content of many pathways, which are potentially distinct from all other bacterial gene clusters to date. These findings portend that future genome-guided secondary metabolite discovery and isolation efforts should be highly productive. PMID:28265051

  17. Integrating multi-omics for uncovering the architecture of cross-talking pathways in breast cancer.

    PubMed

    Wang, Li; Xiao, Yun; Ping, Yanyan; Li, Jing; Zhao, Hongying; Li, Feng; Hu, Jing; Zhang, Hongyi; Deng, Yulan; Tian, Jiawei; Li, Xia

    2014-01-01

    Cross-talk among abnormal pathways widely occurs in human cancer and generally leads to insensitivity to cancer treatment. Moreover, alterations in the abnormal pathways are not limited to single molecular level. Therefore, we proposed a strategy that integrates a large number of biological sources at multiple levels for systematic identification of cross-talk among risk pathways in cancer by random walk on protein interaction network. We applied the method to multi-Omics breast cancer data from The Cancer Genome Atlas (TCGA), including somatic mutation, DNA copy number, DNA methylation and gene expression profiles. We identified close cross-talk among many known cancer-related pathways with complex change patterns. Furthermore, we identified key genes (linkers) bridging these cross-talks and showed that these genes carried out consistent biological functions with the linked cross-talking pathways. Through identification of leader genes in each pathway, the architecture of cross-talking pathways was built. Notably, we observed that linkers cooperated with leaders to form the fundamentation of cross-talk of pathways which play core roles in deterioration of breast cancer. As an example, we observed that KRAS showed a direct connection to numerous cancer-related pathways, such as MAPK signaling pathway, suggesting that it may be a central communication hub. In summary, we offer an effective way to characterize complex cross-talk among disease pathways, which can be applied to other diseases and provide useful information for the treatment of cancer.

  18. Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington's disease models.

    PubMed

    Smalley, Joshua L; Breda, Carlo; Mason, Robert P; Kooner, Gurdeep; Luthi-Carter, Ruth; Gant, Timothy W; Giorgini, Flaviano

    2016-02-01

    Huntington's disease (HD) is a genetic disease caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin (HTT) protein, ultimately leading to neuronal loss and consequent cognitive decline and death. As no treatments for HD currently exist, several chemical screens have been performed using cell-based models of mutant HTT toxicity. These screens measured single disease-related endpoints, such as cell death, but had low 'hit rates' and limited dimensionality for therapeutic detection. Here, we have employed gene expression microarray analysis of HD samples--a snapshot of the expression of 25,000 genes--to define a gene expression signature for HD from publically available data. We used this information to mine a database for chemicals positively and negatively correlated to the HD gene expression signature using the Connectivity Map, a tool for comparing large sets of gene expression patterns. Chemicals with negatively correlated expression profiles were highly enriched for protective characteristics against mutant HTT fragment toxicity in in vitro and in vivo models. This study demonstrates the potential of using gene expression to mine chemical activity, guide chemical screening, and detect potential novel therapeutic compounds. Single-endpoint chemical screens have low therapeutic discovery hit-rates. In the context of HD, we guided a chemical screen using gene expression data. The resulting chemicals were highly enriched for suppressors of mutant HTT fragment toxicity. This study provides a proof of concept for wider usage in all chemical screening.

  19. Quantitative Proteomics Uncovers Novel Factors Involved in Developmental Differentiation of Trypanosoma brucei.

    PubMed

    Dejung, Mario; Subota, Ines; Bucerius, Ferdinand; Dindar, Gülcin; Freiwald, Anja; Engstler, Markus; Boshart, Michael; Butter, Falk; Janzen, Christian J

    2016-02-01

    Developmental differentiation is a universal biological process that allows cells to adapt to different environments to perform specific functions. African trypanosomes progress through a tightly regulated life cycle in order to survive in different host environments when they shuttle between an insect vector and a vertebrate host. Transcriptomics has been useful to gain insight into RNA changes during stage transitions; however, RNA levels are only a moderate proxy for protein abundance in trypanosomes. We quantified 4270 protein groups during stage differentiation from the mammalian-infective to the insect form and provide classification for their expression profiles during development. Our label-free quantitative proteomics study revealed previously unknown components of the differentiation machinery that are involved in essential biological processes such as signaling, posttranslational protein modifications, trafficking and nuclear transport. Furthermore, guided by our proteomic survey, we identified the cause of the previously observed differentiation impairment in the histone methyltransferase DOT1B knock-out strain as it is required for accurate karyokinesis in the first cell division during differentiation. This epigenetic regulator is likely involved in essential chromatin restructuring during developmental differentiation, which might also be important for differentiation in higher eukaryotic cells. Our proteome dataset will serve as a resource for detailed investigations of cell differentiation to shed more light on the molecular mechanisms of this process in trypanosomes and other eukaryotes.

  20. Laser microdissection of narrow sheath mutant maize uncovers novel gene expression in the shoot apical meristem.

    PubMed

    Zhang, Xiaolan; Madi, Shahinez; Borsuk, Lisa; Nettleton, Dan; Elshire, Robert J; Buckner, Brent; Janick-Buckner, Diane; Beck, Jon; Timmermans, Marja; Schnable, Patrick S; Scanlon, Michael J

    2007-06-01

    Microarrays enable comparative analyses of gene expression on a genomic scale, however these experiments frequently identify an abundance of differentially expressed genes such that it may be difficult to identify discrete functional networks that are hidden within large microarray datasets. Microarray analyses in which mutant organisms are compared to nonmutant siblings can be especially problematic when the gene of interest is expressed in relatively few cells. Here, we describe the use of laser microdissection microarray to perform transcriptional profiling of the maize shoot apical meristem (SAM), a ~100-microm pillar of organogenic cells that is required for leaf initiation. Microarray analyses compared differential gene expression within the SAM and incipient leaf primordium of nonmutant and narrow sheath mutant plants, which harbored mutations in the duplicate genes narrow sheath1 (ns1) and narrow sheath2 (ns2). Expressed in eight to ten cells within the SAM, ns1 and ns2 encode paralogous WUSCHEL1-like homeobox (WOX) transcription factors required for recruitment of leaf initials that give rise to a large lateral domain within maize leaves. The data illustrate the utility of laser microdissection-microarray analyses to identify a relatively small number of genes that are differentially expressed within the SAM. Moreover, these analyses reveal potentially conserved WOX gene functions and implicate specific hormonal and signaling pathways during early events in maize leaf development.

  1. Laser Microdissection of Narrow Sheath Mutant Maize Uncovers Novel Gene Expression in the Shoot Apical Meristem

    PubMed Central

    Zhang, Xiaolan; Madi, Shahinez; Borsuk, Lisa; Nettleton, Dan; Elshire, Robert J; Buckner, Brent; Janick-Buckner, Diane; Beck, Jon; Timmermans, Marja; Schnable, Patrick S; Scanlon, Michael J

    2007-01-01

    Microarrays enable comparative analyses of gene expression on a genomic scale, however these experiments frequently identify an abundance of differentially expressed genes such that it may be difficult to identify discrete functional networks that are hidden within large microarray datasets. Microarray analyses in which mutant organisms are compared to nonmutant siblings can be especially problematic when the gene of interest is expressed in relatively few cells. Here, we describe the use of laser microdissection microarray to perform transcriptional profiling of the maize shoot apical meristem (SAM), a ~100-μm pillar of organogenic cells that is required for leaf initiation. Microarray analyses compared differential gene expression within the SAM and incipient leaf primordium of nonmutant and narrow sheath mutant plants, which harbored mutations in the duplicate genes narrow sheath1 (ns1) and narrow sheath2 (ns2). Expressed in eight to ten cells within the SAM, ns1 and ns2 encode paralogous WUSCHEL1-like homeobox (WOX) transcription factors required for recruitment of leaf initials that give rise to a large lateral domain within maize leaves. The data illustrate the utility of laser microdissection-microarray analyses to identify a relatively small number of genes that are differentially expressed within the SAM. Moreover, these analyses reveal potentially conserved WOX gene functions and implicate specific hormonal and signaling pathways during early events in maize leaf development. PMID:17571927

  2. A Comparison of a Fully Covered and an Uncovered Segmented Biodegradable Esophageal Stent in a Porcine Model: Preclinical Evaluation of Degradation, Complications, and Tissue Reactions

    PubMed Central

    Feng, Yadong; Jiao, Chunhua; Cao, Yang; Zhao, Ye; Chen, Yanfang; Fang, Lin; Shi, Ruihua

    2016-01-01

    Aims. This study was to compare the degradation, complications, and tissue reactions of two segmented biodegradable esophageal stents in a porcine model. Methods. Uncovered biodegradable segmented stents and fully covered biodegradable segmented stents (FCBDS) were transplanted into the porcine esophagus lumen. Data on biodegradation, complications, and tissue reactions were collected and compared. Results. All animals kept good general conditions. No severe complications and stents migration occurred. Stents degradation commenced at week 3. Compared with uncovered stents, stents structure breakage and complete stents absorption in FCBDS were postponed for 1-2 weeks. Hyperplasia was prominent at early stage and ameliorated at late stage after stents insertion. Tissue reactions in FCBDS were milder than those in uncovered stents in the early stage. A longer degradation period was present in FCBDS than in uncovered stents, while FCBDS induced tissue reaction at late stage was mild. Conclusions. Biodegradable esophageal stents with a segmented trunk may be further evaluated in refractory benign esophagus strictures. This FCBDS may be advantageous compared with uncovered stents for a longer degradation period. PMID:27022391

  3. Covered stents versus uncovered stents for the palliation of malignant extrahepatic biliary obstruction caused by direct tumor invasion: a cohort comparative study.

    PubMed

    Li, Feng; Wang, Feng; Yang, Xinshun; Ji, Donghua; Li, Jun; Wang, Ningfang; Liu, Yongsheng; Li, Cheng; Zhang, Tao; Li, Ke

    2012-12-01

    Biliary stenting is a well-established palliative treatment in patients with unresectable malignant biliary strictures. The aim of the present study was to compare clinical outcomes of covered and uncovered stents in patients with malignant extrahepatic biliary obstruction caused by direct tumor invasion. Patients diagnosed with malignant extrahepatic biliary obstruction caused by direct tumor invasion were enrolled in this study. Of these patients, 37 received ePTFE-covered stent placement and were prospectively studied, and 47 received uncovered stent placement and were retrospectively studied. The technical success rate, tumor ingrowth rate, complication rate, stent patency, and patient survival were evaluated for both groups. Stent placement was successful in all cases except one in the covered group due to stent kinking. Tumor ingrowth occurred exclusively in the uncovered group. No significant differences were observed for the complication rate and patient survival between the two groups. Three patients in the covered group experienced stent migration, whereas no patients did in the uncovered group. A significant difference was found regarding stent patency, which was greater for the covered group compared to the uncovered group. The placement of ePTFE-covered stents for the treatment of malignant biliary obstruction caused by direct tumor invasion was a safe and an effective method characterized by greater stent patency.

  4. Colorado wind profilers

    NASA Technical Reports Server (NTRS)

    Strauch, R. G.

    1986-01-01

    The Wave Propagation Laboratory (WPL) has operated a network of wind profiling radars in Colorado. The current configuration of the network is described. All radars operate continuously and unattended to supply hourly-averaged wind profiles to a central computer in Boulder in real time. The hardware and software changes made to improve reliability are discussed. This research network will continue to be used to provide wind profiles for operational and research meteorologists and the performance of various wavelength systems will be evaluated.

  5. Nuclear translocation uncovers the amyloid peptide Aβ42 as a regulator of gene transcription.

    PubMed

    Barucker, Christian; Harmeier, Anja; Weiske, Joerg; Fauler, Beatrix; Albring, Kai Frederik; Prokop, Stefan; Hildebrand, Peter; Lurz, Rudi; Heppner, Frank L; Huber, Otmar; Multhaup, Gerhard

    2014-07-18

    Although soluble species of the amyloid-β peptide Aβ42 correlate with disease symptoms in Alzheimer disease, little is known about the biological activities of amyloid-β (Aβ). Here, we show that Aβ peptides varying in lengths from 38 to 43 amino acids are internalized by cultured neuroblastoma cells and can be found in the nucleus. By three independent methods, we demonstrate direct detection of nuclear Aβ42 as follows: (i) biochemical analysis of nuclear fractions; (ii) detection of biotin-labeled Aβ in living cells by confocal laser scanning microscopy; and (iii) transmission electron microscopy of Aβ in cultured cells, as well as brain tissue of wild-type and transgenic APPPS1 mice (overexpression of amyloid precursor protein and presenilin 1 with Swedish and L166P mutations, respectively). Also, this study details a novel role for Aβ42 in nuclear signaling, distinct from the amyloid precursor protein intracellular domain. Chromatin immunoprecipitation showed that Aβ42 specifically interacts as a repressor of gene transcription with LRP1 and KAI1 promoters. By quantitative RT-PCR, we confirmed that mRNA levels of the examined candidate genes were exclusively decreased by the potentially neurotoxic Aβ42 wild-type peptide. Shorter peptides (Aβ38 or Aβ40) and other longer peptides (nontoxic Aβ42 G33A substitution or Aβ43) did not affect mRNA levels. Overall, our data indicate that the nuclear translocation of Aβ42 impacts gene regulation, and deleterious effects of Aβ42 in Alzheimer disease pathogenesis may be influenced by altering the expression profiles of disease-modifying genes.

  6. A deep sequencing approach to uncover the miRNOME in the human heart.

    PubMed

    Leptidis, Stefanos; El Azzouzi, Hamid; Lok, Sjoukje I; de Weger, Roel; Olieslagers, Servé; Olieslagers, Serv; Kisters, Natasja; Silva, Gustavo J; Heymans, Stephane; Cuppen, Edwin; Berezikov, Eugene; De Windt, Leon J; da Costa Martins, Paula

    2013-01-01

    MicroRNAs (miRNAs) are a class of non-coding RNAs of ∼22 nucleotides in length, and constitute a novel class of gene regulators by imperfect base-pairing to the 3'UTR of protein encoding messenger RNAs. Growing evidence indicates that miRNAs are implicated in several pathological processes in myocardial disease. The past years, we have witnessed several profiling attempts using high-density oligonucleotide array-based approaches to identify the complete miRNA content (miRNOME) in the healthy and diseased mammalian heart. These efforts have demonstrated that the failing heart displays differential expression of several dozens of miRNAs. While the total number of experimentally validated human miRNAs is roughly two thousand, the number of expressed miRNAs in the human myocardium remains elusive. Our objective was to perform an unbiased assay to identify the miRNOME of the human heart, both under physiological and pathophysiological conditions. We used deep sequencing and bioinformatics to annotate and quantify microRNA expression in healthy and diseased human heart (heart failure secondary to hypertrophic or dilated cardiomyopathy). Our results indicate that the human heart expresses >800 miRNAs, the majority of which not being annotated nor described so far and some of which being unique to primate species. Furthermore, >250 miRNAs show differential and etiology-dependent expression in human dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM). The human cardiac miRNOME still possesses a large number of miRNAs that remain virtually unexplored. The current study provides a starting point for a more comprehensive understanding of the role of miRNAs in regulating human heart disease.

  7. Nuclear Translocation Uncovers the Amyloid Peptide Aβ42 as a Regulator of Gene Transcription*♦

    PubMed Central

    Barucker, Christian; Harmeier, Anja; Weiske, Joerg; Fauler, Beatrix; Albring, Kai Frederik; Prokop, Stefan; Hildebrand, Peter; Lurz, Rudi; Heppner, Frank L.; Huber, Otmar; Multhaup, Gerhard

    2014-01-01

    Although soluble species of the amyloid-β peptide Aβ42 correlate with disease symptoms in Alzheimer disease, little is known about the biological activities of amyloid-β (Aβ). Here, we show that Aβ peptides varying in lengths from 38 to 43 amino acids are internalized by cultured neuroblastoma cells and can be found in the nucleus. By three independent methods, we demonstrate direct detection of nuclear Aβ42 as follows: (i) biochemical analysis of nuclear fractions; (ii) detection of biotin-labeled Aβ in living cells by confocal laser scanning microscopy; and (iii) transmission electron microscopy of Aβ in cultured cells, as well as brain tissue of wild-type and transgenic APPPS1 mice (overexpression of amyloid precursor protein and presenilin 1 with Swedish and L166P mutations, respectively). Also, this study details a novel role for Aβ42 in nuclear signaling, distinct from the amyloid precursor protein intracellular domain. Chromatin immunoprecipitation showed that Aβ42 specifically interacts as a repressor of gene transcription with LRP1 and KAI1 promoters. By quantitative RT-PCR, we confirmed that mRNA levels of the examined candidate genes were exclusively decreased by the potentially neurotoxic Aβ42 wild-type peptide. Shorter peptides (Aβ38 or Aβ40) and other longer peptides (nontoxic Aβ42 G33A substitution or Aβ43) did not affect mRNA levels. Overall, our data indicate that the nuclear translocation of Aβ42 impacts gene regulation, and deleterious effects of Aβ42 in Alzheimer disease pathogenesis may be influenced by altering the expression profiles of disease-modifying genes. PMID:24878959

  8. Uncovering the Prevalence and Diversity of Integrating Conjugative Elements in Actinobacteria

    PubMed Central

    Beaudin, Julie; Brzezinski, Ryszard; Roy, Sébastien; Burrus, Vincent

    2011-01-01

    Horizontal gene transfer greatly facilitates rapid genetic adaptation of bacteria to shifts in environmental conditions and colonization of new niches by allowing one-step acquisition of novel functions. Conjugation is a major mechanism of horizontal gene transfer mediated by conjugative plasmids and integrating conjugative elements (ICEs). While in most bacterial conjugative systems DNA translocation requires the assembly of a complex type IV secretion system (T4SS), in Actinobacteria a single DNA FtsK/SpoIIIE-like translocation protein is required. To date, the role and diversity of ICEs in Actinobacteria have received little attention. Putative ICEs were searched for in 275 genomes of Actinobacteria using HMM-profiles of proteins involved in ICE maintenance and transfer. These exhaustive analyses revealed 144 putative FtsK/SpoIIIE-type ICEs and 17 putative T4SS-type ICEs. Grouping of the ICEs based on the phylogenetic analyses of maintenance and transfer proteins revealed extensive exchanges between different sub-families of ICEs. 17 ICEs were found in Actinobacteria from the genus Frankia, globally important nitrogen-fixing microorganisms that establish root nodule symbioses with actinorhizal plants. Structural analysis of ICEs from Frankia revealed their unexpected diversity and a vast array of predicted adaptive functions. Frankia ICEs were found to excise by site-specific recombination from their host's chromosome in vitro and in planta suggesting that they are functional mobile elements whether Frankiae live as soil saprophytes or plant endosymbionts. Phylogenetic analyses of proteins involved in ICEs maintenance and transfer suggests that active exchange between ICEs cargo-borne and chromosomal genes took place within the Actinomycetales order. Functionality of Frankia ICEs in vitro as well as in planta lets us anticipate that conjugation and ICEs could allow the development of genetic manipulation tools for this challenging microorganism and for many

  9. Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis.

    PubMed

    Christianson, Dawn R; Dobroff, Andrey S; Proneth, Bettina; Zurita, Amado J; Salameh, Ahmad; Dondossola, Eleonora; Makino, Jun; Bologa, Cristian G; Smith, Tracey L; Yao, Virginia J; Calderone, Tiffany L; O'Connell, David J; Oprea, Tudor I; Kataoka, Kazunori; Cahill, Dolores J; Gershenwald, Jeffrey E; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2015-02-24

    Metastasis is the most lethal step of cancer progression in patients with invasive melanoma. In most human cancers, including melanoma, tumor dissemination through the lymphatic vasculature provides a major route for tumor metastasis. Unfortunately, molecular mechanisms that facilitate interactions between melanoma cells and lymphatic vessels are unknown. Here, we developed an unbiased approach based on molecular mimicry to identify specific receptors that mediate lymphatic endothelial-melanoma cell interactions and metastasis. By screening combinatorial peptide libraries directly on afferent lymphatic vessels resected from melanoma patients during sentinel lymphatic mapping and lymph node biopsies, we identified a significant cohort of melanoma and lymphatic surface binding peptide sequences. The screening approach was designed so that lymphatic endothelium binding peptides mimic cell surface proteins on tumor cells. Therefore, relevant metastasis and lymphatic markers were biochemically identified, and a comprehensive molecular profile of the lymphatic endothelium during melanoma metastasis was generated. Our results identified expression of the phosphatase 2 regulatory subunit A, α-isoform (PPP2R1A) on the cell surfaces of both melanoma cells and lymphatic endothelial cells. Validation experiments showed that PPP2R1A is expressed on the cell surfaces of both melanoma and lymphatic endothelial cells in vitro as well as independent melanoma patient samples. More importantly, PPP2R1A-PPP2R1A homodimers occur at the cellular level to mediate cell-cell interactions at the lymphatic-tumor interface. Our results revealed that PPP2R1A is a new biomarker for melanoma metastasis and show, for the first time to our knowledge, an active interaction between the lymphatic vasculature and melanoma cells during tumor progression.

  10. Deprojecting the nasal profile.

    PubMed

    Papel, I D; Mabrie, D C

    1999-02-01

    The nose is the most prominent aesthetic feature of the facial profile. Nasal length, tip rotation, and tip projection are integral aspects in analysis of the nasal profile. In most rhinoplasties the surgeon has the difficult task of increasing or maintaining tip projection of an underprojected or normally projected nasal tip. Less commonly, the rhinoplastic surgeon is presented with an overprojected nasal tip, and efforts are focused on deprojecting the nasal profile. In this article, the authors present a discussion of the overprojected tip, elucidating strategies of analysis, etiologies, and management of the nasal profile and give clinical examples.

  11. Atmospheric pollution history at Linfen (China) uncovered by magnetic and chemical parameters of sediments from a water reservoir.

    PubMed

    Ma, Mingming; Hu, Shouyun; Cao, Liwan; Appel, Erwin; Wang, Longsheng

    2015-09-01

    We studied magnetic and chemical parameters of sediments from sediments of a water reservoir at Linfen (China) in order to quantitatively reconstruct the atmospheric pollution history in this region. The results show that the main magnetic phases are magnetite and maghemite originating from the surrounding catchment and from anthropogenic activities, and there is a significant positive relationship between magnetic concentration parameters and heavy metals concentrations, indicating that magnetic proxies can be used to monitor the anthropogenic pollution. In order to uncover the atmospheric pollution history, we combined the known events of environmental improvement with variations of magnetic susceptibility (χ) and heavy metals along the cores to obtain a detailed chronological framework. In addition, air comprehensive pollution index (ACPI) was reconstructed from regression equation among magnetic and chemical parameters as well as atmospheric monitoring data. Based on these results, the atmospheric pollution history was successfully reconstructed.

  12. Gap-Closing 3d Building Reconstruction by Aligning Boundaries of Roof Segments and Detecting Uncovered Details

    NASA Astrophysics Data System (ADS)

    Pohl, M.; Bulatov, D.

    2015-03-01

    We describe a work flow to border building faces which aims to obtain a detailed and closed building model. Initially, we use the estimated roof planes and the rasterized binary mask of the corresponding inlier set to generate bordering polygons. To close the gaps between the initial boundary polygons and between the polygons and the building ground outline, we introduce an algorithm to align boundaries which successfully works in 2.5D and 3D. To enhance the accuracy of the boundary alignment, we use additional reliable model entities such as cut lines and step lines between the initial estimated roof planes. All gaps that cannot be avoided by this procedure are afterwards covered by a method searching for uncovered details.

  13. A chemical family-based strategy for uncovering hidden bioactive molecules and multicomponent interactions in herbal medicines.

    PubMed

    Song, Hui-Peng; Wu, Si-Qi; Hao, Haiping; Chen, Jun; Lu, Jun; Xu, Xiaojun; Li, Ping; Yang, Hua

    2016-03-30

    Two concepts involving natural products were proposed and demonstrated in this paper. (1) Natural product libraries (e.g. herbal extract) are not perfect for bioactivity screening because of the vast complexity of compound compositions, and thus a library reconstruction procedure is necessary before screening. (2) The traditional mode of "screening single compound" could be improved to "screening single compound, drug combination and multicomponent interaction" due to the fact that herbal medicines work by integrative effects of multi-components rather than single effective constituents. Based on the two concepts, we established a novel strategy aiming to make screening easier and deeper. Using thrombin as the model enzyme, we firstly uncovered the minor lead compounds, potential drug combinations and multicomponent interactions in an herbal medicine of Dan-Qi pair, showing a significant advantage over previous methods. This strategy was expected to be a new and promising mode for investigation of herbal medicines.

  14. A chemical family-based strategy for uncovering hidden bioactive molecules and multicomponent interactions in herbal medicines

    PubMed Central

    Song, Hui-Peng; Wu, Si-Qi; Hao, Haiping; Chen, Jun; Lu, Jun; Xu, Xiaojun; Li, Ping; Yang, Hua

    2016-01-01

    Two concepts involving natural products were proposed and demonstrated in this paper. (1) Natural product libraries (e.g. herbal extract) are not perfect for bioactivity screening because of the vast complexity of compound compositions, and thus a library reconstruction procedure is necessary before screening. (2) The traditional mode of “screening single compound” could be improved to “screening single compound, drug combination and multicomponent interaction” due to the fact that herbal medicines work by integrative effects of multi-components rather than single effective constituents. Based on the two concepts, we established a novel strategy aiming to make screening easier and deeper. Using thrombin as the model enzyme, we firstly uncovered the minor lead compounds, potential drug combinations and multicomponent interactions in an herbal medicine of Dan-Qi pair, showing a significant advantage over previous methods. This strategy was expected to be a new and promising mode for investigation of herbal medicines. PMID:27025397

  15. The influence of type of incision on the success rate of implant integration at stage II uncovering surgery.

    PubMed

    Casino, A J; Harrison, P; Tarnow, D P; Morris, H F; Ochi, S

    1997-12-01

    In 1991, the Dental Implant Clinical Research Group comprising 30 Department of Veterans Affairs medical centers and two dental schools initiated a long-term clinical study to investigate the clinical performance of implants within the Spectra-System (Core-Vent Corporation, Las Vegas, NV). This article focuses on a portion of the study database related to incision type, implant success rates, and response of crestal bone up to the time of surgical uncovering. The crestal incision was used for 1,705 implants (381 patients) and the remote incision for 593 implants (141 patients). No statistically significant difference (P = .092 chi-square statistic) was found in implant integration or the response of crestal bone.

  16. Surface Proteins of Gram-Positive Pathogens: Using Crystallography to Uncover Novel Features in Drug and Vaccine Candidates

    NASA Astrophysics Data System (ADS)

    Baker, Edward N.; Proft, Thomas; Kang, Haejoo

    Proteins displayed on the cell surfaces of pathogenic organisms are the front-line troops of bacterial attack, playing critical roles in colonization, infection and virulence. Although such proteins can often be recognized from genome sequence data, through characteristic sequence motifs, their functions are often unknown. One such group of surface proteins is attached to the cell surface of Gram-positive pathogens through the action of sortase enzymes. Some of these proteins are now known to form pili: long filamentous structures that mediate attachment to human cells. Crystallographic analyses of these and other cell surface proteins have uncovered novel features in their structure, assembly and stability, including the presence of inter- and intramolecular isopeptide crosslinks. This improved understanding of structures on the bacterial cell surface offers opportunities for the development of some new drug targets and for novel approaches to vaccine design.

  17. Clustering high-dimensional mixed data to uncover sub-phenotypes: joint analysis of phenotypic and genotypic data.

    PubMed

    McParland, D; Phillips, C M; Brennan, L; Roche, H M; Gormley, I C

    2017-06-30

    The LIPGENE-SU.VI.MAX study, like many others, recorded high-dimensional continuous phenotypic data and categorical genotypic data. LIPGENE-SU.VI.MAX focuses on the need to account for both phenotypic and genetic factors when studying the metabolic syndrome (MetS), a complex disorder that can lead to higher risk of type 2 diabetes and cardiovascular disease. Interest lies in clustering the LIPGENE-SU.VI.MAX participants into homogeneous groups or sub-phenotypes, by jointly considering their phenotypic and genotypic data, and in determining which variables are discriminatory. A novel latent variable model that elegantly accommodates high dimensional, mixed data is developed to cluster LIPGENE-SU.VI.MAX participants using a Bayesian finite mixture model. A computationally efficient variable selection algorithm is incorporated, estimation is via a Gibbs sampling algorithm and an approximate BIC-MCMC criterion is developed to select the optimal model. Two clusters or sub-phenotypes ('healthy' and 'at risk') are uncovered. A small subset of variables is deemed discriminatory, which notably includes phenotypic and genotypic variables, highlighting the need to jointly consider both factors. Further, 7 years after the LIPGENE-SU.VI.MAX data were collected, participants underwent further analysis to diagnose presence or absence of the MetS. The two uncovered sub-phenotypes strongly correspond to the 7-year follow-up disease classification, highlighting the role of phenotypic and genotypic factors in the MetS and emphasising the potential utility of the clustering approach in early screening. Additionally, the ability of the proposed approach to define the uncertainty in sub-phenotype membership at the participant level is synonymous with the concepts of precision medicine and nutrition. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  18. Computing the origin and evolution of the ribosome from its structure — Uncovering processes of macromolecular accretion benefiting synthetic biology

    PubMed Central

    Caetano-Anollés, Gustavo; Caetano-Anollés, Derek

    2015-01-01

    Accretion occurs pervasively in nature at widely different timeframes. The process also manifests in the evolution of macromolecules. Here we review recent computational and structural biology studies of evolutionary accretion that make use of the ideographic (historical, retrodictive) and nomothetic (universal, predictive) scientific frameworks. Computational studies uncover explicit timelines of accretion of structural parts in molecular repertoires and molecules. Phylogenetic trees of protein structural domains and proteomes and their molecular functions were built from a genomic census of millions of encoded proteins and associated terminal Gene Ontology terms. Trees reveal a ‘metabolic-first’ origin of proteins, the late development of translation, and a patchwork distribution of proteins in biological networks mediated by molecular recruitment. Similarly, the natural history of ancient RNA molecules inferred from trees of molecular substructures built from a census of molecular features shows patchwork-like accretion patterns. Ideographic analyses of ribosomal history uncover the early appearance of structures supporting mRNA decoding and tRNA translocation, the coevolution of ribosomal proteins and RNA, and a first evolutionary transition that brings ribosomal subunits together into a processive protein biosynthetic complex. Nomothetic structural biology studies of tertiary interactions and ancient insertions in rRNA complement these findings, once concentric layering assumptions are removed. Patterns of coaxial helical stacking reveal a frustrated dynamics of outward and inward ribosomal growth possibly mediated by structural grafting. The early rise of the ribosomal ‘turnstile’ suggests an evolutionary transition in natural biological computation. Results make explicit the need to understand processes of molecular growth and information transfer of macromolecules. PMID:27096056

  19. Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C.

    PubMed

    Xiao, Fei; Fofana, Isabel; Thumann, Christine; Mailly, Laurent; Alles, Roxane; Robinet, Eric; Meyer, Nicolas; Schaeffer, Mickaël; Habersetzer, François; Doffoël, Michel; Leyssen, Pieter; Neyts, Johan; Zeisel, Mirjam B; Baumert, Thomas F

    2015-03-01

    Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy. Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection. Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice. Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  20. Computing the origin and evolution of the ribosome from its structure - Uncovering processes of macromolecular accretion benefiting synthetic biology.

    PubMed

    Caetano-Anollés, Gustavo; Caetano-Anollés, Derek

    2015-01-01

    Accretion occurs pervasively in nature at widely different timeframes. The process also manifests in the evolution of macromolecules. Here we review recent computational and structural biology studies of evolutionary accretion that make use of the ideographic (historical, retrodictive) and nomothetic (universal, predictive) scientific frameworks. Computational studies uncover explicit timelines of accretion of structural parts in molecular repertoires and molecules. Phylogenetic trees of protein structural domains and proteomes and their molecular functions were built from a genomic census of millions of encoded proteins and associated terminal Gene Ontology terms. Trees reveal a 'metabolic-first' origin of proteins, the late development of translation, and a patchwork distribution of proteins in biological networks mediated by molecular recruitment. Similarly, the natural history of ancient RNA molecules inferred from trees of molecular substructures built from a census of molecular features shows patchwork-like accretion patterns. Ideographic analyses of ribosomal history uncover the early appearance of structures supporting mRNA decoding and tRNA translocation, the coevolution of ribosomal proteins and RNA, and a first evolutionary transition that brings ribosomal subunits together into a processive protein biosynthetic complex. Nomothetic structural biology studies of tertiary interactions and ancient insertions in rRNA complement these findings, once concentric layering assumptions are removed. Patterns of coaxial helical stacking reveal a frustrated dynamics of outward and inward ribosomal growth possibly mediated by structural grafting. The early rise of the ribosomal 'turnstile' suggests an evolutionary transition in natural biological computation. Results make explicit the need to understand processes of molecular growth and information transfer of macromolecules.

  1. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene–disease associations and unanticipated rare disorders

    PubMed Central

    van de Warrenburg, Bart P; Schouten, Meyke I; de Bot, Susanne T; Vermeer, Sascha; Meijer, Rowdy; Pennings, Maartje; Gilissen, Christian; Willemsen, Michèl AAP; Scheffer, Hans; Kamsteeg, Erik-Jan

    2016-01-01

    Cerebellar ataxia (CA) and hereditary spastic paraplegia (HSP) are two of the most prevalent motor disorders with extensive locus and allelic heterogeneity. We implemented clinical exome sequencing, followed by filtering data for a ‘movement disorders' gene panel, as a generic test to increase variant detection in 76 patients with these disorders. Segregation analysis or phenotypic re-evaluation was utilized to substantiate findings. Disease-causing variants were identified in 9 of 28 CA patients, and 8 of 48 HSP patients. In addition, possibly disease-causing variants were identified in 1 and 8 of the remaining CA and HSP patients, respectively. In 10 patients with CA, the total disease-causing or possibly disease-causing variants were detected in 8 different genes, whereas 16 HSP patients had such variants in 12 different genes. In the majority of cases, the identified variants were compatible with the patient phenotype. Interestingly, in some patients variants were identified in genes hitherto related to other movement disorders, such as TH variants in two siblings with HSP. In addition, rare disorders were uncovered, for example, a second case of HSP caused by a VCP variant. For some patients, exome sequencing results had implications for treatment, exemplified by the favorable L-DOPA treatment in a patient with HSP due to ATP13A2 variants (Parkinson type 9). Thus, clinical exome sequencing in this cohort of CA and HSP patients suggests broadening of disease spectra, revealed novel gene–disease associations, and uncovered unanticipated rare disorders. In addition, clinical exome sequencing results have shown their value in guiding practical patient management. PMID:27165006

  2. A prospective randomized study for efficacy of an uncovered double bare metal stent compared to a single bare metal stent in malignant biliary obstruction.

    PubMed

    Lee, Hyun Jik; Chung, Moon Jae; Park, Jeong Yup; Park, Seung Woo; Nam, Chung Mo; Song, Si Young; Bang, Seungmin

    2017-08-01

    A biliary self-expandable metal stent (SEMS) is commonly used to relieve malignant biliary obstruction. The aim of this study was to compare the efficacy of a conventional uncovered SEMS with that of a newly developed uncovered double bare metal stent in reducing the risk of stent occlusion caused by tumor ingrowth. We performed a prospective, open-labeled, randomized trial in 71 patients at Severance Hospital, Yonsei University College of Medicine from June 2013 to June 2014. Patients with inoperable malignant biliary obstruction were included and randomized to receive an uncovered single bare metal stent (SBSs; S&G Biotech Inc.), an uncovered single bare metal stent (SBSt; Taewoong Medical), or an uncovered double bare metal stent (DBS; S&G Biotech Inc.). The mean age was 66.6 years (range, 35-83), and 42 (59.2%) were male. The mean duration of stent patency was 212 days (±152) in the DBS group (n = 24) compared with 124 days (±98) in the SBSs group (n = 23; P = 0.022 for noninferiority) and 116 days (±79) in the SBSt group (n = 24; P = 0.010 for noninferiority). There were no differences in the incidences of early and delayed complications or migration. The newly developed DBS is noninferior to the conventional uncovered SEMSs on duration of stent patency and tumor ingrowth occurred less frequently in the DBS group. This might decrease the need for reintervention and offer a better quality of life. The trial is registered with Clinicaltrials.gov no: NCT01869894.

  3. Partially covered versus uncovered self-expandable nitinol stents with anti-migration properties for the palliation of malignant distal biliary obstruction: A randomized controlled trial.

    PubMed

    Yang, Min Jae; Kim, Jin Hong; Yoo, Byung Moo; Hwang, Jae Chul; Yoo, Jun Hwan; Lee, Ki Seong; Kang, Joon Koo; Kim, Soon Sun; Lim, Sun Gyo; Shin, Sung Jae; Cheong, Jae Youn; Lee, Kee Myung; Lee, Kwang Jae; Cho, Sung Won

    2015-01-01

    Covered self-expandable metal stents (SEMSs) are increasingly used as alternatives to uncovered SEMSs for the palliation of inoperable malignant distal biliary obstruction to counteract tumor ingrowth. We aimed to compare the outcomes of partially covered and uncovered SEMSs with identical mesh structures and anti-migration properties, such as low axial force and flared ends. One hundred and three patients who were diagnosed with inoperable malignant distal biliary obstruction between January 2006 and August 2013 were randomly assigned to either the partially covered (n = 51) or uncovered (n = 52) SEMS group. There were no significant differences in the cumulative stent patency, overall patient survival, stent dysfunction-free survival and overall adverse events, including pancreatitis and cholecystitis, between the two groups. Compared to the uncovered group, stent migration (5.9% vs. 0%, p = 0.118) and tumor overgrowth (7.8% vs. 1.9%, p = 0.205) were non-significantly more frequent in the partially covered group, whereas tumor ingrowth showed a significantly higher incidence in the uncovered group (5.9% vs. 19.2%, p = 0.041). Stent migration in the partially covered group occurred only in patients with short stenosis of the utmost distal bile duct (two in ampullary cancer, one in bile duct cancer), and did not occur in any patients with pancreatic cancer. For the palliation of malignant distal biliary obstruction, endoscopic placement of partially covered SEMSs with anti-migration designs and identical mesh structures to uncovered SEMSs failed to prolong cumulative stent patency or reduce stent migration.

  4. Label-free proteomics uncovers energy metabolism and focal adhesion regulations responsive for endometrium receptivity.

    PubMed

    Chen, Qian; Zhang, Aijun; Yu, Feng; Gao, Jing; Liu, Yue; Yu, Chengli; Zhou, Hu; Xu, Chen

    2015-04-03

    The menstrual cycle of the female uterus leads to periodic changes of the endometrium. These changes are important for developing the endometrial receptivity and for achieving competency of embryo implantation. However, the molecular events underlying the endometrial receptivity process remain poorly understood. Here we applied an LC-MS-based label-free quantitative proteomic approach to compare the endometrial tissues in the midsecretory (receptive) phase with the endometrial tissues in the proliferative phase from age-matched woman (n = 6/group). The proteomes of endometrial tissues were extracted using an SDS-based detergent, digested by the filter-aided sample preparation procedures, and subsequently analyzed by nano-LC-MS/MS (Orbitrap XL) with a 4 h gradient. Reliable protein expression profiles were reproducibly obtained from the endometrial tissues in the receptive and proliferative phases. A total of 2138 protein groups were quantified under highly stringent criteria with a false discovery rate of <1% for peptide and protein groups. Among these proteins, 317 proteins had differences in expression that were statistically significant between the receptive and proliferative phases. Direct protein-protein interaction network analyses of these significantly changed proteins showed that the up-regulation of creatine kinase B-type (CKB) in the receptive phase may be related to endometrium receptivity. The interaction network also showed that proteins related to cell-cell adhesion were down-regulated. Moreover, the results from KEGG pathway analyses are consistent with the protein-protein interaction results. The proteins, including alpha-actinin (ACTN), extracellular matrix proteins, integrin alpha-V, and so on, that are involved in the focal adhesion pathway were down-regulated in the receptive phase compared with the proliferative phase, which may facilitate the implantation of the fertilized ovum. Selected proteins were validated by Western blot analysis and

  5. An Integrated Metabolomic and Genomic Mining Workflow To Uncover the Biosynthetic Potential of Bacteria.

    PubMed

    Maansson, Maria; Vynne, Nikolaj G; Klitgaard, Andreas; Nybo, Jane L; Melchiorsen, Jette; Nguyen, Don D; Sanchez, Laura M; Ziemert, Nadine; Dorrestein, Pieter C; Andersen, Mikael R; Gram, Lone

    2016-01-01

    Microorganisms are a rich source of bioactives; however, chemical identification is a major bottleneck. Strategies that can prioritize the most prolific microbial strains and novel compounds are of great interest. Here, we present an integrated approach to evaluate the biosynthetic richness in bacteria and mine the associated chemical diversity. Thirteen strains closely related to Pseudoalteromonas luteoviolacea isolated from all over the Earth were analyzed using an untargeted metabolomics strategy, and metabolomic profiles were correlated with whole-genome sequences of the strains. We found considerable diversity: only 2% of the chemical features and 7% of the biosynthetic genes were common to all strains, while 30% of all features and 24% of the genes were unique to single strains. The list of chemical features was reduced to 50 discriminating features using a genetic algorithm and support vector machines. Features were dereplicated by tandem mass spectrometry (MS/MS) networking to identify molecular families of the same biosynthetic origin, and the associated pathways were probed using comparative genomics. Most of the discriminating features were related to antibacterial compounds, including the thiomarinols that were reported from P. luteoviolacea here for the first time. By comparative genomics, we identified the biosynthetic cluster responsible for the production of the antibiotic indolmycin, which could not be predicted with standard methods. In conclusion, we present an efficient, integrative strategy for elucidating the chemical richness of a given set of bacteria and link the chemistry to biosynthetic genes. IMPORTANCE We here combine chemical analysis and genomics to probe for new bioactive secondary metabolites based on their pattern of distribution within bacterial species. We demonstrate the usefulness of this combined approach in a group of marine Gram-negative bacteria closely related to Pseudoalteromonas luteoviolacea, which is a species known

  6. Microbiological study of fresh herbs from retail premises uncovers an international outbreak of salmonellosis.

    PubMed

    Elviss, N C; Little, C L; Hucklesby, L; Sagoo, S; Surman-Lee, S; de Pinna, E; Threlfall, E J

    2009-08-31

    This Local Authorities Co-ordinators of Regulatory Services/Health Protection Agency study was prompted by the increasing concern regarding the microbiological safety of ready-to-eat salad vegetable products, particularly fresh herbs. During May to October 2007, 3760 ready-to-eat fresh herbs, of different varieties, were sampled across the UK to assess their microbiological safety in relation to salmonella contamination and levels of Escherichia coli. Sixty (1.6%) herb samples were found to be of unsatisfactory quality according to Regulation (EC) No. 2073/2005 on the microbiological criteria of foodstuffs, i.e. contaminated with Salmonella spp. and/or containing E. coli at >10(3) cfu/g. When criteria in the PHLS Microbiological Guidelines for some ready-to-eat foods (2000) were used, 117 (3.9%) of herb samples were of unsatisfactory quality due to the presence of salmonella and/or E. coli at > or = 10(2) cfu/g. Eighteen (0.5%) samples of six different herb types were contaminated with Salmonella spp.: identified as serotypes Senftenberg (8), Agona (2), Anatum (1), Durban (1), Javiana (1), Mgulani (1), Montevideo (1), Unnamed (I 16:g, t: z42) (1), Virchow (1) and mixed Newport & Virchow (1). In each case the retailer and the UK Food Standards Agency were immediately informed and remedial action taken. Samples contaminated with S. Senftenberg were specifically associated with basil grown in Israel. Thirty-two human cases of S. Senftenberg infection were subsequently identified throughout England and Wales and a further 19 in Scotland, Denmark, The Netherlands and the USA. The strain of S. Senftenberg identified from the basil and that from cases had an indistinguishable molecular profile, suggesting a likely connection between consumption of basil and human infection. The presence of Salmonella spp. is unacceptable in ready-to-foods such as fresh herbs. This study highlights the necessity of applying good agricultural and hygiene practices pre-, during and post

  7. The Ortles ice cores: uncovering an extended climate archive from the Eastern Alps

    NASA Astrophysics Data System (ADS)

    Dreossi, Giuliano; Barbante, Carlo; Bertò, Michele; Carturan, Luca; De Blasi, Fabrizio; Gabrieli, Jacopo; Gabrielli, Paolo; Seppi, Roberto; Spolaor, Andrea; Stenni, Barbara; Zanoner, Thomas

    2017-04-01

    During the last half century, oxygen and hydrogen stable isotope content of ice cores has been extensively used for air temperature reconstructions. The most suitable glaciers of the Alpine area, most exclusively in the Western Alps, have been utilized for ice coring for more than four decades. The paleoclimatic potential of the Eastern Alps is still largely unexploited and was scarcely utilized in the past mainly because of the lower elevation (compared to Western Alps) and hence the difficulty to find glaciers in cold conditions. The warming temperature trend appears to be particularly pronounced in the Alps, threatening the preservation of the glaciated areas and creating a sense of urgency in retrieving climatic archives before it is too late. In autumn 2011, four deep cores were drilled on Mt Ortles, South Tyrol, Italy, at 3859 m a.s.l. An extensive reconstructed temperature record for the Ortles summit, based on the surrounding meteorological station data, is available for the last 150 years, while an automatic weather station had been operating from 2011 to 2015 in proximity of the drilling site. The new ice core chronology, based on 210Pb, tritium, beta emissions analysis and 14C measurements of the particulate organic carbon, indicates that the bottom ice is 7000 years old, making it the second most extended glaciological archive ever retrieved in the Alps. The three equally long ice cores have been analyzed for oxygen and hydrogen stable isotopes throughout their length, and the goal is to create an Ortles stacked record for d18O and dD and compare the isotopic data to instrumental temperatures and to other Alpine records. Since 2008, several snow pits were dug in proximity of the drilling site during summer, when the temperature can often exceed the melting point. The isotopic profiles of the 2015 snow pit, dug at the end of an exceptionally warm summer, show how the isotope signal is now affected by the post-depositional processes that have occurred

  8. Of text and gene – using text mining methods to uncover hidden knowledge in toxicogenomics

    PubMed Central

    2014-01-01

    Background Toxicogenomics studies often profile gene expression from assays involving multiple doses and time points. The dose- and time-dependent pattern is of great importance to assess toxicity but computational approaches are lacking to effectively utilize this characteristic in toxicity assessment. Topic modeling is a text mining approach, but may be used analogously in toxicogenomics due to the similar data structures between text and gene dysregulation. Results Topic modeling was applied to a very large toxicogenomics dataset containing microarray gene expression data from >15,000 samples associated with 131 drugs tested in three different assay platforms (i.e., in vitro assay, in vivo repeated dose study and in vivo single dose experiment) with a design including multiple doses and time points. A set of “topics” which each consist of a set of genes was determined, by which the varying sensitivity of three assay systems was observed. We found that the drug-dependent effect was more pronounced in the two in vivo systems than the in vitro system, while the time-dependent effect was most strongly reflected in the in vitro system followed by the single dose study and lastly the repeated dose experiment. The dose-dependent effect was similar across three assay systems. Although the results indicated a challenge to extrapolate the in vitro results to the in vivo situation, we did notice that, for some drugs but not for all the drugs, the similarity in gene expression patterns was observed across all three assay systems, indicating a possibility of using in vitro systems with careful designs (such as the choice of dose and time point), to replace the in vivo testing strategy. Nonetheless, a potential to replace the repeated dose study by the single-dose short-term methodology was strongly implied. Conclusions The study demonstrated that text mining methodologies such as topic modeling provide an alternative method compared to traditional means for data

  9. An Integrated Metabolomic and Genomic Mining Workflow To Uncover the Biosynthetic Potential of Bacteria

    PubMed Central

    Maansson, Maria; Vynne, Nikolaj G.; Klitgaard, Andreas; Nybo, Jane L.; Melchiorsen, Jette; Nguyen, Don D.; Sanchez, Laura M.; Ziemert, Nadine; Dorrestein, Pieter C.

    2016-01-01

    ABSTRACT Microorganisms are a rich source of bioactives; however, chemical identification is a major bottleneck. Strategies that can prioritize the most prolific microbial strains and novel compounds are of great interest. Here, we present an integrated approach to evaluate the biosynthetic richness in bacteria and mine the associated chemical diversity. Thirteen strains closely related to Pseudoalteromonas luteoviolacea isolated from all over the Earth were analyzed using an untargeted metabolomics strategy, and metabolomic profiles were correlated with whole-genome sequences of the strains. We found considerable diversity: only 2% of the chemical features and 7% of the biosynthetic genes were common to all strains, while 30% of all features and 24% of the genes were unique to single strains. The list of chemical features was reduced to 50 discriminating features using a genetic algorithm and support vector machines. Features were dereplicated by tandem mass spectrometry (MS/MS) networking to identify molecular families of the same biosynthetic origin, and the associated pathways were probed using comparative genomics. Most of the discriminating features were related to antibacterial compounds, including the thiomarinols that were reported from P. luteoviolacea here for the first time. By comparative genomics, we identified the biosynthetic cluster responsible for the production of the antibiotic indolmycin, which could not be predicted with standard methods. In conclusion, we present an efficient, integrative strategy for elucidating the chemical richness of a given set of bacteria and link the chemistry to biosynthetic genes. IMPORTANCE We here combine chemical analysis and genomics to probe for new bioactive secondary metabolites based on their pattern of distribution within bacterial species. We demonstrate the usefulness of this combined approach in a group of marine Gram-negative bacteria closely related to Pseudoalteromonas luteoviolacea, which is a

  10. Activity of distinct growth factor receptor network components in breast tumors uncovers two biologically relevant subtypes.

    PubMed

    Rahman, Mumtahena; MacNeil, Shelley M; Jenkins, David F; Shrestha, Gajendra; Wyatt, Sydney R; McQuerry, Jasmine A; Piccolo, Stephen R; Heiser, Laura M; Gray, Joe W; Johnson, W Evan; Bild, Andrea H

    2017-04-26

    The growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns. Novel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection and InteGratioN (ASSIGN) was used to estimate pathway activity for GFRN components in 1119 breast tumors from The Cancer Genome Atlas (TCGA) and across 55 breast cancer cell lines from the Integrative Cancer Biology Program (ICBP43). These signatures were investigated for their relationship to pro- and anti-apoptotic protein expression and drug response in breast cancer cell lines. Application of these signatures to breast tumor gene expression data identified two novel discrete phenotypes characterized by concordant, aberrant activation of either the HER2, IGF1R, and AKT pathways ("the survival phenotype") or the EGFR, KRAS (G12V), RAF1, and BAD pathways ("the growth phenotype"). These phenotypes described a significant amount of the variability in the total expression data across breast cancer tumors and characterized distinctive patterns in apoptosis evasion and drug response. The growth phenotype expressed lower levels of BIM and higher levels of MCL-1 proteins. Further, the growth phenotype was more sensitive to common chemotherapies and targeted therapies directed at EGFR and MEK. Alternatively, the survival phenotype was more sensitive to drugs inhibiting HER2, PI3K, AKT, and mTOR, but more resistant to chemotherapies. Gene expression profiling revealed a bifurcation pattern

  11. Comparison of outcomes among secondary covered metallic, uncovered metallic, and plastic biliary stents in treating occluded primary metallic stents in malignant distal biliary obstruction.

    PubMed

    Cho, Jae Hee; Jeon, Tae Joo; Park, Jeong Youp; Kim, Hee Man; Kim, Yoon Jae; Park, Seung Woo; Chung, Jae Bock; Song, Si Young; Bang, Seungmin

    2011-02-01

    The self-expandable metallic stent (SEMS) has been widely used for unresectable malignant biliary obstruction but eventually becomes occluded by tumor ingrowth/overgrowth and sludge. Therefore, we aimed to determine the therapeutic effectiveness of secondary stents and to find differences according to various combinations of the first and second stents for the management of occluded SEMSs in patients with malignant distal biliary obstruction. Between 1999 and November 2008, 77 patients with malignant biliary obstruction underwent secondary biliary stent placement as "stent-in-stent" at three university hospitals in Korea (40 covered, 26 uncovered, and 11 plastic stents). The membrane of the covered SEMS was regarded as the barrier against tumor ingrowth. We categorized the patients into three groups based on whether the covered SEMS was either the first or the second stent: membrane-SEMS (18 covered-covered; 9 covered-uncovered; 22 uncovered-covered SEMS), bare-SEMS (17 uncovered-uncovered SEMS), and plastic stent (3 covered-plastic; 8 uncovered-plastic). The median patency of second stents was 138, 109, and 88 days (covered, uncovered, and plastic stents). The second covered SEMSs had a significantly longer patency than plastic stents (p=0.047). In a multivariate analysis including membrane-SEMS, bare-SEMS, and plastic stent groups, the bare-SEMS had a worse cumulative stent patency (HR=2.04, CI=1.08-3.86) and survival time (HR=2.37, CI=1.25-4.49) than the membrane-SEMS. Patients with ampulla of Vater cancer had better stent patency (HR=0.27, CI=0.08-0.98) and survival (HR=0.17, CI=0.04-0.77) than those with other pancreatobiliary malignancies. In addition, antitumor treatment prolonged survival time (HR=0.50, CI=0.26-0.99). The placement of additional biliary stents using the "stent-in-stent" method is an effective treatment for an occluded metallic primary stent. In addition, double biliary SEMS placement using at least one covered SEMS (in the primary and

  12. Campus Profile 98.

    ERIC Educational Resources Information Center

    Glendale Community Coll., CA. Planning and Research Office.

    Glendale Community College's Campus Profile is designed to assist faculty, staff, and students in understanding the college's diverse operations. Organized around an outline from the state accountability model, this statistical report focuses on the academic years 1995-1997. "Campus Profile '98" includes more accountability performance…

  13. Profiles of California vegetation

    Treesearch

    William B. Critchfield

    1971-01-01

    This publication brings together 57 elevational profiles illustrating the dominant vegetation of much of the Sierra Nevada, southern Coast Ranges, and montane southern California as it existed in the 1930's. The profiles were drawn by Michael N. Dobrotin for the U.S. Forest Service's Vegetation Type Map survey, which mapped nearly half of the State's...

  14. Florida Language Profile Manual.

    ERIC Educational Resources Information Center

    Wolking, William D.; And Others

    Described in the manual is the Florida Language Profile (funded through Title VI), a flexible set of performance sampling procedures for measuring language cognitive skills of children in kindergarten and grade 1 and remediating diagnosed disabilities. It is said that the Profile may be administered by the trained examiner or classroom teacher on…

  15. Super-resolution ribosome profiling reveals unannotated translation events in Arabidopsis

    PubMed Central

    Hsu, Polly Yingshan; Calviello, Lorenzo; Wu, Hsin-Yen Larry; Li, Fay-Wei; Rothfels, Carl J.; Ohler, Uwe; Benfey, Philip N.

    2016-01-01

    Deep sequencing of ribosome footprints (ribosome profiling) maps and quantifies mRNA translation. Because ribosomes decode mRNA every 3 nt, the periodic property of ribosome footprints could be used to identify novel translated ORFs. However, due to the limited resolution of existing methods, the 3-nt periodicity is observed mostly in a global analysis, but not in individual transcripts. Here, we report a protocol applied to Arabidopsis that maps over 90% of the footprints to the main reading frame and thus offers super-resolution profiles for individual transcripts to precisely define translated regions. The resulting data not only support many annotated and predicted noncanonical translation events but also uncover small ORFs in annotated noncoding RNAs and pseudogenes. A substantial number of these unannotated ORFs are evolutionarily conserved, and some produce stable proteins. Thus, our study provides a valuable resource for plant genomics and an efficient optimization strategy for ribosome profiling in other organisms. PMID:27791167

  16. Estimating Cognitive Profiles Using Profile Analysis via Multidimensional Scaling (PAMS)

    ERIC Educational Resources Information Center

    Kim, Se-Kang; Frisby, Craig L.; Davison, Mark L.

    2004-01-01

    Two of the most popular methods of profile analysis, cluster analysis and modal profile analysis, have limitations. First, neither technique is adequate when the sample size is large. Second, neither method will necessarily provide profile information in terms of both level and pattern. A new method of profile analysis, called Profile Analysis via…

  17. Estimating Cognitive Profiles Using Profile Analysis via Multidimensional Scaling (PAMS)

    ERIC Educational Resources Information Center

    Kim, Se-Kang; Frisby, Craig L.; Davison, Mark L.

    2004-01-01

    Two of the most popular methods of profile analysis, cluster analysis and modal profile analysis, have limitations. First, neither technique is adequate when the sample size is large. Second, neither method will necessarily provide profile information in terms of both level and pattern. A new method of profile analysis, called Profile Analysis via…

  18. What Studying Problems Are Faced by the Adolescent Grade Repeaters in Macao: Uncovering Underlying Mechanisms Based on Evidences from the PISA 2012 Study

    ERIC Educational Resources Information Center

    Sit, Pou-seong; Cheung, Kwok-cheung; Cheong, Wai-cheong; Mak, Soi-kei; Soh, Kay-cheng; Ieong, Man-kai

    2015-01-01

    Most schools in Macao are private schools, and there is a variety of grade repetition policy practiced in the 45 secondary schools. The policies are translated into school-based accountability of some kind of minimum competency standards. The objective of this study is to uncover the mediation mechanisms accounting for the influences of grade…

  19. What Studying Problems Are Faced by the Adolescent Grade Repeaters in Macao: Uncovering Underlying Mechanisms Based on Evidences from the PISA 2012 Study

    ERIC Educational Resources Information Center

    Sit, Pou-seong; Cheung, Kwok-cheung; Cheong, Wai-cheong; Mak, Soi-kei; Soh, Kay-cheng; Ieong, Man-kai

    2015-01-01

    Most schools in Macao are private schools, and there is a variety of grade repetition policy practiced in the 45 secondary schools. The policies are translated into school-based accountability of some kind of minimum competency standards. The objective of this study is to uncover the mediation mechanisms accounting for the influences of grade…

  20. Metabolic profiling reveals key metabolic features of renal cell carcinoma.

    PubMed

    Catchpole, Gareth; Platzer, Alexander; Weikert, Cornelia; Kempkensteffen, Carsten; Johannsen, Manfred; Krause, Hans; Jung, Klaus; Miller, Kurt; Willmitzer, Lothar; Selbig, Joachim; Weikert, Steffen

    2011-01-01

    Recent evidence suggests that metabolic changes play a pivotal role in the biology of cancer and in particular renal cell carcinoma (RCC). Here, a global metabolite profiling approach was applied to characterize the metabolite pool of RCC and normal renal tissue. Advanced decision tree models were applied to characterize the metabolic signature of RCC and to explore features of metastasized tumours. The findings were validated in a second independent dataset. Vitamin E derivates and metabolites of glucose, fatty acid, and inositol phosphate metabolism determined the metabolic profile of RCC. α-tocopherol, hippuric acid, myoinositol, fructose-1-phosphate and glucose-1-phosphate contributed most to the tumour/normal discrimination and all showed pronounced concentration changes in RCC. The identified metabolic profile was characterized by a low recognition error of only 5% for tumour versus normal samples. Data on metastasized tumours suggested a key role for metabolic pathways involving arachidonic acid, free fatty acids, proline, uracil and the tricarboxylic acid cycle. These results illustrate the potential of mass spectroscopy based metabolomics in conjunction with sophisticated data analysis methods to uncover the metabolic phenotype of cancer. Differentially regulated metabolites, such as vitamin E compounds, hippuric acid and myoinositol, provide leads for the characterization of novel pathways in RCC.

  1. Interior Cornice Profile, Interior Pilaster Profile, Lions Head Roof Scupper, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Interior Cornice Profile, Interior Pilaster Profile, Lions Head Roof Scupper, and Interior Panel Moulding - Flanders Field American Cemetery & Memorial, Chapel, Wortegemseweg 117, Waregem, West Flanders (Belgium)

  2. An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration.

    PubMed

    Chen, Ting; Heller, Evan; Beronja, Slobodan; Oshimori, Naoki; Stokes, Nicole; Fuchs, Elaine

    2012-04-04

    Adult stem cells sustain tissue maintenance and regeneration throughout the lifetime of an animal. These cells often reside in specific signalling niches that orchestrate the stem cell's balancing act between quiescence and cell-cycle re-entry based on the demand for tissue regeneration. How stem cells maintain their capacity to replenish themselves after tissue regeneration is poorly understood. Here we use RNA-interference-based loss-of-function screening as a powerful approach to uncover transcriptional regulators that govern the self-renewal capacity and regenerative potential of stem cells. Hair follicle stem cells provide an ideal model. These cells have been purified and characterized from their native niche in vivo and, in contrast to their rapidly dividing progeny, they can be maintained and passaged long-term in vitro. Focusing on the nuclear proteins and/or transcription factors that are enriched in stem cells compared with their progeny, we screened ∼2,000 short hairpin RNAs for their effect on long-term, but not short-term, stem cell self-renewal in vitro. To address the physiological relevance of our findings, we selected one candidate that was uncovered in the screen: TBX1. This transcription factor is expressed in many tissues but has not been studied in the context of stem cell biology. By conditionally ablating Tbx1 in vivo, we showed that during homeostasis, tissue regeneration occurs normally but is markedly delayed. We then devised an in vivo assay for stem cell replenishment and found that when challenged with repetitive rounds of regeneration, the Tbx1-deficient stem cell niche becomes progressively depleted. Addressing the mechanism of TBX1 action, we discovered that TBX1 acts as an intrinsic rheostat of BMP signalling: it is a gatekeeper that governs the transition between stem cell quiescence and proliferation in hair follicles. Our results validate the RNA interference screen and underscore its power in unearthing new molecules that

  3. Profiles in Cancer Research

    Cancer.gov

    These articles put a face to some of the thousands of individuals who contribute to NCI’s cancer research efforts. The profiles highlight the work of scientists and clinicians and describe the circumstances and motivation behind their work.

  4. Profile of Older Americans

    MedlinePlus

    ... Administration on Aging Administration on Disabilities Center for Integrated Programs Center for Performance and Evaluation National Institute ... Project Aging Statistics Profile of Older Americans AGing Integrated Database (AGID) Census Data & Population Estimates Projected Future ...

  5. Expedition 29 Crew Profile

    NASA Image and Video Library

    The six members of Expedition 29 are profiled and interviewed. NASA astronauts Mike Fossum and Dan Burbank; JAXA astronaut Satoshi Furukawa; and cosmonauts Anton Shkaplerov and Anatoly Ivanishin di...

  6. Contaminated Sediment Core Profiling

    EPA Science Inventory

    Evaluating the environmental risk of sites containing contaminated sediments often poses major challenges due in part to the absence of detailed information available for a given location. Sediment core profiling is often utilized during preliminary environmental investigations ...

  7. Attitude profile design program

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The Attitude Profile Design (APD) Program was designed to be used as a stand-alone addition to the Simplex Computation of Optimum Orbital Trajectories (SCOOT). The program uses information from a SCOOT output file and the user defined attitude profile to produce time histories of attitude, angular body rates, and accelerations. The APD program is written in standard FORTRAN77 and should be portable to any machine that has an appropriate compiler. The input and output are through formatted files. The program reads the basic flight data, such as the states of the vehicles, acceleration profiles, and burn information, from the SCOOT output file. The user inputs information about the desired attitude profile during coasts in a high level manner. The program then takes these high level commands and executes the maneuvers, outputting the desired information.

  8. Cassini: the Profiler

    NASA Image and Video Library

    2006-08-08

    The Cassini spacecraft continues to profile the haze structure and opacity in Saturn upper atmosphere with images like this, which captures Rigel, a star in Orion whose brightness is well-known, as it passes behind the planet

  9. Contaminated Sediment Core Profiling

    EPA Science Inventory

    Evaluating the environmental risk of sites containing contaminated sediments often poses major challenges due in part to the absence of detailed information available for a given location. Sediment core profiling is often utilized during preliminary environmental investigations ...

  10. Automated DNA profile analysis.

    PubMed

    Graham, Eleanor A M

    2005-12-01

    DNA profile analysis is not a simple process. Stringent demands are placed on the accuracy and consistency of forensic evidence so that complex, robust, and reproducible guidelines are necessary to assist the analyst and ensure mistakes are eliminated before a final profile is reported. The guidelines used for forensic DNA profile interpretation are formulated by investigation and statistical evaluation of all aspects of the analytical procedure. All the resulting rules, formulas, and thresholds are perfectly suited to programming of "expert systems"-software programs that imitate the human expert in decision-based processes to formulate a conclusion. Expert systems in forensic DNA analysis will contribute greatly to this field by increasing analytical throughput. The net result of this will be an increase in the human resources available for the research and development of improved methodologies, to ensure that forensic DNA profiling continues to advance at its current impressive rate.

  11. P Cygni type profiles.

    NASA Astrophysics Data System (ADS)

    Peraiah, A.; Srinivasa Rao, M.

    The authors present a series of P Cygni type profiles of spectral lines computed by employing different velocity laws of expansion in a spherically symmetric atmosphere. A comparison has been made with those of Beals classification. They have employed the line transfer equation in comoving frame in certain test cases, to obtain the source function which is being used to calculate the profiles observed at infinity.

  12. Minimum Drag Circulation Profile.

    DTIC Science & Technology

    turbulent flow region is followed by a region of minimum skin friction which has a concave surface. The chord trailing edge is a coanda profile. A...tangential jet slot is placed at the trailing edge to blow over and around the coanda profile preventing flow separation and moving the stagnation region aft on the wing. The under surface is cambered to reduce the flow velocity.

  13. Criminal Psychological Profiling

    DTIC Science & Technology

    1993-10-18

    6 2. Literature Review .............................. 7 Profiling in Popular Entertainment ...... 8 Theories of Criminal Behavior ........... 11 Early...of the basic theories of criminal behavior, leading up to the psychological explanations of crime. This is provided in an effort to establish the...style of profiling was not achieved easily. It was a long and involved process that began with a mix of psychology and theories of criminal behavior

  14. BWR AXIAL PROFILE

    SciTech Connect

    J. Huffer

    2004-09-28

    The purpose of this calculation is to develop axial profiles for estimating the axial variation in burnup of a boiling water reactor (BWR) assembly spent nuclear fuel (SNF) given the average burnup of an assembly. A discharged fuel assembly typically exhibits higher burnup in the center and lower burnup at the ends of the assembly. Criticality safety analyses taking credit for SNF burnup must account for axially varying burnup relative to calculations based on uniformly distributed assembly average burnup due to the under-burned tips. Thus, accounting for axially varying burnup in criticality analyses is also referred to as accounting for the ''end effect'' reactivity. The magnitude of the reactivity change due to ''end effect'' is dependent on the initial assembly enrichment, the assembly average burnup, and the particular axial profile characterizing the burnup distribution. The set of bounding axial profiles should incorporate multiple BWR core designs and provide statistical confidence (95 percent confidence that 95 percent of the population is bound by the profile) that end nodes are conservatively represented. The profiles should also conserve the overall burnup of the fuel assembly. More background on BWR axial profiles is provided in Attachment I.

  15. The Penalized Profile Sampler

    PubMed Central

    CHENG, GUANG; KOSOROK, MICHAEL R.

    2010-01-01

    The penalized profile sampler for semiparametric inference is an extension of the profile sampler method [9] obtained by profiling a penalized log-likelihood. The idea is to base inference on the posterior distribution obtained by multiplying a profiled penalized log-likelihood by a prior for the parametric component, where the profiling and penalization are applied to the nuisance parameter. Because the prior is not applied to the full likelihood, the method is not strictly Bayesian. A benefit of this approximately Bayesian method is that it circumvents the need to put a prior on the possibly infinite-dimensional nuisance components of the model. We investigate the first and second order frequentist performance of the penalized profile sampler, and demonstrate that the accuracy of the procedure can be adjusted by the size of the assigned smoothing parameter. The theoretical validity of the procedure is illustrated for two examples: a partly linear model with normal error for current status data and a semiparametric logistic regression model. Simulation studies are used to verify the theoretical results. PMID:20431712

  16. Accelerated Profile HMM Searches.

    PubMed

    Eddy, Sean R

    2011-10-01

    Profile hidden Markov models (profile HMMs) and probabilistic inference methods have made important contributions to the theory of sequence database homology search. However, practical use of profile HMM methods has been hindered by the computational expense of existing software implementations. Here I describe an acceleration heuristic for profile HMMs, the "multiple segment Viterbi" (MSV) algorithm. The MSV algorithm computes an optimal sum of multiple ungapped local alignment segments using a striped vector-parallel approach previously described for fast Smith/Waterman alignment. MSV scores follow the same statistical distribution as gapped optimal local alignment scores, allowing rapid evaluation of significance of an MSV score and thus facilitating its use as a heuristic filter. I also describe a 20-fold acceleration of the standard profile HMM Forward/Backward algorithms using a method I call "sparse rescaling". These methods are assembled in a pipeline in which high-scoring MSV hits are passed on for reanalysis with the full HMM Forward/Backward algorithm. This accelerated pipeline is implemented in the freely available HMMER3 software package. Performance benchmarks show that the use of the heuristic MSV filter sacrifices negligible sensitivity compared to unaccelerated profile HMM searches. HMMER3 is substantially more sensitive and 100- to 1000-fold faster than HMMER2. HMMER3 is now about as fast as BLAST for protein searches.

  17. Construction of differential mRNA-lncRNA crosstalk networks based on ceRNA hypothesis uncover key roles of lncRNAs implicated in esophageal squamous cell carcinoma

    PubMed Central

    Li, Yixue

    2016-01-01

    Increasing evidence has indicated that lncRNAs acting as competing endogenous RNAs (ceRNAs) play crucial roles in tumorigenesis, metastasis and diagnosis of cancer. However, the function of lncRNAs as ceRNAs involved in esophageal squamous cell carcinoma (ESCC) is still largely unknown. In this study, clinical implications of two intrinsic subtypes of ESCC were identified based on expression profiles of lncRNA and mRNA. ESCC subtype-specific differential co-expression networks between mRNAs and lncRNAs were constructed to reveal dynamic changes of their crosstalks mediated by miRNAs during tumorigenesis. Several well-known cancer-associated lncRNAs as the hubs of the two networks were firstly proposed in ESCC. Based on the ceRNA mechanism, we illustrated that the“loss” of miR-186-mediated PVT1-mRNA and miR-26b-mediated LINC00240-mRNA crosstalks were related to the two ESCC subtypes respectively. In addition, crosstalks between LINC00152 and EGFR, LINC00240 and LOX gene family were identified, which were associated with the function of “response to wounding” and “extracellular matrix-receptor interaction”. Furthermore, functional cooperation of multiple lncRNAs was discovered in the two differential mRNA-lncRNA crosstalk networks. These together systematically uncovered the roles of lncRNAs as ceRNAs implicated in ESCC. PMID:27966444

  18. Genome-wide screen uncovers novel pathways for tRNA processing and nuclear–cytoplasmic dynamics

    PubMed Central

    Wu, Jingyan; Bao, Alicia; Chatterjee, Kunal; Wan, Yao; Hopper, Anita K.

    2015-01-01

    Transfer ribonucleic acids (tRNAs) are essential for protein synthesis. However, key gene products involved in tRNA biogenesis and subcellular movement remain to be discovered. We conducted the first comprehensive unbiased analysis of the role of nearly an entire proteome in tRNA biology and describe 162 novel and 12 previously known Saccharomyces cerevisiae gene products that function in tRNA processing, turnover, and subcellular movement. tRNA nuclear export is of particular interest because it is essential, but the known tRNA exporters (Los1 [exportin-t] and Msn5 [exportin-5]) are unessential. We report that mutations of CRM1 (Exportin-1), MEX67/MTR2 (TAP/p15), and five nucleoporins cause accumulation of unspliced tRNA, a hallmark of defective tRNA nuclear export. CRM1 mutation genetically interacts with los1Δ and causes altered tRNA nuclear–cytoplasmic distribution. The data implicate roles for the protein and mRNA nuclear export machineries in tRNA nuclear export. Mutations of genes encoding actin cytoskeleton components and mitochondrial outer membrane proteins also cause accumulation of unspliced tRNA, likely due to defective splicing on mitochondria. Additional gene products, such as chromatin modification enzymes, have unanticipated effects on pre-tRNA end processing. Thus, this genome-wide screen uncovered putative novel pathways for tRNA nuclear export and extensive links between tRNA biology and other aspects of cell physiology. PMID:26680305

  19. A new functional role uncovered for RASGRF2 in control of nuclear migration in cone photoreceptors during postnatal retinal development.

    PubMed

    Jimeno, David; Santos, Eugenio

    2017-01-02

    Despite their homologous structure and central nervous system(CNS) expression patterns, the GRF1 and GRF2 guanine nucleotide exchange factors(GEF) appear to play distinct, non-overlapping functions in cellular excitability, synaptic plasticity or neuromodulation. We recently uncovered a new functional role of GRF2 controlling nuclear migration in cone photoreceptors during postnatal neuroepithelial differentiation of the mouse retina. Analyzing GRF2-KO mice, we detected the specific accumulation of abnormally located, "ectopic" cone photoreceptor nuclei in the photoreceptor segment(PS) layer of their retinas. This alteration was accompanied by defective electroretinograms(ERG) indicative of impaired cone-mediated visual function, and accumulation around the "ectopic" nuclei of signaling molecules known to be functionally relevant for intracellular organelle migration, cytoskeletal reorganization or cell polarity establishment including PAR3, PAR6, and the phosphorylated proteins pPAK, pMLC2 and pVASP. We propose a mechanism whereby the absence of a productive functional interaction between GRF2 and its downstream target CDC42 leads to altered formation/structure of PAR-containing, polarity-related macromolecular complexes and abnormal activation of downstream signaling mediated by activated, phosphorylated forms of PAK, VASP and MLC2. As cone photoreceptors are responsible for color vision and visual acuity, these observations are potentially relevant for degenerative diseases of the human retina, harboring almost double number of cones than mice.

  20. An uncovered XIII century icon: particular use of organic pigments and gilding techniques highlighted by analytical methods.

    PubMed

    Daveri, Alessia; Doherty, Brenda; Moretti, Patrizia; Grazia, Chiara; Romani, Aldo; Fiorin, Enrico; Brunetti, Brunetto Giovanni; Vagnini, Manuela

    2015-01-25

    The restoration of a panel painting depicting a Madonna and Child listed as an unknown Tuscan artist of the nineteenth century, permitted the hidden original version, a XIII century Medieval icon to be uncovered. It is discovery provided the opportunity for an extensive in situ campaign of non-invasive analytical investigations by portable imaging and spectroscopic techniques (infrared, X-ray fluorescence and diffraction, UV-Vis absorption and emission), followed by aimed micro-destructive investigations (Raman and SEM-EDS). This approach permitted characterization of the original ground and paint layers by complementary techniques. Furthermore, this protocol allowed supplementary particularities of great interest to be highlighted. Namely, numerous original gilding techniques have been accentuated in diverse areas and include the use of surrogate gold (disulphur tin), orpiment as a further false gold and an area with an original silver rich layer. Moreover, pigments including azurite mixed with indigo have been non-invasively identified. Micro-invasive analyses also allowed the diagnosis of organic colorants, namely, an animal anthraquinone lake, kermes and an unusual vegetal chalcone pigment, possibly safflower. The identification of the latter is extremely rare as a painting pigment and has been identified using an innovative adaption to surface enhanced Raman techniques on a cross-section. The resulting data contributes new hypotheses to the historic and artistic knowledge of materials and techniques utilized in XIII century icon paintings and ultimately provides scientific technical support of the recent restoration.

  1. Uncovering the Genome-Wide Transcriptional Responses of the Filamentous Fungus Aspergillus niger to Lignocellulose Using RNA Sequencing

    PubMed Central

    Gaddipati, Sanyasi; Kokolski, Matthew; Malla, Sunir; Blythe, Martin J.; Ibbett, Roger; Campbell, Maria; Liddell, Susan; Aboobaker, Aziz; Tucker, Gregory A.; Archer, David B.

    2012-01-01

    A key challenge in the production of second generation biofuels is the conversion of lignocellulosic substrates into fermentable sugars. Enzymes, particularly those from fungi, are a central part of this process, and many have been isolated and characterised. However, relatively little is known of how fungi respond to lignocellulose and produce the enzymes necessary for dis-assembly of plant biomass. We studied the physiological response of the fungus Aspergillus niger when exposed to wheat straw as a model lignocellulosic substrate. Using RNA sequencing we showed that, 24 hours after exposure to straw, gene expression of known and presumptive plant cell wall–degrading enzymes represents a huge investment for the cells (about 20% of the total mRNA). Our results also uncovered new esterases and surface interacting proteins that might form part of the fungal arsenal of enzymes for the degradation of plant biomass. Using transcription factor deletion mutants (xlnR and creA) to study the response to both lignocellulosic substrates and low carbon source concentrations, we showed that a subset of genes coding for degradative enzymes is induced by starvation. Our data support a model whereby this subset of enzymes plays a scouting role under starvation conditions, testing for available complex polysaccharides and liberating inducing sugars, that triggers the subsequent induction of the majority of hydrolases. We also showed that antisense transcripts are abundant and that their expression can be regulated by growth conditions. PMID:22912594

  2. Proteomics and transcriptomics analyses of Arabidopsis floral buds uncover important functions of ARABIDOPSIS SKP1-LIKE1

    SciTech Connect

    Lu, Dihong; Ni, Weimin; Stanley, Bruce A.; Ma, Hong

    2016-03-03

    The ARABIDOPSIS SKP1-LIKE1 (ASK1) protein functions as a subunit of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases. Previous genetic studies showed that ASK1 plays important roles in Arabidopsis flower development and male meiosis. However, the molecular impact of ASK1-containing SCF E3 ubiquitin ligases (ASK1-E3s) on the floral proteome and transcriptome is unknown. Here we identified proteins that are potentially regulated by ASK1-E3s by comparing floral bud proteomes of wild-type and the ask1 mutant plants. More than 200 proteins were detected in the ask1 mutant but not in wild-type and >300 were detected at higher levels in the ask1 mutant than in wild-type, but their RNA levels were not significantly different between wild-type and ask1 floral buds as shown by transcriptomics analysis, suggesting that they are likely regulated at the protein level by ASK1-E3s. Integrated analyses of floral proteomics and transcriptomics of ask1 and wild-type uncovered several potential aspects of ASK1-E3 functions, including regulation of transcription regulators, kinases, peptidases, and ribosomal proteins, with implications on possible mechanisms of ASK1-E3 functions in floral development. In conclusion, our results suggested that ASK1-E3s play important roles in Arabidopsis protein degradation during flower development. This study opens up new possibilities for further functional studies of these candidate E3 substrates.

  3. Endoscopic management of unresectable malignant gastroduodenal obstruction with a nitinol uncovered metal stent: A prospective Japanese multicenter study

    PubMed Central

    Sasaki, Reina; Sakai, Yuji; Tsuyuguchi, Toshio; Nishikawa, Takao; Fujimoto, Tatsuya; Mikami, Shigeru; Sugiyama, Harutoshi; Yokosuka, Osamu

    2016-01-01

    AIM: To determine the safety and efficacy of endoscopic duodenal stent placement in patients with malignant gastric outlet obstruction. METHODS: This prospective, observational, multicenter study included 39 consecutive patients with malignant gastric outlet obstruction. All patients underwent endoscopic placement of a nitinol, uncovered, self-expandable metal stent. The primary outcome was clinical success at 2 wk after stent placement that was defined as improvement in the Gastric Outlet Obstruction Scoring System score relative to the baseline. RESULTS: Technical success was achieved in all duodenal stent procedures. Procedure-related complications occurred in 4 patients (10.3%) in the form of mild pneumonitis. No other morbidities or mortalities were observed. The clinical success rate was 92.3%. The mean survival period after stent placement was 103 d. The mean period of stent patency was 149 d and the patency remained acceptable for the survival period. Stent dysfunction occurred in 3 patients (7.7%) on account of tumor growth. CONCLUSION: Endoscopic management using duodenal stents for patients with incurable malignant gastric outlet obstruction is safe and improved patients’ quality of life. PMID:27076769

  4. An uncovered XIII century icon: Particular use of organic pigments and gilding techniques highlighted by analytical methods

    NASA Astrophysics Data System (ADS)

    Daveri, Alessia; Doherty, Brenda; Moretti, Patrizia; Grazia, Chiara; Romani, Aldo; Fiorin, Enrico; Brunetti, Brunetto Giovanni; Vagnini, Manuela

    2015-01-01

    The restoration of a panel painting depicting a Madonna and Child listed as an unknown Tuscan artist of the nineteenth century, permitted the hidden original version, a XIII century Medieval icon to be uncovered. It is discovery provided the opportunity for an extensive in situ campaign of non-invasive analytical investigations by portable imaging and spectroscopic techniques (infrared, X-ray fluorescence and diffraction, UV-Vis absorption and emission), followed by aimed micro-destructive investigations (Raman and SEM-EDS). This approach permitted characterization of the original ground and paint layers by complementary techniques. Furthermore, this protocol allowed supplementary particularities of great interest to be highlighted. Namely, numerous original gilding techniques have been accentuated in diverse areas and include the use of surrogate gold (disulphur tin), orpiment as a further false gold and an area with an original silver rich layer. Moreover, pigments including azurite mixed with indigo have been non-invasively identified. Micro-invasive analyses also allowed the diagnosis of organic colorants, namely, an animal anthraquinone lake, kermes and an unusual vegetal chalcone pigment, possibly safflower. The identification of the latter is extremely rare as a painting pigment and has been identified using an innovative adaption to surface enhanced Raman techniques on a cross-section. The resulting data contributes new hypotheses to the historic and artistic knowledge of materials and techniques utilized in XIII century icon paintings and ultimately provides scientific technical support of the recent restoration.

  5. Uncovering the composition of microbial community structure and metagenomics among three gut locations in pigs with distinct fatness

    PubMed Central

    Yang, Hui; Huang, Xiaochang; Fang, Shaoming; Xin, Wenshui; Huang, Lusheng; Chen, Congying

    2016-01-01

    Uncovering the phylogenetic composition of microbial community and the potential functional capacity of microbiome in different gut locations is of great importance to pig production. Here we performed a comparative analysis of gut microbiota and metagenomics among jejunum, ileum and cecum in pigs with distinct fatness. 16S rRNA gene sequencing revealed dramatic differences of microbial composition, diversity and species abundance between small intestine and cecum. Clostridium and SMB53 were enriched in the small intestine, while Prevotella, Treponema, Ruminococcus and Faecalibacterium showed a higher abundance in the cecum. Functional capacity analysis of gut microbiome revealed that the microbiome of small intestine plays important roles in the metabolism of small molecule nutrients, while the microbiome of cecum has the stronger ability to degrade xylan, pectin and cellulose. We identified tens of fatness associated-bacterial species including Escherichia spp. that showed a notable increase of relative abundance in all three gut locations of high fatness pigs. We further suggested that the potential pathogens, inflammation process, and microbial metabolism and nutrient sensing are involved in the high fatness of pigs. These results improve our knowledge about microbiota compositions in different gut locations, and give an insight into the effect of gut microbiota on porcine fatness. PMID:27255518

  6. Machine learning classification of cell-specific cardiac enhancers uncovers developmental subnetworks regulating progenitor cell division and cell fate specification

    PubMed Central

    Ahmad, Shaad M.; Busser, Brian W.; Huang, Di; Cozart, Elizabeth J.; Michaud, Sébastien; Zhu, Xianmin; Jeffries, Neal; Aboukhalil, Anton; Bulyk, Martha L.; Ovcharenko, Ivan; Michelson, Alan M.

    2014-01-01

    The Drosophila heart is composed of two distinct cell types, the contractile cardial cells (CCs) and the surrounding non-muscle pericardial cells (PCs), development of which is regulated by a network of conserved signaling molecules and transcription factors (TFs). Here, we used machine learning with array-based chromatin immunoprecipitation (ChIP) data and TF sequence motifs to computationally classify cell type-specific cardiac enhancers. Extensive testing of predicted enhancers at single-cell resolution revealed the added value of ChIP data for modeling cell type-specific activities. Furthermore, clustering the top-scoring classifier sequence features identified novel cardiac and cell type-specific regulatory motifs. For example, we found that the Myb motif learned by the classifier is crucial for CC activity, and the Myb TF acts in concert with two forkhead domain TFs and Polo kinase to regulate cardiac progenitor cell divisions. In addition, differential motif enrichment and cis-trans genetic studies revealed that the Notch signaling pathway TF Suppressor of Hairless [Su(H)] discriminates PC from CC enhancer activities. Collectively, these studies elucidate molecular pathways used in the regulatory decisions for proliferation and differentiation of cardiac progenitor cells, implicate Su(H) in regulating cell fate decisions of these progenitors, and document the utility of enhancer modeling in uncovering developmental regulatory subnetworks. PMID:24496624

  7. Systems dynamic modeling of a guard cell Cl- channel mutant uncovers an emergent homeostatic network regulating stomatal transpiration.

    PubMed

    Wang, Yizhou; Papanatsiou, Maria; Eisenach, Cornelia; Karnik, Rucha; Williams, Mary; Hills, Adrian; Lew, Virgilio L; Blatt, Michael R

    2012-12-01

    Stomata account for much of the 70% of global water usage associated with agriculture and have a profound impact on the water and carbon cycles of the world. Stomata have long been modeled mathematically, but until now, no systems analysis of a plant cell has yielded detail sufficient to guide phenotypic and mutational analysis. Here, we demonstrate the predictive power of a systems dynamic model in Arabidopsis (Arabidopsis thaliana) to explain the paradoxical suppression of channels that facilitate K(+) uptake, slowing stomatal opening, by mutation of the SLAC1 anion channel, which mediates solute loss for closure. The model showed how anion accumulation in the mutant suppressed the H(+) load on the cytosol and promoted Ca(2+) influx to elevate cytosolic pH (pH(i)) and free cytosolic Ca(2+) concentration ([Ca(2+)](i)), in turn regulating the K(+) channels. We have confirmed these predictions, measuring pH(i) and [Ca(2+)](i) in vivo, and report that experimental manipulation of pH(i) and [Ca(2+)](i) is sufficient to recover K(+) channel activities and accelerate stomatal opening in the slac1 mutant. Thus, we uncover a previously unrecognized signaling network that ameliorates the effects of the slac1 mutant on transpiration by regulating the K(+) channels. Additionally, these findings underscore the importance of H(+)-coupled anion transport for pH(i) homeostasis.

  8. GM-CSF in murine psoriasiform dermatitis: Redundant and pathogenic roles uncovered by antibody-induced neutralization and genetic deficiency

    PubMed Central

    Scholz, Tatjana; Weigert, Andreas; Brüne, Bernhard; Sadik, Christian D.; Böhm, Beate

    2017-01-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic, Th17-derived cytokine thought to critically contribute to the pathogenesis of diverse autoimmune diseases, including rheumatoid arthritis and psoriasis. Treatment with monoclonal antibodies that block GM-CSF activity is associated with favorable therapeutic effects in patients with rheumatoid arthritis. We evaluated the role of GM-CSF as a potential target for therapeutic interference in psoriasis using a combined pharmacologic and genetic approach and the mouse model of imiquimod-induced psoriasiform dermatitis (IMQPD). Neutralization of murine GM-CSF by an anti-GM-CSF antibody ameliorated IMQPD. In contrast, genetic deficiency in GM-CSF did not alter the course of IMQPD, suggesting the existence of mechanisms compensating for chronic, but not acute, absence of GM-CSF. Further investigation uncovered an alternative pathogenic pathway for IMQPD in the absence of GM-CSF characterized by an expanded plasmacytoid dendritic cell population and release of IFNα and IL-22. This pathway was not activated in wild-type mice during short-term anti-GM-CSF treatment. Our investigations support the potential value of GM-CSF as a therapeutic target in psoriatic disease. The discovery of an alternative pathogenic pathway for psoriasiform dermatitis in the permanent absence of GM-CSF, however, suggests the need for monitoring during therapeutic use of long-term GM-CSF blockade. PMID:28777803

  9. Classification of protein motifs based on subcellular localization uncovers evolutionary relationships at both sequence and functional levels

    PubMed Central

    2013-01-01

    Background Most proteins have evolved in specific cellular compartments that limit their functions and potential interactions. On the other hand, motifs define amino acid arrangements conserved between protein family members and represent powerful tools for assigning function to protein sequences. The ideal motif would identify all members of a protein family but in practice many motifs identify both family members and unrelated proteins, referred to as True Positive (TP) and False Positive (FP) sequences, respectively. Results To address the relationship between protein motifs, protein function and cellular localization, we systematically assigned subcellular localization data to motif sequences from the comprehensive PROSITE sequence motif database. Using this data we analyzed relationships between localization and function. We find that TPs and FPs have a strong tendency to localize in different compartments. When multiple localizations are considered, TPs are usually distributed between related cellular compartments. We also identified cases where FPs are concentrated in particular subcellular regions, indicating possible functional or evolutionary relationships with TP sequences of the same motif. Conclusions Our findings suggest that the systematic examination of subcellular localization has the potential to uncover evolutionary and functional relationships between motif-containing sequences. We believe that this type of analysis complements existing motif annotations and could aid in their interpretation. Our results shed light on the evolution of cellular organelles and potentially establish the basis for new subcellular localization and function prediction algorithms. PMID:23865897

  10. TUP1 disruption in Cryptococcus neoformans uncovers a peptide-mediated density-dependent growth phenomenon that mimics quorum sensing.

    PubMed

    Lee, Hyeseung; Chang, Yun C; Nardone, Glenn; Kwon-Chung, Kyung J

    2007-05-01

    Cryptococcus neoformans is a pathogenic yeast that causes life-threatening meningoencephalitis and grows well on mycological media regardless of inoculum size. Interestingly, a deletion of the global repressor TUP1 in C. neoformans uncovered a density-dependent growth phenotype reminiscent of the quorum-sensing phenomenon. An inoculum size of lower than 10(3) cells of the tup1Delta strain failed to form colonies on agar media while inocula of 10(5)-10(6) cells per plate formed a lawn. This phenotype, expressed as the inability to grow at low cell densities, was rescued by the culture filtrate from a high cell density tup1Delta culture and the active molecule in this culture filtrate was identified to be an oligopeptide composed of 11 amino acids. Activity assays, using a synthetic version of the peptide with strains harbouring a deletion of the corresponding gene, proved that the oligopeptide functioned as an autoregulatory molecule responsible for the density-dependent phenotype. Although a density-dependent growth phenotype has been reported in several species of Ascomycetes, no peptide has been reported to function as an autoregulator in the Kingdom Fungi. The identification of an 11-mer peptide as an autoregulatory molecule in C. neoformans suggests that a diverse mechanism of cell-to-cell communication exists in the Kingdom Fungi.

  11. Uncovering and treating asymmetry before 6 years in our daily clinical practice: option or obligation? Orthodontics or orthopedics?

    PubMed

    Jaunet, Emmanuelle; Le Guern, Armel; Le Tacon, Pascale; Thery-Dumeix, Corinne; Deshayes, Marie-Josèphe

    2013-03-01

    Skeletal asymmetry of the TMJ or maxillary arch is always associated with basicranium skeletal asymmetry and can become pathogenic for the development of masticatory function. What means do we dispose of in our everyday practice for early screening and treatment of these often little-known asymmetries? This is the focus of our article, which draws on over 10years' experience within our own practices. We have systematically applied the following ground-rules: (a) look for clinical signs of facial asymmetry well before eruption of the deciduous teeth, and when the deciduous teeth have erupted; (b) during extraoral examinations, apply a new diagnostic tool involving a tracing of the soft tissue axes of the ears in order to uncover patients at high risk of intertemporal asymmetry; (c) look for maxillary intra-arch asymmetry using an Orthogrille(®)-type measurement grid; (d) look for inter-arch asymmetries using the "cranial" laterality test. Then, still during the deciduous dentition phase, we initiate treatment. In this paper, we outline the use of symmetrization sectorial screws combined with unlocking sliding plates in order to correct intra-arch and inter-arch asymmetry. We conclude by outlining techniques to remedy canted occlusal plane using a modified Fränkel-type appliance. Copyright © 2012 CEO. Published by Elsevier Masson SAS. All rights reserved.

  12. A new functional role uncovered for RASGRF2 in control of nuclear migration in cone photoreceptors during postnatal retinal development

    PubMed Central

    Jimeno, David; Santos, Eugenio

    2017-01-01

    ABSTRACT Despite their homologous structure and central nervous system(CNS) expression patterns, the GRF1 and GRF2 guanine nucleotide exchange factors(GEF) appear to play distinct, non-overlapping functions in cellular excitability, synaptic plasticity or neuromodulation. We recently uncovered a new functional role of GRF2 controlling nuclear migration in cone photoreceptors during postnatal neuroepithelial differentiation of the mouse retina. Analyzing GRF2-KO mice, we detected the specific accumulation of abnormally located, “ectopic” cone photoreceptor nuclei in the photoreceptor segment(PS) layer of their retinas. This alteration was accompanied by defective electroretinograms(ERG) indicative of impaired cone-mediated visual function, and accumulation around the “ectopic” nuclei of signaling molecules known to be functionally relevant for intracellular organelle migration, cytoskeletal reorganization or cell polarity establishment including PAR3, PAR6, and the phosphorylated proteins pPAK, pMLC2 and pVASP. We propose a mechanism whereby the absence of a productive functional interaction between GRF2 and its downstream target CDC42 leads to altered formation/structure of PAR-containing, polarity-related macromolecular complexes and abnormal activation of downstream signaling mediated by activated, phosphorylated forms of PAK, VASP and MLC2. As cone photoreceptors are responsible for color vision and visual acuity, these observations are potentially relevant for degenerative diseases of the human retina, harboring almost double number of cones than mice. PMID:27221061

  13. LIF independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease

    PubMed Central

    Griffiths, Dean S.; Li, Juan; Dawson, Mark A.; Trotter, Matthew W.B.; Cheng, Yi-Han; Smith, Aileen M.; Mansfield, William; Liu, Pentao; Kouzarides, Tony; Nichols, Jennifer; Bannister, Andrew J.; Green, Anthony R; Göttgens, Berthold

    2010-01-01

    Activating mutations in the tyrosine kinase JAK2 cause myeloproliferative neoplasms, clonal blood stem cell disorders with a propensity for leukaemic transformation. LIF signalling through JAK-STAT enables ES cell self-renewal. Here we show that mouse ES cells carrying the human JAK2V617F mutation could self-renew in chemically defined conditions without cytokines or small molecule inhibitors independently of JAK signalling through STAT3 or PI3K pathways. Phosphorylation of histone H3Y41 by JAK2 was recently shown to interfere with HP1α binding. Chromatin bound HP1α was lower in JAK2V617F ES cells but increased following JAK2 inhibition, coincident with a global reduction in H3Y41ph. JAK2 inhibition reduced Nanog, with a reduction in H3Y41ph and concomitant increase in HP1α at the Nanog promoter. Furthermore, Nanog was required for factor-independence of JAK2V617F ES cells. Taken together, these results uncover a previously unrecognised role for direct signalling to chromatin by JAK2 as an important mediator of ES cell self-renewal. PMID:21151131

  14. Structure and Function of the DUF2233 Domain in Bacteria and in the Human Mannose 6-Phosphate Uncovering Enzyme*

    PubMed Central

    Das, Debanu; Lee, Wang-Sik; Grant, Joanna C.; Chiu, Hsiu-Ju; Farr, Carol L.; Vance, Julie; Klock, Heath E.; Knuth, Mark W.; Miller, Mitchell D.; Elsliger, Marc-André; Deacon, Ashley M.; Godzik, Adam; Lesley, Scott A.; Kornfeld, Stuart; Wilson, Ian A.

    2013-01-01

    DUF2233, a domain of unknown function (DUF), is present in many bacterial and several viral proteins and was also identified in the mammalian transmembrane glycoprotein N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (“uncovering enzyme” (UCE)). We report the crystal structure of BACOVA_00430, a 315-residue protein from the human gut bacterium Bacteroides ovatus that is the first structural representative of the DUF2233 protein family. A notable feature of this structure is the presence of a surface cavity that is populated by residues that are highly conserved across the entire family. The crystal structure was used to model the luminal portion of human UCE (hUCE), which is involved in targeting of lysosomal enzymes. Mutational analysis of several residues in a highly conserved surface cavity of hUCE revealed that they are essential for function. The bacterial enzyme (BACOVA_00430) has ∼1% of the catalytic activity of hUCE toward the substrate GlcNAc-P-mannose, the precursor of the Man-6-P lysosomal targeting signal. GlcNAc-1-P is a poor substrate for both enzymes. We conclude that, for at least a subset of proteins in this family, DUF2233 functions as a phosphodiester glycosidase. PMID:23572527

  15. Structure and function of the DUF2233 domain in bacteria and in the human mannose 6-phosphate uncovering enzyme.

    PubMed

    Das, Debanu; Lee, Wang-Sik; Grant, Joanna C; Chiu, Hsiu-Ju; Farr, Carol L; Vance, Julie; Klock, Heath E; Knuth, Mark W; Miller, Mitchell D; Elsliger, Marc-André; Deacon, Ashley M; Godzik, Adam; Lesley, Scott A; Kornfeld, Stuart; Wilson, Ian A

    2013-06-07

    DUF2233, a domain of unknown function (DUF), is present in many bacterial and several viral proteins and was also identified in the mammalian transmembrane glycoprotein N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase ("uncovering enzyme" (UCE)). We report the crystal structure of BACOVA_00430, a 315-residue protein from the human gut bacterium Bacteroides ovatus that is the first structural representative of the DUF2233 protein family. A notable feature of this structure is the presence of a surface cavity that is populated by residues that are highly conserved across the entire family. The crystal structure was used to model the luminal portion of human UCE (hUCE), which is involved in targeting of lysosomal enzymes. Mutational analysis of several residues in a highly conserved surface cavity of hUCE revealed that they are essential for function. The bacterial enzyme (BACOVA_00430) has ∼1% of the catalytic activity of hUCE toward the substrate GlcNAc-P-mannose, the precursor of the Man-6-P lysosomal targeting signal. GlcNAc-1-P is a poor substrate for both enzymes. We conclude that, for at least a subset of proteins in this family, DUF2233 functions as a phosphodiester glycosidase.

  16. Machine learning classification of cell-specific cardiac enhancers uncovers developmental subnetworks regulating progenitor cell division and cell fate specification.

    PubMed

    Ahmad, Shaad M; Busser, Brian W; Huang, Di; Cozart, Elizabeth J; Michaud, Sébastien; Zhu, Xianmin; Jeffries, Neal; Aboukhalil, Anton; Bulyk, Martha L; Ovcharenko, Ivan; Michelson, Alan M

    2014-02-01

    The Drosophila heart is composed of two distinct cell types, the contractile cardial cells (CCs) and the surrounding non-muscle pericardial cells (PCs), development of which is regulated by a network of conserved signaling molecules and transcription factors (TFs). Here, we used machine learning with array-based chromatin immunoprecipitation (ChIP) data and TF sequence motifs to computationally classify cell type-specific cardiac enhancers. Extensive testing of predicted enhancers at single-cell resolution revealed the added value of ChIP data for modeling cell type-specific activities. Furthermore, clustering the top-scoring classifier sequence features identified novel cardiac and cell type-specific regulatory motifs. For example, we found that the Myb motif learned by the classifier is crucial for CC activity, and the Myb TF acts in concert with two forkhead domain TFs and Polo kinase to regulate cardiac progenitor cell divisions. In addition, differential motif enrichment and cis-trans genetic studies revealed that the Notch signaling pathway TF Suppressor of Hairless [Su(H)] discriminates PC from CC enhancer activities. Collectively, these studies elucidate molecular pathways used in the regulatory decisions for proliferation and differentiation of cardiac progenitor cells, implicate Su(H) in regulating cell fate decisions of these progenitors, and document the utility of enhancer modeling in uncovering developmental regulatory subnetworks.

  17. Their loss is our gain: regressive evolution in vertebrates provides genomic models for uncovering human disease loci.

    PubMed

    Emerling, Christopher A; Widjaja, Andrew D; Nguyen, Nancy N; Springer, Mark S

    2017-08-16

    Throughout Earth's history, evolution's numerous natural 'experiments' have resulted in a diverse range of phenotypes. Though de novo phenotypes receive widespread attention, degeneration of traits inherited from an ancestor is a very common, yet frequently neglected, evolutionary path. The latter phenomenon, known as regressive evolution, often results in vertebrates with phenotypes that mimic inherited disease states in humans. Regressive evolution of anatomical and/or physiological traits is typically accompanied by inactivating mutations underlying these traits, which frequently occur at loci identical to those implicated in human diseases. Here we discuss the potential utility of examining the genomes of vertebrates that have experienced regressive evolution to inform human medical genetics. This approach is low cost and high throughput, giving it the potential to rapidly improve knowledge of disease genetics. We discuss two well-described examples, rod monochromacy (congenital achromatopsia) and amelogenesis imperfecta, to demonstrate the utility of this approach, and then suggest methods to equip non-experts with the ability to corroborate candidate genes and uncover new disease loci. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  18. Transcriptome-wide studies uncover the diversity of modes of mRNA recruitment to eukaryotic ribosomes.

    PubMed

    Shatsky, Ivan N; Dmitriev, Sergey E; Andreev, Dmitri E; Terenin, Ilya M

    2014-01-01

    The conventional paradigm of translation initiation in eukaryotes states that the cap-binding protein complex eIF4F (consisting of eIF4E, eIF4G and eIF4A) plays a central role in the recruitment of capped mRNAs to ribosomes. However, a growing body of evidence indicates that this paradigm should be revised. This review summarizes the data which have been mostly accumulated in a post-genomic era owing to revolutionary techniques of transcriptome-wide analysis. Unexpectedly, these techniques have uncovered remarkable diversity in the recruitment of cellular mRNAs to eukaryotic ribosomes. These data enable a preliminary classification of mRNAs into several groups based on their requirement for particular components of eIF4F. They challenge the widely accepted concept which relates eIF4E-dependence to the extent of secondary structure in the 5' untranslated regions of mRNAs. Moreover, some mRNA species presumably recruit ribosomes to their 5' ends without the involvement of either the 5' m(7)G-cap or eIF4F but instead utilize eIF4G or eIF4G-like auxiliary factors. The long-standing concept of internal ribosome entry site (IRES)-elements in cellular mRNAs is also discussed.

  19. Professional learning opportunities from uncovering cover stories of science and science teaching for a scientist-in-transition

    NASA Astrophysics Data System (ADS)

    Ritchie, Stephen M.; Kidman, Gillian; Vaughan, Tanya

    2007-01-01

    Members of particular communities produce and reproduce cultural practices. This is an important consideration for those teacher educators who need to prepare appropriate learning experiences and programs for scientists, as they attempt to change careers to science teaching. We know little about the transition of career-changing scientists as they encounter different contexts and professional cultures, and how their changing identities might impact on their teaching practices. In this narrative inquiry of the stories told by and shared between career-changing scientists in a teacher-preparation program, we identify cover stories of science and teaching. More importantly, we show how uncovering these stories became opportunities for one of these scientists to learn about what sorts of stories of science she tells or should tell in science classrooms and how these stories might impact on her identities as a scientist-teacher in transition. We highlight self-identified contradictions and treat these as resources for further professional learning. Suggestions for improving the teacher-education experiences of scientist-teachers are made. In particular, teacher educators might consider the merits of creating opportunities for career-changing scientists to share their stories and for these stories to be retold for different audiences.

  20. Uncovering Potential Applications of Cyanobacteria and Algal Metabolites in Biology, Agriculture and Medicine: Current Status and Future Prospects

    PubMed Central

    Singh, Rachana; Parihar, Parul; Singh, Madhulika; Bajguz, Andrzej; Kumar, Jitendra; Singh, Samiksha; Singh, Vijay P.; Prasad, Sheo M.

    2017-01-01

    Cyanobacteria and algae having complex photosynthetic systems can channelize absorbed solar energy into other forms of energy for production of food and metabolites. In addition, they are promising biocatalysts and can be used in the field of “white biotechnology” for enhancing the sustainable production of food, metabolites, and green energy sources such as biodiesel. In this review, an endeavor has been made to uncover the significance of various metabolites like phenolics, phytoene/terpenoids, phytols, sterols, free fatty acids, photoprotective compounds (MAAs, scytonemin, carotenoids, polysaccharides, halogenated compounds, etc.), phytohormones, cyanotoxins, biocides (algaecides, herbicides, and insecticides) etc. Apart from this, the importance of these metabolites as antibiotics, immunosuppressant, anticancer, antiviral, anti-inflammatory agent has also been discussed. Metabolites obtained from cyanobacteria and algae have several biotechnological, industrial, pharmaceutical, and cosmetic uses which have also been discussed in this review along with the emerging technology of their harvesting for enhancing the production of compounds like bioethanol, biofuel etc. at commercial level. In later sections, we have discussed genetically modified organisms and metabolite production from them. We have also briefly discussed the concept of bioprocessing highlighting the functioning of companies engaged in metabolites production as well as their cost effectiveness and challenges that are being addressed by these companies. PMID:28487674

  1. Treg-specific IL-27Rα deletion uncovers a key role for IL-27 in Treg function to control autoimmunity.

    PubMed

    Do, Jeongsu; Kim, Dongkyun; Kim, Sohee; Valentin-Torres, Alice; Dvorina, Nina; Jang, Eunjung; Nagarajavel, Vivekananthan; DeSilva, Tara M; Li, Xiaoxia; Ting, Angela H; Vignali, Dario A A; Stohlman, Stephen A; Baldwin, William M; Min, Booki

    2017-09-19

    Dysregulated Foxp3(+) Treg functions result in uncontrolled immune activation and autoimmunity. Therefore, identifying cellular factors modulating Treg functions is an area of great importance. Here, using Treg-specific Il27ra(-/-) mice, we report that IL-27 signaling in Foxp3(+) Tregs is essential for Tregs to control autoimmune inflammation in the central nervous system (CNS). Following experimental autoimmune encephalomyelitis (EAE) induction, Treg-specific Il27ra(-/-) mice develop more severe EAE. Consistent with the severe disease, the numbers of IFNγ- and IL-17-producing CD4 T cells infiltrating the CNS tissues are greater in these mice. Treg accumulation in the inflamed CNS tissues is not affected by the lack of IL-27 signaling in Tregs, suggesting a functional defect of Il27ra(-/-) Tregs. IL-10 production by conventional CD4 T cells and their CNS accumulation are rather elevated in Treg-specific Il27ra(-/-) mice. Analysis with Treg fate-mapping reporter mice further demonstrates that IL-27 signaling in Tregs may control stability of Foxp3 expression. Finally, systemic administration of recombinant IL-27 in Treg-specific Il27ra(-/-) mice fails to ameliorate the disease even in the presence of IL-27-responsive conventional CD4 T cells. These findings uncover a previously unknown role of IL-27 in regulating Treg function to control autoimmune inflammation.

  2. Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care

    PubMed Central

    Bertocchi, Ilaria; Oberto, Alessandra; Longo, Angela; Mele, Paolo; Sabetta, Marianna; Bartolomucci, Alessandro; Palanza, Paola; Sprengel, Rolf; Eva, Carola

    2011-01-01

    Neuropeptide Y (NPY) plays an important role in stress, anxiety, obesity, and energy homeostasis via activation of NPY-Y1 receptors (Y1Rs) in the brain. However, global knockout of the Npy1r gene has low or no impact on anxiety and body weight. To uncover the role of limbic Y1Rs, we generated conditional knockout mice in which the inactivation of the Npy1r gene was restricted to excitatory neurons of the forebrain, starting from juvenile stages (Npy1rrfb). Npy1rrfb mice exhibited increased anxiety and reduced body weight, less adipose tissue, and lower serum leptin levels. Npy1rrfb mutants also had a hyperactive hypothalamic–pituitary–adrenocortical axis, as indicated by higher peripheral corticosterone and higher density of NPY immunoreactive fibers and corticotropin releasing hormone immunoreactive cell bodies in the paraventricular hypothalamic nucleus. Importantly, through fostering experiments, we determined that differences in phenotype between Npy1rrfb and Npy1r2lox mice became apparent when both genotypes were raised by FVB/J but not by C57BL/6J dams, suggesting that limbic Y1Rs are key targets of maternal care-induced programming of anxiety and energy homeostasis. PMID:22084082

  3. Uncovering temporal transitions and self-organization during slow aging of dense granular media in the absence of shear bands

    NASA Astrophysics Data System (ADS)

    Walker, David M.; Tordesillas, Antoinette; Ren, Jie; Dijksman, Joshua A.; Behringer, Robert P.

    2014-07-01

    We present a method for discovering temporal transitions in the macroscopic response of two granular assemblies of photoelastic disks, subject to prolonged symmetric cyclic pure shear —under uniform deformation. A distance-matrix-based analysis is used in a reconstructed state space formed from the macroscopic stress ratio time series, with the technique of quadrant scans applied to extract transition times from the recurrence plots. Macroscopic measures of pressure and shear stress exhibit limit cycle behavior with respect to the applied cyclic strain. The contact network and the strong force filamentary network, however, show a gradual change across shear cycles. A quantitative characterization of the self-organization process at the mesoscale reveals that the observed transition in system dynamics at the macroscale is consistent with the process of aging. A distinct and consistent pattern of self-organization with respect to the contact topology and the structural stability of force chains is uncovered. The contact topology evolves to a more densely connected and stable truss-laced lattice, embodying force chain columns endowed with higher levels of triangular and rectangular bracing. This results in an increase in the structural stability of force chains, consistent with the prevailing conjecture on the structural mechanism behind the observed increase in shear strength and shear stiffness in an aging sand.

  4. Operationalizing Surface Piercing Profilers

    NASA Astrophysics Data System (ADS)

    Fram, J. P.; Barth, J. A.; Dever, E. P.; Rhoades, B.; Koegler, J. M.

    2016-02-01

    High vertical resolution profiles of surface waters with multi-parameter sensor packages are valuable for understanding coupled physical-biogeochemical ocean processes. Typically, these profilers are only able to be used for short periods of time due to lack of ruggedness, reliability, automation, and battery life. Over the last three years, the Ocean Observatories Initiative has partnered with WET Labs to improve a set of WET Labs Thetis profilers so that OOI can operate six of them year-round in waters up to 100 m in depth. These profiles sample 1-16 Hz while rising 25 cm/s. They include 8 instruments with more than a dozen sensors, and they have room for more. A smart winch on-board these profilers compensates for wave-driven heave, which enables them to surface and telemeter data via Iridium in up to 3 m waves, 10 m/s winds, and 40 cm/s mean water currents. Multiple firmware and electronics upgrades enable these profilers to automatically recover from problems, or at least put themselves in a state that minimizes the chance of loss/damage and allows for remote query & control via acoustic modem from a neighboring surface mooring. These and other improvements enable the system to capture periods of the year such as the beginning of the annual coastal upwelling-dominated period without fear from damage by spring storms. This contribution will show the new features, the overall capabilities, and the limitations of these profilers, and it will show what data are available from them through OOI.

  5. Intercomparison of stratospheric ozone and temperature profiles during the October 2005 Hohenpeissenberg Ozone Profiling Experiment (HOPE)

    NASA Astrophysics Data System (ADS)

    Steinbrecht, W.; McGee, T. J.; Twigg, L. W.; Claude, H.; Schönenborn, F.; Sumnicht, G. K.; Silbert, D.

    2009-01-01

    Thirteen clear nights in October 2005 allowed successful intercomparison of the stationary lidar operated since 1987 by the German Weather Service (DWD) at Hohenpeissenberg (47.8° N, 11.0° E) with the Network for the Detection of Atmospheric Composition Change (NDACC) travelling standard lidar operated by NASA's Goddard Space Flight Center. Both lidars provide ozone profiles in the stratosphere, and temperature profiles in the strato- and mesosphere. Additional ozone profiles came from on-site Brewer/Mast ozonesondes, additional temperature profiles from Vaisala RS92 radiosondes launched at Munich (65 km north-east), and from operational analyses by the US National Centers for Environmental Prediction (NCEP). The intercomparison confirmed a low bias for ozone from the DWD lidar in the 33 to 43 km region, by up to 10%. This bias is caused by the DWD ozone algorithm. It will be removed in a future version. Between 20 and 33 km, agreement between both lidars, and ozonesondes below 30 km, is good with ozone differences less than 3 to 5%. Results are consistent with previous comparisons of the DWD lidar with SAGE, GOMOS and other satellite instruments. The intercomparison did uncover a 290 m upward shift of the DWD lidar data. When this shift is removed, agreement with ozone from the NASA lidar improves below 20 km, with remaining differences usually less than 5%, and not statistically significant. Precision (repeatability) for the lidar ozone data is better than 5% between 20 and 40 km altitude, dropping to 10% near 45 km, and 50% near 50 km. Temperature from the DWD lidar has a 1 to 2 K cold bias from 30 to 65 km against the NASA lidar, and a 2 to 4 K cold bias against radiosondes and NCEP. This is consistent with previous intercomparisons against NCEP or radiosondes. The cold bias against the NASA lidar disappears when the DWD lidar data are corrected for the afore-mentioned 290 m range error, and more appropriate values for the Earth's gravity acceleration are

  6. Effective resist profile control

    NASA Astrophysics Data System (ADS)

    Liu, Chen-Yu; Wang, Chien-Wei; Huang, Chun-Ching; Chang, Ching-Yu; Ku, Yao-Ching

    2014-03-01

    To meet Moore's law, resist resolution improvement has become more and more important. However, it is difficult to improve resist resolution and keep vertical sidewall profile. For example, a high contrast hole resist may cause trench scum, due to very T-top profile. This paper reports several concepts for resist profile tuning without losing performance for lithographic factor , including mask error enhancement factor (MEEF), depth of focus (DOF), and critical dimension uniformity (CDU). To quantitative analysis the resist profile improvement, we define a new factor, Scum fail ratio (F/R%) for new techniques evaluation. The new techniques, including floatable additive, floatable PAG, and new monomer, are discussed. From X-SEM and CD-SEM data, former three concepts could improve resist sidewall profile quantitatively evaluated by Scum fail F/R% and keep lithographic factors. In addition, another key factor, resist residue defect, is also discussed. The high contrast resist with higher receding contact angle (RCA) easily generates more residue defect after development. With the new monomer composition, RCA of Resist E is decreased from 54 to 48 degree after development. Therefore, the residue defect is improved one order.

  7. Estimating Cognitive Profiles Using Profile Analysis via Multidimensional Scaling (PAMS).

    PubMed

    Kim, Se-Kang; Frisby, Craig L; Davison, Mark L

    2004-10-01

    Two of the most popular methods of profile analysis, cluster analysis and modal profile analysis, have limitations. First, neither technique is adequate when the sample size is large. Second, neither method will necessarily provide profile information in terms of both level and pattern. A new method of profile analysis, called Profile Analysis via Multidimensional Scaling (PAMS; Davison, 1996), is introduced to meet the challenge. PAMS extends the use of simple multidimensional scaling methods to identify latent profiles in a multi-test battery. Application of PAMS to profile analysis is described. The PAMS model is then used to identify latent profiles from a subgroup (N = 357) within the sample of the Woodcock-Johnson Psychoeducational Battery-Revised (WJ-R; McGrew, Werder, & Woodcock, 1991; Woodcock & Johnson, 1989), followed by a discussion of procedures for interpreting participants' observed score profiles from the latent PAMS profiles. Finally, advantages and limitations of the PAMS technique are discussed.

  8. Country profile: Hungary

    SciTech Connect

    Not Available

    1991-09-01

    Country Profile: Hungary has been prepared as a background document for use by US Government agencies and US businesses interested in becoming involved with the new democracies of Eastern Europe as they pursue sustainable economic development. The focus of the Profile is on energy and highlights information on Hungary's energy supply, demand, and utilization. It identifies patterns of energy usage in the important economic sectors, especially industry, and provides a preliminary assessment for opportunities to improve efficiencies in energy production, distribution and use by introducing more efficient technologies. The use of more efficient technologies would have the added benefit of reducing the environmental impact which, although is not the focus of the report, is an issue that effects energy choices. The Profile also presents considerable economic information, primarily in the context of how economic restructuring may affect energy supply, demand, and the introduction of more efficient technologies.

  9. Country profile: Hungary

    SciTech Connect

    Not Available

    1991-09-01

    Country Profile: Hungary has been prepared as a background document for use by US Government agencies and US businesses interested in becoming involved with the new democracies of Eastern Europe as they pursue sustainable economic development. The focus of the Profile is on energy and highlights information on Hungary`s energy supply, demand, and utilization. It identifies patterns of energy usage in the important economic sectors, especially industry, and provides a preliminary assessment for opportunities to improve efficiencies in energy production, distribution and use by introducing more efficient technologies. The use of more efficient technologies would have the added benefit of reducing the environmental impact which, although is not the focus of the report, is an issue that effects energy choices. The Profile also presents considerable economic information, primarily in the context of how economic restructuring may affect energy supply, demand, and the introduction of more efficient technologies.

  10. Metabolite profiling in Arabidopsis.

    PubMed

    Fiehn, Oliver

    2006-01-01

    Metabolite profiling is the multiparallel relative quantification of a mixture of compounds or compound classes using chromatography and universal detection technologies (GC-MS, LC-MS). In this respect it is an extension of classical single-target methods from which it can be distinguished by its broader view on profiling major biochemical events. This broader scope of analysis outweighs the disadvantages by making compromises in method development and the reduced accuracy for specific metabolites. This chapter exemplifies the strategies in metabolite profiling of polar compounds by gas chromatography-mass spectrometry (GC-MS). It gives experimental details on the basic steps: harvest, homogenization, extraction, fractionation, concentration, derivatization, data acquisition, raw data processing and result data tranformation.

  11. Practical Differential Profiling

    SciTech Connect

    Schulz, M; De Supinski, B R

    2007-02-04

    Comparing performance profiles from two runs is an essential performance analysis step that users routinely perform. In this work we present eGprof, a tool that facilitates these comparisons through differential profiling inside gprof. We chose this approach, rather than designing a new tool, since gprof is one of the few performance analysis tools accepted and used by a large community of users. eGprof allows users to 'subtract' two performance profiles directly. It also includes callgraph visualization to highlight the differences in graphical form. Along with the design of this tool, we present several case studies that show how eGprof can be used to find and to study the differences of two application executions quickly and hence can aid the user in this most common step in performance analysis. We do this without requiring major changes on the side of the user, the most important factor in guaranteeing the adoption of our tool by code teams.

  12. Detonation Wave Profile

    SciTech Connect

    Menikoff, Ralph

    2015-12-14

    The Zel’dovich-von Neumann-Doering (ZND) profile of a detonation wave is derived. Two basic assumptions are required: i. An equation of state (EOS) for a partly burned explosive; P(V, e, λ). ii. A burn rate for the reaction progress variable; d/dt λ = R(V, e, λ). For a steady planar detonation wave the reactive flow PDEs can be reduced to ODEs. The detonation wave profile can be determined from an ODE plus algebraic equations for points on the partly burned detonation loci with a specified wave speed. Furthermore, for the CJ detonation speed the end of the reaction zone is sonic. A solution to the reactive flow equations can be constructed with a rarefaction wave following the detonation wave profile. This corresponds to an underdriven detonation wave, and the rarefaction is know as a Taylor wave.

  13. Uncovering Earth's virome.

    PubMed

    Paez-Espino, David; Eloe-Fadrosh, Emiley A; Pavlopoulos, Georgios A; Thomas, Alex D; Huntemann, Marcel; Mikhailova, Natalia; Rubin, Edward; Ivanova, Natalia N; Kyrpides, Nikos C

    2016-08-25

    Viruses are the most abundant biological entities on Earth, but challenges in detecting, isolating, and classifying unknown viruses have prevented exhaustive surveys of the global virome. Here we analysed over 5 Tb of metagenomic sequence data from 3,042 geographically diverse samples to assess the global distribution, phylogenetic diversity, and host specificity of viruses. We discovered over 125,000 partial DNA viral genomes, including the largest phage yet identified, and increased the number of known viral genes by 16-fold. Half of the predicted partial viral genomes were clustered into genetically distinct groups, most of which included genes unrelated to those in known viruses. Using CRISPR spacers and transfer RNA matches to link viral groups to microbial host(s), we doubled the number of microbial phyla known to be infected by viruses, and identified viruses that can infect organisms from different phyla. Analysis of viral distribution across diverse ecosystems revealed strong habitat-type specificity for the vast majority of viruses, but also identified some cosmopolitan groups. Our results highlight an extensive global viral diversity and provide detailed insight into viral habitat distribution and host–virus interactions.

  14. Uncovering Discovery Layer Services

    ERIC Educational Resources Information Center

    Kennedy, Sean P.

    2014-01-01

    Today's electronic information landscape is growing exponentially with no signs of slowing. This poses a significant challenge for academic libraries. Librarians must continually learn and adapt to harness this explosion of resources. To fulfill their claim as the leaders in the information field they must be effective in providing access and…

  15. Uncovering Exoplanets using Polarimetry

    NASA Astrophysics Data System (ADS)

    Stam, D. M.

    2012-12-01

    Since the first discovery of a planet around a solar-type star by Mayor & Queloz in 1995, more than 700 of these exoplanets have been detected. Most of these are giant, gaseous planets, but small, presumably solid, exoplanets, that are much harder to detect, have also been found. Among the latter are even some that orbit in their star's habitable zone, where temperatures could be just right to allow liquid water on a planet's surface. Liquid water is generally considered to be essential for the existence of life. Whether liquid water actually exists on a planet depends strongly on the atmosphere's thickness and characteristics, such as the surface pressure and composition. Famous examples in the Solar System are Venus and the Earth, with similar sizes, inner compositions and orbital radii, but wildly different surface conditions. The characterization of the atmospheres of giant, gaseous exoplanets, and of the atmospheres and/or surfaces of small, solid exoplanets will allow a comparison with Solar System planets and it will open up a treasure trove of knowledge about the formation and evolution of planetary atmospheres and surfaces, thanks to the vast range of orbital distances, planet sizes and ages that can be studied. Characterization will also allow studying conditions for life and ultimately the existence of life around other stars. Some information about the upper atmospheric properties has already been derived for a few close-in, hot, giant exoplanets, whose thermal flux can be derived from measurements of the combined flux of the star and the planet. This method has also provided traces of an atmosphere around a large solid planet orbiting red dwarf star GJ1214. Characterization of the atmosphere and/or surface of exoplanets in wide orbits, resembling the cool planets in our Solar System, and in particular of small, solid, Earth-like planets in the habitable zone of Sun-like stars, is virtually impossible with transit observations. Indeed, polarimetry appears to be a strong tool both for the detection and the characterization of such cool exoplanets. Polarimetry helps their detection, because direct starlight is usually unpolarized, while starlight that has been reflected by a planet is usually polarized, especially at the phase angles favorable for observing exoplanets. Polarimetry thus improves the contrast between stars and their planets, and confirms that the detected object is indeed a planet. In my presentation, I will focus on the power of polarimetry for the characterization of exoplanets. This application is known from the derivation of the Venus cloud properties from the planet's polarized phase function by Hansen & Hovenier in 1974. Using numerically simulated flux and polarization phase functions and spectra for both gaseous and solid exoplanets, I will discuss the added value of polarimetry for exoplanet characterization as compared to flux observations, in particular for the retrieval of properties of clouds and hazes. Special attention will be given to the features in polarized phase functions that reveal the existence of liquid water clouds in the atmosphere (rainbows), even in the presence of ice clouds, or liquid water on the surface (glint) of an exoplanet. Using satellite data of the cloud and surface coverage of the Earth, calculated flux and polarization phase functions that should be observable from afar will be presented.

  16. MMS Uncovering of Spacecraft

    NASA Image and Video Library

    2014-10-30

    A technician prepares to remove the protective covering from the lower stack, mini-stack number 1, two of the observatories for NASA's Magnetospheric Multiscale Observatory, or MMS, in Building 1 D high bay at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The MMS upper stack, mini-stack number 2, is scheduled to arrive in about two weeks. MMS is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.

  17. MMS Uncovering of Spacecraft

    NASA Image and Video Library

    2014-10-30

    Technicians prepare to remove the protective covering from the lower stack, mini-stack number 1, two of the observatories for NASA's Magnetospheric Multiscale Observatory, or MMS, in Building 1 D high bay at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The MMS upper stack, mini-stack number 2, is scheduled to arrive in about two weeks. MMS is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.

  18. MMS Uncovering of Spacecraft

    NASA Image and Video Library

    2014-10-30

    Most of the protective covering has been removed from the lower stack, mini-stack number 1, two of the observatories for NASA's Magnetospheric Multiscale Observatory, or MMS, inside Building 1 D high bay at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The MMS upper stack, mini-stack number 2, is scheduled to arrive in about two weeks. MMS is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.

  19. Uncovering Pompeii: Examining Evidence.

    ERIC Educational Resources Information Center

    Yell, Michael M.

    2001-01-01

    Presents a lesson plan on Pompeii (Italy) for middle school students that utilizes a teaching technique called interactive presentation. Describes the technique's five phases: (1) discrepant event inquiry; (2) discussion/presentation; (3) cooperative learning activity; (4) writing for understanding activity; and (5) whole-class discussion and…

  20. Uncovering Pompeii: Examining Evidence.

    ERIC Educational Resources Information Center

    Yell, Michael M.

    2001-01-01

    Presents a lesson plan on Pompeii (Italy) for middle school students that utilizes a teaching technique called interactive presentation. Describes the technique's five phases: (1) discrepant event inquiry; (2) discussion/presentation; (3) cooperative learning activity; (4) writing for understanding activity; and (5) whole-class discussion and…

  1. Charter Schools Uncovered

    ERIC Educational Resources Information Center

    Fowler-Finn, Thomas

    2008-01-01

    In this era of unforgiving accountability and test scores with high-stakes implications, important lessons can be learned from charter school marketing. Scrutiny of the regular public schools has never been more sharp-edged. Charter school proponents are becoming increasingly aggressive in promoting themselves as a viable alternative for…

  2. Ancient Wood Uncovered

    Treesearch

    Daniel C. Dey; Richard Guyette; Michael Stanbaugh

    2003-01-01

    Toppled by an eroding stream bank, a large sycamore, leaves still green, slumps low over the water, nearly blocking the channel. Farther downstream, another fallen tree helps create a pool that shelters a catfish. But this tree has fallen 12,000 years ago!

  3. Uncovering the Movement

    ERIC Educational Resources Information Center

    Scruggs, Afi-Odelia E.

    2010-01-01

    Vickie Malone's students see integration when they gather in her classroom at McComb (Mississippi) High School. Black and white youngsters talk and study with peers they've known since elementary school. She doesn't want them to learn history; she wants them to do history. She accomplishes that goal by prodding, poking and challenging her students…

  4. Uncovering foveal crowding?

    PubMed Central

    Lev, Maria; Yehezkel, Oren; Polat, Uri

    2014-01-01

    Visual crowding, as context modulation, reduce the ability to recognize objects in clutter, sets a fundamental limit on visual perception and object recognition. It's considered that crowding does not exist in the fovea and extensive efforts explored crowding in the periphery revealed various models that consider several aspects of spatial processing. Studies showed that spatial and temporal crowding are correlated, suggesting a tradeoff between spatial and temporal processing of crowding. We hypothesized that limiting stimulus availability should decrease object recognition in clutter. Here we show, for the first time, that robust contour interactions exist in the fovea for much larger target-flanker spacing than reported previously: participants overcome crowded conditions for long presentations times but exhibit contour interaction effects for short presentation times. Thus, by enabling enough processing time in the fovea, contour interactions can be overcome, enabling object recognition. Our results suggest that contemporary models of context modulation should include both time and spatial processing. PMID:24518803

  5. MMS Uncovering of Spacecraft

    NASA Image and Video Library

    2014-10-30

    Technicians begin to remove the protective covering from the lower stack, mini-stack number 1, two of the observatories for NASA's Magnetospheric Multiscale Observatory, or MMS, in Building 1 D high bay at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The MMS upper stack, mini-stack number 2, is scheduled to arrive in about two weeks. MMS is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.

  6. MMS Uncovering of Spacecraft

    NASA Image and Video Library

    2014-10-30

    A technician carefully removes the protective covering from the lower stack, mini-stack number 1, two of the observatories for NASA's Magnetospheric Multiscale Observatory, or MMS, in Building 1 D high bay at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The MMS upper stack, mini-stack number 2, is scheduled to arrive in about two weeks. MMS is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.

  7. MMS Uncovering of Spacecraft

    NASA Image and Video Library

    2014-10-30

    Preparations are underway to remove the protective covering from the lower stack, mini-stack number 1, two of the observatories for NASA's Magnetospheric Multiscale Observatory, or MMS, in Building 1 D high bay at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The MMS upper stack, mini-stack number 2, is scheduled to arrive in about two weeks. MMS is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.

  8. MMS Uncovering of Spacecraft

    NASA Image and Video Library

    2014-10-30

    Technicians have removed most of the protective covering from the lower stack, mini-stack number 1, two of the observatories for NASA's Magnetospheric Multiscale Observatory, or MMS, in Building 1 D high bay at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The MMS upper stack, mini-stack number 2, is scheduled to arrive in about two weeks. MMS is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.

  9. MMS Uncovering of Spacecraft

    NASA Image and Video Library

    2014-10-30

    Technicians remove the protective covering from the lower stack, mini-stack number 1, two of the observatories for NASA's Magnetospheric Multiscale Observatory, or MMS, in Building 1 D high bay at the Astrotech payload processing facility in Titusville, Florida, near Kennedy Space Center. The MMS upper stack, mini-stack number 2, is scheduled to arrive in about two weeks. MMS is a Solar Terrestrial Probes mission comprising four identically instrumented spacecraft that will use Earth’s magnetosphere as a laboratory to study the microphysics of three fundamental plasma processes: magnetic reconnection, energetic particle acceleration and turbulence. Launch aboard a United Launch Alliance Atlas V rocket from Space Launch Complex 41 on Cape Canaveral Air Force Station is targeted for March 12, 2015.

  10. Uncovering the Movement

    ERIC Educational Resources Information Center

    Scruggs, Afi-Odelia E.

    2010-01-01

    Vickie Malone's students see integration when they gather in her classroom at McComb (Mississippi) High School. Black and white youngsters talk and study with peers they've known since elementary school. She doesn't want them to learn history; she wants them to do history. She accomplishes that goal by prodding, poking and challenging her students…

  11. Uncovering Discovery Layer Services

    ERIC Educational Resources Information Center

    Kennedy, Sean P.

    2014-01-01

    Today's electronic information landscape is growing exponentially with no signs of slowing. This poses a significant challenge for academic libraries. Librarians must continually learn and adapt to harness this explosion of resources. To fulfill their claim as the leaders in the information field they must be effective in providing access and…

  12. Temperamental Profiles of Dysregulated Children

    ERIC Educational Resources Information Center

    Althoff, Robert R.; Ayer, Lynsay A.; Crehan, Eileen T.; Rettew, David C.; Baer, Julie R.; Hudziak, James J.

    2012-01-01

    It is crucial to characterize self-regulation in children. We compared the temperamental profiles of children with the Child Behavior Checklist (CBCL) Dysregulation Profile (CBCL-DP) to profiles associated with other CBCL-derived syndromes. 382 children (204 boys; aged 5-18) from a large family study were examined. Temperamental profiles were…

  13. South Carolina Education Profiles 1993.

    ERIC Educational Resources Information Center

    South Carolina State Dept. of Education, Columbia.

    This report provides statistical profiles of South Carolina's 91 school districts in the context of the counties in which they are located. Profiles of each county give information on features such as population, family characteristics, income levels, and the industrial base. Each county profile is followed by a profile of each school district.…

  14. Temperamental Profiles of Dysregulated Children

    ERIC Educational Resources Information Center

    Althoff, Robert R.; Ayer, Lynsay A.; Crehan, Eileen T.; Rettew, David C.; Baer, Julie R.; Hudziak, James J.

    2012-01-01

    It is crucial to characterize self-regulation in children. We compared the temperamental profiles of children with the Child Behavior Checklist (CBCL) Dysregulation Profile (CBCL-DP) to profiles associated with other CBCL-derived syndromes. 382 children (204 boys; aged 5-18) from a large family study were examined. Temperamental profiles were…

  15. Generation of geographical profile

    NASA Astrophysics Data System (ADS)

    Shen, Zhi-Bin; Zhang, Yuan-Biao; Liang, Kai-Fa; Lu, Zhen-Xing

    2010-08-01

    To provide help for the police's investigation on serial criminals, we develop a mathematical model in the paper. First, we use Inherently Continuous Model and Improved Kinetic Model to generate the offender's geographical profile. However, there is a difference in two models' results. For better synthesizing the difference, we develop a Combination Model and generate a new geographical profile. As a result, we estimate the offender's location and carry on a series of analysis. What's more, the models created can be applied in other fields, such as market's investigation, military operations and so on.

  16. Uncovering ultrastructural defences in Daphnia magna--an interdisciplinary approach to assess the predator-induced fortification of the carapace.

    PubMed

    Rabus, Max; Söllradl, Thomas; Clausen-Schaumann, Hauke; Laforsch, Christian

    2013-01-01

    The development of structural defences, such as the fortification of shells or exoskeletons, is a widespread strategy to reduce predator attack efficiency. In unpredictable environments these defences may be more pronounced in the presence of a predator. The cladoceran Daphnia magna (Crustacea: Branchiopoda: Cladocera) has been shown to develop a bulky morphotype as an effective inducible morphological defence against the predatory tadpole shrimp Triops cancriformis (Crustacea: Branchiopoda: Notostraca). Mediated by kairomones, the daphnids express an increased body length, width and an elongated tail spine. Here we examined whether these large scale morphological defences are accompanied by additional ultrastructural defences, i.e. a fortification of the exoskeleton. We employed atomic force microscopy (AFM) based nanoindentation experiments to assess the cuticle hardness along with tapping mode AFM imaging to visualise the surface morphology for predator exposed and non-predator exposed daphnids. We used semi-thin sections of the carapace to measure the cuticle thickness, and finally, we used fluorescence microscopy to analyse the diameter of the pillars connecting the two carapace layers. We found that D. magna indeed expresses ultrastructural defences against Triops predation. The cuticle in predator exposed individuals is approximately five times harder and two times thicker than in control daphnids. Moreover, the pillar diameter is significantly increased in predator exposed daphnids. These predator-cue induced changes in the carapace architecture should provide effective protection against being crushed by the predator's mouthparts and may add to the protective effect of bulkiness. This study highlights the potential of interdisciplinary studies to uncover new and relevant aspects even in extensively studied fields of research.

  17. Study of Mathematically Precocious Youth After 35 Years: Uncovering Antecedents for the Development of Math-Science Expertise.

    PubMed

    Lubinski, David; Benbow, Camilla Persson

    2006-12-01

    This review provides an account of the Study of Mathematically Precocious Youth (SMPY) after 35 years of longitudinal research. Findings from recent 20-year follow-ups from three cohorts, plus 5- or 10-year findings from all five SMPY cohorts (totaling more than 5,000 participants), are presented. SMPY has devoted particular attention to uncovering personal antecedents necessary for the development of exceptional math-science careers and to developing educational interventions to facilitate learning among intellectually precocious youth. Along with mathematical gifts, high levels of spatial ability, investigative interests, and theoretical values form a particularly promising aptitude complex indicative of potential for developing scientific expertise and of sustained commitment to scientific pursuits. Special educational opportunities, however, can markedly enhance the development of talent. Moreover, extraordinary scientific accomplishments require extraordinary commitment both in and outside of school. The theory of work adjustment (TWA) is useful in conceptualizing talent identification and development and bridging interconnections among educational, counseling, and industrial psychology. The lens of TWA can clarify how some sex differences emerge in educational settings and the world of work. For example, in the SMPY cohorts, although more mathematically precocious males than females entered math-science careers, this does not necessarily imply a loss of talent because the women secured similar proportions of advanced degrees and high-level careers in areas more correspondent with the multidimensionality of their ability-preference pattern (e.g., administration, law, medicine, and the social sciences). By their mid-30s, the men and women appeared to be happy with their life choices and viewed themselves as equally successful (and objective measures support these subjective impressions). Given the ever-increasing importance of quantitative and scientific

  18. Proteomics and transcriptomics analyses of Arabidopsis floral buds uncover important functions of ARABIDOPSIS SKP1-LIKE1

    DOE PAGES

    Lu, Dihong; Ni, Weimin; Stanley, Bruce A.; ...

    2016-03-03

    The ARABIDOPSIS SKP1-LIKE1 (ASK1) protein functions as a subunit of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases. Previous genetic studies showed that ASK1 plays important roles in Arabidopsis flower development and male meiosis. However, the molecular impact of ASK1-containing SCF E3 ubiquitin ligases (ASK1-E3s) on the floral proteome and transcriptome is unknown. Here we identified proteins that are potentially regulated by ASK1-E3s by comparing floral bud proteomes of wild-type and the ask1 mutant plants. More than 200 proteins were detected in the ask1 mutant but not in wild-type and >300 were detected at higher levels in the ask1 mutant than in wild-type,more » but their RNA levels were not significantly different between wild-type and ask1 floral buds as shown by transcriptomics analysis, suggesting that they are likely regulated at the protein level by ASK1-E3s. Integrated analyses of floral proteomics and transcriptomics of ask1 and wild-type uncovered several potential aspects of ASK1-E3 functions, including regulation of transcription regulators, kinases, peptidases, and ribosomal proteins, with implications on possible mechanisms of ASK1-E3 functions in floral development. In conclusion, our results suggested that ASK1-E3s play important roles in Arabidopsis protein degradation during flower development. This study opens up new possibilities for further functional studies of these candidate E3 substrates.« less

  19. High genetic diversity and fine-scale spatial structure in the marine flagellate Oxyrrhis marina (Dinophyceae) uncovered by microsatellite loci.

    PubMed

    Lowe, Chris D; Montagnes, David J S; Martin, Laura E; Watts, Phillip C

    2010-12-23

    Free-living marine protists are often assumed to be broadly distributed and genetically homogeneous on large spatial scales. However, an increasing application of highly polymorphic genetic markers (e.g., microsatellites) has provided evidence for high genetic diversity and population structuring on small spatial scales in many free-living protists. Here we characterise a panel of new microsatellite markers for the common marine flagellate Oxyrrhis marina. Nine microsatellite loci were used to assess genotypic diversity at two spatial scales by genotyping 200 isolates of O. marina from 6 broad geographic regions around Great Britain and Ireland; in one region, a single 2 km shore line was sampled intensively to assess fine-scale genetic diversity. Microsatellite loci resolved between 1-6 and 7-23 distinct alleles per region in the least and most variable loci respectively, with corresponding variation in expected heterozygosities (H(e)) of 0.00-0.30 and 0.81-0.93. Across the dataset, genotypic diversity was high with 183 genotypes detected from 200 isolates. Bayesian analysis of population structure supported two model populations. One population was distributed across all sampled regions; the other was confined to the intensively sampled shore, and thus two distinct populations co-occurred at this site. Whilst model-based analysis inferred a single UK-wide population, pairwise regional F(ST) values indicated weak to moderate population sub-division (0.01-0.12), but no clear correlation between spatial and genetic distance was evident. Data presented in this study highlight extensive genetic diversity for O. marina; however, it remains a substantial challenge to uncover the mechanisms that drive genetic diversity in free-living microorganisms.

  20. AMPKα2 deficiency uncovers time dependency in the regulation of contraction-induced palmitate and glucose uptake in mouse muscle.

    PubMed

    Abbott, Marcia J; Bogachus, Lindsey D; Turcotte, Lorraine P

    2011-07-01

    AMP-activated protein kinase (AMPK) is a fuel sensor in skeletal muscle with multiple downstream signaling targets that may be triggered by increases in intracellular Ca(2+) concentration ([Ca(2+)]). The purpose of this study was to determine whether increases in intracellular [Ca(2+)] induced by caffeine act solely via AMPKα(2) and whether AMPKα(2) is essential to increase glucose uptake, fatty acid (FA) uptake, and FA oxidation in contracting skeletal muscle. Hindlimbs from wild-type (WT) or AMPKα(2) dominant-negative (DN) transgene mice were perfused during rest (n = 11), treatment with 3 mM caffeine (n = 10), or muscle contraction (n = 11). Time-dependent effects on glucose and FA uptake were uncovered throughout the 20-min muscle contraction perfusion period (P < 0.05). Glucose uptake rates did not increase in DN mice during muscle contraction until the last 5 min of the protocol (P < 0.05). FA uptake rates were elevated at the onset of muscle contraction and diminished by the end of the protocol in DN mice (P < 0.05). FA oxidation rates were abolished in the DN mice during muscle contraction (P < 0.05). The DN transgene had no effect on caffeine-induced FA uptake and oxidation (P > 0.05). Glucose uptake rates were blunted in caffeine-treated DN mice (P < 0.05). The DN transgene resulted in a greater use of intramuscular triglycerides as a fuel source during muscle contraction. The DN transgene did not alter caffeine- or contraction-mediated changes in the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase I or ERK1/2 (P > 0.05). These data suggest that AMPKα(2) is involved in the regulation of substrate uptake in a time-dependent manner in contracting muscle but is not necessary for regulation of FA uptake and oxidation during caffeine treatment.

  1. A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.

    PubMed

    Cloutier, Philippe; Lavallée-Adam, Mathieu; Faubert, Denis; Blanchette, Mathieu; Coulombe, Benoit

    2013-01-01

    Methylation is a post-translational modification that can affect numerous features of proteins, notably cellular localization, turnover, activity, and molecular interactions. Recent genome-wide analyses have considerably extended the list of human genes encoding putative methyltransferases. Studies on protein methyltransferases have revealed that the regulatory function of methylation is not limited to epigenetics, with many non-histone substrates now being discovered. We present here our findings on a novel family of distantly related putative methyltransferases. Affinity purification coupled to mass spectrometry shows a marked preference for these proteins to associate with various chaperones. Based on the spectral data, we were able to identify methylation sites in substrates, notably trimethylation of K135 of KIN/Kin17, K561 of HSPA8/Hsc70 as well as corresponding lysine residues in other Hsp70 isoforms, and K315 of VCP/p97. All modification sites were subsequently confirmed in vitro. In the case of VCP, methylation by METTL21D was stimulated by the addition of the UBX cofactor ASPSCR1, which we show directly interacts with the methyltransferase. This stimulatory effect was lost when we used VCP mutants (R155H, R159G, and R191Q) known to cause Inclusion Body Myopathy with Paget's disease of bone and Fronto-temporal Dementia (IBMPFD) and/or familial Amyotrophic Lateral Sclerosis (ALS). Lysine 315 falls in proximity to the Walker B motif of VCP's first ATPase/D1 domain. Our results indicate that methylation of this site negatively impacts its ATPase activity. Overall, this report uncovers a new role for protein methylation as a regulatory pathway for molecular chaperones and defines a novel regulatory mechanism for the chaperone VCP, whose deregulation is causative of degenerative neuromuscular diseases.

  2. Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis.

    PubMed

    Cinghu, Senthilkumar; Yellaboina, Sailu; Freudenberg, Johannes M; Ghosh, Swati; Zheng, Xiaofeng; Oldfield, Andrew J; Lackford, Brad L; Zaykin, Dmitri V; Hu, Guang; Jothi, Raja

    2014-04-22

    Identification of genes associated with specific biological phenotypes is a fundamental step toward understanding the molecular basis underlying development and pathogenesis. Although RNAi-based high-throughput screens are routinely used for this task, false discovery and sensitivity remain a challenge. Here we describe a computational framework for systematic integration of published gene expression data to identify genes defining a phenotype of interest. We applied our approach to rank-order all genes based on their likelihood of determining ES cell (ESC) identity. RNAi-mediated loss-of-function experiments on top-ranked genes unearthed many novel determinants of ESC identity, thus validating the derived gene ranks to serve as a rich and valuable resource for those working to uncover novel ESC regulators. Underscoring the value of our gene ranks, functional studies of our top-hit Nucleolin (Ncl), abundant in stem and cancer cells, revealed Ncl's essential role in the maintenance of ESC homeostasis by shielding against differentiation-inducing redox imbalance-induced oxidative stress. Notably, we report a conceptually novel mechanism involving a Nucleolin-dependent Nanog-p53 bistable switch regulating the homeostatic balance between self-renewal and differentiation in ESCs. Our findings connect the dots on a previously unknown regulatory circuitry involving genes associated with traits in both ESCs and cancer and might have profound implications for understanding cell fate decisions in cancer stem cells. The proposed computational framework, by helping to prioritize and preselect candidate genes for tests using complex and expensive genetic screens, provides a powerful yet inexpensive means for identification of key cell identity genes.

  3. Human iPS Cell-Derived Neurons Uncover the Impact of Increased Ras Signaling in Costello Syndrome

    PubMed Central

    Rooney, Gemma E.; Goodwin, Alice F.; Depeille, Philippe; Sharir, Amnon; Schofield, Claude M.; Yeh, Erika; Roose, Jeroen P.; Klein, Ophir D.; Rauen, Katherine A.; Weiss, Lauren A.

    2016-01-01

    Increasing evidence implicates abnormal Ras signaling as a major contributor in neurodevelopmental disorders, yet how such signaling causes cortical pathogenesis is unknown. We examined the consequences of aberrant Ras signaling in the developing mouse brain and uncovered several critical phenotypes, including increased production of cortical neurons and morphological deficits. To determine whether these phenotypes are recapitulated in humans, we generated induced pluripotent stem (iPS) cell lines from patients with Costello syndrome (CS), a developmental disorder caused by abnormal Ras signaling and characterized by neurodevelopmental abnormalities, such as cognitive impairment and autism. Directed differentiation toward a neuroectodermal fate revealed an extended progenitor phase and subsequent increased production of cortical neurons. Morphological analysis of mature neurons revealed significantly altered neurite length and soma size in CS patients. This study demonstrates the synergy between mouse and human models and validates the use of iPS cells as a platform to study the underlying cellular pathologies resulting from signaling deficits. SIGNIFICANCE STATEMENT Increasing evidence implicates Ras signaling dysfunction as a major contributor in psychiatric and neurodevelopmental disorders, such as cognitive impairment and autism, but the underlying cortical cellular pathogenesis remains unclear. This study is the first to reveal human neuronal pathogenesis resulting from abnormal Ras signaling and provides insights into how these phenotypic abnormalities likely contribute to neurodevelopmental disorders. We also demonstrate the synergy between mouse and human models, thereby validating the use of iPS cells as a platform to study underlying cellular pathologies resulting from signaling deficits. Recapitulating human cellular pathologies in vitro facilitates the future high throughput screening of potential therapeutic agents that may reverse phenotypic and

  4. Percutaneous Palliation of Pancreatic Head Cancer: Randomized Comparison of ePTFE/FEP-Covered Versus Uncovered Nitinol Biliary Stents

    SciTech Connect

    Krokidis, Miltiadis; Fanelli, Fabrizio; Orgera, Gianluigi; Tsetis, Dimitrios; Mouzas, Ioannis; Bezzi, Mario; Kouroumalis, Elias; Pasariello, Roberto; Hatzidakis, Adam

    2011-04-15

    The purpose of this study was to compare the clinical effectiveness of expanded polytetrafluoroethylene/fluorinated-ethylene-propylene (ePTFE/FEP)-covered stents with that of uncovered nitinol stents for the palliation of malignant jaundice caused by inoperable pancreatic head cancer. Eighty patients were enrolled in a prospective randomized study. Bare nitinol stents were used in half of the patients, and ePTFE/FEP-covered stents were used in the remaining patients. Patency, survival, complications, and mean cost were calculated in both groups. Mean patency was 166.0 {+-} 13.11 days for the bare-stent group and 234.0 {+-} 20.87 days for the covered-stent group (p = 0.007). Primary patency rates at 3, 6, and 12 months were 77.5, 69.8, and 69.8% for the bare-stent group and 97.5, 92.2, and 87.6% for the covered-stent group, respectively. Mean secondary patency was 123.7 {+-} 22.5 days for the bare-stent group and 130.3 {+-} 21.4 days for the covered-stent group. Tumour ingrowth occurred exclusively in the bare-stent group in 27.5% of cases (p = 0.002). Median survival was 203.2 {+-} 11.8 days for the bare-stent group and 247.0 {+-} 20 days for the covered-stent group (p = 0.06). Complications and mean cost were similar in both groups. Regarding primary patency and ingrowth rate, ePTFE/FEP-covered stents have shown to be significantly superior to bare nitinol stents for the palliation of malignant jaundice caused by inoperable pancreatic head cancer and pose comparable cost and complications. Use of a covered stent does not significantly influence overall survival rate; nevertheless, the covered endoprosthesis seems to offer result in fewer reinterventions and better quality of patient life.

  5. Upregulation of glycans containing 3' fucose in a subset of pancreatic cancers uncovered using fusion-tagged lectins.

    PubMed

    Singh, Sudhir; Pal, Kuntal; Yadav, Jessica; Tang, Huiyuan; Partyka, Katie; Kletter, Doron; Hsueh, Peter; Ensink, Elliot; Kc, Birendra; Hostetter, Galen; Xu, H Eric; Bern, Marshall; Smith, David F; Mehta, Anand S; Brand, Randall; Melcher, Karsten; Haab, Brian B

    2015-06-05

    The fucose post-translational modification is frequently increased in pancreatic cancer, thus forming the basis for promising biomarkers, but a subset of pancreatic cancer patients does not elevate the known fucose-containing biomarkers. We hypothesized that such patients elevate glycan motifs with fucose in linkages and contexts different from the known fucose-containing biomarkers. We used a database of glycan array data to identify the lectins CCL2 to detect glycan motifs with fucose in a 3' linkage; CGL2 for motifs with fucose in a 2' linkage; and RSL for fucose in all linkages. We used several practical methods to test the lectins and determine the optimal mode of detection, and we then tested whether the lectins detected glycans in pancreatic cancer patients who did not elevate the sialyl-Lewis A glycan, which is upregulated in ∼75% of pancreatic adenocarcinomas. Patients who did not upregulate sialyl-Lewis A, which contains fucose in a 4' linkage, tended to upregulate fucose in a 3' linkage, as detected by CCL2, but they did not upregulate total fucose or fucose in a 2' linkage. CCL2 binding was high in cancerous epithelia from pancreatic tumors, including areas negative for sialyl-Lewis A and a related motif containing 3' fucose, sialyl-Lewis X. Thus, glycans containing 3' fucose may complement sialyl-Lewis A to contribute to improved detection of pancreatic cancer. Furthermore, the use of panels of recombinant lectins may uncover details about glycosylation that could be important for characterizing and detecting cancer.

  6. High Genetic Diversity and Fine-Scale Spatial Structure in the Marine Flagellate Oxyrrhis marina (Dinophyceae) Uncovered by Microsatellite Loci

    PubMed Central

    Lowe, Chris D.; Montagnes, David J. S.; Martin, Laura E.; Watts, Phillip C.

    2010-01-01

    Free-living marine protists are often assumed to be broadly distributed and genetically homogeneous on large spatial scales. However, an increasing application of highly polymorphic genetic markers (e.g., microsatellites) has provided evidence for high genetic diversity and population structuring on small spatial scales in many free-living protists. Here we characterise a panel of new microsatellite markers for the common marine flagellate Oxyrrhis marina. Nine microsatellite loci were used to assess genotypic diversity at two spatial scales by genotyping 200 isolates of O. marina from 6 broad geographic regions around Great Britain and Ireland; in one region, a single 2 km shore line was sampled intensively to assess fine-scale genetic diversity. Microsatellite loci resolved between 1–6 and 7–23 distinct alleles per region in the least and most variable loci respectively, with corresponding variation in expected heterozygosities (He) of 0.00–0.30 and 0.81–0.93. Across the dataset, genotypic diversity was high with 183 genotypes detected from 200 isolates. Bayesian analysis of population structure supported two model populations. One population was distributed across all sampled regions; the other was confined to the intensively sampled shore, and thus two distinct populations co-occurred at this site. Whilst model-based analysis inferred a single UK-wide population, pairwise regional FST values indicated weak to moderate population sub-division (0.01–0.12), but no clear correlation between spatial and genetic distance was evident. Data presented in this study highlight extensive genetic diversity for O. marina; however, it remains a substantial challenge to uncover the mechanisms that drive genetic diversity in free-living microorganisms. PMID:21203414

  7. Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening.

    PubMed

    Zhang, Xiaoxiao; Beebe, Tyler; Jen, Nelon; Lee, Chia-An; Tai, Yuchong; Hsiai, Tzung K

    2015-09-15

    Flexible electronics are the next generation of sensors for mobile health and implantation. Zebrafish (Danio rerio) is an emergent strategy for pre-clinical drug development and toxicity testing. To address the confounding effects from sedation of fish and removal from the aquatic habitat for micro-electrocardiogram (µECG) measurements, we developed waterproof and wearable sensors to uncover the circadian variation in heart rate (HR) and heart rate variability (HRV) (Massin et al., 2000). The parylene-C based ECG sensor consisted of an ultra-soft silicone integrated jacket designed to wrap around the fish during swimming. The Young's modulus of this silicone jacket matched with the fish surface, and an extended parylene cable connected the underwater chest electrodes with the out-of water electronics. In addition, embedded micro-glass spheres in the silicone effectively reduced the effective density of the jacket to ~1 g cm(-3). These innovations enabled physiological ECG telemetry in the fish's natural habitat without the need for sedation. Furthermore, a set of non-linear signal processing techniques filtered out the breathing and electromagnetic artifacts from the recorded signals. We observed a reduction in mean HR and an increase in HRV over 24h at 10 dpa, accompanied by QT prolongation as well as diurnal variations, followed by normalization in mean HR and QT intervals at 26 days post ventricular amputation (dpa). We revealed Amiodarone-mediated QTc prolongation, HR reduction and HRV increase otherwise masked by sedation. The novel features of the flexible silicon jacket for µECG telemetry unraveled the biological clock and normalization of QT intervals at 26 dpa, providing the first evidence of new physiological phenomena during cardiac injury and repair as well as cardiac drug-mediated aberrant rhythms. Thus, the light weight and waterproof design holds promise to advance the next generation of mobile health and drug discovery. Published by Elsevier B.V.

  8. Flexible and Waterproof Micro-Sensors to Uncover Zebrafish Circadian Rhythms: The Next Generation of Cardiac Monitoring for Drug Screening

    PubMed Central

    Lee, Chia-An; Tai, Yuchong; Hsiai, Tzung K.

    2015-01-01

    Flexible electronics are the next generation of sensors for mobile health and implantation. Zebrafish (Danio rerio) is an emergent strategy for pre-clinical drug development and toxicity testing. To address the confounding effects from sedation of fish and removal from the aquatic habitat for micro-electrocardiogram (μECG) measurements, we developed waterproof and wearable sensors to uncover the circadian variation in heart rate (HR) and heart rate variability (HRV)[1]. The parylene-C based ECG sensor consisted of an ultra-soft silicone integrated jacket designed to wrap around the fish during swimming. The Young’s modulus of this silicone jacket matched with the fish surface, and an extended parylene cable connected the underwater chest electrodes with the out-of water electronics. In addition, embedded micro-glass spheres in the silicone effectively reduced the effective density of the jacket to ~ 1 g·cm−3. These innovations enabled physiological ECG telemetry in the fish’s natural habitat without the need for sedation. Furthermore, a set of non-linear signal processing techniques filtered out the breathing and electromagnetic artifacts from the recorded signals. We observed a reduction in mean HR and an increase in HRV over 24 hours at 10 dpa, accompanied by QT prolongation as well as diurnal variations, followed by normalization in mean HR and QT intervals at 26 days post ventricular amputation (dpa). We revealed Amiodarone-mediated QTc prolongation, HR reduction and HRV increase otherwise masked by sedation. The novel features of the flexible silicon jacket for μECG telemetry unraveled the biological clock and normalization of QT intervals at 26 dpa, providing the first evidence of new physiological phenomena during cardiac injury and repair as well as cardiac drug-mediated aberrant rhythms. Thus, the light weight and waterproof design holds promise to advance the next generation of mobile health and drug discovery. PMID:25909335

  9. QTL Mapping in Three Rice Populations Uncovers Major Genomic Regions Associated with African Rice Gall Midge Resistance.

    PubMed

    Yao, Nasser; Lee, Cheng-Ruei; Semagn, Kassa; Sow, Mounirou; Nwilene, Francis; Kolade, Olufisayo; Bocco, Roland; Oyetunji, Olumoye; Mitchell-Olds, Thomas; Ndjiondjop, Marie-Noëlle

    2016-01-01

    African rice gall midge (AfRGM) is one of the most destructive pests of irrigated and lowland African ecologies. This study aimed to identify the quantitative trait loci (QTL) associated with AfRGM pest incidence and resistance in three independent bi-parental rice populations (ITA306xBW348-1, ITA306xTOG7106 and ITA306xTOS14519), and to conduct meta QTL (mQTL) analysis to explore whether any genomic regions are conserved across different genetic backgrounds. Composite interval mapping (CIM) conducted on the three populations independently uncovered a total of 28 QTLs associated with pest incidence (12) and pest severity (16). The number of QTLs per population associated with AfRGM resistance varied from three in the ITA306xBW348-1 population to eight in the ITA306xTOG7106 population. Each QTL individually explained 1.3 to 34.1% of the phenotypic variance. The major genomic region for AfRGM resistance had a LOD score and R2 of 60.0 and 34.1% respectively, and mapped at 111 cM on chromosome 4 (qAfrGM4) in the ITA306xTOS14519 population. The meta-analysis reduced the number of QTLs from 28 to 17 mQTLs, each explaining 1.3 to 24.5% of phenotypic variance, and narrowed the confidence intervals by 2.2 cM. There was only one minor effect mQTL on chromosome 1 that was common in the TOS14519 and TOG7106 genetic backgrounds; all other mQTLs were background specific. We are currently fine-mapping and validating the major effect genomic region on chromosome 4 (qAfRGM4). This is the first report in mapping the genomic regions associated with the AfRGM resistance, and will be highly useful for rice breeders.

  10. PathEdEx - Uncovering High-explanatory Visual Diagnostics Heuristics Using Digital Pathology and Multiscale Gaze Data.

    PubMed

    Shin, Dmitriy; Kovalenko, Mikhail; Ersoy, Ilker; Li, Yu; Doll, Donald; Shyu, Chi-Ren; Hammer, Richard

    2017-01-01

    Visual heuristics of pathology diagnosis is a largely unexplored area where reported studies only provided a qualitative insight into the subject. Uncovering and quantifying pathology visual and nonvisual diagnostic patterns have great potential to improve clinical outcomes and avoid diagnostic pitfalls. Here, we present PathEdEx, an informatics computational framework that incorporates whole-slide digital pathology imaging with multiscale gaze-tracking technology to create web-based interactive pathology educational atlases and to datamine visual and nonvisual diagnostic heuristics. We demonstrate the capabilities of PathEdEx for mining visual and nonvisual diagnostic heuristics using the first PathEdEx volume of a hematopathology atlas. We conducted a quantitative study on the time dynamics of zooming and panning operations utilized by experts and novices to come to the correct diagnosis. We then performed association rule mining to determine sets of diagnostic factors that consistently result in a correct diagnosis, and studied differences in diagnostic strategies across different levels of pathology expertise using Markov chain (MC) modeling and MC Monte Carlo simulations. To perform these studies, we translated raw gaze points to high-explanatory semantic labels that represent pathology diagnostic clues. Therefore, the outcome of these studies is readily transformed into narrative descriptors for direct use in pathology education and practice. PathEdEx framework can be used to capture best practices of pathology visual and nonvisual diagnostic heuristics that can be passed over to the next generation of pathologists and have potential to streamline implementation of precision diagnostics in precision medicine settings.

  11. Uncovering the Mechanism of Forkhead-Associated Domain-Mediated TIFA Oligomerization That Plays a Central Role in Immune Responses.

    PubMed

    Weng, Jui-Hung; Hsieh, Yin-Cheng; Huang, Chia-Chi Flora; Wei, Tong-You Wade; Lim, Liang-Hin; Chen, Yu-Hou; Ho, Meng-Ru; Wang, Iren; Huang, Kai-Fa; Chen, Chun-Jung; Tsai, Ming-Daw

    2015-10-13

    Forkhead-associated (FHA) domain is the only signaling domain that recognizes phosphothreonine (pThr) specifically. TRAF-interacting protein with an FHA domain (TIFA) was shown to be involved in immune responses by binding with TRAF2 and TRAF6. We recently reported that TIFA is a dimer in solution and that, upon stimulation by TNF-α, TIFA is phosphorylated at Thr9, which triggers TIFA oligomerization via pThr9-FHA domain binding and activates nuclear factor κB (NF-κB). However, the structural mechanism for the functionally important TIFA oligomerization remains to be established. While FHA domain-pThr binding is known to mediate protein dimerization, its role in oligomerization has not been demonstrated at the structural level. Here we report the crystal structures of TIFA (residues 1-150, with the unstructured C-terminal tail truncated) and its complex with the N-terminal pThr9 peptide (residues 1-15), which show unique features in the FHA structure (intrinsic dimer and extra β-strand) and in its interaction with the pThr peptide (with residues preceding rather than following pThr). These structural features support previous and additional functional analyses. Furthermore, the structure of the complex suggests that the pThr9-FHA domain interaction can occur only between different sets of dimers rather than between the two protomers within a dimer, providing the structural mechanism for TIFA oligomerization. Our results uncover the mechanism of FHA domain-mediated oligomerization in a key step of immune responses and expand the paradigm of FHA domain structure and function.

  12. Using a system of differential equations that models cattle growth to uncover the genetic basis of complex traits.

    PubMed

    Freua, Mateus Castelani; Santana, Miguel Henrique de Almeida; Ventura, Ricardo Vieira; Tedeschi, Luis Orlindo; Ferraz, José Bento Sterman

    2017-08-01

    The interplay between dynamic models of biological systems and genomics is based on the assumption that genetic variation of the complex trait (i.e., outcome of model behavior) arises from component traits (i.e., model parameters) in lower hierarchical levels. In order to provide a proof of concept of this statement for a cattle growth model, we ask whether model parameters map genomic regions that harbor quantitative trait loci (QTLs) already described for the complex trait. We conducted a genome-wide association study (GWAS) with a Bayesian hierarchical LASSO method in two parameters of the Davis Growth Model, a system of three ordinary differential equations describing DNA accretion, protein synthesis and degradation, and fat synthesis. Phenotypic and genotypic data were available for 893 Nellore (Bos indicus) cattle. Computed values for parameter k1 (DNA accretion rate) ranged from 0.005 ± 0.003 and for α (constant for energy for maintenance requirement) 0.134 ± 0.024. The expected biological interpretation of the parameters is confirmed by QTLs mapped for k1 and α. QTLs within genomic regions mapped for k1 are expected to be correlated with the DNA pool: body size and weight. Single nucleotide polymorphisms (SNPs) which were significant for α mapped QTLs that had already been associated with residual feed intake, feed conversion ratio, average daily gain (ADG), body weight, and also dry matter intake. SNPs identified for k1 were able to additionally explain 2.2% of the phenotypic variability of the complex ADG, even when SNPs for k1 did not match the genomic regions associated with ADG. Although improvements are needed, our findings suggest that genomic analysis on component traits may help to uncover the genetic basis of more complex traits, particularly when lower biological hierarchies are mechanistically described by mathematical simulation models.

  13. Decynium-22 Enhances SSRI-Induced Antidepressant-Like Effects in Mice: Uncovering Novel Targets to Treat Depression

    PubMed Central

    Horton, Rebecca E.; Apple, Deana M.; Owens, W. Anthony; Baganz, Nicole L.; Cano, Sonia; Mitchell, Nathan C.; Vitela, Melissa; Gould, Georgianna G.; Koek, Wouter

    2013-01-01

    Mood disorders cause much suffering and lost productivity worldwide, compounded by the fact that many patients are not effectively treated by currently available medications. The most commonly prescribed antidepressant drugs are the selective serotonin (5-HT) reuptake inhibitors (SSRIs), which act by blocking the high-affinity 5-HT transporter (SERT). The increase in extracellular 5-HT produced by SSRIs is thought to be critical to initiate downstream events needed for therapeutic effects. A potential explanation for their limited therapeutic efficacy is the recently characterized presence of low-affinity, high-capacity transporters for 5-HT in brain [i.e., organic cation transporters (OCTs) and plasma membrane monoamine transporter], which may limit the ability of SSRIs to increase extracellular 5-HT. Decynium-22 (D-22) is a blocker of these transporters, and using this compound we uncovered a significant role for OCTs in 5-HT uptake in mice genetically modified to have reduced or no SERT expression (Baganz et al., 2008). This raised the possibility that pharmacological inactivation of D-22-sensitive transporters might enhance the neurochemical and behavioral effects of SSRIs. Here we show that in wild-type mice D-22 enhances the effects of the SSRI fluvoxamine to inhibit 5-HT clearance and to produce antidepressant-like activity. This antidepressant-like activity of D-22 was attenuated in OCT3 KO mice, whereas the effect of D-22 to inhibit 5-HT clearance in the CA3 region of hippocampus persisted. Our findings point to OCT3, as well as other D-22-sensitive transporters, as novel targets for new antidepressant drugs with improved therapeutic potential. PMID:23785165

  14. Whole genome bisulfite sequencing of cell-free DNA and its cellular contributors uncovers placenta hypomethylated domains.

    PubMed

    Jensen, Taylor J; Kim, Sung K; Zhu, Zhanyang; Chin, Christine; Gebhard, Claudia; Lu, Tim; Deciu, Cosmin; van den Boom, Dirk; Ehrich, Mathias

    2015-04-15

    Circulating cell-free fetal DNA has enabled non-invasive prenatal fetal aneuploidy testing without direct discrimination of the maternal and fetal DNA. Testing may be improved by specifically enriching the sample material for fetal DNA. DNA methylation may allow for such a separation of DNA; however, this depends on knowledge of the methylomes of circulating cell-free DNA and its cellular contributors. We perform whole genome bisulfite sequencing on a set of unmatched samples including circulating cell-free DNA from non-pregnant and pregnant female donors and genomic DNA from maternal buffy coat and placenta samples. We find CpG cytosines within longer fragments are more likely to be methylated. Comparison of the methylomes of placenta and non-pregnant circulating cell-free DNA reveal many of the 51,259 identified differentially methylated regions are located in domains exhibiting consistent placenta hypomethylation across millions of consecutive bases. We find these placenta hypomethylated domains are consistently located within regions exhibiting low CpG and gene density. Differentially methylated regions identified when comparing placenta to non-pregnant circulating cell-free DNA are recapitulated in pregnant circulating cell-free DNA, confirming the ability to detect differential methylation in circulating cell-free DNA mixtures. We generate methylome maps for four sample types at single-base resolution, identify a link between DNA methylation and fragment length in circulating cell-free DNA, identify differentially methylated regions between sample groups, and uncover the presence of megabase-size placenta hypomethylated domains.

  15. Uncovering Ultrastructural Defences in Daphnia magna – An Interdisciplinary Approach to Assess the Predator-Induced Fortification of the Carapace

    PubMed Central

    Rabus, Max; Söllradl, Thomas; Clausen-Schaumann, Hauke; Laforsch, Christian

    2013-01-01

    The development of structural defences, such as the fortification of shells or exoskeletons, is a widespread strategy to reduce predator attack efficiency. In unpredictable environments these defences may be more pronounced in the presence of a predator. The cladoceran Daphniamagna (Crustacea: Branchiopoda: Cladocera) has been shown to develop a bulky morphotype as an effective inducible morphological defence against the predatory tadpole shrimp Triopscancriformis (Crustacea: Branchiopoda: Notostraca). Mediated by kairomones, the daphnids express an increased body length, width and an elongated tail spine. Here we examined whether these large scale morphological defences are accompanied by additional ultrastructural defences, i.e. a fortification of the exoskeleton. We employed atomic force microscopy (AFM) based nanoindentation experiments to assess the cuticle hardness along with tapping mode AFM imaging to visualise the surface morphology for predator exposed and non-predator exposed daphnids. We used semi-thin sections of the carapace to measure the cuticle thickness, and finally, we used fluorescence microscopy to analyse the diameter of the pillars connecting the two carapace layers. We found that D. magna indeed expresses ultrastructural defences against Triops predation. The cuticle in predator exposed individuals is approximately five times harder and two times thicker than in control daphnids. Moreover, the pillar diameter is significantly increased in predator exposed daphnids. These predator-cue induced changes in the carapace architecture should provide effective protection against being crushed by the predator’s mouthparts and may add to the protective effect of bulkiness. This study highlights the potential of interdisciplinary studies to uncover new and relevant aspects even in extensively studied fields of research. PMID:23776711

  16. PathEdEx – Uncovering High-explanatory Visual Diagnostics Heuristics Using Digital Pathology and Multiscale Gaze Data

    PubMed Central

    Shin, Dmitriy; Kovalenko, Mikhail; Ersoy, Ilker; Li, Yu; Doll, Donald; Shyu, Chi-Ren; Hammer, Richard

    2017-01-01

    Background: Visual heuristics of pathology diagnosis is a largely unexplored area where reported studies only provided a qualitative insight into the subject. Uncovering and quantifying pathology visual and nonvisual diagnostic patterns have great potential to improve clinical outcomes and avoid diagnostic pitfalls. Methods: Here, we present PathEdEx, an informatics computational framework that incorporates whole-slide digital pathology imaging with multiscale gaze-tracking technology to create web-based interactive pathology educational atlases and to datamine visual and nonvisual diagnostic heuristics. Results: We demonstrate the capabilities of PathEdEx for mining visual and nonvisual diagnostic heuristics using the first PathEdEx volume of a hematopathology atlas. We conducted a quantitative study on the time dynamics of zooming and panning operations utilized by experts and novices to come to the correct diagnosis. We then performed association rule mining to determine sets of diagnostic factors that consistently result in a correct diagnosis, and studied differences in diagnostic strategies across different levels of pathology expertise using Markov chain (MC) modeling and MC Monte Carlo simulations. To perform these studies, we translated raw gaze points to high-explanatory semantic labels that represent pathology diagnostic clues. Therefore, the outcome of these studies is readily transformed into narrative descriptors for direct use in pathology education and practice. Conclusion: PathEdEx framework can be used to capture best practices of pathology visual and nonvisual diagnostic heuristics that can be passed over to the next generation of pathologists and have potential to streamline implementation of precision diagnostics in precision medicine settings. PMID:28828200

  17. Uncovering Structural Diversity of Unsaturated Fatty Acyls in Cholesteryl Esters via Photochemical Reaction and Tandem Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Ren, Jia; Franklin, Elissia T.; Xia, Yu

    2017-07-01

    Mass spectrometry analysis of cholesteryl esters (CEs) faces several challenges, with one of them being the determination of the carbon-carbon double bond (C=C) locations within unsaturated fatty acyl chains. Paternὸ-Büchi (PB) reaction, a photochemical reaction based on the addition of acetone to C=C, is capable of C=C location determination when coupled with tandem mass spectrometry (MS/MS). In this study, the PB reaction conditions were tailored for CEs and subsequent nanoelectrospray ionization (nanoESI). A solvent system containing acetone/methanol/dichloromethane/water (40/30/20/10, volume ratios) and 100 μM LiOH was determined to be optimal, resulting in reasonable PB reaction yield ( 30%) and good ionization efficiency (forming lithium adduct of CEs). Collision-induced dissociation (CID) of the PB reaction products produced characteristic fragment ions of CE together with those modified by the PB reactions, such as lithiated fatty acyl ([FA + Li]+) and its PB product ([FA - PB + Li]+). MS3 CID of [FA - PB + Li]+ led to abundant C=C diagnostic ion formation, which was used for C=C location determination and isomer quantitation. A PB-MS3 CID approach was developed and applied for CE analysis from human plasma. A series of unsaturated CEs was identified with specific C=C locations within fatty acyl chains. Absolute quantitation for each CE species was achieved including coexisting C=C location isomers, such as Δ9 and Δ11 isomers of CE 18:1 and ω-6 and ω-3 isomers of CE 18:3. These results show that PB-MS/MS is useful in uncovering structural diversity of CEs due to unsaturation in fatty acyls, which is often undetected from current lipid analysis approach.

  18. Genome engineering uncovers 54 evolutionarily conserved and testis-enriched genes that are not required for male fertility in mice.

    PubMed

    Miyata, Haruhiko; Castaneda, Julio M; Fujihara, Yoshitaka; Yu, Zhifeng; Archambeault, Denise R; Isotani, Ayako; Kiyozumi, Daiji; Kriseman, Maya L; Mashiko, Daisuke; Matsumura, Takafumi; Matzuk, Ryan M; Mori, Masashi; Noda, Taichi; Oji, Asami; Okabe, Masaru; Prunskaite-Hyyrylainen, Renata; Ramirez-Solis, Ramiro; Satouh, Yuhkoh; Zhang, Qian; Ikawa, Masahito; Matzuk, Martin M

    2016-07-12

    Gene-expression analysis studies from Schultz et al. estimate that more than 2,300 genes in the mouse genome are expressed predominantly in the male germ line. As of their 2003 publication [Schultz N, Hamra FK, Garbers DL (2003) Proc Natl Acad Sci USA 100(21):12201-12206], the functions of the majority of these testis-enriched genes during spermatogenesis and fertilization were largely unknown. Since the study by Schultz et al., functional analysis of hundreds of reproductive-tract-enriched genes have been performed, but there remain many testis-enriched genes for which their relevance to reproduction remain unexplored or unreported. Historically, a gene knockout is the "gold standard" to determine whether a gene's function is essential in vivo. Although knockout mice without apparent phenotypes are rarely published, these knockout mouse lines and their phenotypic information need to be shared to prevent redundant experiments. Herein, we used bioinformatic and experimental approaches to uncover mouse testis-enriched genes that are evolutionarily conserved in humans. We then used gene-disruption approaches, including Knockout Mouse Project resources (targeting vectors and mice) and CRISPR/Cas9, to mutate and quickly analyze the fertility of these mutant mice. We discovered that 54 mutant mouse lines were fertile. Thus, despite evolutionary conservation of these genes in vertebrates and in some cases in all eukaryotes, our results indicate that these genes are not individually essential for male mouse fertility. Our phenotypic data are highly relevant in this fiscally tight funding period and postgenomic age when large numbers of genomes are being analyzed for disease association, and will prevent unnecessary expenditures and duplications of effort by others.

  19. Combinatorial phenotypic screen uncovers unrecognized family of extended thiourea inhibitors with copper-dependent anti-Staphylococcal activity

    PubMed Central

    Dalecki, Alex G.; Malalasekera, Aruni P.; Schaaf, Kaitlyn; Kutsch, Olaf; Bossmann, Stefan H.; Wolschendorf, Frank

    2016-01-01

    The continuous rise of multi-drug resistant pathogenic bacteria has become a significant challenge for the health care system. In particular, novel drugs to treat infections of methicillin-resistant Staphylococcus aureus strains (MRSA) are needed, but traditional drug discovery campaigns have largely failed to deliver clinically suitable antibiotics. More than simply new drugs, new drug discovery approaches are needed to combat bacterial resistance. The recently described phenomenon of copper-dependent inhibitors has galvanized research exploring the use of metal-coordinating molecules to harness copper’s natural antibacterial properties for therapeutic purposes. Here, we describe the results of the first concerted screening effort to identify copper-dependent inhibitors of Staphylococcus aureus. A standard library of 10,000 compounds was assayed for anti-staphylococcal activity, with hits defined as those compounds with a strict copper-dependent inhibitory activity. A total of 53 copper-dependent hit molecules were uncovered, similar to the copper independent hit rate of a traditionally executed campaign conducted in parallel on the same library. Most prominent was a hit family with an extended thiourea core structure, termed the NNSN motif. This motif resulted in copper-dependent and copper-specific S. aureus inhibition, while simultaneously being well tolerated by eukaryotic cells. Importantly, we could demonstrate that copper binding by the NNSN motif is highly unusual and likely responsible for the promising biological qualities of these compounds. A subsequent chemoinformatic meta-analysis of the ChEMBL chemical database confirmed the NNSNs as an unrecognized staphylococcal inhibitor, despite the family’s presence in many chemical screening libraries. Thus, our copper-biased screen has proven able to discover inhibitors within previously screened libraries, offering a mechanism to reinvigorate exhausted molecular collections. PMID:26935206

  20. Upregulation of Glycans Containing 3’ Fucose in a Subset of Pancreatic Cancers Uncovered Using Fusion-Tagged Lectins

    PubMed Central

    Singh, Sudhir; Pal, Kuntal; Yadav, Jessica; Tang, Huiyuan; Partyka, Katie; Kletter, Doron; Hsueh, Peter; Ensink, Elliot; Birendra, KC; Hostetter, Galen; Xu, H. Eric; Bern, Marshall; Smith, David F.; Mehta, Anand S.; Brand, Randall; Melcher, Karsten; Haab, Brian B.

    2015-01-01

    The fucose post-translational modification is frequently increased in pancreatic cancer, thus forming the basis for promising biomarkers, but a subset of pancreatic cancer patients does not elevate the known fucose-containing biomarkers. We hypothesized that such patients elevate glycan motifs with fucose in linkages and contexts different from the known fucose-containing biomarkers. We used a database of glycan array data to identify the lectins CCL2 to detect glycan motifs with fucose in a 3’ linkage; CGL2 for motifs with fucose in a 2’ linkage; and RSL for fucose in all linkages. We used several practical methods to test the lectins and determine the optimal mode of detection, and we then tested whether the lectins detected glycans in pancreatic cancer patients who did not elevate the sialyl-Lewis A glycan, which is upregulated in ~75% of pancreatic adenocarcinomas. Patients who did not upregulate sialyl-Lewis A, which contains fucose in a 4’ linkage, tended to upregulate fucose in a 3’ linkage, as detected by CCL2, but they did not upregulate total fucose or fucose in a 2’ linkage. CCL2 binding was high in cancerous epithelia from pancreatic tumors, including areas negative for sialyl-Lewis A and a related motif containing 3’ fucose, sialyl-Lewis X. Thus glycans containing 3’ fucose may complement sialyl-Lewis A to contribute to improved detection of pancreatic cancer. Furthermore, the use of panels of recombinant lectins may uncover details about glycosylation that could be important for characterizing and detecting cancer. PMID:25938165

  1. PCR fishing for red endophytes in British Columbia Kallymeniaceae (Gigartinales, Florideophyceae) uncovers the species-rich Kallymenicola gen. nov. (Palmariales, Nemaliophycidae).

    PubMed

    Evans, Joshua R; Saunders, Gary W

    2017-02-14

    Unexpected contaminants uncovered during routine COI-5P DNA barcoding of British Columbia Kallymeniaceae indicated the presence of a novel lineage allied to the family Meiodiscaceae, Palmariales. Available rbcL data for species of this family were used to design specific primers to screen for the presence of the meiodiscacean species in 534 kallymeniacean specimens primarily from British Columbia, Canada. Ultimately, 43 positive PCR products representing six diverse genetic groups from nine host species were uncovered; three are described here in the new genus Kallymenicola gen. nov., viz., K. invisiblis sp. nov., K. penetrans sp. nov., and K. superficialis sp. nov. Although genetic groups loosely displayed evidence of host specificity and cospeciation, examples of host switching with interesting biogeographical patterns were also documented. This article is protected by copyright. All rights reserved.

  2. GENOMICS SYMPOSIUM: Using genomic approaches to uncover sources of variation in age at puberty and reproductive longevity in sows

    USDA-ARS?s Scientific Manuscript database

    Genetic variants associated with traits such as age at puberty and litter size could provide insight into the underlying genetic sources of variation impacting sow reproductive longevity and productivity. Genomewide characterization and gene expression profiling were used using gilts from the Univer...

  3. English Teaching Profile: Mexico.

    ERIC Educational Resources Information Center

    British Council, London (England). English Language and Literature Div.

    A profile of the extent of English usage and instruction in Mexico gives an overview of the following elements: its role and status alongside Spanish and within the educational system at all levels; teacher education; program accreditation; required reading skills; the supply and professional support of English teachers; the type and availability…

  4. English Teaching Profile: Lesotho.

    ERIC Educational Resources Information Center

    British Council, London (England). English Language and Literature Div.

    A profile of the role and status of the English language in Lesotho, Africa, is presented. The following topics are outlined: (1) the extent of the use of English as the second official language; (2) instruction in English at the elementary and secondary levels and at each of the postsecondary institutions in the country; (3) the number, ratio,…

  5. English Teaching Profile: Singapore.

    ERIC Educational Resources Information Center

    British Council, London (England). English Language and Literature Div.

    This profile of the English language teaching situation in Singapore examines the role of English in society and in the educational system. It is noted: (1) that English is the most important of the four official languages, (2) that education is provided in the four languages on the primary and secondary levels, and (3) that English is the medium…

  6. Country Profiles, Malaysia.

    ERIC Educational Resources Information Center

    Marzuki, Ariffin Bin; Peng, J. Y.

    A profile of Malaysia is sketched in this paper. Emphasis is placed on the nature, scope, and accomplishments of population activities in the country. Topics and sub-topics include: location and description of the country; population (size, growth patterns, age structure, urban/rural distribution, ethnic and religious composition, migration,…

  7. Adult Competency Education Profile.

    ERIC Educational Resources Information Center

    Bureau of Occupational and Adult Education (DHEW/OE), Washington, DC. Div. of Adult Education.

    A compilation of abstracts of 120 current Adult Performance Level (APL) and Adult Competency Education (ACE) federally supported projects being conducted in 34 States and the District of Columbia, this project profile was developed for adult and secondary education administrators, teachers, and program developers who are beginning or are currently…

  8. Culinary Arts Profile.

    ERIC Educational Resources Information Center

    Missouri Univ., Columbia. Instructional Materials Lab.

    This chart is intended for use in documenting the fact that a student participating in a culinary arts program has achieved the performance standards specified in the Missouri Competency Profile for culinary arts. The chart includes space for recording basic student and instructor information and the student's on-the-job training and work…

  9. Campus Profile '96.

    ERIC Educational Resources Information Center

    Spicer, Scot L.; And Others

    Outlining the demography of the students and community served by Glendale Community College (GCC), in California, as well as providing indicators of institutional effectiveness, this five-part report is designed to assist faculty, staff, and students understand the college's diverse operations. Section I provides a community profile, including…

  10. Country Profiles. France.

    ERIC Educational Resources Information Center

    Bourgeois-Pichat, Jean

    A profile of France is sketched in this paper. Emphasis is placed on the nature, scope, and accomplishments of population activities in the country. Topics and sub-topics include: (1) location and description of the country; (2) population--size, growth patterns, age structure, urban/rural distribution, ethnic and religious composition, education,…

  11. Country Profiles, Jamaica.

    ERIC Educational Resources Information Center

    Population Council, New York, NY.

    A profile of Jamaica is sketched in this paper. Emphasis is placed on the nature, scope, and accomplishments of population activities in the country. Topics and sub-topics include: location and description of the island; population - size, growth patterns, age structure, rural/urban distribution, ethnic and religious composition, literacy, future…

  12. Country Profiles, Indonesia.

    ERIC Educational Resources Information Center

    Population Council, New York, NY.

    A profile of Indonesia is sketched in this paper. Emphasis is placed on the nature, scope, and accomplishments of population activities in the country. Topics and sub-topics include: location and description of the country; population - size, growth patterns, age structure, urban/rural distribution, ethnic and religious composition, migration,…

  13. Country Profiles, Nepal.

    ERIC Educational Resources Information Center

    Taylor, Daniel; Thapa, Rita

    A profile of Nepal is sketched in this paper. Emphasis is placed on the nature, scope, and accomplishments of population activities in the country. Topics and sub-topics include: location and description of the country; population--size, growth patterns, age/sex structure, geographical distribution, topographical obstacles, ethnic and religious…

  14. PSI Member Profile.

    ERIC Educational Resources Information Center

    Professional Secretaries International, Kansas City, MO.

    A survey of 2,700 of the 27,000 members of Professional Secretaries International received 755 responses yielding the following profile of secretarial workers: (1) the average member is female, about 45 years old, married with no dependents living at home, and owns a single-family home in the suburbs; (2) most respondents have worked in office or…

  15. Culinary Arts Profile.

    ERIC Educational Resources Information Center

    Missouri Univ., Columbia. Instructional Materials Lab.

    This chart is intended for use in documenting the fact that a student participating in a culinary arts program has achieved the performance standards specified in the Missouri Competency Profile for culinary arts. The chart includes space for recording basic student and instructor information and the student's on-the-job training and work…

  16. English Teaching Profile: Mexico.

    ERIC Educational Resources Information Center

    British Council, London (England). English Language and Literature Div.

    This profile of the English language teaching situation in Mexico examines the role of English in society and in the educational system. It is noted that the extent to which English is used in Mexico is affected by the country's proximity to the United States. The educational system is described, with emphasis on English instruction which begins…

  17. Profiles in Measurement.

    ERIC Educational Resources Information Center

    Ludlow, Larry H.; Wright, Benjamin Drake; Linacre, John Michael; Webster, Linda; Andrich, David

    1998-01-01

    Four of the articles in this section profile major figures in measurement: (1) Sir Francis Galton (Larry Ludlow); (2) Georg Rasch (Benjamin Wright); (3) Benjamin Wright (John Michael Linacre); and (4) David Andrich (Linda Webster). The fifth article, by David Andrich, presents insights gained into the Rasch model. (SLD)

  18. Rural Incubator Profile.

    ERIC Educational Resources Information Center

    Weinberg, Mark L.

    This profile summarizes the responses of 20 managers of rural business incubators, reporting on their operations, entry and exit policies, facility promotion, service arrangements and economic development outcomes. Incubators assist small businesses in the early stages of growth by providing them with rental space, shared services, management and…

  19. English Teaching Profile: Bahrain

    ERIC Educational Resources Information Center

    British Council, London (England). English Language and Literature Div.

    A profile of the state of English and English instruction in Bahrain covers the following topics: description of the role and status of English language use in industry and commerce, government, and education; the role of English at all levels of the educational system; the availability, characteristics, and qualifications of teachers of English;…

  20. Cinnarizine: Comprehensive Profile.

    PubMed

    Haress, Nadia G

    2015-01-01

    Cinnarizine is a piperazine derivative with antihistaminic, antiserotonergic, antidopaminergic, and calcium channel-blocking activities. A comprehensive profile was performed on cinnarizine including its description and the different methods of analysis. The 1H NMR and 13C one- and two-dimensional NMR methods were used. In addition, infrared and mass spectral analyses were performed which all confirmed the structure of cinnarizine.