Identifying the principal coefficient of parabolic equations with non-divergent form

NASA Astrophysics Data System (ADS)

Jiang, L. S.; Bian, B. J.

2005-01-01

We deal with an inverse problem of determining a coefficient a(x, t) of principal part for second order parabolic equations with non-divergent form when the solution is known. Such a problem has important applications in a large fields of applied science. We propose a well-posed approximate algorithm to identify the coefficient. The existence, uniqueness and stability of such solutions a(x, t) are proved. A necessary condition which is a couple system of a parabolic equation and a parabolic variational inequality is deduced. Our numerical simulations show that the coefficient is recovered very well.

Heritable gene expression differences between apomictic clone members in Taraxacum officinale: Insights into early stages of evolutionary divergence in asexual plants.

PubMed

Ferreira de Carvalho, Julie; Oplaat, Carla; Pappas, Nikolaos; Derks, Martijn; de Ridder, Dick; Verhoeven, Koen J F

2016-03-08

Asexual reproduction has the potential to enhance deleterious mutation accumulation and to constrain adaptive evolution. One source of mutations that can be especially relevant in recent asexuals is activity of transposable elements (TEs), which may have experienced selection for high transposition rates in sexual ancestor populations. Predictions of genomic divergence under asexual reproduction therefore likely include a large contribution of transposable elements but limited adaptive divergence. For plants empirical insight into genome divergence under asexual reproduction remains limited. Here, we characterize expression divergence between clone members of a single apomictic lineage of the common dandelion (Taraxacum officinale) to contribute to our knowledge of genome evolution under asexuality. Using RNA-Seq, we show that about one third of heritable divergence within the apomictic lineage is driven by TEs and TE-related gene activity. In addition, we identify non-random transcriptional differences in pathways related to acyl-lipid and abscisic acid metabolisms which might reflect functional divergence within the apomictic lineage. We analyze SNPs in the transcriptome to assess genetic divergence between the apomictic clone members and reveal that heritable expression differences between the accessions are not explained simply by genome-wide genetic divergence. The present study depicts a first effort towards a more complete understanding of apomictic plant genome evolution. We identify abundant TE activity and ecologically relevant functional genes and pathways affecting heritable within-lineage expression divergence. These findings offer valuable resources for future work looking at epigenetic silencing and Cis-regulation of gene expression with particular emphasis on the effects of TE activity on asexual species' genome.

Transposable Element Misregulation Is Linked to the Divergence between Parental piRNA Pathways in Drosophila Hybrids

PubMed Central

Romero-Soriano, Valèria; Modolo, Laurent; Lopez-Maestre, Hélène; Mugat, Bruno; Pessia, Eugénie; Chambeyron, Séverine; Vieira, Cristina

2017-01-01

Abstract Interspecific hybridization is a genomic stress condition that leads to the activation of transposable elements (TEs) in both animals and plants. In hybrids between Drosophila buzzatii and Drosophila koepferae, mobilization of at least 28 TEs has been described. However, the molecular mechanisms underlying this TE release remain poorly understood. To give insight on the causes of this TE activation, we performed a TE transcriptomic analysis in ovaries (notorious for playing a major role in TE silencing) of parental species and their F1 and backcrossed (BC) hybrids. We find that 15.2% and 10.6% of the expressed TEs are deregulated in F1 and BC1 ovaries, respectively, with a bias toward overexpression in both cases. Although differences between parental piRNA (Piwi-interacting RNA) populations explain only partially these results, we demonstrate that piRNA pathway proteins have divergent sequences and are differentially expressed between parental species. Thus, a functional divergence of the piRNA pathway between parental species, together with some differences between their piRNA pools, might be at the origin of hybrid instabilities and ultimately cause TE misregulation in ovaries. These analyses were complemented with the study of F1 testes, where TEs tend to be less expressed than in D. buzzatii. This can be explained by an increase in piRNA production, which probably acts as a defence mechanism against TE instability in the male germline. Hence, we describe a differential impact of interspecific hybridization in testes and ovaries, which reveals that TE expression and regulation are sex-biased. PMID:28854624

Inductive specification and axonal orientation of spinal neurons mediated by divergent bone morphogenetic protein signaling pathways

PubMed Central

2011-01-01

Background Bone morphogenetic protein (BMP)7 evokes both inductive and axon orienting responses in dorsal interneurons (dI neurons) in the developing spinal cord. These events occur sequentially during the development of spinal neurons but in these and other cell types such inductive and acute chemotactic responses occur concurrently, highlighting the requirement for divergent intracellular signaling. Both type I and type II BMP receptor subtypes have been implicated selectively in orienting responses but it remains unclear how, in a given cell, divergence occurs. We have examined the mechanisms by which disparate BMP7 activities are generated in dorsal spinal neurons. Results We show that widely different threshold concentrations of BMP7 are required to elicit the divergent inductive and axon orienting responses. Type I BMP receptor kinase activity is required for activation of pSmad signaling and induction of dI character by BMP7, a high threshold response. In contrast, neither type I BMP receptor kinase activity nor Smad1/5/8 phosphorylation is involved in the low threshold orienting responses of dI axons to BMP7. Instead, BMP7-evoked axonal repulsion and growth cone collapse are dependent on phosphoinositide-3-kinase (PI3K) activation, plausibly through type II receptor signaling. BMP7 stimulates PI3K-dependent signaling in dI neurons. BMP6, which evokes neural induction but does not have orienting activity, activates Smad signaling but does not stimulate PI3K. Conclusions Divergent signaling through pSmad-dependent and PI3K-dependent (Smad-independent) mechanisms mediates the inductive and orienting responses of dI neurons to BMP7. A model is proposed whereby selective engagement of BMP receptor subunits underlies choice of signaling pathway. PMID:22085733

Genome-wide pathway-based association analysis identifies risk pathways associated with Parkinson's disease.

PubMed

Zhang, Mingming; Mu, Hongbo; Shang, Zhenwei; Kang, Kai; Lv, Hongchao; Duan, Lian; Li, Jin; Chen, Xinren; Teng, Yanbo; Jiang, Yongshuai; Zhang, Ruijie

2017-01-06

Parkinson's disease (PD) is the second most common neurodegenerative disease. It is generally believed that it is influenced by both genetic and environmental factors, but the precise pathogenesis of PD is unknown to date. In this study, we performed a pathway analysis based on genome-wide association study (GWAS) to detect risk pathways of PD in three GWAS datasets. We first mapped all SNP markers to autosomal genes in each GWAS dataset. Then, we evaluated gene risk values using the minimum P-value of the tagSNPs. We took a pathway as a unit to identify the risk pathways based on the cumulative risks of the genes in the pathway. Finally, we combine the analysis results of the three datasets to detect the high risk pathways associated with PD. We found there were five same pathways in the three datasets. Besides, we also found there were five pathways which were shared in two datasets. Most of these pathways are associated with nervoussystem. Five pathways had been reported to be PD-related pathways in the previous literature. Our findings also implied that there was a close association between immune response and PD. Continued investigation of these pathways will further help us explain the pathogenesis of PD. Copyright © 2016. Published by Elsevier Ltd.

Transposable Element Misregulation Is Linked to the Divergence between Parental piRNA Pathways in Drosophila Hybrids.

PubMed

Romero-Soriano, Valèria; Modolo, Laurent; Lopez-Maestre, Hélène; Mugat, Bruno; Pessia, Eugénie; Chambeyron, Séverine; Vieira, Cristina; Garcia Guerreiro, Maria Pilar

2017-06-01

Interspecific hybridization is a genomic stress condition that leads to the activation of transposable elements (TEs) in both animals and plants. In hybrids between Drosophila buzzatii and Drosophila koepferae, mobilization of at least 28 TEs has been described. However, the molecular mechanisms underlying this TE release remain poorly understood. To give insight on the causes of this TE activation, we performed a TE transcriptomic analysis in ovaries (notorious for playing a major role in TE silencing) of parental species and their F1 and backcrossed (BC) hybrids. We find that 15.2% and 10.6% of the expressed TEs are deregulated in F1 and BC1 ovaries, respectively, with a bias toward overexpression in both cases. Although differences between parental piRNA (Piwi-interacting RNA) populations explain only partially these results, we demonstrate that piRNA pathway proteins have divergent sequences and are differentially expressed between parental species. Thus, a functional divergence of the piRNA pathway between parental species, together with some differences between their piRNA pools, might be at the origin of hybrid instabilities and ultimately cause TE misregulation in ovaries. These analyses were complemented with the study of F1 testes, where TEs tend to be less expressed than in D. buzzatii. This can be explained by an increase in piRNA production, which probably acts as a defence mechanism against TE instability in the male germline. Hence, we describe a differential impact of interspecific hybridization in testes and ovaries, which reveals that TE expression and regulation are sex-biased. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

How do environmental factors influence life cycles and development? An experimental framework for early-diverging metazoans

PubMed Central

Bosch, Thomas C. G.; Adamska, Maja; Augustin, René; Domazet-Loso, Tomislav; Foret, Sylvain; Fraune, Sebastian; Funayama, Noriko; Grasis, Juris; Hamada, Mayuko; Hatta, Masayuki; Hobmayer, Bert; Kawai, Kotoe; Klimovich, Alexander; Manuel, Michael; Shinzato, Chuya; Technau, Uli; Yum, Seungshic; Miller, David J.

2014-01-01

Ecological developmental biology (eco-devo) explores the mechanistic relationships between the processes of individual development and environmental factors. Recent studies imply that some of these relationships have deep evolutionary origins, and may even predate the divergences of the simplest extant animals, including cnidarians and sponges. Development of these early diverging metazoans is often sensitive to environmental factors, and these interactions occur in the context of conserved signaling pathways and mechanisms of tissue homeostasis whose detailed molecular logic remain elusive. Efficient methods for transgenesis in cnidarians together with the ease of experimental manipulation in cnidarians and sponges make them ideal models for understanding causal relationships between environmental factors and developmental mechanisms. Here, we identify major questions at the interface between animal evolution and development and outline a road map for research aimed at identifying the mechanisms that link environmental factors to developmental mechanisms in early diverging metazoans. PMID:25205353

Cloning of quantitative trait genes from rice reveals conservation and divergence of photoperiod flowering pathways in Arabidopsis and rice

PubMed Central

Matsubara, Kazuki; Hori, Kiyosumi; Ogiso-Tanaka, Eri; Yano, Masahiro

2014-01-01

Flowering time in rice (Oryza sativa L.) is determined primarily by daylength (photoperiod), and natural variation in flowering time is due to quantitative trait loci involved in photoperiodic flowering. To date, genetic analysis of natural variants in rice flowering time has resulted in the positional cloning of at least 12 quantitative trait genes (QTGs), including our recently cloned QTGs, Hd17, and Hd16. The QTGs have been assigned to specific photoperiodic flowering pathways. Among them, 9 have homologs in the Arabidopsis genome, whereas it was evident that there are differences in the pathways between rice and Arabidopsis, such that the rice Ghd7–Ehd1–Hd3a/RFT1 pathway modulated by Hd16 is not present in Arabidopsis. In this review, we describe QTGs underlying natural variation in rice flowering time. Additionally, we discuss the implications of the variation in adaptive divergence and its importance in rice breeding. PMID:24860584

Identifying metabolic pathways for production of extracellular polymeric substances by the diatom Fragilariopsis cylindrus inhabiting sea ice.

PubMed

Aslam, Shazia N; Strauss, Jan; Thomas, David N; Mock, Thomas; Underwood, Graham J C

2018-05-01

Diatoms are significant primary producers in sea ice, an ephemeral habitat with steep vertical gradients of temperature and salinity characterizing the ice matrix environment. To cope with the variable and challenging conditions, sea ice diatoms produce polysaccharide-rich extracellular polymeric substances (EPS) that play important roles in adhesion, cell protection, ligand binding and as organic carbon sources. Significant differences in EPS concentrations and chemical composition corresponding to temperature and salinity gradients were present in sea ice from the Weddell Sea and Eastern Antarctic regions of the Southern Ocean. To reconstruct the first metabolic pathway for EPS production in diatoms, we exposed Fragilariopsis cylindrus, a key bi-polar diatom species, to simulated sea ice formation. Transcriptome profiling under varying conditions of EPS production identified a significant number of genes and divergent alleles. Their complex differential expression patterns under simulated sea ice formation was aligned with physiological and biochemical properties of the cells, and with field measurements of sea ice EPS characteristics. Thus, the molecular complexity of the EPS pathway suggests metabolic plasticity in F. cylindrus is required to cope with the challenging conditions of the highly variable and extreme sea ice habitat.

Identifying Differentially Abundant Metabolic Pathways in Metagenomic Datasets

NASA Astrophysics Data System (ADS)

Liu, Bo; Pop, Mihai

Enabled by rapid advances in sequencing technology, metagenomic studies aim to characterize entire communities of microbes bypassing the need for culturing individual bacterial members. One major goal of such studies is to identify specific functional adaptations of microbial communities to their habitats. Here we describe a powerful analytical method (MetaPath) that can identify differentially abundant pathways in metagenomic data-sets, relying on a combination of metagenomic sequence data and prior metabolic pathway knowledge. We show that MetaPath outperforms other common approaches when evaluated on simulated datasets. We also demonstrate the power of our methods in analyzing two, publicly available, metagenomic datasets: a comparison of the gut microbiome of obese and lean twins; and a comparison of the gut microbiome of infant and adult subjects. We demonstrate that the subpathways identified by our method provide valuable insights into the biological activities of the microbiome.

Transcriptomic analysis of genes in the nitrogen recycling pathway of meat-type chickens divergently selected for feed efficiency.

PubMed

Aggrey, S E; Lee, J; Karnuah, A B; Rekaya, R

2014-04-01

The understanding of the dynamics of ammonia detoxification and excretion in uricotelic species is lagging behind ureotelic species. The relative expression of genes involved in nitrogen recycling and feed efficiency in chickens is unknown. The objective of this study was to investigate the transcriptomics differences in key genes in the nitrogen (N) metabolism and purine biosynthesis pathway in a chicken population divergently selected for low (LRFI) or high (HRFI) residual feed intake at days 35 and 42 using duodenum, liver, pectoralis major (P. major) and kidney. There was a significant positive correlation between RFI and fecal N. The purine salvage pathway was activated in the LRFI compared with HRFI at days 42. The birds in the LRFI population attained greater feed efficiency by having lower FI, increasing their protein retention and producing adequate glutamine to maintain growth compared with the HRFI line. To maintain growth, excess N is deaminated mostly to generate purine nucleotides. Generating purine nucleotides primarily from the purine biosynthesis pathway is energetically costly, and to preserve energy, they preferentially generate nucleotides from the purine salvage pathway. The LRFI birds need to generate sufficient nucleotides to maintain growth despite reduced FI that then results in reduced fecal N. © 2013 Stichting International Foundation for Animal Genetics.

An examination of the divergent general, specific, and other criminogenic risk/needs across neuropathic and psychopathic pathways to homicide.

PubMed

Gilligan, D G; Lennings, C J

2011-08-01

The social learning theory underlying Andrews and Bonta's Psychology of Criminal Conduct model has generally been seen as guiding risk assessment, with good relevance to mentally ill as well as non-mentally ill offenders. The current study reports a novel approach to qualitative assessment of 26 murderers found not guilty by reason of insanity (NGRI), divided into two groups--neuropathic offenders characterised by frontal lobe deficits and psychosis and psychopathic murderers characterised by high scores on psychopathy and an absence of neuropathic factors. The findings of the present research support the notion that the two pathways are embedded in two diverging theoretical frameworks of psychopathology and social learning theory, with each corresponding to the neuropathic and psychopathic pathways, respectively. Models of social learning theory may have limited utility to the total mentally disordered offender population overall as they apply more specifically to offenders within special offender groups or perhaps more specifically to offenders with psychopathic characteristics. However, the significantly greater association of the other social, physical, and mental health risk/needs with the neuropathic pathway suggests that pathological models are important for understanding the neuropathic pathway in relation to homicide offence and risk of future violence in NGRI samples.

Divergent and convergent modes of interaction between wheat and Puccinia graminis f. sp. tritici isolates revealed by the comparative gene co-expression network and genome analyses.

PubMed

Rutter, William B; Salcedo, Andres; Akhunova, Alina; He, Fei; Wang, Shichen; Liang, Hanquan; Bowden, Robert L; Akhunov, Eduard

2017-04-12

Two opposing evolutionary constraints exert pressure on plant pathogens: one to diversify virulence factors in order to evade plant defenses, and the other to retain virulence factors critical for maintaining a compatible interaction with the plant host. To better understand how the diversified arsenals of fungal genes promote interaction with the same compatible wheat line, we performed a comparative genomic analysis of two North American isolates of Puccinia graminis f. sp. tritici (Pgt). The patterns of inter-isolate divergence in the secreted candidate effector genes were compared with the levels of conservation and divergence of plant-pathogen gene co-expression networks (GCN) developed for each isolate. Comprative genomic analyses revealed substantial level of interisolate divergence in effector gene complement and sequence divergence. Gene Ontology (GO) analyses of the conserved and unique parts of the isolate-specific GCNs identified a number of conserved host pathways targeted by both isolates. Interestingly, the degree of inter-isolate sub-network conservation varied widely for the different host pathways and was positively associated with the proportion of conserved effector candidates associated with each sub-network. While different Pgt isolates tended to exploit similar wheat pathways for infection, the mode of plant-pathogen interaction varied for different pathways with some pathways being associated with the conserved set of effectors and others being linked with the diverged or isolate-specific effectors. Our data suggest that at the intra-species level pathogen populations likely maintain divergent sets of effectors capable of targeting the same plant host pathways. This functional redundancy may play an important role in the dynamic of the "arms-race" between host and pathogen serving as the basis for diverse virulence strategies and creating conditions where mutations in certain effector groups will not have a major effect on the pathogen

Pathways-Driven Sparse Regression Identifies Pathways and Genes Associated with High-Density Lipoprotein Cholesterol in Two Asian Cohorts

PubMed Central

Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

2013-01-01

Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune

Pathways-driven sparse regression identifies pathways and genes associated with high-density lipoprotein cholesterol in two Asian cohorts.

PubMed

Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

2013-11-01

Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune

Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens

PubMed Central

Thomas, Reuben; Phuong, Jimmy; McHale, Cliona M.; Zhang, Luoping

2012-01-01

We have applied bioinformatic approaches to identify pathways common to chemical leukemogens and to determine whether leukemogens could be distinguished from non-leukemogenic carcinogens. From all known and probable carcinogens classified by IARC and NTP, we identified 35 carcinogens that were associated with leukemia risk in human studies and 16 non-leukemogenic carcinogens. Using data on gene/protein targets available in the Comparative Toxicogenomics Database (CTD) for 29 of the leukemogens and 11 of the non-leukemogenic carcinogens, we analyzed for enrichment of all 250 human biochemical pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The top pathways targeted by the leukemogens included metabolism of xenobiotics by cytochrome P450, glutathione metabolism, neurotrophin signaling pathway, apoptosis, MAPK signaling, Toll-like receptor signaling and various cancer pathways. The 29 leukemogens formed 18 distinct clusters comprising 1 to 3 chemicals that did not correlate with known mechanism of action or with structural similarity as determined by 2D Tanimoto coefficients in the PubChem database. Unsupervised clustering and one-class support vector machines, based on the pathway data, were unable to distinguish the 29 leukemogens from 11 non-leukemogenic known and probable IARC carcinogens. However, using two-class random forests to estimate leukemogen and non-leukemogen patterns, we estimated a 76% chance of distinguishing a random leukemogen/non-leukemogen pair from each other. PMID:22851955

Influence maximization in time bounded network identifies transcription factors regulating perturbed pathways

PubMed Central

Jo, Kyuri; Jung, Inuk; Moon, Ji Hwan; Kim, Sun

2016-01-01

Motivation: To understand the dynamic nature of the biological process, it is crucial to identify perturbed pathways in an altered environment and also to infer regulators that trigger the response. Current time-series analysis methods, however, are not powerful enough to identify perturbed pathways and regulators simultaneously. Widely used methods include methods to determine gene sets such as differentially expressed genes or gene clusters and these genes sets need to be further interpreted in terms of biological pathways using other tools. Most pathway analysis methods are not designed for time series data and they do not consider gene-gene influence on the time dimension. Results: In this article, we propose a novel time-series analysis method TimeTP for determining transcription factors (TFs) regulating pathway perturbation, which narrows the focus to perturbed sub-pathways and utilizes the gene regulatory network and protein–protein interaction network to locate TFs triggering the perturbation. TimeTP first identifies perturbed sub-pathways that propagate the expression changes along the time. Starting points of the perturbed sub-pathways are mapped into the network and the most influential TFs are determined by influence maximization technique. The analysis result is visually summarized in TF-Pathway map in time clock. TimeTP was applied to PIK3CA knock-in dataset and found significant sub-pathways and their regulators relevant to the PIP3 signaling pathway. Availability and Implementation: TimeTP is implemented in Python and available at http://biohealth.snu.ac.kr/software/TimeTP/. Supplementary information: Supplementary data are available at Bioinformatics online. Contact: sunkim.bioinfo@snu.ac.kr PMID:27307609

Pathway-GPS and SIGORA: identifying relevant pathways based on the over-representation of their gene-pair signatures

PubMed Central

Foroushani, Amir B.K.; Brinkman, Fiona S.L.

2013-01-01

Motivation. Predominant pathway analysis approaches treat pathways as collections of individual genes and consider all pathway members as equally informative. As a result, at times spurious and misleading pathways are inappropriately identified as statistically significant, solely due to components that they share with the more relevant pathways. Results. We introduce the concept of Pathway Gene-Pair Signatures (Pathway-GPS) as pairs of genes that, as a combination, are specific to a single pathway. We devised and implemented a novel approach to pathway analysis, Signature Over-representation Analysis (SIGORA), which focuses on the statistically significant enrichment of Pathway-GPS in a user-specified gene list of interest. In a comparative evaluation of several published datasets, SIGORA outperformed traditional methods by delivering biologically more plausible and relevant results. Availability. An efficient implementation of SIGORA, as an R package with precompiled GPS data for several human and mouse pathway repositories is available for download from http://sigora.googlecode.com/svn/. PMID:24432194

Systematic identification of genes involved in divergent skeletal muscle growth rates of broiler and layer chickens.

PubMed

Zheng, Qi; Zhang, Yong; Chen, Ying; Yang, Ning; Wang, Xiu-Jie; Zhu, Dahai

2009-02-22

The genetic closeness and divergent muscle growth rates of broilers and layers make them great models for myogenesis study. In order to discover the molecular mechanisms determining the divergent muscle growth rates and muscle mass control in different chicken lines, we systematically identified differentially expressed genes between broiler and layer skeletal muscle cells during different developmental stages by microarray hybridization experiment. Taken together, 543 differentially expressed genes were identified between broilers and layers across different developmental stages. We found that differential regulation of slow-type muscle gene expression, satellite cell proliferation and differentiation, protein degradation rate and genes in some metabolic pathways could give great contributions to the divergent muscle growth rates of the two chicken lines. Interestingly, the expression profiles of a few differentially expressed genes were positively or negatively correlated with the growth rates of broilers and layers, indicating that those genes may function in regulating muscle growth during development. The multiple muscle cell growth regulatory processes identified by our study implied that complicated molecular networks involved in the regulation of chicken muscle growth. These findings will not only offer genetic information for identifying candidate genes for chicken breeding, but also provide new clues for deciphering mechanisms underlining muscle development in vertebrates.

Xtalk: a path-based approach for identifying crosstalk between signaling pathways

PubMed Central

Tegge, Allison N.; Sharp, Nicholas; Murali, T. M.

2016-01-01

Motivation: Cells communicate with their environment via signal transduction pathways. On occasion, the activation of one pathway can produce an effect downstream of another pathway, a phenomenon known as crosstalk. Existing computational methods to discover such pathway pairs rely on simple overlap statistics. Results: We present Xtalk, a path-based approach for identifying pairs of pathways that may crosstalk. Xtalk computes the statistical significance of the average length of multiple short paths that connect receptors in one pathway to the transcription factors in another. By design, Xtalk reports the precise interactions and mechanisms that support the identified crosstalk. We applied Xtalk to signaling pathways in the KEGG and NCI-PID databases. We manually curated a gold standard set of 132 crosstalking pathway pairs and a set of 140 pairs that did not crosstalk, for which Xtalk achieved an area under the receiver operator characteristic curve of 0.65, a 12% improvement over the closest competing approach. The area under the receiver operator characteristic curve varied with the pathway, suggesting that crosstalk should be evaluated on a pathway-by-pathway level. We also analyzed an extended set of 658 pathway pairs in KEGG and to a set of more than 7000 pathway pairs in NCI-PID. For the top-ranking pairs, we found substantial support in the literature (81% for KEGG and 78% for NCI-PID). We provide examples of networks computed by Xtalk that accurately recovered known mechanisms of crosstalk. Availability and implementation: The XTALK software is available at http://bioinformatics.cs.vt.edu/~murali/software. Crosstalk networks are available at http://graphspace.org/graphs?tags=2015-bioinformatics-xtalk. Contact: ategge@vt.edu, murali@cs.vt.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26400040

Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

PubMed

Zhang, Ying-Ying; Li, Hai-Xia; Chen, Yin-Ying; Fang, Hong; Yu, Ya-Nan; Liu, Jun; Jing, Zhi-Wei; Wang, Zhong; Wang, Yong-Yan

2014-03-01

Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance. We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities. We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions. These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations. © 2013 John Wiley & Sons Ltd.

The use of functional chemical-protein associations to identify multi-pathway renoprotectants.

PubMed

Xu, Jia; Meng, Kexin; Zhang, Rui; Yang, He; Liao, Chang; Zhu, Wenliang; Jiao, Jundong

2014-01-01

Typically, most nephropathies can be categorized as complex human diseases in which the cumulative effect of multiple minor genes, combined with environmental and lifestyle factors, determines the disease phenotype. Thus, multi-target drugs would be more likely to facilitate comprehensive renoprotection than single-target agents. In this study, functional chemical-protein association analysis was performed to retrieve multi-target drugs of high pathway wideness from the STITCH 3.1 database. Pathway wideness of a drug evaluated the efficiency of regulation of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in quantity. We identified nine experimentally validated renoprotectants that exerted remarkable impact on KEGG pathways by targeting a limited number of proteins. We selected curcumin as an illustrative compound to display the advantage of multi-pathway drugs on renoprotection. We compared curcumin with hemin, an agonist of heme oxygenase-1 (HO-1), which significantly affects only one KEGG pathway, porphyrin and chlorophyll metabolism (adjusted p = 1.5×10-5). At the same concentration (10 µM), both curcumin and hemin equivalently mitigated oxidative stress in H2O2-treated glomerular mesangial cells. The benefit of using hemin was derived from its agonistic effect on HO-1, providing relief from oxidative stress. Selective inhibition of HO-1 completely blocked the action of hemin but not that of curcumin, suggesting simultaneous multi-pathway intervention by curcumin. Curcumin also increased cellular autophagy levels, enhancing its protective effect; however, hemin had no effects. Based on the fact that the dysregulation of multiple pathways is implicated in the etiology of complex diseases, we proposed a feasible method for identifying multi-pathway drugs from compounds with validated targets. Our efforts will help identify multi-pathway agents capable of providing comprehensive protection against renal injuries.

Application of Monte Carlo cross-validation to identify pathway cross-talk in neonatal sepsis.

PubMed

Zhang, Yuxia; Liu, Cui; Wang, Jingna; Li, Xingxia

2018-03-01

To explore genetic pathway cross-talk in neonates with sepsis, an integrated approach was used in this paper. To explore the potential relationships between differently expressed genes between normal uninfected neonates and neonates with sepsis and pathways, genetic profiling and biologic signaling pathway were first integrated. For different pathways, the score was obtained based upon the genetic expression by quantitatively analyzing the pathway cross-talk. The paired pathways with high cross-talk were identified by random forest classification. The purpose of the work was to find the best pairs of pathways able to discriminate sepsis samples versus normal samples. The results found 10 pairs of pathways, which were probably able to discriminate neonates with sepsis versus normal uninfected neonates. Among them, the best two paired pathways were identified according to analysis of extensive literature. Impact statement To find the best pairs of pathways able to discriminate sepsis samples versus normal samples, an RF classifier, the DS obtained by DEGs of paired pathways significantly associated, and Monte Carlo cross-validation were applied in this paper. Ten pairs of pathways were probably able to discriminate neonates with sepsis versus normal uninfected neonates. Among them, the best two paired pathways ((7) IL-6 Signaling and Phospholipase C Signaling (PLC); (8) Glucocorticoid Receptor (GR) Signaling and Dendritic Cell Maturation) were identified according to analysis of extensive literature.

mRNA export in the apicomplexan parasite Toxoplasma gondii: emerging divergent components of a crucial pathway.

PubMed

Ávila, Andréa Rodrigues; Cabezas-Cruz, Alexjandro; Gissot, Mathieu

2018-01-25

Control of gene expression is crucial for parasite survival and is the result of a series of processes that are regulated to permit fine-tuning of gene expression in response to biological changes during the life-cycle of apicomplexan parasites. Control of mRNA nuclear export is a key process in eukaryotic cells but is poorly understood in apicomplexan parasites. Here, we review recent knowledge regarding this process with an emphasis on T. gondii. We describe the presence of divergent orthologs and discuss structural and functional differences in export factors between apicomplexans and other eukaryotic lineages. Undoubtedly, the use of the CRISPR/Cas9 system in high throughput screenings associated with the discovery of mRNA nuclear export complexes by proteomic analysis will contribute to identify these divergent factors. Ligand-based or structure-based strategies may be applied to investigate the potential use of these proteins as targets for new antiprotozoal agents.

The node-weighted Steiner tree approach to identify elements of cancer-related signaling pathways.

PubMed

Sun, Yahui; Ma, Chenkai; Halgamuge, Saman

2017-12-28

Cancer constitutes a momentous health burden in our society. Critical information on cancer may be hidden in its signaling pathways. However, even though a large amount of money has been spent on cancer research, some critical information on cancer-related signaling pathways still remains elusive. Hence, new works towards a complete understanding of cancer-related signaling pathways will greatly benefit the prevention, diagnosis, and treatment of cancer. We propose the node-weighted Steiner tree approach to identify important elements of cancer-related signaling pathways at the level of proteins. This new approach has advantages over previous approaches since it is fast in processing large protein-protein interaction networks. We apply this new approach to identify important elements of two well-known cancer-related signaling pathways: PI3K/Akt and MAPK. First, we generate a node-weighted protein-protein interaction network using protein and signaling pathway data. Second, we modify and use two preprocessing techniques and a state-of-the-art Steiner tree algorithm to identify a subnetwork in the generated network. Third, we propose two new metrics to select important elements from this subnetwork. On a commonly used personal computer, this new approach takes less than 2 s to identify the important elements of PI3K/Akt and MAPK signaling pathways in a large node-weighted protein-protein interaction network with 16,843 vertices and 1,736,922 edges. We further analyze and demonstrate the significance of these identified elements to cancer signal transduction by exploring previously reported experimental evidences. Our node-weighted Steiner tree approach is shown to be both fast and effective to identify important elements of cancer-related signaling pathways. Furthermore, it may provide new perspectives into the identification of signaling pathways for other human diseases.

Divergence of Erv1-Associated Mitochondrial Import and Export Pathways in Trypanosomes and Anaerobic Protists

PubMed Central

Basu, Somsuvro; Leonard, Joanne C.; Desai, Nishal; Mavridou, Despoina A. I.; Tang, Kong Ho; Goddard, Alan D.

2013-01-01

In yeast (Saccharomyces cerevisiae) and animals, the sulfhydryl oxidase Erv1 functions with Mia40 in the import and oxidative folding of numerous cysteine-rich proteins in the mitochondrial intermembrane space (IMS). Erv1 is also required for Fe-S cluster assembly in the cytosol, which uses at least one mitochondrially derived precursor. Here, we characterize an essential Erv1 orthologue from the protist Trypanosoma brucei (TbERV1), which naturally lacks a Mia40 homolog. We report kinetic parameters for physiologically relevant oxidants cytochrome c and O2, unexpectedly find O2 and cytochrome c are reduced simultaneously, and demonstrate that efficient reduction of O2 by TbERV1 is not dependent upon a simple O2 channel defined by conserved histidine and tyrosine residues. Massive mitochondrial swelling following TbERV1 RNA interference (RNAi) provides evidence that trypanosome Erv1 functions in IMS protein import despite the natural absence of the key player in the yeast and animal import pathways, Mia40. This suggests significant evolutionary divergence from a recently established paradigm in mitochondrial cell biology. Phylogenomic profiling of genes also points to a conserved role for TbERV1 in cytosolic Fe-S cluster assembly. Conversely, loss of genes implicated in precursor delivery for cytosolic Fe-S assembly in Entamoeba, Trichomonas, and Giardia suggests fundamental differences in intracellular trafficking pathways for activated iron or sulfur species in anaerobic versus aerobic eukaryotes. PMID:23264646

Enriched pathways for major depressive disorder identified from a genome-wide association study.

PubMed

Kao, Chung-Feng; Jia, Peilin; Zhao, Zhongming; Kuo, Po-Hsiu

2012-11-01

Major depressive disorder (MDD) has caused a substantial burden of disease worldwide with moderate heritability. Despite efforts through conducting numerous association studies and now, genome-wide association (GWA) studies, the success of identifying susceptibility loci for MDD has been limited, which is partially attributed to the complex nature of depression pathogenesis. A pathway-based analytic strategy to investigate the joint effects of various genes within specific biological pathways has emerged as a powerful tool for complex traits. The present study aimed to identify enriched pathways for depression using a GWA dataset for MDD. For each gene, we estimated its gene-wise p value using combined and minimum p value, separately. Canonical pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and BioCarta were used. We employed four pathway-based analytic approaches (gene set enrichment analysis, hypergeometric test, sum-square statistic, sum-statistic). We adjusted for multiple testing using Benjamini & Hochberg's method to report significant pathways. We found 17 significantly enriched pathways for depression, which presented low-to-intermediate crosstalk. The top four pathways were long-term depression (p⩽1×10-5), calcium signalling (p⩽6×10-5), arrhythmogenic right ventricular cardiomyopathy (p⩽1.6×10-4) and cell adhesion molecules (p⩽2.2×10-4). In conclusion, our comprehensive pathway analyses identified promising pathways for depression that are related to neurotransmitter and neuronal systems, immune system and inflammatory response, which may be involved in the pathophysiological mechanisms underlying depression. We demonstrated that pathway enrichment analysis is promising to facilitate our understanding of complex traits through a deeper interpretation of GWA data. Application of this comprehensive analytic strategy in upcoming GWA data for depression could validate the findings reported in this study.

Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways.

PubMed

Eleftherohorinou, Hariklia; Hoggart, Clive J; Wright, Victoria J; Levin, Michael; Coin, Lachlan J M

2011-09-01

Rheumatoid arthritis (RA) is the commonest chronic, systemic, inflammatory disorder affecting ∼1% of the world population. It has a strong genetic component and a growing number of associated genes have been discovered in genome-wide association studies (GWAS), which nevertheless only account for 23% of the total genetic risk. We aimed to identify additional susceptibility loci through the analysis of GWAS in the context of biological function. We bridge the gap between pathway and gene-oriented analyses of GWAS, by introducing a pathway-driven gene stability-selection methodology that identifies potential causal genes in the top-associated disease pathways that may be driving the pathway association signals. We analysed the WTCCC and the NARAC studies of ∼5000 and ∼2000 subjects, respectively. We examined 700 pathways comprising ∼8000 genes. Ranking pathways by significance revealed that the NARAC top-ranked ∼6% laid within the top 10% of WTCCC. Gene selection on those pathways identified 58 genes in WTCCC and 61 in NARAC; 21 of those were common (P(overlap)< 10(-21)), of which 16 were novel discoveries. Among the identified genes, we validated 10 known RA associations in WTCCC and 13 in NARAC, not discovered using single-SNP approaches on the same data. Gene ontology functional enrichment analysis on the identified genes showed significant over-representation of signalling activity (P< 10(-29)) in both studies. Our findings suggest a novel model of RA genetic predisposition, which involves cell-membrane receptors and genes in second messenger signalling systems, in addition to genes that regulate immune responses, which have been the focus of interest previously.

Large-scale integrative network-based analysis identifies common pathways disrupted by copy number alterations across cancers

PubMed Central

2013-01-01

Background Many large-scale studies analyzed high-throughput genomic data to identify altered pathways essential to the development and progression of specific types of cancer. However, no previous study has been extended to provide a comprehensive analysis of pathways disrupted by copy number alterations across different human cancers. Towards this goal, we propose a network-based method to integrate copy number alteration data with human protein-protein interaction networks and pathway databases to identify pathways that are commonly disrupted in many different types of cancer. Results We applied our approach to a data set of 2,172 cancer patients across 16 different types of cancers, and discovered a set of commonly disrupted pathways, which are likely essential for tumor formation in majority of the cancers. We also identified pathways that are only disrupted in specific cancer types, providing molecular markers for different human cancers. Analysis with independent microarray gene expression datasets confirms that the commonly disrupted pathways can be used to identify patient subgroups with significantly different survival outcomes. We also provide a network view of disrupted pathways to explain how copy number alterations affect pathways that regulate cell growth, cycle, and differentiation for tumorigenesis. Conclusions In this work, we demonstrated that the network-based integrative analysis can help to identify pathways disrupted by copy number alterations across 16 types of human cancers, which are not readily identifiable by conventional overrepresentation-based and other pathway-based methods. All the results and source code are available at http://compbio.cs.umn.edu/NetPathID/. PMID:23822816

Presenilin-Based Genetic Screens in Drosophila melanogaster Identify Novel Notch Pathway Modifiers

PubMed Central

Mahoney, Matt B.; Parks, Annette L.; Ruddy, David A.; Tiong, Stanley Y. K.; Esengil, Hanife; Phan, Alexander C.; Philandrinos, Panos; Winter, Christopher G.; Chatterjee, Runa; Huppert, Kari; Fisher, William W.; L'Archeveque, Lynn; Mapa, Felipa A.; Woo, Wendy; Ellis, Michael C.; Curtis, Daniel

2006-01-01

Presenilin is the enzymatic component of γ-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for γ-tubulin in the pathway. PMID:16415372

Presenilin-based genetic screens in Drosophila melanogaster identify novel notch pathway modifiers.

PubMed

Mahoney, Matt B; Parks, Annette L; Ruddy, David A; Tiong, Stanley Y K; Esengil, Hanife; Phan, Alexander C; Philandrinos, Panos; Winter, Christopher G; Chatterjee, Runa; Huppert, Kari; Fisher, William W; L'Archeveque, Lynn; Mapa, Felipa A; Woo, Wendy; Ellis, Michael C; Curtis, Daniel

2006-04-01

Presenilin is the enzymatic component of gamma-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for gamma-tubulin in the pathway.

Geographically multifarious phenotypic divergence during speciation

PubMed Central

Gompert, Zachariah; Lucas, Lauren K; Nice, Chris C; Fordyce, James A; Alex Buerkle, C; Forister, Matthew L

2013-01-01

Speciation is an important evolutionary process that occurs when barriers to gene flow evolve between previously panmictic populations. Although individual barriers to gene flow have been studied extensively, we know relatively little regarding the number of barriers that isolate species or whether these barriers are polymorphic within species. Herein, we use a series of field and lab experiments to quantify phenotypic divergence and identify possible barriers to gene flow between the butterfly species Lycaeides idas and Lycaeides melissa. We found evidence that L. idas and L. melissa have diverged along multiple phenotypic axes. Specifically, we identified major phenotypic differences in female oviposition preference and diapause initiation, and more moderate divergence in mate preference. Multiple phenotypic differences might operate as barriers to gene flow, as shown by correlations between genetic distance and phenotypic divergence and patterns of phenotypic variation in admixed Lycaeides populations. Although some of these traits differed primarily between species (e.g., diapause initiation), several traits also varied among conspecific populations (e.g., male mate preference and oviposition preference). PMID:23532669

GWAS-identified schizophrenia risk SNPs at TSPAN18 are highly diverged between Europeans and East Asians.

PubMed

Liu, Jiewei; Li, Ming; Su, Bing

2016-12-01

Genome-wide association studies (GWASs) have identified multiple schizophrenia (SCZ) risk variants for samples of European and East Asian descent, but most of the identified susceptibility variants are population-specific to either Europeans or East Asians. This strong genetic heterogeneity suggests that differential population histories may play a role in SCZ susceptibility. Here, we explored this possibility by examining the allele frequency divergence of 136 previously reported genome-wide SCZ risk SNPs between European and East Asian populations. Our results showed that two SNPs (rs11038167 and rs11038172) at TSPAN18, reported as genome-wide significant SCZ risk variants in Han Chinese, were entirely monomorphic in Europeans, indicating a deep between-population divergence at this gene locus. To explore the evolutionary history of TSPAN18 in East Asians, we conducted population genetic analyses including multiple neutrality tests, the haplotype-based iHS and EHH tests, as well as haplotype bifurcation map and network constructions. We found that the protective allele of rs11038172 (G allele) had a long extended haplotype with much slower decay compared to the A allele. The star-like shape of the G-allele-carrying haplotypes indicates a recent enrichment in East Asians. Together, the evidences suggest that the protective allele of rs11038172 has experienced recent Darwinian positive selection in East Asians. These findings provide new insights that may help explain the strong genetic heterogeneity in SCZ risk and previous inconsistent association results for SCZ among both Europeans and East Asians. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

TGMI: an efficient algorithm for identifying pathway regulators through evaluation of triple-gene mutual interaction

PubMed Central

Gunasekara, Chathura; Zhang, Kui; Deng, Wenping; Brown, Laura

2018-01-01

Abstract Despite their important roles, the regulators for most metabolic pathways and biological processes remain elusive. Presently, the methods for identifying metabolic pathway and biological process regulators are intensively sought after. We developed a novel algorithm called triple-gene mutual interaction (TGMI) for identifying these regulators using high-throughput gene expression data. It first calculated the regulatory interactions among triple gene blocks (two pathway genes and one transcription factor (TF)), using conditional mutual information, and then identifies significantly interacted triple genes using a newly identified novel mutual interaction measure (MIM), which was substantiated to reflect strengths of regulatory interactions within each triple gene block. The TGMI calculated the MIM for each triple gene block and then examined its statistical significance using bootstrap. Finally, the frequencies of all TFs present in all significantly interacted triple gene blocks were calculated and ranked. We showed that the TFs with higher frequencies were usually genuine pathway regulators upon evaluating multiple pathways in plants, animals and yeast. Comparison of TGMI with several other algorithms demonstrated its higher accuracy. Therefore, TGMI will be a valuable tool that can help biologists to identify regulators of metabolic pathways and biological processes from the exploded high-throughput gene expression data in public repositories. PMID:29579312

Conceptual issues in Bayesian divergence time estimation

PubMed Central

2016-01-01

Bayesian inference of species divergence times is an unusual statistical problem, because the divergence time parameters are not identifiable unless both fossil calibrations and sequence data are available. Commonly used marginal priors on divergence times derived from fossil calibrations may conflict with node order on the phylogenetic tree causing a change in the prior on divergence times for a particular topology. Care should be taken to avoid confusing this effect with changes due to informative sequence data. This effect is illustrated with examples. A topology-consistent prior that preserves the marginal priors is defined and examples are constructed. Conflicts between fossil calibrations and relative branch lengths (based on sequence data) can cause estimates of divergence times that are grossly incorrect, yet have a narrow posterior distribution. An example of this effect is given; it is recommended that overly narrow posterior distributions of divergence times should be carefully scrutinized. This article is part of the themed issue ‘Dating species divergences using rocks and clocks’. PMID:27325831

Systems-Based Analysis of the Sarcocystis neurona Genome Identifies Pathways That Contribute to a Heteroxenous Life Cycle

PubMed Central

Blazejewski, Tomasz; Nursimulu, Nirvana; Pszenny, Viviana; Dangoudoubiyam, Sriveny; Namasivayam, Sivaranjani; Chiasson, Melissa A.; Chessman, Kyle; Tonkin, Michelle; Swapna, Lakshmipuram S.; Hung, Stacy S.; Bridgers, Joshua; Ricklefs, Stacy M.; Boulanger, Martin J.; Dubey, Jitender P.; Porcella, Stephen F.; Kissinger, Jessica C.; Howe, Daniel K.

2015-01-01

ABSTRACT Sarcocystis neurona is a member of the coccidia, a clade of single-celled parasites of medical and veterinary importance including Eimeria, Sarcocystis, Neospora, and Toxoplasma. Unlike Eimeria, a single-host enteric pathogen, Sarcocystis, Neospora, and Toxoplasma are two-host parasites that infect and produce infectious tissue cysts in a wide range of intermediate hosts. As a genus, Sarcocystis is one of the most successful protozoan parasites; all vertebrates, including birds, reptiles, fish, and mammals are hosts to at least one Sarcocystis species. Here we sequenced Sarcocystis neurona, the causal agent of fatal equine protozoal myeloencephalitis. The S. neurona genome is 127 Mbp, more than twice the size of other sequenced coccidian genomes. Comparative analyses identified conservation of the invasion machinery among the coccidia. However, many dense-granule and rhoptry kinase genes, responsible for altering host effector pathways in Toxoplasma and Neospora, are absent from S. neurona. Further, S. neurona has a divergent repertoire of SRS proteins, previously implicated in tissue cyst formation in Toxoplasma. Systems-based analyses identified a series of metabolic innovations, including the ability to exploit alternative sources of energy. Finally, we present an S. neurona model detailing conserved molecular innovations that promote the transition from a purely enteric lifestyle (Eimeria) to a heteroxenous parasite capable of infecting a wide range of intermediate hosts. PMID:25670772

Systematic analysis of microarray datasets to identify Parkinson's disease‑associated pathways and genes.

PubMed

Feng, Yinling; Wang, Xuefeng

2017-03-01

In order to investigate commonly disturbed genes and pathways in various brain regions of patients with Parkinson's disease (PD), microarray datasets from previous studies were collected and systematically analyzed. Different normalization methods were applied to microarray datasets from different platforms. A strategy combining gene co‑expression networks and clinical information was adopted, using weighted gene co‑expression network analysis (WGCNA) to screen for commonly disturbed genes in different brain regions of patients with PD. Functional enrichment analysis of commonly disturbed genes was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Co‑pathway relationships were identified with Pearson's correlation coefficient tests and a hypergeometric distribution‑based test. Common genes in pathway pairs were selected out and regarded as risk genes. A total of 17 microarray datasets from 7 platforms were retained for further analysis. Five gene coexpression modules were identified, containing 9,745, 736, 233, 101 and 93 genes, respectively. One module was significantly correlated with PD samples and thus the 736 genes it contained were considered to be candidate PD‑associated genes. Functional enrichment analysis demonstrated that these genes were implicated in oxidative phosphorylation and PD. A total of 44 pathway pairs and 52 risk genes were revealed, and a risk gene pathway relationship network was constructed. Eight modules were identified and were revealed to be associated with PD, cancers and metabolism. A number of disturbed pathways and risk genes were unveiled in PD, and these findings may help advance understanding of PD pathogenesis.

Whole-Exome Sequencing to Identify Novel Biological Pathways Associated With Infertility After Pelvic Inflammatory Disease.

PubMed

Taylor, Brandie D; Zheng, Xiaojing; Darville, Toni; Zhong, Wujuan; Konganti, Kranti; Abiodun-Ojo, Olayinka; Ness, Roberta B; O'Connell, Catherine M; Haggerty, Catherine L

2017-01-01

Ideal management of sexually transmitted infections (STI) may require risk markers for pathology or vaccine development. Previously, we identified common genetic variants associated with chlamydial pelvic inflammatory disease (PID) and reduced fecundity. As this explains only a proportion of the long-term morbidity risk, we used whole-exome sequencing to identify biological pathways that may be associated with STI-related infertility. We obtained stored DNA from 43 non-Hispanic black women with PID from the PID Evaluation and Clinical Health Study. Infertility was assessed at a mean of 84 months. Principal component analysis revealed no population stratification. Potential covariates did not significantly differ between groups. Sequencing kernel association test was used to examine associations between aggregates of variants on a single gene and infertility. The results from the sequencing kernel association test were used to choose "focus genes" (P < 0.01; n = 150) for subsequent Ingenuity Pathway Analysis to identify "gene sets" that are enriched in biologically relevant pathways. Pathway analysis revealed that focus genes were enriched in canonical pathways including, IL-1 signaling, P2Y purinergic receptor signaling, and bone morphogenic protein signaling. Focus genes were enriched in pathways that impact innate and adaptive immunity, protein kinase A activity, cellular growth, and DNA repair. These may alter host resistance or immunopathology after infection. Targeted sequencing of biological pathways identified in this study may provide insight into STI-related infertility.

Conceptual issues in Bayesian divergence time estimation.

PubMed

Rannala, Bruce

2016-07-19

Bayesian inference of species divergence times is an unusual statistical problem, because the divergence time parameters are not identifiable unless both fossil calibrations and sequence data are available. Commonly used marginal priors on divergence times derived from fossil calibrations may conflict with node order on the phylogenetic tree causing a change in the prior on divergence times for a particular topology. Care should be taken to avoid confusing this effect with changes due to informative sequence data. This effect is illustrated with examples. A topology-consistent prior that preserves the marginal priors is defined and examples are constructed. Conflicts between fossil calibrations and relative branch lengths (based on sequence data) can cause estimates of divergence times that are grossly incorrect, yet have a narrow posterior distribution. An example of this effect is given; it is recommended that overly narrow posterior distributions of divergence times should be carefully scrutinized.This article is part of the themed issue 'Dating species divergences using rocks and clocks'. © 2016 The Author(s).

Local divergence and curvature divergence in first order optics

NASA Astrophysics Data System (ADS)

Mafusire, Cosmas; Krüger, Tjaart P. J.

2018-06-01

The far-field divergence of a light beam propagating through a first order optical system is presented as a square root of the sum of the squares of the local divergence and the curvature divergence. The local divergence is defined as the ratio of the beam parameter product to the beam width whilst the curvature divergence is a ratio of the space-angular moment also to the beam width. It is established that the beam’s focusing parameter can be defined as a ratio of the local divergence to the curvature divergence. The relationships between the two divergences and other second moment-based beam parameters are presented. Their various mathematical properties are presented such as their evolution through first order systems. The efficacy of the model in the analysis of high power continuous wave laser-based welding systems is briefly discussed.

Molecular evolution accompanying functional divergence of duplicated genes along the plant starch biosynthesis pathway

PubMed Central

2014-01-01

Background Starch is the main source of carbon storage in the Archaeplastida. The starch biosynthesis pathway (sbp) emerged from cytosolic glycogen metabolism shortly after plastid endosymbiosis and was redirected to the plastid stroma during the green lineage divergence. The SBP is a complex network of genes, most of which are members of large multigene families. While some gene duplications occurred in the Archaeplastida ancestor, most were generated during the sbp redirection process, and the remaining few paralogs were generated through compartmentalization or tissue specialization during the evolution of the land plants. In the present study, we tested models of duplicated gene evolution in order to understand the evolutionary forces that have led to the development of SBP in angiosperms. We combined phylogenetic analyses and tests on the rates of evolution along branches emerging from major duplication events in six gene families encoding sbp enzymes. Results We found evidence of positive selection along branches following cytosolic or plastidial specialization in two starch phosphorylases and identified numerous residues that exhibited changes in volume, polarity or charge. Starch synthases, branching and debranching enzymes functional specializations were also accompanied by accelerated evolution. However, none of the sites targeted by selection corresponded to known functional domains, catalytic or regulatory. Interestingly, among the 13 duplications tested, 7 exhibited evidence of positive selection in both branches emerging from the duplication, 2 in only one branch, and 4 in none of the branches. Conclusions The majority of duplications were followed by accelerated evolution targeting specific residues along both branches. This pattern was consistent with the optimization of the two sub-functions originally fulfilled by the ancestral gene before duplication. Our results thereby provide strong support to the so-called “Escape from Adaptive Conflict�

Divergence in Morris Water Maze-Based Cognitive Performance under Chronic Stress Is Associated with the Hippocampal Whole Transcriptomic Modification in Mice

PubMed Central

Jung, Seung H.; Brownlow, Milene L.; Pellegrini, Matteo; Jankord, Ryan

2017-01-01

Individual susceptibility determines the magnitude of stress effects on cognitive function. The hippocampus, a brain region of memory consolidation, is vulnerable to stressful environments, and the impact of stress on hippocampus may determine individual variability in cognitive performance. Therefore, the purpose of this study was to define the relationship between the divergence in spatial memory performance under chronically unpredictable stress and an associated transcriptomic alternation in hippocampus, the brain region of spatial memory consolidation. Multiple strains of BXD (B6 × D2) recombinant inbred mice went through a 4-week chronic variable stress (CVS) paradigm, and the Morris water maze (MWM) test was conducted during the last week of CVS to assess hippocampal-dependent spatial memory performance and grouped animals into low and high performing groups based on the cognitive performance. Using hippocampal whole transcriptome RNA-sequencing data, differential expression, PANTHER analysis, WGCNA, Ingenuity's upstream regulator analysis in the Ingenuity Pathway Analysis® and phenotype association analysis were conducted. Our data identified multiple genes and pathways that were significantly associated with chronic stress-associated cognitive modification and the divergence in hippocampal dependent memory performance under chronic stress. Biological pathways associated with memory performance following chronic stress included metabolism, neurotransmitter and receptor regulation, immune response and cellular process. The Ingenuity's upstream regulator analysis identified 247 upstream transcriptional regulators from 16 different molecule types. Transcripts predictive of cognitive performance under high stress included genes that are associated with a high occurrence of Alzheimer's and cognitive impairments (e.g., Ncl, Eno1, Scn9a, Slc19a3, Ncstn, Fos, Eif4h, Copa, etc.). Our results show that the variable effects of chronic stress on the hippocampal

Meta-dimensional data integration identifies critical pathways for susceptibility, tumorigenesis and progression of endometrial cancer.

PubMed

Wei, Runmin; De Vivo, Immaculata; Huang, Sijia; Zhu, Xun; Risch, Harvey; Moore, Jason H; Yu, Herbert; Garmire, Lana X

2016-08-23

Endometrial Cancer (EC) is one of the most common female cancers. Genome-wide association studies (GWAS) have been investigated to identify genetic polymorphisms that are predictive of EC risks. Here we utilized a meta-dimensional integrative approach to seek genetically susceptible pathways that may be associated with tumorigenesis and progression of EC. We analyzed GWAS data obtained from Connecticut Endometrial Cancer Study (CECS) and identified the top 20 EC susceptible pathways. To further verify the significance of top 20 EC susceptible pathways, we conducted pathway-level multi-omics analyses using EC exome-Seq, RNA-Seq and survival data, all based on The Cancer Genome Atlas (TCGA) samples. We measured the overall consistent rankings of these pathways in all four data types. Some well-studied pathways, such as p53 signaling and cell cycle pathways, show consistently high rankings across different analyses. Additionally, other cell signaling pathways (e.g. IGF-1/mTOR, rac-1 and IL-5 pathway), genetic information processing pathway (e.g. homologous recombination) and metabolism pathway (e.g. sphingolipid metabolism) are also highly associated with EC risks, diagnosis and prognosis. In conclusion, the meta-dimensional integration of EC cohorts has suggested some common pathways that may be associated from predisposition, tumorigenesis to progression.

Predicting hepatocellular carcinoma through cross-talk genes identified by risk pathways

PubMed Central

Shao, Zhuo; Huo, Diwei; Zhang, Denan; Xie, Hongbo; Yang, Jingbo; Liu, Qiuqi; Chen, Xiujie

2018-01-01

Hepatocellular carcinoma (HCC) is the most frequent type of liver cancer with poor survival rate and high mortality. Despite efforts on the mechanism of HCC, new molecular markers are needed for exact diagnosis, evaluation and treatment. Here, we combined transcriptome of HCC with networks and pathways to identify reliable molecular markers. Through integrating 249 differentially expressed genes with syncretic protein interaction networks, we constructed a HCC-specific network, from which we further extracted 480 pivotal genes. Based on the cross-talk between the enriched pathways of the pivotal genes, we finally identified a HCC signature of 45 genes, which could accurately distinguish HCC patients with normal individuals and reveal the prognosis of HCC patients. Among these 45 genes, 15 showed dysregulated expression patterns and a part have been reported to be associated with HCC and/or other cancers. These findings suggested that our identified 45 gene signature could be potential and valuable molecular markers for diagnosis and evaluation of HCC. PMID:29765536

Vergence Neural Pathways: A Systematic Narrative Literature Review

PubMed Central

Searle, Annabelle; Rowe, Fiona J.

2016-01-01

ABSTRACT Research in the neural pathway for vergence is less understood in comparison to the other four visual eye movements. The aim of this study was to review the literature on vergence neural pathways and associated disorders. A review of previous published literature though to March 2016 was conducted. Intracranial pathologies that affect entire neural functioning were found to cause convergence insufficiencies. In contrast, pathologies with a more localised intracranial lesion cause more specific vergence disorders. There is debate as to the potential presence of a “divergence centre.” Detailed information on the divergence pathway is lacking and warrants further research. PMID:27928407

ICSNPathway: identify candidate causal SNPs and pathways from genome-wide association study by one analytical framework.

PubMed

Zhang, Kunlin; Chang, Suhua; Cui, Sijia; Guo, Liyuan; Zhang, Liuyan; Wang, Jing

2011-07-01

Genome-wide association study (GWAS) is widely utilized to identify genes involved in human complex disease or some other trait. One key challenge for GWAS data interpretation is to identify causal SNPs and provide profound evidence on how they affect the trait. Currently, researches are focusing on identification of candidate causal variants from the most significant SNPs of GWAS, while there is lack of support on biological mechanisms as represented by pathways. Although pathway-based analysis (PBA) has been designed to identify disease-related pathways by analyzing the full list of SNPs from GWAS, it does not emphasize on interpreting causal SNPs. To our knowledge, so far there is no web server available to solve the challenge for GWAS data interpretation within one analytical framework. ICSNPathway is developed to identify candidate causal SNPs and their corresponding candidate causal pathways from GWAS by integrating linkage disequilibrium (LD) analysis, functional SNP annotation and PBA. ICSNPathway provides a feasible solution to bridge the gap between GWAS and disease mechanism study by generating hypothesis of SNP → gene → pathway(s). The ICSNPathway server is freely available at http://icsnpathway.psych.ac.cn/.

An integrative somatic mutation analysis to identify pathways linked with survival outcomes across 19 cancer types

PubMed Central

Park, Sunho; Kim, Seung-Jun; Yu, Donghyeon; Peña-Llopis, Samuel; Gao, Jianjiong; Park, Jin Suk; Chen, Beibei; Norris, Jessie; Wang, Xinlei; Chen, Min; Kim, Minsoo; Yong, Jeongsik; Wardak, Zabi; Choe, Kevin; Story, Michael; Starr, Timothy; Cheong, Jae-Ho; Hwang, Tae Hyun

2016-01-01

Motivation: Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. Results: We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. Availability and implementation: The code is available at: http://www.taehyunlab.org. Contact: jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26635139

Dynamic Investigation of Static Divergence: Analysis and Testing

NASA Technical Reports Server (NTRS)

Heeg, Jennifer

2000-01-01

The phenomenon known as aeroelastic divergence is the focus of this work. The analyses and experiment presented here show that divergence can occur without a structural dynamic mode losing its oscillatory nature. Aeroelastic divergence occurs when the structural restorative capability or stiffness of a structure is overwhelmed by the static aerodynamic moment. This static aeroelastic coupling does not require the structural dynamic system behavior to cease, however. Aeroelastic changes in the dynamic mode behavior are governed not only by the stiffness, but by damping and inertial properties. The work presented here supports these fundamental assertions by examining a simple system: a typical section airfoil with only a rotational structural degree of freedom. Analytical results identified configurations that exhibit different types of dynamic mode behavior as the system encounters divergence. A wind tunnel model was designed and tested to examine divergence experimentally. The experimental results validate the analytical calculations and explicitly examine the divergence phenomenon where the dynamic mode persists. Three configurations of the wind tunnel model were tested. The experimental results agree very well with the analytical predictions of subcritical characteristics, divergence velocity, and behavior of the noncritical dynamic mode at divergence.

PathScore: a web tool for identifying altered pathways in cancer data.

PubMed

Gaffney, Stephen G; Townsend, Jeffrey P

2016-12-01

PathScore quantifies the level of enrichment of somatic mutations within curated pathways, applying a novel approach that identifies pathways enriched across patients. The application provides several user-friendly, interactive graphic interfaces for data exploration, including tools for comparing pathway effect sizes, significance, gene-set overlap and enrichment differences between projects. Web application available at pathscore.publichealth.yale.edu. Site implemented in Python and MySQL, with all major browsers supported. Source code available at: github.com/sggaffney/pathscore with a GPLv3 license. stephen.gaffney@yale.edu. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Comparative Analysis of the Full Genome of Helicobacter pylori Isolate Sahul64 Identifies Genes of High Divergence

PubMed Central

Lu, Wei; Wise, Michael J.; Tay, Chin Yen; Windsor, Helen M.; Marshall, Barry J.; Peacock, Christopher

2014-01-01

Isolates of Helicobacter pylori can be classified phylogeographically. High genetic diversity and rapid microevolution are a hallmark of H. pylori genomes, a phenomenon that is proposed to play a functional role in persistence and colonization of diverse human populations. To provide further genomic evidence in the lineage of H. pylori and to further characterize diverse strains of this pathogen in different human populations, we report the finished genome sequence of Sahul64, an H. pylori strain isolated from an indigenous Australian. Our analysis identified genes that were highly divergent compared to the 38 publically available genomes, which include genes involved in the biosynthesis and modification of lipopolysaccharide, putative prophage genes, restriction modification components, and hypothetical genes. Furthermore, the virulence-associated vacA locus is a pseudogene and the cag pathogenicity island (cagPAI) is not present. However, the genome does contain a gene cluster associated with pathogenicity, including dupA. Our analysis found that with the addition of Sahul64 to the 38 genomes, the core genome content of H. pylori is reduced by approximately 14% (∼170 genes) and the pan-genome has expanded from 2,070 to 2,238 genes. We have identified three putative horizontally acquired regions, including one that is likely to have been acquired from the closely related Helicobacter cetorum prior to speciation. Our results suggest that Sahul64, with the absence of cagPAI, highly divergent cell envelope proteins, and a predicted nontransportable VacA protein, could be more highly adapted to ancient indigenous Australian people but with lower virulence potential compared to other sequenced and cagPAI-positive H. pylori strains. PMID:24375107

Comparative analysis of the full genome of Helicobacter pylori isolate Sahul64 identifies genes of high divergence.

PubMed

Lu, Wei; Wise, Michael J; Tay, Chin Yen; Windsor, Helen M; Marshall, Barry J; Peacock, Christopher; Perkins, Tim

2014-03-01

Isolates of Helicobacter pylori can be classified phylogeographically. High genetic diversity and rapid microevolution are a hallmark of H. pylori genomes, a phenomenon that is proposed to play a functional role in persistence and colonization of diverse human populations. To provide further genomic evidence in the lineage of H. pylori and to further characterize diverse strains of this pathogen in different human populations, we report the finished genome sequence of Sahul64, an H. pylori strain isolated from an indigenous Australian. Our analysis identified genes that were highly divergent compared to the 38 publically available genomes, which include genes involved in the biosynthesis and modification of lipopolysaccharide, putative prophage genes, restriction modification components, and hypothetical genes. Furthermore, the virulence-associated vacA locus is a pseudogene and the cag pathogenicity island (cagPAI) is not present. However, the genome does contain a gene cluster associated with pathogenicity, including dupA. Our analysis found that with the addition of Sahul64 to the 38 genomes, the core genome content of H. pylori is reduced by approximately 14% (∼170 genes) and the pan-genome has expanded from 2,070 to 2,238 genes. We have identified three putative horizontally acquired regions, including one that is likely to have been acquired from the closely related Helicobacter cetorum prior to speciation. Our results suggest that Sahul64, with the absence of cagPAI, highly divergent cell envelope proteins, and a predicted nontransportable VacA protein, could be more highly adapted to ancient indigenous Australian people but with lower virulence potential compared to other sequenced and cagPAI-positive H. pylori strains.

Isolation driven divergence: speciation in a widespread North American songbird (Aves: Certhiidae)

PubMed Central

Manthey, Joseph D.; Klicka, John; Spellman, Garth M.

2011-01-01

Lineage, or true “species,” trees may differ from gene trees because of stochastic processes in molecular evolution leading to gene-tree heterogeneity. Problems with inferring species trees due to excessive incomplete lineage sorting may be exacerbated in lineages with rapid diversification or recent divergences necessitating the use of multiple loci and individuals. Many recent multilocus studies that investigate divergence times identify lineage splitting to be more recent than single locus studies, forcing the revision of biogeographic scenarios driving divergence. Here we use 21 nuclear loci from regional populations to reevaluate hypotheses identified in an mtDNA phylogeographic study of the Brown Creeper (Certhia americana), as well as identify processes driving divergence. Nuclear phylogeographic analyses identified hierarchical genetic structure, supporting a basal split at roughly 32°N latitude, splitting northern and southern populations, with mixed patterns of genealogical concordance and discordance between datasets within the major lineages. Coalescent-based analyses identify isolation, with little to no gene flow, as the primary driver of divergence between lineages. Recent isolation appears to have caused genetic bottlenecks in populations in the Sierra Madre Oriental and coastal mountain ranges of California, which may be targets for conservation concerns. PMID:21933295

Gene Expression Profiling Identifies Downregulation of the Neurotrophin-MAPK Signaling Pathway in Female Diabetic Peripheral Neuropathy Patients.

PubMed

Luo, Lin; Zhou, Wen-Hua; Cai, Jiang-Jia; Feng, Mei; Zhou, Mi; Hu, Su-Pei; Xu, Jin; Ji, Lin-Dan

2017-01-01

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). It is not diagnosed or managed properly in the majority of patients because its pathogenesis remains controversial. In this study, human whole genome microarrays identified 2898 and 4493 differentially expressed genes (DEGs) in DM and DPN patients, respectively. A further KEGG pathway analysis indicated that DPN and DM share four pathways, including apoptosis, B cell receptor signaling pathway, endocytosis, and Toll-like receptor signaling pathway. The DEGs identified through comparison of DPN and DM were significantly enriched in MAPK signaling pathway, NOD-like receptor signaling pathway, and neurotrophin signaling pathway, while the "neurotrophin-MAPK signaling pathway" was notably downregulated. Seven DEGs from the neurotrophin-MAPK signaling pathway were validated in additional 78 samples, and the results confirmed the initial microarray findings. These findings demonstrated that downregulation of the neurotrophin-MAPK signaling pathway may be the major mechanism of DPN pathogenesis, thus providing a potential approach for DPN treatment.

Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells.

PubMed

Sato, Tatsuhiro; Higuchi, Yutaka; Shibagaki, Yoshio; Hattori, Seisuke

2017-09-01

Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Ecological divergence and evolutionary transition of resprouting types in Banksia attenuata.

PubMed

He, Tianhua

2014-08-01

Resprouting is a key functional trait that allows plants to survive diverse disturbances. The fitness benefits associated with resprouting include a rapid return to adult growth, early flowering, and setting seed. The resprouting responses observed following fire are varied, as are the ecological outcomes. Understanding the ecological divergence and evolutionary pathways of different resprouting types and how the environment and genetics interact to drive such morphological evolution represents an important, but under-studied, topic. In the present study, microsatellite markers and microevolutionary approaches were used to better understand: (1) whether genetic differentiation is related to morphological divergence among resprouting types and if so, whether there are any specific genetic variations associated with morphological divergence and (2) the evolutionary pathway of the transitions between two resprouting types in Banksia attenuata (epicormic resprouting from aerial stems or branch; resprouting from a underground lignotuber). The results revealed an association between population genetic differentiation and the morphological divergence of postfire resprouting types in B. attenuata. A microsatellite allele has been shown to be associated with epicormic populations. Approximate Bayesian Computation analysis revealed a likely evolutionary transition from epicormic to lignotuberous resprouting in B. attenuata. It is concluded that the postfire resprouting type in B. attenuata is likely determined by the fire's characteristics. The differentiated expression of postfire resprouting types in different environments is likely a consequence of local genetic adaptation. The capacity to shift the postfire resprouting type to adapt to diverse fire regimes is most likely the key factor explaining why B. attenuata is the most widespread member of the Banksia genus.

Gene Expression Profiling Identifies Downregulation of the Neurotrophin-MAPK Signaling Pathway in Female Diabetic Peripheral Neuropathy Patients

PubMed Central

Luo, Lin; Zhou, Wen-Hua; Cai, Jiang-Jia; Feng, Mei; Zhou, Mi; Hu, Su-Pei

2017-01-01

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). It is not diagnosed or managed properly in the majority of patients because its pathogenesis remains controversial. In this study, human whole genome microarrays identified 2898 and 4493 differentially expressed genes (DEGs) in DM and DPN patients, respectively. A further KEGG pathway analysis indicated that DPN and DM share four pathways, including apoptosis, B cell receptor signaling pathway, endocytosis, and Toll-like receptor signaling pathway. The DEGs identified through comparison of DPN and DM were significantly enriched in MAPK signaling pathway, NOD-like receptor signaling pathway, and neurotrophin signaling pathway, while the “neurotrophin-MAPK signaling pathway” was notably downregulated. Seven DEGs from the neurotrophin-MAPK signaling pathway were validated in additional 78 samples, and the results confirmed the initial microarray findings. These findings demonstrated that downregulation of the neurotrophin-MAPK signaling pathway may be the major mechanism of DPN pathogenesis, thus providing a potential approach for DPN treatment. PMID:28900628

Behavioural divergence, interfertility and speciation: a review.

PubMed

Pillay, Neville; Rymer, Tasmin L

2012-11-01

Behavioural compatibility between mates is fundamental for maintaining species boundaries and is achieved through appropriate communication between males and females. A breakdown in communication will lead to behavioural divergence and reduced interfertility. In this review, we summarise the current knowledge on male signals and female perception of these signals, integrating the literature from several taxa. We advocate that signaller-perceiver coevolution, which is usually under strong stabilising selection to enable mating, forms the basis of species-specific mate recognition systems. The mechanisms (phylogeny, geography, ecology, biology) shaping signaller-perceiver systems are briefly discussed to demonstrate the factors underpinning the evolution of signaller-perceiver couplings. Since divergence and diversification of communication systems is driven by changes in the mechanical properties of sensory pathways and morphology of sensory organs, we highlight signal modalities (auditory, olfactory, visual, tactile) and their importance in communication, particularly in mate selection. Next, using available examples and generating a stylised model, we suggest how disruption (biological, ecological, stochastic) of signaller-perceiver systems drives behavioural divergence and consequently results in reduced interfertility and speciation. Future studies should adopt an integrative approach, combining multiple parameters (phylogeny, adaptive utility of communication systems, genetics and biomechanical/biochemical properties of signals and perception) to explore how disruption of signaller-perceiver systems results in behavioural divergence and reduced interfertility. Finally, we question the impact that rapid environmental change will have on disruption of communication systems, potentially interfering with signaller-perceiver couplings. Copyright © 2012 Elsevier B.V. All rights reserved.

Identifiability and estimation of multiple transmission pathways in cholera and waterborne disease.

PubMed

Eisenberg, Marisa C; Robertson, Suzanne L; Tien, Joseph H

2013-05-07

Cholera and many waterborne diseases exhibit multiple characteristic timescales or pathways of infection, which can be modeled as direct and indirect transmission. A major public health issue for waterborne diseases involves understanding the modes of transmission in order to improve control and prevention strategies. An important epidemiological question is: given data for an outbreak, can we determine the role and relative importance of direct vs. environmental/waterborne routes of transmission? We examine whether parameters for a differential equation model of waterborne disease transmission dynamics can be identified, both in the ideal setting of noise-free data (structural identifiability) and in the more realistic setting in the presence of noise (practical identifiability). We used a differential algebra approach together with several numerical approaches, with a particular emphasis on identifiability of the transmission rates. To examine these issues in a practical public health context, we apply the model to a recent cholera outbreak in Angola (2006). Our results show that the model parameters-including both water and person-to-person transmission routes-are globally structurally identifiable, although they become unidentifiable when the environmental transmission timescale is fast. Even for water dynamics within the identifiable range, when noisy data are considered, only a combination of the water transmission parameters can practically be estimated. This makes the waterborne transmission parameters difficult to estimate, leading to inaccurate estimates of important epidemiological parameters such as the basic reproduction number (R0). However, measurements of pathogen persistence time in environmental water sources or measurements of pathogen concentration in the water can improve model identifiability and allow for more accurate estimation of waterborne transmission pathway parameters as well as R0. Parameter estimates for the Angola outbreak suggest

Hydrograph Separations can Identify Contaminant-Specific Pathways for Conservation Targeting in a Tile-Drained Watershed

USDA-ARS?s Scientific Manuscript database

Water quality issues continue to vex agriculture. Understanding contaminant-specific pathways could help clarify effective water quality management strategies in watersheds. Hypothesis: If conducted at nested scales, hydrograph separation techniques can identify contaminant-specific pathways that co...

Positive selection and functional divergence of farnesyl pyrophosphate synthase genes in plants.

PubMed

Qian, Jieying; Liu, Yong; Chao, Naixia; Ma, Chengtong; Chen, Qicong; Sun, Jian; Wu, Yaosheng

2017-02-04

Farnesyl pyrophosphate synthase (FPS) belongs to the short-chain prenyltransferase family, and it performs a conserved and essential role in the terpenoid biosynthesis pathway. However, its classification, evolutionary history, and the forces driving the evolution of FPS genes in plants remain poorly understood. Phylogeny and positive selection analysis was used to identify the evolutionary forces that led to the functional divergence of FPS in plants, and recombinant detection was undertaken using the Genetic Algorithm for Recombination Detection (GARD) method. The dataset included 68 FPS variation pattern sequences (2 gymnosperms, 10 monocotyledons, 54 dicotyledons, and 2 outgroups). This study revealed that the FPS gene was under positive selection in plants. No recombinant within the FPS gene was found. Therefore, it was inferred that the positive selection of FPS had not been influenced by a recombinant episode. The positively selected sites were mainly located in the catalytic center and functional areas, which indicated that the 98S and 234D were important positively selected sites for plant FPS in the terpenoid biosynthesis pathway. They were located in the FPS conserved domain of the catalytic site. We inferred that the diversification of FPS genes was associated with functional divergence and could be driven by positive selection. It was clear that protein sequence evolution via positive selection was able to drive adaptive diversification in plant FPS proteins. This study provides information on the classification and positive selection of plant FPS genes, and the results could be useful for further research on the regulation of triterpenoid biosynthesis.

Identifying novel glioma associated pathways based on systems biology level meta-analysis.

PubMed

Hu, Yangfan; Li, Jinquan; Yan, Wenying; Chen, Jiajia; Li, Yin; Hu, Guang; Shen, Bairong

2013-01-01

With recent advances in microarray technology, including genomics, proteomics, and metabolomics, it brings a great challenge for integrating this "-omics" data to analysis complex disease. Glioma is an extremely aggressive and lethal form of brain tumor, and thus the study of the molecule mechanism underlying glioma remains very important. To date, most studies focus on detecting the differentially expressed genes in glioma. However, the meta-analysis for pathway analysis based on multiple microarray datasets has not been systematically pursued. In this study, we therefore developed a systems biology based approach by integrating three types of omics data to identify common pathways in glioma. Firstly, the meta-analysis has been performed to study the overlapping of signatures at different levels based on the microarray gene expression data of glioma. Among these gene expression datasets, 12 pathways were found in GeneGO database that shared by four stages. Then, microRNA expression profiles and ChIP-seq data were integrated for the further pathway enrichment analysis. As a result, we suggest 5 of these pathways could be served as putative pathways in glioma. Among them, the pathway of TGF-beta-dependent induction of EMT via SMAD is of particular importance. Our results demonstrate that the meta-analysis based on systems biology level provide a more useful approach to study the molecule mechanism of complex disease. The integration of different types of omics data, including gene expression microarrays, microRNA and ChIP-seq data, suggest some common pathways correlated with glioma. These findings will offer useful potential candidates for targeted therapeutic intervention of glioma.

Quantitative Proteomics Identifies Activation of Hallmark Pathways of Cancer in Patient Melanoma.

PubMed

Byrum, Stephanie D; Larson, Signe K; Avaritt, Nathan L; Moreland, Linley E; Mackintosh, Samuel G; Cheung, Wang L; Tackett, Alan J

2013-03-01

Molecular pathways regulating melanoma initiation and progression are potential targets of therapeutic development for this aggressive cancer. Identification and molecular analysis of these pathways in patients has been primarily restricted to targeted studies on individual proteins. Here, we report the most comprehensive analysis of formalin-fixed paraffin-embedded human melanoma tissues using quantitative proteomics. From 61 patient samples, we identified 171 proteins varying in abundance among benign nevi, primary melanoma, and metastatic melanoma. Seventy-three percent of these proteins were validated by immunohistochemistry staining of malignant melanoma tissues from the Human Protein Atlas database. Our results reveal that molecular pathways involved with tumor cell proliferation, motility, and apoptosis are mis-regulated in melanoma. These data provide the most comprehensive proteome resource on patient melanoma and reveal insight into the molecular mechanisms driving melanoma progression.

The HEART Pathway randomized trial: identifying emergency department patients with acute chest pain for early discharge.

PubMed

Mahler, Simon A; Riley, Robert F; Hiestand, Brian C; Russell, Gregory B; Hoekstra, James W; Lefebvre, Cedric W; Nicks, Bret A; Cline, David M; Askew, Kim L; Elliott, Stephanie B; Herrington, David M; Burke, Gregory L; Miller, Chadwick D

2015-03-01

The HEART Pathway is a decision aid designed to identify emergency department patients with acute chest pain for early discharge. No randomized trials have compared the HEART Pathway with usual care. Adult emergency department patients with symptoms related to acute coronary syndrome without ST-elevation on ECG (n=282) were randomized to the HEART Pathway or usual care. In the HEART Pathway arm, emergency department providers used the HEART score, a validated decision aid, and troponin measures at 0 and 3 hours to identify patients for early discharge. Usual care was based on American College of Cardiology/American Heart Association guidelines. The primary outcome, objective cardiac testing (stress testing or angiography), and secondary outcomes, index length of stay, early discharge, and major adverse cardiac events (death, myocardial infarction, or coronary revascularization), were assessed at 30 days by phone interview and record review. Participants had a mean age of 53 years, 16% had previous myocardial infarction, and 6% (95% confidence interval, 3.6%-9.5%) had major adverse cardiac events within 30 days of randomization. Compared with usual care, use of the HEART Pathway decreased objective cardiac testing at 30 days by 12.1% (68.8% versus 56.7%; P=0.048) and length of stay by 12 hours (9.9 versus 21.9 hours; P=0.013) and increased early discharges by 21.3% (39.7% versus 18.4%; P<0.001). No patients identified for early discharge had major adverse cardiac events within 30 days. The HEART Pathway reduces objective cardiac testing during 30 days, shortens length of stay, and increases early discharges. These important efficiency gains occurred without any patients identified for early discharge suffering MACE at 30 days. URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01665521. © 2015 American Heart Association, Inc.

An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome.

PubMed

Guedj, Faycal; Pennings, Jeroen LA; Massingham, Lauren J; Wick, Heather C; Siegel, Ashley E; Tantravahi, Umadevi; Bianchi, Diana W

2016-09-02

Anatomical and functional brain abnormalities begin during fetal life in Down syndrome (DS). We hypothesize that novel prenatal treatments can be identified by targeting signaling pathways that are consistently perturbed in cell types/tissues obtained from human fetuses with DS and mouse embryos. We analyzed transcriptome data from fetuses with trisomy 21, age and sex-matched euploid controls, and embryonic day 15.5 forebrains from Ts1Cje, Ts65Dn, and Dp16 mice. The new datasets were compared to other publicly available datasets from humans with DS. We used the human Connectivity Map (CMap) database and created a murine adaptation to identify FDA-approved drugs that can rescue affected pathways. USP16 and TTC3 were dysregulated in all affected human cells and two mouse models. DS-associated pathway abnormalities were either the result of gene dosage specific effects or the consequence of a global cell stress response with activation of compensatory mechanisms. CMap analyses identified 56 molecules with high predictive scores to rescue abnormal gene expression in both species. Our novel integrated human/murine systems biology approach identified commonly dysregulated genes and pathways. This can help to prioritize therapeutic molecules on which to further test safety and efficacy. Additional studies in human cells are ongoing prior to pre-clinical prenatal treatment in mice.

Meta-Analysis of Placental Transcriptome Data Identifies a Novel Molecular Pathway Related to Preeclampsia.

PubMed

van Uitert, Miranda; Moerland, Perry D; Enquobahrie, Daniel A; Laivuori, Hannele; van der Post, Joris A M; Ris-Stalpers, Carrie; Afink, Gijs B

2015-01-01

Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies. Microarray data were pre-processed and analyzed using standardized bioinformatics and statistical procedures and the effect sizes were combined using an inverse-variance random-effects model. Interactions between genes in the resulting gene expression signature were identified by pathway analysis (Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, Graphite) and protein-protein associations (STRING). This approach has resulted in a comprehensive list of differentially expressed genes that led to a 388-gene meta-signature of preeclamptic placenta. Pathway analysis highlights the involvement of the previously identified hypoxia/HIF1A pathway in the establishment of the preeclamptic gene expression profile, while analysis of protein interaction networks indicates CREBBP/EP300 as a novel element central to the preeclamptic placental transcriptome. In addition, there is an apparent high incidence of preeclampsia in women carrying a child with a mutation in CREBBP/EP300 (Rubinstein-Taybi Syndrome). The 388-gene preeclampsia meta-signature offers a vital starting point for further studies into the relevance of these genes (in particular CREBBP/EP300) and their concomitant pathways as biomarkers or functional molecules in preeclampsia. This will result in a better understanding of the molecular basis of this disease and opens up the opportunity to develop rational therapies targeting the placental dysfunction causal to preeclampsia.

RNAseq Analysis of the Parasitic Nematode Strongyloides stercoralis Reveals Divergent Regulation of Canonical Dauer Pathways

PubMed Central

Stoltzfus, Jonathan D.; Minot, Samuel; Berriman, Matthew; Nolan, Thomas J.; Lok, James B.

2012-01-01

The infectious form of many parasitic nematodes, which afflict over one billion people globally, is a developmentally arrested third-stage larva (L3i). The parasitic nematode Strongyloides stercoralis differs from other nematode species that infect humans, in that its life cycle includes both parasitic and free-living forms, which can be leveraged to investigate the mechanisms of L3i arrest and activation. The free-living nematode Caenorhabditis elegans has a similar developmentally arrested larval form, the dauer, whose formation is controlled by four pathways: cyclic GMP (cGMP) signaling, insulin/IGF-1-like signaling (IIS), transforming growth factor β (TGFβ) signaling, and biosynthesis of dafachronic acid (DA) ligands that regulate a nuclear hormone receptor. We hypothesized that homologous pathways are present in S. stercoralis, have similar developmental regulation, and are involved in L3i arrest and activation. To test this, we undertook a deep-sequencing study of the polyadenylated transcriptome, generating over 2.3 billion paired-end reads from seven developmental stages. We constructed developmental expression profiles for S. stercoralis homologs of C. elegans dauer genes identified by BLAST searches of the S. stercoralis genome as well as de novo assembled transcripts. Intriguingly, genes encoding cGMP pathway components were coordinately up-regulated in L3i. In comparison to C. elegans, S. stercoralis has a paucity of genes encoding IIS ligands, several of which have abundance profiles suggesting involvement in L3i development. We also identified seven S. stercoralis genes encoding homologs of the single C. elegans dauer regulatory TGFβ ligand, three of which are only expressed in L3i. Putative DA biosynthetic genes did not appear to be coordinately regulated in L3i development. Our data suggest that while dauer pathway genes are present in S. stercoralis and may play a role in L3i development, there are significant differences between the two species

RNAseq analysis of the parasitic nematode Strongyloides stercoralis reveals divergent regulation of canonical dauer pathways.

PubMed

Stoltzfus, Jonathan D; Minot, Samuel; Berriman, Matthew; Nolan, Thomas J; Lok, James B

2012-01-01

The infectious form of many parasitic nematodes, which afflict over one billion people globally, is a developmentally arrested third-stage larva (L3i). The parasitic nematode Strongyloides stercoralis differs from other nematode species that infect humans, in that its life cycle includes both parasitic and free-living forms, which can be leveraged to investigate the mechanisms of L3i arrest and activation. The free-living nematode Caenorhabditis elegans has a similar developmentally arrested larval form, the dauer, whose formation is controlled by four pathways: cyclic GMP (cGMP) signaling, insulin/IGF-1-like signaling (IIS), transforming growth factor β (TGFβ) signaling, and biosynthesis of dafachronic acid (DA) ligands that regulate a nuclear hormone receptor. We hypothesized that homologous pathways are present in S. stercoralis, have similar developmental regulation, and are involved in L3i arrest and activation. To test this, we undertook a deep-sequencing study of the polyadenylated transcriptome, generating over 2.3 billion paired-end reads from seven developmental stages. We constructed developmental expression profiles for S. stercoralis homologs of C. elegans dauer genes identified by BLAST searches of the S. stercoralis genome as well as de novo assembled transcripts. Intriguingly, genes encoding cGMP pathway components were coordinately up-regulated in L3i. In comparison to C. elegans, S. stercoralis has a paucity of genes encoding IIS ligands, several of which have abundance profiles suggesting involvement in L3i development. We also identified seven S. stercoralis genes encoding homologs of the single C. elegans dauer regulatory TGFβ ligand, three of which are only expressed in L3i. Putative DA biosynthetic genes did not appear to be coordinately regulated in L3i development. Our data suggest that while dauer pathway genes are present in S. stercoralis and may play a role in L3i development, there are significant differences between the two species

Divergence Boundary Conditions for Vector Helmholtz Equations with Divergence Constraints

NASA Technical Reports Server (NTRS)

Kangro, Urve; Nicolaides, Roy

1997-01-01

The idea of replacing a divergence constraint by a divergence boundary condition is investigated. The connections between the formulations are considered in detail. It is shown that the most common methods of using divergence boundary conditions do not always work properly. Necessary and sufficient conditions for the equivalence of the formulations are given.

Integrated Analysis of Mutation Data from Various Sources Identifies Key Genes and Signaling Pathways in Hepatocellular Carcinoma

PubMed Central

Wei, Lin; Tang, Ruqi; Lian, Baofeng; Zhao, Yingjun; He, Xianghuo; Xie, Lu

2014-01-01

Background Recently, a number of studies have performed genome or exome sequencing of hepatocellular carcinoma (HCC) and identified hundreds or even thousands of mutations in protein-coding genes. However, these studies have only focused on a limited number of candidate genes, and many important mutation resources remain to be explored. Principal Findings In this study, we integrated mutation data obtained from various sources and performed pathway and network analysis. We identified 113 pathways that were significantly mutated in HCC samples and found that the mutated genes included in these pathways contained high percentages of known cancer genes, and damaging genes and also demonstrated high conservation scores, indicating their important roles in liver tumorigenesis. Five classes of pathways that were mutated most frequently included (a) proliferation and apoptosis related pathways, (b) tumor microenvironment related pathways, (c) neural signaling related pathways, (d) metabolic related pathways, and (e) circadian related pathways. Network analysis further revealed that the mutated genes with the highest betweenness coefficients, such as the well-known cancer genes TP53, CTNNB1 and recently identified novel mutated genes GNAL and the ADCY family, may play key roles in these significantly mutated pathways. Finally, we highlight several key genes (e.g., RPS6KA3 and PCLO) and pathways (e.g., axon guidance) in which the mutations were associated with clinical features. Conclusions Our workflow illustrates the increased statistical power of integrating multiple studies of the same subject, which can provide biological insights that would otherwise be masked under individual sample sets. This type of bioinformatics approach is consistent with the necessity of making the best use of the ever increasing data provided in valuable databases, such as TCGA, to enhance the speed of deciphering human cancers. PMID:24988079

Integrated analysis of mutation data from various sources identifies key genes and signaling pathways in hepatocellular carcinoma.

PubMed

Zhang, Yuannv; Qiu, Zhaoping; Wei, Lin; Tang, Ruqi; Lian, Baofeng; Zhao, Yingjun; He, Xianghuo; Xie, Lu

2014-01-01

Recently, a number of studies have performed genome or exome sequencing of hepatocellular carcinoma (HCC) and identified hundreds or even thousands of mutations in protein-coding genes. However, these studies have only focused on a limited number of candidate genes, and many important mutation resources remain to be explored. In this study, we integrated mutation data obtained from various sources and performed pathway and network analysis. We identified 113 pathways that were significantly mutated in HCC samples and found that the mutated genes included in these pathways contained high percentages of known cancer genes, and damaging genes and also demonstrated high conservation scores, indicating their important roles in liver tumorigenesis. Five classes of pathways that were mutated most frequently included (a) proliferation and apoptosis related pathways, (b) tumor microenvironment related pathways, (c) neural signaling related pathways, (d) metabolic related pathways, and (e) circadian related pathways. Network analysis further revealed that the mutated genes with the highest betweenness coefficients, such as the well-known cancer genes TP53, CTNNB1 and recently identified novel mutated genes GNAL and the ADCY family, may play key roles in these significantly mutated pathways. Finally, we highlight several key genes (e.g., RPS6KA3 and PCLO) and pathways (e.g., axon guidance) in which the mutations were associated with clinical features. Our workflow illustrates the increased statistical power of integrating multiple studies of the same subject, which can provide biological insights that would otherwise be masked under individual sample sets. This type of bioinformatics approach is consistent with the necessity of making the best use of the ever increasing data provided in valuable databases, such as TCGA, to enhance the speed of deciphering human cancers.

Bounds on Nonsymmetric Divergence Measure in terms of Other Symmetric and Nonsymmetric Divergence Measures

PubMed Central

Jain, K. C.; Chhabra, Praphull

2014-01-01

Vajda (1972) studied a generalized divergence measure of Csiszar's class, so called “Chi-m divergence measure.” Variational distance and Chi-square divergence are the special cases of this generalized divergence measure at m = 1 and m = 2, respectively. In this work, nonparametric nonsymmetric measure of divergence, a particular part of Vajda generalized divergence at m = 4, is taken and characterized. Its bounds are studied in terms of some well-known symmetric and nonsymmetric divergence measures of Csiszar's class by using well-known information inequalities. Comparison of this divergence with others is done. Numerical illustrations (verification) regarding bounds of this divergence are presented as well. PMID:27437464

Computational Investigations in Rectangular Convergent and Divergent Ribbed Channels

NASA Astrophysics Data System (ADS)

Sivakumar, Karthikeyan; Kulasekharan, N.; Natarajan, E.

2018-05-01

Computational investigations on the rib turbulated flow inside a convergent and divergent rectangular channel with square ribs of different rib heights and different Reynolds numbers (Re=20,000, 40,000 and 60,000). The ribs were arranged in a staggered fashion between the upper and lower surfaces of the test section. Computational investigations are carried out using computational fluid dynamic software ANSYS Fluent 14.0. Suitable solver settings like turbulence models were identified from the literature and the boundary conditions for the simulations on a solution of independent grid. Computations were carried out for both convergent and divergent channels with 0 (smooth duct), 1.5, 3, 6, 9 and 12 mm rib heights, to identify the ribbed channel with optimal performance, assessed using a thermo hydraulic performance parameter. The convergent and divergent rectangular channels show higher Nu values than the standard correlation values.

Regulation of the Carnitine Pathway in Escherichia coli: Investigation of the cai-fix Divergent Promoter Region

PubMed Central

Buchet, Anne; Eichler, Knut; Mandrand-Berthelot, Marie-Andrée

1998-01-01

The divergent structural operons caiTABCDE and fixABCX of Escherichia coli are required for anaerobic carnitine metabolism. Transcriptional monocopy lacZ fusion studies showed that both operons are coexpressed during anaerobic growth in the presence of carnitine, respond to common environmental stimuli (like glucose and nitrate), and are modulated positively by the same general regulators, CRP and FNR, and negatively by H-NS. Overproduction of the CaiF specific regulatory protein mediating the carnitine signal restored induction in an fnr mutant, corresponding to its role as the primary target for anaerobiosis. Transcript analysis identified two divergent transcription start points initiating 289 bp apart. DNase I footprinting revealed three sites with various affinities for the binding of the cAMP-CRP complex inside this regulatory region. Site-directed mutagenesis experiments indicated that previously reported perfect CRP motif 1, centered at −41.5 of the cai transcriptional start site, plays a direct role in the sole cai activation. In contrast, mutation in CRP site 2, positioned at −69.5 of the fix promoter, caused only a threefold reduction in fix expression. Thus, the role of the third CRP site, located at −126.5 of fix, might be to reinforce the action of site 2. A critical 50-bp cis-acting sequence overlapping the fix mRNA start site was found, by deletion analysis, to be necessary for cai transcription. This region is thought to be involved in transduction of the signal mediated by the CaiF regulator. PMID:9573142

Conifer species adapt to low-rainfall climates by following one of two divergent pathways.

PubMed

Brodribb, Timothy J; McAdam, Scott A M; Jordan, Gregory J; Martins, Samuel C V

2014-10-07

Water stress is one of the primary selective forces in plant evolution. There are characters often cited as adaptations to water stress, but links between the function of these traits and adaptation to drying climates are tenuous. Here we combine distributional, climatic, and physiological evidence from 42 species of conifers to show that the evolution of drought resistance follows two distinct pathways, both involving the coordinated evolution of tissues regulating water supply (xylem) and water loss (stomatal pores) in leaves. Only species with very efficient stomatal closure, and hence low minimum rates of water loss, inhabit dry habitats, but species diverged in their apparent mechanism for maintaining closed stomata during drought. An ancestral mechanism found in Pinaceae and Araucariaceae species relies on high levels of the hormone abscisic acid (ABA) to close stomata during water stress. A second mechanism, found in the majority of Cupressaceae species, uses leaf desiccation rather than high ABA levels to close stomata during sustained water stress. Species in the latter group were characterized by xylem tissues with extreme resistance to embolism but low levels of foliar ABA after 30 d without water. The combination of low levels of ABA under stress with cavitation-resistant xylem enables these species to prolong stomatal opening during drought, potentially extending their photosynthetic activity between rainfall events. Our data demonstrate a surprising simplicity in the way conifers evolved to cope with water shortage, indicating a critical interaction between xylem and stomatal tissues during the process of evolution to dry climates.

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

PubMed

Juraeva, Dilafruz; Haenisch, Britta; Zapatka, Marc; Frank, Josef; Witt, Stephanie H; Mühleisen, Thomas W; Treutlein, Jens; Strohmaier, Jana; Meier, Sandra; Degenhardt, Franziska; Giegling, Ina; Ripke, Stephan; Leber, Markus; Lange, Christoph; Schulze, Thomas G; Mössner, Rainald; Nenadic, Igor; Sauer, Heinrich; Rujescu, Dan; Maier, Wolfgang; Børglum, Anders; Ophoff, Roel; Cichon, Sven; Nöthen, Markus M; Rietschel, Marcella; Mattheisen, Manuel; Brors, Benedikt

2014-06-01

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.

A Whole-Cell Phenotypic Screening Platform for Identifying Methylerythritol Phosphate Pathway-Selective Inhibitors as Novel Antibacterial Agents

PubMed Central

Johnson, L. Jeffrey

2012-01-01

Isoprenoid biosynthesis is essential for survival of all living organisms. More than 50,000 unique isoprenoids occur naturally, with each constructed from two simple five-carbon precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Two pathways for the biosynthesis of IPP and DMAPP are found in nature. Humans exclusively use the mevalonate (MVA) pathway, while most bacteria, including all Gram-negative and many Gram-positive species, use the unrelated methylerythritol phosphate (MEP) pathway. Here we report the development of a novel, whole-cell phenotypic screening platform to identify compounds that selectively inhibit the MEP pathway. Strains of Salmonella enterica serovar Typhimurium were engineered to have separately inducible MEP (native) and MVA (nonnative) pathways. These strains, RMC26 and CT31-7d, were then used to differentiate MVA pathway- and MEP pathway-specific perturbation. Compounds that inhibit MEP pathway-dependent bacterial growth but leave MVA-dependent growth unaffected represent MEP pathway-selective antibacterials. This screening platform offers three significant results. First, the compound is antibacterial and is therefore cell permeant, enabling access to the intracellular target. Second, the compound inhibits one or more MEP pathway enzymes. Third, the MVA pathway is unaffected, suggesting selectivity for targeting the bacterial versus host pathway. The cell lines also display increased sensitivity to two reported MEP pathway-specific inhibitors, further biasing the platform toward inhibitors selective for the MEP pathway. We demonstrate development of a robust, high-throughput screening platform that combines phenotypic and target-based screening that can identify MEP pathway-selective antibacterials simply by monitoring optical density as the readout for cell growth/inhibition. PMID:22777049

Evidence for Divergent Evolution of Growth Temperature Preference in Sympatric Saccharomyces Species

PubMed Central

Gonçalves, Paula; Valério, Elisabete; Correia, Cláudia; de Almeida, João M. G. C. F.; Sampaio, José Paulo

2011-01-01

The genus Saccharomyces currently includes eight species in addition to the model yeast Saccharomyces cerevisiae, most of which can be consistently isolated from tree bark and soil. We recently found sympatric pairs of Saccharomyces species, composed of one cryotolerant and one thermotolerant species in oak bark samples of various geographic origins. In order to contribute to explain the occurrence in sympatry of Saccharomyces species, we screened Saccharomyces genomic data for protein divergence that might be correlated to distinct growth temperature preferences of the species, using the dN/dS ratio as a measure of protein evolution rates and pair-wise species comparisons. In addition to proteins previously implicated in growth at suboptimal temperatures, we found that glycolytic enzymes were among the proteins exhibiting higher than expected divergence when one cryotolerant and one thermotolerant species are compared. By measuring glycolytic fluxes and glycolytic enzymatic activities in different species and at different temperatures, we subsequently show that the unusual divergence of glycolytic genes may be related to divergent evolution of the glycolytic pathway aligning its performance to the growth temperature profiles of the different species. In general, our results support the view that growth temperature preference is a trait that may have undergone divergent selection in the course of ecological speciation in Saccharomyces. PMID:21674061

Internal Performance of Several Divergent-Shroud Ejector Nozzles with High Divergence Angles

NASA Technical Reports Server (NTRS)

Trout, Arthur M.; Papell, S. Stephen; Povolny, John H.

1957-01-01

Nine divergent-shroud ejector configurations were investigated to determine the effect of shroud divergence angle on ejector internal performance. Unheated dry air was used for both the primary and secondary flows. The decrease in the design-point thrust coefficient with increasing flow divergence angle (angle measured from primary exit to shroud exit) followed very closely a simple relation involving the cosine of the angle. This indicates that design-point thrust performance for divergent-shroud ejectors can be predicted with reasonable accuracy within the range investigated. The decrease in design-point thrust coefficient due to increasing the flow divergence engle from 120deg to 30deg (half-singles) was approximately 6 percent. Ejector air-handling characteristics and the primary-nozzle flow coefficient were not significantly affected by change in shroud divergence angle.

Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer’s disease

PubMed Central

Li, Xinzhong; Long, Jintao; He, Taigang; Belshaw, Robert; Scott, James

2015-01-01

Previous studies have evaluated gene expression in Alzheimer’s disease (AD) brains to identify mechanistic processes, but have been limited by the size of the datasets studied. Here we have implemented a novel meta-analysis approach to identify differentially expressed genes (DEGs) in published datasets comprising 450 late onset AD (LOAD) brains and 212 controls. We found 3124 DEGs, many of which were highly correlated with Braak stage and cerebral atrophy. Pathway Analysis revealed the most perturbed pathways to be (a) nitric oxide and reactive oxygen species in macrophages (NOROS), (b) NFkB and (c) mitochondrial dysfunction. NOROS was also up-regulated, and mitochondrial dysfunction down-regulated, in healthy ageing subjects. Upstream regulator analysis predicted the TLR4 ligands, STAT3 and NFKBIA, for activated pathways and RICTOR for mitochondrial genes. Protein-protein interaction network analysis emphasised the role of NFKB; identified a key interaction of CLU with complement; and linked TYROBP, TREM2 and DOK3 to modulation of LPS signalling through TLR4 and to phosphatidylinositol metabolism. We suggest that NEUROD6, ZCCHC17, PPEF1 and MANBAL are potentially implicated in LOAD, with predicted links to calcium signalling and protein mannosylation. Our study demonstrates a highly injurious combination of TLR4-mediated NFKB signalling, NOROS inflammatory pathway activation, and mitochondrial dysfunction in LOAD. PMID:26202100

Divergences in holographic complexity

NASA Astrophysics Data System (ADS)

Reynolds, Alan; Ross, Simon F.

2017-05-01

We study the UV divergences in the action of the ‘Wheeler-de Witt patch’ in asymptotically AdS spacetimes, which has been conjectured to be dual to the computational complexity of the state of the dual field theory on a spatial slice of the boundary. We show that including a surface term in the action on the null boundaries which ensures invariance under coordinate transformations has the additional virtue of removing a stronger than expected divergence, making the leading divergence proportional to the proper volume of the boundary spatial slice. We compare the divergences in the action to divergences in the volume of a maximal spatial slice in the bulk, finding that the qualitative structure is the same, but subleading divergences have different relative coefficients in the two cases.

Comparative qualitative phosphoproteomics analysis identifies shared phosphorylation motifs and associated biological processes in evolutionary divergent plants.

PubMed

Al-Momani, Shireen; Qi, Da; Ren, Zhe; Jones, Andrew R

2018-06-15

Phosphorylation is one of the most prevalent post-translational modifications and plays a key role in regulating cellular processes. We carried out a bioinformatics analysis of pre-existing phosphoproteomics data, to profile two model species representing the largest subclasses in flowering plants the dicot Arabidopsis thaliana and the monocot Oryza sativa, to understand the extent to which phosphorylation signaling and function is conserved across evolutionary divergent plants. We identified 6537 phosphopeptides from 3189 phosphoproteins in Arabidopsis and 2307 phosphopeptides from 1613 phosphoproteins in rice. We identified phosphorylation motifs, finding nineteen pS motifs and two pT motifs shared in rice and Arabidopsis. The majority of shared motif-containing proteins were mapped to the same biological processes with similar patterns of fold enrichment, indicating high functional conservation. We also identified shared patterns of crosstalk between phosphoserines with enrichment for motifs pSXpS, pSXXpS and pSXXXpS, where X is any amino acid. Lastly, our results identified several pairs of motifs that are significantly enriched to co-occur in Arabidopsis proteins, indicating cross-talk between different sites, but this was not observed in rice. Our results demonstrate that there are evolutionary conserved mechanisms of phosphorylation-mediated signaling in plants, via analysis of high-throughput phosphorylation proteomics data from key monocot and dicot species: rice and Arabidposis thaliana. The results also suggest that there is increased crosstalk between phosphorylation sites in A. thaliana compared with rice. The results are important for our general understanding of cell signaling in plants, and the ability to use A. thaliana as a general model for plant biology. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Serum Metabolomic Profiling in Acute Alcoholic Hepatitis Identifies Multiple Dysregulated Pathways

PubMed Central

Rachakonda, Vikrant; Gabbert, Charles; Raina, Amit; Bell, Lauren N.; Cooper, Sara; Malik, Shahid; Behari, Jaideep

2014-01-01

Background and Objectives While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. Methods This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Results Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Conclusion Severe AAH is

Sunitinib Possible Sex-Divergent Therapeutic Outcomes.

PubMed

Segarra, Ignacio; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L

2016-10-01

Sunitinib is a tyrosine kinase inhibitor used for the treatment of renal cell carcinoma and metastatic brain tumors. Preclinical pharmacokinetic studies have shown higher sunitinib hepatic and brain exposure in female mice and higher sunitinib kidney concentrations in male mice. We explored whether sex-divergent tissue pharmacokinetics may anticipate sex-divergent therapeutic and toxicology responses in male and female patients. The review of the available scientific literature identified case reports, case series reports, clinical trials, and other studies associating sex with sunitinib outcomes. The results suggest male patients may respond better to renal cell carcinoma treatment and female patients may have better brain tumor treatment outcomes but a higher incidence of adverse events. Although more high-quality evidence is needed, these results, as anticipated by the preclinical data, may indicate possible sunitinib sex-divergent therapeutic outcomes in patients. In addition, we propose the systematic analysis of sex-based outcomes in clinical trial reports and their inclusion and review in the ethics committees and review boards to prevent, amongst others, patient burden in upcoming clinical trials.

Genomic patterns of species diversity and divergence in Eucalyptus.

PubMed

Hudson, Corey J; Freeman, Jules S; Myburg, Alexander A; Potts, Brad M; Vaillancourt, René E

2015-06-01

We examined genome-wide patterns of DNA sequence diversity and divergence among six species of the important tree genus Eucalyptus and investigated their relationship with genomic architecture. Using c. 90 range-wide individuals of each Eucalyptus species (E. grandis, E. urophylla, E. globulus, E. nitens, E. dunnii and E. camaldulensis), genetic diversity and divergence were estimated from 2840 polymorphic diversity arrays technology markers covering the 11 chromosomes. Species differentiating markers (SDMs) identified in each of 15 pairwise species comparisons, along with species diversity (HHW ) and divergence (FST ), were projected onto the E. grandis reference genome. Across all species comparisons, SDMs totalled 1.1-5.3% of markers and were widely distributed throughout the genome. Marker divergence (FST and SDMs) and diversity differed among and within chromosomes. Patterns of diversity and divergence were broadly conserved across species and significantly associated with genomic features, including the proximity of markers to genes, the relative number of clusters of tandem duplications, and gene density within or among chromosomes. These results suggest that genomic architecture influences patterns of species diversity and divergence in the genus. This influence is evident across the six species, encompassing diverse phylogenetic lineages, geography and ecology. © 2015 University of Tasmania New Phytologist © 2015 New Phytologist Trust.

Novel Myopia Genes and Pathways Identified From Syndromic Forms of Myopia

PubMed Central

Loughman, James; Wildsoet, Christine F.; Williams, Cathy; Guggenheim, Jeremy A.

2018-01-01

Purpose To test the hypothesis that genes known to cause clinical syndromes featuring myopia also harbor polymorphisms contributing to nonsyndromic refractive errors. Methods Clinical phenotypes and syndromes that have refractive errors as a recognized feature were identified using the Online Mendelian Inheritance in Man (OMIM) database. One hundred fifty-four unique causative genes were identified, of which 119 were specifically linked with myopia and 114 represented syndromic myopia (i.e., myopia and at least one other clinical feature). Myopia was the only refractive error listed for 98 genes and hyperopia and the only refractive error noted for 28 genes, with the remaining 28 genes linked to phenotypes with multiple forms of refractive error. Pathway analysis was carried out to find biological processes overrepresented within these sets of genes. Genetic variants located within 50 kb of the 119 myopia-related genes were evaluated for involvement in refractive error by analysis of summary statistics from genome-wide association studies (GWAS) conducted by the CREAM Consortium and 23andMe, using both single-marker and gene-based tests. Results Pathway analysis identified several biological processes already implicated in refractive error development through prior GWAS analyses and animal studies, including extracellular matrix remodeling, focal adhesion, and axon guidance, supporting the research hypothesis. Novel pathways also implicated in myopia development included mannosylation, glycosylation, lens development, gliogenesis, and Schwann cell differentiation. Hyperopia was found to be linked to a different pattern of biological processes, mostly related to organogenesis. Comparison with GWAS findings further confirmed that syndromic myopia genes were enriched for genetic variants that influence refractive errors in the general population. Gene-based analyses implicated 21 novel candidate myopia genes (ADAMTS18, ADAMTS2, ADAMTSL4, AGK, ALDH18A1, ASXL1, COL4A1

A new screening pathway for identifying asymptomatic patients using dental panoramic radiographs

NASA Astrophysics Data System (ADS)

Hayashi, Tatsuro; Matsumoto, Takuya; Sawagashira, Tsuyoshi; Tagami, Motoki; Katsumata, Akitoshi; Hayashi, Yoshinori; Muramatsu, Chisako; Zhou, Xiangrong; Iida, Yukihiro; Matsuoka, Masato; Katagi, Kiyoji; Fujita, Hiroshi

2012-03-01

To identify asymptomatic patients is the challenging task and the essential first step in diagnosis. Findings of dental panoramic radiographs include not only dental conditions but also radiographic signs that are suggestive of possible systemic diseases such as osteoporosis, arteriosclerosis, and maxillary sinusitis. Detection of such signs on panoramic radiographs has a potential to provide supplemental benefits for patients. However, it is not easy for general dental practitioners to pay careful attention to such signs. We addressed the development of a computer-aided detection (CAD) system that detects radiographic signs of pathology on panoramic images, and the design of the framework of new screening pathway by cooperation of dentists and our CAD system. The performance evaluation of our CAD system showed the sensitivity and specificity in the identification of osteoporotic patients were 92.6 % and 100 %, respectively, and those of the maxillary sinus abnormality were 89.6 % and 73.6 %, respectively. The detection rate of carotid artery calcifications that suggests the need for further medical evaluation was approximately 93.6 % with 4.4 false-positives per image. To validate the utility of the new screening pathway, preliminary clinical trials by using our CAD system were conducted. To date, 223 panoramic images were processed and 4 asymptomatic patients with suspected osteoporosis, 7 asymptomatic patients with suspected calcifications, and 40 asymptomatic patients with suspected maxillary sinusitis were detected in our initial trial. It was suggested that our new screening pathway could be useful to identify asymptomatic patients with systemic diseases.

The alignment of enzymatic steps reveals similar metabolic pathways and probable recruitment events in Gammaproteobacteria.

PubMed

Poot-Hernandez, Augusto Cesar; Rodriguez-Vazquez, Katya; Perez-Rueda, Ernesto

2015-11-17

It is generally accepted that gene duplication followed by functional divergence is one of the main sources of metabolic diversity. In this regard, there is an increasing interest in the development of methods that allow the systematic identification of these evolutionary events in metabolism. Here, we used a method not based on biomolecular sequence analysis to compare and identify common and variable routes in the metabolism of 40 Gammaproteobacteria species. The metabolic maps deposited in the KEGG database were transformed into linear Enzymatic Step Sequences (ESS) by using the breadth-first search algorithm. These ESS represent subsequent enzymes linked to each other, where their catalytic activities are encoded in the Enzyme Commission numbers. The ESS were compared in an all-against-all (pairwise comparisons) approach by using a dynamic programming algorithm, leaving only a set of significant pairs. From these comparisons, we identified a set of functionally conserved enzymatic steps in different metabolic maps, in which cell wall components and fatty acid and lysine biosynthesis were included. In addition, we found that pathways associated with biosynthesis share a higher proportion of similar ESS than degradation pathways and secondary metabolism pathways. Also, maps associated with the metabolism of similar compounds contain a high proportion of similar ESS, such as those maps from nucleotide metabolism pathways, in particular the inosine monophosphate pathway. Furthermore, diverse ESS associated with the low part of the glycolysis pathway were identified as functionally similar to multiple metabolic pathways. In summary, our comparisons may help to identify similar reactions in different metabolic pathways and could reinforce the patchwork model in the evolution of metabolism in Gammaproteobacteria.

Divergence thrust loss calculations for convergent-divergent nozzles: Extensions to the classical case

NASA Technical Reports Server (NTRS)

Berton, Jeffrey J.

1991-01-01

The analytical derivations of the non-axial thrust divergence losses for convergent-divergent nozzles are described as well as how these calculations are embodied in the Navy/NASA engine computer program. The convergent-divergent geometries considered are simple classic axisymmetric nozzles, two dimensional rectangular nozzles, and axisymmetric and two dimensional plug nozzles. A simple, traditional, inviscid mathematical approach is used to deduce the influence of the ineffectual non-axial thrust as a function of the nozzle exit divergence angle.

Noise Characteristics of Overexpanded Jets from Convergent-Divergent Nozzles

NASA Technical Reports Server (NTRS)

Zaman, K. B. M. Q.

2008-01-01

A broadband noise component occurring in the overexpanded flow regime with convergent-divergent nozzles is identified. Relative to a convergent nozzle, at same pressure ratios, this excess noise can lead to a large increase in the overall sound pressure levels. Several features distinguish it from the more familiar broadband shock associated noise. Unlike the latter, it is observed even at shallow polar locations and there is no noticeable shift of the spectral content in frequency with observation angle. The amplitudes are found to be more pronounced with nozzles having larger half-angle of the divergent section. The noise apparently occurs when a shock resides within the divergent section of the nozzle and results from random unsteady motion of the shock.

Transcriptome profiling identified differentially expressed genes and pathways associated with tamoxifen resistance in human breast cancer

PubMed Central

Men, Xin; Ma, Jun; Wu, Tong; Pu, Junyi; Wen, Shaojia; Shen, Jianfeng; Wang, Xun; Wang, Yamin; Chen, Chao; Dai, Penggao

2018-01-01

Tamoxifen (TAM) resistance is an important clinical problem in the treatment of breast cancer. In order to identify the mechanism of TAM resistance for estrogen receptor (ER)-positive breast cancer, we screened the transcriptome using RNA-seq and compared the gene expression profiles between the MCF-7 mamma carcinoma cell line and the TAM-resistant cell line TAMR/MCF-7, 52 significant differential expression genes (DEGs) were identified including SLIT2, ROBO, LHX, KLF, VEGFC, BAMBI, LAMA1, FLT4, PNMT, DHRS2, MAOA and ALDH. The DEGs were annotated in the GO, COG and KEGG databases. Annotation of the function of the DEGs in the KEGG database revealed the top three pathways enriched with the most DEGs, including pathways in cancer, the PI3K-AKT pathway, and focal adhesion. Then we compared the gene expression profiles between the Clinical progressive disease (PD) and the complete response (CR) from the cancer genome altas (TCGA). 10 common DEGs were identified through combining the clinical and cellular analysis results. Protein-protein interaction network was applied to analyze the association of ER signal pathway with the 10 DEGs. 3 significant genes (GFRA3, NPY1R and PTPRN2) were closely related to ER related pathway. These significant DEGs regulated many biological activities such as cell proliferation and survival, motility and migration, and tumor cell invasion. The interactions between these DEGs and drug resistance phenomenon need to be further elucidated at a functional level in further studies. Based on our findings, we believed that these DEGs could be therapeutic targets, which can be explored to develop new treatment options. PMID:29423105

Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging.

PubMed

Mangold, Colleen A; Wronowski, Benjamin; Du, Mei; Masser, Dustin R; Hadad, Niran; Bixler, Georgina V; Brucklacher, Robert M; Ford, Matthew M; Sonntag, William E; Freeman, Willard M

2017-07-21

The necessity of including both males and females in molecular neuroscience research is now well understood. However, there is relatively limited basic biological data on brain sex differences across the lifespan despite the differences in age-related neurological dysfunction and disease between males and females. Whole genome gene expression of young (3 months), adult (12 months), and old (24 months) male and female C57BL6 mice hippocampus was analyzed. Subsequent bioinformatic analyses and confirmations of age-related changes and sex differences in hippocampal gene and protein expression were performed. Males and females demonstrate both common expression changes with aging and marked sex differences in the nature and magnitude of the aging responses. Age-related hippocampal induction of neuroinflammatory gene expression was sexually divergent and enriched for microglia-specific genes such as complement pathway components. Sexually divergent C1q protein expression was confirmed by immunoblotting and immunohistochemistry. Similar patterns of cortical sexually divergent gene expression were also evident. Additionally, inter-animal gene expression variability increased with aging in males, but not females. These findings demonstrate sexually divergent neuroinflammation with aging that may contribute to sex differences in age-related neurological diseases such as stroke and Alzheimer's, specifically in the complement system. The increased expression variability in males suggests a loss of fidelity in gene expression regulation with aging. These findings reveal a central role of sex in the transcriptomic response of the hippocampus to aging that warrants further, in depth, investigations.

Mapping cellular Fe-S cluster uptake and exchange reactions - divergent pathways for iron-sulfur cluster delivery to human ferredoxins.

PubMed

Fidai, Insiya; Wachnowsky, Christine; Cowan, J A

2016-12-07

Ferredoxins are protein mediators of biological electron-transfer reactions and typically contain either [2Fe-2S] or [4Fe-4S] clusters. Two ferredoxin homologues have been identified in the human genome, Fdx1 and Fdx2, that share 43% identity and 69% similarity in protein sequence and both bind [2Fe-2S] clusters. Despite the high similarity, the two ferredoxins play very specific roles in distinct physiological pathways and cannot replace each other in function. Both eukaryotic and prokaryotic ferredoxins and homologues have been reported to receive their Fe-S cluster from scaffold/delivery proteins such as IscU, Isa, glutaredoxins, and Nfu. However, the preferred and physiologically relevant pathway for receiving the [2Fe-2S] cluster by ferredoxins is subject to speculation and is not clearly identified. In this work, we report on in vitro UV-visible (UV-vis) circular dichroism studies of [2Fe-2S] cluster transfer to the ferredoxins from a variety of partners. The results reveal rapid and quantitative transfer to both ferredoxins from several donor proteins (IscU, Isa1, Grx2, and Grx3). Transfer from Isa1 to Fdx2 was also observed to be faster than that of IscU to Fdx2, suggesting that Fdx2 could receive its cluster from Isa1 instead of IscU. Several other transfer combinations were also investigated and the results suggest a complex, but kinetically detailed map for cellular cluster trafficking. This is the first step toward building a network map for all of the possible iron-sulfur cluster transfer pathways in the mitochondria and cytosol, providing insights on the most likely cellular pathways and possible redundancies in these pathways.

Evolutionary analysis of vision genes identifies potential drivers of visual differences between giraffe and okapi

PubMed Central

Agaba, Morris; Cavener, Douglas R.

2017-01-01

Background The capacity of visually oriented species to perceive and respond to visual signal is integral to their evolutionary success. Giraffes are closely related to okapi, but the two species have broad range of phenotypic differences including their visual capacities. Vision studies rank giraffe’s visual acuity higher than all other artiodactyls despite sharing similar vision ecological determinants with many of them. The extent to which the giraffe’s unique visual capacity and its difference with okapi is reflected by changes in their vision genes is not understood. Methods The recent availability of giraffe and okapi genomes provided opportunity to identify giraffe and okapi vision genes. Multiple strategies were employed to identify thirty-six candidate mammalian vision genes in giraffe and okapi genomes. Quantification of selection pressure was performed by a combination of branch-site tests of positive selection and clade models of selection divergence through comparing giraffe and okapi vision genes and orthologous sequences from other mammals. Results Signatures of selection were identified in key genes that could potentially underlie giraffe and okapi visual adaptations. Importantly, some genes that contribute to optical transparency of the eye and those that are critical in light signaling pathway were found to show signatures of adaptive evolution or selection divergence. Comparison between giraffe and other ruminants identifies significant selection divergence in CRYAA and OPN1LW. Significant selection divergence was identified in SAG while positive selection was detected in LUM when okapi is compared with ruminants and other mammals. Sequence analysis of OPN1LW showed that at least one of the sites known to affect spectral sensitivity of the red pigment is uniquely divergent between giraffe and other ruminants. Discussion By taking a systemic approach to gene function in vision, the results provide the first molecular clues associated with

Evolutionary analysis of vision genes identifies potential drivers of visual differences between giraffe and okapi.

PubMed

Ishengoma, Edson; Agaba, Morris; Cavener, Douglas R

2017-01-01

The capacity of visually oriented species to perceive and respond to visual signal is integral to their evolutionary success. Giraffes are closely related to okapi, but the two species have broad range of phenotypic differences including their visual capacities. Vision studies rank giraffe's visual acuity higher than all other artiodactyls despite sharing similar vision ecological determinants with many of them. The extent to which the giraffe's unique visual capacity and its difference with okapi is reflected by changes in their vision genes is not understood. The recent availability of giraffe and okapi genomes provided opportunity to identify giraffe and okapi vision genes. Multiple strategies were employed to identify thirty-six candidate mammalian vision genes in giraffe and okapi genomes. Quantification of selection pressure was performed by a combination of branch-site tests of positive selection and clade models of selection divergence through comparing giraffe and okapi vision genes and orthologous sequences from other mammals. Signatures of selection were identified in key genes that could potentially underlie giraffe and okapi visual adaptations. Importantly, some genes that contribute to optical transparency of the eye and those that are critical in light signaling pathway were found to show signatures of adaptive evolution or selection divergence. Comparison between giraffe and other ruminants identifies significant selection divergence in CRYAA and OPN1LW . Significant selection divergence was identified in SAG while positive selection was detected in LUM when okapi is compared with ruminants and other mammals. Sequence analysis of OPN1LW showed that at least one of the sites known to affect spectral sensitivity of the red pigment is uniquely divergent between giraffe and other ruminants. By taking a systemic approach to gene function in vision, the results provide the first molecular clues associated with giraffe and okapi vision adaptations. At

Divergent Selection Drives Genetic Differentiation in an R2R3-MYB Transcription Factor That Contributes to Incipient Speciation in Mimulus aurantiacus

PubMed Central

Streisfeld, Matthew A.; Young, Wambui N.; Sobel, James M.

2013-01-01

Identifying the molecular genetic basis of traits contributing to speciation is of crucial importance for understanding the ecological and evolutionary mechanisms that generate biodiversity. Despite several examples describing putative “speciation genes,” it is often uncertain to what extent these genetic changes have contributed to gene flow reductions in nature. Therefore, considerable interest lies in characterizing the molecular basis of traits that actively confer reproductive isolation during the early stages of speciation, as these loci can be attributed directly to the process of divergence. In Southern California, two ecotypes of Mimulus aurantiacus are parapatric and differ primarily in flower color, with an anthocyanic, red-flowered morph in the west and an anthocyanin-lacking, yellow-flowered morph in the east. Evidence suggests that the genetic changes responsible for this shift in flower color have been essential for divergence and have become fixed in natural populations of each ecotype due to almost complete differences in pollinator preference. In this study, we demonstrate that a cis-regulatory mutation in an R2R3-MYB transcription factor results in differential regulation of enzymes in the anthocyanin biosynthetic pathway and is the major contributor to differences in floral pigmentation. In addition, molecular population genetic data show that, despite gene flow at neutral loci, divergent selection has driven the fixation of alternate alleles at this gene between ecotypes. Therefore, by identifying the genetic basis underlying ecologically based divergent selection in flower color between these ecotypes, we have revealed the ecological and functional mechanisms involved in the evolution of pre-mating isolation at the early stages of incipient speciation. PMID:23555295

Patterns of Z chromosome divergence among Heliconius species highlight the importance of historical demography.

PubMed

Van Belleghem, Steven M; Baquero, Margarita; Papa, Riccardo; Salazar, Camilo; McMillan, W Owen; Counterman, Brian A; Jiggins, Chris D; Martin, Simon H

2018-03-22

Sex chromosomes are disproportionately involved in reproductive isolation and adaptation. In support of such a "large-X" effect, genome scans between recently diverged populations and species pairs often identify distinct patterns of divergence on the sex chromosome compared to autosomes. When measures of divergence between populations are higher on the sex chromosome compared to autosomes, such patterns could be interpreted as evidence for faster divergence on the sex chromosome, that is "faster-X", barriers to gene flow on the sex chromosome. However, demographic changes can strongly skew divergence estimates and are not always taken into consideration. We used 224 whole-genome sequences representing 36 populations from two Heliconius butterfly clades (H. erato and H. melpomene) to explore patterns of Z chromosome divergence. We show that increased divergence compared to equilibrium expectations can in many cases be explained by demographic change. Among Heliconius erato populations, for instance, population size increase in the ancestral population can explain increased absolute divergence measures on the Z chromosome compared to the autosomes, as a result of increased ancestral Z chromosome genetic diversity. Nonetheless, we do identify increased divergence on the Z chromosome relative to the autosomes in parapatric or sympatric species comparisons that imply postzygotic reproductive barriers. Using simulations, we show that this is consistent with reduced gene flow on the Z chromosome, perhaps due to greater accumulation of incompatibilities. Our work demonstrates the importance of taking demography into account to interpret patterns of divergence on the Z chromosome, but nonetheless provides evidence to support the Z chromosome as a strong barrier to gene flow in incipient Heliconius butterfly species. © 2018 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.

CNL Disease Resistance Genes in Soybean and Their Evolutionary Divergence

PubMed Central

Nepal, Madhav P; Benson, Benjamin V

2015-01-01

Disease resistance genes (R-genes) encode proteins involved in detecting pathogen attack and activating downstream defense molecules. Recent availability of soybean genome sequences makes it possible to examine the diversity of gene families including disease-resistant genes. The objectives of this study were to identify coiled-coil NBS-LRR (= CNL) R-genes in soybean, infer their evolutionary relationships, and assess structural as well as functional divergence of the R-genes. Profile hidden Markov models were used for sequence identification and model-based maximum likelihood was used for phylogenetic analysis, and variation in chromosomal positioning, gene clustering, and functional divergence were assessed. We identified 188 soybean CNL genes nested into four clades consistent to their orthologs in Arabidopsis. Gene clustering analysis revealed the presence of 41 gene clusters located on 13 different chromosomes. Analyses of the Ks-values and chromosomal positioning suggest duplication events occurring at varying timescales, and an extrapericentromeric positioning may have facilitated their rapid evolution. Each of the four CNL clades exhibited distinct patterns of gene expression. Phylogenetic analysis further supported the extrapericentromeric positioning effect on the divergence and retention of the CNL genes. The results are important for understanding the diversity and divergence of CNL genes in soybean, which would have implication in soybean crop improvement in future. PMID:25922568

CNL Disease Resistance Genes in Soybean and Their Evolutionary Divergence.

PubMed

Nepal, Madhav P; Benson, Benjamin V

2015-01-01

Disease resistance genes (R-genes) encode proteins involved in detecting pathogen attack and activating downstream defense molecules. Recent availability of soybean genome sequences makes it possible to examine the diversity of gene families including disease-resistant genes. The objectives of this study were to identify coiled-coil NBS-LRR (= CNL) R-genes in soybean, infer their evolutionary relationships, and assess structural as well as functional divergence of the R-genes. Profile hidden Markov models were used for sequence identification and model-based maximum likelihood was used for phylogenetic analysis, and variation in chromosomal positioning, gene clustering, and functional divergence were assessed. We identified 188 soybean CNL genes nested into four clades consistent to their orthologs in Arabidopsis. Gene clustering analysis revealed the presence of 41 gene clusters located on 13 different chromosomes. Analyses of the K s-values and chromosomal positioning suggest duplication events occurring at varying timescales, and an extrapericentromeric positioning may have facilitated their rapid evolution. Each of the four CNL clades exhibited distinct patterns of gene expression. Phylogenetic analysis further supported the extrapericentromeric positioning effect on the divergence and retention of the CNL genes. The results are important for understanding the diversity and divergence of CNL genes in soybean, which would have implication in soybean crop improvement in future.

Optimal projection method determination by Logdet Divergence and perturbed von-Neumann Divergence.

PubMed

Jiang, Hao; Ching, Wai-Ki; Qiu, Yushan; Cheng, Xiao-Qing

2017-12-14

Positive semi-definiteness is a critical property in kernel methods for Support Vector Machine (SVM) by which efficient solutions can be guaranteed through convex quadratic programming. However, a lot of similarity functions in applications do not produce positive semi-definite kernels. We propose projection method by constructing projection matrix on indefinite kernels. As a generalization of the spectrum method (denoising method and flipping method), the projection method shows better or comparable performance comparing to the corresponding indefinite kernel methods on a number of real world data sets. Under the Bregman matrix divergence theory, we can find suggested optimal λ in projection method using unconstrained optimization in kernel learning. In this paper we focus on optimal λ determination, in the pursuit of precise optimal λ determination method in unconstrained optimization framework. We developed a perturbed von-Neumann divergence to measure kernel relationships. We compared optimal λ determination with Logdet Divergence and perturbed von-Neumann Divergence, aiming at finding better λ in projection method. Results on a number of real world data sets show that projection method with optimal λ by Logdet divergence demonstrate near optimal performance. And the perturbed von-Neumann Divergence can help determine a relatively better optimal projection method. Projection method ia easy to use for dealing with indefinite kernels. And the parameter embedded in the method can be determined through unconstrained optimization under Bregman matrix divergence theory. This may provide a new way in kernel SVMs for varied objectives.

Divergent forms of endoplasmic reticulum stress trigger a robust unfolded protein response in honey bees.

PubMed

Johnston, Brittany A; Hooks, Katarzyna B; McKinstry, Mia; Snow, Jonathan W

2016-03-01

Honey bee colonies in the United States have suffered from an increased rate of die-off in recent years, stemming from a complex set of interacting stresses that remain poorly described. While we have some understanding of the physiological stress responses in the honey bee, our molecular understanding of honey bee cellular stress responses is incomplete. Thus, we sought to identify and began functional characterization of the components of the UPR in honey bees. The IRE1-dependent splicing of the mRNA for the transcription factor Xbp1, leading to translation of an isoform with more transactivation potential, represents the most conserved of the UPR pathways. Honey bees and other Apoidea possess unique features in the Xbp1 mRNA splice site, which we reasoned could have functional consequences for the IRE1 pathway. However, we find robust induction of target genes upon UPR stimulation. In addition, the IRE1 pathway activation, as assessed by splicing of Xbp1 mRNA upon UPR, is conserved. By providing foundational knowledge about the UPR in the honey bee and the relative sensitivity of this species to divergent stresses, this work stands to improve our understanding of the mechanistic underpinnings of honey bee health and disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

FamNet: A Framework to Identify Multiplied Modules Driving Pathway Expansion in Plants1

PubMed Central

Tohge, Takayuki; Klie, Sebastian; Fernie, Alisdair R.

2016-01-01

Gene duplications generate new genes that can acquire similar but often diversified functions. Recent studies of gene coexpression networks have indicated that, not only genes, but also pathways can be multiplied and diversified to perform related functions in different parts of an organism. Identification of such diversified pathways, or modules, is needed to expand our knowledge of biological processes in plants and to understand how biological functions evolve. However, systematic explorations of modules remain scarce, and no user-friendly platform to identify them exists. We have established a statistical framework to identify modules and show that approximately one-third of the genes of a plant’s genome participate in hundreds of multiplied modules. Using this framework as a basis, we implemented a platform that can explore and visualize multiplied modules in coexpression networks of eight plant species. To validate the usefulness of the platform, we identified and functionally characterized pollen- and root-specific cell wall modules that multiplied to confer tip growth in pollen tubes and root hairs, respectively. Furthermore, we identified multiplied modules involved in secondary metabolite synthesis and corroborated them by metabolite profiling of tobacco (Nicotiana tabacum) tissues. The interactive platform, referred to as FamNet, is available at http://www.gene2function.de/famnet.html. PMID:26754669

Divergence of Gene Body DNA Methylation and Evolution of Plant Duplicate Genes

PubMed Central

Wang, Jun; Marowsky, Nicholas C.; Fan, Chuanzhu

2014-01-01

It has been shown that gene body DNA methylation is associated with gene expression. However, whether and how deviation of gene body DNA methylation between duplicate genes can influence their divergence remains largely unexplored. Here, we aim to elucidate the potential role of gene body DNA methylation in the fate of duplicate genes. We identified paralogous gene pairs from Arabidopsis and rice (Oryza sativa ssp. japonica) genomes and reprocessed their single-base resolution methylome data. We show that methylation in paralogous genes nonlinearly correlates with several gene properties including exon number/gene length, expression level and mutation rate. Further, we demonstrated that divergence of methylation level and pattern in paralogs indeed positively correlate with their sequence and expression divergences. This result held even after controlling for other confounding factors known to influence the divergence of paralogs. We observed that methylation level divergence might be more relevant to the expression divergence of paralogs than methylation pattern divergence. Finally, we explored the mechanisms that might give rise to the divergence of gene body methylation in paralogs. We found that exonic methylation divergence more closely correlates with expression divergence than intronic methylation divergence. We show that genomic environments (e.g., flanked by transposable elements and repetitive sequences) of paralogs generated by various duplication mechanisms are associated with the methylation divergence of paralogs. Overall, our results suggest that the changes in gene body DNA methylation could provide another avenue for duplicate genes to develop differential expression patterns and undergo different evolutionary fates in plant genomes. PMID:25310342

A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis.

PubMed

Azad, T; Janse van Rensburg, H J; Lightbody, E D; Neveu, B; Champagne, A; Ghaffari, A; Kay, V R; Hao, Y; Shen, H; Yeung, B; Croy, B A; Guan, K L; Pouliot, F; Zhang, J; Nicol, C J B; Yang, X

2018-03-13

The Hippo pathway is a central regulator of tissue development and homeostasis, and has been reported to have a role during vascular development. Here we develop a bioluminescence-based biosensor that monitors the activity of the Hippo core component LATS kinase. Using this biosensor and a library of small molecule kinase inhibitors, we perform a screen for kinases modulating LATS activity and identify VEGFR as an upstream regulator of the Hippo pathway. We find that VEGFR activation by VEGF triggers PI3K/MAPK signaling, which subsequently inhibits LATS and activates the Hippo effectors YAP and TAZ. We further show that the Hippo pathway is a critical mediator of VEGF-induced angiogenesis and tumor vasculogenic mimicry. Thus, our work offers a biosensor tool for the study of the Hippo pathway and suggests a role for Hippo signaling in regulating blood vessel formation in physiological and pathological settings.

A Powerful Procedure for Pathway-Based Meta-analysis Using Summary Statistics Identifies 43 Pathways Associated with Type II Diabetes in European Populations

PubMed Central

Zhang, Han; Wheeler, William; Hyland, Paula L.; Yang, Yifan; Shi, Jianxin; Chatterjee, Nilanjan; Yu, Kai

2016-01-01

Meta-analysis of multiple genome-wide association studies (GWAS) has become an effective approach for detecting single nucleotide polymorphism (SNP) associations with complex traits. However, it is difficult to integrate the readily accessible SNP-level summary statistics from a meta-analysis into more powerful multi-marker testing procedures, which generally require individual-level genetic data. We developed a general procedure called Summary based Adaptive Rank Truncated Product (sARTP) for conducting gene and pathway meta-analysis that uses only SNP-level summary statistics in combination with genotype correlation estimated from a panel of individual-level genetic data. We demonstrated the validity and power advantage of sARTP through empirical and simulated data. We conducted a comprehensive pathway-based meta-analysis with sARTP on type 2 diabetes (T2D) by integrating SNP-level summary statistics from two large studies consisting of 19,809 T2D cases and 111,181 controls with European ancestry. Among 4,713 candidate pathways from which genes in neighborhoods of 170 GWAS established T2D loci were excluded, we detected 43 T2D globally significant pathways (with Bonferroni corrected p-values < 0.05), which included the insulin signaling pathway and T2D pathway defined by KEGG, as well as the pathways defined according to specific gene expression patterns on pancreatic adenocarcinoma, hepatocellular carcinoma, and bladder carcinoma. Using summary data from 8 eastern Asian T2D GWAS with 6,952 cases and 11,865 controls, we showed 7 out of the 43 pathways identified in European populations remained to be significant in eastern Asians at the false discovery rate of 0.1. We created an R package and a web-based tool for sARTP with the capability to analyze pathways with thousands of genes and tens of thousands of SNPs. PMID:27362418

A Powerful Procedure for Pathway-Based Meta-analysis Using Summary Statistics Identifies 43 Pathways Associated with Type II Diabetes in European Populations.

PubMed

Zhang, Han; Wheeler, William; Hyland, Paula L; Yang, Yifan; Shi, Jianxin; Chatterjee, Nilanjan; Yu, Kai

2016-06-01

Meta-analysis of multiple genome-wide association studies (GWAS) has become an effective approach for detecting single nucleotide polymorphism (SNP) associations with complex traits. However, it is difficult to integrate the readily accessible SNP-level summary statistics from a meta-analysis into more powerful multi-marker testing procedures, which generally require individual-level genetic data. We developed a general procedure called Summary based Adaptive Rank Truncated Product (sARTP) for conducting gene and pathway meta-analysis that uses only SNP-level summary statistics in combination with genotype correlation estimated from a panel of individual-level genetic data. We demonstrated the validity and power advantage of sARTP through empirical and simulated data. We conducted a comprehensive pathway-based meta-analysis with sARTP on type 2 diabetes (T2D) by integrating SNP-level summary statistics from two large studies consisting of 19,809 T2D cases and 111,181 controls with European ancestry. Among 4,713 candidate pathways from which genes in neighborhoods of 170 GWAS established T2D loci were excluded, we detected 43 T2D globally significant pathways (with Bonferroni corrected p-values < 0.05), which included the insulin signaling pathway and T2D pathway defined by KEGG, as well as the pathways defined according to specific gene expression patterns on pancreatic adenocarcinoma, hepatocellular carcinoma, and bladder carcinoma. Using summary data from 8 eastern Asian T2D GWAS with 6,952 cases and 11,865 controls, we showed 7 out of the 43 pathways identified in European populations remained to be significant in eastern Asians at the false discovery rate of 0.1. We created an R package and a web-based tool for sARTP with the capability to analyze pathways with thousands of genes and tens of thousands of SNPs.

Expression Divergence Is Correlated with Sequence Evolution but Not Positive Selection in Conifers.

PubMed

Hodgins, Kathryn A; Yeaman, Sam; Nurkowski, Kristin A; Rieseberg, Loren H; Aitken, Sally N

2016-06-01

The evolutionary and genomic determinants of sequence evolution in conifers are poorly understood, and previous studies have found only limited evidence for positive selection. Using RNAseq data, we compared gene expression profiles to patterns of divergence and polymorphism in 44 seedlings of lodgepole pine (Pinus contorta) and 39 seedlings of interior spruce (Picea glauca × engelmannii) to elucidate the evolutionary forces that shape their genomes and their plastic responses to abiotic stress. We found that rapidly diverging genes tend to have greater expression divergence, lower expression levels, reduced levels of synonymous site diversity, and longer proteins than slowly diverging genes. Similar patterns were identified for the untranslated regions, but with some exceptions. We found evidence that genes with low expression levels had a larger fraction of nearly neutral sites, suggesting a primary role for negative selection in determining the association between evolutionary rate and expression level. There was limited evidence for differences in the rate of positive selection among genes with divergent versus conserved expression profiles and some evidence supporting relaxed selection in genes diverging in expression between the species. Finally, we identified a small number of genes that showed evidence of site-specific positive selection using divergence data alone. However, estimates of the proportion of sites fixed by positive selection (α) were in the range of other plant species with large effective population sizes suggesting relatively high rates of adaptive divergence among conifers. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases

PubMed Central

Arakelyan, Arsen; Nersisyan, Lilit; Petrek, Martin; Löffler-Wirth, Henry; Binder, Hans

2016-01-01

Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent. PMID:27200087

Divergence in an obligate mutualism is not explained by divergent climatic factors

USGS Publications Warehouse

Godsoe, W.; Strand, Espen; Smith, C.I.; Yoder, J.B.; Esque, T.C.; Pellmyr, O.

2009-01-01

Adaptation to divergent environments creates and maintains biological diversity, but we know little about the importance of different agents of ecological divergence. Coevolution in obligate mutualisms has been hypothesized to drive divergence, but this contention has rarely been tested against alternative ecological explanations. Here, we use a well-established example of coevolution in an obligate pollination mutualism, Yucca brevifolia and its two pollinating yucca moths, to test the hypothesis that divergence in this system is the result of mutualists adapting to different abiotic environments as opposed to coevolution between mutualists. ??? We used a combination of principal component analyses and ecological niche modeling to determine whether varieties of Y. brevifolia associated with different pollinators specialize on different environments. ??? Yucca brevifolia occupies a diverse range of climates. When the two varieties can disperse to similar environments, they occupy similar habitats. ??? This suggests that the two varieties have not specialized on distinct habitats. In turn, this suggests that nonclimatic factors, such as the biotic interaction between Y. brevifolia and its pollinators, are responsible for evolutionary divergence in this system. ?? New Phytologist (2009).

Molecular population genetics of the insulin/TOR signal transduction pathway: a network-level analysis in Drosophila melanogaster.

PubMed

Alvarez-Ponce, David; Guirao-Rico, Sara; Orengo, Dorcas J; Segarra, Carmen; Rozas, Julio; Aguadé, Montserrat

2012-01-01

The IT-insulin/target of rapamycin (TOR)-signal transduction pathway is a relatively well-characterized pathway that plays a central role in fundamental biological processes. Network-level analyses of DNA divergence in Drosophila and vertebrates have revealed a clear gradient in the levels of purifying selection along this pathway, with the downstream genes being the most constrained. Remarkably, this feature does not result from factors known to affect selective constraint such as gene expression, codon bias, protein length, and connectivity. The present work aims to establish whether the selective constraint gradient detected along the IT pathway at the between-species level can also be observed at a shorter time scale. With this purpose, we have surveyed DNA polymorphism in Drosophila melanogaster and divergence from D. simulans along the IT pathway. Our network-level analysis shows that DNA polymorphism exhibits the same polarity in the strength of purifying selection as previously detected at the divergence level. This equivalent feature detected both within species and between closely and distantly related species points to the action of a general mechanism, whose action is neither organism specific nor evolutionary time dependent. The detected polarity would be, therefore, intrinsic to the IT pathway architecture and function.

Divergent pathways in the reaction of Fischer carbenes and palladium.

PubMed

López-Alberca, María P; Mancheño, María J; Fernandez, Israel; Gómez-Gallego, Mar; Sierra, Miguel A; Torres, Rosario

2007-04-26

[reaction: see text] The Pd-catalyzed reaction of beta-arylaminochromium(0) carbene complexes produces by transmetalation the first isolated and X-ray structurally characterized bis-Pd(II) carbene complex, as well as other alternative reaction pathways, such as the oxidative addition-transmetalation sequence, not seen before in this chemistry.

Identifying Pathways of Teachers' PCK Development

ERIC Educational Resources Information Center

Wongsopawiro, Dirk S.; Zwart, Rosanne C.; van Driel, Jan H.

2017-01-01

This paper describes a method of analysing teacher growth in the context of science education. It focuses on the identification of pathways in the development of secondary school teachers' pedagogical content knowledge (PCK) by the use of the interconnected model of teachers' professional growth (IMTPG).The teachers (n = 12) participated in a…

The right time to happen: play developmental divergence in the two Pan species.

PubMed

Palagi, Elisabetta; Cordoni, Giada

2012-01-01

Bonobos, compared to chimpanzees, are highly motivated to play as adults. Therefore, it is interesting to compare the two species at earlier developmental stages to determine how and when these differences arise. We measured and compared some play parameters between the two species including frequency, number of partners (solitary, dyadic, and polyadic play), session length, and escalation into overt aggression. Since solitary play has a role in developing cognitive and physical skills, it is not surprising that chimpanzees and bonobos share similar developmental trajectories in the motivation to engage in this activity. The striking divergence in play developmental pathways emerged for social play. Infants of the two species showed comparable social play levels, which began to diverge during the juvenile period, a 'timing hotspot' for play development. Compared to chimpanzees, social play sessions in juvenile bonobos escalated less frequently into overt aggression, lasted longer, and frequently involved more than two partners concurrently (polyadic play). In this view, play fighting in juvenile bonobos seems to maintain a cooperative mood, whereas in juvenile chimpanzees it acquires more competitive elements. The retention of juvenile traits into adulthood typical of bonobos can be due to a developmental delay in social inhibition. Our findings show that the divergence of play ontogenetic pathways between the two Pan species and the relative emergence of play neotenic traits in bonobos can be detected before individuals reach sexual maturity. The high play motivation showed by adult bonobos compared to chimpanzees is probably the result of a long developmental process, rooted in the delicate transitional phase, which leads subjects from infancy to juvenility.

Care pathway, towards the establishment of tailored funding: Reasons and criteria for success.

PubMed

Emery, Grégory; Le Fur, Camille; Epis-de-Fleurian, Anne-Aurélie; Josseran, Anne

2018-02-01

Care pathways are often at the forefront of political thinking about health care practices in France without ever finding a durable means for their extension. Closely linked to funding of healthcare system, they have, once again, been the object of so many economical discussions in 2017, as part of a more optimistic climate of governance which is therefore more open to change. Our changing system, the development and increasingly chronic nature of diseases, the scale of technological breakthroughs, these are all factors driving this topic forward. The object of this work, after a necessary study of the semantics of the term "pathway" and even "funding", was to identify all prerequisites and good practices for the stakeholders to develop a pilot pathway and then its relevant implementation in France. To do so, the members of the Round Table have relied on the presentation of examples of care pathways in order to identify triggers to a progressive, adapted extension to the whole territory. The group has identified key elements and priorities for the establishment of public funding beyond existing funding to incentive team work, particularly in the case of treatment rupture points and/or when they have diverging interests. Finally, creating a climate of confidence among patients, professionals, hospitals, the ARS, payers and manufacturers in handling change management will become the key challenges of the implementation of future pathways. Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Genome-Wide RNAi Screen Identifies Broadly-Acting Host Factors That Inhibit Arbovirus Infection

PubMed Central

Yasunaga, Ari; Hanna, Sheri L.; Li, Jianqing; Cho, Hyelim; Rose, Patrick P.; Spiridigliozzi, Anna; Gold, Beth; Diamond, Michael S.; Cherry, Sara

2014-01-01

Vector-borne viruses are an important class of emerging and re-emerging pathogens; thus, an improved understanding of the cellular factors that modulate infection in their respective vertebrate and insect hosts may aid control efforts. In particular, cell-intrinsic antiviral pathways restrict vector-borne viruses including the type I interferon response in vertebrates and the RNA interference (RNAi) pathway in insects. However, it is likely that additional cell-intrinsic mechanisms exist to limit these viruses. Since insects rely on innate immune mechanisms to inhibit virus infections, we used Drosophila as a model insect to identify cellular factors that restrict West Nile virus (WNV), a flavivirus with a broad and expanding geographical host range. Our genome-wide RNAi screen identified 50 genes that inhibited WNV infection. Further screening revealed that 17 of these genes were antiviral against additional flaviviruses, and seven of these were antiviral against other vector-borne viruses, expanding our knowledge of invertebrate cell-intrinsic immunity. Investigation of two newly identified factors that restrict diverse viruses, dXPO1 and dRUVBL1, in the Tip60 complex, demonstrated they contributed to antiviral defense at the organismal level in adult flies, in mosquito cells, and in mammalian cells. These data suggest the existence of broadly acting and functionally conserved antiviral genes and pathways that restrict virus infections in evolutionarily divergent hosts. PMID:24550726

Suppressors of systemin signaling identify genes in the tomato wound response pathway.

PubMed Central

Howe, G A; Ryan, C A

1999-01-01

In tomato plants, systemic induction of defense genes in response to herbivory or mechanical wounding is regulated by an 18-amino-acid peptide signal called systemin. Transgenic plants that overexpress prosystemin, the systemin precursor, from a 35S::prosystemin (35S::prosys) transgene exhibit constitutive expression of wound-inducible defense proteins including proteinase inhibitors and polyphenol oxidase. To study further the role of (pro)systemin in the wound response pathway, we isolated and characterized mutations that suppress 35S::prosys-mediated phenotypes. Ten recessive, extragenic suppressors were identified. Two of these define new alleles of def-1, a previously identified mutation that blocks both wound- and systemin-induced gene expression and renders plants susceptible to herbivory. The remaining mutants defined four loci designated Spr-1, Spr-2, Spr-3, and Spr-4 (for Suppressed in 35S::prosystemin-mediated responses). spr-3 and spr-4 mutants were not significantly affected in their response to either systemin or mechanical wounding. In contrast, spr-1 and spr-2 plants lacked systemic wound responses and were insensitive to systemin. These results confirm the function of (pro)systemin in the transduction of systemic wound signals and further establish that wounding, systemin, and 35S::prosys induce defensive gene expression through a common signaling pathway defined by at least three genes (Def-1, Spr-1, and Spr-2). PMID:10545469

Implementing 'translational' biomedical research: convergence and divergence among clinical and basic scientists.

PubMed

Morgan, Myfanwy; Barry, Christine A; Donovan, Jenny L; Sandall, Jane; Wolfe, Charles D A; Boaz, Annette

2011-10-01

Universities are increasingly regarded as key actors in the new 'knowledge economy', with requirements to produce market-oriented knowledge and engage in commercialization. This is of particular significance in the biomedical field, reflecting the perceived gap between success in terms of scientific discoveries and its transformation into products. The dominant discourse attributes this situation to 'blocks' in the translational pathway from 'bench to bedside', leading to policies to 'reengineer' the research enterprise. This study examines a pilot initiative established by the UK's Medical Research Council (MRC). This involved employing a change agent (Research Translator) supported by a small amount of translational funding to promote the culture and practice of translational research at a university/hospital site in England. An ethnographically informed case study involving semi-structured and open exploratory interviews, observation and document review, was conducted in 2008. Analysis and interpretation were informed by Bourdieu's logic of practice applied to science. The requirements of translational research promoted by the Research Translator and its sources of capital (authority, prestige etc) were largely congruent with the 'field' of clinical science. In contrast, translational research diverged from perceptions of 'legitimate' science and requirements for capital accumulation held by the majority of basic scientists who often described this research as 'high risk' and were resistant to the Research Translator's advice. However some differences in motivations and practices were identified within groups of scientists associated with career stage, work environment and specialty. We argue that there are convergent and divergent forces that influence scientists' readiness to adopt a market-oriented translational research model and in turn facilitate or constrain the effectiveness of a knowledge broker. We also identify ways in which current structures and

Identifying mutant pathways in the histiocytoses.

PubMed

Prince, H Miles

2014-11-06

In this issue of Blood, the findings of Chakraborty et al and Emile et al support a model in which the mitogen-activated protein kinase (MAPK) and PI3K/AKT pathways are critical in the pathogenesis of 2 of the most common histiocytoses—Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD)—whereas their respective mutational profiles demonstrate important similarities and differences.

Divergent branches of mitochondrial signaling regulate specific genes and the viability of specialized cell types of differentiated yeast colonies.

PubMed

Podholová, Kristýna; Plocek, Vítězslav; Rešetárová, Stanislava; Kučerová, Helena; Hlaváček, Otakar; Váchová, Libuše; Palková, Zdena

2016-03-29

Mitochondrial retrograde signaling mediates communication from altered mitochondria to the nucleus and is involved in many normal and pathophysiological changes, including cell metabolic reprogramming linked to cancer development and progression in mammals. The major mitochondrial retrograde pathway described in yeast includes three activators, Rtg1p, Rtg2p and Rtg3p, and repressors, Mks1p and Bmh1p/Bmh2p. Using differentiated yeast colonies, we show that Mks1p-Rtg pathway regulation is complex and includes three branches that divergently regulate the properties and fate of three specifically localized cell subpopulations via signals from differently altered mitochondria. The newly identified RTG pathway-regulated genes ATO1/ATO2 are expressed in colonial upper (U) cells, the cells with active TORC1 that metabolically resemble tumor cells, while CIT2 is a typical target induced in one subpopulation of starving lower (L) cells. The viability of the second L cell subpopulation is strictly dependent on RTG signaling. Additional co-activators of Rtg1p-Rtg3p specific to particular gene targets of each branch are required to regulate cell differentiation.

Consequences of divergent selection for residual feed intake in pigs on muscle energy metabolism and meat quality.

PubMed

Faure, J; Lefaucheur, L; Bonhomme, N; Ecolan, P; Meteau, K; Coustard, S Metayer; Kouba, M; Gilbert, H; Lebret, B

2013-01-01

Selection to decrease Residual Feed Intake (RFI) is a relevant way to improve feed efficiency in growing pigs. However, RFI criterion is correlated with body composition and muscle characteristics. Present study evaluated adaptive responses to divergent selection on RFI on muscle metabolism and homeostasis through AMP-activated protein kinase pathway. Consequences on technological and sensory meat quality were also analyzed in two lines of Large White pigs after six generations of divergent selection on RFI. RFI(-) pigs (n=60) exhibited similar growth rate but lower feed intake and conversion ratio, and were leaner than RFI(+) pigs (n=57). Despite higher glycogen content, metabolic enzyme capacities involved in glycolytic, fatty acid oxidation pathway and energy balance were reduced in the Longissimus muscle of the RFI(-) pigs. Reduced muscle homeostasis in the RFI(-) line influenced post-mortem metabolism and impaired technological quality traits of loin and ham but had only slight effects on meat eating quality. Copyright © 2012 Elsevier Ltd. All rights reserved.

A high-resolution genetic map of yellow monkeyflower identifies chemical defense QTLs and recombination rate variation.

PubMed

Holeski, Liza M; Monnahan, Patrick; Koseva, Boryana; McCool, Nick; Lindroth, Richard L; Kelly, John K

2014-03-13

Genotyping-by-sequencing methods have vastly improved the resolution and accuracy of genetic linkage maps by increasing both the number of marker loci as well as the number of individuals genotyped at these loci. Using restriction-associated DNA sequencing, we construct a dense linkage map for a panel of recombinant inbred lines derived from a cross between divergent ecotypes of Mimulus guttatus. We used this map to estimate recombination rate across the genome and to identify quantitative trait loci for the production of several secondary compounds (PPGs) of the phenylpropanoid pathway implicated in defense against herbivores. Levels of different PPGs are correlated across recombinant inbred lines suggesting joint regulation of the phenylpropanoid pathway. However, the three quantitative trait loci identified in this study each act on a distinct PPG. Finally, we map three putative genomic inversions differentiating the two parental populations, including a previously characterized inversion that contributes to life-history differences between the annual/perennial ecotypes. Copyright © 2014 Holeski et al.

Divergent Task Performance in Older Adults: Declarative Memory or Creative Potential?

PubMed Central

Leon, Susan A; Altmann, Lori JP; Abrams, Lise; Rothi, Leslie J Gonzalez; Heilman, Kenneth M

2016-01-01

Divergent thinking is the ability to produce a range of responses or solutions and is an element of creative processing. Divergent thinking requires disengagement, the ability to associate between words or ideas, and the production of responses. Lesion and imaging studies have shown frontal-lobe involvement for these activities, and frontal lobe function is highly dependent on white matter pathways. Normal aging often results in deficits in functions controlled by the frontal lobes as well as decrements in white matter connectivity. The objectives of this study were to compare non time-constrained tasks of verbal divergent processing in young adults (YAs) and older adults (OAs) and correlate performance with tasks of working memory, language ability, and disengagement/inhibition. Participants were 30 YAs and 30 OAs. Contrary to the a priori hypothesis, OAs produced significantly more unique responses than YAs, although total fluency was not significantly different. Correlational analyses examining the groups together and separately revealed a number of differences suggesting that the groups were utilizing different underlying cognitive abilities to complete these tasks. The authors propose that the primary factor resulting in higher uniqueness scores for the OAs was a greater wealth of experience as well as longer exposure to language use. PMID:28446859

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways

PubMed Central

Cappi, C; Brentani, H; Lima, L; Sanders, S J; Zai, G; Diniz, B J; Reis, V N S; Hounie, A G; Conceição do Rosário, M; Mariani, D; Requena, G L; Puga, R; Souza-Duran, F L; Shavitt, R G; Pauls, D L; Miguel, E C; Fernandez, T V

2016-01-01

Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein–protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10−8 per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular

Use of RNA-seq to identify cardiac genes and gene pathways differentially expressed between dogs with and without dilated cardiomyopathy

PubMed Central

Friedenberg, Steven G.; Chdid, Lhoucine; Keene, Bruce; Sherry, Barbara; Motsinger-Reif, Alison; Meurs, Kathryn M.

2017-01-01

OBJECTIVE To identify cardiac tissue genes and gene pathways differentially expressed between dogs with and without dilated cardiomyopathy (DCM). ANIMALS 8 dogs with and 5 dogs without DCM. PROCEDURES Following euthanasia, samples of left ventricular myocardium were collected from each dog. Total RNA was extracted from tissue samples, and RNA sequencing was performed on each sample. Samples from dogs with and without DCM were grouped to identify genes that were differentially regulated between the 2 populations. Overrepresentation analysis was performed on upregulated and downregulated gene sets to identify altered molecular pathways in dogs with DCM. RESULTS Genes involved in cellular energy metabolism, especially metabolism of carbohydrates and fats, were significantly downregulated in dogs with DCM. Expression of cardiac structural proteins was also altered in affected dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that RNA sequencing may provide important insights into the pathogenesis of DCM in dogs and highlight pathways that should be explored to identify causative mutations and develop novel therapeutic interventions. PMID:27347821

Use of RNA-seq to identify cardiac genes and gene pathways differentially expressed between dogs with and without dilated cardiomyopathy.

PubMed

Friedenberg, Steven G; Chdid, Lhoucine; Keene, Bruce; Sherry, Barbara; Motsinger-Reif, Alison; Meurs, Kathryn M

2016-07-01

OBJECTIVE To identify cardiac tissue genes and gene pathways differentially expressed between dogs with and without dilated cardiomyopathy (DCM). ANIMALS 8 dogs with and 5 dogs without DCM. PROCEDURES Following euthanasia, samples of left ventricular myocardium were collected from each dog. Total RNA was extracted from tissue samples, and RNA sequencing was performed on each sample. Samples from dogs with and without DCM were grouped to identify genes that were differentially regulated between the 2 populations. Overrepresentation analysis was performed on upregulated and downregulated gene sets to identify altered molecular pathways in dogs with DCM. RESULTS Genes involved in cellular energy metabolism, especially metabolism of carbohydrates and fats, were significantly downregulated in dogs with DCM. Expression of cardiac structural proteins was also altered in affected dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that RNA sequencing may provide important insights into the pathogenesis of DCM in dogs and highlight pathways that should be explored to identify causative mutations and develop novel therapeutic interventions.

Divergent thinking and constructing episodic simulations.

PubMed

Addis, Donna Rose; Pan, Ling; Musicaro, Regina; Schacter, Daniel L

2016-01-01

Divergent thinking likely plays an important role in simulating autobiographical events. We investigated whether divergent thinking is differentially associated with the ability to construct detailed imagined future and imagined past events as opposed to recalling past events. We also examined whether age differences in divergent thinking might underlie the reduced episodic detail generated by older adults. The richness of episodic detail comprising autobiographical events in young and older adults was assessed using the Autobiographical Interview. Divergent thinking abilities were measured using the Alternative Uses Task. Divergent thinking was significantly associated with the amount of episodic detail for imagined future events. Moreover, while age was significantly associated with imagined episodic detail, this effect was strongly related to age-related changes in episodic retrieval rather than divergent thinking.

Convexity of quantum χ2-divergence.

PubMed

Hansen, Frank

2011-06-21

The general quantum χ(2)-divergence has recently been introduced by Temme et al. [Temme K, Kastoryano M, Ruskai M, Wolf M, Verstrate F (2010) J Math Phys 51:122201] and applied to quantum channels (quantum Markov processes). The quantum χ(2)-divergence is not unique, as opposed to the classical χ(2)-divergence, but depends on the choice of quantum statistics. It was noticed that the elements in a particular one-parameter family of quantum χ(2)-divergences are convex functions in the density matrices (ρ,σ), thus mirroring the convexity of the classical χ(2)(p,q)-divergence in probability distributions (p,q). We prove that any quantum χ(2)-divergence is a convex function in its two arguments.

Extending double modulation: combinatorial rules for identifying the modulations necessary for determining elasticities in metabolic pathways.

PubMed

Giersch, C; Cornish-Bowden, A

1996-10-07

The double modulation method for determining the elasticities of pathway enzymes, originally devised by Kacser & Burns (Biochem. Soc. Trans. 7, 1149-1160, 1979), is extended to pathways of complex topological structure, including branching and feedback loops. An explicit system of linear equations for the unknown elasticities is derived. The constraints imposed on this linear system imply that modulations of more than one enzyme are not necessarily independent. Simple combinatorial rules are described for identifying without using any algebra the set of independent modulations that allow the determination of the elasticities of any enzyme. By repeated application, the minimum numbers of modulations required to determine the elasticities of all enzymes of a given pathway can be determined. The procedure is illustrated with numerous examples.

Computational Approaches for Identifying Adverse Outcome Pathways

EPA Science Inventory

Adverse Outcome Pathways (AOPs) provide a framework for organizing toxicity information to improve predictions of the potential adverse impact of environment stressors on humans or wildlife populations, but these benefits are currently limited by the small number of AOPs currentl...

Repeated divergent selection on pigmentation genes in a rapid finch radiation

PubMed Central

Campagna, Leonardo; Repenning, Márcio; Silveira, Luís Fábio; Fontana, Carla Suertegaray; Tubaro, Pablo L.; Lovette, Irby J.

2017-01-01

Instances of recent and rapid speciation are suitable for associating phenotypes with their causal genotypes, especially if gene flow homogenizes areas of the genome that are not under divergent selection. We study a rapid radiation of nine sympatric bird species known as capuchino seedeaters, which are differentiated in sexually selected characters of male plumage and song. We sequenced the genomes of a phenotypically diverse set of species to search for differentiated genomic regions. Capuchinos show differences in a small proportion of their genomes, yet selection has acted independently on the same targets in different members of this radiation. Many divergent regions contain genes involved in the melanogenesis pathway, with the strongest signal originating from putative regulatory regions. Selection has acted on these same genomic regions in different lineages, likely shaping the evolution of cis-regulatory elements, which control how more conserved genes are expressed and thereby generate diversity in classically sexually selected traits. PMID:28560331

Divergent Thinking and Constructing Episodic Simulations

PubMed Central

Addis, Donna Rose; Pan, Ling; Musicaro, Regina; Schacter, Daniel L.

2014-01-01

Divergent thinking likely plays an important role in simulating autobiographical events. We investigated whether divergent thinking is differentially associated with the ability to construct detailed imagined future and imagined past events as opposed to recalling past events. We also examined whether age differences in divergent thinking might underlie the reduced episodic detail generated by older adults. The richness of episodic detail comprising autobiographical events in young and older adults was assessed using the Autobiographical Interview. Divergent thinking abilities were measured using the Alternate Uses Task. Divergent thinking was significantly associated with the amount of episodic detail for imagined future events. Moreover, while age was significantly associated with imagined episodic detail, this effect was strongly related to age-related changes in episodic retrieval rather than divergent thinking. PMID:25483132

Detection of novel divergent arenaviruses in boid snakes with inclusion body disease in The Netherlands.

PubMed

Bodewes, R; Kik, M J L; Raj, V Stalin; Schapendonk, C M E; Haagmans, B L; Smits, S L; Osterhaus, A D M E

2013-06-01

Arenaviruses are bi-segmented negative-stranded RNA viruses, which were until recently only detected in rodents and humans. Now highly divergent arenaviruses have been identified in boid snakes with inclusion body disease (IBD). Here, we describe the identification of a new species and variants of the highly divergent arenaviruses, which were detected in tissues of captive boid snakes with IBD in The Netherlands by next-generation sequencing. Phylogenetic analysis of the complete sequence of the open reading frames of the four predicted proteins of one of the detected viruses revealed that this virus was most closely related to the recently identified Golden Gate virus, while considerable sequence differences were observed between the highly divergent arenaviruses detected in this study. These findings add to the recent identification of the highly divergent arenaviruses in boid snakes with IBD in the United States and indicate that these viruses also circulate among boid snakes in Europe.

Three Types of Flower Structures in a Divergent-Wrench Fault Zone

NASA Astrophysics Data System (ADS)

Huang, Lei; Liu, Chi-yang

2017-12-01

Flower structures are typical features of wrench fault zones. In conventional studies, two distinct kinds of flower structures have been identified based on differences in their internal structural architecture: (1) negative flower structures characterized by synforms and normal separations and (2) positive flower structures characterized by antiforms and reverse separations. In addition to negative and positive flower structures, in this study, a third kind of flower structure was identified in a divergent-wrench fault zone, a hybrid characterized by both antiforms and normal separations. Negative flower structures widely occur in divergent-wrench fault zones, and their presence indicates the combined effects of extensional and strike-slip motion. In contrast, positive and hybrid flower structures occur only in fault restraining bends and step overs. A hybrid flower structure can be considered as product of a kind of structural deformation typical of divergent-wrench zones; it is the result of the combined effects of extensional, compressional, and strike-slip strains under a locally appropriate compressional environment. The strain situation in it represents the transition stage that in between positive and negative flower structures. Kinematic and dynamic characteristics of the hybrid flower structures indicate the salient features of structural deformation in restraining bends and step overs along divergent-wrench faults, including the coexistence of three kinds of strains (i.e., compression, extension, and strike-slip) and synchronous presence of compressional (i.e., typical fault-bend fold) and extensional (normal faults) deformation in the same place. Hybrid flower structures are also favorable for the accumulation of hydrocarbons because of their special structural configuration in divergent-wrench fault zones.

Divergence of Mammalian Higher Order Chromatin Structure Is Associated with Developmental Loci

PubMed Central

Chambers, Emily V.; Bickmore, Wendy A.; Semple, Colin A.

2013-01-01

Several recent studies have examined different aspects of mammalian higher order chromatin structure – replication timing, lamina association and Hi-C inter-locus interactions — and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin

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

PubMed Central

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

2015-01-01

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

Soft pair excitations and double-log divergences due to carrier interactions in graphene

NASA Astrophysics Data System (ADS)

Lewandowski, Cyprian; Levitov, L. S.

2018-03-01

Interactions between charge carriers in graphene lead to logarithmic renormalization of observables mimicking the behavior known in (3+1)-dimensional quantum electrodynamics (QED). Here we analyze soft electron-hole (e -h ) excitations generated as a result of fast charge dynamics, a direct analog of the signature QED effect—multiple soft photons produced by the QED vacuum shakeup. We show that such excitations are generated in photon absorption, when a photogenerated high-energy e -h pair cascades down in energy and gives rise to multiple soft e -h excitations. This fundamental process is manifested in a double-log divergence in the emission rate of soft pairs and a characteristic power-law divergence in their energy spectrum of the form 1/ω ln(ω/Δ ) . Strong carrier-carrier interactions make pair production a prominent pathway in the photoexcitation cascade.

Nevus density and melanoma risk in women: a pooled analysis to test the divergent pathway hypothesis

PubMed Central

Olsen, Catherine M.; Zens, Michael S.; Stukel, Therese A.; Sacerdote, Carlotta; Chang, Yu-mei; Armstrong, Bruce K.; Bataille, Veronique; Berwick, Marianne; Elwood, J. Mark; Holly, Elizabeth A.; Kirkpatrick, Connie; Mack, Thomas; Bishop, Julia Newton; Østerlind, Anne; Swerdlow, Anthony J.; Zanetti, Roberto; Green, Adèle C.; Karagas, Margaret R.; Whiteman, David C

2009-01-01

A “divergent pathway” model for the development of cutaneous melanoma has been proposed. The model hypothesizes that melanomas occurring in people with a low tendency to develop nevi will, on average, arise more commonly on habitually sun-exposed body sites such as the head and neck. In contrast, people with an inherent propensity to develop nevi will tend to develop melanomas most often on body sites with large melanocyte populations, such as on the back. We conducted a collaborative analysis to test this hypothesis using the original data from ten case-control studies of melanoma in women (2406 cases and 3119 controls), with assessment of the potential confounding effects of socioeconomic, pigmentary, and sun exposure-related factors. Higher nevus count on the arm was associated specifically with an increased risk of melanoma of the trunk (p for trend=0.0004) and limbs (both upper and lower limb p for trends=0.01), but not of the head and neck (p for trend=0.25). The pooled odds ratios for the highest quartile of non-zero nevus count versus none were 4.6 (95% confidence interval (CI) 2.7–7.6) for melanoma of the trunk, 2.0 (95% CI 0.9–4.5) for the head and neck, 4.2 (95% CI 2.3–7.5) for the upper limbs and 3.4 (95% CI 1.5–7.9) for the lower limbs. Aggregate data from these studies suggest that high nevus counts are strongly associated with melanoma of the trunk but less so if at all of the head and neck. This finding supports different etiologic pathways of melanoma development by anatomic site. PMID:19035450

Expression of cytokine genes and receptors in white blood cells associated with divergent body weight gain in beef steers

USDA-ARS?s Scientific Manuscript database

Previous work examining the transcriptome of steer tissue samples from animals with divergent gain have shown a relationship with the expression of genes with functions in immune and inflammatory pathways. The process of mounting an immune or inflammatory response is energetically expensive and vari...

Chained Kullback-Leibler Divergences

PubMed Central

Pavlichin, Dmitri S.; Weissman, Tsachy

2017-01-01

We define and characterize the “chained” Kullback-Leibler divergence minw D(p‖w) + D(w‖q) minimized over all intermediate distributions w and the analogous k-fold chained K-L divergence min D(p‖wk−1) + … + D(w2‖w1) + D(w1‖q) minimized over the entire path (w1,…,wk−1). This quantity arises in a large deviations analysis of a Markov chain on the set of types – the Wright-Fisher model of neutral genetic drift: a population with allele distribution q produces offspring with allele distribution w, which then produce offspring with allele distribution p, and so on. The chained divergences enjoy some of the same properties as the K-L divergence (like joint convexity in the arguments) and appear in k-step versions of some of the same settings as the K-L divergence (like information projections and a conditional limit theorem). We further characterize the optimal k-step “path” of distributions appearing in the definition and apply our findings in a large deviations analysis of the Wright-Fisher process. We make a connection to information geometry via the previously studied continuum limit, where the number of steps tends to infinity, and the limiting path is a geodesic in the Fisher information metric. Finally, we offer a thermodynamic interpretation of the chained divergence (as the rate of operation of an appropriately defined Maxwell’s demon) and we state some natural extensions and applications (a k-step mutual information and k-step maximum likelihood inference). We release code for computing the objects we study. PMID:29130024

Divergent strategy for the synthesis of alpha-aryl-substituted fosmidomycin analogues.

PubMed

Devreux, Vincent; Wiesner, Jochen; Jomaa, Hassan; Rozenski, Jef; Van der Eycken, Johan; Van Calenbergh, Serge

2007-05-11

Fosmidomycin is the first representative of a new class of antimalarial drugs acting through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway for the synthesis of isoprenoids. This work describes a divergent strategy for the synthesis of a series of alpha-aryl-substituted fosmidomycin analogues, featuring a palladium-catalyzed Stille coupling as the key step. An alpha-(4-cyanophenyl)fosmidomycin analogue emerged as the most potent analogue in the present series. Its antimalarial activity clearly surpasses that of the reference compound fosmidomycin.

Genetic Variation of the SusC/SusD Homologs from a Polysaccharide Utilization Locus Underlies Divergent Fructan Specificities and Functional Adaptation in Bacteroides thetaiotaomicron Strains.

PubMed

Joglekar, Payal; Sonnenburg, Erica D; Higginbottom, Steven K; Earle, Kristen A; Morland, Carl; Shapiro-Ward, Sarah; Bolam, David N; Sonnenburg, Justin L

2018-01-01

Genomic differences between gut-resident bacterial strains likely underlie significant interindividual variation in microbiome function. Traditional methods of determining community composition, such as 16S rRNA gene amplicon sequencing, fail to capture this functional diversity. Metagenomic approaches are a significant step forward in identifying strain-level sequence variants; however, given the current paucity of biochemical information, they too are limited to mainly low-resolution and incomplete functional predictions. Using genomic, biochemical, and molecular approaches, we identified differences in the fructan utilization profiles of two closely related Bacteroides thetaiotaomicron strains. B. thetaiotaomicron 8736 ( Bt-8736 ) contains a fructan polysaccharide utilization locus (PUL) with a divergent susC / susD homolog gene pair that enables it to utilize inulin, differentiating this strain from other characterized Bt strains. Transfer of the distinct pair of susC / susD genes from Bt-8736 into the noninulin using type strain B. thetaiotaomicron VPI-5482 resulted in inulin use by the recipient strain, Bt ( 8736-2 ). The presence of the divergent susC / susD gene pair alone enabled the hybrid Bt ( 8736-2 ) strain to outcompete the wild-type strain in vivo in mice fed an inulin diet. Further, we discovered that the susC / susD homolog gene pair facilitated import of inulin into the periplasm without surface predigestion by an endo-acting enzyme, possibly due to the short average chain length of inulin compared to many other polysaccharides. Our data builds upon recent reports of dietary polysaccharide utilization mechanisms found in members of the Bacteroides genus and demonstrates how the acquisition of two genes can alter the functionality and success of a strain within the gut. IMPORTANCE Dietary polysaccharides play a dominant role in shaping the composition and functionality of our gut microbiota. Dietary interventions using these m icrobiota- a

Genetic Variation of the SusC/SusD Homologs from a Polysaccharide Utilization Locus Underlies Divergent Fructan Specificities and Functional Adaptation in Bacteroides thetaiotaomicron Strains

PubMed Central

Joglekar, Payal; Sonnenburg, Erica D.; Higginbottom, Steven K.; Earle, Kristen A.; Morland, Carl; Shapiro-Ward, Sarah; Bolam, David N.

2018-01-01

ABSTRACT Genomic differences between gut-resident bacterial strains likely underlie significant interindividual variation in microbiome function. Traditional methods of determining community composition, such as 16S rRNA gene amplicon sequencing, fail to capture this functional diversity. Metagenomic approaches are a significant step forward in identifying strain-level sequence variants; however, given the current paucity of biochemical information, they too are limited to mainly low-resolution and incomplete functional predictions. Using genomic, biochemical, and molecular approaches, we identified differences in the fructan utilization profiles of two closely related Bacteroides thetaiotaomicron strains. B. thetaiotaomicron 8736 (Bt-8736) contains a fructan polysaccharide utilization locus (PUL) with a divergent susC/susD homolog gene pair that enables it to utilize inulin, differentiating this strain from other characterized Bt strains. Transfer of the distinct pair of susC/susD genes from Bt-8736 into the noninulin using type strain B. thetaiotaomicron VPI-5482 resulted in inulin use by the recipient strain, Bt(8736-2). The presence of the divergent susC/susD gene pair alone enabled the hybrid Bt(8736-2) strain to outcompete the wild-type strain in vivo in mice fed an inulin diet. Further, we discovered that the susC/susD homolog gene pair facilitated import of inulin into the periplasm without surface predigestion by an endo-acting enzyme, possibly due to the short average chain length of inulin compared to many other polysaccharides. Our data builds upon recent reports of dietary polysaccharide utilization mechanisms found in members of the Bacteroides genus and demonstrates how the acquisition of two genes can alter the functionality and success of a strain within the gut. IMPORTANCE Dietary polysaccharides play a dominant role in shaping the composition and functionality of our gut microbiota. Dietary interventions using these microbiota

Brain evolution by brain pathway duplication

PubMed Central

Chakraborty, Mukta; Jarvis, Erich D.

2015-01-01

Understanding the mechanisms of evolution of brain pathways for complex behaviours is still in its infancy. Making further advances requires a deeper understanding of brain homologies, novelties and analogies. It also requires an understanding of how adaptive genetic modifications lead to restructuring of the brain. Recent advances in genomic and molecular biology techniques applied to brain research have provided exciting insights into how complex behaviours are shaped by selection of novel brain pathways and functions of the nervous system. Here, we review and further develop some insights to a new hypothesis on one mechanism that may contribute to nervous system evolution, in particular by brain pathway duplication. Like gene duplication, we propose that whole brain pathways can duplicate and the duplicated pathway diverge to take on new functions. We suggest that one mechanism of brain pathway duplication could be through gene duplication, although other mechanisms are possible. We focus on brain pathways for vocal learning and spoken language in song-learning birds and humans as example systems. This view presents a new framework for future research in our understanding of brain evolution and novel behavioural traits. PMID:26554045

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

PubMed

Cordell, Heather J; Han, Younghun; Mells, George F; Li, Yafang; Hirschfield, Gideon M; Greene, Casey S; Xie, Gang; Juran, Brian D; Zhu, Dakai; Qian, David C; Floyd, James A B; Morley, Katherine I; Prati, Daniele; Lleo, Ana; Cusi, Daniele; Gershwin, M Eric; Anderson, Carl A; Lazaridis, Konstantinos N; Invernizzi, Pietro; Seldin, Michael F; Sandford, Richard N; Amos, Christopher I; Siminovitch, Katherine A

2015-09-22

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Morphological covariance in anatomical MRI scans can identify discrete neural pathways in the brain and their disturbances in persons with neuropsychiatric disorders.

PubMed

Bansal, Ravi; Hao, Xuejun; Peterson, Bradley S

2015-05-01

We hypothesize that coordinated functional activity within discrete neural circuits induces morphological organization and plasticity within those circuits. Identifying regions of morphological covariation that are independent of morphological covariation in other regions therefore may therefore allow us to identify discrete neural systems within the brain. Comparing the magnitude of these variations in individuals who have psychiatric disorders with the magnitude of variations in healthy controls may allow us to identify aberrant neural pathways in psychiatric illnesses. We measured surface morphological features by applying nonlinear, high-dimensional warping algorithms to manually defined brain regions. We transferred those measures onto the surface of a unit sphere via conformal mapping and then used spherical wavelets and their scaling coefficients to simplify the data structure representing these surface morphological features of each brain region. We used principal component analysis (PCA) to calculate covariation in these morphological measures, as represented by their scaling coefficients, across several brain regions. We then assessed whether brain subregions that covaried in morphology, as identified by large eigenvalues in the PCA, identified specific neural pathways of the brain. To do so, we spatially registered the subnuclei for each eigenvector into the coordinate space of a Diffusion Tensor Imaging dataset; we used these subnuclei as seed regions to track and compare fiber pathways with known fiber pathways identified in neuroanatomical atlases. We applied these procedures to anatomical MRI data in a cohort of 82 healthy participants (42 children, 18 males, age 10.5 ± 2.43 years; 40 adults, 22 males, age 32.42 ± 10.7 years) and 107 participants with Tourette's Syndrome (TS) (71 children, 59 males, age 11.19 ± 2.2 years; 36 adults, 21 males, age 37.34 ± 10.9 years). We evaluated the construct validity of the identified covariation in morphology

DNA Barcoding of Recently Diverged Species: Relative Performance of Matching Methods

PubMed Central

van Velzen, Robin; Weitschek, Emanuel; Felici, Giovanni; Bakker, Freek T.

2012-01-01

Recently diverged species are challenging for identification, yet they are frequently of special interest scientifically as well as from a regulatory perspective. DNA barcoding has proven instrumental in species identification, especially in insects and vertebrates, but for the identification of recently diverged species it has been reported to be problematic in some cases. Problems are mostly due to incomplete lineage sorting or simply lack of a ‘barcode gap’ and probably related to large effective population size and/or low mutation rate. Our objective was to compare six methods in their ability to correctly identify recently diverged species with DNA barcodes: neighbor joining and parsimony (both tree-based), nearest neighbor and BLAST (similarity-based), and the diagnostic methods DNA-BAR, and BLOG. We analyzed simulated data assuming three different effective population sizes as well as three selected empirical data sets from published studies. Results show, as expected, that success rates are significantly lower for recently diverged species (∼75%) than for older species (∼97%) (P<0.00001). Similarity-based and diagnostic methods significantly outperform tree-based methods, when applied to simulated DNA barcode data (P<0.00001). The diagnostic method BLOG had highest correct query identification rate based on simulated (86.2%) as well as empirical data (93.1%), indicating that it is a consistently better method overall. Another advantage of BLOG is that it offers species-level information that can be used outside the realm of DNA barcoding, for instance in species description or molecular detection assays. Even though we can confirm that identification success based on DNA barcoding is generally high in our data, recently diverged species remain difficult to identify. Nevertheless, our results contribute to improved solutions for their accurate identification. PMID:22272356

DNA barcoding of recently diverged species: relative performance of matching methods.

PubMed

van Velzen, Robin; Weitschek, Emanuel; Felici, Giovanni; Bakker, Freek T

2012-01-01

Recently diverged species are challenging for identification, yet they are frequently of special interest scientifically as well as from a regulatory perspective. DNA barcoding has proven instrumental in species identification, especially in insects and vertebrates, but for the identification of recently diverged species it has been reported to be problematic in some cases. Problems are mostly due to incomplete lineage sorting or simply lack of a 'barcode gap' and probably related to large effective population size and/or low mutation rate. Our objective was to compare six methods in their ability to correctly identify recently diverged species with DNA barcodes: neighbor joining and parsimony (both tree-based), nearest neighbor and BLAST (similarity-based), and the diagnostic methods DNA-BAR, and BLOG. We analyzed simulated data assuming three different effective population sizes as well as three selected empirical data sets from published studies. Results show, as expected, that success rates are significantly lower for recently diverged species (∼75%) than for older species (∼97%) (P<0.00001). Similarity-based and diagnostic methods significantly outperform tree-based methods, when applied to simulated DNA barcode data (P<0.00001). The diagnostic method BLOG had highest correct query identification rate based on simulated (86.2%) as well as empirical data (93.1%), indicating that it is a consistently better method overall. Another advantage of BLOG is that it offers species-level information that can be used outside the realm of DNA barcoding, for instance in species description or molecular detection assays. Even though we can confirm that identification success based on DNA barcoding is generally high in our data, recently diverged species remain difficult to identify. Nevertheless, our results contribute to improved solutions for their accurate identification.

Systems-based analysis of the Sarcocystis neurona genome identifies pathways that contribute to a heteroxenous life cycle.

PubMed

Blazejewski, Tomasz; Nursimulu, Nirvana; Pszenny, Viviana; Dangoudoubiyam, Sriveny; Namasivayam, Sivaranjani; Chiasson, Melissa A; Chessman, Kyle; Tonkin, Michelle; Swapna, Lakshmipuram S; Hung, Stacy S; Bridgers, Joshua; Ricklefs, Stacy M; Boulanger, Martin J; Dubey, Jitender P; Porcella, Stephen F; Kissinger, Jessica C; Howe, Daniel K; Grigg, Michael E; Parkinson, John

2015-02-10

Sarcocystis neurona is a member of the coccidia, a clade of single-celled parasites of medical and veterinary importance including Eimeria, Sarcocystis, Neospora, and Toxoplasma. Unlike Eimeria, a single-host enteric pathogen, Sarcocystis, Neospora, and Toxoplasma are two-host parasites that infect and produce infectious tissue cysts in a wide range of intermediate hosts. As a genus, Sarcocystis is one of the most successful protozoan parasites; all vertebrates, including birds, reptiles, fish, and mammals are hosts to at least one Sarcocystis species. Here we sequenced Sarcocystis neurona, the causal agent of fatal equine protozoal myeloencephalitis. The S. neurona genome is 127 Mbp, more than twice the size of other sequenced coccidian genomes. Comparative analyses identified conservation of the invasion machinery among the coccidia. However, many dense-granule and rhoptry kinase genes, responsible for altering host effector pathways in Toxoplasma and Neospora, are absent from S. neurona. Further, S. neurona has a divergent repertoire of SRS proteins, previously implicated in tissue cyst formation in Toxoplasma. Systems-based analyses identified a series of metabolic innovations, including the ability to exploit alternative sources of energy. Finally, we present an S. neurona model detailing conserved molecular innovations that promote the transition from a purely enteric lifestyle (Eimeria) to a heteroxenous parasite capable of infecting a wide range of intermediate hosts. Sarcocystis neurona is a member of the coccidia, a clade of single-celled apicomplexan parasites responsible for major economic and health care burdens worldwide. A cousin of Plasmodium, Cryptosporidium, Theileria, and Eimeria, Sarcocystis is one of the most successful parasite genera; it is capable of infecting all vertebrates (fish, reptiles, birds, and mammals-including humans). The past decade has witnessed an increasing number of human outbreaks of clinical significance associated with

Adaptive Genetic Divergence along Narrow Environmental Gradients in Four Stream Insects

PubMed Central

Watanabe, Kozo; Kazama, So; Omura, Tatsuo; Monaghan, Michael T.

2014-01-01

A central question linking ecology with evolutionary biology is how environmental heterogeneity can drive adaptive genetic divergence among populations. We examined adaptive divergence of four stream insects from six adjacent catchments in Japan by combining field measures of habitat and resource components with genome scans of non-neutral Amplified Fragment Length Polymorphism (AFLP) loci. Neutral genetic variation was used to measure gene flow and non-neutral genetic variation was used to test for adaptive divergence. We identified the environmental characteristics contributing to divergence by comparing genetic distances at non-neutral loci between sites with Euclidean distances for each of 15 environmental variables. Comparisons were made using partial Mantel tests to control for geographic distance. In all four species, we found strong evidence for non-neutral divergence along environmental gradients at between 6 and 21 loci per species. The relative contribution of these environmental variables to each species' ecological niche was quantified as the specialization index, S, based on ecological data. In each species, the variable most significantly correlated with genetic distance at non-neutral loci was the same variable along which each species was most narrowly distributed (i.e., highest S). These were gradients of elevation (two species), chlorophyll-a, and ammonia-nitrogen. This adaptive divergence occurred in the face of ongoing gene flow (F st = 0.01–0.04), indicating that selection was strong enough to overcome homogenization at the landscape scale. Our results suggest that adaptive divergence is pronounced, occurs along different environmental gradients for different species, and may consistently occur along the narrowest components of species' niche. PMID:24681871

Functional Conservation of the Transportin Nuclear Import Pathway in Divergent Organisms

PubMed Central

Siomi, Mikiko C.; Fromont, Micheline; Rain, Jean-Christophe; Wan, Lili; Wang, Fan; Legrain, Pierre; Dreyfuss, Gideon

1998-01-01

Human transportin1 (hTRN1) is the nuclear import receptor for a group of pre-mRNA/mRNA-binding proteins (heterogeneous nuclear ribonucleoproteins [hnRNP]) represented by hnRNP A1, which shuttle continuously between the nucleus and the cytoplasm. hTRN1 interacts with the M9 region of hnRNP A1, a 38-amino-acid domain rich in Gly, Ser, and Asn, and mediates the nuclear import of M9-bearing proteins in vitro. Saccharomyces cerevisiae transportin (yTRN; also known as YBR017c or Kap104p) has been identified and cloned. To understanding the nuclear import mediated by yTRN, we searched with a yeast two-hybrid system for proteins that interact with it. In an exhaustive screen of the S. cerevisiae genome, the most frequently selected open reading frame was the nuclear mRNA-binding protein, Nab2p. We delineated a ca.-50-amino-acid region in Nab2p, termed NAB35, which specifically binds yTRN and is similar to the M9 motif. NAB35 also interacts with hTRN1 and functions as a nuclear localization signal in mammalian cells. Interestingly, yTRN can also mediate the import of NAB35-bearing proteins into mammalian nuclei in vitro. We also report on additional substrates for TRN as well as sequences of Drosophila melanogaster, Xenopus laevis, and Schizosaccharomyces pombe TRNs. Together, these findings demonstrate that both the M9 signal and the nuclear import machinery utilized by the transportin pathway are conserved in evolution. PMID:9632798

Inferring species divergence times using pairwise sequential Markovian coalescent modelling and low-coverage genomic data.

PubMed

Cahill, James A; Soares, André E R; Green, Richard E; Shapiro, Beth

2016-07-19

Understanding when species diverged aids in identifying the drivers of speciation, but the end of gene flow between populations can be difficult to ascertain from genetic data. We explore the use of pairwise sequential Markovian coalescent (PSMC) modelling to infer the timing of divergence between species and populations. PSMC plots generated using artificial hybrid genomes show rapid increases in effective population size at the time when the two parent lineages diverge, and this approach has been used previously to infer divergence between human lineages. We show that, even without high coverage or phased input data, PSMC can detect the end of significant gene flow between populations by comparing the PSMC output from artificial hybrids to the output of simulations with known demographic histories. We then apply PSMC to detect divergence times among lineages within two real datasets: great apes and bears within the genus Ursus Our results confirm most previously proposed divergence times for these lineages, and suggest that gene flow between recently diverged lineages may have been common among bears and great apes, including up to one million years of continued gene flow between chimpanzees and bonobos after the formation of the Congo River.This article is part of the themed issue 'Dating species divergences using rocks and clocks'. © 2016 The Author(s).

Insulin-like signaling (IIS) responses to temperature, genetic background, and growth variation in garter snakes with divergent life histories.

PubMed

Reding, Dawn M; Addis, Elizabeth A; Palacios, Maria G; Schwartz, Tonia S; Bronikowski, Anne M

2016-07-01

The insulin/insulin-like signaling pathway (IIS) has been shown to mediate life history trade-offs in mammalian model organisms, but the function of this pathway in wild and non-mammalian organisms is understudied. Populations of western terrestrial garter snakes (Thamnophis elegans) around Eagle Lake, California, have evolved variation in growth and maturation rates, mortality senescence rates, and annual reproductive output that partition into two ecotypes: "fast-living" and "slow-living". Thus, genes associated with the IIS network are good candidates for investigating the mechanisms underlying ecological divergence in this system. We reared neonates from each ecotype for 1.5years under two thermal treatments. We then used qPCR to compare mRNA expression levels in three tissue types (brain, liver, skeletal muscle) for four genes (igf1, igf2, igf1r, igf2r), and we used radioimmunoassay to measure plasma IGF-1 and IGF-2 protein levels. Our results show that, in contrast to most mammalian model systems, igf2 mRNA and protein levels exceed those of igf1 and suggest an important role for igf2 in postnatal growth in reptiles. Thermal rearing treatment and recent growth had greater impacts on IGF levels than genetic background (i.e., ecotype), and the two ecotypes responded similarly. This suggests that observed ecotypic differences in field measures of IGFs may more strongly reflect plastic responses in different environments than evolutionary divergence. Future analyses of additional components of the IIS pathway and sequence divergence between the ecotypes will further illuminate how environmental and genetic factors influence the endocrine system and its role in mediating life history trade-offs. Copyright © 2016 Elsevier Inc. All rights reserved.

Semantic search during divergent thinking.

PubMed

Hass, Richard W

2017-09-01

Divergent thinking, as a method of examining creative cognition, has not been adequately analyzed in the context of modern cognitive theories. This article casts divergent thinking responding in the context of theories of memory search. First, it was argued that divergent thinking tasks are similar to semantic fluency tasks, but are more constrained, and less well structured. Next, response time distributions from 54 participants were analyzed for temporal and semantic clustering. Participants responded to two prompts from the alternative uses test: uses for a brick and uses for a bottle, for two minutes each. Participants' cumulative response curves were negatively accelerating, in line with theories of search of associative memory. However, results of analyses of semantic and temporal clustering suggested that clustering is less evident in alternative uses responding compared to semantic fluency tasks. This suggests either that divergent thinking responding does not involve an exhaustive search through a clustered memory trace, but rather that the process is more exploratory, yielding fewer overall responses that tend to drift away from close associates of the divergent thinking prompt. Copyright © 2017 Elsevier B.V. All rights reserved.

Numerical modeling of divergent detonation wave

NASA Astrophysics Data System (ADS)

Li, Zhiwei; Liu, Bangdi

1987-11-01

The indefinite nature of divergent detonations under the assumption of instantaneous stable detonation is described. In the numerical modeling method for divergent detonation, the artificial cohesiveness was improved and the Cochran reaction rate and the JWL equations of state were used to describe the ignition process of the explosion. Several typical divergent detonation problems were computed obtaining rather satisfying results.

Multiplatform serum metabolic phenotyping combined with pathway mapping to identify biochemical differences in smokers.

PubMed

Kaluarachchi, Manuja R; Boulangé, Claire L; Garcia-Perez, Isabel; Lindon, John C; Minet, Emmanuel F

2016-10-01

Determining perturbed biochemical functions associated with tobacco smoking should be helpful for establishing causal relationships between exposure and adverse events. A multiplatform comparison of serum of smokers (n = 55) and never-smokers (n = 57) using nuclear magnetic resonance spectroscopy, UPLC-MS and statistical modeling revealed clustering of the classes, distinguished by metabolic biomarkers. The identified metabolites were subjected to metabolic pathway enrichment, modeling adverse biological events using available databases. Perturbation of metabolites involved in chronic obstructive pulmonary disease, cardiovascular diseases and cancer were identified and discussed. Combining multiplatform metabolic phenotyping with knowledge-based mapping gives mechanistic insights into disease development, which can be applied to next-generation tobacco and nicotine products for comparative risk assessment.

A high throughput screening for TLR3-IRF3 signaling pathway modulators identifies several antipsychotic drugs as TLR inhibitors1

PubMed Central

Zhu, Jianzhong; Smith, Kevin; Hsieh, Paishiun N.; Mburu, Yvonne K.; Chattopadhyay, Saurabh; Sen, Ganes C.; Sarkar, Saumendra N.

2010-01-01

Toll-like Receptor 3 (TLR3) is one of the major innate immune sensors of double stranded RNA (dsRNA). The signal transduction pathway activated by TLR3, upon binding to dsRNA, leads to the activation of two major transcription factors: NF-κB and IRF3. In an effort to identify specific chemical modulators of TLR3-IRF3 signal transduction pathway we developed a cell-based read out system. Using the interferon stimulated gene 56 (ISG56) promoter driven firefly luciferase gene stably integrated in a TLR3 expressing HEK293 cell line, we were able to generate a cell line where treatment with dsRNA resulted in a dose dependent induction of luciferase activity. A screen of two pharmacologically active compound libraries using this system, identified a number of TLR3-IRF3 signaling pathway modulators. Among them we focused on a subset of inhibitors and characterized their mode of action. Several antipsychotic drugs, such as Sertraline, Trifluoperazine and Fluphenazine were found to be direct inhibitors of the innate immune signaling pathway. These inhibitors also showed the ability to inhibit ISG56 induction mediated by TLR4 and TLR7/8 pathways. Interestingly, they did not show significant effect on TLR3, TLR7 and TLR8 mediated NF-κB activation. Detailed analysis of the signaling pathway indicated that these drugs may be exerting their inhibitory effects on IRF3 via PI3K signaling pathway. The data presented here provides mechanistic explanation of possible anti-inflammatory roles of some antipsychotic drugs. PMID:20382888

Genetic and morphometric divergence in threespine stickleback in the Chignik catchment, Alaska

PubMed Central

Taugbøl, Annette; Junge, Claudia; Quinn, Thomas P; Herland, Anders; Vøllestad, Leif Asbjørn

2014-01-01

Divergent selection pressures induced by different environmental conditions typically lead to variation in life history, behavior, and morphology. When populations are locally adapted to their current environment, selection may limit movement into novel sites, leading to neutral and adaptive genetic divergence in allopatric populations. Subsequently, divergence can be reinforced by development of pre-or postzygotic barriers to gene flow. The threespine stickleback, Gasterosteus aculeatus, is a primarily marine fish that has invaded freshwater repeatedly in postglacial times. After invasion, the established freshwater populations typically show rapid diversification of several traits as they become reproductively isolated from their ancestral marine population. In this study, we examine the genetic and morphometric differentiation between sticklebacks living in an open system comprising a brackish water lagoon, two freshwater lakes, and connecting rivers. By applying a set of microsatellite markers, we disentangled the genetic relationship of the individuals across the diverse environments and identified two genetic populations: one associated with brackish and the other with the freshwater environments. The “brackish” sticklebacks were larger and had a different body shape than those in freshwater. However, we found evidence for upstream migration from the brackish lagoon into the freshwater environments, as fish that were genetically and morphometrically similar to the lagoon fish were found in all freshwater sampling sites. Regardless, few F1-hybrids were identified, and it therefore appears that some pre-and/or postzygotic barriers to gene flow rather than geographic distance are causing the divergence in this system. PMID:24558570

Use of a bovine genome chip to identify new biological pathways for beef quality in cattle.

PubMed

Guifen, Liu; Xiaomu, Liu; Fachun, Wan; Xiuwen, Tan; Haijian, Cheng; Enliang, Song

2012-12-01

The accumulation of muscle is largely influenced by the genetic background of cattle. Muscle tissue was collected from the longissimus muscle of Lilu beef cattle at 12, 18, 24 and 30 months old. Using meat quality analysis, we found that the Lilu beef cattle have good production and slaughter performance, the performance meets the criterion of beef cattle. Microarray analysis was able to identify a total of 4,219 genes that are differentially expressed (P ≤ 0.01) between the two groups of cattle (12 vs 18; 18 vs 24; 24 vs 30). Bioinformatics analysis results suggested that most of the differentially expressed genes are involved in the metabolic pathways and neuroactive ligand-receptor interaction pathways. In the future study that aims to look for genes relating to growth and meat quality, we will focus on the genes that have been shown to have a significant variation between groups and are involved in the two pathways.

Divergence in Siblings' Adult Attachment Security: Potential Contributors and Consequences

ERIC Educational Resources Information Center

Fortuna, Keren

2009-01-01

Previous research has revealed only modest concordance in attachment security between siblings during childhood and adolescence. The first goal of this dissertation was to estimate sibling concordance in adult attachment security and identify factors contributing to divergence. The Adult Attachment Interview (AAI) was administered to young adult…

Divergence and adaptive evolution of the gibberellin oxidase genes in plants.

PubMed

Huang, Yuan; Wang, Xi; Ge, Song; Rao, Guang-Yuan

2015-09-29

The important phytohormone gibberellins (GAs) play key roles in various developmental processes. GA oxidases (GAoxs) are critical enzymes in GA synthesis pathway, but their classification, evolutionary history and the forces driving the evolution of plant GAox genes remain poorly understood. This study provides the first large-scale evolutionary analysis of GAox genes in plants by using an extensive whole-genome dataset of 41 species, representing green algae, bryophytes, pteridophyte, and seed plants. We defined eight subfamilies under the GAox family, namely C19-GA2ox, C20-GA2ox, GA20ox,GA3ox, GAox-A, GAox-B, GAox-C and GAox-D. Of these, subfamilies GAox-A, GAox-B, GAox-C and GAox-D are described for the first time. On the basis of phylogenetic analyses and characteristic motifs of GAox genes, we demonstrated a rapid expansion and functional divergence of the GAox genes during the diversification of land plants. We also detected the subfamily-specific motifs and potential sites of some GAox genes, which might have evolved under positive selection. GAox genes originated very early-before the divergence of bryophytes and the vascular plants and the diversification of GAox genes is associated with the functional divergence and could be driven by positive selection. Our study not only provides information on the classification of GAox genes, but also facilitates the further functional characterization and analysis of GA oxidases.

Genetic divergence of common bean cultivars.

PubMed

Veloso, J S; Silva, W; Pinheiro, L R; Dos Santos, J B; Fonseca, N S; Euzebio, M P

2015-09-22

The aim of this study was to evaluate genetic divergence in the 'Carioca' (beige with brown stripes) common bean cultivar used by different institutions and in 16 other common bean cultivars used in the Rede Cooperativa de Pesquisa de Feijão (Cooperative Network of Common Bean Research), by using simple sequence repeats associated with agronomic traits that are highly distributed in the common bean genome. We evaluated 22 polymorphic loci using bulks containing DNA from 30 plants. There was genetic divergence among the Carioca cultivar provided by the institutions. Nevertheless, there was lower divergence among them than among the other cultivars. The cultivar used by Instituto Agronômico do Paraná was the most divergent in relation to the Carioca samples. The least divergence was observed among the samples used by Universidade Federal de Lavras and by Embrapa Arroz e Feijão. Of all the cultivars, 'CNFP 10104' and 'BRSMG Realce' showed the greatest dissimilarity. The cultivars were separated in two groups of greatest similarity using the Structure software. Genetic variation among cultivars was greater than the variation within or between the groups formed. This fact, together with the high estimate of heterozygosity observed and the genetic divergence of the samples of the Carioca cultivar in relation to the original provided by Instituto Agronômico de Campinas, indicates a mixture of cultivars. The high divergence among cultivars provides potential for the utilization of this genetic variability in plant breeding.

Mutually exclusive signaling signatures define the hepatic and pancreatic progenitor cell lineage divergence

PubMed Central

Rodríguez-Seguel, Elisa; Mah, Nancy; Naumann, Heike; Pongrac, Igor M.; Cerdá-Esteban, Nuria; Fontaine, Jean-Fred; Wang, Yongbo; Chen, Wei; Andrade-Navarro, Miguel A.; Spagnoli, Francesca M.

2013-01-01

Understanding how distinct cell types arise from multipotent progenitor cells is a major quest in stem cell biology. The liver and pancreas share many aspects of their early development and possibly originate from a common progenitor. However, how liver and pancreas cells diverge from a common endoderm progenitor population and adopt specific fates remains elusive. Using RNA sequencing (RNA-seq), we defined the molecular identity of liver and pancreas progenitors that were isolated from the mouse embryo at two time points, spanning the period when the lineage decision is made. The integration of temporal and spatial gene expression profiles unveiled mutually exclusive signaling signatures in hepatic and pancreatic progenitors. Importantly, we identified the noncanonical Wnt pathway as a potential developmental regulator of this fate decision and capable of inducing the pancreas program in endoderm and liver cells. Our study offers an unprecedented view of gene expression programs in liver and pancreas progenitors and forms the basis for formulating lineage-reprogramming strategies to convert adult hepatic cells into pancreatic cells. PMID:24013505

Adaptation to different host plant ages facilitates insect divergence without a host shift

PubMed Central

Zhang, Bin; Segraves, Kari A.; Xue, Huai-Jun; Nie, Rui-E; Li, Wen-Zhu; Yang, Xing-Ke

2015-01-01

Host shifts and subsequent adaption to novel host plants are important drivers of speciation among phytophagous insects. However, there is considerably less evidence for host plant-mediated speciation in the absence of a host shift. Here, we investigated divergence of two sympatric sister elm leaf beetles, Pyrrhalta maculicollis and P. aenescens, which feed on different age classes of the elm Ulmus pumila L. (seedling versus adult trees). Using a field survey coupled with preference and performance trials, we show that these beetle species are highly divergent in both feeding and oviposition preference and specialize on either seedling or adult stages of their host plant. An experiment using artificial leaf discs painted with leaf surface wax extracts showed that host plant chemistry is a critical element that shapes preference. Specialization appears to be driven by adaptive divergence as there was also evidence of divergent selection; beetles had significantly higher survival and fecundity when reared on their natal host plant age class. Together, the results identify the first probable example of divergence induced by host plant age, thus extending how phytophagous insects might diversify in the absence of host shifts. PMID:26378220

Divergently expressed gene identification and interaction prediction of long noncoding RNA and mRNA involved in duck reproduction.

PubMed

Ren, Jindong; Du, Xue; Zeng, Tao; Chen, Li; Shen, Junda; Lu, Lizhi; Hu, Jianhong

2017-10-01

Long noncoding RNAs (lncRNAs) and divergently expressed genes exist widely in different tissues of mammals and birds, in which they are involved in various biological processes. However, there is limited information on their role in the regulation of normal biological processes during differentiation, development, and reproduction in birds. In this study, whole transcriptome strand-specific RNA sequencing of the ovary from young ducks (60days), first-laying ducks (160days), and old ducks, i.e., ducks that stopped laying eggs (490days) was performed. The lncRNAs and mRNAs from these ducks were systematically analyzed and identified by duck genome sequencing in the three study groups. The transcriptome from the duck ovary comprised 15,011 protein-coding genes and 2905 lncRNAs; all the lncRNAs were identified as novel long noncoding transcripts. The comparison of transcriptome data from different study groups identified 2240 divergent transcription genes and 135 divergently expressed lncRNAs, which differed among the groups; most of them were significantly downregulated with age. Among the divergent genes, 38 genes were related to the reproductive process and 6 genes were upregulated. Further prediction analysis revealed that 52 lncRNAs were closely correlated with divergent reproductive mRNAs. More importantly, 6 remarkable lncRNAs were correlated significantly with the conversion of the ovary in different phases. Our results aid in the understanding of the divergent transcriptome of duck ovary in different phases and the underlying mechanisms that drive the specificity of protein-coding genes and lncRNAs in duck ovary. Copyright © 2017. Published by Elsevier B.V.

Divergence and Necessary Conditions for Extremums

NASA Technical Reports Server (NTRS)

Quirein, J. A.

1973-01-01

The problem is considered of finding a dimension reducing transformation matrix B that maximizes the divergence in the reduced dimension for multi-class cases. A comparitively simple expression for the gradient of the average divergence with respect to B is developed. The developed expression for the gradient contains no eigenvectors or eigenvalues; also, all matrix inversions necessary to evaluate the gradient are available from computing the average divergence.

Mitochondrial and nuclear DNA sequences reveal recent divergence in morphologically indistinguishable petrels.

PubMed

Welch, Andreanna J; Yoshida, Allison A; Fleischer, Robert C

2011-04-01

Often during the process of divergence, genetic markers will only gradually obtain the signal of isolation. Studies of recently diverged taxa utilizing both mitochondrial and nuclear data sets may therefore yield gene trees with differing levels of phylogenetic signal as a result of differences in coalescence times. However, several factors can lead to this same pattern, and it is important to distinguish between them to gain a better understanding of the process of divergence and the factors driving it. Here, we employ three nuclear intron loci in addition to the mitochondrial Cytochrome b gene to investigate the magnitude and timing of divergence between two endangered and nearly indistinguishable petrel taxa: the Galapagos (GAPE) and Hawaiian (HAPE) petrels (Pterodroma phaeopygia and P. sandwichensis). Phylogenetic analyses indicated reciprocal monophyly between these two taxa for the mitochondrial data set, but trees derived from the nuclear introns were unresolved. Coalescent analyses revealed effectively no migration between GAPE and HAPE over the last 100,000 generations and that they diverged relatively recently, approximately 550,000 years ago, coincident with a time of intense ecological change in both the Galapagos and Hawaiian archipelagoes. This indicates that recent divergence and incomplete lineage sorting are causing the difference in the strength of the phylogenetic signal of each data set, instead of insufficient variability or ongoing male-biased dispersal. Further coalescent analyses show that gene flow is low even between islands within each archipelago suggesting that divergence may be continuing at a local scale. Accurately identifying recently isolated taxa is becoming increasingly important as many clearly recognizable species are already threatened by extinction. © 2011 Blackwell Publishing Ltd.

Identification of differential pathways in papillary thyroid carcinoma utilizing pathway co-expression analysis.

PubMed

Qiu, Wei-Hai; Chen, Gui-Yan; Cui, Lu; Zhang, Ting-Ming; Wei, Feng; Yang, Yong

2016-01-01

To identify differential pathways between papillary thyroid carcinoma (PTC) patients and normal controls utilizing a novel method which combined pathway with co-expression network. The proposed method included three steps. In the first step, we conducted pretreatments for background pathways and gained representative pathways in PTC. Subsequently, a co-expression network for representative pathways was constructed using empirical Bayes (EB) approach to assign a weight value for each pathway. Finally, random model was extracted to set the thresholds of identifying differential pathways. We obtained 1267 representative pathways and their weight values based on the co-expressed pathway network, and then by meeting the criterion (Weight > 0.0296), 87 differential pathways in total across PTC patients and normal controls were identified. The top three ranked differential pathways were CREB phosphorylation, attachment of GPI anchor to urokinase plasminogen activator receptor (uPAR) and loss of function of SMAD2/3 in cancer. In conclusion, we successfully identified differential pathways (such as CREB phosphorylation, attachment of GPI anchor to uPAR and post-translational modification: synthesis of GPI-anchored proteins) for PTC using the proposed pathway co-expression method, and these pathways might be potential biomarkers for target therapy and detection of PTC.

Mitochondrial divergence between slow- and fast-aging garter snakes.

PubMed

Schwartz, Tonia S; Arendsee, Zebulun W; Bronikowski, Anne M

2015-11-01

Mitochondrial function has long been hypothesized to be intimately involved in aging processes--either directly through declining efficiency of mitochondrial respiration and ATP production with advancing age, or indirectly, e.g., through increased mitochondrial production of damaging free radicals with age. Yet we lack a comprehensive understanding of the evolution of mitochondrial genotypes and phenotypes across diverse animal models, particularly in species that have extremely labile physiology. Here, we measure mitochondrial genome-types and transcription in ecotypes of garter snakes (Thamnophis elegans) that are adapted to disparate habitats and have diverged in aging rates and lifespans despite residing in close proximity. Using two RNA-seq datasets, we (1) reconstruct the garter snake mitochondrial genome sequence and bioinformatically identify regulatory elements, (2) test for divergence of mitochondrial gene expression between the ecotypes and in response to heat stress, and (3) test for sequence divergence in mitochondrial protein-coding regions in these slow-aging (SA) and fast-aging (FA) naturally occurring ecotypes. At the nucleotide sequence level, we confirmed two (duplicated) mitochondrial control regions one of which contains a glucocorticoid response element (GRE). Gene expression of protein-coding genes was higher in FA snakes relative to SA snakes for most genes, but was neither affected by heat stress nor an interaction between heat stress and ecotype. SA and FA ecotypes had unique mitochondrial haplotypes with amino acid substitutions in both CYTB and ND5. The CYTB amino acid change (Isoleucine → Threonine) was highly segregated between ecotypes. This divergence of mitochondrial haplotypes between SA and FA snakes contrasts with nuclear gene-flow estimates, but correlates with previously reported divergence in mitochondrial function (mitochondrial oxygen consumption, ATP production, and reactive oxygen species consequences). Copyright © 2015

Adolescents Can Know Best: Using concept mapping to identify factors and pathways driving adolescent sexuality in Lima, Peru

PubMed Central

Bayer, Angela M.; Cabrera, Lilia Z.; Gilman, Robert H.; Hindin, Michelle J.; Tsui, Amy O.

2011-01-01

The primary objective of this study was to identify and describe individual- and environmental-level factors that Peruvian adolescents perceive to be related to adolescent sexuality. A series of concept mapping sessions were carried out from January-March 2006 with 63 15–17 year olds from a low-income community near Lima in order for adolescents to (1) brainstorm items that they thought were related to sexuality (2) sort, group and rate items to score their importance for sexuality-related outcomes, and (3) create pathways from the groups of items to engaging in sex. Brainstorming resulted in 61 items, which participants grouped into 11 clusters. The highest rated clusters were personal values, respect and confidence in relationships, future achievements and parent-child communication. The pathway of decision-making about having sex primarily contained items rated as only moderately important. This study identified important understudied factors, new perspectives on previously-recognized factors, and possible pathways to sexual behavior. These interesting, provocative findings underscore the importance of directly integrating adolescent voices into future sexual and reproductive health research, policies and programs that target this population. PMID:20382462

Retroviral insertions in the VISION database identify molecular pathways in mouse lymphoid leukemia and lymphoma

PubMed Central

Weiser, Keith C.; Liu, Bin; Hansen, Gwenn M.; Skapura, Darlene; Hentges, Kathryn E.; Yarlagadda, Sujatha; Morse III, Herbert C.

2007-01-01

AKXD recombinant inbred (RI) strains develop a variety of leukemias and lymphomas due to somatically acquired insertions of retroviral DNA into the genome of hematopoetic cells that can mutate cellular proto-oncogenes and tumor suppressor genes. We generated a new set of tumors from nine AKXD RI strains selected for their propensity to develop B-cell tumors, the most common type of human hematopoietic cancers. We employed a PCR technique called viral insertion site amplification (VISA) to rapidly isolate genomic sequence at the site of provirus insertion. Here we describe 550 VISA sequence tags (VSTs) that identify 74 common insertion sites (CISs), of which 21 have not been identified previously. Several suspected proto-oncogenes and tumor suppressor genes lie near CISs, providing supportive evidence for their roles in cancer. Furthermore, numerous previously uncharacterized genes lie near CISs, providing a pool of candidate disease genes for future research. Pathway analysis of candidate genes identified several signaling pathways as common and powerful routes to blood cancer, including Notch, E-protein, NFκB, and Ras signaling. Misregulation of several Notch signaling genes was confirmed by quantitative RT-PCR. Our data suggest that analyses of insertional mutagenesis on a single genetic background are biased toward the identification of cooperating mutations. This tumor collection represents the most comprehensive study of the genetics of B-cell leukemia and lymphoma development in mice. We have deposited the VST sequences, CISs in a genome viewer, histopathology, and molecular tumor typing data in a public web database called VISION (Viral Insertion Sites Identifying Oncogenes), which is located at http://www.mouse-genome.bcm.tmc.edu/vision. PMID:17926094

Retroviral insertions in the VISION database identify molecular pathways in mouse lymphoid leukemia and lymphoma.

PubMed

Weiser, Keith C; Liu, Bin; Hansen, Gwenn M; Skapura, Darlene; Hentges, Kathryn E; Yarlagadda, Sujatha; Morse Iii, Herbert C; Justice, Monica J

2007-10-01

AKXD recombinant inbred (RI) strains develop a variety of leukemias and lymphomas due to somatically acquired insertions of retroviral DNA into the genome of hematopoetic cells that can mutate cellular proto-oncogenes and tumor suppressor genes. We generated a new set of tumors from nine AKXD RI strains selected for their propensity to develop B-cell tumors, the most common type of human hematopoietic cancers. We employed a PCR technique called viral insertion site amplification (VISA) to rapidly isolate genomic sequence at the site of provirus insertion. Here we describe 550 VISA sequence tags (VSTs) that identify 74 common insertion sites (CISs), of which 21 have not been identified previously. Several suspected proto-oncogenes and tumor suppressor genes lie near CISs, providing supportive evidence for their roles in cancer. Furthermore, numerous previously uncharacterized genes lie near CISs, providing a pool of candidate disease genes for future research. Pathway analysis of candidate genes identified several signaling pathways as common and powerful routes to blood cancer, including Notch, E-protein, NFkappaB, and Ras signaling. Misregulation of several Notch signaling genes was confirmed by quantitative RT-PCR. Our data suggest that analyses of insertional mutagenesis on a single genetic background are biased toward the identification of cooperating mutations. This tumor collection represents the most comprehensive study of the genetics of B-cell leukemia and lymphoma development in mice. We have deposited the VST sequences, CISs in a genome viewer, histopathology, and molecular tumor typing data in a public web database called VISION (Viral Insertion Sites Identifying Oncogenes), which is located at http://www.mouse-genome.bcm.tmc.edu/vision .

A novel dysregulated pathway-identification analysis based on global influence of within-pathway effects and crosstalk between pathways

PubMed Central

Han, Junwei; Li, Chunquan; Yang, Haixiu; Xu, Yanjun; Zhang, Chunlong; Ma, Jiquan; Shi, Xinrui; Liu, Wei; Shang, Desi; Yao, Qianlan; Zhang, Yunpeng; Su, Fei; Feng, Li; Li, Xia

2015-01-01

Identifying dysregulated pathways from high-throughput experimental data in order to infer underlying biological insights is an important task. Current pathway-identification methods focus on single pathways in isolation; however, consideration of crosstalk between pathways could improve our understanding of alterations in biological states. We propose a novel method of pathway analysis based on global influence (PAGI) to identify dysregulated pathways, by considering both within-pathway effects and crosstalk between pathways. We constructed a global gene–gene network based on the relationships among genes extracted from a pathway database. We then evaluated the extent of differential expression for each gene, and mapped them to the global network. The random walk with restart algorithm was used to calculate the extent of genes affected by global influence. Finally, we used cumulative distribution functions to determine the significance values of the dysregulated pathways. We applied the PAGI method to five cancer microarray datasets, and compared our results with gene set enrichment analysis and five other methods. Based on these analyses, we demonstrated that PAGI can effectively identify dysregulated pathways associated with cancer, with strong reproducibility and robustness. We implemented PAGI using the freely available R-based and Web-based tools (http://bioinfo.hrbmu.edu.cn/PAGI). PMID:25551156

Novel Angiogenic Domains: Use in Identifying Unique Transforming and Tumor Promoting Pathways in Human Breast Cancer

DTIC Science & Technology

2004-10-01

Cancer PRINCIPAL INVESTIGATOR: Thomas F. Deuel, M.D. CONTRACTING ORGANIZATION: The Scripps Research Institute...NUMBER Novel Angiogenic Domains: Use in Identifying Unique Transforming and Tumor Promoting Pathways in Human Breast Cancer 5b. GRANT NUMBER DAMD17...SUPPLEMENTARY NOTES 14. ABSTRACT Breast cancers in humans often grow slowly or even remain undetectable for long periods of time only to

Sexual selection and population divergence II. Divergence in different sexual traits and signal modalities in field crickets (Teleogryllus oceanicus).

PubMed

Pascoal, Sonia; Mendrok, Magdalena; Wilson, Alastair J; Hunt, John; Bailey, Nathan W

2017-06-01

Sexual selection can target many different types of traits. However, the relative influence of different sexually selected traits during evolutionary divergence is poorly understood. We used the field cricket Teleogryllus oceanicus to quantify and compare how five traits from each of three sexual signal modalities and components diverge among allopatric populations: male advertisement song, cuticular hydrocarbon (CHC) profiles and forewing morphology. Population divergence was unexpectedly consistent: we estimated the among-population (genetic) variance-covariance matrix, D, for all 15 traits, and D max explained nearly two-thirds of its variation. CHC and wing traits were most tightly integrated, whereas song varied more independently. We modeled the dependence of among-population trait divergence on genetic distance estimated from neutral markers to test for signatures of selection versus neutral divergence. For all three sexual trait types, phenotypic variation among populations was largely explained by a neutral model of divergence. Our findings illustrate how phenotypic integration across different types of sexual traits might impose constraints on the evolution of mating isolation and divergence via sexual selection. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

Century-scale Methylome Stability in a Recently Diverged Arabidopsis thaliana Lineage

PubMed Central

Müller, Jonas; Stegle, Oliver; Meyer, Rhonda C.; Wang, George; Schneeberger, Korbinian; Fitz, Joffrey; Altmann, Thomas; Bergelson, Joy; Borgwardt, Karsten; Weigel, Detlef

2015-01-01

There has been much excitement about the possibility that exposure to specific environments can induce an ecological memory in the form of whole-sale, genome-wide epigenetic changes that are maintained over many generations. In the model plant Arabidopsis thaliana, numerous heritable DNA methylation differences have been identified in greenhouse-grown isogenic lines, but it remains unknown how natural, highly variable environments affect the rate and spectrum of such changes. Here we present detailed methylome analyses in a geographically dispersed A. thaliana population that constitutes a collection of near-isogenic lines, diverged for at least a century from a common ancestor. Methylome variation largely reflected genetic distance, and was in many aspects similar to that of lines raised in uniform conditions. Thus, even when plants are grown in varying and diverse natural sites, genome-wide epigenetic variation accumulates mostly in a clock-like manner, and epigenetic divergence thus parallels the pattern of genome-wide DNA sequence divergence. PMID:25569172

Verbal and visual divergent thinking in aging.

PubMed

Palmiero, Massimiliano; Nori, Raffaella; Piccardi, Laura

2017-04-01

According to the peak and decline model divergent thinking declines at a specific age (in or after middle age). However, if divergent thinking declines steadily in aging still has to be clarified. In order to explore the age-related changes in verbal and visual divergent thinking, in the present study a sample of 159 participants was divided in five age groups: young adults (18-35 years), middle-aged adults (36-55), young old (56-74), old (75-85) and the oldest-old (86-98). Two divergent thinking tasks were administered: the alternative uses for cardboard boxes, aimed at assessing verbal ideational fluency, flexibility and originality; the completion drawing task, aimed at assessing visual ideational fluency, flexibility and originality. Results showed that after peaking in the young adult group (20-35 years) all components of verbal and visual divergent thinking stabilized in the middle-aged adult group (36-55 years) and then started declining in the young old group (56-75). Interestingly, all components were found to be preserved after declining. Yet, verbal and visual divergent thinking were found at the same extent across age groups, with the exception of visual ideational fluency, that was higher in the young old group, the old group and the oldest-old group than verbal ideational fluency. These results support the idea that divergent thinking does not decline steadily in the elderly. Given that older people can preserve to some extent verbal and visual divergent thinking, these findings have important implications for active aging, that is, divergent thinking might be fostered in aging in order to prevent the cognitive decline.

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

PubMed

Cirulli, Elizabeth T; Lasseigne, Brittany N; Petrovski, Slavé; Sapp, Peter C; Dion, Patrick A; Leblond, Claire S; Couthouis, Julien; Lu, Yi-Fan; Wang, Quanli; Krueger, Brian J; Ren, Zhong; Keebler, Jonathan; Han, Yujun; Levy, Shawn E; Boone, Braden E; Wimbish, Jack R; Waite, Lindsay L; Jones, Angela L; Carulli, John P; Day-Williams, Aaron G; Staropoli, John F; Xin, Winnie W; Chesi, Alessandra; Raphael, Alya R; McKenna-Yasek, Diane; Cady, Janet; Vianney de Jong, J M B; Kenna, Kevin P; Smith, Bradley N; Topp, Simon; Miller, Jack; Gkazi, Athina; Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan; Silani, Vincenzo; Ticozzi, Nicola; Shaw, Christopher E; Baloh, Robert H; Appel, Stanley; Simpson, Ericka; Lagier-Tourenne, Clotilde; Pulst, Stefan M; Gibson, Summer; Trojanowski, John Q; Elman, Lauren; McCluskey, Leo; Grossman, Murray; Shneider, Neil A; Chung, Wendy K; Ravits, John M; Glass, Jonathan D; Sims, Katherine B; Van Deerlin, Vivianna M; Maniatis, Tom; Hayes, Sebastian D; Ordureau, Alban; Swarup, Sharan; Landers, John; Baas, Frank; Allen, Andrew S; Bedlack, Richard S; Harper, J Wade; Gitler, Aaron D; Rouleau, Guy A; Brown, Robert; Harms, Matthew B; Cooper, Gregory M; Harris, Tim; Myers, Richard M; Goldstein, David B

2015-03-27

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention. Copyright © 2015, American Association for the Advancement of Science.

Using Smoke Injection in Drains to Identify Potential Preferential Pathways in a Drained Arable Field

NASA Astrophysics Data System (ADS)

Nielsen, M. H.; Petersen, C. T.; Hansen, S.

2014-12-01

Macropores forming a continuous pathway between the soil surface and subsurface drains favour the transport of many contaminants from agricultural fields to surface waters. The smoke injection method presented by Shipitalo and Gibbs (2000) used for demonstrating and quantifying such pathways has been further developed and used on a drained Danish sandy loam. In order to identify the preferential pathways to drains, smoke was injected in three 1.15 m deep tile drains (total drain length 93 m), and smoke emitting macropores (SEMP) at the soil surface were counted and characterized as producing either strong or weak plumes compared to reference plumes from 3 and 6 mm wide tubes. In the two situations investigated in the present study - an early spring and an autumn situation, smoke only penetrated the soil surface layer via earthworm burrows located in a 1.0 m wide belt directly above the drain lines. However, it is known from previous studies that desiccation fractures in a dry summer situation also can contribute to the smoke pattern. The distance between SEMP measured along the drain lines was on average 0.46 m whereas the average spacing between SEMP with strong plumes was 2.3 m. Ponded water was applied in 6 cm wide rings placed above 52 burrows including 17 reference burrows which did not emit smoke. Thirteen pathways in the soil were examined using dye tracer and profile excavation. SEMP with strong plumes marked the entrance of highly efficient transport pathways conducting surface applied water and dye tracer into the drain. However, no single burrow was traced all the way from the surface into the drain, the dye patterns branched off in a network of other macropores. Water infiltration rates were significantly higher (P < 0.05) in SEMP with strong plumes (average rate: 247 mL min-1 n = 19) compared to SEMP with weak plumes (average rate: 87 mL min-1 n = 16) and no plumes (average rate: 56 mL min-1 n = 17). The results suggest that the smoke injection method

Updating Status: Tracing College Women's Diverging Educational Pathways with Facebook

ERIC Educational Resources Information Center

Allaman, Erin

2013-01-01

As young people incorporate digital media into the ecologies of their daily lives, new technologies play an important role in how they experience higher education while simultaneously creating a digital record of their educational pathways. Little research has been conducted that explores how Millennials' forays into college life are defined…

Identification of altered pathways in breast cancer based on individualized pathway aberrance score.

PubMed

Shi, Sheng-Hong; Zhang, Wei; Jiang, Jing; Sun, Long

2017-08-01

The objective of the present study was to identify altered pathways in breast cancer based on the individualized pathway aberrance score (iPAS) method combined with the normal reference (nRef). There were 4 steps to identify altered pathways using the iPAS method: Data preprocessing conducted by the robust multi-array average (RMA) algorithm; gene-level statistics based on average Z ; pathway-level statistics according to iPAS; and a significance test dependent on 1 sample Wilcoxon test. The altered pathways were validated by calculating the changed percentage of each pathway in tumor samples and comparing them with pathways from differentially expressed genes (DEGs). A total of 688 altered pathways with P<0.01 were identified, including kinesin (KIF)- and polo-like kinase (PLK)-mediated events. When the percentage of change reached 50%, 310 pathways were involved in the total 688 altered pathways, which may validate the present results. In addition, there were 324 DEGs and 155 common genes between DEGs and pathway genes. DEGs and common genes were enriched in the same 9 significant terms, which also were members of altered pathways. The iPAS method was suitable for identifying altered pathways in breast cancer. Altered pathways (such as KIF and PLK mediated events) were important for understanding breast cancer mechanisms and for the future application of customized therapeutic decisions.

Transcriptional analysis of abdominal fat in chickens divergently selected on bodyweight at two ages reveals novel mechanisms controlling adiposity: validating visceral adipose tissue as a dynamic endocrine and metabolic organ.

PubMed

Resnyk, C W; Carré, W; Wang, X; Porter, T E; Simon, J; Le Bihan-Duval, E; Duclos, M J; Aggrey, S E; Cogburn, L A

2017-08-16

Decades of intensive genetic selection in the domestic chicken (Gallus gallus domesticus) have enabled the remarkable rapid growth of today's broiler (meat-type) chickens. However, this enhanced growth rate was accompanied by several unfavorable traits (i.e., increased visceral fatness, leg weakness, and disorders of metabolism and reproduction). The present descriptive analysis of the abdominal fat transcriptome aimed to identify functional genes and biological pathways that likely contribute to an extreme difference in visceral fatness of divergently selected broiler chickens. We used the Del-Mar 14 K Chicken Integrated Systems microarray to take time-course snapshots of global gene transcription in abdominal fat of juvenile [1-11 weeks of age (wk)] chickens divergently selected on bodyweight at two ages (8 and 36 wk). Further, a RNA sequencing analysis was completed on the same abdominal fat samples taken from high-growth (HG) and low-growth (LG) cockerels at 7 wk, the age with the greatest divergence in body weight (3.2-fold) and visceral fatness (19.6-fold). Time-course microarray analysis revealed 312 differentially expressed genes (FDR ≤ 0.05) as the main effect of genotype (HG versus LG), 718 genes in the interaction of age and genotype, and 2918 genes as the main effect of age. The RNA sequencing analysis identified 2410 differentially expressed genes in abdominal fat of HG versus LG chickens at 7 wk. The HG chickens are fatter and over-express numerous genes that support higher rates of visceral adipogenesis and lipogenesis. In abdominal fat of LG chickens, we found higher expression of many genes involved in hemostasis, energy catabolism and endocrine signaling, which likely contribute to their leaner phenotype and slower growth. Many transcription factors and their direct target genes identified in HG and LG chickens could be involved in their divergence in adiposity and growth rate. The present analyses of the visceral fat transcriptome in

MMTV insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer.

PubMed

Theodorou, Vassiliki; Kimm, Melanie A; Boer, Mandy; Wessels, Lodewyk; Theelen, Wendy; Jonkers, Jos; Hilkens, John

2007-06-01

We performed a high-throughput retroviral insertional mutagenesis screen in mouse mammary tumor virus (MMTV)-induced mammary tumors and identified 33 common insertion sites, of which 17 genes were previously not known to be associated with mammary cancer and 13 had not previously been linked to cancer in general. Although members of the Wnt and fibroblast growth factors (Fgf) families were frequently tagged, our exhaustive screening for MMTV insertion sites uncovered a new repertoire of candidate breast cancer oncogenes. We validated one of these genes, Rspo3, as an oncogene by overexpression in a p53-deficient mammary epithelial cell line. The human orthologs of the candidate oncogenes were frequently deregulated in human breast cancers and associated with several tumor parameters. Computational analysis of all MMTV-tagged genes uncovered specific gene families not previously associated with cancer and showed a significant overrepresentation of protein domains and signaling pathways mainly associated with development and growth factor signaling. Comparison of all tagged genes in MMTV and Moloney murine leukemia virus-induced malignancies showed that both viruses target mostly different genes that act predominantly in distinct pathways.

Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees.

PubMed

Segarra, Ignacio; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L

2017-01-01

The efforts toward individualized medicine have constantly increased in an attempt to improve treatment options. These efforts have led to the development of small molecules which target specific molecular pathways involved in cancer progression. We have reviewed preclinical studies of sunitinib that incorporate sex as a covariate to explore possible sex-based differences in pharmacokinetics and drug-drug interactions (DDI) to attempt a relationship with published clinical outputs. We observed that covariate sex is lacking in most clinical outcome reports and suggest a series of ethic-based proposals to improve research activities and identify relevant different sex outcomes. We propose a deeper integration of preclinical, clinical, and translational research addressing statistical and clinical significance jointly; to embed specific sex-divergent endpoints to evaluate possible gender differences objectively during all stages of research; to pay greater attention to sex-divergent outcomes in polypharmacy scenarios, DDI and bioequivalence studies; the clear reporting of preclinical and clinical findings regarding sex-divergent outcomes; as well as to encourage the active role of scientists and the pharmaceutical industry to foster a new scientific culture through their research programs, practice, and participation in editorial boards and Institutional Ethics Review Boards (IRBs) and Research Ethics Committees (RECs). We establish the IRB/REC as the centerpiece for the implementation of these proposals. We suggest the expansion of its competence to follow up clinical trials to ensure that sex differences are addressed and recognized; to engage in data monitoring committees to improve clinical research cooperation and ethically address those potential clinical outcome differences between male and female patients to analyze their social and clinical implications in research and healthcare policies.

Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees

PubMed Central

Segarra, Ignacio; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L.

2017-01-01

The efforts toward individualized medicine have constantly increased in an attempt to improve treatment options. These efforts have led to the development of small molecules which target specific molecular pathways involved in cancer progression. We have reviewed preclinical studies of sunitinib that incorporate sex as a covariate to explore possible sex-based differences in pharmacokinetics and drug–drug interactions (DDI) to attempt a relationship with published clinical outputs. We observed that covariate sex is lacking in most clinical outcome reports and suggest a series of ethic-based proposals to improve research activities and identify relevant different sex outcomes. We propose a deeper integration of preclinical, clinical, and translational research addressing statistical and clinical significance jointly; to embed specific sex-divergent endpoints to evaluate possible gender differences objectively during all stages of research; to pay greater attention to sex-divergent outcomes in polypharmacy scenarios, DDI and bioequivalence studies; the clear reporting of preclinical and clinical findings regarding sex-divergent outcomes; as well as to encourage the active role of scientists and the pharmaceutical industry to foster a new scientific culture through their research programs, practice, and participation in editorial boards and Institutional Ethics Review Boards (IRBs) and Research Ethics Committees (RECs). We establish the IRB/REC as the centerpiece for the implementation of these proposals. We suggest the expansion of its competence to follow up clinical trials to ensure that sex differences are addressed and recognized; to engage in data monitoring committees to improve clinical research cooperation and ethically address those potential clinical outcome differences between male and female patients to analyze their social and clinical implications in research and healthcare policies. PMID:28785221

Investigating multiple dysregulated pathways in rheumatoid arthritis based on pathway interaction network.

PubMed

Song, Xian-Dong; Song, Xian-Xu; Liu, Gui-Bo; Ren, Chun-Hui; Sun, Yuan-Bo; Liu, Ke-Xin; Liu, Bo; Liang, Shuang; Zhu, Zhu

2018-03-01

The traditional methods of identifying biomarkers in rheumatoid arthritis (RA) have focussed on the differentially expressed pathways or individual pathways, which however, neglect the interactions between pathways. To better understand the pathogenesis of RA, we aimed to identify dysregulated pathway sets using a pathway interaction network (PIN), which considered interactions among pathways. Firstly, RA-related gene expression profile data, protein-protein interactions (PPI) data and pathway data were taken up from the corresponding databases. Secondly, principal component analysis method was used to calculate the pathway activity of each of the pathway, and then a seed pathway was identified using data gleaned from the pathway activity. A PIN was then constructed based on the gene expression profile, pathway data, and PPI information. Finally, the dysregulated pathways were extracted from the PIN based on the seed pathway using the method of support vector machines and an area under the curve (AUC) index. The PIN comprised of a total of 854 pathways and 1064 pathway interactions. The greatest change in the activity score between RA and control samples was observed in the pathway of epigenetic regulation of gene expression, which was extracted and regarded as the seed pathway. Starting with this seed pathway, one maximum pathway set containing 10 dysregulated pathways was extracted from the PIN, having an AUC of 0.8249, and the result indicated that this pathway set could distinguish RA from the controls. These 10 dysregulated pathways might be potential biomarkers for RA diagnosis and treatment in the future.

Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats

EPA Science Inventory

This study was performed to characterize the gene expression profile and to identify the major carcinogenic pathways involved in rat peritoneal mesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Oligo a...

Combining a nontargeted and targeted metabolomics approach to identify metabolic pathways significantly altered in polycystic ovary syndrome.

PubMed

Chang, Alice Y; Lalia, Antigoni Z; Jenkins, Gregory D; Dutta, Tumpa; Carter, Rickey E; Singh, Ravinder J; Nair, K Sreekumaran

2017-06-01

Polycystic ovary syndrome (PCOS) is a condition of androgen excess and chronic anovulation frequently associated with insulin resistance. We combined a nontargeted and targeted metabolomics approach to identify pathways and metabolites that distinguished PCOS from metabolic syndrome (MetS). Twenty obese women with PCOS were compared with 18 obese women without PCOS. Both groups met criteria for MetS but could not have diabetes mellitus or take medications that treat PCOS or affect lipids or insulin sensitivity. Insulin sensitivity was derived from the frequently sampled intravenous glucose tolerance test. A nontargeted metabolomics approach was performed on fasting plasma samples to identify differentially expressed metabolites, which were further evaluated by principal component and pathway enrichment analysis. Quantitative targeted metabolomics was then applied on candidate metabolites. Measured metabolites were tested for associations with PCOS and clinical variables by logistic and linear regression analyses. This multiethnic, obese sample was matched by age (PCOS, 37±6; MetS, 40±6years) and body mass index (BMI) (PCOS, 34.6±5.1; MetS, 33.7±5.2kg/m 2 ). Principal component analysis of the nontargeted metabolomics data showed distinct group separation of PCOS from MetS controls. From the subset of 385 differentially expressed metabolites, 22% were identified by accurate mass, resulting in 19 canonical pathways significantly altered in PCOS, including amino acid, lipid, steroid, carbohydrate, and vitamin D metabolism. Targeted metabolomics identified many essential amino acids, including branched-chain amino acids (BCAA) that were elevated in PCOS compared with MetS. PCOS was most associated with BCAA (P=.02), essential amino acids (P=.03), the essential amino acid lysine (P=.02), and the lysine metabolite α-aminoadipic acid (P=.02) in models adjusted for surrogate variables representing technical variation in metabolites. No significant differences between

Combining a Nontargeted and Targeted Metabolomics Approach to Identify Metabolic Pathways Significantly Altered in Polycystic Ovary Syndrome

PubMed Central

Chang, Alice Y.; Lalia, Antigoni Z.; Jenkins, Gregory D.; Dutta, Tumpa; Carter, Rickey E.; Singh, Ravinder J.; Sreekumaran Nair, K.

2017-01-01

Objective Polycystic ovary syndrome (PCOS) is a condition of androgen excess and chronic anovulation frequently associated with insulin resistance. We combined a nontargeted and targeted metabolomics approach to identify pathways and metabolites that distinguished PCOS from metabolic syndrome (MetS). Methods Twenty obese women with PCOS were compared with 18 obese women without PCOS. Both groups met criteria for MetS but could not have diabetes mellitus or take medications that treat PCOS or affect lipids or insulin sensitivity. Insulin sensitivity was derived from the frequently sampled intravenous glucose tolerance test. A nontargeted metabolomics approach was performed on fasting plasma samples to identify differentially expressed metabolites, which were further evaluated by principal component and pathway enrichment analysis. Quantitative targeted metabolomics was then applied on candidate metabolites. Measured metabolites were tested for associations with PCOS and clinical variables by logistic and linear regression analyses. Results This multiethnic, obese sample was matched by age (PCOS, 37 ± 6; MetS, 40 ± 6 years) and body mass index (BMI) (PCOS, 34.6 ± 5.1; MetS, 33.7 ± 5.2 kg/m2). Principal component analysis of the nontargeted metabolomics data showed distinct group separation of PCOS from MetS controls. From the subset of 385 differentially expressed metabolites, 22% were identified by accurate mass, resulting in 19 canonical pathways significantly altered in PCOS, including amino acid, lipid, steroid, carbohydrate, and vitamin D metabolism. Targeted metabolomics identified many essential amino acids, including branched-chain amino acids (BCAA) that were elevated in PCOS compared with MetS. PCOS was most associated with BCAA (P = .02), essential amino acids (P = .03), the essential amino acid lysine (P = .02), and the lysine metabolite α-aminoadipic acid (P = .02) in models adjusted for surrogate variables representing technical variation in

Alternative haplotypes of antigen processing genes in zebrafish diverged early in vertebrate evolution

PubMed Central

McConnell, Sean C.; Hernandez, Kyle M.; Wcisel, Dustin J.; Kettleborough, Ross N.; Stemple, Derek L.; Andrade, Jorge; de Jong, Jill L. O.

2016-01-01

Antigen processing and presentation genes found within the MHC are among the most highly polymorphic genes of vertebrate genomes, providing populations with diverse immune responses to a wide array of pathogens. Here, we describe transcriptome, exome, and whole-genome sequencing of clonal zebrafish, uncovering the most extensive diversity within the antigen processing and presentation genes of any species yet examined. Our CG2 clonal zebrafish assembly provides genomic context within a remarkably divergent haplotype of the core MHC region on chromosome 19 for six expressed genes not found in the zebrafish reference genome: mhc1uga, proteasome-β 9b (psmb9b), psmb8f, and previously unknown genes psmb13b, tap2d, and tap2e. We identify ancient lineages for Psmb13 within a proteasome branch previously thought to be monomorphic and provide evidence of substantial lineage diversity within each of three major trifurcations of catalytic-type proteasome subunits in vertebrates: Psmb5/Psmb8/Psmb11, Psmb6/Psmb9/Psmb12, and Psmb7/Psmb10/Psmb13. Strikingly, nearby tap2 and MHC class I genes also retain ancient sequence lineages, indicating that alternative lineages may have been preserved throughout the entire MHC pathway since early diversification of the adaptive immune system ∼500 Mya. Furthermore, polymorphisms within the three MHC pathway steps (antigen cleavage, transport, and presentation) are each predicted to alter peptide specificity. Lastly, comparative analysis shows that antigen processing gene diversity is far more extensive than previously realized (with ancient coelacanth psmb8 lineages, shark psmb13, and tap2t and psmb10 outside the teleost MHC), implying distinct immune functions and conserved roles in shaping MHC pathway evolution throughout vertebrates. PMID:27493218

Exploring the effect of asymmetric mitochondrial DNA introgression on estimating niche divergence in morphologically cryptic species.

PubMed

Wielstra, Ben; Arntzen, Jan W

2014-01-01

If potential morphologically cryptic species, identified based on differentiated mitochondrial DNA, express ecological divergence, this increases support for their treatment as distinct species. However, mitochondrial DNA introgression hampers the correct estimation of ecological divergence. We test the hypothesis that estimated niche divergence differs when considering nuclear DNA composition or mitochondrial DNA type as representing the true species range. We use empirical data of two crested newt species (Amphibia: Triturus) which possess introgressed mitochondrial DNA from a third species in part of their ranges. We analyze the data in environmental space by determining Fisher distances in a principal component analysis and in geographical space by determining geographical overlap of species distribution models. We find that under mtDNA guidance in one of the two study cases niche divergence is overestimated, whereas in the other it is underestimated. In the light of our results we discuss the role of estimated niche divergence in species delineation.

mom identifies a receptor for the Drosophila JAK/STAT signal transduction pathway and encodes a protein distantly related to the mammalian cytokine receptor family

PubMed Central

Chen, Hua-Wei; Chen, Xiu; Oh, Su-Wan; Marinissen, Maria J.; Gutkind, J. Silvio; Hou, Steven X.

2002-01-01

The JAK/STAT signal transduction pathway controls numerous events in Drosophila melanogaster development. Receptors for the pathway have yet to be identified. Here we have identified a Drosophila gene that shows embryonic mutant phenotypes identical to those in the hopscotch (hop)/JAK kinase and marelle (mrl)/Stat92e mutations. We named this gene master of marelle (mom). Genetic analyses place mom's function between upd (the ligand) and hop. We further show that cultured cells transfected with the mom gene bind UPD and activate the HOP/STAT92E signal transduction pathway. mom encodes a protein distantly related to the mammalian cytokine receptor family. These data show that mom functions as a receptor of the Drosophila JAK/STAT signal transduction pathway. PMID:11825879

A highly divergent Puumala virus lineage in southern Poland.

PubMed

Rosenfeld, Ulrike M; Drewes, Stephan; Ali, Hanan Sheikh; Sadowska, Edyta T; Mikowska, Magdalena; Heckel, Gerald; Koteja, Paweł; Ulrich, Rainer G

2017-05-01

Puumala virus (PUUV) represents one of the most important hantaviruses in Central Europe. Phylogenetic analyses of PUUV strains indicate a strong genetic structuring of this hantavirus. Recently, PUUV sequences were identified in the natural reservoir, the bank vole (Myodes glareolus), collected in the northern part of Poland. The objective of this study was to evaluate the presence of PUUV in bank voles from southern Poland. A total of 72 bank voles were trapped in 2009 at six sites in this part of Poland. RT-PCR and IgG-ELISA analyses detected three PUUV positive voles at one trapping site. The PUUV-infected animals were identified by cytochrome b gene analysis to belong to the Carpathian and Eastern evolutionary lineages of bank vole. The novel PUUV S, M and L segment nucleotide sequences showed the closest similarity to sequences of the Russian PUUV lineage from Latvia, but were highly divergent to those previously found in northern Poland, Slovakia and Austria. In conclusion, the detection of a highly divergent PUUV lineage in southern Poland indicates the necessity of further bank vole monitoring in this region allowing rational public health measures to prevent human infections.

Whole genome association study identifies regions of the bovine genome and biological pathways involved in carcass trait performance in Holstein-Friesian cattle.

PubMed

Doran, Anthony G; Berry, Donagh P; Creevey, Christopher J

2014-10-01

Four traits related to carcass performance have been identified as economically important in beef production: carcass weight, carcass fat, carcass conformation of progeny and cull cow carcass weight. Although Holstein-Friesian cattle are primarily utilized for milk production, they are also an important source of meat for beef production and export. Because of this, there is great interest in understanding the underlying genomic structure influencing these traits. Several genome-wide association studies have identified regions of the bovine genome associated with growth or carcass traits, however, little is known about the mechanisms or underlying biological pathways involved. This study aims to detect regions of the bovine genome associated with carcass performance traits (employing a panel of 54,001 SNPs) using measures of genetic merit (as predicted transmitting abilities) for 5,705 Irish Holstein-Friesian animals. Candidate genes and biological pathways were then identified for each trait under investigation. Following adjustment for false discovery (q-value < 0.05), 479 quantitative trait loci (QTL) were associated with at least one of the four carcass traits using a single SNP regression approach. Using a Bayesian approach, 46 QTL were associated (posterior probability > 0.5) with at least one of the four traits. In total, 557 unique bovine genes, which mapped to 426 human orthologs, were within 500kbs of QTL found associated with a trait using the Bayesian approach. Using this information, 24 significantly over-represented pathways were identified across all traits. The most significantly over-represented biological pathway was the peroxisome proliferator-activated receptor (PPAR) signaling pathway. A large number of genomic regions putatively associated with bovine carcass traits were detected using two different statistical approaches. Notably, several significant associations were detected in close proximity to genes with a known role in animal growth

Polyketide synthase chemistry does not direct biosynthetic divergence between 9- and 10-membered enediynes

PubMed Central

Horsman, Geoff P.; Chen, Yihua; Thorson, Jon S.; Shen, Ben

2010-01-01

Enediynes are potent antitumor antibiotics that are classified as 9- or 10-membered according to the size of the enediyne core structure. However, almost nothing is known about enediyne core biosynthesis, and the determinants of 9- versus 10-membered enediyne core biosynthetic divergence remain elusive. Previous work identified enediyne-specific polyketide synthases (PKSEs) that can be phylogenetically distinguished as being involved in 9- versus 10-membered enediyne biosynthesis, suggesting that biosynthetic divergence might originate from differing PKSE chemistries. Recent in vitro studies have identified several compounds produced by the PKSE and associated thioesterase (TE), but condition-dependent product profiles make it difficult to ascertain a true catalytic difference between 9- and 10-membered PKSE-TE systems. Here we report that PKSE chemistry does not direct 9- versus 10-membered enediyne core biosynthetic divergence as revealed by comparing the products from three 9-membered and two 10-membered PKSE-TE systems under identical conditions using robust in vivo assays. Three independent experiments support a common catalytic function for 9- and 10-membered PKSEs by the production of a heptaene metabolite from: (i) all five cognate PKSE-TE pairs in Escherichia coli; (ii) the C-1027 and calicheamicin cognate PKSE-TEs in Streptomyces lividans K4-114; and (iii) selected native producers of both 9- and 10-membered enediynes. Furthermore, PKSEs and TEs from different 9- and 10-membered enediyne biosynthetic machineries are freely interchangeable, revealing that 9- versus 10-membered enediyne core biosynthetic divergence occurs beyond the PKSE-TE level. These findings establish a starting point for determining the origins of this biosynthetic divergence. PMID:20534556

Identifying alternate pathways for climate change to impact inland recreational fishers

USGS Publications Warehouse

Hunt, Len M.; Fenichel, Eli P.; Fulton, David C.; Mendelsohn, Robert; Smith, Jordan W.; Tunney, Tyler D.; Lynch, Abigail J.; Paukert, Craig P.; Whitney, James E.

2016-01-01

Fisheries and human dimensions literature suggests that climate change influences inland recreational fishers in North America through three major pathways. The most widely recognized pathway suggests that climate change impacts habitat and fish populations (e.g., water temperature impacting fish survival) and cascades to impact fishers. Climate change also impacts recreational fishers by influencing environmental conditions that directly affect fishers (e.g., increased temperatures in northern climates resulting in extended open water fishing seasons and increased fishing effort). The final pathway occurs from climate change mitigation and adaptation efforts (e.g., refined energy policies result in higher fuel costs, making distant trips more expensive). To address limitations of past research (e.g., assessing climate change impacts for only one pathway at a time and not accounting for climate variability, extreme weather events, or heterogeneity among fishers), we encourage researchers to refocus their efforts to understand and document climate change impacts to inland fishers.

Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Yongbaek; Thai-Vu Ton; De Angelo, Anthony B.

2006-07-15

This study was performed to characterize the gene expression profile and to identify the major carcinogenic pathways involved in rat peritoneal mesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Oligo arrays, with over 20,000 target genes, were used to evaluate o-NT- and BCA-induced RPMs, when compared to a non-transformed mesothelial cell line (Fred-PE). Analysis using Ingenuity Pathway Analysis software revealed 169 cancer-related genes that were categorized into binding activity, growth and proliferation, cell cycle progression, apoptosis, and invasion and metastasis. The microarray data were validated by positive correlation with quantitative real-time RT-PCRmore » on 16 selected genes including igf1, tgfb3 and nov. Important carcinogenic pathways involved in RPM formation included insulin-like growth factor 1 (IGF-1), p38 MAPkinase, Wnt/{beta}-catenin and integrin signaling pathways. This study demonstrated that mesotheliomas in rats exposed to o-NT- and BCA were similar to mesotheliomas in humans, at least at the cellular and molecular level.« less

Soldier, civilian, criminal: identifying pathways to offending of ex-armed forces personnel in prison

PubMed Central

Wainwright, Verity; McDonnell, Sharon; Lennox, Charlotte; Shaw, Jenny; Senior, Jane

2016-01-01

ABSTRACT Little is known about why some ex-armed forces personnel become involved in the criminal justice system, however, they represent the largest known occupational group in prison. In-depth interviews were employed to explore possible pathways to offending. Twenty ex-armed forces personnel in prison were recruited from five prisons in England. Data were analysed using a combination of thematic analysis and constant comparison methods rooted in grounded theory. Four predominant themes were identified: experiences of trauma and adversity; belonging; impulsivity and creating a soldier. Participants had experienced a number of traumatic incidents and adversity in their lives, encompassing pre, during and post-service but felt a sense of belonging in the armed forces. Participants demonstrated impulsivity in a number of areas with links to both their service in the armed forces and offending behaviour. The creation of the identity of ‘soldier’ was perceived to impact participants’ lives in a number of ways, including their offending, alcohol use and coping with trauma. The interplay of these themes and their potential impact on participants’ pathways to offending are discussed. PMID:27570440

Vorticity and divergence in the solar photosphere

NASA Technical Reports Server (NTRS)

Wang, YI; Noyes, Robert W.; Tarbell, Theodore D.; Title, Alan M.

1995-01-01

We have studied an outstanding sequence of continuum images of the solar granulation from Pic du Midi Observatory. We have calculated the horizontal vector flow field using a correlation tracking algorithm, and from this determined three scalar field: the vertical component of the curl; the horizontal divergence; and the horizontal flow speed. The divergence field has substantially longer coherence time and more power than does the curl field. Statistically, curl is better correlated with regions of negative divergence - that is, the vertical vorticity is higher in downflow regions, suggesting excess vorticity in intergranular lanes. The average value of the divergence is largest (i.e., outflow is largest) where the horizontal speed is large; we associate these regions with exploding granules. A numerical simulation of general convection also shows similar statistical differences between curl and divergence. Some individual small bright points in the granulation pattern show large local vorticities.

Divergence Palsy due to Divalproex and Oxcarbazepine.

PubMed

Bouffard, Marc Albert; Caplan, Louis R; Torun, Nurhan

This case series is the first to describe divergence palsy as an adverse effect of antiepileptic drug use. Diplopia is a common adverse effect of antiepileptic drugs, but no explanatory motility deficit has ever been reported. We present 2 patients, 1 on oxcarbazepine and 1 on divalproex, each with a normal examination result between spells and divergency palsy when symptomatic. Discontinuation of the antiepileptic medication led to resolution of the episodes in both cases. Rechallenge with the offending agent after washout in one patient resulted in recurrence of diplopia and divergence palsy, both resolving after subsequent withdrawal of the antiepileptic. Antiepileptic drugs may cause divergence palsy.

Active PI3K Pathway Causes an Invasive Phenotype Which Can Be Reversed or Promoted by Blocking the Pathway at Divergent Nodes

PubMed Central

Wallin, Jeffrey J.; Guan, Jane; Edgar, Kyle A.; Zhou, Wei; Francis, Ross; Torres, Anthony C.; Haverty, Peter M.; Eastham-Anderson, Jeffrey; Arena, Sabrina; Bardelli, Alberto; Griffin, Sue; Goodall, John E.; Grimshaw, Kyla M.; Hoeflich, Klaus P.; Torrance, Christopher; Belvin, Marcia; Friedman, Lori S.

2012-01-01

The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP3 production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis. PMID:22570710

Application of Gene Expression Trajectories Initiated from ErbB Receptor Activation Highlights the Dynamics of Divergent Promoter Usage.

PubMed

Carbajo, Daniel; Magi, Shigeyuki; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Arner, Erik; Forrest, Alistair R R; Carninci, Piero; Hayashizaki, Yoshihide; Daub, Carsten O; Okada-Hatakeyama, Mariko; Mar, Jessica C

2015-01-01

Understanding how cells use complex transcriptional programs to alter their fate in response to specific stimuli is an important question in biology. For the MCF-7 human breast cancer cell line, we applied gene expression trajectory models to identify the genes involved in driving cell fate transitions. We modified trajectory models to account for the scenario where cells were exposed to different stimuli, in this case epidermal growth factor and heregulin, to arrive at different cell fates, i.e. proliferation and differentiation respectively. Using genome-wide CAGE time series data collected from the FANTOM5 consortium, we identified the sets of promoters that were involved in the transition of MCF-7 cells to their specific fates versus those with expression changes that were generic to both stimuli. Of the 1,552 promoters identified, 1,091 had stimulus-specific expression while 461 promoters had generic expression profiles over the time course surveyed. Many of these stimulus-specific promoters mapped to key regulators of the ERK (extracellular signal-regulated kinases) signaling pathway such as FHL2 (four and a half LIM domains 2). We observed that in general, generic promoters peaked in their expression early on in the time course, while stimulus-specific promoters tended to show activation of their expression at a later stage. The genes that mapped to stimulus-specific promoters were enriched for pathways that control focal adhesion, p53 signaling and MAPK signaling while generic promoters were enriched for cell death, transcription and the cell cycle. We identified 162 genes that were controlled by an alternative promoter during the time course where a subset of 37 genes had separate promoters that were classified as stimulus-specific and generic. The results of our study highlighted the degree of complexity involved in regulating a cell fate transition where multiple promoters mapping to the same gene can demonstrate quite divergent expression profiles.

NAViGaTing the Micronome – Using Multiple MicroRNA Prediction Databases to Identify Signalling Pathway-Associated MicroRNAs

PubMed Central

Shirdel, Elize A.; Xie, Wing; Mak, Tak W.; Jurisica, Igor

2011-01-01

Background MicroRNAs are a class of small RNAs known to regulate gene expression at the transcript level, the protein level, or both. Since microRNA binding is sequence-based but possibly structure-specific, work in this area has resulted in multiple databases storing predicted microRNA:target relationships computed using diverse algorithms. We integrate prediction databases, compare predictions to in vitro data, and use cross-database predictions to model the microRNA:transcript interactome – referred to as the micronome – to study microRNA involvement in well-known signalling pathways as well as associations with disease. We make this data freely available with a flexible user interface as our microRNA Data Integration Portal — mirDIP (http://ophid.utoronto.ca/mirDIP). Results mirDIP integrates prediction databases to elucidate accurate microRNA:target relationships. Using NAViGaTOR to produce interaction networks implicating microRNAs in literature-based, KEGG-based and Reactome-based pathways, we find these signalling pathway networks have significantly more microRNA involvement compared to chance (p<0.05), suggesting microRNAs co-target many genes in a given pathway. Further examination of the micronome shows two distinct classes of microRNAs; universe microRNAs, which are involved in many signalling pathways; and intra-pathway microRNAs, which target multiple genes within one signalling pathway. We find universe microRNAs to have more targets (p<0.0001), to be more studied (p<0.0002), and to have higher degree in the KEGG cancer pathway (p<0.0001), compared to intra-pathway microRNAs. Conclusions Our pathway-based analysis of mirDIP data suggests microRNAs are involved in intra-pathway signalling. We identify two distinct classes of microRNAs, suggesting a hierarchical organization of microRNAs co-targeting genes both within and between pathways, and implying differential involvement of universe and intra-pathway microRNAs at the disease level. PMID

Candidate adaptive genes associated with lineage divergence: identifying SNPs via next-generation targeted resequencing in mule deer (Odocoileus hemionus).

PubMed

Powell, John H; Amish, Stephen J; Haynes, Gwilym D; Luikart, Gordon; Latch, Emily K

2016-09-01

Mule deer (Odocoileus hemionus) are an excellent nonmodel species for empirically testing hypotheses in landscape and population genomics due to their large population sizes (low genetic drift), relatively continuous distribution, diversity of occupied habitats and phenotypic variation. Because few genomic resources are currently available for this species, we used exon data from a cattle (Bos taurus) reference genome to direct targeted resequencing of 5935 genes in mule deer. We sequenced approximately 3.75 Mbp at minimum 20X coverage in each of the seven mule deer, identifying 23 204 single nucleotide polymorphisms (SNPs) within, or adjacent to, 6886 exons in 3559 genes. We found 91 SNP loci (from 69 genes) with putatively fixed allele frequency differences between the two major lineages of mule deer (mule deer and black-tailed deer), and our estimate of mean genetic divergence (genome-wide FST  = 0.123) between these lineages was consistent with previous findings using microsatellite loci. We detected an over-representation of gamete generation and amino acid transport genes among the genes with SNPs exhibiting potentially fixed allele frequency differences between lineages. This targeted resequencing approach using exon capture techniques has identified a suite of loci that can be used in future research to investigate the genomic basis of adaptation and differentiation between black-tailed deer and mule deer. This study also highlights techniques (and an exon capture array) that will facilitate population genomic research in other cervids and nonmodel organisms. © 2016 John Wiley & Sons Ltd.

A hierarchical approach employing metabolic and gene expression profiles to identify the pathways that confer cytotoxicity in HepG2 cells

PubMed Central

Li, Zheng; Srivastava, Shireesh; Yang, Xuerui; Mittal, Sheenu; Norton, Paul; Resau, James; Haab, Brian; Chan, Christina

2007-01-01

Background Free fatty acids (FFA) and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of many obesity-related metabolic disorders. When human hepatoblastoma cells (HepG2) were exposed to different types of FFA and TNF-α, saturated fatty acid was found to be cytotoxic and its toxicity was exacerbated by TNF-α. In order to identify the processes associated with the toxicity of saturated FFA and TNF-α, the metabolic and gene expression profiles were measured to characterize the cellular states. A computational model was developed to integrate these disparate data to reveal the underlying pathways and mechanisms involved in saturated fatty acid toxicity. Results A hierarchical framework consisting of three stages was developed to identify the processes and genes that regulate the toxicity. First, discriminant analysis identified that fatty acid oxidation and intracellular triglyceride accumulation were the most relevant in differentiating the cytotoxic phenotype. Second, gene set enrichment analysis (GSEA) was applied to the cDNA microarray data to identify the transcriptionally altered pathways and processes. Finally, the genes and gene sets that regulate the metabolic responses identified in step 1 were identified by integrating the expression of the enriched gene sets and the metabolic profiles with a multi-block partial least squares (MBPLS) regression model. Conclusion The hierarchical approach suggested potential mechanisms involved in mediating the cytotoxic and cytoprotective pathways, as well as identified novel targets, such as NADH dehydrogenases, aldehyde dehydrogenases 1A1 (ALDH1A1) and endothelial membrane protein 3 (EMP3) as modulator of the toxic phenotypes. These predictions, as well as, some specific targets that were suggested by the analysis were experimentally validated. PMID:17498300

Common functional targets of adaptive micro- and macro-evolutionary divergence in killifish.

PubMed

Whitehead, Andrew; Zhang, Shujun; Roach, Jennifer L; Galvez, Fernando

2013-07-01

Environmental salinity presents a key barrier to dispersal for most aquatic organisms, and adaptation to alternate osmotic environments likely enables species diversification. Little is known of the functional basis for derived tolerance to environmental salinity. We integrate comparative physiology and functional genomics to explore the mechanistic underpinnings of evolved variation in osmotic plasticity within and among two species of killifish; Fundulus majalis harbours the ancestral mainly salt-tolerant phenotype, whereas Fundulus heteroclitus harbours a derived physiology that retains extreme salt tolerance but with expanded osmotic plasticity towards the freshwater end of the osmotic continuum. Common-garden comparative hypo-osmotic challenge experiments show that F. heteroclitus is capable of remodelling gill epithelia more quickly and at more extreme osmotic challenge than F. majalis. We detect an unusual pattern of baseline transcriptome divergence, where neutral evolutionary processes appear to govern expression divergence within species, but patterns of divergence for these genes between species do not follow neutral expectations. During acclimation, genome expression profiling identifies mechanisms of acclimation-associated response that are conserved within the genus including regulation of paracellular permeability. In contrast, several responses vary among species including those putatively associated with cell volume regulation, and these same mechanisms are targets for adaptive physiological divergence along osmotic gradients within F. heteroclitus. As such, the genomic and physiological mechanisms that are associated with adaptive fine-tuning within species also contribute to macro-evolutionary divergence as species diversify across osmotic niches. © 2013 John Wiley & Sons Ltd.

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

PubMed Central

Moriarity, Branden S; Otto, George M; Rahrmann, Eric P; Rathe, Susan K; Wolf, Natalie K; Weg, Madison T; Manlove, Luke A; LaRue, Rebecca S; Temiz, Nuri A; Molyneux, Sam D; Choi, Kwangmin; Holly, Kevin J; Sarver, Aaron L; Scott, Milcah C; Forster, Colleen L; Modiano, Jaime F; Khanna, Chand; Hewitt, Stephen M; Khokha, Rama; Yang, Yi; Gorlick, Richard; Dyer, Michael A; Largaespada, David A

2016-01-01

Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma. PMID:25961939

Genomic architecture of adaptive color pattern divergence and convergence in Heliconius butterflies

PubMed Central

Supple, Megan A.; Hines, Heather M.; Dasmahapatra, Kanchon K.; Lewis, James J.; Nielsen, Dahlia M.; Lavoie, Christine; Ray, David A.; Salazar, Camilo; McMillan, W. Owen; Counterman, Brian A.

2013-01-01

Identifying the genetic changes driving adaptive variation in natural populations is key to understanding the origins of biodiversity. The mosaic of mimetic wing patterns in Heliconius butterflies makes an excellent system for exploring adaptive variation using next-generation sequencing. In this study, we use a combination of techniques to annotate the genomic interval modulating red color pattern variation, identify a narrow region responsible for adaptive divergence and convergence in Heliconius wing color patterns, and explore the evolutionary history of these adaptive alleles. We use whole genome resequencing from four hybrid zones between divergent color pattern races of Heliconius erato and two hybrid zones of the co-mimic Heliconius melpomene to examine genetic variation across 2.2 Mb of a partial reference sequence. In the intergenic region near optix, the gene previously shown to be responsible for the complex red pattern variation in Heliconius, population genetic analyses identify a shared 65-kb region of divergence that includes several sites perfectly associated with phenotype within each species. This region likely contains multiple cis-regulatory elements that control discrete expression domains of optix. The parallel signatures of genetic differentiation in H. erato and H. melpomene support a shared genetic architecture between the two distantly related co-mimics; however, phylogenetic analysis suggests mimetic patterns in each species evolved independently. Using a combination of next-generation sequencing analyses, we have refined our understanding of the genetic architecture of wing pattern variation in Heliconius and gained important insights into the evolution of novel adaptive phenotypes in natural populations. PMID:23674305

Flame balls dynamics in divergent channel

NASA Astrophysics Data System (ADS)

Fursenko, R.; Minaev, S.

2011-12-01

A three-dimensional reaction-diffusion model for lean low-Lewis-number premixed flames with radiative heat losses propagating in divergent channel is studied numerically. Effects of inlet gas velocity and heat-loss intensity on flame structure at low Lewis numbers are investigated. It is found that continuous flame front exists at small heat losses and the separate flame balls settled within restricted domain inside the divergent channel at large heat losses. It is shown that the time averaged flame balls coordinate may be considered as important characteristic analogous to coordinate of continuous flame stabilized in divergent channel.

Sensible and latent heat forced divergent circulations in the West African Monsoon System

NASA Astrophysics Data System (ADS)

Hagos, S.; Zhang, C.

2008-12-01

Field properties of divergent circulation are utilized to identify the roles of various diabatic processes in forcing moisture transport in the dynamics of the West African Monsoon and its seasonal cycle. In this analysis, the divergence field is treated as a set of point sources and is partitioned into two sub-sets corresponding to latent heat release and surface sensible heat flux at each respective point. The divergent circulation associated with each set is then calculated from the Poisson's equation using Gauss-Seidel iteration. Moisture transport by each set of divergent circulation is subsequently estimated. The results show different roles of the divergent circulations forced by surface sensible and latent heating in the monsoon dynamics. Surface sensible heating drives a shallow meridional circulation, which transports moisture deep into the continent at the polar side of the monsoon rain band and thereby promotes the seasonal northward migration of monsoon precipitation during the monsoon onset season. In contrast, the circulation directly associated with latent heating is deep and the corresponding moisture convergence is within the region of precipitation. Latent heating also induces dry air advection from the north. Neither effect promotes the seasonal northward migration of precipitation. The relative contributions of the processes associated with latent and sensible heating to the net moisture convergence, and hence the seasonal evolution of monsoon precipitation, depend on the background moisture.

Structural and Functional Divergence of the Aldolase Fold in Toxoplasma gondii

DOE PAGES

Tonkin, Michelle L.; Halavaty, Andrei S.; Ramaswamy, Raghavendran; ...

2014-10-02

Parasites of the phylum Apicomplexa are highly successful pathogens of humans and animals worldwide. As obligate intracellular parasites, they have significant energy requirements for invasion and gliding motility that are supplied by various metabolic pathways. Aldolases have emerged as key enzymes involved in these pathways, and all apicomplexans express one or both of fructose 1,6-bisphosphate (F16BP) aldolase and 2-deoxyribose 5-phosphate (dR5P) aldolase (DERA). Intriguingly, Toxoplasma gondii, a highly successful apicomplexan parasite, expresses F16BP aldolase (TgALD1), d5RP aldolase (TgDERA), and a divergent dR5P aldolase-like protein (TgDPA) exclusively in the latent bradyzoite stage. While the importance of TgALD1 in glycolysis is wellmore » established and TgDERA is also likely to be involved in parasite metabolism, the detailed function of TgDPA remains elusive. Here, to gain mechanistic insight into the function of different T. gondii aldolases, we first determined the crystal structures of TgALD1 and TgDPA. Structural analysis revealed that both aldolases adopt a TIM barrel fold accessorized with divergent secondary structure elements. Structural comparison of TgALD1 and TgDPA with members of their respective enzyme families revealed that, while the active-site residues are conserved in TgALD1, key catalytic residues are absent in TgDPA. Consistent with this observation, biochemical assays showed that, while TgALD1 was active on F16BP, TgDPA was inactive on dR5P. In conclusion, intriguingly, both aldolases are competent to bind polymerized actin in vitro. Altogether, structural and biochemical analyses of T. gondii aldolase and aldolase-like proteins reveal diverse functionalization of the classic TIM barrel aldolase fold.« less

Structural and functional divergence of the aldolase fold in Toxoplasma gondii.

PubMed

Tonkin, Michelle L; Halavaty, Andrei S; Ramaswamy, Raghavendran; Ruan, Jiapeng; Igarashi, Makoto; Ngô, Huân M; Boulanger, Martin J

2015-02-27

Parasites of the phylum Apicomplexa are highly successful pathogens of humans and animals worldwide. As obligate intracellular parasites, they have significant energy requirements for invasion and gliding motility that are supplied by various metabolic pathways. Aldolases have emerged as key enzymes involved in these pathways, and all apicomplexans express one or both of fructose 1,6-bisphosphate (F16BP) aldolase and 2-deoxyribose 5-phosphate (dR5P) aldolase (DERA). Intriguingly, Toxoplasma gondii, a highly successful apicomplexan parasite, expresses F16BP aldolase (TgALD1), d5RP aldolase (TgDERA), and a divergent dR5P aldolase-like protein (TgDPA) exclusively in the latent bradyzoite stage. While the importance of TgALD1 in glycolysis is well established and TgDERA is also likely to be involved in parasite metabolism, the detailed function of TgDPA remains elusive. To gain mechanistic insight into the function of different T. gondii aldolases, we first determined the crystal structures of TgALD1 and TgDPA. Structural analysis revealed that both aldolases adopt a TIM barrel fold accessorized with divergent secondary structure elements. Structural comparison of TgALD1 and TgDPA with members of their respective enzyme families revealed that, while the active-site residues are conserved in TgALD1, key catalytic residues are absent in TgDPA. Consistent with this observation, biochemical assays showed that, while TgALD1 was active on F16BP, TgDPA was inactive on dR5P. Intriguingly, both aldolases are competent to bind polymerized actin in vitro. Altogether, structural and biochemical analyses of T. gondii aldolase and aldolase-like proteins reveal diverse functionalization of the classic TIM barrel aldolase fold. Copyright © 2014 Elsevier Ltd. All rights reserved.

The interplay between local ecology, divergent selection, and genetic drift in population divergence of a sexually antagonistic female trait.

PubMed

Green, Kristina Karlsson; Svensson, Erik I; Bergsten, Johannes; Härdling, Roger; Hansson, Bengt

2014-07-01

Genetically polymorphic species offer the possibility to study maintenance of genetic variation and the potential role for genetic drift in population divergence. Indirect inference of the selection regimes operating on polymorphic traits can be achieved by comparing population divergence in neutral genetic markers with population divergence in trait frequencies. Such an approach could further be combined with ecological data to better understand agents of selection. Here, we infer the selective regimes acting on a polymorphic mating trait in an insect group; the dorsal structures (either rough or smooth) of female diving beetles. Our recent work suggests that the rough structures have a sexually antagonistic function in reducing male mating attempts. For two species (Dytiscus lapponicus and Graphoderus zonatus), we could not reject genetic drift as an explanation for population divergence in morph frequencies, whereas for the third (Hygrotus impressopunctatus) we found that divergent selection pulls morph frequencies apart across populations. Furthermore, population morph frequencies in H. impressopunctatus were significantly related to local bioclimatic factors, providing an additional line of evidence for local adaptation in this species. These data, therefore, suggest that local ecological factors and sexual conflict interact over larger spatial scales to shape population divergence in the polymorphism. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

Testing evolutionary hypotheses for phenotypic divergence using landscape genetics.

PubMed

Funk, W Chris; Murphy, Melanie A

2010-02-01

Understanding the evolutionary causes of phenotypic variation among populations has long been a central theme in evolutionary biology. Several factors can influence phenotypic divergence, including geographic isolation, genetic drift, divergent natural or sexual selection, and phenotypic plasticity. But the relative importance of these factors in generating phenotypic divergence in nature is still a tantalizing and unresolved problem in evolutionary biology. The origin and maintenance of phenotypic divergence is also at the root of many ongoing debates in evolutionary biology, such as the extent to which gene flow constrains adaptive divergence (Garant et al. 2007) and the relative importance of genetic drift, natural selection, and sexual selection in initiating reproductive isolation and speciation (Coyne & Orr 2004). In this issue, Wang & Summers (2010) test the causes of one of the most fantastic examples of phenotypic divergence in nature: colour pattern divergence among populations of the strawberry poison frog (Dendrobates pumilio) in Panama and Costa Rica (Fig. 1). This study provides a beautiful example of the use of the emerging field of landscape genetics to differentiate among hypotheses for phenotypic divergence. Using landscape genetic analyses, Wang & Summers were able to reject the hypotheses that colour pattern divergence is due to isolation-by-distance (IBD) or landscape resistance. Instead, the hypothesis left standing is that colour divergence is due to divergent selection, in turn driving reproductive isolation among populations with different colour morphs. More generally, this study provides a wonderful example of how the emerging field of landscape genetics, which has primarily been applied to questions in conservation and ecology, now plays an essential role in evolutionary research.

Human-specific protein isoforms produced by novel splice sites in the human genome after the human-chimpanzee divergence.

PubMed

Kim, Dong Seon; Hahn, Yoonsoo

2012-11-13

Evolution of splice sites is a well-known phenomenon that results in transcript diversity during human evolution. Many novel splice sites are derived from repetitive elements and may not contribute to protein products. Here, we analyzed annotated human protein-coding exons and identified human-specific splice sites that arose after the human-chimpanzee divergence. We analyzed multiple alignments of the annotated human protein-coding exons and their respective orthologous mammalian genome sequences to identify 85 novel splice sites (50 splice acceptors and 35 donors) in the human genome. The novel protein-coding exons, which are expressed either constitutively or alternatively, produce novel protein isoforms by insertion, deletion, or frameshift. We found three cases in which the human-specific isoform conferred novel molecular function in the human cells: the human-specific IMUP protein isoform induces apoptosis of the trophoblast and is implicated in pre-eclampsia; the intronization of a part of SMOX gene exon produces inactive spermine oxidase; the human-specific NUB1 isoform shows reduced interaction with ubiquitin-like proteins, possibly affecting ubiquitin pathways. Although the generation of novel protein isoforms does not equate to adaptive evolution, we propose that these cases are useful candidates for a molecular functional study to identify proteomic changes that might bring about novel phenotypes during human evolution.

Boreal tree hydrodynamics: asynchronous, diverging, yet complementary.

PubMed

Pappas, Christoforos; Matheny, Ashley M; Baltzer, Jennifer L; Barr, Alan G; Black, T Andrew; Bohrer, Gil; Detto, Matteo; Maillet, Jason; Roy, Alexandre; Sonnentag, Oliver; Stephens, Jilmarie

2018-05-08

Water stress has been identified as a key mechanism of the contemporary increase in tree mortality rates in northwestern North America. However, a detailed analysis of boreal tree hydrodynamics and their interspecific differences is still lacking. Here we examine the hydraulic behaviour of co-occurring larch (Larix laricina) and black spruce (Picea mariana), two characteristic boreal tree species, near the southern limit of the boreal ecozone in central Canada. Sap flux density (Js), concurrently recorded stem radius fluctuations and meteorological conditions are used to quantify tree hydraulic functioning and to scrutinize tree water-use strategies. Our analysis revealed asynchrony in the diel hydrodynamics of the two species with the initial rise in Js occurring 2 h earlier in larch than in black spruce. Interspecific differences in larch and black spruce crown architecture explained the observed asynchrony in their hydraulic functioning. Furthermore, the two species exhibited diverging stomatal regulation strategies with larch and black spruce employing relatively isohydric and anisohydric behaviour, respectively. Such asynchronous and diverging tree-level hydrodynamics provide new insights into the ecosystem-level complementarity in tree form and function, with implications for understanding boreal forests' water and carbon dynamics and their resilience to environmental stress.

Convergence from divergence

NASA Astrophysics Data System (ADS)

Costin, Ovidiu; Dunne, Gerald V.

2018-01-01

We show how to convert divergent series, which typically occur in many applications in physics, into rapidly convergent inverse factorial series. This can be interpreted physically as a novel resummation of perturbative series. Being convergent, these new series allow rigorous extrapolation from an asymptotic region with a large parameter, to the opposite region where the parameter is small. We illustrate the method with various physical examples, and discuss how these convergent series relate to standard methods such as Borel summation, and also how they incorporate the physical Stokes phenomenon. We comment on the relation of these results to Dyson’s physical argument for the divergence of perturbation theory. This approach also leads naturally to a wide class of relations between bosonic and fermionic partition functions, and Klein-Gordon and Dirac determinants.

Gain-of-function mutations in beet DODA2 identify key residues for betalain pigment evolution.

PubMed

Bean, Alexander; Sunnadeniya, Rasika; Akhavan, Neda; Campbell, Annabelle; Brown, Matthew; Lloyd, Alan

2018-05-13

The key enzymatic step in betalain biosynthesis involves conversion of l-3,4-dihydroxyphenylalanine (l-DOPA) to betalamic acid. One class of enzymes capable of this is 3,4-dihydroxyphenylalanine 4,5-dioxygenase (DODA). In betalain-producing species, multiple paralogs of this gene are maintained. This study demonstrates which paralogs function in the betalain pathway and determines the residue changes required to evolve a betalain-nonfunctional DODA into a betalain-functional DODA. Functionalities of two pairs of DODAs were tested by expression in beets, Arabidopsis and yeast, and gene silencing was performed by virus-induced gene silencing. Site-directed mutagenesis identified amino acid residues essential for betalamic acid production. Beta vulgaris and Mirabilis jalapa both possess a DODA1 lineage that functions in the betalain pathway and at least one other lineage, DODA2, that does not. Site-directed mutagenesis resulted in betalain biosynthesis by a previously nonfunctional DODA, revealing key residues required for evolution of the betalain pathway. Divergent functionality of DODA paralogs, one clade involved in betalain biosynthesis but others not, is present in various Caryophyllales species. A minimum of seven amino acid residue changes conferred betalain enzymatic activity to a betalain-nonfunctional DODA paralog, providing insight into the evolution of the betalain pigment pathway in plants. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

Spectrum transformation for divergent iterations

NASA Technical Reports Server (NTRS)

Gupta, Murli M.

1991-01-01

Certain spectrum transformation techniques are described that can be used to transform a diverging iteration into a converging one. Two techniques are considered called spectrum scaling and spectrum enveloping and how to obtain the optimum values of the transformation parameters is discussed. Numerical examples are given to show how this technique can be used to transform diverging iterations into converging ones; this technique can also be used to accelerate the convergence of otherwise convergent iterations.

Genomics of the divergence continuum in an African plant biodiversity hotspot, I: drivers of population divergence in Restio capensis (Restionaceae).

PubMed

Lexer, C; Wüest, R O; Mangili, S; Heuertz, M; Stölting, K N; Pearman, P B; Forest, F; Salamin, N; Zimmermann, N E; Bossolini, E

2014-09-01

Understanding the drivers of population divergence, speciation and species persistence is of great interest to molecular ecology, especially for species-rich radiations inhabiting the world's biodiversity hotspots. The toolbox of population genomics holds great promise for addressing these key issues, especially if genomic data are analysed within a spatially and ecologically explicit context. We have studied the earliest stages of the divergence continuum in the Restionaceae, a species-rich and ecologically important plant family of the Cape Floristic Region (CFR) of South Africa, using the widespread CFR endemic Restio capensis (L.) H.P. Linder & C.R. Hardy as an example. We studied diverging populations of this morphotaxon for plastid DNA sequences and >14 400 nuclear DNA polymorphisms from Restriction site Associated DNA (RAD) sequencing and analysed the results jointly with spatial, climatic and phytogeographic data, using a Bayesian generalized linear mixed modelling (GLMM) approach. The results indicate that population divergence across the extreme environmental mosaic of the CFR is mostly driven by isolation by environment (IBE) rather than isolation by distance (IBD) for both neutral and non-neutral markers, consistent with genome hitchhiking or coupling effects during early stages of divergence. Mixed modelling of plastid DNA and single divergent outlier loci from a Bayesian genome scan confirmed the predominant role of climate and pointed to additional drivers of divergence, such as drift and ecological agents of selection captured by phytogeographic zones. Our study demonstrates the usefulness of population genomics for disentangling the effects of IBD and IBE along the divergence continuum often found in species radiations across heterogeneous ecological landscapes. © 2014 John Wiley & Sons Ltd.

Identifying biological pathways that underlie primordial short stature using network analysis.

PubMed

Hanson, Dan; Stevens, Adam; Murray, Philip G; Black, Graeme C M; Clayton, Peter E

2014-06-01

Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. © 2014 The authors.

Divergence with gene flow within the recent chipmunk radiation (Tamias)

PubMed Central

Sullivan, J; Demboski, J R; Bell, K C; Hird, S; Sarver, B; Reid, N; Good, J M

2014-01-01

Increasing data have supported the importance of divergence with gene flow (DGF) in the generation of biological diversity. In such cases, lineage divergence occurs on a shorter timescale than does the completion of reproductive isolation. Although it is critical to explore the mechanisms driving divergence and preventing homogenization by hybridization, it is equally important to document cases of DGF in nature. Here we synthesize data that have accumulated over the last dozen or so years on DGF in the chipmunk (Tamias) radiation with new data that quantify very high rates of mitochondrial DNA (mtDNA) introgression among para- and sympatric species in the T. quadrivittatus group in the central and southern Rocky Mountains. These new data (188 cytochrome b sequences) bring the total number of sequences up to 1871; roughly 16% (298) of the chipmunks we have sequenced exhibit introgressed mtDNA. This includes ongoing introgression between subspecies and between both closely related and distantly related taxa. In addition, we have identified several taxa that are apparently fixed for ancient introgressions and in which there is no evidence of ongoing introgression. A recurrent observation is that these introgressions occur between ecologically and morphologically diverged, sometimes non-sister taxa that engage in well-documented niche partitioning. Thus, the chipmunk radiation in western North America represents an excellent mammalian example of speciation in the face of recurrent gene flow among lineages and where biogeography, habitat differentiation and mating systems suggest important roles for both ecological and sexual selection. PMID:24781803

Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer

PubMed Central

Grisham, Rachel N.; Sylvester, Brooke E.; Won, Helen; McDermott, Gregory; DeLair, Deborah; Ramirez, Ricardo; Yao, Zhan; Shen, Ronglai; Dao, Fanny; Bogomolniy, Faina; Makker, Vicky; Sala, Evis; Soumerai, Tara E.; Hyman, David M.; Socci, Nicholas D.; Viale, Agnes; Gershenson, David M.; Farley, John; Levine, Douglas A.; Rosen, Neal; Berger, Michael F.; Spriggs, David R.; Aghajanian, Carol A.; Solit, David B.; Iyer, Gopa

2015-01-01

Purpose No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor. Patients and Methods Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed. Results Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor–based combination therapy. Conclusion Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional

Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis.

PubMed

Collins, Mahlon A; An, Jiyan; Hood, Brian L; Conrads, Thomas P; Bowser, Robert P

2015-11-06

Analysis of the cerebrospinal fluid (CSF) proteome has proven valuable to the study of neurodegenerative disorders. To identify new protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis (ALS), we performed comparative proteomic profiling of CSF from sporadic ALS (sALS), healthy control (HC), and other neurological disease (OND) subjects using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1712 CSF proteins were detected and relatively quantified by spectral counting. Levels of several proteins with diverse biological functions were significantly altered in sALS samples. Enrichment analysis was used to link these alterations to biological pathways, which were predominantly related to inflammation, neuronal activity, and extracellular matrix regulation. We then used our CSF proteomic profiles to create a support vector machines classifier capable of discriminating training set ALS from non-ALS (HC and OND) samples. Four classifier proteins, WD repeat-containing protein 63, amyloid-like protein 1, SPARC-like protein 1, and cell adhesion molecule 3, were identified by feature selection and externally validated. The resultant classifier distinguished ALS from non-ALS samples with 83% sensitivity and 100% specificity in an independent test set. Collectively, our results illustrate the utility of CSF proteomic profiling for identifying ALS protein/pathway alterations and candidate disease biomarkers.

Analysis of a native whitefly transcriptome and its sequence divergence with two invasive whitefly species.

PubMed

Wang, Xiao-Wei; Zhao, Qiong-Yi; Luan, Jun-Bo; Wang, Yu-Jun; Yan, Gen-Hong; Liu, Shu-Sheng

2012-10-04

Genomic divergence between invasive and native species may provide insight into the molecular basis underlying specific characteristics that drive the invasion and displacement of closely related species. In this study, we sequenced the transcriptome of an indigenous species, Asia II 3, of the Bemisia tabaci complex and compared its genetic divergence with the transcriptomes of two invasive whiteflies species, Middle East Asia Minor 1 (MEAM1) and Mediterranean (MED), respectively. More than 16 million reads of 74 base pairs in length were obtained for the Asia II 3 species using the Illumina sequencing platform. These reads were assembled into 52,535 distinct sequences (mean size: 466 bp) and 16,596 sequences were annotated with an E-value above 10-5. Protein family comparisons revealed obvious diversification among the transcriptomes of these species suggesting species-specific adaptations during whitefly evolution. On the contrary, substantial conservation of the whitefly transcriptomes was also evident, despite their differences. The overall divergence of coding sequences between the orthologous gene pairs of Asia II 3 and MEAM1 is 1.73%, which is comparable to the average divergence of Asia II 3 and MED transcriptomes (1.84%) and much higher than that of MEAM1 and MED (0.83%). This is consistent with the previous phylogenetic analyses and crossing experiments suggesting these are distinct species. We also identified hundreds of highly diverged genes and compiled sequence identify data into gene functional groups and found the most divergent gene classes are Cytochrome P450, Glutathione metabolism and Oxidative phosphorylation. These results strongly suggest that the divergence of genes related to metabolism might be the driving force of the MEAM1 and Asia II 3 differentiation. We also analyzed single nucleotide polymorphisms within the orthologous gene pairs of indigenous and invasive whiteflies which are helpful for the investigation of association between

Analysis of a native whitefly transcriptome and its sequence divergence with two invasive whitefly species

PubMed Central

2012-01-01

Background Genomic divergence between invasive and native species may provide insight into the molecular basis underlying specific characteristics that drive the invasion and displacement of closely related species. In this study, we sequenced the transcriptome of an indigenous species, Asia II 3, of the Bemisia tabaci complex and compared its genetic divergence with the transcriptomes of two invasive whiteflies species, Middle East Asia Minor 1 (MEAM1) and Mediterranean (MED), respectively. Results More than 16 million reads of 74 base pairs in length were obtained for the Asia II 3 species using the Illumina sequencing platform. These reads were assembled into 52,535 distinct sequences (mean size: 466 bp) and 16,596 sequences were annotated with an E-value above 10-5. Protein family comparisons revealed obvious diversification among the transcriptomes of these species suggesting species-specific adaptations during whitefly evolution. On the contrary, substantial conservation of the whitefly transcriptomes was also evident, despite their differences. The overall divergence of coding sequences between the orthologous gene pairs of Asia II 3 and MEAM1 is 1.73%, which is comparable to the average divergence of Asia II 3 and MED transcriptomes (1.84%) and much higher than that of MEAM1 and MED (0.83%). This is consistent with the previous phylogenetic analyses and crossing experiments suggesting these are distinct species. We also identified hundreds of highly diverged genes and compiled sequence identify data into gene functional groups and found the most divergent gene classes are Cytochrome P450, Glutathione metabolism and Oxidative phosphorylation. These results strongly suggest that the divergence of genes related to metabolism might be the driving force of the MEAM1 and Asia II 3 differentiation. We also analyzed single nucleotide polymorphisms within the orthologous gene pairs of indigenous and invasive whiteflies which are helpful for the investigation of

The impact of selection, gene flow and demographic history on heterogeneous genomic divergence: three-spine sticklebacks in divergent environments.

PubMed

Ferchaud, Anne-Laure; Hansen, Michael M

2016-01-01

Heterogeneous genomic divergence between populations may reflect selection, but should also be seen in conjunction with gene flow and drift, particularly population bottlenecks. Marine and freshwater three-spine stickleback (Gasterosteus aculeatus) populations often exhibit different lateral armour plate morphs. Moreover, strikingly parallel genomic footprints across different marine-freshwater population pairs are interpreted as parallel evolution and gene reuse. Nevertheless, in some geographic regions like the North Sea and Baltic Sea, different patterns are observed. Freshwater populations in coastal regions are often dominated by marine morphs, suggesting that gene flow overwhelms selection, and genomic parallelism may also be less pronounced. We used RAD sequencing for analysing 28 888 SNPs in two marine and seven freshwater populations in Denmark, Europe. Freshwater populations represented a variety of environments: river populations accessible to gene flow from marine sticklebacks and large and small isolated lakes with and without fish predators. Sticklebacks in an accessible river environment showed minimal morphological and genomewide divergence from marine populations, supporting the hypothesis of gene flow overriding selection. Allele frequency spectra suggested bottlenecks in all freshwater populations, and particularly two small lake populations. However, genomic footprints ascribed to selection could nevertheless be identified. No genomic regions were consistent freshwater-marine outliers, and parallelism was much lower than in other comparable studies. Two genomic regions previously described to be under divergent selection in freshwater and marine populations were outliers between different freshwater populations. We ascribe these patterns to stronger environmental heterogeneity among freshwater populations in our study as compared to most other studies, although the demographic history involving bottlenecks should also be considered in the

Divergent Thinking and Age-Related Changes

ERIC Educational Resources Information Center

Palmiero, Massimiliano; Di Giacomo, Dina; Passafiume, Domenico

2014-01-01

Aging can affect cognition in different ways. The extent to which aging affects divergent thinking is unclear. In this study, younger and older adults were compared at the performance on the Torrance Test of Creative Thinking in visual and verbal form. Results showed that older adults can think divergently as younger participants, although they…

Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making.

PubMed

Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha; Zhou, Xiaolin

2017-09-01

The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. © The Author (2017). Published by Oxford University Press.

Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making

PubMed Central

Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha

2017-01-01

Abstract The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. PMID:28431168

Genomic divergence across ecological gradients in the Central African rainforest songbird (Andropadus virens).

PubMed

Zhen, Ying; Harrigan, Ryan J; Ruegg, Kristen C; Anderson, Eric C; Ng, Thomas C; Lao, Sirena; Lohmueller, Kirk E; Smith, Thomas B

2017-10-01

The little greenbul, a common rainforest passerine from sub-Saharan Africa, has been the subject of long-term evolutionary studies to understand the mechanisms leading to rainforest speciation. Previous research found morphological and behavioural divergence across rainforest-savannah transition zones (ecotones), and a pattern of divergence with gene flow suggesting divergent natural selection has contributed to adaptive divergence and ecotones could be important areas for rainforests speciation. Recent advances in genomics and environmental modelling make it possible to examine patterns of genetic divergence in a more comprehensive fashion. To assess the extent to which natural selection may drive patterns of differentiation, here we investigate patterns of genomic differentiation among populations across environmental gradients and regions. We find compelling evidence that individuals form discrete genetic clusters corresponding to distinctive environmental characteristics and habitat types. Pairwise F ST between populations in different habitats is significantly higher than within habitats, and this differentiation is greater than what is expected from geographic distance alone. Moreover, we identified 140 SNPs that showed extreme differentiation among populations through a genomewide selection scan. These outliers were significantly enriched in exonic and coding regions, suggesting their functional importance. Environmental association analysis of SNP variation indicates that several environmental variables, including temperature and elevation, play important roles in driving the pattern of genomic diversification. Results lend important new genomic evidence for environmental gradients being important in population differentiation. © 2017 John Wiley & Sons Ltd.

The Divergence of Neandertal and Modern Human Y Chromosomes

PubMed Central

Mendez, Fernando L.; Poznik, G. David; Castellano, Sergi; Bustamante, Carlos D.

2016-01-01

Sequencing the genomes of extinct hominids has reshaped our understanding of modern human origins. Here, we analyze ∼120 kb of exome-captured Y-chromosome DNA from a Neandertal individual from El Sidrón, Spain. We investigate its divergence from orthologous chimpanzee and modern human sequences and find strong support for a model that places the Neandertal lineage as an outgroup to modern human Y chromosomes—including A00, the highly divergent basal haplogroup. We estimate that the time to the most recent common ancestor (TMRCA) of Neandertal and modern human Y chromosomes is ∼588 thousand years ago (kya) (95% confidence interval [CI]: 447–806 kya). This is ∼2.1 (95% CI: 1.7–2.9) times longer than the TMRCA of A00 and other extant modern human Y-chromosome lineages. This estimate suggests that the Y-chromosome divergence mirrors the population divergence of Neandertals and modern human ancestors, and it refutes alternative scenarios of a relatively recent or super-archaic origin of Neandertal Y chromosomes. The fact that the Neandertal Y we describe has never been observed in modern humans suggests that the lineage is most likely extinct. We identify protein-coding differences between Neandertal and modern human Y chromosomes, including potentially damaging changes to PCDH11Y, TMSB4Y, USP9Y, and KDM5D. Three of these changes are missense mutations in genes that produce male-specific minor histocompatibility (H-Y) antigens. Antigens derived from KDM5D, for example, are thought to elicit a maternal immune response during gestation. It is possible that incompatibilities at one or more of these genes played a role in the reproductive isolation of the two groups. PMID:27058445

The Divergence of Neandertal and Modern Human Y Chromosomes.

PubMed

Mendez, Fernando L; Poznik, G David; Castellano, Sergi; Bustamante, Carlos D

2016-04-07

Sequencing the genomes of extinct hominids has reshaped our understanding of modern human origins. Here, we analyze ∼120 kb of exome-captured Y-chromosome DNA from a Neandertal individual from El Sidrón, Spain. We investigate its divergence from orthologous chimpanzee and modern human sequences and find strong support for a model that places the Neandertal lineage as an outgroup to modern human Y chromosomes-including A00, the highly divergent basal haplogroup. We estimate that the time to the most recent common ancestor (TMRCA) of Neandertal and modern human Y chromosomes is ∼588 thousand years ago (kya) (95% confidence interval [CI]: 447-806 kya). This is ∼2.1 (95% CI: 1.7-2.9) times longer than the TMRCA of A00 and other extant modern human Y-chromosome lineages. This estimate suggests that the Y-chromosome divergence mirrors the population divergence of Neandertals and modern human ancestors, and it refutes alternative scenarios of a relatively recent or super-archaic origin of Neandertal Y chromosomes. The fact that the Neandertal Y we describe has never been observed in modern humans suggests that the lineage is most likely extinct. We identify protein-coding differences between Neandertal and modern human Y chromosomes, including potentially damaging changes to PCDH11Y, TMSB4Y, USP9Y, and KDM5D. Three of these changes are missense mutations in genes that produce male-specific minor histocompatibility (H-Y) antigens. Antigens derived from KDM5D, for example, are thought to elicit a maternal immune response during gestation. It is possible that incompatibilities at one or more of these genes played a role in the reproductive isolation of the two groups. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Use of an activated beta-catenin to identify Wnt pathway target genes in caenorhabditis elegans, including a subset of collagen genes expressed in late larval development.

PubMed

Jackson, Belinda M; Abete-Luzi, Patricia; Krause, Michael W; Eisenmann, David M

2014-04-16

The Wnt signaling pathway plays a fundamental role during metazoan development, where it regulates diverse processes, including cell fate specification, cell migration, and stem cell renewal. Activation of the beta-catenin-dependent/canonical Wnt pathway up-regulates expression of Wnt target genes to mediate a cellular response. In the nematode Caenorhabditis elegans, a canonical Wnt signaling pathway regulates several processes during larval development; however, few target genes of this pathway have been identified. To address this deficit, we used a novel approach of conditionally activated Wnt signaling during a defined stage of larval life by overexpressing an activated beta-catenin protein, then used microarray analysis to identify genes showing altered expression compared with control animals. We identified 166 differentially expressed genes, of which 104 were up-regulated. A subset of the up-regulated genes was shown to have altered expression in mutants with decreased or increased Wnt signaling; we consider these genes to be bona fide C. elegans Wnt pathway targets. Among these was a group of six genes, including the cuticular collagen genes, bli-1 col-38, col-49, and col-71. These genes show a peak of expression in the mid L4 stage during normal development, suggesting a role in adult cuticle formation. Consistent with this finding, reduction of function for several of the genes causes phenotypes suggestive of defects in cuticle function or integrity. Therefore, this work has identified a large number of putative Wnt pathway target genes during larval life, including a small subset of Wnt-regulated collagen genes that may function in synthesis of the adult cuticle.

Structure of rapidity divergences in multi-parton scattering soft factors

NASA Astrophysics Data System (ADS)

Vladimirov, Alexey

2018-04-01

We discuss the structure of rapidity divergences that are presented in the soft factors of transverse momentum dependent (TMD) factorization theorems. To provide the discussion on the most general level we consider soft factors for multi-parton scattering. We show that the rapidity divergences are result of the gluon exchanges with the distant transverse plane, and are structurally equivalent to the ultraviolet divergences. It allows to formulate and to prove the renormalization theorem for rapidity divergences. The proof is made with the help the conformal transformation which maps rapidity divergences to ultraviolet divergences. The theorem is the systematic form of the factorization of rapidity divergences, which is required for the definition of TMD parton distributions. In particular, the definition of multi parton distributions is presented. The equivalence of ultraviolet and rapidity divergences leads to the exact relation between soft and rapidity anomalous dimensions. Using this relation we derive the rapidity anomalous dimension at the three-loop order.

A chemical proteomic atlas of brain serine hydrolases identifies cell type-specific pathways regulating neuroinflammation

PubMed Central

Viader, Andreu; Ogasawara, Daisuke; Joslyn, Christopher M; Sanchez-Alavez, Manuel; Mori, Simone; Nguyen, William; Conti, Bruno; Cravatt, Benjamin F

2016-01-01

Metabolic specialization among major brain cell types is central to nervous system function and determined in large part by the cellular distribution of enzymes. Serine hydrolases are a diverse enzyme class that plays fundamental roles in CNS metabolism and signaling. Here, we perform an activity-based proteomic analysis of primary mouse neurons, astrocytes, and microglia to furnish a global portrait of the cellular anatomy of serine hydrolases in the brain. We uncover compelling evidence for the cellular compartmentalization of key chemical transmission pathways, including the functional segregation of endocannabinoid (eCB) biosynthetic enzymes diacylglycerol lipase-alpha (DAGLα) and –beta (DAGLβ) to neurons and microglia, respectively. Disruption of DAGLβ perturbed eCB-eicosanoid crosstalk specifically in microglia and suppressed neuroinflammatory events in vivo independently of broader effects on eCB content. Mapping the cellular distribution of metabolic enzymes thus identifies pathways for regulating specialized inflammatory responses in the brain while avoiding global alterations in CNS function. DOI: http://dx.doi.org/10.7554/eLife.12345.001 PMID:26779719

A genomic island integrated into recA of Vibrio cholerae contains a divergent recA and provides multi-pathway protection from DNA damage.

PubMed

Rapa, Rita A; Islam, Atiqul; Monahan, Leigh G; Mutreja, Ankur; Thomson, Nicholas; Charles, Ian G; Stokes, Harold W; Labbate, Maurizio

2015-04-01

Lateral gene transfer (LGT) has been crucial in the evolution of the cholera pathogen, Vibrio cholerae. The two major virulence factors are present on two different mobile genetic elements, a bacteriophage containing the cholera toxin genes and a genomic island (GI) containing the intestinal adhesin genes. Non-toxigenic V. cholerae in the aquatic environment are a major source of novel DNA that allows the pathogen to morph via LGT. In this study, we report a novel GI from a non-toxigenic V. cholerae strain containing multiple genes involved in DNA repair including the recombination repair gene recA that is 23% divergent from the indigenous recA and genes involved in the translesion synthesis pathway. This is the first report of a GI containing the critical gene recA and the first report of a GI that targets insertion into a specific site within recA. We show that possession of the island in Escherichia coli is protective against DNA damage induced by UV-irradiation and DNA targeting antibiotics. This study highlights the importance of genetic elements such as GIs in the evolution of V. cholerae and emphasizes the importance of environmental strains as a source of novel DNA that can influence the pathogenicity of toxigenic strains. © 2014 The Authors. Environmental Microbiology published by Society for Applied Microbiology and John Wiley & Sons Ltd.

The Genetic Basis of Upland/Lowland Ecotype Divergence in Switchgrass (Panicum virgatum)

PubMed Central

Milano, Elizabeth R.; Lowry, David B.; Juenger, Thomas E.

2016-01-01

The evolution of locally adapted ecotypes is a common phenomenon that generates diversity within plant species. However, we know surprisingly little about the genetic mechanisms underlying the locally adapted traits involved in ecotype formation. The genetic architecture underlying locally adapted traits dictates how an organism will respond to environmental selection pressures, and has major implications for evolutionary ecology, conservation, and crop breeding. To understand the genetic architecture underlying the divergence of switchgrass (Panicum virgatum) ecotypes, we constructed a genetic mapping population through a four-way outbred cross between two northern upland and two southern lowland accessions. Trait segregation in this mapping population was largely consistent with multiple independent loci controlling the suite of traits that characterizes ecotype divergence. We assembled a joint linkage map using ddRADseq, and mapped quantitative trait loci (QTL) for traits that are divergent between ecotypes, including flowering time, plant size, physiological processes, and disease resistance. Overall, we found that most QTL had small to intermediate effects. While we identified colocalizing QTL for multiple traits, we did not find any large-effect QTL that clearly controlled multiple traits through pleiotropy or tight physical linkage. These results indicate that ecologically important traits in switchgrass have a complex genetic basis, and that similar loci may underlie divergence across the geographic range of the ecotypes. PMID:27613751

The Genetic Basis of Upland/Lowland Ecotype Divergence in Switchgrass (Panicum virgatum)

DOE PAGES

Milano, E. R.; Lowry, D. B.; Juenger, T. E.

2016-09-09

The evolution of locally adapted ecotypes is a common phenomenon that generates diversity within plant species. However, we know surprisingly little about the genetic mechanisms underlying the locally adapted traits involved in ecotype formation. The genetic architecture underlying locally adapted traits dictates how an organism will respond to environmental selection pressures, and has major implications for evolutionary ecology, conservation, and crop breeding. To understand the genetic architecture underlying the divergence of switchgrass (Panicum virgatum) ecotypes, we constructed a genetic mapping population through a four-way outbred cross between two northern upland and two southern lowland accessions. Trait segregation in this mappingmore » population was largely consistent with multiple independent loci controlling the suite of traits that characterizes ecotype divergence. We assembled a joint linkage map using ddRADseq, and mapped quantitative trait loci (QTL) for traits that are divergent between ecotypes, including flowering time, plant size, physiological processes, and disease resistance. Overall, we found that most QTL had small to intermediate effects. While we identified colocalizing QTL for multiple traits, we did not find any large-effect QTL that clearly controlled multiple traits through pleiotropy or tight physical linkage. These results indicate that ecologically important traits in switchgrass have a complex genetic basis, and that similar loci may underlie divergence across the geographic range of the ecotypes.« less

The Genetic Basis of Upland/Lowland Ecotype Divergence in Switchgrass (Panicum virgatum)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milano, E. R.; Lowry, D. B.; Juenger, T. E.

The evolution of locally adapted ecotypes is a common phenomenon that generates diversity within plant species. However, we know surprisingly little about the genetic mechanisms underlying the locally adapted traits involved in ecotype formation. The genetic architecture underlying locally adapted traits dictates how an organism will respond to environmental selection pressures, and has major implications for evolutionary ecology, conservation, and crop breeding. To understand the genetic architecture underlying the divergence of switchgrass (Panicum virgatum) ecotypes, we constructed a genetic mapping population through a four-way outbred cross between two northern upland and two southern lowland accessions. Trait segregation in this mappingmore » population was largely consistent with multiple independent loci controlling the suite of traits that characterizes ecotype divergence. We assembled a joint linkage map using ddRADseq, and mapped quantitative trait loci (QTL) for traits that are divergent between ecotypes, including flowering time, plant size, physiological processes, and disease resistance. Overall, we found that most QTL had small to intermediate effects. While we identified colocalizing QTL for multiple traits, we did not find any large-effect QTL that clearly controlled multiple traits through pleiotropy or tight physical linkage. These results indicate that ecologically important traits in switchgrass have a complex genetic basis, and that similar loci may underlie divergence across the geographic range of the ecotypes.« less

Emergent biological properties of arrestin pathway-selective biased agonism.

PubMed

Appleton, Kathryn M; Luttrell, Louis M

2013-06-01

Our growing appreciation of the pluridimensionality of G protein-coupled receptor (GPCR) signaling, combined with the phenomenon of orthosteric ligand "bias", has created the possibility of drugs that selectively modulate different aspects of GPCR function for therapeutic benefit. When viewed from the short-term perspective, e.g. changes in receptor conformation, effector coupling or second messenger generation, biased ligands appear to activate a subset of the response profile produced by a conventional agonist. Yet when examined in vivo, the limited data available suggest that biased ligand effects can diverge from their conventional counterparts in ways that cannot be predicted from their in vitro efficacy profile. What is currently missing, at least with respect to G protein and arrestin pathway-selective ligands, is a rational framework for relating the in vitro efficacy of a "biased" agonist to its in vivo actions that will enable drug screening programs to identify ligands with the desired biological effects.

Predicting pathway cross-talks in ankylosing spondylitis through investigating the interactions among pathways.

PubMed

Gu, Xiang; Liu, Cong-Jian; Wei, Jian-Jie

2017-11-13

Given that the pathogenesis of ankylosing spondylitis (AS) remains unclear, the aim of this study was to detect the potentially functional pathway cross-talk in AS to further reveal the pathogenesis of this disease. Using microarray profile of AS and biological pathways as study objects, Monte Carlo cross-validation method was used to identify the significant pathway cross-talks. In the process of Monte Carlo cross-validation, all steps were iterated 50 times. For each run, detection of differentially expressed genes (DEGs) between two groups was conducted. The extraction of the potential disrupted pathways enriched by DEGs was then implemented. Subsequently, we established a discriminating score (DS) for each pathway pair according to the distribution of gene expression levels. After that, we utilized random forest (RF) classification model to screen out the top 10 paired pathways with the highest area under the curve (AUCs), which was computed using 10-fold cross-validation approach. After 50 bootstrap, the best pairs of pathways were identified. According to their AUC values, the pair of pathways, antigen presentation pathway and fMLP signaling in neutrophils, achieved the best AUC value of 1.000, which indicated that this pathway cross-talk could distinguish AS patients from normal subjects. Moreover, the paired pathways of SAPK/JNK signaling and mitochondrial dysfunction were involved in 5 bootstraps. Two paired pathways (antigen presentation pathway and fMLP signaling in neutrophil, as well as SAPK/JNK signaling and mitochondrial dysfunction) can accurately distinguish AS and control samples. These paired pathways may be helpful to identify patients with AS for early intervention.

High levels of effective long-distance dispersal may blur ecotypic divergence in a rare terrestrial orchid.

PubMed

Vanden Broeck, An; Van Landuyt, Wouter; Cox, Karen; De Bruyn, Luc; Gyselings, Ralf; Oostermeijer, Gerard; Valentin, Bertille; Bozic, Gregor; Dolinar, Branko; Illyés, Zoltán; Mergeay, Joachim

2014-07-07

Gene flow and adaptive divergence are key aspects of metapopulation dynamics and ecological speciation. Long-distance dispersal is hard to detect and few studies estimate dispersal in combination with adaptive divergence. The aim of this study was to investigate effective long-distance dispersal and adaptive divergence in the fen orchid (Liparis loeselii (L.) Rich.). We used amplified fragment length polymorphism (AFLP)-based assignment tests to quantify effective long-distance dispersal at two different regions in Northwest Europe. In addition, genomic divergence between fen orchid populations occupying two distinguishable habitats, wet dune slacks and alkaline fens, was investigated by a genome scan approach at different spatial scales (continental, landscape and regional) and based on 451 AFLP loci. We expected that different habitats would contribute to strong divergence and restricted gene flow resulting in isolation-by-adaptation. Instead, we found remarkably high levels of effective long-distance seed dispersal and low levels of adaptive divergence. At least 15% of the assigned individuals likely originated from among-population dispersal events with dispersal distances up to 220 km. Six (1.3%) 'outlier' loci, potentially reflecting local adaptation to habitat-type, were identified with high statistical support. Of these, only one (0.22%) was a replicated outlier in multiple independent dune-fen population comparisons and thus possibly reflecting truly parallel divergence. Signals of adaptation in response to habitat type were most evident at the scale of individual populations. The findings of this study suggest that the homogenizing effect of effective long-distance seed dispersal may overwhelm divergent selection associated to habitat type in fen orchids in Northwest Europe.

High levels of effective long-distance dispersal may blur ecotypic divergence in a rare terrestrial orchid

PubMed Central

2014-01-01

Background Gene flow and adaptive divergence are key aspects of metapopulation dynamics and ecological speciation. Long-distance dispersal is hard to detect and few studies estimate dispersal in combination with adaptive divergence. The aim of this study was to investigate effective long-distance dispersal and adaptive divergence in the fen orchid (Liparis loeselii (L.) Rich.). We used amplified fragment length polymorphism (AFLP)-based assignment tests to quantify effective long-distance dispersal at two different regions in Northwest Europe. In addition, genomic divergence between fen orchid populations occupying two distinguishable habitats, wet dune slacks and alkaline fens, was investigated by a genome scan approach at different spatial scales (continental, landscape and regional) and based on 451 AFLP loci. Results We expected that different habitats would contribute to strong divergence and restricted gene flow resulting in isolation-by-adaptation. Instead, we found remarkably high levels of effective long-distance seed dispersal and low levels of adaptive divergence. At least 15% of the assigned individuals likely originated from among-population dispersal events with dispersal distances up to 220 km. Six (1.3%) ‘outlier’ loci, potentially reflecting local adaptation to habitat-type, were identified with high statistical support. Of these, only one (0.22%) was a replicated outlier in multiple independent dune-fen population comparisons and thus possibly reflecting truly parallel divergence. Signals of adaptation in response to habitat type were most evident at the scale of individual populations. Conclusions The findings of this study suggest that the homogenizing effect of effective long-distance seed dispersal may overwhelm divergent selection associated to habitat type in fen orchids in Northwest Europe. PMID:24998243

The study of flavonolignan association patterns in fruits of diverging Silybum marianum (L.) Gaertn. chemotypes provides new insights into the silymarin biosynthetic pathway.

PubMed

Martinelli, Tommaso; Whittaker, Anne; Benedettelli, Stefano; Carboni, Andrea; Andrzejewska, Jadwiga

2017-12-01

Silymarin is the phytochemical with medicinal properties extracted from Silybum marianum (L.) Gaertn. fruits. Yet, little information is available about silymarin biosynthesis. Moreover, the generally accepted pathway, formulated thus far, is not in agreement with actual experimental measurements on flavonolignan contents. The present work analyses flavonolignan and taxifolin content in 201 S. marianum samples taking into consideration a wide phenotypic variability. Two stable chemotypes were identified: one characterized by both high silychristin and silybin content (chemotype A) and another by a high silydianin content (chemotype B). Through the correlation analysis of samples divided according to chemotype, it was possible to construct a simplified silymarin biosynthetic pathway that is sufficiently versatile in explaining experimental results responding to the actually unresolved questions about this process. The proposed pathway highlights that three separate and equally sized metabolite pools exist, namely: diastereoisomers A (silybin A plus isosilybin A), diastereoisomers B (silybin B plus isosilybin B) and silychristin. In both A and B diastereoisomers pools, isosilybin A and isosilybin B always represent a given amount of the metabolite flux through the specific metabolite pool suggesting the possible involvement of dirigent protein-like enzymes. We suggest that chemotype B possesses a complete silymarin biosynthetic pathway in which silydianin biosynthesis is enzymatically controlled. On the contrary, chemotype A is probably a natural mutant unable to biosynthesize silydianin. The present simplified pathway for silymarin biosynthesis will constitute an important tool for the further understanding of the reactions that drive flavonolignan biosynthesis in S. marianum. Copyright © 2017 Elsevier Ltd. All rights reserved.

Investigating dysregulated pathways in Staphylococcus aureus (SA) exposed macrophages based on pathway interaction network.

PubMed

Zhou, Wei; Zhang, Yan; Li, Yue-Hua; Wang, Shuang; Zhang, Jing-Jing; Zhang, Cui-Xia; Zhang, Zhi-Sheng

2017-02-01

This work aimed to identify dysregulated pathways for Staphylococcus aureus (SA) exposed macrophages based on pathway interaction network (PIN). The inference of dysregulated pathways was comprised of four steps: preparing gene expression data, protein-protein interaction (PPI) data and pathway data; constructing a PIN dependent on the data and Pearson correlation coefficient (PCC); selecting seed pathway from PIN by computing activity score for each pathway according to principal component analysis (PCA) method; and investigating dysregulated pathways in a minimum set of pathways (MSP) utilizing seed pathway and the area under the receiver operating characteristics curve (AUC) index implemented in support vector machines (SVM) model. A total of 20,545 genes, 449,833 interactions and 1189 pathways were obtained in the gene expression data, PPI data and pathway data, respectively. The PIN was consisted of 8388 interactions and 1189 nodes, and Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins was identified as the seed pathway. Finally, 15 dysregulated pathways in MSP (AUC=0.999) were obtained for SA infected samples, such as Respiratory electron transport and DNA Replication. We have identified 15 dysregulated pathways for SA infected macrophages based on PIN. The findings might provide potential biomarkers for early detection and therapy of SA infection, and give insights to reveal the molecular mechanism underlying SA infections. However, how these dysregulated pathways worked together still needs to be studied. Copyright © 2016 Elsevier Ltd. All rights reserved.

Extensive Local Gene Duplication and Functional Divergence among Paralogs in Atlantic Salmon

PubMed Central

Warren, Ian A.; Ciborowski, Kate L.; Casadei, Elisa; Hazlerigg, David G.; Martin, Sam; Jordan, William C.; Sumner, Seirian

2014-01-01

Many organisms can generate alternative phenotypes from the same genome, enabling individuals to exploit diverse and variable environments. A prevailing hypothesis is that such adaptation has been favored by gene duplication events, which generate redundant genomic material that may evolve divergent functions. Vertebrate examples of recent whole-genome duplications are sparse although one example is the salmonids, which have undergone a whole-genome duplication event within the last 100 Myr. The life-cycle of the Atlantic salmon, Salmo salar, depends on the ability to produce alternating phenotypes from the same genome, to facilitate migration and maintain its anadromous life history. Here, we investigate the hypothesis that genome-wide and local gene duplication events have contributed to the salmonid adaptation. We used high-throughput sequencing to characterize the transcriptomes of three key organs involved in regulating migration in S. salar: Brain, pituitary, and olfactory epithelium. We identified over 10,000 undescribed S. salar sequences and designed an analytic workflow to distinguish between paralogs originating from local gene duplication events or from whole-genome duplication events. These data reveal that substantial local gene duplications took place shortly after the whole-genome duplication event. Many of the identified paralog pairs have either diverged in function or become noncoding. Future functional genomics studies will reveal to what extent this rich source of divergence in genetic sequence is likely to have facilitated the evolution of extreme phenotypic plasticity required for an anadromous life-cycle. PMID:24951567

Long-term consequences of pubertal timing for youth depression: Identifying personal and contextual pathways of risk

PubMed Central

RUDOLPH, KAREN D.; TROOP-GORDON, WENDY; LAMBERT, SHARON F.; NATSUAKI, MISAKI N.

2015-01-01

This research explored sex differences in the pathways linking pubertal timing to depression across 4 years. A sample of 167 youth (M age = 12.41 years, SD = 1.19) and their caregivers completed measures of puberty and semistructured interviews of interpersonal stress and youth depression. Youth reported on psychological (negative self-focus, anxious arousal) and social–behavioral (coping) characteristics; parents reported on youths’ social–behavioral characteristics (withdrawal/social problems) and deviant peer affiliations. Early maturation predicted stable high trajectories of depression in girls; although early maturing boys showed low initial levels of depression, they did not differ from girls by the final wave of the study. Latent growth curve analyses identified several psychological, social–behavioral, and interpersonal pathways accounting for the contribution of pubertal timing to initial and enduring risk for depression in girls as well as emerging risk for depression in boys. These findings provide novel insight into multilevel processes accounting for sex differences in depression across the adolescent transition. PMID:25422971

Molecular evolution and functional divergence of alcohol dehydrogenases in animals, fungi and plants.

PubMed

Thompson, Claudia E; Freitas, Loreta B; Salzano, Francisco M

2018-01-01

Alcohol dehydrogenases belong to the large superfamily of medium-chain dehydrogenases/reductases, which occur throughout the biological world and are involved with many important metabolic routes. We considered the phylogeny of 190 ADH sequences of animals, fungi, and plants. Non-class III Caenorhabditis elegans ADHs were seen closely related to tetrameric fungal ADHs. ADH3 forms a sister group to amphibian, reptilian, avian and mammalian non-class III ADHs. In fishes, two main forms are identified: ADH1 and ADH3, whereas in amphibians there is a new ADH form (ADH8). ADH2 is found in Mammalia and Aves, and they formed a monophyletic group. Additionally, mammalian ADH4 seems to result from an ADH1 duplication, while in Fungi, ADH formed clusters based on types and genera. The plant ADH isoforms constitute a basal clade in relation to ADHs from animals. We identified amino acid residues responsible for functional divergence between ADH types in fungi, mammals, and fishes. In mammals, these differences occur mainly between ADH1/ADH4 and ADH3/ADH5, whereas functional divergence occurred in fungi between ADH1/ADH5, ADH5/ADH4, and ADH5/ADH3. In fishes, the forms also seem to be functionally divergent. The ADH family expansion exemplifies a neofunctionalization process where reiterative duplication events are related to new activities.

A MicroRNA Screen Identifies the Wnt Signaling Pathway as a Regulator of the Interferon Response during Flavivirus Infection

PubMed Central

Smith, Jessica L.; Jeng, Sophia; McWeeney, Shannon K.

2017-01-01

ABSTRACT The impact of mosquito-borne flavivirus infections worldwide is significant, and many critical aspects of these viruses' biology, including virus-host interactions, host cell requirements for replication, and how virus-host interactions impact pathology, remain to be fully understood. The recent reemergence and spread of flaviviruses, including dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV), highlight the importance of performing basic research on this important group of pathogens. MicroRNAs (miRNAs) are small, noncoding RNAs that modulate gene expression posttranscriptionally and have been demonstrated to regulate a broad range of cellular processes. Our research is focused on identifying pro- and antiflaviviral miRNAs as a means of characterizing cellular pathways that support or limit viral replication. We have screened a library of known human miRNA mimics for their effect on the replication of three flaviviruses, DENV, WNV, and Japanese encephalitis virus (JEV), using a high-content immunofluorescence screen. Several families of miRNAs were identified as inhibiting multiple flaviviruses, including the miRNA miR-34, miR-15, and miR-517 families. Members of the miR-34 family, which have been extensively characterized for their ability to repress Wnt/β-catenin signaling, demonstrated strong antiflaviviral effects, and this inhibitory activity extended to other viruses, including ZIKV, alphaviruses, and herpesviruses. Previous research suggested a possible link between the Wnt and type I interferon (IFN) signaling pathways. Therefore, we investigated the role of type I IFN induction in the antiviral effects of the miR-34 family and confirmed that these miRNAs potentiate interferon regulatory factor 3 (IRF3) phosphorylation and translocation to the nucleus, the induction of IFN-responsive genes, and the release of type I IFN from transfected cells. We further demonstrate that the intersection between the Wnt and IFN signaling pathways

A MicroRNA Screen Identifies the Wnt Signaling Pathway as a Regulator of the Interferon Response during Flavivirus Infection.

PubMed

Smith, Jessica L; Jeng, Sophia; McWeeney, Shannon K; Hirsch, Alec J

2017-04-15

The impact of mosquito-borne flavivirus infections worldwide is significant, and many critical aspects of these viruses' biology, including virus-host interactions, host cell requirements for replication, and how virus-host interactions impact pathology, remain to be fully understood. The recent reemergence and spread of flaviviruses, including dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV), highlight the importance of performing basic research on this important group of pathogens. MicroRNAs (miRNAs) are small, noncoding RNAs that modulate gene expression posttranscriptionally and have been demonstrated to regulate a broad range of cellular processes. Our research is focused on identifying pro- and antiflaviviral miRNAs as a means of characterizing cellular pathways that support or limit viral replication. We have screened a library of known human miRNA mimics for their effect on the replication of three flaviviruses, DENV, WNV, and Japanese encephalitis virus (JEV), using a high-content immunofluorescence screen. Several families of miRNAs were identified as inhibiting multiple flaviviruses, including the miRNA miR-34, miR-15, and miR-517 families. Members of the miR-34 family, which have been extensively characterized for their ability to repress Wnt/β-catenin signaling, demonstrated strong antiflaviviral effects, and this inhibitory activity extended to other viruses, including ZIKV, alphaviruses, and herpesviruses. Previous research suggested a possible link between the Wnt and type I interferon (IFN) signaling pathways. Therefore, we investigated the role of type I IFN induction in the antiviral effects of the miR-34 family and confirmed that these miRNAs potentiate interferon regulatory factor 3 (IRF3) phosphorylation and translocation to the nucleus, the induction of IFN-responsive genes, and the release of type I IFN from transfected cells. We further demonstrate that the intersection between the Wnt and IFN signaling pathways occurs at

Mining pathway associations for disease-related pathway activity analysis based on gene expression and methylation data.

PubMed

Lee, Hyeonjeong; Shin, Miyoung

2017-01-01

The problem of discovering genetic markers as disease signatures is of great significance for the successful diagnosis, treatment, and prognosis of complex diseases. Even if many earlier studies worked on identifying disease markers from a variety of biological resources, they mostly focused on the markers of genes or gene-sets (i.e., pathways). However, these markers may not be enough to explain biological interactions between genetic variables that are related to diseases. Thus, in this study, our aim is to investigate distinctive associations among active pathways (i.e., pathway-sets) shown each in case and control samples which can be observed from gene expression and/or methylation data. The pathway-sets are obtained by identifying a set of associated pathways that are often active together over a significant number of class samples. For this purpose, gene expression or methylation profiles are first analyzed to identify significant (active) pathways via gene-set enrichment analysis. Then, regarding these active pathways, an association rule mining approach is applied to examine interesting pathway-sets in each class of samples (case or control). By doing so, the sets of associated pathways often working together in activity profiles are finally chosen as our distinctive signature of each class. The identified pathway-sets are aggregated into a pathway activity network (PAN), which facilitates the visualization of differential pathway associations between case and control samples. From our experiments with two publicly available datasets, we could find interesting PAN structures as the distinctive signatures of breast cancer and uterine leiomyoma cancer, respectively. Our pathway-set markers were shown to be superior or very comparable to other genetic markers (such as genes or gene-sets) in disease classification. Furthermore, the PAN structure, which can be constructed from the identified markers of pathway-sets, could provide deeper insights into

Spatially restricted G protein-coupled receptor activity via divergent endocytic compartments.

PubMed

Jean-Alphonse, Frederic; Bowersox, Shanna; Chen, Stanford; Beard, Gemma; Puthenveedu, Manojkumar A; Hanyaloglu, Aylin C

2014-02-14

Postendocytic sorting of G protein-coupled receptors (GPCRs) is driven by their interactions between highly diverse receptor sequence motifs with their interacting proteins, such as postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), zonula occludens-1 protein (zo-1) (PDZ) domain proteins. However, whether these diverse interactions provide an underlying functional specificity, in addition to driving sorting, is unknown. Here we identify GPCRs that recycle via distinct PDZ ligand/PDZ protein pairs that exploit their recycling machinery primarily for targeted endosomal localization and signaling specificity. The luteinizing hormone receptor (LHR) and β2-adrenergic receptor (B2AR), two GPCRs sorted to the regulated recycling pathway, underwent divergent trafficking to distinct endosomal compartments. Unlike B2AR, which traffics to early endosomes (EE), LHR internalizes to distinct pre-early endosomes (pre-EEs) for its recycling. Pre-EE localization required interactions of the LHR C-terminal tail with the PDZ protein GAIP-interacting protein C terminus, inhibiting its traffic to EEs. Rerouting the LHR to EEs, or EE-localized GPCRs to pre-EEs, spatially reprograms MAPK signaling. Furthermore, LHR-mediated activation of MAPK signaling requires internalization and is maintained upon loss of the EE compartment. We propose that combinatorial specificity between GPCR sorting sequences and interacting proteins dictates an unprecedented spatiotemporal control in GPCR signal activity.

Numerical Optimization of converging diverging miniature cavitating nozzles

NASA Astrophysics Data System (ADS)

Chavan, Kanchan; Bhingole, B.; Raut, J.; Pandit, A. B.

2015-12-01

The work focuses on the numerical optimization of converging diverging cavitating nozzles through nozzle dimensions and wall shape. The objective is to develop design rules for the geometry of cavitating nozzles for desired end-use. Two main aspects of nozzle design which affects the cavitation have been studied i.e. end dimensions of the geometry (i.e. angle and/or curvature of the inlet, outlet and the throat and the lengths of the converging and diverging sections) and wall curvatures(concave or convex). Angle of convergence at the inlet was found to control the cavity growth whereas angle of divergence of the exit controls the collapse of cavity. CFD simulations were carried out for the straight line converging and diverging sections by varying converging and diverging angles to study its effect on the collapse pressure generated by the cavity. Optimized geometry configurations were obtained on the basis of maximum Cavitational Efficacy Ratio (CER)i.e. cavity collapse pressure generated for a given permanent pressure drop across the system. With increasing capabilities in machining and fabrication, it is possible to exploit the effect of wall curvature to create nozzles with further increase in the CER. Effect of wall curvature has been studied for the straight, concave and convex shapes. Curvature has been varied and effect of concave and convex wall curvatures vis-à-vis straight walls studied for fixed converging and diverging angles.It is concluded that concave converging-diverging nozzles with converging angle of 20° and diverging angle of 5° with the radius of curvature 0.03 m and 0.1530 m respectively gives maximum CER. Preliminary experiments using optimized geometry are indicating similar trends and are currently being carried out. Refinements of the CFD technique using two phase flow simulations are planned.

Ecological Divergence of a Novel Group of Chloroflexus Strains along a Geothermal Gradient

PubMed Central

Weltzer, Michael L.

2013-01-01

Environmental gradients are expected to promote the diversification and coexistence of ecological specialists adapted to local conditions. Consistent with this view, genera of phototrophic microorganisms in alkaline geothermal systems generally appear to consist of anciently divergent populations which have specialized on different temperature habitats. At White Creek (Lower Geyser Basin, Yellowstone National Park), however, a novel, 16S rRNA-defined lineage of the filamentous anoxygenic phototroph Chloroflexus (OTU 10, phylum Chloroflexi) occupies a much wider thermal niche than other 16S rRNA-defined groups of phototrophic bacteria. This suggests that Chloroflexus OTU 10 is either an ecological generalist or, alternatively, a group of cryptic thermal specialists which have recently diverged. To distinguish between these alternatives, we first isolated laboratory strains of Chloroflexus OTU 10 from along the White Creek temperature gradient. These strains are identical for partial gene sequences encoding the 16S rRNA and malonyl coenzyme A (CoA) reductase. However, strains isolated from upstream and downstream samples could be distinguished based on sequence variation at pcs, which encodes the propionyl-CoA synthase of the 3-hydroxypropionate pathway of carbon fixation used by the genus Chloroflexus. We next demonstrated that strains have diverged in temperature range for growth. Specifically, we obtained evidence for a positive correlation between thermal niche breadth and temperature optimum, with strains isolated from lower temperatures exhibiting greater thermal specialization than the most thermotolerant strain. The study has implications for our understanding of both the process of niche diversification of microorganisms and how diversity is organized in these hot spring communities. PMID:23263946

Ecological divergence of a novel group of Chloroflexus strains along a geothermal gradient.

PubMed

Weltzer, Michael L; Miller, Scott R

2013-02-01

Environmental gradients are expected to promote the diversification and coexistence of ecological specialists adapted to local conditions. Consistent with this view, genera of phototrophic microorganisms in alkaline geothermal systems generally appear to consist of anciently divergent populations which have specialized on different temperature habitats. At White Creek (Lower Geyser Basin, Yellowstone National Park), however, a novel, 16S rRNA-defined lineage of the filamentous anoxygenic phototroph Chloroflexus (OTU 10, phylum Chloroflexi) occupies a much wider thermal niche than other 16S rRNA-defined groups of phototrophic bacteria. This suggests that Chloroflexus OTU 10 is either an ecological generalist or, alternatively, a group of cryptic thermal specialists which have recently diverged. To distinguish between these alternatives, we first isolated laboratory strains of Chloroflexus OTU 10 from along the White Creek temperature gradient. These strains are identical for partial gene sequences encoding the 16S rRNA and malonyl coenzyme A (CoA) reductase. However, strains isolated from upstream and downstream samples could be distinguished based on sequence variation at pcs, which encodes the propionyl-CoA synthase of the 3-hydroxypropionate pathway of carbon fixation used by the genus Chloroflexus. We next demonstrated that strains have diverged in temperature range for growth. Specifically, we obtained evidence for a positive correlation between thermal niche breadth and temperature optimum, with strains isolated from lower temperatures exhibiting greater thermal specialization than the most thermotolerant strain. The study has implications for our understanding of both the process of niche diversification of microorganisms and how diversity is organized in these hot spring communities.

A pathway closely related to the (D)-tagatose pathway of gram-negative enterobacteria identified in the gram-positive bacterium Bacillus licheniformis.

PubMed

Van der Heiden, Edwige; Delmarcelle, Michaël; Lebrun, Sarah; Freichels, Régine; Brans, Alain; Vastenavond, Christian M; Galleni, Moreno; Joris, Bernard

2013-06-01

We report the first identification of a gene cluster involved in d-tagatose catabolism in Bacillus licheniformis. The pathway is closely related to the d-tagatose pathway of the Gram-negative bacterium Klebsiella oxytoca, in contrast to the d-tagatose 6-phosphate pathway described in the Gram-positive bacterium Staphylococcus aureus.

Divergence compensation for hardware-in-the-loop simulation of stiffness-varying discrete contact in space

NASA Astrophysics Data System (ADS)

Qi, Chenkun; Zhao, Xianchao; Gao, Feng; Ren, Anye; Hu, Yan

2016-11-01

The hardware-in-the-loop (HIL) contact simulation for flying objects in space is challenging due to the divergence caused by the time delay. In this study, a divergence compensation approach is proposed for the stiffness-varying discrete contact. The dynamic response delay of the motion simulator and the force measurement delay are considered. For the force measurement delay, a phase lead based force compensation approach is used. For the dynamic response delay of the motion simulator, a response error based force compensation approach is used, where the compensation force is obtained from the real-time identified contact stiffness and real-time measured position response error. The dynamic response model of the motion simulator is not required. The simulations and experiments show that the simulation divergence can be compensated effectively and satisfactorily by using the proposed approach.

Conserved and species-specific transcription factor co-binding patterns drive divergent gene regulation in human and mouse

PubMed Central

Diehl, Adam G

2018-01-01

Abstract The mouse is widely used as system to study human genetic mechanisms. However, extensive rewiring of transcriptional regulatory networks often confounds translation of findings between human and mouse. Site-specific gain and loss of individual transcription factor binding sites (TFBS) has caused functional divergence of orthologous regulatory loci, and so we must look beyond this positional conservation to understand common themes of regulatory control. Fortunately, transcription factor co-binding patterns shared across species often perform conserved regulatory functions. These can be compared to ‘regulatory sentences’ that retain the same meanings regardless of sequence and species context. By analyzing TFBS co-occupancy patterns observed in four human and mouse cell types, we learned a regulatory grammar: the rules by which TFBS are combined into meaningful regulatory sentences. Different parts of this grammar associate with specific sets of functional annotations regardless of sequence conservation and predict functional signatures more accurately than positional conservation. We further show that both species-specific and conserved portions of this grammar are involved in gene expression divergence and human disease risk. These findings expand our understanding of transcriptional regulatory mechanisms, suggesting that phenotypic divergence and disease risk are driven by a complex interplay between deeply conserved and species-specific transcriptional regulatory pathways. PMID:29361190

Genetic variants in two pathways influence serum urate levels and gout risk: a systematic pathway analysis.

PubMed

Dong, Zheng; Zhou, Jingru; Xu, Xia; Jiang, Shuai; Li, Yuan; Zhao, Dongbao; Yang, Chengde; Ma, Yanyun; Wang, Yi; He, Hongjun; Ji, Hengdong; Zhang, Juan; Yuan, Ziyu; Yang, Yajun; Wang, Xiaofeng; Pang, Yafei; Jin, Li; Zou, Hejian; Wang, Jiucun

2018-03-01

The aims of this study were to identify candidate pathways associated with serum urate and to explore the genetic effect of those pathways on the risk of gout. Pathway analysis of the loci identified in genome-wide association studies (GWASs) showed that the ion transmembrane transporter activity pathway (GO: 0015075) and the secondary active transmembrane transporter activity pathway (GO: 0015291) were both associated with serum urate concentrations, with P FDR values of 0.004 and 0.007, respectively. In a Chinese population of 4,332 individuals, the two pathways were also found to be associated with serum urate (P FDR  = 1.88E-05 and 3.44E-04, separately). In addition, these two pathways were further associated with the pathogenesis of gout (P FDR  = 1.08E-08 and 2.66E-03, respectively) in the Chinese population and a novel gout-associated gene, SLC17A2, was identified (OR = 0.83, P FDR  = 0.017). The mRNA expression of candidate genes also showed significant differences among different groups at pathway level. The present study identified two transmembrane transporter activity pathways (GO: 0015075 and GO: 0015291) were associations with serum urate concentrations and the risk of gout. SLC17A2 was identified as a novel gene that influenced the risk of gout.

A Pathway Closely Related to the d-Tagatose Pathway of Gram-Negative Enterobacteria Identified in the Gram-Positive Bacterium Bacillus licheniformis

PubMed Central

Van der Heiden, Edwige; Lebrun, Sarah; Freichels, Régine; Brans, Alain; Vastenavond, Christian M.; Galleni, Moreno; Joris, Bernard

2013-01-01

We report the first identification of a gene cluster involved in d-tagatose catabolism in Bacillus licheniformis. The pathway is closely related to the d-tagatose pathway of the Gram-negative bacterium Klebsiella oxytoca, in contrast to the d-tagatose 6-phosphate pathway described in the Gram-positive bacterium Staphylococcus aureus. PMID:23524682

Unexpected Functional Divergence of Bat Influenza Virus NS1 Proteins.

PubMed

Turkington, Hannah L; Juozapaitis, Mindaugas; Tsolakos, Nikos; Corrales-Aguilar, Eugenia; Schwemmle, Martin; Hale, Benjamin G

2018-03-01

Recently, two influenza A virus (FLUAV) genomes were identified in Central and South American bats. These sequences exhibit notable divergence from classical FLUAV counterparts, and functionally, bat FLUAV glycoproteins lack canonical receptor binding and destroying activity. Nevertheless, other features that distinguish these viruses from classical FLUAVs have yet to be explored. Here, we studied the viral nonstructural protein NS1, a virulence factor that modulates host signaling to promote efficient propagation. Like all FLUAV NS1 proteins, bat FLUAV NS1s bind double-stranded RNA and act as interferon antagonists. Unexpectedly, we found that bat FLUAV NS1s are unique in being unable to bind host p85β, a regulatory subunit of the cellular metabolism-regulating enzyme, phosphoinositide 3-kinase (PI3K). Furthermore, neither bat FLUAV NS1 alone nor infection with a chimeric bat FLUAV efficiently activates Akt, a PI3K effector. Structure-guided mutagenesis revealed that the bat FLUAV NS1-p85β interaction can be reengineered (in a strain-specific manner) by changing two to four NS1 residues (96L, 99M, 100I, and 145T), thereby creating a hydrophobic patch. Notably, ameliorated p85β-binding is insufficient for bat FLUAV NS1 to activate PI3K, and a chimeric bat FLUAV expressing NS1 with engineered hydrophobic patch mutations exhibits cell-type-dependent, but species-independent, propagation phenotypes. We hypothesize that bat FLUAV hijacking of PI3K in the natural bat host has been selected against, perhaps because genes in this metabolic pathway were differentially shaped by evolution to suit the unique energy use strategies of this flying mammal. These data expand our understanding of the enigmatic functional divergence between bat FLUAVs and classical mammalian and avian FLUAVs. IMPORTANCE The potential for novel influenza A viruses to establish infections in humans from animals is a source of continuous concern due to possible severe outbreaks or pandemics. The

Unexpected Functional Divergence of Bat Influenza Virus NS1 Proteins

PubMed Central

Turkington, Hannah L.; Juozapaitis, Mindaugas; Tsolakos, Nikos; Corrales-Aguilar, Eugenia; Schwemmle, Martin

2017-01-01

ABSTRACT Recently, two influenza A virus (FLUAV) genomes were identified in Central and South American bats. These sequences exhibit notable divergence from classical FLUAV counterparts, and functionally, bat FLUAV glycoproteins lack canonical receptor binding and destroying activity. Nevertheless, other features that distinguish these viruses from classical FLUAVs have yet to be explored. Here, we studied the viral nonstructural protein NS1, a virulence factor that modulates host signaling to promote efficient propagation. Like all FLUAV NS1 proteins, bat FLUAV NS1s bind double-stranded RNA and act as interferon antagonists. Unexpectedly, we found that bat FLUAV NS1s are unique in being unable to bind host p85β, a regulatory subunit of the cellular metabolism-regulating enzyme, phosphoinositide 3-kinase (PI3K). Furthermore, neither bat FLUAV NS1 alone nor infection with a chimeric bat FLUAV efficiently activates Akt, a PI3K effector. Structure-guided mutagenesis revealed that the bat FLUAV NS1-p85β interaction can be reengineered (in a strain-specific manner) by changing two to four NS1 residues (96L, 99M, 100I, and 145T), thereby creating a hydrophobic patch. Notably, ameliorated p85β-binding is insufficient for bat FLUAV NS1 to activate PI3K, and a chimeric bat FLUAV expressing NS1 with engineered hydrophobic patch mutations exhibits cell-type-dependent, but species-independent, propagation phenotypes. We hypothesize that bat FLUAV hijacking of PI3K in the natural bat host has been selected against, perhaps because genes in this metabolic pathway were differentially shaped by evolution to suit the unique energy use strategies of this flying mammal. These data expand our understanding of the enigmatic functional divergence between bat FLUAVs and classical mammalian and avian FLUAVs. IMPORTANCE The potential for novel influenza A viruses to establish infections in humans from animals is a source of continuous concern due to possible severe outbreaks or

Degradation of ibuprofen by hydrodynamic cavitation: Reaction pathways and effect of operational parameters.

PubMed

Musmarra, Dino; Prisciandaro, Marina; Capocelli, Mauro; Karatza, Despina; Iovino, Pasquale; Canzano, Silvana; Lancia, Amedeo

2016-03-01

Ibuprofen (IBP) is an anti-inflammatory drug whose residues can be found worldwide in natural water bodies resulting in harmful effects to aquatic species even at low concentrations. This paper deals with the degradation of IBP in water by hydrodynamic cavitation in a convergent-divergent nozzle. Over 60% of ibuprofen was degraded in 60 min with an electrical energy per order (EEO) of 10.77 kWh m(-3) at an initial concentration of 200 μg L(-1) and a relative inlet pressure pin=0.35 MPa. Five intermediates generated from different hydroxylation reactions were identified; the potential mechanisms of degradation were sketched and discussed. The reaction pathways recognized are in line with the relevant literature, both experimental and theoretical. By varying the pressure upstream the constriction, different degradation rates were observed. This effect was discussed according to a numerical simulation of the hydroxyl radical production identifying a clear correspondence between the maximum kinetic constant kOH and the maximum calculated OH production. Furthermore, in the investigated experimental conditions, the pH parameter was found not to affect the extent of degradation; this peculiar feature agrees with a recently published kinetic insight and has been explained in the light of the intermediates of the different reaction pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy.

PubMed

Zhang, Yi-Xiang; van Oosterwijk, Jolieke G; Sicinska, Ewa; Moss, Samuel; Remillard, Stephen P; van Wezel, Tom; Bühnemann, Claudia; Hassan, Andrew B; Demetri, George D; Bovée, Judith V M G; Wagner, Andrew J

2013-07-15

Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model. Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas. RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors.

Pathway Distiller - multisource biological pathway consolidation.

PubMed

Doderer, Mark S; Anguiano, Zachry; Suresh, Uthra; Dashnamoorthy, Ravi; Bishop, Alexander J R; Chen, Yidong

2012-01-01

One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/PathwayDistiller), is established to allow

Variational divergence in wave scattering theory with Kirchhoffean trial functions

NASA Technical Reports Server (NTRS)

Bird, J. F.

1986-01-01

In a recent study of variational improvement of the Kirchhoff approximation for electromagnetic scattering by rough surfaces, a key ingredient in the variational principle was found to diverge for important configurations (e.g., backscatter) if the polarization had any vertical component. The cause and a cure of this divergence are discussed here. The divergence is demonstrated to occur for arbitrary perfectly conducting scatterers and its universal characterstics are determined, by means of a general divergence criterion that is derived. A variational cure for the divergence is prescribed, and it is tested successfully on a standard scattering model.

Genetic divergence through joint analysis of morphoagronomic and molecular characters in accessions of Jatropha curcas.

PubMed

Pestana-Caldas, C N; Silva, S A; Machado, E L; de Souza, D R; Cerqueira-Pereira, E C; Silva, M S

2016-10-05

The aim of this study was to investigate the genetic divergence between accessions of Jatropha curcas through joint analysis of morphoagronomic and molecular characters. To this end, we investigated 11 morphoagronomic characters and performed molecular genotyping, using 23 inter-simple sequence repeat (ISSR) primers in 46 accessions of J. curcas. We calculated the contribution of each character on divergence using analysis of variance. The grouping among accessions was performed using the Ward-MLM (modified location model) method, using morphoagronomic and molecular data, whereas the cophenetic correlation was obtained based on Gower's algorithm. There were significant differences in all growth-related characteristics: number of primary and secondary branches per plant, plant height, and stem diameter. For characters related to grain production, differences were found for number of fruit clusters per plant and number of inflorescence clusters per plant and average number of seeds per fruit. The greatest phenotypic variation was found in plant height (59.67- 222.33 cm), whereas the smallest variation was found in average number of seeds per fruit (0-2.90), followed by the number of fruit clusters per plant (0-8.67). In total, 94 polymorphic ISSR fragments were obtained. The genotypic grouping identified six groups, indicating that there is genetic divergence among the accessions. The most promising crossings for future hybridization were identified among accessions UFRB60 and UFVJC45, and UFRB61 and UFVJC18. In conclusion, the joint analysis of morphoagronomic characters and ISSR markers is an efficient method to assess the genetic divergence in J. curcas.

Sandwiched Rényi divergence satisfies data processing inequality

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beigi, Salman

2013-12-15

Sandwiched (quantum) α-Rényi divergence has been recently defined in the independent works of Wilde et al. [“Strong converse for the classical capacity of entanglement-breaking channels,” preprint http://arxiv.org/abs/arXiv:1306.1586 (2013)] and Müller-Lennert et al. [“On quantum Rényi entropies: a new definition, some properties and several conjectures,” preprint http://arxiv.org/abs/arXiv:1306.3142v1 (2013)]. This new quantum divergence has already found applications in quantum information theory. Here we further investigate properties of this new quantum divergence. In particular, we show that sandwiched α-Rényi divergence satisfies the data processing inequality for all values of α > 1. Moreover we prove that α-Holevo information, a variant of Holevo informationmore » defined in terms of sandwiched α-Rényi divergence, is super-additive. Our results are based on Hölder's inequality, the Riesz-Thorin theorem and ideas from the theory of complex interpolation. We also employ Sion's minimax theorem.« less

Effects of Inversions on Within- and Between-Species Recombination and Divergence

PubMed Central

Stevison, Laurie S.; Hoehn, Kenneth B.; Noor, Mohamed A. F.

2011-01-01

Chromosomal inversions disrupt recombination in heterozygotes by both reducing crossing-over within inverted regions and increasing it elsewhere in the genome. The reduction of recombination in inverted regions facilitates the maintenance of hybridizing species, as outlined by various models of chromosomal speciation. We present a comprehensive comparison of the effects of inversions on recombination rates and on nucleotide divergence. Within an inversion differentiating Drosophila pseudoobscura and Drosophila persimilis, we detected one double recombinant among 9,739 progeny from F1 hybrids screened, consistent with published double-crossover frequencies observed within species. Despite similar rates of exchange within and between species, we found no sequence-based evidence of ongoing gene exchange between species within this inversion, but significant exchange was inferred within species. We also observed greater differentiation at regions near inversion breakpoints between species versus within species. Moreover, we observed strong “interchromosomal effect” (higher recombination in inversion heterozygotes between species) with up to 9-fold higher recombination rates along collinear segments of chromosome two in hybrids. Further, we observed that regions most susceptible to changes in recombination rates corresponded to regions with lower recombination rates in homokaryotypes. Finally, we showed that interspecies nucleotide divergence is lower in regions with greater increases in recombination rate, potentially resulting from greater interspecies exchange. Overall, we have identified several similarities and differences between inversions segregating within versus between species in their effects on recombination and divergence. We conclude that these differences are most likely due to lower frequency of heterokaryotypes and to fitness consequences from the accumulation of various incompatibilities between species. Additionally, we have identified possible

Human-specific protein isoforms produced by novel splice sites in the human genome after the human-chimpanzee divergence

PubMed Central

2012-01-01

Background Evolution of splice sites is a well-known phenomenon that results in transcript diversity during human evolution. Many novel splice sites are derived from repetitive elements and may not contribute to protein products. Here, we analyzed annotated human protein-coding exons and identified human-specific splice sites that arose after the human-chimpanzee divergence. Results We analyzed multiple alignments of the annotated human protein-coding exons and their respective orthologous mammalian genome sequences to identify 85 novel splice sites (50 splice acceptors and 35 donors) in the human genome. The novel protein-coding exons, which are expressed either constitutively or alternatively, produce novel protein isoforms by insertion, deletion, or frameshift. We found three cases in which the human-specific isoform conferred novel molecular function in the human cells: the human-specific IMUP protein isoform induces apoptosis of the trophoblast and is implicated in pre-eclampsia; the intronization of a part of SMOX gene exon produces inactive spermine oxidase; the human-specific NUB1 isoform shows reduced interaction with ubiquitin-like proteins, possibly affecting ubiquitin pathways. Conclusions Although the generation of novel protein isoforms does not equate to adaptive evolution, we propose that these cases are useful candidates for a molecular functional study to identify proteomic changes that might bring about novel phenotypes during human evolution. PMID:23148531

Exploring divergent trajectories: Disorder-specific moderators of the association between negative urgency and dysregulated eating.

PubMed

Racine, Sarah E; Martin, Shelby J

2016-08-01

Negative urgency (i.e., the tendency to act impulsively when experiencing negative emotions) is a well-established risk factor for dysregulated eating (e.g., binge eating, loss of control eating, emotional eating). However, negative urgency is transdiagnostic, in that it is associated with multiple forms of psychopathology. It is currently unclear why some individuals with high negative urgency develop dysregulated eating while others experience depressive symptoms or problematic alcohol use. Investigating disorder-specific moderators of the association between negative urgency and psychopathology may help elucidate these divergent trajectories. The current study examined interactions among negative urgency and eating disorder-specific risk factors specified in the well-established dual-pathway model of bulimic pathology (i.e., appearance pressures, thin-ideal internalization, body dissatisfaction, dietary restraint). We hypothesized that these interactions would predict dysregulated eating, but not depressive symptoms or problematic alcohol use. Latent moderated structural equation modeling was used to test this hypothesis in a large (N = 313) sample of female college students. Negative urgency was significantly associated with dysregulated eating, depressive symptoms, and problematic alcohol use. However, interactions among negative urgency and dual-pathway model variables were specific to dysregulated eating and accounted for an additional 3-5% of the variance beyond main effects. Findings suggest that eating disorder-specific risk factors may shape negative urgency into manifesting as dysregulated eating versus another form of psychopathology. Future research should use longitudinal designs to further test the impact of interactions among disorder-specific risk factors and negative urgency on divergent psychopathology trajectories. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sex-biased transcriptome divergence along a latitudinal gradient.

PubMed

Allen, Scott L; Bonduriansky, Russell; Sgro, Carla M; Chenoweth, Stephen F

2017-03-01

Sex-dependent gene expression is likely an important genomic mechanism that allows sex-specific adaptation to environmental changes. Among Drosophila species, sex-biased genes display remarkably consistent evolutionary patterns; male-biased genes evolve faster than unbiased genes in both coding sequence and expression level, suggesting sex differences in selection through time. However, comparatively little is known of the evolutionary process shaping sex-biased expression within species. Latitudinal clines offer an opportunity to examine how changes in key ecological parameters also influence sex-specific selection and the evolution of sex-biased gene expression. We assayed male and female gene expression in Drosophila serrata along a latitudinal gradient in eastern Australia spanning most of its endemic distribution. Analysis of 11 631 genes across eight populations revealed strong sex differences in the frequency, mode and strength of divergence. Divergence was far stronger in males than females and while latitudinal clines were evident in both sexes, male divergence was often population specific, suggesting responses to localized selection pressures that do not covary predictably with latitude. While divergence was enriched for male-biased genes, there was no overrepresentation of X-linked genes in males. By contrast, X-linked divergence was elevated in females, especially for female-biased genes. Many genes that diverged in D. serrata have homologs also showing latitudinal divergence in Drosophila simulans and Drosophila melanogaster on other continents, likely indicating parallel adaptation in these distantly related species. Our results suggest that sex differences in selection play an important role in shaping the evolution of gene expression over macro- and micro-ecological spatial scales. © 2017 John Wiley & Sons Ltd.

Active learning for noisy oracle via density power divergence.

PubMed

Sogawa, Yasuhiro; Ueno, Tsuyoshi; Kawahara, Yoshinobu; Washio, Takashi

2013-10-01

The accuracy of active learning is critically influenced by the existence of noisy labels given by a noisy oracle. In this paper, we propose a novel pool-based active learning framework through robust measures based on density power divergence. By minimizing density power divergence, such as β-divergence and γ-divergence, one can estimate the model accurately even under the existence of noisy labels within data. Accordingly, we develop query selecting measures for pool-based active learning using these divergences. In addition, we propose an evaluation scheme for these measures based on asymptotic statistical analyses, which enables us to perform active learning by evaluating an estimation error directly. Experiments with benchmark datasets and real-world image datasets show that our active learning scheme performs better than several baseline methods. Copyright © 2013 Elsevier Ltd. All rights reserved.

Renewable Fuel Pathways II Final Rule to Identify Additional Fuel Pathways under Renewable Fuel Standard Program

EPA Pesticide Factsheets

This final rule describes EPA’s evaluation of biofuels derived from biogas fuel pathways under the RFS program and other minor amendments related to survey requirements associated with ULSD program and misfueling mitigation regulations for E15.

Decoding divergent series in nonparaxial optics.

PubMed

Borghi, Riccardo; Gori, Franco; Guattari, Giorgio; Santarsiero, Massimo

2011-03-15

A theoretical analysis aimed at investigating the divergent character of perturbative series involved in the study of free-space nonparaxial propagation of vectorial optical beams is proposed. Our analysis predicts a factorial divergence for such series and provides a theoretical framework within which the results of recently published numerical experiments concerning nonparaxial propagation of vectorial Gaussian beams find a meaningful interpretation in terms of the decoding operated on such series by the Weniger transformation.

On the Lamb vector divergence as a momentum field diagnostic employed in turbulent channel flow

NASA Astrophysics Data System (ADS)

Hamman, Curtis W.; Kirby, Robert M.; Klewicki, Joseph C.

2006-11-01

Vorticity, enstrophy, helicity, and other derived field variables provide invaluable information about the kinematics and dynamics of fluids. However, whether or not derived field variables exist that intrinsically identify spatially localized motions having a distinct capacity to affect a time rate of change of linear momentum is seldom addressed in the literature. The purpose of the present study is to illustrate the unique attributes of the divergence of the Lamb vector in order to qualify its potential for characterizing such spatially localized motions. Toward this aim, we describe the mathematical properties, near-wall behavior, and scaling characteristics of the divergence of the Lamb vector for turbulent channel flow. When scaled by inner variables, the mean divergence of the Lamb vector merges to a single curve in the inner layer, and the fluctuating quantities exhibit a strong correlation with the Bernoulli function throughout much of the inner layer.

Divergent and convergent evolution in metastases suggest treatment strategies based on specific metastatic sites

PubMed Central

Cunningham, Jessica J.; Brown, Joel S.; Vincent, Thomas L.

2015-01-01

Background and objective: Systemic therapy for metastatic cancer is currently determined exclusively by the site of tumor origin. Yet, there is increasing evidence that the molecular characteristics of metastases significantly differ from the primary tumor. We define the evolutionary dynamics of metastases that govern this molecular divergence and examine their potential contribution to variations in response to targeted therapies. Methodology: Darwinian interactions of transformed cells with the tissue microenvironments at primary and metastatic sites are analyzed using evolutionary game theory. Computational models simulate responses to targeted therapies in different organs within the same patient. Results: Tumor cells, although maximally fit at their primary site, typically have lower fitness on the adaptive landscapes offered by the metastatic sites due to organ-specific variations in mesenchymal properties and signaling pathways. Clinically evident metastases usually exhibit time-dependent divergence from the phenotypic mean of the primary population as the tumor cells evolve and adapt to their new circumstances. In contrast, tumors from different primary sites evolving on identical metastatic adaptive landscapes exhibit phenotypic convergence. Thus, metastases in the liver from different primary tumors and even in different hosts will evolve toward similar adaptive phenotypes. The combination of evolutionary divergence from the primary cancer phenotype and convergence towards similar adaptive strategies in the same tissue cause significant variations in treatment responses particularly for highly targeted therapies. Conclusion and implications: The results suggest that optimal therapies for disseminated cancer must take into account the site(s) of metastatic growth as well as the primary organ. PMID:25794501

System Members at Odds: Managing Divergent Perspectives in the Higher Education Change Process

ERIC Educational Resources Information Center

Barnett, Kathy

2011-01-01

Achieving a shared vision is often cited as a prerequisite to successful organisational change. What change strategists do not take into consideration is how this concept applies to complex systems such as those found in higher education. This paper explores and identifies the divergent perspectives and meanings found among the multiplicity of…

Lithium ion beam divergence on SABRE extraction ion diode experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanson, D.L.; Cuneo, M.E.; Johnson, D.J.

Intense lithium beams are of particular interest for light ion inertial confinement fusion applications because lithium ions can be accelerated at high voltage in a single charge state (Li{sup +}) with a high mass-to-charge ratio and appropriate range for efficient focusing and heating of a hohlraum ICF target. Scaling to ion power densities adequate to drive high gain pellet implosions (600 TW at 30 MeV) will require a large number of beams transported, temporally bunched, and focused onto a target, with the necessary target standoff to ensure survival of the driver modules. For efficient long distance transport and focusing tomore » a small pellet, lithium beam divergence must be reduced to about 12 mrad or less (depending on the transport scheme). To support the eventual development of a light ion driver module for ICF applications, the authors are currently working to improve the composition, uniformity, and divergence of lithium ion beams produced by both passive LiF and active laser-generated lithium ion sources on extraction applied-B ion diodes on the SABRE accelerator (1 TW, 5 MV, 250 kA). While lithium beam divergence accounting and control are an essential goal of these experiments, divergence measurements for lithium beams present some unique problems not encountered to the same degree in divergence measurements on proton sources. To avoid these difficulties, the authors have developed a large aperture ion imaging diagnostic for time-resolved lithium divergence measurements. The authors will report on the operation of this lithium beam divergence diagnostic and on results of time-resolved divergence measurements in progress for passive LiF ion sources and laser-produced active lithium sources operated in diode configurations designed to control divergence growth. Comparisons will also be made with time-integrated divergence results obtained with small entrance aperture ultracompact pinhole cameras.« less

Estrogen Degraders and Estrogen Degradation Pathway Identified in an Activated Sludge.

PubMed

Chen, Yi-Lung; Fu, Han-Yi; Lee, Tzong-Huei; Shih, Chao-Jen; Huang, Lina; Wang, Yu-Sheng; Ismail, Wael; Chiang, Yin-Ru

2018-05-15

The environmental release and fate of estrogens are becoming an increasing public concern. Bacterial degradation has been considered the main process for eliminating estrogens from wastewater treatment plants. Various bacterial isolates are reportedly capable of aerobic estrogen degradation, and several estrogen degradation pathways have been proposed in proteobacteria and actinobacteria. However, the ecophysiological relevance of estrogen-degrading bacteria in the environment is unclear. In this study, we investigated the estrogen degradation pathway and corresponding degraders in activated sludge collected from the Dihua Sewage Treatment Plant, Taipei, Taiwan. Cultivation-dependent and cultivation-independent methods were used to assess estrogen biodegradation in the collected activated sludge. Estrogen metabolite profile analysis revealed the production of pyridinestrone acid and two A/B-ring cleavage products in activated sludge incubated with estrone (1 mM), which are characteristic of the 4,5- seco pathway. PCR-based functional assays detected sequences closely related to alphaproteobacterial oecC , a key gene of the 4,5- seco pathway. Metagenomic analysis suggested that Novosphingobium spp. are major estrogen degraders in estrone-amended activated sludge. Novosphingobium sp. strain SLCC, an estrone-degrading alphaproteobacterium, was isolated from the examined activated sludge. The general physiology and metabolism of this strain were characterized. Pyridinestrone acid and the A/B-ring cleavage products were detected in estrone-grown strain SLCC cultures. The production of pyridinestrone acid was also observed during the aerobic incubation of strain SLCC with 3.7 nM (1 μg/liter) estrone. This concentration is close to that detected in many natural and engineered aquatic ecosystems. The presented data suggest the ecophysiological relevance of Novosphingobium spp. in activated sludge. IMPORTANCE Estrogens, which persistently contaminate surface water

Divergent transcription is associated with promoters of transcriptional regulators

PubMed Central

2013-01-01

Background Divergent transcription is a wide-spread phenomenon in mammals. For instance, short bidirectional transcripts are a hallmark of active promoters, while longer transcripts can be detected antisense from active genes in conditions where the RNA degradation machinery is inhibited. Moreover, many described long non-coding RNAs (lncRNAs) are transcribed antisense from coding gene promoters. However, the general significance of divergent lncRNA/mRNA gene pair transcription is still poorly understood. Here, we used strand-specific RNA-seq with high sequencing depth to thoroughly identify antisense transcripts from coding gene promoters in primary mouse tissues. Results We found that a substantial fraction of coding-gene promoters sustain divergent transcription of long non-coding RNA (lncRNA)/mRNA gene pairs. Strikingly, upstream antisense transcription is significantly associated with genes related to transcriptional regulation and development. Their promoters share several characteristics with those of transcriptional developmental genes, including very large CpG islands, high degree of conservation and epigenetic regulation in ES cells. In-depth analysis revealed a unique GC skew profile at these promoter regions, while the associated coding genes were found to have large first exons, two genomic features that might enforce bidirectional transcription. Finally, genes associated with antisense transcription harbor specific H3K79me2 epigenetic marking and RNA polymerase II enrichment profiles linked to an intensified rate of early transcriptional elongation. Conclusions We concluded that promoters of a class of transcription regulators are characterized by a specialized transcriptional control mechanism, which is directly coupled to relaxed bidirectional transcription. PMID:24365181

Pathway Distiller - multisource biological pathway consolidation

PubMed Central

2012-01-01

Background One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. Methods After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. Results We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/Pathway

Neural networks application to divergence-based passive ranging

NASA Technical Reports Server (NTRS)

Barniv, Yair

1992-01-01

The purpose of this report is to summarize the state of knowledge and outline the planned work in divergence-based/neural networks approach to the problem of passive ranging derived from optical flow. Work in this and closely related areas is reviewed in order to provide the necessary background for further developments. New ideas about devising a monocular passive-ranging system are then introduced. It is shown that image-plan divergence is independent of image-plan location with respect to the focus of expansion and of camera maneuvers because it directly measures the object's expansion which, in turn, is related to the time-to-collision. Thus, a divergence-based method has the potential of providing a reliable range complementing other monocular passive-ranging methods which encounter difficulties in image areas close to the focus of expansion. Image-plan divergence can be thought of as some spatial/temporal pattern. A neural network realization was chosen for this task because neural networks have generally performed well in various other pattern recognition applications. The main goal of this work is to teach a neural network to derive the divergence from the imagery.

Means for counteracting charged particle beam divergence

DOEpatents

Hooper, Jr., Edwin B.

1978-01-01

To counteract charge particle beam divergence, magnetic field-generating means are positioned along the edges of a charged particle beam to be controlled, such as to deflect and redirect particles tending to diverge from a desired beam direction. By selective arrangement of the magnetic field-generating means, the entire beam may be deflected and guided into different directions.

Analysis of porcine adipose tissue transcriptome reveals differences in de novo fatty acid synthesis in pigs with divergent muscle fatty acid composition.

PubMed

Corominas, Jordi; Ramayo-Caldas, Yuliaxis; Puig-Oliveras, Anna; Estellé, Jordi; Castelló, Anna; Alves, Estefania; Pena, Ramona N; Ballester, Maria; Folch, Josep M

2013-12-01

In pigs, adipose tissue is one of the principal organs involved in the regulation of lipid metabolism. It is particularly involved in the overall fatty acid synthesis with consequences in other lipid-target organs such as muscles and the liver. With this in mind, we have used massive, parallel high-throughput sequencing technologies to characterize the porcine adipose tissue transcriptome architecture in six Iberian x Landrace crossbred pigs showing extreme phenotypes for intramuscular fatty acid composition (three per group). High-throughput RNA sequencing was used to generate a whole characterization of adipose tissue (backfat) transcriptome. A total of 4,130 putative unannotated protein-coding sequences were identified in the 20% of reads which mapped in intergenic regions. Furthermore, 36% of the unmapped reads were represented by interspersed repeats, SINEs being the most abundant elements. Differential expression analyses identified 396 candidate genes among divergent animals for intramuscular fatty acid composition. Sixty-two percent of these genes (247/396) presented higher expression in the group of pigs with higher content of intramuscular SFA and MUFA, while the remaining 149 showed higher expression in the group with higher content of PUFA. Pathway analysis related these genes to biological functions and canonical pathways controlling lipid and fatty acid metabolisms. In concordance with the phenotypic classification of animals, the major metabolic pathway differentially modulated between groups was de novo lipogenesis, the group with more PUFA being the one that showed lower expression of lipogenic genes. These results will help in the identification of genetic variants at loci that affect fatty acid composition traits. The implications of these results range from the improvement of porcine meat quality traits to the application of the pig as an animal model of human metabolic diseases.

RECENT ECOLOGICAL DIVERGENCE DESPITE MIGRATION IN SOCKEYE SALMON (ONCORHYNCHUS NERKA)

PubMed Central

Pavey, Scott A; Nielsen, Jennifer L; Hamon, Troy R

2010-01-01

Ecological divergence may result when populations experience different selection regimes, but there is considerable discussion about the role of migration at the beginning stages of divergence before reproductive isolating mechanisms have evolved. However, detection of past migration is difficult in current populations and tools to differentiate genetic similarities due to migration versus recent common ancestry are only recently available. Using past volcanic eruption times as a framework, we combine morphological analyses of traits important to reproduction with a coalescent-based genetic analysis of two proximate sockeye salmon (Oncorhynchus nerka) populations. We find that this is the most recent (∼500 years, 100 generations) natural ecological divergence recorded in a fish species, and report that this divergence is occurring despite migration. Although studies of fish divergence following the retreat of glaciers (10,000–15,000 years ago) have contributed extensively to our understanding of speciation, the Aniakchak system of sockeye salmon provides a rare example of the initial stages of ecological divergence following natural colonization. Our results show that even in the face of continued migration, populations may diverge in the absence of a physical barrier. PMID:20030707

Recent ecological divergence despite migration in sockeye salmon (Oncorhynchus nerka).

PubMed

Pavey, Scott A; Nielsen, Jennifer L; Hamon, Troy R

2010-06-01

Ecological divergence may result when populations experience different selection regimes, but there is considerable discussion about the role of migration at the beginning stages of divergence before reproductive isolating mechanisms have evolved. However, detection of past migration is difficult in current populations and tools to differentiate genetic similarities due to migration versus recent common ancestry are only recently available. Using past volcanic eruption times as a framework, we combine morphological analyses of traits important to reproduction with a coalescent-based genetic analysis of two proximate sockeye salmon (Oncorhynchus nerka) populations. We find that this is the most recent (approximately 500 years, 100 generations) natural ecological divergence recorded in a fish species, and report that this divergence is occurring despite migration. Although studies of fish divergence following the retreat of glaciers (10,000-15,000 years ago) have contributed extensively to our understanding of speciation, the Aniakchak system of sockeye salmon provides a rare example of the initial stages of ecological divergence following natural colonization. Our results show that even in the face of continued migration, populations may diverge in the absence of a physical barrier.

Recent ecological divergence despite migration in sockeye salmon (Oncorhynchus nerka)

USGS Publications Warehouse

Pavey, Scott A.; Nielsen, Jennifer L.; Hamon, Troy R.

2010-01-01

Ecological divergence may result when populations experience different selection regimes, but there is considerable discussion about the role of migration at the beginning stages of divergence before reproductive isolating mechanisms have evolved. However, detection of past migration is difficult in current populations and tools to differentiate genetic similarities due to migration versus recent common ancestry are only recently available. Using past volcanic eruption times as a framework, we combine morphological analyses of traits important to reproduction with a coalescent-based genetic analysis of two proximate sockeye salmon (Oncorhynchus nerka) populations. We find that this is the most recent (~500 years, 100 generations) natural ecological divergence recorded in a fish species, and report that this divergence is occurring despite migration. Although studies of fish divergence following the retreat of glaciers (10,000–15,000 years ago) have contributed extensively to our understanding of speciation, the Aniakchak system of sockeye salmon provides a rare example of the initial stages of ecological divergence following natural colonization. Our results show that even in the face of continued migration, populations may diverge in the absence of a physical barrier.

Total Bregman Divergence and its Applications to Shape Retrieval.

PubMed

Liu, Meizhu; Vemuri, Baba C; Amari, Shun-Ichi; Nielsen, Frank

2010-01-01

Shape database search is ubiquitous in the world of biometric systems, CAD systems etc. Shape data in these domains is experiencing an explosive growth and usually requires search of whole shape databases to retrieve the best matches with accuracy and efficiency for a variety of tasks. In this paper, we present a novel divergence measure between any two given points in [Formula: see text] or two distribution functions. This divergence measures the orthogonal distance between the tangent to the convex function (used in the definition of the divergence) at one of its input arguments and its second argument. This is in contrast to the ordinate distance taken in the usual definition of the Bregman class of divergences [4]. We use this orthogonal distance to redefine the Bregman class of divergences and develop a new theory for estimating the center of a set of vectors as well as probability distribution functions. The new class of divergences are dubbed the total Bregman divergence (TBD). We present the l 1 -norm based TBD center that is dubbed the t-center which is then used as a cluster center of a class of shapes The t-center is weighted mean and this weight is small for noise and outliers. We present a shape retrieval scheme using TBD and the t-center for representing the classes of shapes from the MPEG-7 database and compare the results with other state-of-the-art methods in literature.

Genomic characterization of a new endophytic Streptomyces kebangsaanensis identifies biosynthetic pathway gene clusters for novel phenazine antibiotic production

PubMed Central

Remali, Juwairiah; Sarmin, Nurul ‘Izzah Mohd; Ng, Chyan Leong; Tiong, John J.L.; Aizat, Wan M.; Keong, Loke Kok

2017-01-01

Background Streptomyces are well known for their capability to produce many bioactive secondary metabolites with medical and industrial importance. Here we report a novel bioactive phenazine compound, 6-((2-hydroxy-4-methoxyphenoxy) carbonyl) phenazine-1-carboxylic acid (HCPCA) extracted from Streptomyces kebangsaanensis, an endophyte isolated from the ethnomedicinal Portulaca oleracea. Methods The HCPCA chemical structure was determined using nuclear magnetic resonance spectroscopy. We conducted whole genome sequencing for the identification of the gene cluster(s) believed to be responsible for phenazine biosynthesis in order to map its corresponding pathway, in addition to bioinformatics analysis to assess the potential of S. kebangsaanensis in producing other useful secondary metabolites. Results The S. kebangsaanensis genome comprises an 8,328,719 bp linear chromosome with high GC content (71.35%) consisting of 12 rRNA operons, 81 tRNA, and 7,558 protein coding genes. We identified 24 gene clusters involved in polyketide, nonribosomal peptide, terpene, bacteriocin, and siderophore biosynthesis, as well as a gene cluster predicted to be responsible for phenazine biosynthesis. Discussion The HCPCA phenazine structure was hypothesized to derive from the combination of two biosynthetic pathways, phenazine-1,6-dicarboxylic acid and 4-methoxybenzene-1,2-diol, originated from the shikimic acid pathway. The identification of a biosynthesis pathway gene cluster for phenazine antibiotics might facilitate future genetic engineering design of new synthetic phenazine antibiotics. Additionally, these findings confirm the potential of S. kebangsaanensis for producing various antibiotics and secondary metabolites. PMID:29201559

A Novel Hydrolase Identified by Genomic-Proteomic Analysis of Phenylurea Herbicide Mineralization by Variovorax sp. Strain SRS16▿†

PubMed Central

Bers, Karolien; Leroy, Baptiste; Breugelmans, Philip; Albers, Pieter; Lavigne, Rob; Sørensen, Sebastian R.; Aamand, Jens; De Mot, René; Wattiez, Ruddy; Springael, Dirk

2011-01-01

The soil bacterial isolate Variovorax sp. strain SRS16 mineralizes the phenylurea herbicide linuron. The proposed pathway initiates with hydrolysis of linuron to 3,4-dichloroaniline (DCA) and N,O-dimethylhydroxylamine, followed by conversion of DCA to Krebs cycle intermediates. Differential proteomic analysis showed a linuron-dependent upregulation of several enzymes that fit into this pathway, including an amidase (LibA), a multicomponent chloroaniline dioxygenase, and enzymes associated with a modified chlorocatechol ortho-cleavage pathway. Purified LibA is a monomeric linuron hydrolase of ∼55 kDa with a Km and a Vmax for linuron of 5.8 μM and 0.16 nmol min−1, respectively. This novel member of the amidase signature family is unrelated to phenylurea-hydrolyzing enzymes from Gram-positive bacteria and lacks activity toward other tested phenylurea herbicides. Orthologues of libA are present in all other tested linuron-degrading Variovorax strains with the exception of Variovorax strains WDL1 and PBS-H4, suggesting divergent evolution of the linuron catabolic pathway in different Variovorax strains. The organization of the linuron degradation genes identified in the draft SRS16 genome sequence indicates that gene patchwork assembly is at the origin of the pathway. Transcription analysis suggests that a catabolic intermediate, rather than linuron itself, acts as effector in activation of the pathway. Our study provides the first report on the genetic organization of a bacterial pathway for complete mineralization of a phenylurea herbicide and the first report on a linuron hydrolase in Gram-negative bacteria. PMID:22003008

Tracing ancient evolutionary divergence in parasites.

PubMed

Tinsley, Richard C; Tinsley, Matthew C

2016-12-01

For parasitic platyhelminths that generally lack a fossil record, there is little information on the pathways of morphological change during evolution. Polystomatid monogeneans are notable for their evolutionary diversification, having originated from ancestors on fish and radiated in parallel with tetrapod vertebrates over more than 425 million years (My). This study focuses on the genus Polystomoides that occurs almost worldwide on freshwater chelonian reptiles. Morphometric data show a major divergence in structural adaptations for attachment; this correlates with a dichotomy in micro-environmental conditions in habitats within the hosts. Species infecting the urinary tract have attachment organs with large hamuli and small suckers; species in the oro-nasal tract differ fundamentally, having small hamuli and large suckers. Zoogeographical and molecular evidence supports ancient separation of these site-specific clades: a new genus is proposed - Uropolystomoides - containing urinary tract species distinct from Polystomoides sensu stricto in oro-nasal sites. Aside from differences in attachment adaptations, body plans have probably changed little over perhaps 150 My. This case contrasts markedly with polystomatids in other vertebrate groups where major morphological changes have evolved over much shorter timescales; the chelonian parasites show highly stable morphology across their global distribution over a long period of evolution, exemplifying 'living fossils'.

Three Divergent Subpopulations of the Malaria Parasite Plasmodium knowlesi

PubMed Central

Lin, Lee C.; Rovie-Ryan, Jeffrine J.; Kadir, Khamisah A.; Anderios, Fread; Hisam, Shamilah; Sharma, Reuben S.K.; Singh, Balbir; Conway, David J.

2017-01-01

Multilocus microsatellite genotyping of Plasmodium knowlesi isolates previously indicated 2 divergent parasite subpopulations in humans on the island of Borneo, each associated with a different macaque reservoir host species. Geographic divergence was also apparent, and independent sequence data have indicated particularly deep divergence between parasites from mainland Southeast Asia and Borneo. To resolve the overall population structure, multilocus microsatellite genotyping was conducted on a new sample of 182 P. knowlesi infections (obtained from 134 humans and 48 wild macaques) from diverse areas of Malaysia, first analyzed separately and then in combination with previous data. All analyses confirmed 2 divergent clusters of human cases in Malaysian Borneo, associated with long-tailed macaques and pig-tailed macaques, and a third cluster in humans and most macaques in peninsular Malaysia. High levels of pairwise divergence between each of these sympatric and allopatric subpopulations have implications for the epidemiology and control of this zoonotic species. PMID:28322705

Comparing Multiple Criteria for Species Identification in Two Recently Diverged Seabirds

PubMed Central

Militão, Teresa; Gómez-Díaz, Elena; Kaliontzopoulou, Antigoni; González-Solís, Jacob

2014-01-01

Correct species identification is a crucial issue in systematics with key implications for prioritising conservation effort. However, it can be particularly challenging in recently diverged species due to their strong similarity and relatedness. In such cases, species identification requires multiple and integrative approaches. In this study we used multiple criteria, namely plumage colouration, biometric measurements, geometric morphometrics, stable isotopes analysis (SIA) and genetics (mtDNA), to identify the species of 107 bycatch birds from two closely related seabird species, the Balearic (Puffinus mauretanicus) and Yelkouan (P. yelkouan) shearwaters. Biometric measurements, stable isotopes and genetic data produced two stable clusters of bycatch birds matching the two study species, as indicated by reference birds of known origin. Geometric morphometrics was excluded as a species identification criterion since the two clusters were not stable. The combination of plumage colouration, linear biometrics, stable isotope and genetic criteria was crucial to infer the species of 103 of the bycatch specimens. In the present study, particularly SIA emerged as a powerful criterion for species identification, but temporal stability of the isotopic values is critical for this purpose. Indeed, we found some variability in stable isotope values over the years within each species, but species differences explained most of the variance in the isotopic data. Yet this result pinpoints the importance of examining sources of variability in the isotopic data in a case-by-case basis prior to the cross-application of the SIA approach to other species. Our findings illustrate how the integration of several methodological approaches can help to correctly identify individuals from recently diverged species, as each criterion measures different biological phenomena and species divergence is not expressed simultaneously in all biological traits. PMID:25541978

Experimentally-Derived Fibroblast Gene Signatures Identify Molecular Pathways Associated with Distinct Subsets of Systemic Sclerosis Patients in Three Independent Cohorts

PubMed Central

Johnson, Michael E.; Mahoney, J. Matthew; Taroni, Jaclyn; Sargent, Jennifer L.; Marmarelis, Eleni; Wu, Ming-Ru; Varga, John; Hinchcliff, Monique E.; Whitfield, Michael L.

2015-01-01

Genome-wide expression profiling in systemic sclerosis (SSc) has identified four ‘intrinsic’ subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling. PMID:25607805

SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology.

PubMed

Shimano, Hitoshi; Sato, Ryuichiro

2017-12-01

Cellular lipid metabolism and homeostasis are controlled by sterol regulatory-element binding proteins (SREBPs). In addition to performing canonical functions in the transcriptional regulation of genes involved in the biosynthesis and uptake of lipids, genome-wide system analyses have revealed that these versatile transcription factors act as important nodes of convergence and divergence within biological signalling networks. Thus, they are involved in myriad physiological and pathophysiological processes, highlighting the importance of lipid metabolism in biology. Changes in cell metabolism and growth are reciprocally linked through SREBPs. Anabolic and growth signalling pathways branch off and connect to multiple steps of SREBP activation and form complex regulatory networks. In addition, SREBPs are implicated in numerous pathogenic processes such as endoplasmic reticulum stress, inflammation, autophagy and apoptosis, and in this way, they contribute to obesity, dyslipidaemia, diabetes mellitus, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, neurodegenerative diseases and cancers. This Review aims to provide a comprehensive understanding of the role of SREBPs in physiology and pathophysiology at the cell, organ and organism levels.

The Pathway Coexpression Network: Revealing pathway relationships

PubMed Central

Tanzi, Rudolph E.

2018-01-01

A goal of genomics is to understand the relationships between biological processes. Pathways contribute to functional interplay within biological processes through complex but poorly understood interactions. However, limited functional references for global pathway relationships exist. Pathways from databases such as KEGG and Reactome provide discrete annotations of biological processes. Their relationships are currently either inferred from gene set enrichment within specific experiments, or by simple overlap, linking pathway annotations that have genes in common. Here, we provide a unifying interpretation of functional interaction between pathways by systematically quantifying coexpression between 1,330 canonical pathways from the Molecular Signatures Database (MSigDB) to establish the Pathway Coexpression Network (PCxN). We estimated the correlation between canonical pathways valid in a broad context using a curated collection of 3,207 microarrays from 72 normal human tissues. PCxN accounts for shared genes between annotations to estimate significant correlations between pathways with related functions rather than with similar annotations. We demonstrate that PCxN provides novel insight into mechanisms of complex diseases using an Alzheimer’s Disease (AD) case study. PCxN retrieved pathways significantly correlated with an expert curated AD gene list. These pathways have known associations with AD and were significantly enriched for genes independently associated with AD. As a further step, we show how PCxN complements the results of gene set enrichment methods by revealing relationships between enriched pathways, and by identifying additional highly correlated pathways. PCxN revealed that correlated pathways from an AD expression profiling study include functional clusters involved in cell adhesion and oxidative stress. PCxN provides expanded connections to pathways from the extracellular matrix. PCxN provides a powerful new framework for interrogation of

Phylogenetic divergence of cell biological features

PubMed Central

2018-01-01

Most cellular features have a range of states, but understanding the mechanisms responsible for interspecific divergence is a challenge for evolutionary cell biology. Models are developed for the distribution of mean phenotypes likely to evolve under the joint forces of mutation and genetic drift in the face of constant selection pressures. Mean phenotypes will deviate from optimal states to a degree depending on the effective population size, potentially leading to substantial divergence in the absence of diversifying selection. The steady-state distribution for the mean can even be bimodal, with one domain being largely driven by selection and the other by mutation pressure, leading to the illusion of phenotypic shifts being induced by movement among alternative adaptive domains. These results raise questions as to whether lineage-specific selective pressures are necessary to account for interspecific divergence, providing a possible platform for the establishment of null models for the evolution of cell-biological traits. PMID:29927740

Using Ambystoma mexicanum (Mexican Axolotl) Embryos, Chemical Genetics, and Microarray Analysis to Identify Signaling Pathways Associated with Tissue Regeneration

PubMed Central

Ponomareva, Larissa V.; Athippozhy, Antony; Thorson, Jon S.; Voss, S. Randal

2015-01-01

Amphibian vertebrates are important models in regenerative biology because they present exceptional regenerative capabilities throughout life. However, it takes considerable effort to rear amphibians to juvenile and adult stages for regeneration studies and the relatively large sizes that frogs and salamanders achieve during development make them difficult to use in chemical screens. Here we introduce a new tail regeneration model using late stage Mexican axolotl embryos. We show that axolotl embryos completely regenerate amputated tails in 7 days before they exhaust their yolk supply and begin to feed. Further, we show that axolotl embryos can be efficiently reared in microtiter plates to achieve moderate throughput screening of soluble chemicals to investigate toxicity and identify molecules that alter regenerative outcome. As proof of principle, we identified integration 1 / wingless (Wnt), transforming growth factor beta (Tgf-β), and fibroblast growth factor (Fgf) pathway antagonists that completely block tail regeneration and additional chemicals that significantly affected tail outgrowth. Furthermore, we used microarray analysis to show that inhibition of Wnt signaling broadly affects transcription of genes associated with Wnt, Fgf, Tgf-β, epidermal growth factor (Egf), Notch, nerve growth factor (Ngf), homeotic gene (Hox), rat sarcoma/mitogen-activated protein kinase (Ras/Mapk), myelocytomatosis viral oncogene (Myc), tumor protein 53 (p53), and retinoic acid (RA) pathways. Punctuated changes in the expression of genes known to regulate vertebrate development were observed; this suggests the tail regeneration transcriptional program is hierarchically structured and temporally ordered. Our study establishes the axolotl as a chemical screening model to investigate signaling pathways associated with tissue regeneration. PMID:26092703

Pathway to care for drug resistant tuberculosis cases identified during a retrospective study conducted in high TB burden wards in Mumbai.

PubMed

Lobo, Eunice; Shah, Shimoni; Rangan, Sheela; Dholakia, Yatin; Mistry, Nerges

2018-05-10

Background: Mumbai is witnessing a rising incidence of all forms of drug resistant tuberculosis (DR-TB). Methods: A population-based, retrospective study was conducted between April and July 2014, in 15 high TB burden wards in Mumbai, to capture the patient pathways to TB care. A total of 23 DR-TB patients were identified and their pathways to access DR-TB care were recorded using semi-structured interviews. Results: The total DR-TB pathway time of new patients (who did not report any past episode of TB) (180 days; IQR 123,346) was found to be more than twice that of retreatment patients (who reported a past episode of TB) (69 days; IQR 42,128). Conclusions: The unacceptable delay for diagnosis and treatment of DR-TB in Mumbai advocates for consistent implementation of early screening of patients using rapid gene-based technologies.

Sequence divergence in the 3'-untranslated region has an effect on the subfunctionalization of duplicate genes.

PubMed

Tong, Ying; Zheng, Kang; Zhao, Shufang; Xiao, Guanxiu; Luo, Chen

2012-11-01

Recent studies demonstrated that sequence divergence in both transcriptional regulatory region and coding region contributes to the subfunctionalization of duplicate gene. However, whether sequence divergence in the 3'-untranslated region (3'-UTR) has an impact on the subfunctionalization of duplicate genes remains unclear. Here, we identified two diverging duplicate vsx1 (visual system homeobox-1) loci in goldfish, named vsx1A1 and vsx1A2. Phylogenetic analysis suggests that vsx1A1 and vsx1A2 may arise from a duplication of vsx1 after the separation of goldfish and zebrafish. Sequence comparison revealed that divergence in both transcriptional and translational regulatory regions is higher than divergence in the introns. vsx1A2 expresses during blastula and gastrula stages and in adult retina but silences from segmentation stage to hatching stage, vsx1A1 starts expression from segmentation onward. Comparing to that zebrafish vsx1 expresses in all the developmental stages and in the adult retina, it appears that goldfish vsx1A1 and vsx1A2 are under going to share the functions of ancestral vsx1. The different but overlapping temporal expression patterns of vsx1A1 and vsx1A2 suggest that sequence divergence in the promoter region of duplicate vsx1 is not sufficient for partitioning the functions of ancestral vsx1. By comparing vsx1A1 and vsx1A2 3'-UTR-linked green fluorescent protein gene expression patterns, we demonstrated that the 3'-UTR of vsx1A1 remains but the 3'-UTR of vsx1A2 has lost the capability of mediating bipolar cell specific expression during retina development. These results indicate that sequence divergence in the 3'-UTRs has a clear effect on subfunctionalization of the duplicate genes. © 2012 WILEY PERIODICALS, INC.

Comparative functional characterization of the CSR-1 22G-RNA pathway in Caenorhabditis nematodes

PubMed Central

Tu, Shikui; Wu, Monica Z.; Wang, Jie; Cutter, Asher D.; Weng, Zhiping; Claycomb, Julie M.

2015-01-01

As a champion of small RNA research for two decades, Caenorhabditis elegans has revealed the essential Argonaute CSR-1 to play key nuclear roles in modulating chromatin, chromosome segregation and germline gene expression via 22G-small RNAs. Despite CSR-1 being preserved among diverse nematodes, the conservation and divergence in function of the targets of small RNA pathways remains poorly resolved. Here we apply comparative functional genomic analysis between C. elegans and Caenorhabditis briggsae to characterize the CSR-1 pathway, its targets and their evolution. C. briggsae CSR-1-associated small RNAs that we identified by immunoprecipitation-small RNA sequencing overlap with 22G-RNAs depleted in cbr-csr-1 RNAi-treated worms. By comparing 22G-RNAs and target genes between species, we defined a set of CSR-1 target genes with conserved germline expression, enrichment in operons and more slowly evolving coding sequences than other genes, along with a small group of evolutionarily labile targets. We demonstrate that the association of CSR-1 with chromatin is preserved, and show that depletion of cbr-csr-1 leads to chromosome segregation defects and embryonic lethality. This first comparative characterization of a small RNA pathway in Caenorhabditis establishes a conserved nuclear role for CSR-1 and highlights its key role in germline gene regulation across multiple animal species. PMID:25510497

Pathway enrichment analysis approach based on topological structure and updated annotation of pathway.

PubMed

Yang, Qian; Wang, Shuyuan; Dai, Enyu; Zhou, Shunheng; Liu, Dianming; Liu, Haizhou; Meng, Qianqian; Jiang, Bin; Jiang, Wei

2017-08-16

Pathway enrichment analysis has been widely used to identify cancer risk pathways, and contributes to elucidating the mechanism of tumorigenesis. However, most of the existing approaches use the outdated pathway information and neglect the complex gene interactions in pathway. Here, we first reviewed the existing widely used pathway enrichment analysis approaches briefly, and then, we proposed a novel topology-based pathway enrichment analysis (TPEA) method, which integrated topological properties and global upstream/downstream positions of genes in pathways. We compared TPEA with four widely used pathway enrichment analysis tools, including database for annotation, visualization and integrated discovery (DAVID), gene set enrichment analysis (GSEA), centrality-based pathway enrichment (CePa) and signaling pathway impact analysis (SPIA), through analyzing six gene expression profiles of three tumor types (colorectal cancer, thyroid cancer and endometrial cancer). As a result, we identified several well-known cancer risk pathways that could not be obtained by the existing tools, and the results of TPEA were more stable than that of the other tools in analyzing different data sets of the same cancer. Ultimately, we developed an R package to implement TPEA, which could online update KEGG pathway information and is available at the Comprehensive R Archive Network (CRAN): https://cran.r-project.org/web/packages/TPEA/. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhir

Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl{sub 4})-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl{sub 4} (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day formore » 3 weeks) and with continued CCl{sub 4}. We observed that combined treatment with CCl{sub 4} and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis.« less

Divergence between human populations estimated from linkage disequilibrium.

PubMed

Sved, John A; McRae, Allan F; Visscher, Peter M

2008-12-01

Observed linkage disequilibrium (LD) between genetic markers in different populations descended independently from a common ancestral population can be used to estimate their absolute time of divergence, because the correlation of LD between populations will be reduced each generation by an amount that, approximately, depends only on the recombination rate between markers. Although drift leads to divergence in allele frequencies, it has less effect on divergence in LD values. We derived the relationship between LD and time of divergence and verified it with coalescent simulations. We then used HapMap Phase II data to estimate time of divergence between human populations. Summed over large numbers of pairs of loci, we find a positive correlation of LD between African and non-African populations at levels of up to approximately 0.3 cM. We estimate that the observed correlation of LD is consistent with an effective separation time of approximately 1,000 generations or approximately 25,000 years before present. The most likely explanation for such relatively low separation times is the existence of substantial levels of migration between populations after the initial separation. Theory and results from coalescent simulations confirm that low levels of migration can lead to a downward bias in the estimate of separation time.

A stratified transcriptomics analysis of polygenic fat and lean mouse adipose tissues identifies novel candidate obesity genes.

PubMed

Morton, Nicholas M; Nelson, Yvonne B; Michailidou, Zoi; Di Rollo, Emma M; Ramage, Lynne; Hadoke, Patrick W F; Seckl, Jonathan R; Bunger, Lutz; Horvat, Simon; Kenyon, Christopher J; Dunbar, Donald R

2011-01-01

Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain. To enrich for adipose tissue obesity genes a 'snap-shot' pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity. A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity.

Evolution and functional divergence of the anoctamin family of membrane proteins

PubMed Central

2010-01-01

Background The anoctamin family of transmembrane proteins are found in all eukaryotes and consists of 10 members in vertebrates. Ano1 and ano2 were observed to have Ca2+ activated Cl- channel activity. Recent findings however have revealed that ano6, and ano7 can also produce chloride currents, although with different properties. In contrast, ano9 and ano10 suppress baseline Cl- conductance when co-expressed with ano1 thus suggesting that different anoctamins can interfere with each other. In order to elucidate intrinsic functional diversity, and underlying evolutionary mechanism among anoctamins, we performed comprehensive bioinformatics analysis of anoctamin gene family. Results Our results show that anoctamin protein paralogs evolved from several gene duplication events followed by functional divergence of vertebrate anoctamins. Most of the amino acid replacements responsible for the functional divergence were fixed by adaptive evolution and this seem to be a common pattern in anoctamin gene family evolution. Strong purifying selection and the loss of many gene duplication products indicate rigid structure-function relationships among anoctamins. Conclusions Our study suggests that anoctamins have evolved by series of duplication events, and that they are constrained by purifying selection. In addition we identified a number of protein domains, and amino acid residues which contribute to predicted functional divergence. Hopefully, this work will facilitate future functional characterization of the anoctamin membrane protein family. PMID:20964844

EDdb: a web resource for eating disorder and its application to identify an extended adipocytokine signaling pathway related to eating disorder.

PubMed

Zhao, Min; Li, XiaoMo; Qu, Hong

2013-12-01

Eating disorder is a group of physiological and psychological disorders affecting approximately 1% of the female population worldwide. Although the genetic epidemiology of eating disorder is becoming increasingly clear with accumulated studies, the underlying molecular mechanisms are still unclear. Recently, integration of various high-throughput data expanded the range of candidate genes and started to generate hypotheses for understanding potential pathogenesis in complex diseases. This article presents EDdb (Eating Disorder database), the first evidence-based gene resource for eating disorder. Fifty-nine experimentally validated genes from the literature in relation to eating disorder were collected as the core dataset. Another four datasets with 2824 candidate genes across 601 genome regions were expanded based on the core dataset using different criteria (e.g., protein-protein interactions, shared cytobands, and related complex diseases). Based on human protein-protein interaction data, we reconstructed a potential molecular sub-network related to eating disorder. Furthermore, with an integrative pathway enrichment analysis of genes in EDdb, we identified an extended adipocytokine signaling pathway in eating disorder. Three genes in EDdb (ADIPO (adiponectin), TNF (tumor necrosis factor) and NR3C1 (nuclear receptor subfamily 3, group C, member 1)) link the KEGG (Kyoto Encyclopedia of Genes and Genomes) "adipocytokine signaling pathway" with the BioCarta "visceral fat deposits and the metabolic syndrome" pathway to form a joint pathway. In total, the joint pathway contains 43 genes, among which 39 genes are related to eating disorder. As the first comprehensive gene resource for eating disorder, EDdb ( http://eddb.cbi.pku.edu.cn ) enables the exploration of gene-disease relationships and cross-talk mechanisms between related disorders. Through pathway statistical studies, we revealed that abnormal body weight caused by eating disorder and obesity may both be

Divergent and convergent roles for insulin-like peptides in the worm, fly and mammalian nervous systems.

PubMed

Lau, Hiu E; Chalasani, Sreekanth H

2014-09-01

Insulin signaling plays a critical role in coupling external changes to animal physiology and behavior. Despite remarkable conservation in the insulin signaling pathway components across species, divergence in the mechanism and function of the signal is evident. Focusing on recent findings from C. elegans, D. melanogaster and mammals, we discuss the role of insulin signaling in regulating adult neuronal function and behavior. In particular, we describe the transcription-dependent and transcription-independent aspects of insulin signaling across these three species. Interestingly, we find evidence of diverse mechanisms underlying complex networks of peptide action in modulating nervous system function.

Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor

PubMed Central

Killian, J. Keith; Kim, Su Young; Miettinen, Markku; Smith, Carly; Merino, Maria; Tsokos, Maria; Quezado, Martha; Smith, William I.; Jahromi, Mona S.; Xekouki, Paraskevi; Szarek, Eva; Walker, Robert L.; Lasota, Jerzy; Raffeld, Mark; Klotzle, Brandy; Wang, Zengfeng; Jones, Laura; Zhu, Yuelin; Wang, Yonghong; Waterfall, Joshua J.; O’Sullivan, Maureen J.; Bibikova, Marina; Pacak, Karel; Stratakis, Constantine; Janeway, Katherine A.; Schiffman, Joshua D.; Fan, Jian-Bing; Helman, Lee; Meltzer, Paul S.

2014-01-01

Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT, or, alternatively, manifest loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle and electron transport chain. We have uncovered a striking divergence between the DNA methylation profiles of SDH-deficient GIST (n = 24) versus KIT tyrosine kinase pathway–mutated GIST (n = 39). Infinium 450K methylation array analysis of formalin-fixed paraffin-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-deficient GIST versus the KIT-mutant group (84.9 K vs. 8.4 K targets). Epigenomic divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (n = 29), a developmentally distinct SDH-deficient tumor system. Comparison of SDH -mutant GIST with isocitrate dehydrogenase -mutant glioma, another Krebs cycle–defective tumor type, revealed comparable measures of global hypo- and hypermethylation. These data expose a vital connection between succinate metabolism and genomic DNA methylation during tumorigenesis, and generally implicate the mitochondrial Krebs cycle in nuclear epigenomic maintenance. SIGNIFICANCE This study shows that SDH deficiency underlies pervasive DNA hypermethylation in multiple tumor lineages, generally defining the Krebs cycle as mitochondrial custodian of the methylome. We propose that this phenomenon may result from a failure of maintenance CpG demethylation, secondary to inhibition of the TET 5-methylcytosine dioxgenase demethylation pathway, by inhibitory metabolites that accumulate in tumors with Krebs cycle dysfunction. PMID:23550148

The Evolution of Ribosomal DNA: Divergent Paralogues and Phylogenetic Implications

PubMed Central

Buckler-IV, E. S.; Ippolito, A.; Holtsford, T. P.

1997-01-01

Although nuclear ribosomal DNA (rDNA) repeats evolve together through concerted evolution, some genomes contain a considerable diversity of paralogous rDNA. This diversity includes not only multiple functional loci but also putative pseudogenes and recombinants. We examined the occurrence of divergent paralogues and recombinants in Gossypium, Nicotiana, Tripsacum, Winteraceae, and Zea ribosomal internal transcribed spacer (ITS) sequences. Some of the divergent paralogues are probably rDNA pseudogenes, since they have low predicted secondary structure stability, high substitution rates, and many deamination-driven substitutions at methylation sites. Under standard PCR conditions, the low stability paralogues amplified well, while many high-stability paralogues amplified poorly. Under highly denaturing PCR conditions (i.e., with dimethylsulfoxide), both low- and high-stability paralogues amplified well. We also found recombination between divergent paralogues. For phylogenetics, divergent ribosomal paralogues can aid in reconstructing ancestral states and thus serve as good outgroups. Divergent paralogues can also provide companion rDNA phylogenies. However, phylogeneticists must discriminate among families of divergent paralogues and recombinants or suffer from muddled and inaccurate organismal phylogenies. PMID:9055091

Divergent modes of enzyme inhibition in a homologous structure-activity series.

PubMed

Ferreira, Rafaela S; Bryant, Clifford; Ang, Kenny K H; McKerrow, James H; Shoichet, Brian K; Renslo, Adam R

2009-08-27

A docking screen identified reversible, noncovalent inhibitors (e.g., 1) of the parasite cysteine protease cruzain. Chemical optimization of 1 led to a series of oxadiazoles possessing interpretable SAR and potencies as much as 500-fold greater than 1. Detailed investigation of the SAR series subsequently revealed that many members of the oxadiazole class (and surprisingly also 1) act via divergent modes of inhibition (competitive or via colloidal aggregation) depending on the assay conditions employed.

Island biology and morphological divergence of the Skyros wall lizard Podarcis gaigeae: a combined role for local selection and genetic drift on color morph frequency divergence?

PubMed Central

2010-01-01

Background Patterns of spatial variation in discrete phenotypic traits can be used to draw inferences about the adaptive significance of traits and evolutionary processes, especially when compared to patterns of neutral genetic variation. Population divergence in adaptive traits such as color morphs can be influenced by both local ecology and stochastic factors such as genetic drift or founder events. Here, we use quantitative color measurements of males and females of Skyros wall lizard, Podarcis gaigeae, to demonstrate that this species is polymorphic with respect to throat color, and the morphs form discrete phenotypic clusters with limited overlap between categories. We use divergence in throat color morph frequencies and compare that to neutral genetic variation to infer the evolutionary processes acting on islet- and mainland populations. Results Geographically close islet- and mainland populations of the Skyros wall lizard exhibit strong divergence in throat color morph frequencies. Population variation in throat color morph frequencies between islets was higher than that between mainland populations, and the effective population sizes on the islets were small (Ne:s < 100). Population divergence (FST) for throat color morph frequencies fell within the neutral FST-distribution estimated from microsatellite markers, and genetic drift could thus not be rejected as an explanation for the pattern. Moreover, for both comparisons among mainland-mainland population pairs and between mainland-islet population pairs, morph frequency divergence was significantly correlated with neutral divergence, further pointing to some role for genetic drift in divergence also at the phenotypic level of throat color morphs. Conclusions Genetic drift could not be rejected as an explanation for the pattern of population divergence in morph frequencies. In spite of an expected stabilising selection, throat color frequencies diverged in the islet populations. These results suggest that

A transcriptome multi-tissue analysis identifies biological pathways and genes associated with variations in feed efficiency of growing pigs.

PubMed

Gondret, Florence; Vincent, Annie; Houée-Bigot, Magalie; Siegel, Anne; Lagarrigue, Sandrine; Causeur, David; Gilbert, Hélène; Louveau, Isabelle

2017-03-21

Animal's efficiency in converting feed into lean gain is a critical issue for the profitability of meat industries. This study aimed to describe shared and specific molecular responses in different tissues of pigs divergently selected over eight generations for residual feed intake (RFI). Pigs from the low RFI line had an improved gain-to-feed ratio during the test period and displayed higher leanness but similar adiposity when compared with pigs from the high RFI line at 132 days of age. Transcriptomics data were generated from longissimus muscle, liver and two adipose tissues using a porcine microarray and analyzed for the line effect (n = 24 pigs per line). The most apparent effect of the line was seen in muscle, whereas subcutaneous adipose tissue was the less affected tissue. Molecular data were analyzed by bioinformatics and subjected to multidimensional statistics to identify common biological processes across tissues and key genes participating to differences in the genetics of feed efficiency. Immune response, response to oxidative stress and protein metabolism were the main biological pathways shared by the four tissues that distinguished pigs from the low or high RFI lines. Many immune genes were under-expressed in the four tissues of the most efficient pigs. The main genes contributing to difference between pigs from the low vs high RFI lines were CD40, CTSC and NTN1. Different genes associated with energy use were modulated in a tissue-specific manner between the two lines. The gene expression program related to glycogen utilization was specifically up-regulated in muscle of pigs from the low RFI line (more efficient). Genes involved in fatty acid oxidation were down-regulated in muscle but were promoted in adipose tissues of the same pigs when compared with pigs from the high RFI line (less efficient). This underlined opposite line-associated strategies for energy use in skeletal muscle and adipose tissue. Genes related to cholesterol synthesis

Sufficient Statistics for Divergence and the Probability of Misclassification

NASA Technical Reports Server (NTRS)

Quirein, J.

1972-01-01

One particular aspect is considered of the feature selection problem which results from the transformation x=Bz, where B is a k by n matrix of rank k and k is or = to n. It is shown that in general, such a transformation results in a loss of information. In terms of the divergence, this is equivalent to the fact that the average divergence computed using the variable x is less than or equal to the average divergence computed using the variable z. A loss of information in terms of the probability of misclassification is shown to be equivalent to the fact that the probability of misclassification computed using variable x is greater than or equal to the probability of misclassification computed using variable z. First, the necessary facts relating k-dimensional and n-dimensional integrals are derived. Then the mentioned results about the divergence and probability of misclassification are derived. Finally it is shown that if no information is lost (in x = Bz) as measured by the divergence, then no information is lost as measured by the probability of misclassification.

Probabilistic pathway construction.

PubMed

Yousofshahi, Mona; Lee, Kyongbum; Hassoun, Soha

2011-07-01

Expression of novel synthesis pathways in host organisms amenable to genetic manipulations has emerged as an attractive metabolic engineering strategy to overproduce natural products, biofuels, biopolymers and other commercially useful metabolites. We present a pathway construction algorithm for identifying viable synthesis pathways compatible with balanced cell growth. Rather than exhaustive exploration, we investigate probabilistic selection of reactions to construct the pathways. Three different selection schemes are investigated for the selection of reactions: high metabolite connectivity, low connectivity and uniformly random. For all case studies, which involved a diverse set of target metabolites, the uniformly random selection scheme resulted in the highest average maximum yield. When compared to an exhaustive search enumerating all possible reaction routes, our probabilistic algorithm returned nearly identical distributions of yields, while requiring far less computing time (minutes vs. years). The pathways identified by our algorithm have previously been confirmed in the literature as viable, high-yield synthesis routes. Prospectively, our algorithm could facilitate the design of novel, non-native synthesis routes by efficiently exploring the diversity of biochemical transformations in nature. Copyright © 2011 Elsevier Inc. All rights reserved.

Segmenting the human genome based on states of neutral genetic divergence.

PubMed

Kuruppumullage Don, Prabhani; Ananda, Guruprasad; Chiaromonte, Francesca; Makova, Kateryna D

2013-09-03

Many studies have demonstrated that divergence levels generated by different mutation types vary and covary across the human genome. To improve our still-incomplete understanding of the mechanistic basis of this phenomenon, we analyze several mutation types simultaneously, anchoring their variation to specific regions of the genome. Using hidden Markov models on insertion, deletion, nucleotide substitution, and microsatellite divergence estimates inferred from human-orangutan alignments of neutrally evolving genomic sequences, we segment the human genome into regions corresponding to different divergence states--each uniquely characterized by specific combinations of divergence levels. We then parsed the mutagenic contributions of various biochemical processes associating divergence states with a broad range of genomic landscape features. We find that high divergence states inhabit guanine- and cytosine (GC)-rich, highly recombining subtelomeric regions; low divergence states cover inner parts of autosomes; chromosome X forms its own state with lowest divergence; and a state of elevated microsatellite mutability is interspersed across the genome. These general trends are mirrored in human diversity data from the 1000 Genomes Project, and departures from them highlight the evolutionary history of primate chromosomes. We also find that genes and noncoding functional marks [annotations from the Encyclopedia of DNA Elements (ENCODE)] are concentrated in high divergence states. Our results provide a powerful tool for biomedical data analysis: segmentations can be used to screen personal genome variants--including those associated with cancer and other diseases--and to improve computational predictions of noncoding functional elements.

Highly divergent ancient gene families in metagenomic samples are compatible with additional divisions of life.

PubMed

Lopez, Philippe; Halary, Sébastien; Bapteste, Eric

2015-10-26

Microbial genetic diversity is often investigated via the comparison of relatively similar 16S molecules through multiple alignments between reference sequences and novel environmental samples using phylogenetic trees, direct BLAST matches, or phylotypes counts. However, are we missing novel lineages in the microbial dark universe by relying on standard phylogenetic and BLAST methods? If so, how can we probe that universe using alternative approaches? We performed a novel type of multi-marker analysis of genetic diversity exploiting the topology of inclusive sequence similarity networks. Our protocol identified 86 ancient gene families, well distributed and rarely transferred across the 3 domains of life, and retrieved their environmental homologs among 10 million predicted ORFs from human gut samples and other metagenomic projects. Numerous highly divergent environmental homologs were observed in gut samples, although the most divergent genes were over-represented in non-gut environments. In our networks, most divergent environmental genes grouped exclusively with uncultured relatives, in maximal cliques. Sequences within these groups were under strong purifying selection and presented a range of genetic variation comparable to that of a prokaryotic domain. Many genes families included environmental homologs that were highly divergent from cultured homologs: in 79 gene families (including 18 ribosomal proteins), Bacteria and Archaea were less divergent than some groups of environmental sequences were to any cultured or viral homologs. Moreover, some groups of environmental homologs branched very deeply in phylogenetic trees of life, when they were not too divergent to be aligned. These results underline how limited our understanding of the most diverse elements of the microbial world remains, and encourage a deeper exploration of natural communities and their genetic resources, hinting at the possibility that still unknown yet major divisions of life have yet to

Pathway to care for drug resistant tuberculosis cases identified during a retrospective study conducted in high TB burden wards in Mumbai

PubMed Central

Lobo, Eunice; Shah, Shimoni; Rangan, Sheela; Dholakia, Yatin; Mistry, Nerges

2018-01-01

Background: Mumbai is witnessing a rising incidence of all forms of drug resistant tuberculosis (DR-TB). Methods: A population-based, retrospective study was conducted between April and July 2014, in 15 high TB burden wards in Mumbai, to capture the patient pathways to TB care. A total of 23 DR-TB patients were identified and their pathways to access DR-TB care were recorded using semi-structured interviews. Results: The total DR-TB pathway time of new patients (who did not report any past episode of TB) (180 days; IQR 123,346) was found to be more than twice that of retreatment patients (who reported a past episode of TB) (69 days; IQR 42,128). Conclusions: The unacceptable delay for diagnosis and treatment of DR-TB in Mumbai advocates for consistent implementation of early screening of patients using rapid gene-based technologies. PMID:29863175

CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells

PubMed Central

Wilen, Craig; Gopal, Ramya; Huq, Rumana; Wu, Vernon; Sunseri, Nicole; Bhardwaj, Nina

2016-01-01

Plasmacytoid dendritic cells (pDC) are innate immune cells that sense viral nucleic acids through endosomal Toll-like receptor (TLR) 7/9 to produce type I interferon (IFN) and to differentiate into potent antigen presenting cells (APC). Engagement of TLR7/9 in early endosomes appears to trigger the IRF7 pathway for IFN production whereas engagement in lysosomes seems to trigger the NF-κB pathway for maturation into APC. We showed previously that HIV-1 (HIV) localizes predominantly to early endosomes, not lysosomes, and mainly stimulate IRF7 rather than NF-κB signaling pathways in pDC. This divergent signaling may contribute to disease progression through production of pro-apoptotic and pro-inflammatory IFN and inadequate maturation of pDCs. We now demonstrate that HIV virions may be re-directed to lysosomes for NF-κB signaling by either pseudotyping HIV with influenza hemagglutinin envelope or modification of CD4 mediated-intracellular trafficking. These data suggest that HIV envelope-CD4 receptor interactions drive pDC activation toward an immature IFN producing phenotype rather than differentiation into a mature dendritic cell phenotype. PMID:27082754

Integrated Proteomic and Transcriptomic-Based Approaches to Identifying Signature Biomarkers and Pathways for Elucidation of Daoy and UW228 Subtypes.

PubMed

Higdon, Roger; Kala, Jessie; Wilkins, Devan; Yan, Julia Fangfei; Sethi, Manveen K; Lin, Liang; Liu, Siqi; Montague, Elizabeth; Janko, Imre; Choiniere, John; Kolker, Natali; Hancock, William S; Kolker, Eugene; Fanayan, Susan

2017-02-03

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Patient survival has remained largely the same for the past 20 years, with therapies causing significant health, cognitive, behavioral and developmental complications for those who survive the tumor. In this study, we profiled the total transcriptome and proteome of two established MB cell lines, Daoy and UW228, using high-throughput RNA sequencing (RNA-Seq) and label-free nano-LC-MS/MS-based quantitative proteomics, coupled with advanced pathway analysis. While Daoy has been suggested to belong to the sonic hedgehog (SHH) subtype, the exact UW228 subtype is not yet clearly established. Thus, a goal of this study was to identify protein markers and pathways that would help elucidate their subtype classification. A number of differentially expressed genes and proteins, including a number of adhesion, cytoskeletal and signaling molecules, were observed between the two cell lines. While several cancer-associated genes/proteins exhibited similar expression across the two cell lines, upregulation of a number of signature proteins and enrichment of key components of SHH and WNT signaling pathways were uniquely observed in Daoy and UW228, respectively. The novel information on differentially expressed genes/proteins and enriched pathways provide insights into the biology of MB, which could help elucidate their subtype classification.

Divergent Effects of Arsenic on NF-κB Signaling in Different Cells or Tissues: A Systematic Review and Meta-Analysis.

PubMed

Wei, Meng; Liu, Jiaming; Xu, Mengchuan; Rui, Dongsheng; Xu, Shangzhi; Feng, Gangling; Ding, Yusong; Li, Shugang; Guo, Shuxia

2016-01-26

Arsenic is ubiquitously present in human lives, including in the environment and organisms, and has divergent effects between different cells and tissues and between different exposure times and doses. These observed effects have been attributed to the nuclear transcription factor kappa B(NF-κB) signaling pathway. Herein, a meta-analysis was performed by independently searching databases including the Cochrane Library, PubMed, Springer, Embase, and China National Knowledge Infrastructure, to analyze effects of arsenic exposure on NF-κB signaling. Compared to controls, in the exposed group, p-IκB levels were found to be 8.13-fold higher (95% CI, 2.40-13.85; Z = 2.78; p = 0.005), IκB levels were 16.19-fold lower (95% CI, -27.44--4.94; Z = 2.78; p = 0.005), and NF-κBp65 levels were 0.77-fold higher (95% CI, 0.13-1.42; Z = 2.34; p = 0.02) for normal cells and tissue, while NF-κBp65 levels were 4.90-fold lower (95% CI, -8.49-1.31; Z = 2.62; p = 0.009), NF-κB activity was 2.45-fold lower (95% CI, -3.66-1.25; Z = 4.00; p < 0.0001), and DNA-binding activity of NF-κB was 9.75-fold lower (95% CI, -18.66-4.54; Z = 2.15; p = 0.03) for abnormal cells and tissue. Short exposure to high arsenic doses activated the NF-κB signaling pathway, while long exposure to low arsenic doses suppressed NF-κB signaling pathway activation. These findings may provide a theoretical basis for injurious and therapeutic mechanisms of divergent effects of arsenic.

The role of immunohistochemistry in medullomyoblastoma--a case series highlighting divergent differentiation.

PubMed

Sachdeva, Man Updesh S; Vankalakunti, Mahesha; Rangan, Aruna; Radotra, Bishan D; Chhabra, Rajesh; Vasishta, Rakesh K

2008-04-25

To analyse the histo-morphology of cases of medullomyoblastoma and identifying its divergent differentiation. A retrospective review of all cases reported as medulloblastoma between the period of Jan 2000 to Dec 2006 was carried out on Hematoxylin and eosin (H & E) stained slides. The cases were screened on light microscopy for primitive neuroectodermal component of a medulloblastoma accompanied by areas of "myoid" differentiation, identified on the basis of presence of strap cells (indicating a clear skeletal muscle differentiation) and/or large anaplastic cells with vescicular nuclei and moderate to abundant amount of eosinophilic cytoplasm. All these cases were subjected to a panel of immunohistochemical stains, including Desmin, GFAP, NFP, HMB45, SMA, S100, CK and EMA. Ultrastructural analysis was done on tissue obtained from paraffin blocks in 2 cases. Male predominance (M:F = 5:1) was noted with an incidence of five percent of all cases of medulloblastoma (6 out of 120 cases) over a period of 6 years. Primitive neuroectodermal areas were accompanied with areas of "myoid" differentiation, 5 cases showing strap cells. Two cases with epithelial and cartilaginous differentiation were seen. Three cases showed focal melanocytic differentiation, identified only on HMB45 immunostaining. Four cases showed glial differentiation. Neuronal differentiation again was very focally seen in two cases, of which one was identified only by NFP immunostain. Seventh case is included in the study, however it is not considered to calculate incidence as it occurred beyond the period of 6 years of records search. Medullomyoblastoma is a rare childhood tumor of cerebellum. Majority of cases reveal divergent differentiation, which are identified with the help of panel of immunostains indicating multi-potential nature of primitive neuroectodermal cells.

Sensory specificity and speciation: a potential neuronal pathway for host fruit odour discrimination in Rhagoletis pomonella

PubMed Central

Batra, Srishti; Ramaswamy, Sree Subha; Feder, Jeffrey L.

2016-01-01

Behavioural changes in habitat or mate choice can trigger population divergence, leading to speciation. However, little is known about the neurological bases for such changes. Rhagoletis pomonella (Diptera: Tephritidae) is a model for ecological speciation via host plant shifts. Within the past 180 years, Rhagoletis flies infesting hawthorn (Crataegus spp.) shifted to attack domesticated apple (Malus pumila). The two populations differ in their olfactory preferences for apple versus hawthorn fruit. Here, we looked for patterns of sensory organization that may have contributed to this shift by characterizing the morphology, specificity and distribution of olfactory sensory neurons (OSNs) on the antennae of Rhagoletis responding to host fruit and non-host volatiles. Of 28 OSN classes identified, two colocalized OSN pairs were found that specifically responded to the major behavioural attractant and antagonist volatiles for each fly population. A reversal in the response of these OSNs to fruit volatiles, either through a switch in receptor expression between these paired neurons or changes in neuronal projections in the brain, could therefore account for the behavioural difference between apple and hawthorn flies. The finding supports the hypothesis that relatively minor changes in olfactory sensory pathways may contribute to rapid host shifting and divergence in Rhagoletis. PMID:28003447

Divergent host-plant use promotes reproductive isolation among cynipid gall wasp populations

PubMed Central

Egan, Scott P.; Hood, Glen R.; Feder, Jeff L.; Ott, James R.

2012-01-01

Ecological speciation occurs when reproductive isolation evolves as a consequence of divergent natural selection among environments. A direct prediction of this process is that ecologically divergent pairs of populations will exhibit greater reproductive isolation than ecologically similar pairs of populations. By comparing allopatric populations of the cynipid gall wasp Belonocnema treatae infesting Quercus virginiana and Quercus geminata, we tested the role that divergent host use plays in generating ecological divergence and sexual isolation. We found differences in body size and gall structure associated with divergent host use, but no difference in neutral genetic divergence between populations on the same or different host plant. We observed significant assortative mating between populations from alternative host plants but not between allopatric populations on the same host plant. Thus, we provide evidence that divergent host use promotes speciation among gall wasp populations. PMID:22337505

Using Ambystoma mexicanum (Mexican axolotl) embryos, chemical genetics, and microarray analysis to identify signaling pathways associated with tissue regeneration.

PubMed

Ponomareva, Larissa V; Athippozhy, Antony; Thorson, Jon S; Voss, S Randal

2015-12-01

Amphibian vertebrates are important models in regenerative biology because they present exceptional regenerative capabilities throughout life. However, it takes considerable effort to rear amphibians to juvenile and adult stages for regeneration studies, and the relatively large sizes that frogs and salamanders achieve during development make them difficult to use in chemical screens. Here, we introduce a new tail regeneration model using late stage Mexican axolotl embryos. We show that axolotl embryos completely regenerate amputated tails in 7days before they exhaust their yolk supply and begin to feed. Further, we show that axolotl embryos can be efficiently reared in microtiter plates to achieve moderate throughput screening of soluble chemicals to investigate toxicity and identify molecules that alter regenerative outcome. As proof of principle, we identified integration 1 / wingless (Wnt), transforming growth factor beta (Tgf-β), and fibroblast growth factor (Fgf) pathway antagonists that completely block tail regeneration and additional chemicals that significantly affected tail outgrowth. Furthermore, we used microarray analysis to show that inhibition of Wnt signaling broadly affects transcription of genes associated with Wnt, Fgf, Tgf-β, epidermal growth factor (Egf), Notch, nerve growth factor (Ngf), homeotic gene (Hox), rat sarcoma/mitogen-activated protein kinase (Ras/Mapk), myelocytomatosis viral oncogene (Myc), tumor protein 53 (p53), and retinoic acid (RA) pathways. Punctuated changes in the expression of genes known to regulate vertebrate development were observed; this suggests the tail regeneration transcriptional program is hierarchically structured and temporally ordered. Our study establishes the axolotl as a chemical screening model to investigate signaling pathways associated with tissue regeneration. Copyright © 2015 Elsevier Inc. All rights reserved.

Hemispheric Connectivity and the Visual-Spatial Divergent-Thinking Component of Creativity

ERIC Educational Resources Information Center

Moore, Dana W.; Bhadelia, Rafeeque A.; Billings, Rebecca L.; Fulwiler, Carl; Heilman, Kenneth M.; Rood, Kenneth M. J.; Gansler, David A.

2009-01-01

Background/hypothesis: Divergent thinking is an important measurable component of creativity. This study tested the postulate that divergent thinking depends on large distributed inter- and intra-hemispheric networks. Although preliminary evidence supports increased brain connectivity during divergent thinking, the neural correlates of this…

Performance characteristics of axisymmetric convergent-divergent exhaust nozzles with longitudinal slots in the divergent

NASA Technical Reports Server (NTRS)

Leavitt, L. D.; Bangert, L. S.

1982-01-01

An investigation was conducted in the Langley 16 foot Transonic Tunnel and in the static test facility of that tunnel to determine the effects of divergent flap ventilation of an axisymmetric nozzle on nozzle internal (static) and wind on performance. Tests were conducted at 0 deg angle of attack at static conditions and at Mach numbers from 0.6 to 1.2. Ratios of jet total pressure to free stream static pressure were varied from 1.0 (jet off) to approximately 14.0 depending on Mach number. The results of this study indicate that divergent flap ventilation generally provided large performance benefits at overexpanded nozzle conditions and performance reductions at underexpanded nozzle conditions when compared to the baseline (unventilated) nozzles. Ventilation also reduced the peak static and wind on performance levels.

Anthropogenic ecosystem fragmentation drives shared and unique patterns of sexual signal divergence among three species of Bahamian mosquitofish.

PubMed

Giery, Sean T; Layman, Craig A; Langerhans, R Brian

2015-08-01

When confronted with similar environmental challenges, different organisms can exhibit dissimilar phenotypic responses. Therefore, understanding patterns of phenotypic divergence for closely related species requires considering distinct evolutionary histories. Here, we investigated how a common form of human-induced environmental alteration, habitat fragmentation, may drive phenotypic divergence among three closely related species of Bahamian mosquitofish (Gambusia spp.). Focusing on one phenotypic trait (male coloration), having a priori predictions of divergence, we tested whether populations persisting in fragmented habitats differed from those inhabiting unfragmented habitats and examined the consistency of the pattern across species. Species exhibited both shared and unique patterns of phenotypic divergence between the two types of habitats, with shared patterns representing the stronger effect. For all species, populations in fragmented habitats had fewer dorsal-fin spots. In contrast, the magnitude and trajectory of divergence in dorsal-fin color, a sexually selected trait, differed among species. We identified fragmentation-mediated increased turbidity as a possible driver of these trait shifts. These results suggest that even closely related species can exhibit diverse phenotypic responses when encountering similar human-mediated selection regimes. This element of unpredictability complicates forecasting the phenotypic responses of wild organisms faced with anthropogenic change - an important component of biological conservation and ecosystem management.

Anthropogenic ecosystem fragmentation drives shared and unique patterns of sexual signal divergence among three species of Bahamian mosquitofish

PubMed Central

Giery, Sean T; Layman, Craig A; Langerhans, R Brian

2015-01-01

When confronted with similar environmental challenges, different organisms can exhibit dissimilar phenotypic responses. Therefore, understanding patterns of phenotypic divergence for closely related species requires considering distinct evolutionary histories. Here, we investigated how a common form of human-induced environmental alteration, habitat fragmentation, may drive phenotypic divergence among three closely related species of Bahamian mosquitofish (Gambusia spp.). Focusing on one phenotypic trait (male coloration), having a priori predictions of divergence, we tested whether populations persisting in fragmented habitats differed from those inhabiting unfragmented habitats and examined the consistency of the pattern across species. Species exhibited both shared and unique patterns of phenotypic divergence between the two types of habitats, with shared patterns representing the stronger effect. For all species, populations in fragmented habitats had fewer dorsal-fin spots. In contrast, the magnitude and trajectory of divergence in dorsal-fin color, a sexually selected trait, differed among species. We identified fragmentation-mediated increased turbidity as a possible driver of these trait shifts. These results suggest that even closely related species can exhibit diverse phenotypic responses when encountering similar human-mediated selection regimes. This element of unpredictability complicates forecasting the phenotypic responses of wild organisms faced with anthropogenic change – an important component of biological conservation and ecosystem management. PMID:26240605

Divergence with gene flow across a speciation continuum of Heliconius butterflies.

PubMed

Supple, Megan A; Papa, Riccardo; Hines, Heather M; McMillan, W Owen; Counterman, Brian A

2015-09-24

A key to understanding the origins of species is determining the evolutionary processes that drive the patterns of genomic divergence during speciation. New genomic technologies enable the study of high-resolution genomic patterns of divergence across natural speciation continua, where taxa pairs with different levels of reproductive isolation can be used as proxies for different stages of speciation. Empirical studies of these speciation continua can provide valuable insights into how genomes diverge during speciation. We examine variation across a handful of genomic regions in parapatric and allopatric populations of Heliconius butterflies with varying levels of reproductive isolation. Genome sequences were mapped to 2.2-Mb of the H. erato genome, including 1-Mb across the red color pattern locus and multiple regions unlinked to color pattern variation. Phylogenetic analyses reveal a speciation continuum of pairs of hybridizing races and incipient species in the Heliconius erato clade. Comparisons of hybridizing pairs of divergently colored races and incipient species reveal that genomic divergence increases with ecological and reproductive isolation, not only across the locus responsible for adaptive variation in red wing coloration, but also at genomic regions unlinked to color pattern. We observe high levels of divergence between the incipient species H. erato and H. himera, suggesting that divergence may accumulate early in the speciation process. Comparisons of genomic divergence between the incipient species and allopatric races suggest that limited gene flow cannot account for the observed high levels of divergence between the incipient species. Our results provide a reconstruction of the speciation continuum across the H. erato clade and provide insights into the processes that drive genomic divergence during speciation, establishing the H. erato clade as a powerful framework for the study of speciation.

Are habitat fragmentation, local adaptation and isolation-by-distance driving population divergence in wild rice Oryza rufipogon?

PubMed

Zhao, Yao; Vrieling, Klaas; Liao, Hui; Xiao, Manqiu; Zhu, Yongqing; Rong, Jun; Zhang, Wenju; Wang, Yuguo; Yang, Ji; Chen, Jiakuan; Song, Zhiping

2013-11-01

Habitat fragmentation weakens the connection between populations and is accompanied with isolation by distance (IBD) and local adaptation (isolation by adaptation, IBA), both leading to genetic divergence between populations. To understand the evolutionary potential of a population and to formulate proper conservation strategies, information on the roles of IBD and IBA in driving population divergence is critical. The putative ancestor of Asian cultivated rice (Oryza sativa) is endangered in China due to habitat loss and fragmentation. We investigated the genetic variation in 11 Chinese Oryza rufipogon populations using 79 microsatellite loci to infer the effects of habitat fragmentation, IBD and IBA on genetic structure. Historical and current gene flows were found to be rare (mh  = 0.0002-0.0013, mc  = 0.007-0.029), indicating IBD and resulting in a high level of population divergence (FST  = 0.343). High within-population genetic variation (HE  = 0.377-0.515), relatively large effective population sizes (Ne  = 96-158), absence of bottlenecks and limited gene flow were found, demonstrating little impact of recent habitat fragmentation on these populations. Eleven gene-linked microsatellite loci were identified as outliers, indicating local adaptation. Hierarchical AMOVA and partial Mantel tests indicated that population divergence of Chinese O. rufipogon was significantly correlated with environmental factors, especially habitat temperature. Common garden trials detected a significant adaptive population divergence associated with latitude. Collectively, these findings imply that IBD due to historical rather than recent fragmentation, followed by local adaptation, has driven population divergence in O. rufipogon. © 2013 John Wiley & Sons Ltd.

Genome-Wide siRNA-Based Functional Genomics of Pigmentation Identifies Novel Genes and Pathways That Impact Melanogenesis in Human Cells

PubMed Central

Bodemann, Brian; Petersen, Sean; Aruri, Jayavani; Koshy, Shiney; Richardson, Zachary; Le, Lu Q.; Krasieva, Tatiana; Roth, Michael G.; Farmer, Pat; White, Michael A.

2008-01-01

Melanin protects the skin and eyes from the harmful effects of UV irradiation, protects neural cells from toxic insults, and is required for sound conduction in the inner ear. Aberrant regulation of melanogenesis underlies skin disorders (melasma and vitiligo), neurologic disorders (Parkinson's disease), auditory disorders (Waardenburg's syndrome), and opthalmologic disorders (age related macular degeneration). Much of the core synthetic machinery driving melanin production has been identified; however, the spectrum of gene products participating in melanogenesis in different physiological niches is poorly understood. Functional genomics based on RNA-mediated interference (RNAi) provides the opportunity to derive unbiased comprehensive collections of pharmaceutically tractable single gene targets supporting melanin production. In this study, we have combined a high-throughput, cell-based, one-well/one-gene screening platform with a genome-wide arrayed synthetic library of chemically synthesized, small interfering RNAs to identify novel biological pathways that govern melanin biogenesis in human melanocytes. Ninety-two novel genes that support pigment production were identified with a low false discovery rate. Secondary validation and preliminary mechanistic studies identified a large panel of targets that converge on tyrosinase expression and stability. Small molecule inhibition of a family of gene products in this class was sufficient to impair chronic tyrosinase expression in pigmented melanoma cells and UV-induced tyrosinase expression in primary melanocytes. Isolation of molecular machinery known to support autophagosome biosynthesis from this screen, together with in vitro and in vivo validation, exposed a close functional relationship between melanogenesis and autophagy. In summary, these studies illustrate the power of RNAi-based functional genomics to identify novel genes, pathways, and pharmacologic agents that impact a biological phenotype and operate

Calibrated tree priors for relaxed phylogenetics and divergence time estimation.

PubMed

Heled, Joseph; Drummond, Alexei J

2012-01-01

The use of fossil evidence to calibrate divergence time estimation has a long history. More recently, Bayesian Markov chain Monte Carlo has become the dominant method of divergence time estimation, and fossil evidence has been reinterpreted as the specification of prior distributions on the divergence times of calibration nodes. These so-called "soft calibrations" have become widely used but the statistical properties of calibrated tree priors in a Bayesian setting hashave not been carefully investigated. Here, we clarify that calibration densities, such as those defined in BEAST 1.5, do not represent the marginal prior distribution of the calibration node. We illustrate this with a number of analytical results on small trees. We also describe an alternative construction for a calibrated Yule prior on trees that allows direct specification of the marginal prior distribution of the calibrated divergence time, with or without the restriction of monophyly. This method requires the computation of the Yule prior conditional on the height of the divergence being calibrated. Unfortunately, a practical solution for multiple calibrations remains elusive. Our results suggest that direct estimation of the prior induced by specifying multiple calibration densities should be a prerequisite of any divergence time dating analysis.

Genetic divergence between populations of feral and domestic forms of a mosquito disease vector assessed by transcriptomics

PubMed Central

2015-01-01

Culex pipiens, an invasive mosquito and vector of West Nile virus in the US, has two morphologically indistinguishable forms that differ dramatically in behavior and physiology. Cx. pipiens form pipiens is primarily a bird-feeding temperate mosquito, while the sub-tropical Cx. pipiens form molestus thrives in sewers and feeds on mammals. Because the feral form can diapause during the cold winters but the domestic form cannot, the two Cx. pipiens forms are allopatric in northern Europe and, although viable, hybrids are rare. Cx. pipiens form molestus has spread across all inhabited continents and hybrids of the two forms are common in the US. Here we elucidate the genes and gene families with the greatest divergence rates between these phenotypically diverged mosquito populations, and discuss them in light of their potential biological and ecological effects. After generating and assembling novel transcriptome data for each population, we performed pairwise tests for nonsynonymous divergence (Ka) of homologous coding sequences and examined gene ontology terms that were statistically over-represented in those sequences with the greatest divergence rates. We identified genes involved in digestion (serine endopeptidases), innate immunity (fibrinogens and α-macroglobulins), hemostasis (D7 salivary proteins), olfaction (odorant binding proteins) and chitin binding (peritrophic matrix proteins). By examining molecular divergence between closely related yet phenotypically divergent forms of the same species, our results provide insights into the identity of rapidly-evolving genes between incipient species. Additionally, we found that families of signal transducers, ATP synthases and transcription regulators remained identical at the amino acid level, thus constituting conserved components of the Cx. pipiens proteome. We provide a reference with which to gauge the divergence reported in this analysis by performing a comparison of transcriptome sequences from conspecific

Divergence Considerations, 1

NASA Technical Reports Server (NTRS)

Quirein, J. A.

1973-01-01

The case is considered of n distinct, normally distributed classes or populations of two dimensional response vectors x = (lambda sub 1, lambda sub 2), where lambda sub i is a measurement of the relative reponse of x along channel i. The problem dealt with is to determine the best channel in the sense of divergence and in the sense of minimizing the probability of misclassification.

[The application of cortical and subcortical stimulation threshold in identifying the motor pathway and guiding the resection of gliomas in the functional areas].

PubMed

Ren, X H; Yang, X C; Huang, W; Yang, K Y; Liu, L; Qiao, H; Guo, L J; Cui, Y; Lin, S

2018-03-06

Objective: This study aimed to analyze the application of cortical and subcortical stimulation threshold in identifying the motor pathway and guiding the resection of gliomas in the functional area, and to illustrate the minimal safe threshold by ROC method. Methods: Fifty-seven patients with gliomas in the functional areas were enrolled in the study at Beijing Tiantan Hospital from 2015 to 2017. Anesthesia was maintained intravenously with propofol 10% and remifentanil. Throughout the resection process, cortical or subcortical stimulation threshold was determined along tumor border using monopolar or bipolar electrodes. The motor pathway was identified and protected from resection according to the stimulation threshold and transcranial MEPs. Minimal threshold in each case was recorded. Results: Total resection was achieved in 32 cases(56.1%), sub-total resection in 22 cases(38.6%), and partial resection in 3 cases(5.3%). Pre-operative motor disability was found in 9 cases. Compared with pre-operative motor scores, 19 exhibited impaired motor functions on day 1 after surgery, 5 had quick recovery by day 7 after surgery, and 7 had late recovery by 3 months after surgery. At 3 months, 7 still had impaired motor function. The frequency of intraoperative seizure was 1.8%(1/57). No other side effect was found during electronic monitoring in the operation. The ROC curve revealed that the minimal safe monopolar subcortical threshold was 5.70 mA for strength deterioration on day 1 and day 7 after surgery. Univariate analysis revealed that decreased transcranial MEPs and minimal subcortical threshold ≤5.7 mA were correlated with postoperative strength deterioration. Conclusions: Cortical and subcortical stimulation threshold has its merit in identifying the motor pathway and guiding the resection for tumors within the functional areas. 5.7 mA can be used as the minimal safe threshold to protect the motor pathway from injury.

Concrete ensemble Kalman filters with rigorous catastrophic filter divergence

PubMed Central

Kelly, David; Majda, Andrew J.; Tong, Xin T.

2015-01-01

The ensemble Kalman filter and ensemble square root filters are data assimilation methods used to combine high-dimensional, nonlinear dynamical models with observed data. Ensemble methods are indispensable tools in science and engineering and have enjoyed great success in geophysical sciences, because they allow for computationally cheap low-ensemble-state approximation for extremely high-dimensional turbulent forecast models. From a theoretical perspective, the dynamical properties of these methods are poorly understood. One of the central mysteries is the numerical phenomenon known as catastrophic filter divergence, whereby ensemble-state estimates explode to machine infinity, despite the true state remaining in a bounded region. In this article we provide a breakthrough insight into the phenomenon, by introducing a simple and natural forecast model that transparently exhibits catastrophic filter divergence under all ensemble methods and a large set of initializations. For this model, catastrophic filter divergence is not an artifact of numerical instability, but rather a true dynamical property of the filter. The divergence is not only validated numerically but also proven rigorously. The model cleanly illustrates mechanisms that give rise to catastrophic divergence and confirms intuitive accounts of the phenomena given in past literature. PMID:26261335

Concrete ensemble Kalman filters with rigorous catastrophic filter divergence.

PubMed

Kelly, David; Majda, Andrew J; Tong, Xin T

2015-08-25

The ensemble Kalman filter and ensemble square root filters are data assimilation methods used to combine high-dimensional, nonlinear dynamical models with observed data. Ensemble methods are indispensable tools in science and engineering and have enjoyed great success in geophysical sciences, because they allow for computationally cheap low-ensemble-state approximation for extremely high-dimensional turbulent forecast models. From a theoretical perspective, the dynamical properties of these methods are poorly understood. One of the central mysteries is the numerical phenomenon known as catastrophic filter divergence, whereby ensemble-state estimates explode to machine infinity, despite the true state remaining in a bounded region. In this article we provide a breakthrough insight into the phenomenon, by introducing a simple and natural forecast model that transparently exhibits catastrophic filter divergence under all ensemble methods and a large set of initializations. For this model, catastrophic filter divergence is not an artifact of numerical instability, but rather a true dynamical property of the filter. The divergence is not only validated numerically but also proven rigorously. The model cleanly illustrates mechanisms that give rise to catastrophic divergence and confirms intuitive accounts of the phenomena given in past literature.

Patterns and rates of intron divergence between humans and chimpanzees

PubMed Central

Gazave, Elodie; Marqués-Bonet, Tomàs; Fernando, Olga; Charlesworth, Brian; Navarro, Arcadi

2007-01-01

Background Introns, which constitute the largest fraction of eukaryotic genes and which had been considered to be neutral sequences, are increasingly acknowledged as having important functions. Several studies have investigated levels of evolutionary constraint along introns and across classes of introns of different length and location within genes. However, thus far these studies have yielded contradictory results. Results We present the first analysis of human-chimpanzee intron divergence, in which differences in the number of substitutions per intronic site (Ki) can be interpreted as the footprint of different intensities and directions of the pressures of natural selection. Our main findings are as follows: there was a strong positive correlation between intron length and divergence; there was a strong negative correlation between intron length and GC content; and divergence rates vary along introns and depending on their ordinal position within genes (for instance, first introns are more GC rich, longer and more divergent, and divergence is lower at the 3' and 5' ends of all types of introns). Conclusion We show that the higher divergence of first introns is related to their larger size. Also, the lower divergence of short introns suggests that they may harbor a relatively greater proportion of regulatory elements than long introns. Moreover, our results are consistent with the presence of functionally relevant sequences near the 5' and 3' ends of introns. Finally, our findings suggest that other parts of introns may also be under selective constraints. PMID:17309804

Divergent conservation laws in hyperbolic thermoelasticity

NASA Astrophysics Data System (ADS)

Murashkin, E. V.; Radayev, Y. N.

2018-05-01

The present study is devoted to the problem of formulation of conservation laws in divergent form for hyperbolic thermoelastic continua. The field formalism is applied to study the problem. A natural density of thermoelastic action and the corresponding variational least action principle are formulated. A special form of the first variation of the action is employed to obtain 4-covariant divergent conservation laws. Differential field equations and constitutive laws are derived from a special form of the first variation of the action integral. The objectivity of constitutive equations is provided by the rotationally invariant forms of the Lagrangian employed.

Temporary divergence paralysis in viral meningitis.

PubMed

Bakker, Stef L M; Gan, Ivan M

2008-06-01

A 43-year-old woman who reported diplopia and headache was found to have comitant esotropia at distance fixation and normal alignment at reading distance (divergence paralysis). Eye movement, including abduction, was normal as was the rest of the neurologic examination. Brain MRI was normal. Lumbar puncture showed an elevated opening pressure and a cerebrospinal fluid formula consistent with viral meningitis. The patient was treated with intravenous fluids and analgesics and with a temporary prism to alleviate diplopia. Within 3 weeks, she had fully recovered. This is the first report of divergence palsy in viral meningitis.

Adaptation to Low Salinity Promotes Genomic Divergence in Atlantic Cod (Gadus morhua L.)

PubMed Central

Berg, Paul R.; Jentoft, Sissel; Star, Bastiaan; Ring, Kristoffer H.; Knutsen, Halvor; Lien, Sigbjørn; Jakobsen, Kjetill S.; André, Carl

2015-01-01

How genomic selection enables species to adapt to divergent environments is a fundamental question in ecology and evolution. We investigated the genomic signatures of local adaptation in Atlantic cod (Gadus morhua L.) along a natural salinity gradient, ranging from 35‰ in the North Sea to 7‰ within the Baltic Sea. By utilizing a 12 K SNPchip, we simultaneously assessed neutral and adaptive genetic divergence across the Atlantic cod genome. Combining outlier analyses with a landscape genomic approach, we identified a set of directionally selected loci that are strongly correlated with habitat differences in salinity, oxygen, and temperature. Our results show that discrete regions within the Atlantic cod genome are subject to directional selection and associated with adaptation to the local environmental conditions in the Baltic- and the North Sea, indicating divergence hitchhiking and the presence of genomic islands of divergence. We report a suite of outlier single nucleotide polymorphisms within or closely located to genes associated with osmoregulation, as well as genes known to play important roles in the hydration and development of oocytes. These genes are likely to have key functions within a general osmoregulatory framework and are important for the survival of eggs and larvae, contributing to the buildup of reproductive isolation between the low-salinity adapted Baltic cod and the adjacent cod populations. Hence, our data suggest that adaptive responses to the environmental conditions in the Baltic Sea may contribute to a strong and effective reproductive barrier, and that Baltic cod can be viewed as an example of ongoing speciation. PMID:25994933

Adaptive divergence in wine yeasts and their wild relatives suggests a prominent role for introgressions and rapid evolution at noncoding sites.

PubMed

Almeida, Pedro; Barbosa, Raquel; Bensasson, Douda; Gonçalves, Paula; Sampaio, José Paulo

2017-04-01

In Saccharomyces cerevisiae, the main yeast in wine fermentation, the opportunity to examine divergence at the molecular level between a domesticated lineage and its wild counterpart arose recently due to the identification of the closest relatives of wine strains, a wild population associated with Mediterranean oaks. As genomic data are available for a considerable number of representatives belonging to both groups, we used population genomics to estimate the degree and distribution of nucleotide variation between wine yeasts and their closest wild relatives. We found widespread genomewide divergence, particularly at noncoding sites, which, together with above average divergence in trans-acting DNA binding proteins, may suggest an important role for divergence at the level of transcriptional regulation. Nine outlier regions putatively under strong divergent selection were highlighted by a genomewide scan under stringent conditions. Several cases of introgressions, originating in the sibling species Saccharomyces paradoxus, were also identified in the Mediterranean oak population. FZF1 and SSU1, mostly known for conferring sulphite resistance in wine yeasts, were among the introgressed genes, although not fixed. Because the introgressions detected in our study are not found in wine strains, we hypothesize that ongoing divergent ecological selection segregates the two forms between the different niches. Together, our results provide a first insight into the extent and kind of divergence between wine yeasts and their closest wild relatives. © 2017 John Wiley & Sons Ltd.

Divergence hitchhiking and the spread of genomic isolation during ecological speciation-with-gene-flow

PubMed Central

Via, Sara

2012-01-01

In allopatric populations, geographical separation simultaneously isolates the entire genome, allowing genetic divergence to accumulate virtually anywhere in the genome. In sympatric populations, however, the strong divergent selection required to overcome migration produces a genetic mosaic of divergent and non-divergent genomic regions. In some recent genome scans, each divergent genomic region has been interpreted as an independent incidence of migration/selection balance, such that the reduction of gene exchange is restricted to a few kilobases around each divergently selected gene. I propose an alternative mechanism, ‘divergence hitchhiking’ (DH), in which divergent selection can reduce gene exchange for several megabases around a gene under strong divergent selection. Not all genes/markers within a DH region are divergently selected, yet the entire region is protected to some degree from gene exchange, permitting genetic divergence from mechanisms other than divergent selection to accumulate secondarily. After contrasting DH and multilocus migration/selection balance (MM/SB), I outline a model in which genomic isolation at a given genomic location is jointly determined by DH and genome-wide effects of the progressive reduction in realized migration, then illustrate DH using data from several pairs of incipient species in the wild. PMID:22201174

Metabolomic profiling and genomic analysis of wheat aneuploid lines to identify genes controlling biochemical pathways in mature grain.

PubMed

Francki, Michael G; Hayton, Sarah; Gummer, Joel P A; Rawlinson, Catherine; Trengove, Robert D

2016-02-01

Metabolomics is becoming an increasingly important tool in plant genomics to decipher the function of genes controlling biochemical pathways responsible for trait variation. Although theoretical models can integrate genes and metabolites for trait variation, biological networks require validation using appropriate experimental genetic systems. In this study, we applied an untargeted metabolite analysis to mature grain of wheat homoeologous group 3 ditelosomic lines, selected compounds that showed significant variation between wheat lines Chinese Spring and at least one ditelosomic line, tracked the genes encoding enzymes of their biochemical pathway using the wheat genome survey sequence and determined the genetic components underlying metabolite variation. A total of 412 analytes were resolved in the wheat grain metabolome, and principal component analysis indicated significant differences in metabolite profiles between Chinese Spring and each ditelosomic lines. The grain metabolome identified 55 compounds positively matched against a mass spectral library where the majority showed significant differences between Chinese Spring and at least one ditelosomic line. Trehalose and branched-chain amino acids were selected for detailed investigation, and it was expected that if genes encoding enzymes directly related to their biochemical pathways were located on homoeologous group 3 chromosomes, then corresponding ditelosomic lines would have a significant reduction in metabolites compared with Chinese Spring. Although a proportion showed a reduction, some lines showed significant increases in metabolites, indicating that genes directly and indirectly involved in biosynthetic pathways likely regulate the metabolome. Therefore, this study demonstrated that wheat aneuploid lines are suitable experimental genetic system to validate metabolomics-genomics networks. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Divergence, hybridization, and recombination in the mitochondrial genome of the human pathogenic yeast Cryptococcus gattii.

PubMed

Xu, Jianping; Yan, Zhun; Guo, Hong

2009-06-01

The inheritance of mitochondrial genes and genomes are uniparental in most sexual eukaryotes. This pattern of inheritance makes mitochondrial genomes in natural populations effectively clonal. Here, we examined the mitochondrial population genetics of the emerging human pathogenic fungus Cryptococcus gattii. The DNA sequences for five mitochondrial DNA fragments were obtained from each of 50 isolates belonging to two evolutionary divergent lineages, VGI and VGII. Our analyses revealed a greater sequence diversity within VGI than that within VGII, consistent with observations of the nuclear genes. The combined analyses of all five gene fragments indicated significant divergence between VGI and VGII. However, the five individual genealogies showed different relationships among the isolates, consistent with recent hybridization and mitochondrial gene transfer between the two lineages. Population genetic analyses of the multilocus data identified evidence for predominantly clonal mitochondrial population structures within both lineages. Interestingly, there were clear signatures of recombination among mitochondrial genes within the VGII lineage. Our analyses suggest historical mitochondrial genome divergence within C. gattii, but there is evidence for recent hybridization and recombination in the mitochondrial genome of this important human yeast pathogen.

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

PubMed Central

Sims, Jennifer S.; Grinshpun, Boris; Feng, Yaping; Ung, Timothy H.; Neira, Justin A.; Samanamud, Jorge L.; Canoll, Peter; Shen, Yufeng; Sims, Peter A.; Bruce, Jeffrey N.

2016-01-01

Although immune signaling has emerged as a defining feature of the glioma microenvironment, how the underlying structure of the glioma-infiltrating T-cell population differs from that of the blood from which it originates has been difficult to measure directly in patients. High-throughput sequencing of T-cell receptor (TCR) repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. We have defined immunophenotypes of whole repertoires based on TCRseq of the α- and β-chains from glioma tissue, nonneoplastic brain tissue, and peripheral blood from patients. Using information theory, we partitioned the diversity of these TCR repertoires into that from the distribution of VJ cassette combinations and diversity due to VJ-independent factors, such as selection due to antigen binding. Tumor-infiltrating lymphocytes (TILs) possessed higher VJ-independent diversity than nonneoplastic tissue, stratifying patients according to tumor grade. We found that the VJ-independent components of tumor-associated repertoires diverge more from their corresponding peripheral repertoires than T-cell populations in nonneoplastic brain tissue, particularly for low-grade gliomas. Finally, we identified a “signature” set of TCRs whose use in peripheral blood is associated with patients exhibiting low TIL divergence and is depleted in patients with highly divergent TIL repertoires. This signature is detectable in peripheral blood, and therefore accessible noninvasively. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to antiglioma vaccines and immunotherapy. PMID:27261081

Downstream divergence of the ethylene signaling pathway for harpin-stimulated Arabidopsis growth and insect defense.

PubMed

Dong, Hong-Ping; Peng, Jianling; Bao, Zhilong; Meng, Xiangdong; Bonasera, Jean M; Chen, Guangyong; Beer, Steven V; Dong, Hansong

2004-11-01

Ethylene (ET) signal transduction may regulate plant growth and defense, depending on which components are recruited into the pathway in response to different stimuli. We report here that the ET pathway controls both insect resistance (IR) and plant growth enhancement (PGE) in Arabidopsis (Arabidopsis thaliana) plants responding to harpin, a protein produced by a plant pathogenic bacterium. PGE may result from spraying plant tops with harpin or by soaking seeds in harpin solution; the latter especially enhances root growth. Plants treated similarly develop resistance to the green peach aphid (Myzus persicae). The salicylic acid pathway, although activated by harpin, does not lead to PGE and IR. By contrast, PGE and IR are induced in both wild-type plants and genotypes that have defects in salicylic acid signaling. In response to harpin, levels of jasmonic acid (JA) decrease, and the COI1 gene, which is indispensable for JA signal transduction, is not expressed in wild-type plants. However, PGE and IR are stimulated in the JA-resistant mutant jar1-1. In the wild type, PGE and IR develop coincidently with increases in ET levels and the expression of several genes essential for ET signaling. The ET receptor gene ETR1 is required because both phenotypes are arrested in the etr1-1 mutant. Consistently, inhibition of ET perception nullifies the induction of both PGE and IR. The signal transducer EIN2 is required for IR, and EIN5 is required for PGE because IR and PGE are impaired correspondingly in the ein2-1 and ein5-1 mutants. Therefore, harpin activates ET signaling while conscribing EIN2 and EIN5 to confer IR and PGE, respectively.

Morphological divergence and flow-induced phenotypic plasticity in a native fish from anthropogenically altered stream habitats.

PubMed

Franssen, Nathan R; Stewart, Laura K; Schaefer, Jacob F

2013-11-01

Understanding population-level responses to human-induced changes to habitats can elucidate the evolutionary consequences of rapid habitat alteration. Reservoirs constructed on streams expose stream fishes to novel selective pressures in these habitats. Assessing the drivers of trait divergence facilitated by these habitats will help identify evolutionary and ecological consequences of reservoir habitats. We tested for morphological divergence in a stream fish that occupies both stream and reservoir habitats. To assess contributions of genetic-level differences and phenotypic plasticity induced by flow variation, we spawned and reared individuals from both habitats types in flow and no flow conditions. Body shape significantly and consistently diverged in reservoir habitats compared with streams; individuals from reservoirs were shallower bodied with smaller heads compared with individuals from streams. Significant population-level differences in morphology persisted in offspring but morphological variation compared with field-collected individuals was limited to the head region. Populations demonstrated dissimilar flow-induced phenotypic plasticity when reared under flow, but phenotypic plasticity in response to flow variation was an unlikely explanation for observed phenotypic divergence in the field. Our results, together with previous investigations, suggest the environmental conditions currently thought to drive morphological change in reservoirs (i.e., predation and flow regimes) may not be the sole drivers of phenotypic change.

An Integrative Data Mining Approach to Identify Adverse Outcome Pathway Signatures

EPA Science Inventory

Adverse Outcome Pathways (AOPs) provide a formal framework for describing the mechanisms underlying the toxicity of chemicals in our environment. This process improves our ability to incorporate high-throughput toxicity testing (HTT) results and biomarker information on early key...

Chimeric exchange of coronavirus nsp5 proteases (3CLpro) identifies common and divergent regulatory determinants of protease activity.

PubMed

Stobart, Christopher C; Sexton, Nicole R; Munjal, Havisha; Lu, Xiaotao; Molland, Katrina L; Tomar, Sakshi; Mesecar, Andrew D; Denison, Mark R

2013-12-01

Human coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) cause epidemics of severe human respiratory disease. A conserved step of CoV replication is the translation and processing of replicase polyproteins containing 16 nonstructural protein domains (nsp's 1 to 16). The CoV nsp5 protease (3CLpro; Mpro) processes nsp's at 11 cleavage sites and is essential for virus replication. CoV nsp5 has a conserved 3-domain structure and catalytic residues. However, the intra- and intermolecular determinants of nsp5 activity and their conservation across divergent CoVs are unknown, in part due to challenges in cultivating many human and zoonotic CoVs. To test for conservation of nsp5 structure-function determinants, we engineered chimeric betacoronavirus murine hepatitis virus (MHV) genomes encoding nsp5 proteases of human and bat alphacoronaviruses and betacoronaviruses. Exchange of nsp5 proteases from HCoV-HKU1 and HCoV-OC43, which share the same genogroup, genogroup 2a, with MHV, allowed for immediate viral recovery with efficient replication albeit with impaired fitness in direct competition with wild-type MHV. Introduction of MHV nsp5 temperature-sensitive mutations into chimeric HKU1 and OC43 nsp5 proteases resulted in clear differences in viability and temperature-sensitive phenotypes compared with MHV nsp5. These data indicate tight genetic linkage and coevolution between nsp5 protease and the genomic background and identify differences in intramolecular networks regulating nsp5 function. Our results also provide evidence that chimeric viruses within coronavirus genogroups can be used to test nsp5 determinants of function and inhibition in common isogenic backgrounds and cell types.

Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana

2014-10-15

According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro.more » Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2{sup +} neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. - Highlights: • HESCs derived neuronal cells serve as benchmark for iPSC based neuronal toxicity test development. • Comparisons between hESCs and hiPSCs demonstrated variability of the epigenetic state • CREB pathway modulation have been explored in relation to the neurotoxicant exposure KG-501 • hiPSC might be promising tools to translate theoretical AoPs into toxicological in vitro tests.« less

French Medico-Administrative Data to Identify the Care Pathways of Women With Breast Cancer.

PubMed

Lefeuvre, Delphine; Le Bihan-Benjamin, Christine; Pauporté, Iris; Medioni, Jacques; Bousquet, Philippe-Jean

2017-07-01

Study of the care pathways is an important topic for care planning, as well as to observe guidelines application. This study aimed to describe care pathways and the period of time between treatments of women with breast cancer (BC), at a population level. Women with in situ, local and regional BC who were hospitalized and newly treated in 2012 were included and followed for 1 year. Care pathways were described, focusing on surgery (partial mastectomy [PM], total mastectomy [TM]), chemotherapy, and radiotherapy. The periods of time between treatments were measured and compared with the guidelines. The study involved 52,128 women. The most common care pathways among the 2845 women with in situ BC were PM-radiotherapy (46.7%) and TM (28.5%). Among the 41,470 women with local BC, they were: PM-radiotherapy (44.8%) or PM-chemotherapy-radiotherapy (16.0%). The 7813 women with regional BC had similar care pathways, although chemotherapy was given more frequently (73%). The periods of time between surgery and chemotherapy were in accordance with the guidelines for 98% of the women; those between surgery and radiotherapy were affected by adjuvant chemotherapy. Finally, the time between chemotherapy and radiotherapy was longer than recommended for 40% of the women. The French medicoadministrative databases allow the study, at a national population level, of the care pathways and periods of time between treatments of women with BC according to the stage of the disease. They were close to the guidelines, although an improvement is highly necessary. Copyright © 2017 Elsevier Inc. All rights reserved.

Expansion of divergent SEA domains in cell surface proteins and nucleoporin 54.

PubMed

Pei, Jimin; Grishin, Nick V

2017-03-01

SEA (sea urchin sperm protein, enterokinase, agrin) domains, many of which possess autoproteolysis activity, have been found in a number of cell surface and secreted proteins. Despite high sequence divergence, SEA domains were also proposed to be present in dystroglycan based on a conserved autoproteolysis motif and receptor-type protein phosphatase IA-2 based on structural similarity. The presence of a SEA domain adjacent to the transmembrane segment appears to be a recurring theme in quite a number of type I transmembrane proteins on the cell surface, such as MUC1, dystroglycan, IA-2, and Notch receptors. By comparative sequence and structural analyses, we identified dystroglycan-like proteins with SEA domains in Capsaspora owczarzaki of the Filasterea group, one of the closest single-cell relatives of metazoans. We also detected novel and divergent SEA domains in a variety of cell surface proteins such as EpCAM, α/ε-sarcoglycan, PTPRR, collectrin/Tmem27, amnionless, CD34, KIAA0319, fibrocystin-like protein, and a number of cadherins. While these proteins are mostly from metazoans or their single cell relatives such as choanoflagellates and Filasterea, fibrocystin-like proteins with SEA domains were found in several other eukaryotic lineages including green algae, Alveolata, Euglenozoa, and Haptophyta, suggesting an ancient evolutionary origin. In addition, the intracellular protein Nucleoporin 54 (Nup54) acquired a divergent SEA domain in choanoflagellates and metazoans. © 2016 The Protein Society.

Divergence of dim-light vision among bats (order: Chiroptera) as estimated by molecular and electrophysiological methods.

PubMed

Liu, He-Qun; Wei, Jing-Kuan; Li, Bo; Wang, Ming-Shan; Wu, Rui-Qi; Rizak, Joshua D; Zhong, Li; Wang, Lu; Xu, Fu-Qiang; Shen, Yong-Yi; Hu, Xin-Tian; Zhang, Ya-Ping

2015-06-23

Dim-light vision is present in all bats, but is divergent among species. Old-World fruit bats (Pteropodidae) have fully developed eyes; the eyes of insectivorous bats are generally degraded, and these bats rely on well-developed echolocation. An exception is the Emballonuridae, which are capable of laryngeal echolocation but prefer to use vision for navigation and have normal eyes. In this study, integrated methods, comprising manganese-enhanced magnetic resonance imaging (MEMRI), f-VEP and RNA-seq, were utilized to verify the divergence. The results of MEMRI showed that Pteropodidae bats have a much larger superior colliculus (SC)/ inferior colliculus (IC) volume ratio (3:1) than insectivorous bats (1:7). Furthermore, the absolute visual thresholds (log cd/m(2)•s) of Pteropodidae (-6.30 and -6.37) and Emballonuridae (-3.71) bats were lower than those of other insectivorous bats (-1.90). Finally, genes related to the visual pathway showed signs of positive selection, convergent evolution, upregulation and similar gene expression patterns in Pteropodidae and Emballonuridae bats. Different results imply that Pteropodidae and Emballonuridae bats have more developed vision than the insectivorous bats and suggest that further research on bat behavior is warranted.

Convergent and divergent evolution in carnivorous pitcher plant traps.

PubMed

Thorogood, Chris J; Bauer, Ulrike; Hiscock, Simon J

2018-02-01

Contents Summary 1035 I. Introduction 1035 II. Evolution of the pitcher 1036 III. Convergent evolution 1036 IV. Divergent evolution 1038 V. Adaptive radiation and speciation 1040 VI. Conclusions and perspectives 1040 Acknowledgements 1040 References 1040 SUMMARY: The pitcher trap is a striking example of convergent evolution across unrelated carnivorous plant lineages. Convergent traits that have evolved across pitcher plant lineages are essential for trap function, suggesting that key selective pressures are in action. Recent studies have also revealed patterns of divergent evolution in functional pitcher morphology within genera. Adaptations to differences in local prey assemblages may drive such divergence and, ultimately, speciation. Here, we review recent research on convergent and divergent evolution in pitcher plant traps, with a focus on the genus Nepenthes, which we propose as a new model for research into adaptive radiation and speciation. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma

PubMed Central

Hassan, Khaled A.; Wang, Luo; Korkaya, Hasan; Chen, Guoan; Maillard, Ivan; Beer, David G.; Kalemkerian, Gregory P.; Wicha, Max S.

2013-01-01

Purpose The cancer stem cell theory postulates that tumors contain a subset of cells with stem cell properties of self-renewal, differentiation and tumor-initiation. The purpose of this study is to determine the role of Notch activity in identifying lung cancer stem cells. Experimental Design We investigated the role of Notch activity in lung adenocarcinoma utilizing a Notch GFP-reporter construct and a gamma-secretase inhibitor (GSI), which inhibits Notch pathway activity. Results Transduction of lung cancer cells with Notch GFP-reporter construct identified a subset of cells with high Notch activity (GFP-bright). GFP-bright cells had the ability to form more tumor spheres in serum-free media, and were able to generate both GFP-bright and GFP-dim (lower Notch activity) cell populations. GFP-bright cells were resistant to chemotherapy and were tumorigenic in serial xenotransplantation assays. Tumor xenografts of mice treated with GSI had decreased expression of downstream effectors of Notch pathway and failed to regenerate tumors upon reimplantation in NOD/SCID mice. Using multivariate analysis, we detected a statistically significant correlation between poor clinical outcome and Notch activity (reflected in increased Notch ligand expression or decreased expression of the negative modulators), in a group of 441 lung adenocarcinoma patients. This correlation was further confirmed in an independent group of 89 adenocarcinoma patients where Hes-1 overexpression correlated with poor overall survival. Conclusions Notch activity can identify lung cancer stem cell-like population and its inhibition may be an appropriate target for treating lung adenocarcinoma. PMID:23444212

Dysregulated Pathway Identification of Alzheimer's Disease Based on Internal Correlation Analysis of Genes and Pathways.

PubMed

Kong, Wei; Mou, Xiaoyang; Di, Benteng; Deng, Jin; Zhong, Ruxing; Wang, Shuaiqun

2017-11-20

Dysregulated pathway identification is an important task which can gain insight into the underlying biological processes of disease. Current pathway-identification methods focus on a set of co-expression genes and single pathways and ignore the correlation between genes and pathways. The method proposed in this study, takes into account the internal correlations not only between genes but also pathways to identifying dysregulated pathways related to Alzheimer's disease (AD), the most common form of dementia. In order to find the significantly differential genes for AD, mutual information (MI) is used to measure interdependencies between genes other than expression valves. Then, by integrating the topology information from KEGG, the significant pathways involved in the feature genes are identified. Next, the distance correlation (DC) is applied to measure the pairwise pathway crosstalks since DC has the advantage of detecting nonlinear correlations when compared to Pearson correlation. Finally, the pathway pairs with significantly different correlations between normal and AD samples are known as dysregulated pathways. The molecular biology analysis demonstrated that many dysregulated pathways related to AD pathogenesis have been discovered successfully by the internal correlation detection. Furthermore, the insights of the dysregulated pathways in the development and deterioration of AD will help to find new effective target genes and provide important theoretical guidance for drug design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multiple-channel, total-reflection optic with controllable divergence

DOEpatents

Gibson, David M.; Downing, Robert G.

1997-01-01

An apparatus and method for providing focused x-ray, gamma-ray, charged particle and neutral particle, including neutron, radiation beams with a controllable amount of divergence are disclosed. The apparatus features a novel use of a radiation blocking structure, which, when combined with multiple-channel total reflection optics, increases the versatility of the optics by providing user-controlled output-beam divergence.

Multiple-channel, total-reflection optic with controllable divergence

DOEpatents

Gibson, D.M.; Downing, R.G.

1997-02-18

An apparatus and method for providing focused x-ray, gamma-ray, charged particle and neutral particle, including neutron, radiation beams with a controllable amount of divergence are disclosed. The apparatus features a novel use of a radiation blocking structure, which, when combined with multiple-channel total reflection optics, increases the versatility of the optics by providing user-controlled output-beam divergence. 11 figs.

Neural Mechanisms of Episodic Retrieval Support Divergent Creative Thinking.

PubMed

Madore, Kevin P; Thakral, Preston P; Beaty, Roger E; Addis, Donna Rose; Schacter, Daniel L

2017-11-17

Prior research has indicated that brain regions and networks that support semantic memory, top-down and bottom-up attention, and cognitive control are all involved in divergent creative thinking. Kernels of evidence suggest that neural processes supporting episodic memory-the retrieval of particular elements of prior experiences-may also be involved in divergent thinking, but such processes have typically been characterized as not very relevant for, or even a hindrance to, creative output. In the present study, we combine functional magnetic resonance imaging with an experimental manipulation to test formally, for the first time, episodic memory's involvement in divergent thinking. Following a manipulation that facilitates detailed episodic retrieval, we observed greater neural activity in the hippocampus and stronger connectivity between a core brain network linked to episodic processing and a frontoparietal brain network linked to cognitive control during divergent thinking relative to an object association control task that requires little divergent thinking. Stronger coupling following the retrieval manipulation extended to a subsequent resting-state scan. Neural effects of the episodic manipulation were consistent with behavioral effects of enhanced idea production on divergent thinking but not object association. The results indicate that conceptual frameworks should accommodate the idea that episodic retrieval can function as a component process of creative idea generation, and highlight how the brain flexibly utilizes the retrieval of episodic details for tasks beyond simple remembering. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Identifying Creativity during Problem Solving Using Linguistic Features

ERIC Educational Resources Information Center

Skalicky, Stephen; Crossley, Scott A.; McNamara, Danielle S.; Muldner, Kasia

2017-01-01

Creativity is commonly assessed using divergent thinking tasks, which measure the fluency, flexibility, originality, and elaboration of participant output on a variety of different tasks. This study assesses the degree to which creativity can be identified based on linguistic features of participants' language while completing collaborative…

Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis).

PubMed

Funk, W Chris; Lovich, Robert E; Hohenlohe, Paul A; Hofman, Courtney A; Morrison, Scott A; Sillett, T Scott; Ghalambor, Cameron K; Maldonado, Jesus E; Rick, Torben C; Day, Mitch D; Polato, Nicholas R; Fitzpatrick, Sarah W; Coonan, Timothy J; Crooks, Kevin R; Dillon, Adam; Garcelon, David K; King, Julie L; Boser, Christina L; Gould, Nicholas; Andelt, William F

2016-05-01

The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of six subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1-89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland grey foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6-6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness and reduced adaptive potential. © 2016 John Wiley & Sons Ltd.

Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis)

PubMed Central

FUNK, W. CHRIS; LOVICH, ROBERT E.; HOHENLOHE, PAUL A.; HOFMAN, COURTNEY A.; MORRISON, SCOTT A.; SILLETT, T. SCOTT; GHALAMBOR, CAMERON K.; MALDONADO, JESUS E.; RICK, TORBEN C.; DAY, MITCH D.; POLATO, NICHOLAS R.; FITZPATRICK, SARAH W.; COONAN, TIMOTHY J.; CROOKS, KEVIN R.; DILLON, ADAM; GARCELON, DAVID K.; KING, JULIE L.; BOSER, CHRISTINA L.; GOULD, NICHOLAS; ANDELT, WILLIAM F.

2016-01-01

The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of 6 subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1–89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland gray foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6–6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness, and reduced adaptive potential. PMID:26992010

Ecological divergence in the yellow-bellied kingsnake (Lampropeltis calligaster) at two North American biodiversity hotspots.

PubMed

McKelvy, A D; Burbrink, F T

2017-01-01

Several biogeographic barriers in the Eastern Nearctic appear to reduce gene flow among populations of many species in predictable ways, however these patterns used to infer process of divergence may be deceiving if alternative modes of diversification are not considered. By using a multilocus statistical phylogeographic approach to examine diversity within a North American snake, Lampropeltis calligaster, we find that mode and timing of speciation near the Mississippi River embayment and peninsular Florida, two main biodiversity hotspots in eastern North America, challenge previously held notions of strict vicariance as the causal factor behind patterns of divergence seen among taxa at these locations. We found three species inhabiting distinct ecological niches with divergences dating to the mid- and early-Pleistocene with subsequently stable or increasing effective population sizes, further supporting the idea that the Pleistocene was an important driver of diversification in North America. Our results lead to a revised hypothesis that ecological divergence has occurred in this group across environments associated with the Mississippi River and at the Florida peninsula. Importantly, in their western distributions, we show that species divergence is associated with the ecological transition from distinct forested habitats to grasslands, rather than the nearby Mississippi River, a barrier often implicated for many other organisms. Additionally, we stress the importance of examining each delimited lineage with respect to conservation, since ecological niche models suggest that by the end of the century changes in climate may negatively alter habitat suitability and, barring adaptation, substantially reduce the suitable range of two of the three species we identified. Copyright © 2016 Elsevier Inc. All rights reserved.

Do Growth Mindsets in Math Benefit Females? Identifying Pathways between Gender, Mindset, and Motivation.

PubMed

Degol, Jessica L; Wang, Ming-Te; Zhang, Ya; Allerton, Julie

2018-05-01

Despite efforts to increase female representation in science, technology, engineering, and mathematics (STEM), females continue to be less motivated to pursue STEM careers than males. A short-term longitudinal study used a sample of 1449 high school students (grades 9-12; 49% females) to examine pathways from gender and mindset onto STEM outcomes via motivational beliefs (i.e., expectancy beliefs, task value, and cost). Mindset, motivational beliefs, and STEM career aspirations were assessed between the fall and winter months of the 2014-2015 school year and math grades were obtained at the conclusion of the same year. Student growth mindset beliefs predicted higher task values in math. Task values also mediated the pathway from a growth mindset to higher STEM career aspirations. Expectancy beliefs mediated the pathway between gender and math achievement. This mediated pathway was stronger for females than for males, such that females had higher math achievement than males when they endorsed a growth mindset. Findings suggest possible avenues for improving female's interest in STEM.

Comparative functional characterization of the CSR-1 22G-RNA pathway in Caenorhabditis nematodes.

PubMed

Tu, Shikui; Wu, Monica Z; Wang, Jie; Cutter, Asher D; Weng, Zhiping; Claycomb, Julie M

2015-01-01

As a champion of small RNA research for two decades, Caenorhabditis elegans has revealed the essential Argonaute CSR-1 to play key nuclear roles in modulating chromatin, chromosome segregation and germline gene expression via 22G-small RNAs. Despite CSR-1 being preserved among diverse nematodes, the conservation and divergence in function of the targets of small RNA pathways remains poorly resolved. Here we apply comparative functional genomic analysis between C. elegans and Caenorhabditis briggsae to characterize the CSR-1 pathway, its targets and their evolution. C. briggsae CSR-1-associated small RNAs that we identified by immunoprecipitation-small RNA sequencing overlap with 22G-RNAs depleted in cbr-csr-1 RNAi-treated worms. By comparing 22G-RNAs and target genes between species, we defined a set of CSR-1 target genes with conserved germline expression, enrichment in operons and more slowly evolving coding sequences than other genes, along with a small group of evolutionarily labile targets. We demonstrate that the association of CSR-1 with chromatin is preserved, and show that depletion of cbr-csr-1 leads to chromosome segregation defects and embryonic lethality. This first comparative characterization of a small RNA pathway in Caenorhabditis establishes a conserved nuclear role for CSR-1 and highlights its key role in germline gene regulation across multiple animal species. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

The evolution of cortical development: the synapsid-diapsid divergence.

PubMed

Goffinet, Andre M

2017-11-15

The cerebral cortex covers the rostral part of the brain and, in higher mammals and particularly humans, plays a key role in cognition and consciousness. It is populated with neuronal cell bodies distributed in radially organized layers. Understanding the common and lineage-specific molecular mechanisms that orchestrate cortical development and evolution are key issues in neurobiology. During evolution, the cortex appeared in stem amniotes and evolved divergently in two main branches of the phylogenetic tree: the synapsids (which led to present day mammals) and the diapsids (reptiles and birds). Comparative studies in organisms that belong to those two branches have identified some common principles of cortical development and organization that are possibly inherited from stem amniotes and regulated by similar molecular mechanisms. These comparisons have also highlighted certain essential features of mammalian cortices that are absent or different in diapsids and that probably evolved after the synapsid-diapsid divergence. Chief among these is the size and multi-laminar organization of the mammalian cortex, and the propensity to increase its area by folding. Here, I review recent data on cortical neurogenesis, neuronal migration and cortical layer formation and folding in this evolutionary perspective, and highlight important unanswered questions for future investigation. © 2017. Published by The Company of Biologists Ltd.

Identifying Potential Therapeutics for Osteoporosis by Exploiting the Relationship between Mevalonate Pathway and Bone Metabolism.

PubMed

Wan Hasan, Wan Nuraini; Chin, Kok-Yong; Jolly, James Jam; Abd Ghafar, Norzana; Soelaiman, Ima Nirwana

2018-04-23

Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling. This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential. Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans. mevalonate pathway can be exploited to develop effective antiosteoporosis agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Identification of parallel and divergent optimization solutions for homologous metabolic enzymes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Standaert, Robert F.; Giannone, Richard J.; Michener, Joshua K.

Here, metabolic pathway assembly typically involves the expression of enzymes from multiple organisms in a single heterologous host. Ensuring that each enzyme functions effectively can be challenging, since many potential factors can disrupt proper pathway flux. Here, we compared the performance of two enzyme homologs in a pathway engineered to allow Escherichia coli to grow on 4-hydroxybenzoate (4-HB), a byproduct of lignocellulosic biomass deconstruction. Single chromosomal copies of the 4-HB 3-monooxygenase genes pobA and praI, from Pseudomonas putida KT2440 and Paenibacillus sp. JJ-1B, respectively, were introduced into a strain able to metabolize protocatechuate (PCA), the oxidation product of 4-HB. Neithermore » enzyme initially supported consistent growth on 4-HB. Experimental evolution was used to identify mutations that improved pathway activity. For both enzymes, silent mRNA mutations were identified that increased enzyme expression. With pobA, duplication of the genes for PCA metabolism allowed growth on 4-HB. However, with praI, growth required a mutation in the 4-HB/PCA transporter pcaK that increased intracellular concentrations of 4-HB, suggesting that flux through PraI was limiting. These findings demonstrate the value of directed evolution strategies to rapidly identify and overcome diverse factors limiting enzyme activity.« less

Identification of parallel and divergent optimization solutions for homologous metabolic enzymes

DOE PAGES

Standaert, Robert F.; Giannone, Richard J.; Michener, Joshua K.

2018-04-18

Here, metabolic pathway assembly typically involves the expression of enzymes from multiple organisms in a single heterologous host. Ensuring that each enzyme functions effectively can be challenging, since many potential factors can disrupt proper pathway flux. Here, we compared the performance of two enzyme homologs in a pathway engineered to allow Escherichia coli to grow on 4-hydroxybenzoate (4-HB), a byproduct of lignocellulosic biomass deconstruction. Single chromosomal copies of the 4-HB 3-monooxygenase genes pobA and praI, from Pseudomonas putida KT2440 and Paenibacillus sp. JJ-1B, respectively, were introduced into a strain able to metabolize protocatechuate (PCA), the oxidation product of 4-HB. Neithermore » enzyme initially supported consistent growth on 4-HB. Experimental evolution was used to identify mutations that improved pathway activity. For both enzymes, silent mRNA mutations were identified that increased enzyme expression. With pobA, duplication of the genes for PCA metabolism allowed growth on 4-HB. However, with praI, growth required a mutation in the 4-HB/PCA transporter pcaK that increased intracellular concentrations of 4-HB, suggesting that flux through PraI was limiting. These findings demonstrate the value of directed evolution strategies to rapidly identify and overcome diverse factors limiting enzyme activity.« less

Identification of parallel and divergent optimization solutions for homologous metabolic enzymes.

PubMed

Standaert, Robert F; Giannone, Richard J; Michener, Joshua K

2018-06-01

Metabolic pathway assembly typically involves the expression of enzymes from multiple organisms in a single heterologous host. Ensuring that each enzyme functions effectively can be challenging, since many potential factors can disrupt proper pathway flux. Here, we compared the performance of two enzyme homologs in a pathway engineered to allow Escherichia coli to grow on 4-hydroxybenzoate (4-HB), a byproduct of lignocellulosic biomass deconstruction. Single chromosomal copies of the 4-HB 3-monooxygenase genes pobA and praI , from Pseudomonas putida KT2440 and Paenibacillus sp. JJ-1B, respectively, were introduced into a strain able to metabolize protocatechuate (PCA), the oxidation product of 4-HB. Neither enzyme initially supported consistent growth on 4-HB. Experimental evolution was used to identify mutations that improved pathway activity. For both enzymes, silent mRNA mutations were identified that increased enzyme expression. With pobA , duplication of the genes for PCA metabolism allowed growth on 4-HB. However, with praI , growth required a mutation in the 4-HB/PCA transporter pcaK that increased intracellular concentrations of 4-HB, suggesting that flux through PraI was limiting. These findings demonstrate the value of directed evolution strategies to rapidly identify and overcome diverse factors limiting enzyme activity.

Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution.

PubMed

Medina-Carmona, Encarnación; Fuchs, Julian E; Gavira, Jose A; Mesa-Torres, Noel; Neira, Jose L; Salido, Eduardo; Palomino-Morales, Rogelio; Burgos, Miguel; Timson, David J; Pey, Angel L

2017-09-15

Human proteins are vulnerable towards disease-associated single amino acid replacements affecting protein stability and function. Interestingly, a few studies have shown that consensus amino acids from mammals or vertebrates can enhance protein stability when incorporated into human proteins. Here, we investigate yet unexplored relationships between the high vulnerability of human proteins towards disease-associated inactivation and recent evolutionary site-specific divergence of stabilizing amino acids. Using phylogenetic, structural and experimental analyses, we show that divergence from the consensus amino acids at several sites during mammalian evolution has caused local protein destabilization in two human proteins linked to disease: cancer-associated NQO1 and alanine:glyoxylate aminotransferase, mutated in primary hyperoxaluria type I. We demonstrate that a single consensus mutation (H80R) acts as a disease suppressor on the most common cancer-associated polymorphism in NQO1 (P187S). The H80R mutation reactivates P187S by enhancing FAD binding affinity through local and dynamic stabilization of its binding site. Furthermore, we show how a second suppressor mutation (E247Q) cooperates with H80R in protecting the P187S polymorphism towards inactivation through long-range allosteric communication within the structural ensemble of the protein. Our results support that recent divergence of consensus amino acids may have occurred with neutral effects on many functional and regulatory traits of wild-type human proteins. However, divergence at certain sites may have increased the propensity of some human proteins towards inactivation due to disease-associated mutations and polymorphisms. Consensus mutations also emerge as a potential strategy to identify structural hot-spots in proteins as targets for pharmacological rescue in loss-of-function genetic diseases. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please

Estimating linear-nonlinear models using Renyi divergences.

PubMed

Kouh, Minjoon; Sharpee, Tatyana O

2009-01-01

This article compares a family of methods for characterizing neural feature selectivity using natural stimuli in the framework of the linear-nonlinear model. In this model, the spike probability depends in a nonlinear way on a small number of stimulus dimensions. The relevant stimulus dimensions can be found by optimizing a Rényi divergence that quantifies a change in the stimulus distribution associated with the arrival of single spikes. Generally, good reconstructions can be obtained based on optimization of Rényi divergence of any order, even in the limit of small numbers of spikes. However, the smallest error is obtained when the Rényi divergence of order 1 is optimized. This type of optimization is equivalent to information maximization, and is shown to saturate the Cramer-Rao bound describing the smallest error allowed for any unbiased method. We also discuss conditions under which information maximization provides a convenient way to perform maximum likelihood estimation of linear-nonlinear models from neural data.

Decrease of Population Divergence in Eurasian Perch (Perca fluviatilis) in Browning Waters: Role of Fatty Acids and Foraging Efficiency

PubMed Central

Scharnweber, Kristin; Strandberg, Ursula; Karlsson, Konrad; Eklöv, Peter

2016-01-01

Due to altered biogeochemical processes related to climate change, highly colored dissolved organic carbon (DOC) from terrestrial sources will lead to a water “brownification” in many freshwater systems of the Northern Hemisphere. This will create deteriorated visual conditions that have been found to affect habitat-specific morphological variations in Eurasian perch (Perca fluviatilis) in a previous study. So far, potential drivers and ultimate causes of these findings have not been identified. We conducted a field study to investigate the connection between morphological divergence and polyunsaturated fatty acid (PUFA) composition of perch from six lakes across a gradient of DOC concentration. We expected a decrease in the prevalence of PUFAs, which are important for perch growth and divergence with increasing DOC concentrations, due to the restructuring effects of DOC on aquatic food webs. In general, rate of morphological divergence in perch decreased with increasing DOC concentrations. Proportions of specific PUFAs (22:6n-3, 18:3n-3, 20:5n-3, and 20:4n-6) identified to primarily contribute to overall differences between perch caught in clear and brown-water lakes tended to be connected to overall decline of morphological divergence. However, no overall significant relationship was found, indicating no severe limitation of essential fatty acids for perch inhabiting brown water lakes. We further broaden our approach by conducting a laboratory experiment on foraging efficiency of perch. Therefore, we induced pelagic and littoral phenotypes by differences in habitat-structure and feeding mode and recorded attack rate in a feeding experiment. Generally, fish were less efficient in foraging on littoral prey (Ephemeroptera) when visual conditions were degraded by brown water color. We concluded that browning water may have a strong effect on the forager’s ability to find particular food resources, resulting in the reduced development of evolutionary traits

Divergence in Ynone Reactivity: Atypical Cyclization by 3,4-Difunctionalization versus Rare Bis(cyclization).

PubMed

Alcaide, Benito; Almendros, Pedro; Lázaro-Milla, Carlos; Delgado-Martínez, Patricia

2018-04-06

Functionalized ynones can be activated by Tf 2 C=CH 2 , which was generated in situ, to form zwitterionic species. These species were trapped in an intramolecular fashion by several nucleophiles to generate two major types of triflones in a divergent manner. Through fine-tuning of the reaction temperature, bis(triflyl)-6-membered- or (triflyl)-5-membered-fused-heterocycles were achieved in reasonable yields in a totally selective manner. In this way, bis(triflyl)flavones, bis(triflyl)thioflavones, bis(triflyl)selenoflavones, (triflyl)benzothienopyrans, (triflyl)benzoselenophenopyrans, (triflyl)vinyl aurones, and (triflyl)pyranoindoles were constructed. Conceivable mechanistic pathways were suggested on the basis of the isolation of several intermediates and the results from control experiments. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Surprisal analysis of genome-wide transcript profiling identifies differentially expressed genes and pathways associated with four growth conditions in the microalga Chlamydomonas.

PubMed

Bogaert, Kenny A; Manoharan-Basil, Sheeba S; Perez, Emilie; Levine, Raphael D; Remacle, Francoise; Remacle, Claire

2018-01-01

The usual cultivation mode of the green microalga Chlamydomonas is liquid medium and light. However, the microalga can also be grown on agar plates and in darkness. Our aim is to analyze and compare gene expression of cells cultivated in these different conditions. For that purpose, RNA-seq data are obtained from Chlamydomonas samples of two different labs grown in four environmental conditions (agar@light, agar@dark, liquid@light, liquid@dark). The RNA seq data are analyzed by surprisal analysis, which allows the simultaneous meta-analysis of all the samples. First we identify a balance state, which defines a state where the expression levels are similar in all the samples irrespectively of their growth conditions, or lab origin. In addition our analysis identifies additional constraints needed to quantify the deviation with respect to the balance state. The first constraint differentiates the agar samples versus the liquid ones; the second constraint the dark samples versus the light ones. The two constraints are almost of equal importance. Pathways involved in stress responses are found in the agar phenotype while the liquid phenotype comprises ATP and NADH production pathways. Remodeling of membrane is suggested in the dark phenotype while photosynthetic pathways characterize the light phenotype. The same trends are also present when performing purely statistical analysis such as K-means clustering and differentially expressed genes.

Identifying Likely Transmission Pathways within a 10-Year Community Outbreak of Tuberculosis by High-Depth Whole Genome Sequencing

PubMed Central

Sadsad, Rosemarie; Martinez, Elena; Jelfs, Peter; Hill-Cawthorne, Grant A.; Gilbert, Gwendolyn L.; Marais, Ben J.; Sintchenko, Vitali

2016-01-01

Background Improved tuberculosis control and the need to contain the spread of drug-resistant strains provide a strong rationale for exploring tuberculosis transmission dynamics at the population level. Whole-genome sequencing provides optimal strain resolution, facilitating detailed mapping of potential transmission pathways. Methods We sequenced 22 isolates from a Mycobacterium tuberculosis cluster in New South Wales, Australia, identified during routine 24-locus mycobacterial interspersed repetitive unit typing. Following high-depth paired-end sequencing using the Illumina HiSeq 2000 platform, two independent pipelines were employed for analysis, both employing read mapping onto reference genomes as well as de novo assembly, to control biases in variant detection. In addition to single-nucleotide polymorphisms, the analyses also sought to identify insertions, deletions and structural variants. Results Isolates were highly similar, with a distance of 13 variants between the most distant members of the cluster. The most sensitive analysis classified the 22 isolates into 18 groups. Four of the isolates did not appear to share a recent common ancestor with the largest clade; another four isolates had an uncertain ancestral relationship with the largest clade. Conclusion Whole genome sequencing, with analysis of single-nucleotide polymorphisms, insertions, deletions, structural variants and subpopulations, enabled the highest possible level of discrimination between cluster members, clarifying likely transmission pathways and exposing the complexity of strain origin. The analysis provides a basis for targeted public health intervention and enhanced classification of future isolates linked to the cluster. PMID:26938641

Gauge-invariance and infrared divergences in the luminosity distance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Biern, Sang Gyu; Yoo, Jaiyul, E-mail: sgbiern@physik.uzh.ch, E-mail: jyoo@physik.uzh.ch

2017-04-01

Measurements of the luminosity distance have played a key role in discovering the late-time cosmic acceleration. However, when accounting for inhomogeneities in the Universe, its interpretation has been plagued with infrared divergences in its theoretical predictions, which are in some cases used to explain the cosmic acceleration without dark energy. The infrared divergences in most calculations are artificially removed by imposing an infrared cut-off scale. We show that a gauge-invariant calculation of the luminosity distance is devoid of such divergences and consistent with the equivalence principle, eliminating the need to impose a cut-off scale. We present proper numerical calculations ofmore » the luminosity distance using the gauge-invariant expression and demonstrate that the numerical results with an ad hoc cut-off scale in previous calculations have negligible systematic errors as long as the cut-off scale is larger than the horizon scale. We discuss the origin of infrared divergences and their cancellation in the luminosity distance.« less

Role of mantle flow in Nubia-Somalia plate divergence

NASA Astrophysics Data System (ADS)

Stamps, D. S.; Iaffaldano, G.; Calais, E.

2015-01-01

Present-day continental extension along the East African Rift System (EARS) has often been attributed to diverging sublithospheric mantle flow associated with the African Superplume. This implies a degree of viscous coupling between mantle and lithosphere that remains poorly constrained. Recent advances in estimating present-day opening rates along the EARS from geodesy offer an opportunity to address this issue with geodynamic modeling of the mantle-lithosphere system. Here we use numerical models of the global mantle-plates coupled system to test the role of present-day mantle flow in Nubia-Somalia plate divergence across the EARS. The scenario yielding the best fit to geodetic observations is one where torques associated with gradients of gravitational potential energy stored in the African highlands are resisted by weak continental faults and mantle basal drag. These results suggest that shear tractions from diverging mantle flow play a minor role in present-day Nubia-Somalia divergence.

Genome-wide evidence for divergent selection between populations of a major agricultural pathogen.

PubMed

Hartmann, Fanny E; McDonald, Bruce A; Croll, Daniel

2018-06-01

The genetic and environmental homogeneity in agricultural ecosystems is thought to impose strong and uniform selection pressures. However, the impact of this selection on plant pathogen genomes remains largely unknown. We aimed to identify the proportion of the genome and the specific gene functions under positive selection in populations of the fungal wheat pathogen Zymoseptoria tritici. First, we performed genome scans in four field populations that were sampled from different continents and on distinct wheat cultivars to test which genomic regions are under recent selection. Based on extended haplotype homozygosity and composite likelihood ratio tests, we identified 384 and 81 selective sweeps affecting 4% and 0.5% of the 35 Mb core genome, respectively. We found differences both in the number and the position of selective sweeps across the genome between populations. Using a XtX-based outlier detection approach, we identified 51 extremely divergent genomic regions between the allopatric populations, suggesting that divergent selection led to locally adapted pathogen populations. We performed an outlier detection analysis between two sympatric populations infecting two different wheat cultivars to identify evidence for host-driven selection. Selective sweep regions harboured genes that are likely to play a role in successfully establishing host infections. We also identified secondary metabolite gene clusters and an enrichment in genes encoding transporter and protein localization functions. The latter gene functions mediate responses to environmental stress, including interactions with the host. The distinct gene functions under selection indicate that both local host genotypes and abiotic factors contributed to local adaptation. © 2018 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.

An integrative framework for Bayesian variable selection with informative priors for identifying genes and pathways.

PubMed

Peng, Bin; Zhu, Dianwen; Ander, Bradley P; Zhang, Xiaoshuai; Xue, Fuzhong; Sharp, Frank R; Yang, Xiaowei

2013-01-01

The discovery of genetic or genomic markers plays a central role in the development of personalized medicine. A notable challenge exists when dealing with the high dimensionality of the data sets, as thousands of genes or millions of genetic variants are collected on a relatively small number of subjects. Traditional gene-wise selection methods using univariate analyses face difficulty to incorporate correlational, structural, or functional structures amongst the molecular measures. For microarray gene expression data, we first summarize solutions in dealing with 'large p, small n' problems, and then propose an integrative Bayesian variable selection (iBVS) framework for simultaneously identifying causal or marker genes and regulatory pathways. A novel partial least squares (PLS) g-prior for iBVS is developed to allow the incorporation of prior knowledge on gene-gene interactions or functional relationships. From the point view of systems biology, iBVS enables user to directly target the joint effects of multiple genes and pathways in a hierarchical modeling diagram to predict disease status or phenotype. The estimated posterior selection probabilities offer probabilitic and biological interpretations. Both simulated data and a set of microarray data in predicting stroke status are used in validating the performance of iBVS in a Probit model with binary outcomes. iBVS offers a general framework for effective discovery of various molecular biomarkers by combining data-based statistics and knowledge-based priors. Guidelines on making posterior inferences, determining Bayesian significance levels, and improving computational efficiencies are also discussed.

Estimation of divergence from Hardy-Weinberg form.

PubMed

Stark, Alan E

2015-08-01

The Hardy–Weinberg (HW) principle explains how random mating (RM) can produce and maintain a population in equilibrium, that is, with constant genotypic proportions. When proportions diverge from HW form, it is of interest to estimate the fixation index F, which reflects the degree of divergence. Starting from a sample of genotypic counts, a mixed procedure gives first the orthodox estimate of gene frequency q and then a Bayesian estimate of F, based on a credible prior distribution of F, which is described here.

Temperature, energy metabolism, and adaptive divergence in two oyster subspecies.

PubMed

Li, Ao; Li, Li; Song, Kai; Wang, Wei; Zhang, Guofan

2017-08-01

Comparisons of related species that have diverse spatial distributions provide an efficient way to investigate adaptive evolution in face of increasing global warming. The oyster subjected to high environmental selections is a model species as sessile marine invertebrate. This study aimed to detect the adaptive divergence of energy metabolism in two oyster subspecies from the genus Crassostrea - C. gigas gigas and C. gigas angulata -which are broadly distributed along the northern and southern coasts of China, respectively. We examined the effects of acute thermal stress on energy metabolism in two oyster subspecies after being common gardened for one generation in identical conditions. Thermal responses were assessed by incorporating physiological, molecular, and genomic approaches. Southern oysters exhibited higher fluctuations in metabolic rate, activities of key energetic enzymes, and levels of thermally induced gene expression than northern oysters. For genes involved in energy metabolism, the former displayed higher basal levels of gene expression and a more pronounced downregulation of thermally induced expression, while the later exhibited lower basal levels and a less pronounced downregulation of gene expression. Contrary expression pattern was observed in oxidative stress gene. Besides, energy metabolic tradeoffs were detected in both subspecies. Furthermore, the genetic divergence of a nonsynonymous SNP ( SOD-132 ) and five synonymous SNPs in other genes was identified and validated in these two subspecies, which possibly affects downstream functions and explains the aforementioned phenotypic variations. Our study demonstrates that differentiations in energy metabolism underlie the plasticity of adaptive divergence in two oyster subspecies and suggest C. gigas angulata with moderate phenotypic plasticity has higher adaptive potential to cope with exacerbated global warming.

Evolution of vocal patterns: tuning hindbrain circuits during species divergence.

PubMed

Barkan, Charlotte L; Zornik, Erik; Kelley, Darcy B

2017-03-01

The neural circuits underlying divergent courtship behaviors of closely related species provide a framework for insight into the evolution of motor patterns. In frogs, male advertisement calls serve as unique species identifiers and females prefer conspecific to heterospecific calls. Advertisement calls of three relatively recently (∼8.5 Mya) diverged species - Xenopus laevis , X. petersii and X. victorianus - include rapid trains of sound pulses (fast trills). We show that while fast trills are similar in pulse rate (∼60 pulses s -1 ) across the three species, they differ in call duration and period (time from the onset of one call to the onset of the following call). Previous studies of call production in X. laevis used an isolated brain preparation in which the laryngeal nerve produces compound action potentials that correspond to the advertisement call pattern (fictive calling). Here, we show that serotonin evokes fictive calling in X. petersii and X. victorianus as it does in X. laevis As in X. laevis , fictive fast trill in X. petersii and X. victorianus is accompanied by an N -methyl-d-aspartate receptor-dependent local field potential wave in a rostral hindbrain nucleus, DTAM. Across the three species, wave duration and period are strongly correlated with species-specific fast trill duration and period, respectively. When DTAM is isolated from the more rostral forebrain and midbrain and/or more caudal laryngeal motor nucleus, the wave persists at species-typical durations and periods. Thus, intrinsic differences within DTAM could be responsible for the evolutionary divergence of call patterns across these related species. © 2017. Published by The Company of Biologists Ltd.

"Which Pathway Am I?" Using a Game Approach to Teach Students about Biochemical Pathways

ERIC Educational Resources Information Center

Ooi, Beng Guat; Sanger, Michael J.

2009-01-01

This game was designed to provide students with an alternative way to learn biochemical pathways through an interactive approach. In this game, students worked in pairs to help each other identify pathways taped to each other's backs by asking simple "yes or no" questions related to these pathways. This exercise was conducted after the traditional…

A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway Is Associated With Major Depressive Disorder.

PubMed

Zeng, Yanni; Navarro, Pau; Fernandez-Pujals, Ana M; Hall, Lynsey S; Clarke, Toni-Kim; Thomson, Pippa A; Smith, Blair H; Hocking, Lynne J; Padmanabhan, Sandosh; Hayward, Caroline; MacIntyre, Donald J; Wray, Naomi R; Deary, Ian J; Porteous, David J; Haley, Chris S; McIntosh, Andrew M

2017-02-15

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have identified few significant associations. Testing the aggregation of genetic variants, in particular biological pathways, may be more powerful. Regional heritability analysis can be used to detect genomic regions that contribute to disease risk. We integrated pathway analysis and multilevel regional heritability analyses in a pipeline designed to identify MDD-associated pathways. The pipeline was applied to two independent GWAS samples [Generation Scotland: The Scottish Family Health Study (GS:SFHS, N = 6455) and Psychiatric Genomics Consortium (PGC:MDD) (N = 18,759)]. A polygenic risk score (PRS) composed of single nucleotide polymorphisms from the pathway most consistently associated with MDD was created, and its accuracy to predict MDD, using area under the curve, logistic regression, and linear mixed model analyses, was tested. In GS:SFHS, four pathways were significantly associated with MDD, and two of these explained a significant amount of pathway-level regional heritability. In PGC:MDD, one pathway was significantly associated with MDD. Pathway-level regional heritability was significant in this pathway in one subset of PGC:MDD. For both samples the regional heritabilities were further localized to the gene and subregion levels. The NETRIN1 signaling pathway showed the most consistent association with MDD across the two samples. PRSs from this pathway showed competitive predictive accuracy compared with the whole-genome PRSs when using area under the curve statistics, logistic regression, and linear mixed model. These post-GWAS analyses highlight the value of combining multiple methods on multiple GWAS data for the identification of risk pathways for MDD. The NETRIN1 signaling pathway is identified as a candidate pathway for MDD and should be explored in further large population studies. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights

Converging or Diverging Lens?

ERIC Educational Resources Information Center

Branca, Mario

2013-01-01

Why does a lens magnify? Why does it shrink objects? Why does this happen? The activities that we propose here are useful in helping us to understand how lenses work, and they show that the same lens can have different magnification capabilities. A converging lens can also act as a diverging lens. (Contains 4 figures.)

Individual Differences and Age-Related Changes in Divergent Thinking in Toddlers and Preschoolers

ERIC Educational Resources Information Center

Bijvoet-van den Berg, Simone; Hoicka, Elena

2014-01-01

Divergent thinking shows the ability to search for new ideas, which is an important factor contributing to innovation and problem solving. Current divergent thinking tests allow researchers to study children's divergent thinking from the age of 3 years on. This article presents the first measure of divergent thinking that can be used with children…

Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome.

PubMed

Morine, Melissa J; McMonagle, Jolene; Toomey, Sinead; Reynolds, Clare M; Moloney, Aidan P; Gormley, Isobel C; Gaora, Peadar O; Roche, Helen M

2010-10-07

constituent genes, as well as strong correlations between gene expression and plasma markers of metabolic syndrome independent of the dietary effect. Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of analysis has the potential to generate novel transcriptome-based biomarkers of disease.

Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome

PubMed Central

2010-01-01

-sensitive changes in constituent genes, as well as strong correlations between gene expression and plasma markers of metabolic syndrome independent of the dietary effect. Conclusion Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of analysis has the potential to generate novel transcriptome-based biomarkers of disease. PMID:20929581

Functional magnetic resonance imaging of divergent and convergent thinking in Big-C creativity.

PubMed

Japardi, Kevin; Bookheimer, Susan; Knudsen, Kendra; Ghahremani, Dara G; Bilder, Robert M

2018-02-15

The cognitive and physiological processes underlying creativity remain unclear, and very few studies to date have attempted to identify the behavioral and brain characteristics that distinguish exceptional ("Big-C") from everyday ("little-c") creativity. The Big-C Project examined functional brain responses during tasks demanding divergent and convergent thinking in 35 Big-C Visual Artists (VIS), 41 Big-C Scientists (SCI), and 31 individuals in a "smart comparison group" (SCG) matched to the Big-C groups on parental educational attainment and estimated IQ. Functional MRI (fMRI) scans included two activation paradigms widely used in prior creativity research, the Alternate Uses Task (AUT) and Remote Associates Task (RAT), to assess brain function during divergent and convergent thinking, respectively. Task performance did not differ between groups. Functional MRI activation in Big-C and SCG groups differed during the divergent thinking task. No differences in activation were seen during the convergent thinking task. Big-C groups had less activation than SCG in frontal pole, right frontal operculum, left middle frontal gyrus, and bilaterally in occipital cortex. SCI displayed lower frontal and parietal activation relative to the SCG when generating alternate uses in the AUT, while VIS displayed lower frontal activation than SCI and SCG when generating typical qualities (the control condition in the AUT). VIS showed more activation in right inferior frontal gyrus and left supramarginal gyrus relative to SCI. All groups displayed considerable overlapping activation during the RAT. The results confirm substantial overlap in functional activation across groups, but suggest that exceptionally creative individuals may depend less on task-positive networks during tasks that demand divergent thinking. Published by Elsevier Ltd.

Whole genome investigation of a divergent clade of the pathogen Streptococcus suis

PubMed Central

Baig, Abiyad; Weinert, Lucy A.; Peters, Sarah E.; Howell, Kate J.; Chaudhuri, Roy R.; Wang, Jinhong; Holden, Matthew T. G.; Parkhill, Julian; Langford, Paul R.; Rycroft, Andrew N.; Wren, Brendan W.; Tucker, Alexander W.; Maskell, Duncan J.

2015-01-01

Streptococcus suis is a major porcine and zoonotic pathogen responsible for significant economic losses in the pig industry and an increasing number of human cases. Multiple isolates of S. suis show marked genomic diversity. Here, we report the analysis of whole genome sequences of nine pig isolates that caused disease typical of S. suis and had phenotypic characteristics of S. suis, but their genomes were divergent from those of many other S. suis isolates. Comparison of protein sequences predicted from divergent genomes with those from normal S. suis reduced the size of core genome from 793 to only 397 genes. Divergence was clear if phylogenetic analysis was performed on reduced core genes and MLST alleles. Phylogenies based on certain other genes (16S rRNA, sodA, recN, and cpn60) did not show divergence for all isolates, suggesting recombination between some divergent isolates with normal S. suis for these genes. Indeed, there is evidence of recent recombination between the divergent and normal S. suis genomes for 249 of 397 core genes. In addition, phylogenetic analysis based on the 16S rRNA gene and 132 genes that were conserved between the divergent isolates and representatives of the broader Streptococcus genus showed that divergent isolates were more closely related to S. suis. Six out of nine divergent isolates possessed a S. suis-like capsule region with variation in capsular gene sequences but the remaining three did not have a discrete capsule locus. The majority (40/70), of virulence-associated genes in normal S. suis were present in the divergent genomes. Overall, the divergent isolates extend the current diversity of S. suis species but the phenotypic similarities and the large amount of gene exchange with normal S. suis gives insufficient evidence to assign these isolates to a new species or subspecies. Further, sampling and whole genome analysis of more isolates is warranted to understand the diversity of the species. PMID:26583006

Determining the Effect of Natural Selection on Linked Neutral Divergence across Species.

PubMed

Phung, Tanya N; Huber, Christian D; Lohmueller, Kirk E

2016-08-01

A major goal in evolutionary biology is to understand how natural selection has shaped patterns of genetic variation across genomes. Studies in a variety of species have shown that neutral genetic diversity (intra-species differences) has been reduced at sites linked to those under direct selection. However, the effect of linked selection on neutral sequence divergence (inter-species differences) remains ambiguous. While empirical studies have reported correlations between divergence and recombination, which is interpreted as evidence for natural selection reducing linked neutral divergence, theory argues otherwise, especially for species that have diverged long ago. Here we address these outstanding issues by examining whether natural selection can affect divergence between both closely and distantly related species. We show that neutral divergence between closely related species (e.g. human-primate) is negatively correlated with functional content and positively correlated with human recombination rate. We also find that neutral divergence between distantly related species (e.g. human-rodent) is negatively correlated with functional content and positively correlated with estimates of background selection from primates. These patterns persist after accounting for the confounding factors of hypermutable CpG sites, GC content, and biased gene conversion. Coalescent models indicate that even when the contribution of ancestral polymorphism to divergence is small, background selection in the ancestral population can still explain a large proportion of the variance in divergence across the genome, generating the observed correlations. Our findings reveal that, contrary to previous intuition, natural selection can indirectly affect linked neutral divergence between both closely and distantly related species. Though we cannot formally exclude the possibility that the direct effects of purifying selection drive some of these patterns, such a scenario would be possible only

Determining the Effect of Natural Selection on Linked Neutral Divergence across Species

PubMed Central

Phung, Tanya N.; Lohmueller, Kirk E.

2016-01-01

A major goal in evolutionary biology is to understand how natural selection has shaped patterns of genetic variation across genomes. Studies in a variety of species have shown that neutral genetic diversity (intra-species differences) has been reduced at sites linked to those under direct selection. However, the effect of linked selection on neutral sequence divergence (inter-species differences) remains ambiguous. While empirical studies have reported correlations between divergence and recombination, which is interpreted as evidence for natural selection reducing linked neutral divergence, theory argues otherwise, especially for species that have diverged long ago. Here we address these outstanding issues by examining whether natural selection can affect divergence between both closely and distantly related species. We show that neutral divergence between closely related species (e.g. human-primate) is negatively correlated with functional content and positively correlated with human recombination rate. We also find that neutral divergence between distantly related species (e.g. human-rodent) is negatively correlated with functional content and positively correlated with estimates of background selection from primates. These patterns persist after accounting for the confounding factors of hypermutable CpG sites, GC content, and biased gene conversion. Coalescent models indicate that even when the contribution of ancestral polymorphism to divergence is small, background selection in the ancestral population can still explain a large proportion of the variance in divergence across the genome, generating the observed correlations. Our findings reveal that, contrary to previous intuition, natural selection can indirectly affect linked neutral divergence between both closely and distantly related species. Though we cannot formally exclude the possibility that the direct effects of purifying selection drive some of these patterns, such a scenario would be possible only

Evolutionary relationships and divergence times among the native rats of Australia.

PubMed

Robins, Judith H; McLenachan, Patricia A; Phillips, Matthew J; McComish, Bennet J; Matisoo-Smith, Elizabeth; Ross, Howard A

2010-12-02

The genus Rattus is highly speciose and has a complex taxonomy that is not fully resolved. As shown previously there are two major groups within the genus, an Asian and an Australo-Papuan group. This study focuses on the Australo-Papuan group and particularly on the Australian rats. There are uncertainties regarding the number of species within the group and the relationships among them. We analysed 16 mitochondrial genomes, including seven novel genomes from six species, to help elucidate the evolutionary history of the Australian rats. We also demonstrate, from a larger dataset, the usefulness of short regions of the mitochondrial genome in identifying these rats at the species level. Analyses of 16 mitochondrial genomes representing species sampled from Australo-Papuan and Asian clades of Rattus indicate divergence of these two groups ~2.7 million years ago (Mya). Subsequent diversification of at least 4 lineages within the Australo-Papuan clade was rapid and occurred over the period from ~ 0.9-1.7 Mya, a finding that explains the difficulty in resolving some relationships within this clade. Phylogenetic analyses of our 126 taxon, but shorter sequence (1952 nucleotides long), Rattus database generally give well supported species clades. Our whole mitochondrial genome analyses are concordant with a taxonomic division that places the native Australian rats into the Rattus fuscipes species group. We suggest the following order of divergence of the Australian species. R. fuscipes is the oldest lineage among the Australian rats and is not part of a New Guinean radiation. R. lutreolus is also within this Australian clade and shallower than R. tunneyi while the R. sordidus group is the shallowest lineage in the clade. The divergences within the R. sordidus and R. leucopus lineages occurring about half a million years ago support the hypotheses of more recent interchanges of rats between Australia and New Guinea. While problematic for inference of deeper divergences, we

Identifying Barriers and Pathways to Success for Renewable Energy Development on American Indian Lands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Necefer, Len Edward; Jones, Thomas Elisha

American Indian tribes possess lands rich with renewable energy (RE) resources. Tribes have great potential and need to develop these resources, yet face a host of barriers that continue to impede development. Understanding these challenges as well as the pathways that can be taken to overcome them may facilitate more economic development to meet community needs and better position tribes to play a role in securing a low-carbon energy future for the United States. This paper presents the results of an expert elicitation of 24 tribal energy experts from federal, tribal, academic, and private industry backgrounds to identify barriers andmore » opportunities for federally recognized tribes in the lower 48 states. Experts identified a number of unique challenges facing tribes including financing and funding, infrastructure, tribal leadership and staff, state-level influence, and partnerships. Cultural factors were seen only to be of concern with large-scale development. Tribal sovereignty is a significant motivation for RE development and has yet to be fully realized. Cultural considerations are critical to the success of future projects; smaller residential and community-scale projects may be a better fit. Improving partnerships between tribes and the private sector can increase RE deployment and overcome historical distrust. States can have a double-ended influence on projects within tribal lands through taxation.« less

Diverging diamond interchange : informational guide.

DOT National Transportation Integrated Search

2014-08-01

This document provides information and guidance on the Diverging Diamond Interchange (DDI). To the extent possible, the guide : addresses a variety of conditions found in the United States, to achieve designs suitable for a wide array of potential us...

Divergent Thinking and Creative Ideation of High School Students

ERIC Educational Resources Information Center

Ramzan, Shaikh Imran; Perveen, Shaheen

2011-01-01

Divergent thinking is an integral process in creativity. Openness to experience is a personality trait that relates to divergent thinking and, therefore, is hypothesized to be related to creative performance among the students. The effects of openness to experience are likely to be partially mediated by an individual's attitude toward divergent…

Regulatory Divergence between Parental Alleles Determines Gene Expression Patterns in Hybrids

PubMed Central

Combes, Marie-Christine; Hueber, Yann; Dereeper, Alexis; Rialle, Stéphanie; Herrera, Juan-Carlos; Lashermes, Philippe

2015-01-01

Both hybridization and allopolyploidization generate novel phenotypes by conciliating divergent genomes and regulatory networks in the same cellular context. To understand the rewiring of gene expression in hybrids, the total expression of 21,025 genes and the allele-specific expression of over 11,000 genes were quantified in interspecific hybrids and their parental species, Coffea canephora and Coffea eugenioides using RNA-seq technology. Between parental species, cis- and trans-regulatory divergences affected around 32% and 35% of analyzed genes, respectively, with nearly 17% of them showing both. The relative importance of trans-regulatory divergences between both species could be related to their low genetic divergence and perennial habit. In hybrids, among divergently expressed genes between parental species and hybrids, 77% was expressed like one parent (expression level dominance), including 65% like C. eugenioides. Gene expression was shown to result from the expression of both alleles affected by intertwined parental trans-regulatory factors. A strong impact of C. eugenioides trans-regulatory factors on the upregulation of C. canephora alleles was revealed. The gene expression patterns appeared determined by complex combinations of cis- and trans-regulatory divergences. In particular, the observed biased expression level dominance seemed to be derived from the asymmetric effects of trans-regulatory parental factors on regulation of alleles. More generally, this study illustrates the effects of divergent trans-regulatory parental factors on the gene expression pattern in hybrids. The characteristics of the transcriptional response to hybridization appear to be determined by the compatibility of gene regulatory networks and therefore depend on genetic divergences between the parental species and their evolutionary history. PMID:25819221

Accelerating 4D flow MRI by exploiting vector field divergence regularization.

PubMed

Santelli, Claudio; Loecher, Michael; Busch, Julia; Wieben, Oliver; Schaeffter, Tobias; Kozerke, Sebastian

2016-01-01

To improve velocity vector field reconstruction from undersampled four-dimensional (4D) flow MRI by penalizing divergence of the measured flow field. Iterative image reconstruction in which magnitude and phase are regularized separately in alternating iterations was implemented. The approach allows incorporating prior knowledge of the flow field being imaged. In the present work, velocity data were regularized to reduce divergence, using either divergence-free wavelets (DFW) or a finite difference (FD) method using the ℓ1-norm of divergence and curl. The reconstruction methods were tested on a numerical phantom and in vivo data. Results of the DFW and FD approaches were compared with data obtained with standard compressed sensing (CS) reconstruction. Relative to standard CS, directional errors of vector fields and divergence were reduced by 55-60% and 38-48% for three- and six-fold undersampled data with the DFW and FD methods. Velocity vector displays of the numerical phantom and in vivo data were found to be improved upon DFW or FD reconstruction. Regularization of vector field divergence in image reconstruction from undersampled 4D flow data is a valuable approach to improve reconstruction accuracy of velocity vector fields. © 2014 Wiley Periodicals, Inc.