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Sample records for ongoing positive selection

  1. Science Selections. Accounts of Ongoing Scientific Research.

    ERIC Educational Resources Information Center

    Kornberg, Warren, Ed.

    This publication is intended to present science teachers with an opportunity to communicate to students the idea that science is an ongoing and never-ending process. The booklet contains supplemental materials, valuable as enrichment materials. A selection of ongoing research in the biological sciences, physics and astronomy, oceanography,…

  2. Evidence for ongoing brain injury in human immunodeficiency virus–positive patients treated with antiretroviral therapy

    PubMed Central

    Cardenas, VA; Meyerhoff, DJ; Studholme, C; Kornak, J; Rothlind, J; Lampiris, H; Neuhaus, J; Grant, RM; Chao, LL; Truran, D; Weiner, MW

    2009-01-01

    Treatment with antiretroviral therapy (ART) has greatly reduced the incidence of dementia. The goal of this longitudinal study was to determine if there are ongoing macrostructural brain changes in human immunodeficiency virus–positive (HIV+) individuals treated with ART. To quantify brain structure, three-dimensional T1-weighted magnetic resonance imaging (MRI) scans were performed at baseline and again after 24 months in 39 HIV+ patients on ART and 30 HIV− controls. Longitudinal changes in brain volume were measured using tissue segmentation within regions of interest and deformation morphometry. Measured by tissue segmentation, HIV+ patients on ART had significantly (all P < .05) greater rates of white matter volume loss than HIV− control individuals. Compared with controls, the subgroup of HIV+ individuals on ART with viral suppression also had significantly greater rates of white matter volume loss. Deformation morphometry confirmed these results with more specific spatial localization. Deformation morphometry also detected greater rates of gray matter and white matter loss in the subgroup of HIV+ individuals with detectable viral loads. These results provide evidence of ongoing brain volume loss in HIV+ individuals on stable ART, possibly suggesting ongoing cerebral injury. The presence of continuing injury raises the possibility that HIV+ individuals—even in the presence of viral suppression in the periphery—are at greater risk for future cognitive impairments and dementia and possibly faster cognitive decline. Therefore, HIV+ individuals on ART should be monitored for cognitive decline, and treatments that reduce ongoing neurological injury should be considered. PMID:19499454

  3. Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions.

    PubMed

    Petersen, Gitte L; Finnerup, Nanna B; Grosen, Kasper; Pilegaard, Hans K; Tracey, Irene; Benedetti, Fabrizio; Price, Donald D; Jensen, Troels S; Vase, Lene

    2014-12-01

    Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M-VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind-up-like pain). There was a significant placebo effect on both ongoing (P=.009 to .019) and evoked neuropathic pain (P=.0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P⩽.001). Pain increases during nocebo were nonsignificant (P=.394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo-induced reduction in hyperalgesia and suggests that patients' expectations coexist with emotional feelings about treatments.

  4. Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives.

    PubMed

    Mirghani, H; Amen, F; Blanchard, P; Moreau, F; Guigay, J; Hartl, D M; Lacau St Guily, J

    2015-04-01

    Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High-risk human papillomavirus (HR-HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de-escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de-escalation in HPV-positive OPSCC.

  5. X-ray selected Type-2 QSOs: ongoing star formation and obscured accretion.

    NASA Astrophysics Data System (ADS)

    Mainieri, Vincenzo; Cosmos Collaboration

    2009-09-01

    Although the fraction of obscured AGN is found to decrease with luminosity from several studies, a non-negligible population of obscured QSOs is still required by the X-ray background synthesis models. We present a large sample (121 objects) of X-ray selected Type-2 QSOs from the XMM-COSMOS survey: sources with high X-ray luminosity (LX>10^{44} erg s^{-1}) and heavy obscuration (NH>10^{22} cm^{-2}), as derived from a detailed X-ray spectral analysis (see Mainieri et al.,2007, ApJS, 172, 368) of the 1800 X-ray point-like sources in this survey. Few (˜5%) of the Type-2 QSOs are best fitted with a pure reflection model. We have performed optical spectroscopy for ˜ 30% of the sample and for the remaining sources we have derived accurate photometric redshifts. The redshift range covered is wide, 0.30.8).We compare the general properties of the host galaxies with the ongoing accretion in their nuclei. Morphology: using five non-parametric diagnostics (asymmetry, concentration, Gini coefficient, M20, ellipticity) we found that ˜10% of the Type-2 QSOs are in elliptical galaxies, ˜55% in disk galaxies and ˜35% in irregular galaxies. The majority of the irregular hosts can be described as undergoing merger activity or show tidal debris. Stellar masses have been derived from SED fitting to the observed photometry(from 0.3 to 4.5 micron) and star formation rates from the [OII] or Hα line fluxes. The majority (˜75%) of QSO-2 host galaxies have stellar masses above log(Mstar)˜10.5 MSun and have ongoing star formation (˜100 MSun/yr). The value of 10.5 MSun is similar to the characteristic mass for obscured AGN (Kauffmann et al. 2003) and radio-loud AGN (Best et al. 2005) in the SDSS. It is also consistent with the more general result that the fraction of galaxies hosting AGN increases with the stellar mass.

  6. Ongoing characterization of the forced electron beam induced arc discharge ion source for the selective production of exotic species facility

    SciTech Connect

    Manzolaro, M. Andrighetto, A.; Monetti, A.; Scarpa, D.; Rossignoli, M.; Vasquez, J.; Corradetti, S.; Calderolla, M.; Prete, G.; Meneghetti, G.

    2014-02-15

    An intense research and development activity to finalize the design of the target ion source system for the selective production of exotic species (SPES) facility (operating according to the isotope separation on line technique) is at present ongoing at Legnaro National Laboratories. In particular, the characterization of ion sources in terms of ionization efficiency and transversal emittance is currently in progress, and a preliminary set of data is already available. In this work, the off-line ionization efficiency and emittance measurements for the SPES forced electron beam induced arc discharge ion source in the case of a stable Ar beam are presented in detail.

  7. Fish oil–based lipid emulsions in the treatment of parenteral nutrition-associated liver disease: An ongoing positive experience

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We previously reported the beneficial effect of fish oil-based lipid emulsions (FOLEs) as monotherapy in the treatment of parenteral nutrition-associated liver disease (PNALD). In this report, we share our ongoing experience at Texas Children's Hospital, Houston, in the use of FOLE in treatment of P...

  8. Ongoing Inquiry

    ERIC Educational Resources Information Center

    Ashbrook, Peggy

    2011-01-01

    An in-depth science inquiry is an ongoing investigation in which children are introduced to materials through hands-on experiences and, with teacher guidance, begin to investigate a question that they can answer through their own actions, observations, and with teacher-assisted research. Qualities that make an experience appropriate to include in…

  9. Guiding transcranial brain stimulation by EEG/MEG to interact with ongoing brain activity and associated functions: A position paper.

    PubMed

    Thut, Gregor; Bergmann, Til Ole; Fröhlich, Flavio; Soekadar, Surjo R; Brittain, John-Stuart; Valero-Cabré, Antoni; Sack, Alexander; Miniussi, Carlo; Antal, Andrea; Siebner, Hartwig Roman; Ziemann, Ulf; Herrmann, Christoph S

    2017-01-29

    Non-invasive transcranial brain stimulation (NTBS) techniques have a wide range of applications but also suffer from a number of limitations mainly related to poor specificity of intervention and variable effect size. These limitations motivated recent efforts to focus on the temporal dimension of NTBS with respect to the ongoing brain activity. Temporal patterns of ongoing neuronal activity, in particular brain oscillations and their fluctuations, can be traced with electro- or magnetoencephalography (EEG/MEG), to guide the timing as well as the stimulation settings of NTBS. These novel, online and offline EEG/MEG-guided NTBS-approaches are tailored to specifically interact with the underlying brain activity. Online EEG/MEG has been used to guide the timing of NTBS (i.e., when to stimulate): by taking into account instantaneous phase or power of oscillatory brain activity, NTBS can be aligned to fluctuations in excitability states. Moreover, offline EEG/MEG recordings prior to interventions can inform researchers and clinicians how to stimulate: by frequency-tuning NTBS to the oscillation of interest, intrinsic brain oscillations can be up- or down-regulated. In this paper, we provide an overview of existing approaches and ideas of EEG/MEG-guided interventions, and their promises and caveats. We point out potential future lines of research to address challenges.

  10. Global Positioning System Satellite Selection Method

    NASA Technical Reports Server (NTRS)

    Niles, Frederick A. (Inventor)

    2001-01-01

    The satellite selection method as utilized by the spaceborne Global Positioning System receiver provides navigational solutions and is designed for use in low Earth orbit. The satellite selection method is a robust algorithm that can be used a GPS receiver to select appropriate GPS satellites for use in calculating point solutions or attitude solutions. The method is takes into account the difficulty of finding a particular GPS satellite phase code, especially when the search range in greatly increased due to Doppler shifts introduced into the carrier frequency. The method starts with an update of the antenna pointing and spacecraft vectors to determine the antenna backplane direction. Next, the GPS satellites that will potentially be in view of the antenna are ranked on a list, whereby the list is generated based on the estimated attitude and position of each GPS satellite. Satellites blocked by the Earth are not entered on this list. A second list is created, whereby the GPS satellites are ranked according to their desirability for use in attitude determination. GPS satellites are ranked according to their orthogonality to the antenna backplane, and according to geometric dilution of precision considerations. After the lists are created, the channels of the spaceborne GPS receiver are assigned to various GPS satellites for acquisition and lock. Preliminary Doppler frequencies for searching are assigned to the various channels.

  11. Positive Psychology in Context: Effects of Expressing Gratitude in Ongoing Relationships Depend on Perceptions of Enactor Responsiveness

    PubMed Central

    Algoe, Sara B.; Zhaoyang, Ruixue

    2016-01-01

    Recent correlational evidence implicates gratitude in personal and relational growth, for both members of ongoing relationships. From these observations, it would be tempting to prescribe interpersonal gratitude exercises to improve relationships. In this experiment, couples were randomly assigned to express gratitude over a month, or to a relationally-active control condition. Results showed modest effects of condition on personal and relational well-being. However, those whose partners were perceived as being particularly responsive when expressing gratitude at the initial lab session showed greater well-being across a range of outcomes, whereas this was not so for people in the control condition. Notably, evidence raises concerns about the effectiveness of artificial injections of gratitude when the partner is perceived to be low in responsiveness. Given the importance of close relationships, this work highlights the need for more theory-driven basic research tested in context before assuming what appears to work naturally will also work artificially. PMID:27800009

  12. Results of the Ongoing Monitoring of the Position of a Geostationary Telecommunication Satellite by the Method of Spatially Separated Basis Receiving of Digital Satellite Television Signals

    NASA Astrophysics Data System (ADS)

    Bushuev, F.; Kaliuzhnyi, M.; Sybiryakova, Y.; Shulga, O.; Moskalenko, S.; Balagura, O.; Kulishenko, V.

    2016-10-01

    The results of the ongoing monitoring of the position of geostationary telecommunication satellite Eutelsat-13B (13° East) are presented in the article. The results were obtained using a radio engineering complex (RC) of four stations receiving digital satellite television and a data processing centre. The stations are located in Kyiv, Mukachevo, Kharkiv and Mykolaiv. The equipment of each station allows synchronous recording (by the GPS) of fragments of DVB-S signal from the quadrature detector output of the satellite television receiver. Samples of the complex signal are archived and sent to the data processing center through the Internet. Here three linearly independent slant range differences (Δr) for three pairs of the stations are determined as a result of correlation processing of received signals. Every second measured values of Δr are used to calculate Cartesian coordinates (XYZ) of the satellite in the coordinate system WGS84 by multilateration method. The time series of Δr, X, Y and Z obtained during continuous observations from March to May 2015 are presented in the article. Single-measurement errors of Δr, X, Y and Z are equal to 2.6 m, 3540 m, 705 m and 455 m, respectively. The complex is compared with known analogues. Ways of reduction of measurement errors of satellite coordinates are considered. The radio engineering complex could be considered a prototype of a system of independent ongoing monitoring of the position of geostationary telecommunication satellites.

  13. What Drives Positive Selection in the Drosophila piRNA Machinery? The Genomic Autoimmunity Hypothesis

    PubMed Central

    Blumenstiel, Justin P.; Erwin, Alexandra A.; Hemmer, Lucas W.

    2016-01-01

    In animals, PIWI-interacting RNAs (piRNAs) play a crucial role in genome defense. Moreover, because piRNAs can be maternally transmitted, they contribute to the epigenetic profile of inheritance. Multiple studies, especially in Drosophila, have demonstrated that the machinery of piRNA biogenesis is often the target of positive selection. Because transposable elements (TEs) are a form of genetic parasite, positive selection in the piRNA machinery is often explained by analogy to the signatures of positive selection commonly observed in genes that play a role in host-parasite dynamics. However, the precise mechanisms that drive positive selection in the piRNA machinery are not known. In this review, we outline several mechanistic models that might explain pervasive positive selection in the piRNA machinery of Drosophila species. We propose that recurrent positive selection in the piRNA machinery can be partly explained by an ongoing tension between selection for sensitivity required by genome defense and selection for specificity to avoid the off-target effects of maladaptive genic silencing by piRNA. PMID:28018141

  14. Outgroups and Positive Selection: The Nothobranchius furzeri Case.

    PubMed

    Sahm, Arne; Platzer, Matthias; Cellerino, Alessandro

    2016-09-01

    Applications of positive selection analysis increase with the number of species for which genome/transcriptome sequences become available. Using the recently sequenced turquoise killifish (Nothobranchius furzeri) genome as an example, we compare two different approaches based on different outgroup selection. The combination of these two methods allows the origin of positively selected sites in aging-related genes of the N. furzeri genome to be determined.

  15. The SEDIBUD (Sediment Budgets in Cold Environments) Programme: Ongoing activities and selected key tasks for the coming years

    NASA Astrophysics Data System (ADS)

    Beylich, Achim A.; Lamoureux, Scott F.; Decaulne, Armelle

    2012-09-01

    Projected climate change in cold environments is expected to alter melt-season duration and intensity, along with the number of extreme rainfall events, total annual precipitation and the balance between snowfall and rainfall. In addition, changes to the thermal balance are expected to reduce the extent of permafrost and seasonal ground frost and increase active layer depths. The combined effects of these changes will alter surface environments in cold climate regions and change the fluxes of sediments, nutrients and solutes, but the absence of data, coordinated process monitoring and coordinated quantitative analysis to understand the sensitivity of the Earth surface environment are acute in cold climate environments. The International Association of Geomorphologists (I.A.G./A.I.G.) SEDIBUD (Sediment Budgets in Cold Environments) Programme has been formed to address this key knowledge gap and builds on the earlier European Science Foundation (ESF) SEDIFLUX (Sedimentary Source-to-Sink-Fluxes in Cold Environments) Network. Coordinated efforts are carried out to monitor, quantify, compare and model sedimentary fluxes and possible effects of predicted climate change in currently 44 selected SEDIBUD Key Test Sites (cold climate environment catchments) worldwide.

  16. Widespread positive selection in the photosynthetic Rubisco enzyme

    PubMed Central

    Kapralov, Maxim V; Filatov, Dmitry A

    2007-01-01

    Background Rubisco enzyme catalyzes the first step in net photosynthetic CO2 assimilation and photorespiratory carbon oxidation and is responsible for almost all carbon fixation on Earth. The large subunit of Rubisco is encoded by the chloroplast rbcL gene, which is widely used for reconstruction of plant phylogenies due to its conservative nature. Plant systematicists have mainly used rbcL paying little attention to its function, and the question whether it evolves under Darwinian selection has received little attention. The purpose of our study was to evaluate how common is positive selection in Rubisco among the phototrophs and where in the Rubisco structure does positive selection occur. Results We searched for positive selection in rbcL sequences from over 3000 species representing all lineages of green plants and some lineages of other phototrophs, such as brown and red algae, diatoms, euglenids and cyanobacteria. Our molecular phylogenetic analysis found the presence of positive selection in rbcL of most analyzed land plants, but not in algae and cyanobacteria. The mapping of the positively selected residues on the Rubisco tertiary structure revealed that they are located in regions important for dimer-dimer, intradimer, large subunit-small subunit and Rubisco-Rubisco activase interactions, and that some of the positively selected residues are close to the active site. Conclusion Our results demonstrate that despite its conservative nature, Rubisco evolves under positive selection in most lineages of land plants, and after billions of years of evolution Darwinian selection still fine-tunes its performance. Widespread positive selection in rbcL has to be taken into account when this gene is used for phylogenetic reconstructions. PMID:17498284

  17. Constructing genomic maps of positive selection in humans: Where do we go from here?

    PubMed Central

    Akey, Joshua M.

    2009-01-01

    Identifying targets of positive selection in humans has, until recently, been frustratingly slow, relying on the analysis of individual candidate genes. Genomics, however, has provided the necessary resources to systematically interrogate the entire genome for signatures of natural selection. To date, 21 genome-wide scans for recent or ongoing positive selection have been performed in humans. A key challenge is to begin synthesizing these newly constructed maps of positive selection into a coherent narrative of human evolutionary history and derive a deeper mechanistic understanding of how natural populations evolve. Here, I chronicle the recent history of the burgeoning field of human population genomics, critically assess genome-wide scans for positive selection in humans, identify important gaps in knowledge, and discuss both short- and long-term strategies for traversing the path from the low-resolution, incomplete, and error-prone maps of selection today to the ultimate goal of a detailed molecular, mechanistic, phenotypic, and population genetics characterization of adaptive alleles. PMID:19411596

  18. Control selection and participation in an ongoing, population-based, case-control study of birth defects: the National Birth Defects Prevention Study.

    PubMed

    Cogswell, Mary E; Bitsko, Rebecca H; Anderka, Marlene; Caton, Alissa R; Feldkamp, Marcia L; Hockett Sherlock, Stacey M; Meyer, Robert E; Ramadhani, Tunu; Robbins, James M; Shaw, Gary M; Mathews, T J; Royle, Marjorie; Reefhuis, Jennita

    2009-10-15

    To evaluate the representativeness of controls in an ongoing, population-based, case-control study of birth defects in 10 centers across the United States, researchers compared 1997-2003 birth certificate data linked to selected controls (n = 6,681) and control participants (n = 4,395) with those from their base populations (n = 2,468,697). Researchers analyzed differences in population characteristics (e.g., percentage of births at > or =2,500 g) for each group. Compared with their base populations, control participants did not differ in distributions of maternal or paternal age, previous livebirths, maternal smoking, or diabetes, but they did differ in other maternal (i.e., race/ethnicity, education, entry into prenatal care) and infant (i.e., birth weight, gestational age, and plurality) characteristics. Differences in distributions of maternal, but not infant, characteristics were associated with participation by selected controls. Absolute differences in infant characteristics for the base population versus control participants were < or =1.3 percentage points. Differences in infant characteristics were greater at centers that selected controls from hospitals compared with centers that selected controls from electronic birth certificates. These findings suggest that control participants in the National Birth Defects Prevention Study generally are representative of their base populations. Hospital-based control selection may slightly underascertain infants affected by certain adverse birth outcomes.

  19. Evolution under domestication: ongoing artificial selection and divergence of wild and managed Stenocereus pruinosus (Cactaceae) populations in the Tehuacán Valley, Mexico

    PubMed Central

    Parra, Fabiola; Casas, Alejandro; Peñaloza-Ramírez, Juan Manuel; Cortés-Palomec, Aurea C.; Rocha-Ramírez, Víctor; González-Rodríguez, Antonio

    2010-01-01

    Background and Aims The Tehuacán Valley in Mexico is a principal area of plant domestication in Mesoamerica. There, artificial selection is currently practised on nearly 120 native plant species with coexisting wild, silvicultural and cultivated populations, providing an excellent setting for studying ongoing mechanisms of evolution under domestication. One of these species is the columnar cactus Stenocereus pruinosus, in which we studied how artificial selection is operating through traditional management and whether it has determined morphological and genetic divergence between wild and managed populations. Methods Semi-structured interviews were conducted with 83 households of three villages to investigate motives and mechanisms of artificial selection. Management effects were studied by comparing variation patterns of 14 morphological characters and population genetics (four microsatellite loci) of 264 plants from nine wild, silvicultural and cultivated populations. Key Results Variation in fruit characters was recognized by most people, and was the principal target of artificial selection directed to favour larger and sweeter fruits with thinner or thicker peel, fewer spines and pulp colours others than red. Artificial selection operates in agroforestry systems favouring abundance (through not felling plants and planting branches) of the preferred phenotypes, and acts more intensely in household gardens. Significant morphological divergence between wild and managed populations was observed in fruit characters and plant vigour. On average, genetic diversity in silvicultural populations (HE = 0·743) was higher than in wild (HE = 0·726) and cultivated (HE = 0·700) populations. Most of the genetic variation (90·58 %) occurred within populations. High gene flow (NmFST > 2) was identified among almost all populations studied, but was slightly limited by mountains among wild populations, and by artificial selection among wild and managed populations. Conclusions

  20. Position paper - peer review and design verification of selected activities

    SciTech Connect

    Stine, M.D.

    1994-09-01

    Position Paper to develop and document a position on the performance of independent peer reviews on selected design and analysis components of the Title I (preliminary) and Title II (detailed) design phases of the Multi-Function Waste Tank Facility project.

  1. Erasing Errors due to Alignment Ambiguity When Estimating Positive Selection

    PubMed Central

    Redelings, Benjamin

    2014-01-01

    Current estimates of diversifying positive selection rely on first having an accurate multiple sequence alignment. Simulation studies have shown that under biologically plausible conditions, relying on a single estimate of the alignment from commonly used alignment software can lead to unacceptably high false-positive rates in detecting diversifying positive selection. We present a novel statistical method that eliminates excess false positives resulting from alignment error by jointly estimating the degree of positive selection and the alignment under an evolutionary model. Our model treats both substitutions and insertions/deletions as sequence changes on a tree and allows site heterogeneity in the substitution process. We conduct inference starting from unaligned sequence data by integrating over all alignments. This approach naturally accounts for ambiguous alignments without requiring ambiguously aligned sites to be identified and removed prior to analysis. We take a Bayesian approach and conduct inference using Markov chain Monte Carlo to integrate over all alignments on a fixed evolutionary tree topology. We introduce a Bayesian version of the branch-site test and assess the evidence for positive selection using Bayes factors. We compare two models of differing dimensionality using a simple alternative to reversible-jump methods. We also describe a more accurate method of estimating the Bayes factor using Rao-Blackwellization. We then show using simulated data that jointly estimating the alignment and the presence of positive selection solves the problem with excessive false positives from erroneous alignments and has nearly the same power to detect positive selection as when the true alignment is known. We also show that samples taken from the posterior alignment distribution using the software BAli-Phy have substantially lower alignment error compared with MUSCLE, MAFFT, PRANK, and FSA alignments. PMID:24866534

  2. Selection and the cell cycle: positive Darwinian selection in a well-known DNA damage response pathway.

    PubMed

    O'Connell, Mary J

    2010-12-01

    Cancer is a common occurrence in multi-cellular organisms and is not strictly limited to the elderly in a population. It is therefore possible that individuals with genotypes that protect against early onset cancers have a selective advantage. In this study the patterns of mutation in the proteins of a well-studied DNA damage response pathway have been examined for evidence of adaptive evolutionary change. Using a maximum likelihood framework and the mammalian species phylogeny, together with codon models of evolution, selective pressure variation across the interacting network of proteins has been detected. The presence of signatures of adaptive evolution in BRCA1 and BRCA2 has already been documented but the effect on the entire network of interacting proteins in this damage response pathway has, until now, been unknown. Positive selection is evident throughout the network with a total of 11 proteins out of 15 examined displaying patterns of substitution characteristic of positive selection. It is also shown here that modern human populations display evidence of an ongoing selective sweep in 9 of these DNA damage repair proteins. The results presented here provide the community with new residues that may be relevant to cancer susceptibility while also highlighting those proteins where human and mouse have undergone lineage-specific functional shift. An understanding of this damage response pathway from an evolutionary perspective will undoubtedly contribute to future cancer treatment approaches.

  3. Molecules and mating: positive selection and reproductive behaviour in primates.

    PubMed

    Knapp, Leslie A; Innocent, Simeon H S

    2012-01-01

    Sexual reproduction is generally thought to be more costly than asexual reproduction. However, it does have the advantage of accelerating rates of adaptation through processes such as recombination and positive selection. Comparative studies of the human and nonhuman primate genomes have demonstrated that positive selection has played an important role in the evolutionary history of humans and other primates. To date, many dozens of genes, thought to be affected by positive selection, have been identified. In this chapter, we will focus on genes that are associated with mating behaviours and reproductive processes, concentrating on genes that are most likely to enhance reproductive success and that also show evidence of positive selection. The genes encode phenotypic features that potentially influence mate choice decisions or impact the evolution and function of genes involved in the perception and regulation of, and the response to, phenotypic signals. We will also consider genes that influence precopulatory behavioural traits in humans and nonhuman primates, such as social bonding and aggression. The evolution of post-copulatory strategies such as sperm competition and selective abortion may also evolve in the presence of intense competition and these adaptations will also be considered. Although behaviour may not be solely determined by genes, the evidence suggests that the genes discussed in this chapter have some influence on human and nonhuman primate behaviour and that positive selection on these genes results in some degree of population differentiation and diversity.

  4. Genes associated with SLE are targets of recent positive selection.

    PubMed

    Ramos, Paula S; Shaftman, Stephanie R; Ward, Ralph C; Langefeld, Carl D

    2014-01-01

    The reasons for the ethnic disparities in the prevalence of systemic lupus erythematosus (SLE) and the relative high frequency of SLE risk alleles in the population are not fully understood. Population genetic factors such as natural selection alter allele frequencies over generations and may help explain the persistence of such common risk variants in the population and the differential risk of SLE. In order to better understand the genetic basis of SLE that might be due to natural selection, a total of 74 genomic regions with compelling evidence for association with SLE were tested for evidence of recent positive selection in the HapMap and HGDP populations, using population differentiation, allele frequency, and haplotype-based tests. Consistent signs of positive selection across different studies and statistical methods were observed at several SLE-associated loci, including PTPN22, TNFSF4, TET3-DGUOK, TNIP1, UHRF1BP1, BLK, and ITGAM genes. This study is the first to evaluate and report that several SLE-associated regions show signs of positive natural selection. These results provide corroborating evidence in support of recent positive selection as one mechanism underlying the elevated population frequency of SLE risk loci and supports future research that integrates signals of natural selection to help identify functional SLE risk alleles.

  5. The effect of selective availability on differential GPS positioning

    NASA Astrophysics Data System (ADS)

    Tolman, Brian W.; Coco, David S.; Leach, Mark P.; Clynch, James R.

    The effect of Selective Availability (SA) on differential positioning is considered, using an extensive two-frequency P code data set which was collected during two periods: a publicly announced test of the GPS constellation in October, 1989, and after it was announced that SA had been implemented, in April 1990. The data were collected with the cooperation of several organizations, using TI 4100 receivers and atomic clocks at 6 sites, spanning baselines from 8 to 1350 kilometers, over a total of more than 25 days. A subset of this data set shows strong characteristics which are probably due to SA. Differential positions which have been computed using this 'unhealthy' data are compared to truth positions, and to identically computed positions using apparently 'healthy' data from the same period. The results and their implications for the impact that SA could have on differential positioning are presented.

  6. A Demonstration of Regression False Positive Selection in Data Mining

    ERIC Educational Resources Information Center

    Pinder, Jonathan P.

    2014-01-01

    Business analytics courses, such as marketing research, data mining, forecasting, and advanced financial modeling, have substantial predictive modeling components. The predictive modeling in these courses requires students to estimate and test many linear regressions. As a result, false positive variable selection ("type I errors") is…

  7. Methods and reagents. Reducing background colonies with positive selection vectors.

    PubMed

    Hengen, P N

    1997-03-01

    Methods and reagents is a unique monthly column that highlights current discussions in the newsgroup bionet.molbio.methds-reagnts, available on the Internet. This month's column discusses the pros and cons of eliminating unwanted background colonies by using the positive selection vector pZErO. For details on how to partake in the newsgroup, see the accompanying box.

  8. Positively selected sites in cetacean myoglobins contribute to protein stability.

    PubMed

    Dasmeh, Pouria; Serohijos, Adrian W R; Kepp, Kasper P; Shakhnovich, Eugene I

    2013-01-01

    Since divergence ∼50 Ma ago from their terrestrial ancestors, cetaceans underwent a series of adaptations such as a ∼10-20 fold increase in myoglobin (Mb) concentration in skeletal muscle, critical for increasing oxygen storage capacity and prolonging dive time. Whereas the O2-binding affinity of Mbs is not significantly different among mammals (with typical oxygenation constants of ∼0.8-1.2 µM(-1)), folding stabilities of cetacean Mbs are ∼2-4 kcal/mol higher than for terrestrial Mbs. Using ancestral sequence reconstruction, maximum likelihood and bayesian tests to describe the evolution of cetacean Mbs, and experimentally calibrated computation of stability effects of mutations, we observe accelerated evolution in cetaceans and identify seven positively selected sites in Mb. Overall, these sites contribute to Mb stabilization with a conditional probability of 0.8. We observe a correlation between Mb folding stability and protein abundance, suggesting that a selection pressure for stability acts proportionally to higher expression. We also identify a major divergence event leading to the common ancestor of whales, during which major stabilization occurred. Most of the positively selected sites that occur later act against other destabilizing mutations to maintain stability across the clade, except for the shallow divers, where late stability relaxation occurs, probably due to the shorter aerobic dive limits of these species. The three main positively selected sites 66, 5, and 35 undergo changes that favor hydrophobic folding, structural integrity, and intra-helical hydrogen bonds.

  9. Selective assessment and positivity bias in environmental valuation.

    PubMed

    Posavac, Steven S; Brakus, J Josko; Jain, Shailendra Pratap; Cronley, Maria L

    2006-03-01

    The need to determine the value of environmental entities has generated substantial research regarding optimal methods for obtaining valuations from survey respondents. The literature suggests the importance of providing clear, complete descriptions of the entity being valued prior to respondents indicating their valuations. The target entity's attributes are often presented in isolation or in greater detail compared with other entities. Two experiments were conducted to explore whether selective exposure to and assessment of an environmental entity can bias survey respondents' judgments. This article adds to the environmental valuation literature by demonstrating a new process that leads to value overestimates. Specifically, the article shows that (a) when an environmental entity is the focus of assessment in a survey, positively biased evaluations often result; (b) positivity bias in evaluation translates to real monetary allocation decisions; and (c) selective information processing contributes to these effects.

  10. Positive darwinian selection at the imprinted MEDEA locus in plants.

    PubMed

    Spillane, Charles; Schmid, Karl J; Laoueillé-Duprat, Sylvia; Pien, Stéphane; Escobar-Restrepo, Juan-Miguel; Baroux, Célia; Gagliardini, Valeria; Page, Damian R; Wolfe, Kenneth H; Grossniklaus, Ueli

    2007-07-19

    In mammals and seed plants, a subset of genes is regulated by genomic imprinting where an allele's activity depends on its parental origin. The parental conflict theory suggests that genomic imprinting evolved after the emergence of an embryo-nourishing tissue (placenta and endosperm), resulting in an intragenomic parental conflict over the allocation of nutrients from mother to offspring. It was predicted that imprinted genes, which arose through antagonistic co-evolution driven by a parental conflict, should be subject to positive darwinian selection. Here we show that the imprinted plant gene MEDEA (MEA), which is essential for seed development, originated during a whole-genome duplication 35 to 85 million years ago. After duplication, MEA underwent positive darwinian selection consistent with neo-functionalization and the parental conflict theory. MEA continues to evolve rapidly in the out-crossing species Arabidopsis lyrata but not in the self-fertilizing species Arabidopsis thaliana, where parental conflicts are reduced. The paralogue of MEA, SWINGER (SWN; also called EZA1), is not imprinted and evolved under strong purifying selection because it probably retained the ancestral function of the common precursor gene. The evolution of MEA suggests a late origin of genomic imprinting within the Brassicaceae, whereas imprinting is thought to have originated early within the mammalian lineage.

  11. Using two on-going HIV studies to obtain clinical data from before, during and after pregnancy for HIV-positive women

    PubMed Central

    2012-01-01

    Background The UK Collaborative HIV Cohort (UK CHIC) is an observational study that collates data on HIV-positive adults accessing HIV clinical care at (currently) 13 large clinics in the UK but does not collect pregnancy specific data. The National Study of HIV in Pregnancy and Childhood (NSHPC) collates data on HIV-positive women receiving antenatal care from every maternity unit in the UK and Ireland. Both studies collate pseudonymised data and neither dataset contains unique patient identifiers. A methodology was developed to find and match records for women reported to both studies thereby obtaining clinical and treatment data on pregnant HIV-positive women not available from either dataset alone. Results Women in UK CHIC receiving HIV-clinical care in 1996–2009, were found in the NSHPC dataset by initially ‘linking’ records with identical date-of-birth, linked records were then accepted as a genuine ‘match’, if they had further matching fields including CD4 test date. In total, 2063 women were found in both datasets, representing 23.1% of HIV-positive women with a pregnancy in the UK (n = 8932). Clinical data was available in UK CHIC following most pregnancies (92.0%, 2471/2685 pregnancies starting before 2009). There was bias towards matching women with repeat pregnancies (35.9% (741/2063) of women found in both datasets had a repeat pregnancy compared to 21.9% (1502/6869) of women in NSHPC only) and matching women HIV diagnosed before their first reported pregnancy (54.8% (1131/2063) compared to 47.7% (3278/6869), respectively). Conclusions Through the use of demographic data and clinical dates, records from two independent studies were successfully matched, providing data not available from either study alone. PMID:22839414

  12. A Genome Scan for Positive Selection in Thoroughbred Horses

    PubMed Central

    Gu, Jingjing; Orr, Nick; Park, Stephen D.; Katz, Lisa M.; Sulimova, Galina; MacHugh, David E.; Hill, Emmeline W.

    2009-01-01

    Thoroughbred horses have been selected for exceptional racing performance resulting in system-wide structural and functional adaptations contributing to elite athletic phenotypes. Because selection has been recent and intense in a closed population that stems from a small number of founder animals Thoroughbreds represent a unique population within which to identify genomic contributions to exercise-related traits. Employing a population genetics-based hitchhiking mapping approach we performed a genome scan using 394 autosomal and X chromosome microsatellite loci and identified positively selected loci in the extreme tail-ends of the empirical distributions for (1) deviations from expected heterozygosity (Ewens-Watterson test) in Thoroughbred (n = 112) and (2) global differentiation among four geographically diverse horse populations (FST). We found positively selected genomic regions in Thoroughbred enriched for phosphoinositide-mediated signalling (3.2-fold enrichment; P<0.01), insulin receptor signalling (5.0-fold enrichment; P<0.01) and lipid transport (2.2-fold enrichment; P<0.05) genes. We found a significant overrepresentation of sarcoglycan complex (11.1-fold enrichment; P<0.05) and focal adhesion pathway (1.9-fold enrichment; P<0.01) genes highlighting the role for muscle strength and integrity in the Thoroughbred athletic phenotype. We report for the first time candidate athletic-performance genes within regions targeted by selection in Thoroughbred horses that are principally responsible for fatty acid oxidation, increased insulin sensitivity and muscle strength: ACSS1 (acyl-CoA synthetase short-chain family member 1), ACTA1 (actin, alpha 1, skeletal muscle), ACTN2 (actinin, alpha 2), ADHFE1 (alcohol dehydrogenase, iron containing, 1), MTFR1 (mitochondrial fission regulator 1), PDK4 (pyruvate dehydrogenase kinase, isozyme 4) and TNC (tenascin C). Understanding the genetic basis for exercise adaptation will be crucial for the identification of genes

  13. Positive allometry and the prehistory of sexual selection.

    PubMed

    Tomkins, Joseph L; LeBas, Natasha R; Witton, Mark P; Martill, David M; Humphries, Stuart

    2010-08-01

    The function of the exaggerated structures that adorn many fossil vertebrates remains largely unresolved. One recurrent hypothesis is that these elaborated traits had a role in thermoregulation. This orthodoxy persists despite the observation that traits exaggerated to the point of impracticality in extant organisms are almost invariably sexually selected. We use allometric scaling to investigate the role of sexual selection and thermoregulation in the evolution of exaggerated traits of the crested pterosaur Pteranodon longiceps and the sail-backed eupelycosaurs Dimetrodon and Edaphosaurus. The extraordinarily steep positive allometry of the head crest of Pteranodon rules out all of the current hypotheses for this trait's main function other than sexual signaling. We also find interspecific patterns of allometry and sexual dimorphism in the sails of Dimetrodon and patterns of elaboration in Edaphosaurus consistent with a sexually selected function. Furthermore, small ancestral, sail-backed pelycosaurs would have been too small to need adaptations to thermoregulation. Our results question the popular view that the elaborated structures of these fossil species evolved as thermoregulatory organs and provide evidence in support of the hypothesis that Pteranodon crests and eupelycosaur sails are among the earliest and most extreme examples of elaborate sexual signals in the evolution of terrestrial vertebrates.

  14. The role of positive selection in hepatitis C virus.

    PubMed

    Cuevas, José M; Gonzalez, Michael; Torres-Puente, Manuela; Jiménez-Hernández, Nuria; Bracho, María A; García-Robles, Inmaculada; González-Candelas, Fernando; Moya, Andrés

    2009-09-01

    Hepatitis C virus (HCV) is a major health problem worldwide, infecting an estimated 170 million people. In this study, we have employed a large data set of sequences (14,654 sequences from between 25 and 100 clone sequences per analyzed region and per patient) from 67 patients infected with HCV genotype 1 (23 subtype 1a and 44 subtype 1b). For all patients, a sample prior to combined therapy with alpha interferon plus ribavirin was available, whereas for some patients additional samples after 6 or 12 months of treatment were also available. Twenty-seven patients responded to treatment (12 subtype 1a and 15 subtype 1b) and forty patients did not respond to treatment (11 subtype 1a vs. 29 subtype 1b). Two regions of the HCV genome were analyzed, one compressing the hypervariable regions (HVR1, HVR2 and HVR3) of the envelope 2 glycoprotein and another one including the interferon sensitive determining region (ISDR) and the V3 domain of the NS5A protein. Previously (Cuevas, J.M., Torres-Puente, M., Jiménez-Hernández, N., Bracho, M.A., García-Robles, I., Wrobel, B., Carnicer, F., del Olmo, J., Ortega, E., Moya, A., González-Candelas, F., 2008b. Genetic variability of hepatitis C virus before and after combined therapy of interferon plus ribavirin. Plos One 3 (8), e3058), several amino acid positions in both regions analyzed were detected to be under positive selection. Here, we have compared the amino acid composition of each positively selected position between responder and non-responder patients for both subtypes. If we exclude some non-conclusive cases, no clear differences were detected in any case. In conclusion, identifying specific positions as completely discriminatory of treatment response seems to be a difficult task. Our results, in concordance with previous studies, suggest that HCV evasion strategies are more likely based on a global increased variability, which would yield combinations of mutations with an increased resistance, than on the fixation of

  15. Positive selection driving diversification in plant secondary metabolism

    PubMed Central

    Benderoth, Markus; Textor, Susanne; Windsor, Aaron J.; Mitchell-Olds, Thomas; Gershenzon, Jonathan; Kroymann, Juergen

    2006-01-01

    In Arabidopsis thaliana and related plants, glucosinolates are a major component in the blend of secondary metabolites and contribute to resistance against herbivorous insects. Methylthioalkylmalate synthases (MAM) encoded at the MAM gene cluster control an early step in the biosynthesis of glucosinolates and, therefore, are central to the diversification of glucosinolate metabolism. We sequenced bacterial artificial chromosomes containing the MAM cluster from several Arabidopsis relatives, conducted enzyme assays with heterologously expressed MAM genes, and analyzed MAM nucleotide variation patterns. Our results show that gene duplication, neofunctionalization, and positive selection provide the mechanism for biochemical adaptation in plant defense. These processes occur repeatedly in the history of the MAM gene family, indicating their fundamental importance for the evolution of plant metabolic diversity both within and among species. PMID:16754868

  16. Evidence of recombination and positive selection in cetacean papillomaviruses.

    PubMed

    Robles-Sikisaka, Refugio; Rivera, Rebecca; Nollens, Hendrik H; St Leger, Judy; Durden, Wendy N; Stolen, Megan; Burchell, Jennifer; Wellehan, James F X

    2012-06-05

    Papillomaviruses (PVs) are small DNA viruses that have been associated with increased epithelial proliferation. Over one hundred PV types have been identified in humans; however, only three have been identified in bottlenose dolphins (Tursiops truncatus) to date. Using rolling circle amplification and degenerate PCR, we identified four novel PV genomes of bottlenose dolphins. TtPV4, TtPV5 and TtPV6 were identified in genital lesions while TtPV7 was identified in normal genital mucosa. Bayesian analysis of the full-length L1 genes found that TtPV4 and TtPV7 group within the Upsilonpapillomavirus genus while TtPV5 and TtPV6 group with Omikronpapillomavirus. However, analysis of the E1 gene did not distinguish these genera, implying that these genes may not share a common history, consistent with recombination. Recombination analyses identified several probable events. Signals of positive selection were found mostly in the E1 and E2 genes. Recombination and diversifying selection pressures constitute important driving forces of cetacean PV evolution.

  17. Evidence of recombination and positive selection in cetacean papillomaviruses

    SciTech Connect

    Robles-Sikisaka, Refugio; Rivera, Rebecca; Nollens, Hendrik H.; St Leger, Judy; Durden, Wendy N.; Stolen, Megan; Burchell, Jennifer; Wellehan, James F.X.

    2012-06-05

    Papillomaviruses (PVs) are small DNA viruses that have been associated with increased epithelial proliferation. Over one hundred PV types have been identified in humans; however, only three have been identified in bottlenose dolphins (Tursiops truncatus) to date. Using rolling circle amplification and degenerate PCR, we identified four novel PV genomes of bottlenose dolphins. TtPV4, TtPV5 and TtPV6 were identified in genital lesions while TtPV7 was identified in normal genital mucosa. Bayesian analysis of the full-length L1 genes found that TtPV4 and TtPV7 group within the Upsilonpapillomavirus genus while TtPV5 and TtPV6 group with Omikronpapillomavirus. However, analysis of the E1 gene did not distinguish these genera, implying that these genes may not share a common history, consistent with recombination. Recombination analyses identified several probable events. Signals of positive selection were found mostly in the E1 and E2 genes. Recombination and diversifying selection pressures constitute important driving forces of cetacean PV evolution.

  18. Effect of sound similarity and word position on lexical selection

    PubMed Central

    Reilly, Megan; Blumstein, Sheila E.

    2014-01-01

    Spoken word production research has shown that phonological information influences lexical selection. It remains unclear, however, whether this phonological information is specified for its phonological environment (e.g., word position) or its phonetic (allophonic) realization. To examine this, two definition naming experiments were performed during which subjects produced lexical targets (e.g., “balcony”) in response to the targets’ definitions (“deck higher than a building’s first floor”) after naming a series of phonologically related or unrelated primes. Subjects produced target responses significantly more often when the primes were phonologically related to the target, regardless of whether the phonologically related primes matched the target’s word position or did not. For example, subjects were equally primed to produce the target “balcony” after the prime “ballast” or “unbalanced” relative to unrelated primes. Moreover, equal priming occurred irrespective of phonological environment or phonetic realization. The results support models of spoken word production which include context-independent phonological representations. PMID:25436217

  19. Rapidly evolving genes in pathogens: methods for detecting positive selection and examples among fungi, bacteria, viruses and protists.

    PubMed

    Aguileta, Gabriela; Refrégier, Guislaine; Yockteng, Roxana; Fournier, Elisabeth; Giraud, Tatiana

    2009-07-01

    The ongoing coevolutionary struggle between hosts and pathogens, with hosts evolving to escape pathogen infection and pathogens evolving to escape host defences, can generate an 'arms race', i.e., the occurrence of recurrent selective sweeps that each favours a novel resistance or virulence allele that goes to fixation. Host-pathogen coevolution can alternatively lead to a 'trench warfare', i.e., balancing selection, maintaining certain alleles at loci involved in host-pathogen recognition over long time scales. Recently, technological and methodological progress has enabled detection of footprints of selection directly on genes, which can provide useful insights into the processes of coevolution. This knowledge can also have practical applications, for instance development of vaccines or drugs. Here we review the methods for detecting genes under positive selection using divergence data (i.e., the ratio of nonsynonymous to synonymous substitution rates, d(N)/d(S)). We also review methods for detecting selection using polymorphisms, such as methods based on F(ST) measures, frequency spectrum, linkage disequilibrium and haplotype structure. In the second part, we review examples where targets of selection have been identified in pathogens using these tests. Genes under positive selection in pathogens have mostly been sought among viruses, bacteria and protists, because of their paramount importance for human health. Another focus is on fungal pathogens owing to their agronomic importance. We finally discuss promising directions in pathogen studies, such as detecting selection in non-coding regions.

  20. Transcriptome Sequencing and Positive Selected Genes Analysis of Bombyx mandarina

    PubMed Central

    Wu, Yuqian; Long, Renwen; Liu, Chun; Xia, Qingyou

    2015-01-01

    The wild silkworm Bombyx mandarina is widely believed to be an ancestor of the domesticated silkworm, Bombyx mori. Silkworms are often used as a model for studying the mechanism of species domestication. Here, we performed transcriptome sequencing of the wild silkworm using an Illumina HiSeq2000 platform. We produced 100,004,078 high-quality reads and assembled them into 50,773 contigs with an N50 length of 1764 bp and a mean length of 941.62 bp. A total of 33,759 unigenes were identified, with 12,805 annotated in the Nr database, 8273 in the Pfam database, and 9093 in the Swiss-Prot database. Expression profile analysis found significant differential expression of 1308 unigenes between the middle silk gland (MSG) and posterior silk gland (PSG). Three sericin genes (sericin 1, sericin 2, and sericin 3) were expressed specifically in the MSG and three fibroin genes (fibroin-H, fibroin-L, and fibroin/P25) were expressed specifically in the PSG. In addition, 32,297 Single-nucleotide polymorphisms (SNPs) and 361 insertion-deletions (INDELs) were detected. Comparison with the domesticated silkworm p50/Dazao identified 5,295 orthologous genes, among which 400 might have experienced or to be experiencing positive selection by Ka/Ks analysis. These data and analyses presented here provide insights into silkworm domestication and an invaluable resource for wild silkworm genomics research. PMID:25806526

  1. Impact of selected troposphere models on Precise Point Positioning convergence

    NASA Astrophysics Data System (ADS)

    Kalita, Jakub; Rzepecka, Zofia

    2016-04-01

    The Precise Point Positioning (PPP) absolute method is currently intensively investigated in order to reach fast convergence time. Among various sources that influence the convergence of the PPP, the tropospheric delay is one of the most important. Numerous models of tropospheric delay are developed and applied to PPP processing. However, with rare exceptions, the quality of those models does not allow fixing the zenith path delay tropospheric parameter, leaving difference between nominal and final value to the estimation process. Here we present comparison of several PPP result sets, each of which based on different troposphere model. The respective nominal values are adopted from models: VMF1, GPT2w, MOPS and ZERO-WET. The PPP solution admitted as reference is based on the final troposphere product from the International GNSS Service (IGS). The VMF1 mapping function was used for all processing variants in order to provide capability to compare impact of applied nominal values. The worst case initiates zenith wet delay with zero value (ZERO-WET). Impact from all possible models for tropospheric nominal values should fit inside both IGS and ZERO-WET border variants. The analysis is based on data from seven IGS stations located in mid-latitude European region from year 2014. For the purpose of this study several days with the most active troposphere were selected for each of the station. All the PPP solutions were determined using gLAB open-source software, with the Kalman filter implemented independently by the authors of this work. The processing was performed on 1 hour slices of observation data. In addition to the analysis of the output processing files, the presented study contains detailed analysis of the tropospheric conditions for the selected data. The overall results show that for the height component the VMF1 model outperforms GPT2w and MOPS by 35-40% and ZERO-WET variant by 150%. In most of the cases all solutions converge to the same values during first

  2. Autonomous site selection and instrument positioning for sample acquisition

    NASA Astrophysics Data System (ADS)

    Shaw, A.; Barnes, D.; Pugh, S.

    The European Space Agency Aurora Exploration Program aims to establish a European long-term programme for the exploration of Space, culminating in a human mission to space in the 2030 timeframe. Two flagship missions, namely Mars Sample Return and ExoMars, have been proposed as recognised steps along the way. The Exomars Rover is the first of these flagship missions and includes a rover carrying the Pasteur Payload, a mobile exobiology instrumentation package, and the Beagle 2 arm. The primary objective is the search for evidence of past or present life on mars, but the payload will also study the evolution of the planet and the atmosphere, look for evidence of seismological activity and survey the environment in preparation for future missions. The operation of rovers in unknown environments is complicated, and requires large resources not only on the planet but also in ground based operations. Currently, this can be very labour intensive, and costly, if large teams of scientists and engineers are required to assess mission progress, plan mission scenarios, and construct a sequence of events or goals for uplink. Furthermore, the constraints in communication imposed by the time delay involved over such large distances, and line-of-sight required, make autonomy paramount to mission success, affording the ability to operate in the event of communications outages and be opportunistic with respect to scientific discovery. As part of this drive to reduce mission costs and increase autonomy the Space Robotics group at the University of Wales, Aberystwyth is researching methods of autonomous site selection and instrument positioning, directly applicable to the ExoMars mission. The site selection technique used builds on the geometric reasoning algorithms used previously for localisation and navigation [Shaw 03]. It is proposed that a digital elevation model (DEM) of the local surface, generated during traverse and without interaction from ground based operators, can be

  3. Extensive Positive Selection Drives the Evolution of Nonstructural Proteins in Lineage C Betacoronaviruses

    PubMed Central

    Cagliani, Rachele; Mozzi, Alessandra; Pozzoli, Uberto; Al-Daghri, Nasser; Clerici, Mario; Sironi, Manuela

    2016-01-01

    ABSTRACT Middle East respiratory syndrome-related coronavirus (MERS-CoV) spreads to humans via zoonotic transmission from camels. MERS-CoV belongs to lineage C of betacoronaviruses (betaCoVs), which also includes viruses isolated from bats and hedgehogs. A large portion of the betaCoV genome consists of two open reading frames (ORF1a and ORF1b) that are translated into polyproteins. These are cleaved by viral proteases to generate 16 nonstructural proteins (nsp1 to nsp16) which compose the viral replication-transcription complex. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs. Results indicated widespread positive selection, acting mostly on ORF1a. The proportion of positively selected sites in ORF1a was much higher than that previously reported for the surface-exposed spike protein. Selected sites were unevenly distributed, with nsp3 representing the preferential target. Several pairs of coevolving sites were also detected, possibly indicating epistatic interactions; most of these were located in nsp3. Adaptive evolution at nsp3 is ongoing in MERS-CoV strains, and two selected sites (G720 and R911) were detected in the protease domain. While position 720 is variable in camel-derived viruses, suggesting that the selective event does not represent a specific adaptation to humans, the R911C substitution was observed only in human-derived MERS-CoV isolates, including the viral strain responsible for the recent South Korean outbreak. It will be extremely important to assess whether these changes affect host range or other viral phenotypes. More generally, data herein indicate that CoV nsp3 represents a major selection target and that nsp3 sequencing should be envisaged in monitoring programs and field surveys. IMPORTANCE Both severe acute respiratory syndrome coronavirus (SARS-CoV) and MERS-CoV originated in bats and spread to humans via an intermediate host. This clearly highlights the potential for coronavirus host shifting and the relevance

  4. Immunology (1955-1975): the natural selection theory, the two signal hypothesis and positive repertoire selection.

    PubMed

    Forsdyke, Donald R

    2012-01-01

    Observations suggesting the existence of natural antibody prior to exposure of an organism to the corresponding antigen, led to the natural selection theory of antibody formation of Jerne in 1955, and to the two signal hypothesis of Forsdyke in 1968. Aspects of these were not only first discoveries but also foundational discoveries in that they influenced contemporaries in a manner that, from our present vantage point, appears to have been constructive. Jerne's later hypothesis (1971, European Journal of Immunology 1: 1-9), that antibody-like receptors on lymphocytes were selected over evolutionary time for reactivity with the major histocompatibility complex (MHC) antigens of the species, was a first, but it was incorrect, and was foundational only to the extent that it emphasized the need to explain the Simonsen phenomenon. Although easily construed as derivative of Jerne (1971), the affinity/avidity model of Forsdyke (1975, Journal of Theoretical Biology 52: 187-198), which predicted that cell-surface components, including MHC antigens, would restrict antigen-reactivity by somatically shaping lymphocyte repertoires, was actually an extension of the two signal hypothesis. While presenting a mechanism for the positive selection of lymphocyte repertoires, and explaining the Simonsen phenomenon, the affinity/avidity model was not foundational in that it had to be independently rediscovered. For science to advance optimally we must seek to close temporal gaps so that first discoveries are also foundational. Listening to young scientists may be part of the solution.

  5. Selecting Reinforcers for Positive Classroom Projects in Inner City Schools.

    ERIC Educational Resources Information Center

    Reyes, Donald

    1981-01-01

    Suggests several positive reinforcement methods that teachers may employ with inner-city students to improve student responsibility, organization, and motivation. These methods include offering incentives for grade improvement, tangible and nontangible reinforcers, token systems, and social reinforcement. (GC)

  6. Automatic Omega Station and LOP (Line of Position) Selection,

    DTIC Science & Technology

    1987-09-01

    huit postes de transmission r~partis autour du globe. La diff~rence de phase entre les signaux de deux postes donne un ligne de position (LDP) sur la... puissance du signal. Ce rapport d~crit ces facteurs et leur 6valuation. Il d6crit 6galement l’ensemble des algorithmes employ6 par MINS pour s4lectionner

  7. The role of Parenting and Goal Selection in Positive Youth Development: A Person-Centered Approach

    ERIC Educational Resources Information Center

    Napolitano, Christopher M.; Bowers, Edmond P.; Gestsdottir, Steinunn; Depping, Miriam; von Eye, Alexander; Chase, Paul; Lerner, Jacqueline V.

    2011-01-01

    Using a person-centered approach, we examined the relations between goal selection, various indicators of parenting, and positive development among 510 Grades 9 to 11 participants (68% female) in the 4-H Study of Positive Youth Development (PYD), a longitudinal study involving U.S. adolescents. Goal selection was operationalized by the "Selection"…

  8. How to select and apply positive-displacement rotary pumps

    SciTech Connect

    Neerken, R.F.

    1980-04-07

    The advantages of rotary pumps for process applications are promoted by these practical guidelines concerning the types available, facts about their operation and performance, and the fluid systems in which they can be used. Basic types of rotary pumps discussed include internal gear, sliding vane, single-screw (progressing cavity), cam and piston, flexible tube, flexible liner, external gear, circumferential piston, twin screw, triple screw, single lobe, and 3 lobe. Factors which are examined to make pump selection include suction requirements, viscosity of fluids, temperature at which process fluid is handled, working and allowable pressures, pump capacity, pump horsepower, materials of construction, and intended applications.

  9. Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment

    PubMed Central

    Zeldovich, Konstantin B.; Liu, Ping; Renzette, Nicholas; Foll, Matthieu; Pham, Serena T.; Venev, Sergey V.; Gallagher, Glen R.; Bolon, Daniel N.; Kurt-Jones, Evelyn A.; Jensen, Jeffrey D.; Caffrey, Daniel R.; Schiffer, Celia A.; Kowalik, Timothy F.; Wang, Jennifer P.; Finberg, Robert W.

    2015-01-01

    Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 and the remaining six segments from H3N2. By deep sequencing the entire viral genome, we monitored the evolution of reassortment, quantifying the relative abundance of all IAV genome segments from the two parent strains over time and measuring the selection coefficients of the reassorting segments. Additionally, we observed several mutations coemerging with reassortment that were not found during passaging of pure parental IAV strains. Our results demonstrate how reassortment of the segmented genome can accelerate viral evolution in IAV, potentially enabled by the emergence of a small number of individual mutations. PMID:25713211

  10. Selective reduction of CAD false-positive findings

    NASA Astrophysics Data System (ADS)

    Camarlinghi, N.; Gori, I.; Retico, A.; Bagagli, F.

    2010-03-01

    Computer-Aided Detection (CAD) systems are becoming widespread supporting tools to radiologists' diagnosis, especially in screening contexts. However, a large amount of false positive (FP) alarms would inevitably lead both to an undesired possible increase in time for diagnosis, and to a reduction in radiologists' confidence in CAD as a useful tool. Most CAD systems implement as final step of the analysis a classifier which assigns a score to each entry of a list of findings; by thresholding this score it is possible to define the system performance on an annotated validation dataset in terms of a FROC curve (sensitivity vs. FP per scan). To use a CAD as a supportive tool for most clinical activities, an operative point has to be chosen on the system FROC curve, according to the obvious criterion of keeping the sensitivity as high as possible, while maintaining the number of FP alarms still acceptable. The strategy proposed in this study is to choose an operative point with high sensitivity on the CAD FROC curve, then to implement in cascade a further classification step, constituted by a smarter classifier. The key issue of this approach is that the smarter classifier is actually a meta-classifier of more then one decision system, each specialized in rejecting a particular type of FP findings generated by the CAD. The application of this approach to a dataset of 16 lung CT scans previously processed by the VBNACAD system is presented. The lung CT VBNACAD performance of 87.1% sensitivity to juxtapleural nodules with 18.5 FP per scan is improved up to 10.1 FP per scan while maintaining the same value of sensitivity. This work has been carried out in the framework of the MAGIC-V collaboration.

  11. Human and Non-Human Primate Genomes Share Hotspots of Positive Selection

    PubMed Central

    Enard, David; Depaulis, Frantz; Roest Crollius, Hugues

    2010-01-01

    Among primates, genome-wide analysis of recent positive selection is currently limited to the human species because it requires extensive sampling of genotypic data from many individuals. The extent to which genes positively selected in human also present adaptive changes in other primates therefore remains unknown. This question is important because a gene that has been positively selected independently in the human and in other primate lineages may be less likely to be involved in human specific phenotypic changes such as dietary habits or cognitive abilities. To answer this question, we analysed heterozygous Single Nucleotide Polymorphisms (SNPs) in the genomes of single human, chimpanzee, orangutan, and macaque individuals using a new method aiming to identify selective sweeps genome-wide. We found an unexpectedly high number of orthologous genes exhibiting signatures of a selective sweep simultaneously in several primate species, suggesting the presence of hotspots of positive selection. A similar significant excess is evident when comparing genes positively selected during recent human evolution with genes subjected to positive selection in their coding sequence in other primate lineages and identified using a different test. These findings are further supported by comparing several published human genome scans for positive selection with our findings in non-human primate genomes. We thus provide extensive evidence that the co-occurrence of positive selection in humans and in other primates at the same genetic loci can be measured with only four species, an indication that it may be a widespread phenomenon. The identification of positive selection in humans alongside other primates is a powerful tool to outline those genes that were selected uniquely during recent human evolution. PMID:20140238

  12. Positive Darwinian selection drives the evolution of several female reproductive proteins in mammals

    PubMed Central

    Swanson, Willie J.; Yang, Ziheng; Wolfner, Mariana F.; Aquadro, Charles F.

    2001-01-01

    Rapid evolution driven by positive Darwinian selection is a recurrent theme in male reproductive protein evolution. In contrast, positive selection has never been demonstrated for female reproductive proteins. Here, we perform phylogeny-based tests on three female mammalian fertilization proteins and demonstrate positive selection promoting their divergence. Two of these female fertilization proteins, the zona pellucida glycoproteins ZP2 and ZP3, are part of the mammalian egg coat. Several sites identified in ZP3 as likely to be under positive selection are located in a region previously demonstrated to be involved in species-specific sperm-egg interaction, suggesting the selective pressure is related to male-female interaction. The results provide long-sought evidence for two evolutionary hypotheses: sperm competition and sexual conflict. PMID:11226269

  13. Genomic Patterns of Positive Selection at the Origin of Rust Fungi

    PubMed Central

    Silva, Diogo N.; Duplessis, Sebastien; Talhinhas, Pedro; Azinheira, Helena

    2015-01-01

    Understanding the origin and evolution of pathogenicity and biotrophic life-style of rust fungi has remained a conundrum for decades. Research on the molecular mechanisms responsible for rust fungi evolution has been hampered by their biotrophic life-style until the sequencing of some rust fungi genomes. With the availability of multiple whole genomes and EST data for this group, it is now possible to employ genome-wide surveys and investigate how natural selection shaped their evolution. In this work, we employed a phylogenomics approach to search for positive selection and genes undergoing accelerated evolution at the origin of rust fungi on an assembly of single copy genes conserved across a broad range of basidiomycetes. Up to 985 genes were screened for positive selection on the phylogenetic branch leading to rusts, revealing a pervasive signal of positive selection throughout the data set with the proportion of positively selected genes ranging between 19.6–33.3%. Additionally, 30 genes were found to be under accelerated evolution at the origin of rust fungi, probably due to a mixture of positive selection and relaxation of purifying selection. Functional annotation of the positively selected genes revealed an enrichment in genes involved in the biosynthesis of secondary metabolites and several metabolism and transporter classes. PMID:26632820

  14. On the Choice of Access Point Selection Criterion and Other Position Estimation Characteristics for WLAN-Based Indoor Positioning

    PubMed Central

    Laitinen, Elina; Lohan, Elena Simona

    2016-01-01

    The positioning based on Wireless Local Area Networks (WLAN) is one of the most promising technologies for indoor location-based services, generally using the information carried by Received Signal Strengths (RSS). One challenge, however, is the huge amount of data in the radiomap database due to the enormous number of hearable Access Points (AP) that could make the positioning system very complex. This paper concentrates on WLAN-based indoor location by comparing fingerprinting, path loss and weighted centroid based positioning approaches in terms of complexity and performance and studying the effects of grid size and AP reduction with several choices for appropriate selection criterion. All results are based on real field measurements in three multi-floor buildings. We validate our earlier findings concerning several different AP selection criteria and conclude that the best results are obtained with a maximum RSS-based criterion, which also proved to be the most consistent among the different investigated approaches. We show that the weighted centroid based low-complexity method is very sensitive to AP reduction, while the path loss-based method is also very robust to high percentage removals. Indeed, for fingerprinting, 50% of the APs can be removed safely with a properly chosen removal criterion without increasing the positioning error much. PMID:27213395

  15. Isolating "Unknown" Bacteria in the Introductory Microbiology Laboratory: A New Selective Medium for Gram-Positives.

    ERIC Educational Resources Information Center

    McKillip, John L.; Drake, MaryAnne

    1999-01-01

    Describes the development, preparation, and use of a medium that can select against a wide variety of Gram-negative bacteria while still allowing growth and differentiation of a wide range of Gram-positives. (WRM)

  16. Recent Positive Selection in Genes of the Mammalian Epidermal Differentiation Complex Locus

    PubMed Central

    Goodwin, Zane A.; de Guzman Strong, Cristina

    2017-01-01

    The epidermal differentiation complex (EDC) is the most rapidly evolving locus in the human genome compared to that of the chimpanzee. Yet the EDC genes that are undergoing positive selection across mammals and in humans are not known. We sought to identify the positively selected genetic variants and determine the evolutionary events of the EDC using mammalian-wide and clade-specific branch- and branch-site likelihood ratio tests and a genetic algorithm (GA) branch test. Significant non-synonymous substitutions were found in filaggrin, SPRR4, LELP1, and S100A2 genes across 14 mammals. By contrast, we identified recent positive selection in SPRR4 in primates. Additionally, the GA branch test discovered lineage-specific evolution for distinct EDC genes occurring in each of the nodes in the 14-mammal phylogenetic tree. Multiple instances of positive selection for FLG, TCHHL1, SPRR4, LELP1, and S100A2 were noted among the primate branch nodes. Branch-site likelihood ratio tests further revealed positive selection in specific sites in SPRR4, LELP1, filaggrin, and repetin across 14 mammals. However, in addition to continuous evolution of SPRR4, site-specific positive selection was also found in S100A11, KPRP, SPRR1A, S100A7L2, and S100A3 in primates and filaggrin, filaggrin2, and S100A8 in great apes. Very recent human positive selection was identified in the filaggrin2 L41 site that was present in Neanderthal. Together, our results identifying recent positive selection in distinct EDC genes reveal an underappreciated evolution of epidermal skin barrier function in primates and humans. PMID:28119736

  17. Positive selection neighboring functionally essential sites and disease-implicated regions of mammalian reproductive proteins

    PubMed Central

    2010-01-01

    Background Reproductive proteins are central to the continuation of all mammalian species. The evolution of these proteins has been greatly influenced by environmental pressures induced by pathogens, rival sperm, sexual selection and sexual conflict. Positive selection has been demonstrated in many of these proteins with particular focus on primate lineages. However, the mammalia are a diverse group in terms of mating habits, population sizes and germ line generation times. We have examined the selective pressures at work on a number of novel reproductive proteins across a wide variety of mammalia. Results We show that selective pressures on reproductive proteins are highly varied. Of the 10 genes analyzed in detail, all contain signatures of positive selection either across specific sites or in specific lineages or a combination of both. Our analysis of SP56 and Col1a1 are entirely novel and the results show positively selected sites present in each gene. Our findings for the Col1a1 gene are suggestive of a link between positive selection and severe disease type. We find evidence in our dataset to suggest that interacting proteins are evolving in symphony: most likely to maintain interacting functionality. Conclusion Our in silico analyses show positively selected sites are occurring near catalytically important regions suggesting selective pressure to maximize efficient fertilization. In those cases where a mechanism of protein function is not fully understood, the sites presented here represent ideal candidates for mutational study. This work has highlighted the widespread rate heterogeneity in mutational rates across the mammalia and specifically has shown that the evolution of reproductive proteins is highly varied depending on the species and interacting partners. We have shown that positive selection and disease are closely linked in the Col1a1 gene. PMID:20149245

  18. Widespread signatures of recent selection linked to nucleosome positioning in the human lineage.

    PubMed

    Prendergast, James G D; Semple, Colin A M

    2011-11-01

    In this study we investigated the strengths and modes of selection associated with nucleosome positioning in the human lineage through the comparison of interspecies and intraspecies rates of divergence. We identify significant evidence for both positive and negative selection linked to human nucleosome positioning for the first time, implicating a widespread and important role for DNA sequence in the location of well-positioned nucleosomes. Selection appears to be acting on particular base substitutions to maintain optimum GC compositions in core and linker regions, with, e.g., unexpectedly elevated rates of C→T substitutions during recent human evolution at linker regions 60-90 bp from the nucleosome dyad but significant depletion of the same substitutions within nucleosome core regions. These patterns are strikingly consistent with the known relationships between genomic sequence composition and nucleosome assembly. By stratifying nucleosomes according to the GC content of their genomic neighborhood, we also show that the strength and direction of selection detected is dictated by local GC content. Intriguingly these signatures of selection are not restricted to nucleosomes in close proximity to exons, suggesting the correct positioning of nucleosomes is not only important in and around coding regions. This analysis provides strong evidence that the genomic sequences associated with nucleosomes are not evolving neutrally, and suggests that underlying DNA sequence is an important factor in nucleosome positioning. Recent signatures of selection linked to genomic features as ubiquitous as the nucleosome have important implications for human genome evolution and disease.

  19. HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection.

    PubMed

    Philips, Rachael L; Chen, Meibo W; McWilliams, Douglas C; Belmonte, Paul J; Constans, Megan M; Shapiro, Virginia Smith

    2016-07-15

    To generate functional peripheral T cells, proper gene regulation during T cell development is critical. In this study, we found that histone deacetylase (HDAC) 3 is required for T cell development. T cell development in CD2-icre HDAC3 conditional knockout (cKO) mice (HDAC3-cKO) was blocked at positive selection, resulting in few CD4 and CD8 T cells, and it could not be rescued by a TCR transgene. These single-positive thymocytes failed to upregulate Bcl-2, leading to increased apoptosis. HDAC3-cKO mice failed to downregulate retinoic acid-related orphan receptor (ROR) γt during positive selection, similar to the block in positive selection in RORγt transgenic mice. In the absence of HDAC3, the RORC promoter was hyperacetylated. In the periphery, the few CD4 T cells present were skewed toward RORγt(+) IL-17-producing Th17 cells, leading to inflammatory bowel disease. Positive selection of CD8 single-positive thymocytes was restored in RORγt-KO Bcl-xL transgenic HDAC3-cKO mice, demonstrating that HDAC3 is required at positive selection to downregulate RORγt.

  20. Positive Darwinian selection at single amino acid sites conferring plant virus resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Explicit evaluation of the accuracy and power of Maximum Likelihood and Bayesian methods for detecting site-specific positive Darwinian selection presents a challenge because selective consequences of single amino acid changes are generally unknown. We exploit extensive molecular and functional cha...

  1. Continental-Scale Footprint of Balancing and Positive Selection in a Small Rodent (Microtus arvalis)

    PubMed Central

    Fischer, Martin C.; Foll, Matthieu; Heckel, Gerald; Excoffier, Laurent

    2014-01-01

    Genetic adaptation to different environmental conditions is expected to lead to large differences between populations at selected loci, thus providing a signature of positive selection. Whereas balancing selection can maintain polymorphisms over long evolutionary periods and even geographic scale, thus leads to low levels of divergence between populations at selected loci. However, little is known about the relative importance of these two selective forces in shaping genomic diversity, partly due to difficulties in recognizing balancing selection in species showing low levels of differentiation. Here we address this problem by studying genomic diversity in the European common vole (Microtus arvalis) presenting high levels of differentiation between populations (average FST = 0.31). We studied 3,839 Amplified Fragment Length Polymorphism (AFLP) markers genotyped in 444 individuals from 21 populations distributed across the European continent and hence over different environmental conditions. Our statistical approach to detect markers under selection is based on a Bayesian method specifically developed for AFLP markers, which treats AFLPs as a nearly codominant marker system, and therefore has increased power to detect selection. The high number of screened populations allowed us to detect the signature of balancing selection across a large geographic area. We detected 33 markers potentially under balancing selection, hence strong evidence of stabilizing selection in 21 populations across Europe. However, our analyses identified four-times more markers (138) being under positive selection, and geographical patterns suggest that some of these markers are probably associated with alpine regions, which seem to have environmental conditions that favour adaptation. We conclude that despite favourable conditions in this study for the detection of balancing selection, this evolutionary force seems to play a relatively minor role in shaping the genomic diversity of the

  2. Continental-scale footprint of balancing and positive selection in a small rodent (Microtus arvalis).

    PubMed

    Fischer, Martin C; Foll, Matthieu; Heckel, Gerald; Excoffier, Laurent

    2014-01-01

    Genetic adaptation to different environmental conditions is expected to lead to large differences between populations at selected loci, thus providing a signature of positive selection. Whereas balancing selection can maintain polymorphisms over long evolutionary periods and even geographic scale, thus leads to low levels of divergence between populations at selected loci. However, little is known about the relative importance of these two selective forces in shaping genomic diversity, partly due to difficulties in recognizing balancing selection in species showing low levels of differentiation. Here we address this problem by studying genomic diversity in the European common vole (Microtus arvalis) presenting high levels of differentiation between populations (average F ST = 0.31). We studied 3,839 Amplified Fragment Length Polymorphism (AFLP) markers genotyped in 444 individuals from 21 populations distributed across the European continent and hence over different environmental conditions. Our statistical approach to detect markers under selection is based on a Bayesian method specifically developed for AFLP markers, which treats AFLPs as a nearly codominant marker system, and therefore has increased power to detect selection. The high number of screened populations allowed us to detect the signature of balancing selection across a large geographic area. We detected 33 markers potentially under balancing selection, hence strong evidence of stabilizing selection in 21 populations across Europe. However, our analyses identified four-times more markers (138) being under positive selection, and geographical patterns suggest that some of these markers are probably associated with alpine regions, which seem to have environmental conditions that favour adaptation. We conclude that despite favourable conditions in this study for the detection of balancing selection, this evolutionary force seems to play a relatively minor role in shaping the genomic diversity of the

  3. The role of positive selection in determining the molecular cause of species differences in disease

    PubMed Central

    2008-01-01

    Background Related species, such as humans and chimpanzees, often experience the same disease with varying degrees of pathology, as seen in the cases of Alzheimer's disease, or differing symptomatology as in AIDS. Furthermore, certain diseases such as schizophrenia, epithelial cancers and autoimmune disorders are far more frequent in humans than in other species for reasons not associated with lifestyle. Genes that have undergone positive selection during species evolution are indicative of functional adaptations that drive species differences. Thus we investigate whether biomedical disease differences between species can be attributed to positively selected genes. Results We identified genes that putatively underwent positive selection during the evolution of humans and four mammals which are often used to model human diseases (mouse, rat, chimpanzee and dog). We show that genes predicted to have been subject to positive selection pressure during human evolution are implicated in diseases such as epithelial cancers, schizophrenia, autoimmune diseases and Alzheimer's disease, all of which differ in prevalence and symptomatology between humans and their mammalian relatives. In agreement with previous studies, the chimpanzee lineage was found to have more genes under positive selection than any of the other lineages. In addition, we found new evidence to support the hypothesis that genes that have undergone positive selection tend to interact with each other. This is the first such evidence to be detected widely among mammalian genes and may be important in identifying molecular pathways causative of species differences. Conclusion Our dataset of genes predicted to have been subject to positive selection in five species serves as an informative resource that can be consulted prior to selecting appropriate animal models during drug target validation. We conclude that studying the evolution of functional and biomedical disease differences between species is an

  4. Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses

    PubMed Central

    Sironi, Manuela; Forni, Diego; Clerici, Mario; Cagliani, Rachele

    2016-01-01

    The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian

  5. Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

    PubMed Central

    Patrick, Michael S.; Oda, Hiroyo; Hayakawa, Kunihiro; Sato, Yoshinori; Eshima, Koji; Kirikae, Teruo; Iemura, Shun-ichiro; Shirai, Mutsunori; Abe, Takaya; Natsume, Tohru; Sasazuki, Takehiko; Suzuki, Harumi

    2009-01-01

    T cells develop in the thymus through positive and negative selection, which are responsible for shaping the T cell receptor (TCR) repertoire. To elucidate the molecular mechanisms involved in selection remains an area of intense interest. Here, we identified and characterized a gene product Gasp (Grb2-associating protein, also called Themis) that is critically required for positive selection. Gasp is a cytosolic protein with no known functional motifs that is expressed only in T cells, especially immature CD4/CD8 double positive (DP) thymocytes. In the absence of Gasp, differentiation of both CD4 and CD8 single positive cells in the thymus was severely inhibited, whereas all other TCR-induced events such as β-selection, negative selection, peripheral activation, and homeostatic proliferation were unaffected. We found that Gasp constitutively associates with Grb2 via its N-terminal Src homology 3 domain, suggesting that Gasp acts as a thymocyte-specific adaptor for Grb2 or regulates Ras signaling in DP thymocytes. Collectively, we have described a gene called Gasp that is critical for positive selection. PMID:19805304

  6. Population differentiation as an indicator of recent positive selection in humans: an empirical evaluation.

    PubMed

    Xue, Yali; Zhang, Xuelong; Huang, Ni; Daly, Allan; Gillson, Christopher J; Macarthur, Daniel G; Yngvadottir, Bryndis; Nica, Alexandra C; Woodwark, Cara; Chen, Yuan; Conrad, Donald F; Ayub, Qasim; Mehdi, S Qasim; Li, Pu; Tyler-Smith, Chris

    2009-11-01

    We have evaluated the extent to which SNPs identified by genomewide surveys as showing unusually high levels of population differentiation in humans have experienced recent positive selection, starting from a set of 32 nonsynonymous SNPs in 27 genes highlighted by the HapMap1 project. These SNPs were genotyped again in the HapMap samples and in the Human Genome Diversity Project-Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) panel of 52 populations representing worldwide diversity; extended haplotype homozygosity was investigated around all of them, and full resequence data were examined for 9 genes (5 from public sources and 4 from new data sets). For 7 of the genes, genotyping errors were responsible for an artifactual signal of high population differentiation and for 2, the population differentiation did not exceed our significance threshold. For the 18 genes with confirmed high population differentiation, 3 showed evidence of positive selection as measured by unusually extended haplotypes within a population, and 7 more did in between-population analyses. The 9 genes with resequence data included 7 with high population differentiation, and 5 showed evidence of positive selection on the haplotype carrying the nonsynonymous SNP from skewed allele frequency spectra; in addition, 2 showed evidence of positive selection on unrelated haplotypes. Thus, in humans, high population differentiation is (apart from technical artifacts) an effective way of enriching for recently selected genes, but is not an infallible pointer to recent positive selection supported by other lines of evidence.

  7. Positive selection drives accelerated evolution of mosquito salivary genes associated with blood-feeding

    PubMed Central

    Arcà, Bruno; Struchiner, Cláudio J.; Pham, Van M.; Sferra, Gabriella; Lombardo, Fabrizio; Pombi, Marco; Ribeiro, José M. C.

    2013-01-01

    Saliva of bloodsucking animals contains dozens to hundreds of proteins that counteract their hosts’ hemostasis, inflammation, and immunity. It was previously observed that salivary proteins involved in hematophagy are much more divergent in their primary sequence than those of housekeeping function, when comparisons were made between closely related organisms. While this pattern of evolution could result from relaxed selection or drift, it could alternatively be the result of positive selection driven by the intense pressure of the host immune system. We investigated the polymorphism of five different genes associated with blood feeding in the mosquito Anopheles gambiae and obtained evidence in four genes for sites with signatures of positive selection. These results add salivary gland genes from bloodsucking arthropods to the small list of genes driven by positive selection. PMID:24237399

  8. Voluntary strategy suppresses the positive impact of preferential selection in prisoner’s dilemma

    NASA Astrophysics Data System (ADS)

    Sun, Lei; Lin, Pei-jie; Chen, Ya-shan

    2014-11-01

    Impact of aspiration is ubiquitous in social and biological disciplines. In this work, we try to explore the impact of such a trait on voluntary prisoners’ dilemma game via a selection parameter w. w=0 returns the traditional version of random selection. For positive w, the opponent of high payoff will be selected; while negative w means that the partner of low payoff will be chosen. We find that for positive w, cooperation will be greatly promoted in the interval of small b, at variance cooperation is inhibited with large b. For negative w, cooperation is fully restrained, irrespective of b value. It is found that the positive impact of preferential selection is suppressed by the voluntary strategy in prisoner’s dilemma. These observations can be supported by the spatial patterns. Our work may shed light on the emergence and persistence of cooperation with voluntary participation in social dilemma.

  9. dbPSHP: a database of recent positive selection across human populations.

    PubMed

    Li, Mulin Jun; Wang, Lily Yan; Xia, Zhengyuan; Wong, Maria P; Sham, Pak Chung; Wang, Junwen

    2014-01-01

    The dbPSHP database (http://jjwanglab.org/dbpshp) aims to help researchers to efficiently identify, validate and visualize putative positively selected loci in human evolution and further discover the mechanism governing these natural selections. Recent evolution of human populations at the genomic level reflects the adaptations to the living environments, including climate change and availability and stability of nutrients. Many genetic regions under positive selection have been identified, which assist us to understand how natural selection has shaped population differences. Here, we manually collect recent positive selections in different human populations, consisting of 15,472 loci from 132 publications. We further compiled a database that used 15 statistical terms of different evolutionary attributes for single nucleotide variant sites from the HapMap 3 and 1000 Genomes Project to identify putative regions under positive selection. These attributes include variant allele/genotype properties, variant heterozygosity, within population diversity, long-range haplotypes, pairwise population differentiation and evolutionary conservation. We also provide interactive pages for visualization and annotation of different selective signals. The database is freely available to the public and will be frequently updated.

  10. Determination of Azimuth Angle at Burnout for Placing a Satellite Over a Selected Earth Position

    NASA Technical Reports Server (NTRS)

    Skopinski, T. H.; Johnson, Katherine G.

    1960-01-01

    Expressions are presented for relating the satellite position in the orbital plane with the projected latitude and longitude on a rotating earth surface. An expression is also presented for determining the azimuth angle at a given burnout position on the basis of a selected passage position on the earth's surface. Examples are presented of a satellite launched eastward and one launched westward, each passing over a selected position sometime after having completed three orbits. Incremental changes from the desired latitude and longitude due to the earth's oblateness are included in the iteration for obtaining the azimuth angles of the two examples. The results for both cases are then compared with those obtained from a computing program using an oblate rotating earth. Changes from the selected latitude and longitude resulting from incremental changes from the burn-out azimuth angle and latitude are also analyzed.

  11. Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder

    PubMed Central

    2017-01-01

    The human brain is the outcome of innumerable evolutionary processes; the systems genetics of psychiatric disorders could bear their signatures. On this basis, we analyzed five psychiatric disorders, attention deficit hyperactivity disorder, autism spectrum disorder (ASD), bipolar disorder, major depressive disorder, and schizophrenia (SCZ), using GWAS summary statistics from the Psychiatric Genomics Consortium. Machine learning-derived scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele reached fixation) and incomplete selection (loci where a selected allele has not yet reached fixation). ASD GWAS results positively correlated with incomplete-selection (p = 3.53*10−4). Variants with ASD GWAS p<0.1 were shown to have a 19%-increased probability to be in the top-5% for incomplete-selection score (OR = 1.19, 95%CI = 1.11–1.8, p = 9.56*10−7). Investigating the effect directions of minor alleles, we observed an enrichment for positive associations in SNPs with ASD GWAS p<0.1 and top-5% incomplete-selection score (permutation p<10−4). Considering the set of these ASD-positive-associated variants, we observed gene-expression enrichments for brain and pituitary tissues (p = 2.3*10−5 and p = 3*10−5, respectively) and 53 gene ontology (GO) enrichments, such as nervous system development (GO:0007399, p = 7.57*10−12), synapse organization (GO:0050808, p = 8.29*10−7), and axon guidance (GO:0007411, p = 1.81*10−7). Previous genetic studies demonstrated that ASD positively correlates with childhood intelligence, college completion, and years of schooling. Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability. PMID:28187187

  12. A Novel Method for Optimum Global Positioning System Satellite Selection Based on a Modified Genetic Algorithm

    PubMed Central

    Song, Jiancai; Xue, Guixiang; Kang, Yanan

    2016-01-01

    In this paper, a novel method for selecting a navigation satellite subset for a global positioning system (GPS) based on a genetic algorithm is presented. This approach is based on minimizing the factors in the geometric dilution of precision (GDOP) using a modified genetic algorithm (MGA) with an elite conservation strategy, adaptive selection, adaptive mutation, and a hybrid genetic algorithm that can select a subset of the satellites represented by specific numbers in the interval (4 ∼ n) while maintaining position accuracy. A comprehensive simulation demonstrates that the MGA-based satellite selection method effectively selects the correct number of optimal satellite subsets using receiver autonomous integrity monitoring (RAIM) or fault detection and exclusion (FDE). This method is more adaptable and flexible for GPS receivers, particularly for those used in handset equipment and mobile phones. PMID:26943638

  13. A Novel Method for Optimum Global Positioning System Satellite Selection Based on a Modified Genetic Algorithm.

    PubMed

    Song, Jiancai; Xue, Guixiang; Kang, Yanan

    2016-01-01

    In this paper, a novel method for selecting a navigation satellite subset for a global positioning system (GPS) based on a genetic algorithm is presented. This approach is based on minimizing the factors in the geometric dilution of precision (GDOP) using a modified genetic algorithm (MGA) with an elite conservation strategy, adaptive selection, adaptive mutation, and a hybrid genetic algorithm that can select a subset of the satellites represented by specific numbers in the interval (4 ∼ n) while maintaining position accuracy. A comprehensive simulation demonstrates that the MGA-based satellite selection method effectively selects the correct number of optimal satellite subsets using receiver autonomous integrity monitoring (RAIM) or fault detection and exclusion (FDE). This method is more adaptable and flexible for GPS receivers, particularly for those used in handset equipment and mobile phones.

  14. Characterising private and shared signatures of positive selection in 37 Asian populations.

    PubMed

    Liu, Xuanyao; Lu, Dongsheng; Saw, Woei-Yuh; Shaw, Philip J; Wangkumhang, Pongsakorn; Ngamphiw, Chumpol; Fucharoen, Suthat; Lert-Itthiporn, Worachart; Chin-Inmanu, Kwanrutai; Chau, Tran Nguyen Bich; Anders, Katie; Kasturiratne, Anuradhani; de Silva, H Janaka; Katsuya, Tomohiro; Kimura, Ryosuke; Nabika, Toru; Ohkubo, Takayoshi; Tabara, Yasuharu; Takeuchi, Fumihiko; Yamamoto, Ken; Yokota, Mitsuhiro; Mamatyusupu, Dolikun; Yang, Wenjun; Chung, Yeun-Jun; Jin, Li; Hoh, Boon-Peng; Wickremasinghe, Ananda R; Ong, RickTwee-Hee; Khor, Chiea-Chuen; Dunstan, Sarah J; Simmons, Cameron; Tongsima, Sissades; Suriyaphol, Prapat; Kato, Norihiro; Xu, Shuhua; Teo, Yik-Ying

    2017-04-01

    The Asian Diversity Project (ADP) assembled 37 cosmopolitan and ethnic minority populations in Asia that have been densely genotyped across over half a million markers to study patterns of genetic diversity and positive natural selection. We performed population structure analyses of the ADP populations and divided these populations into four major groups based on their genographic information. By applying a highly sensitive algorithm haploPS to locate genomic signatures of positive selection, 140 distinct genomic regions exhibiting evidence of positive selection in at least one population were identified. We examined the extent of signal sharing for regions that were selected in multiple populations and observed that populations clustered in a similar fashion to that of how the ancestry clades were phylogenetically defined. In particular, populations predominantly located in South Asia underwent considerably different adaptation as compared with populations from the other geographical regions. Signatures of positive selection present in multiple geographical regions were predicted to be older and have emerged prior to the separation of the populations in the different regions. In contrast, selection signals present in a single population group tended to be of lower frequencies and thus can be attributed to recent evolutionary events.

  15. Tracing evolutionary relicts of positive selection on eight malaria-related immune genes in mammals.

    PubMed

    Huang, Bing-Hong; Liao, Pei-Chun

    2015-07-01

    Plasmodium-induced malaria widely infects primates and other mammals. Multiple past studies have revealed that positive selection could be the main evolutionary force triggering the genetic diversity of anti-malaria resistance-associated genes in human or primates. However, researchers focused most of their attention on the infra-generic and intra-specific genome evolution rather than analyzing the complete evolutionary history of mammals. Here we extend previous research by testing the evolutionary link of natural selection on eight candidate genes associated with malaria resistance in mammals. Three of the eight genes were detected to be affected by recombination, including TNF-α, iNOS and DARC. Positive selection was detected in the rest five immunogenes multiple times in different ancestral lineages of extant species throughout the mammalian evolution. Signals of positive selection were exposed in four malaria-related immunogenes in primates: CCL2, IL-10, HO1 and CD36. However, selection signals of G6PD have only been detected in non-primate eutherians. Significantly higher evolutionary rates and more radical amino acid replacement were also detected in primate CD36, suggesting its functional divergence from other eutherians. Prevalent positive selection throughout the evolutionary trajectory of mammalian malaria-related genes supports the arms race evolutionary hypothesis of host genetic response of mammalian immunogenes to infectious pathogens.

  16. 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.

  17. Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1

    PubMed Central

    Ishikawa, Eri; Kosako, Hidetaka; Yasuda, Tomoharu; Ohmuraya, Masaki; Araki, Kimi; Kurosaki, Tomohiro; Saito, Takashi; Yamasaki, Sho

    2016-01-01

    Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected. PKD is activated in CD4+CD8+ double positive (DP) thymocytes on stimulation with positively selecting peptides. By phosphoproteomic analysis, we identify SH2-containing protein tyrosine phosphatase-1 (SHP-1) as a direct substrate of PKD. Substitution of wild-type SHP-1 by phosphorylation-defective mutant (SHP-1S557A) impairs generation of CD4+ thymocytes. These results suggest that the PKD–SHP-1 axis positively regulates TCR signalling to promote CD4+ T cell development. PMID:27670070

  18. Functional role of positively selected amino acid substitutions in mammalian rhodopsin evolution

    PubMed Central

    Fernández-Sampedro, Miguel A.; Invergo, Brandon M.; Ramon, Eva; Bertranpetit, Jaume; Garriga, Pere

    2016-01-01

    Visual rhodopsins are membrane proteins that function as light photoreceptors in the vertebrate retina. Specific amino acids have been positively selected in visual pigments during mammal evolution, which, as products of adaptive selection, would be at the base of important functional innovations. We have analyzed the top candidates for positive selection at the specific amino acids and the corresponding reverse changes (F13M, Q225R and A346S) in order to unravel the structural and functional consequences of these important sites in rhodopsin evolution. We have constructed, expressed and immunopurified the corresponding mutated pigments and analyzed their molecular phenotypes. We find that position 13 is very important for the folding of the receptor and also for proper protein glycosylation. Position 225 appears to be important for the function of the protein affecting the G-protein activation process, and position 346 would also regulate functionality of the receptor by enhancing G-protein activation and presumably affecting protein phosphorylation by rhodopsin kinase. Our results represent a link between the evolutionary analysis, which pinpoints the specific amino acid positions in the adaptive process, and the structural and functional analysis, closer to the phenotype, making biochemical sense of specific selected genetic sequences in rhodopsin evolution. PMID:26865329

  19. Keeping It Local: Evidence for Positive Selection in Swedish Arabidopsis thaliana

    PubMed Central

    Huber, Christian D.; Nordborg, Magnus; Hermisson, Joachim; Hellmann, Ines

    2014-01-01

    Detecting positive selection in species with heterogeneous habitats and complex demography is notoriously difficult and prone to statistical biases. The model plant Arabidopsis thaliana exemplifies this problem: In spite of the large amounts of data, little evidence for classic selective sweeps has been found. Moreover, many aspects of the demography are unclear, which makes it hard to judge whether the few signals are indeed signs of selection, or false positives caused by demographic events. Here, we focus on Swedish A. thaliana and we find that the demography can be approximated as a two-population model. Careful analysis of the data shows that such a two island model is characterized by a very old split time that significantly predates the last glacial maximum followed by secondary contact with strong migration. We evaluate selection based on this demography and find that this secondary contact model strongly affects the power to detect sweeps. Moreover, it affects the power differently for northern Sweden (more false positives) as compared with southern Sweden (more false negatives). However, even when the demographic history is accounted for, sweep signals in northern Sweden are stronger than in southern Sweden, with little or no positional overlap. Further simulations including the complex demography and selection confirm that this is not compatible with global selection acting on both populations, and thus can be taken as evidence for local selection within subpopulations of Swedish A. thaliana. This study demonstrates the necessity of combining demographic analyses and sweep scans for the detection of selection, particularly when selection acts predominantly local. PMID:25158800

  20. The influence of phylogenetic uncertainty on the detection of positive Darwinian selection.

    PubMed

    Pie, Marcio R

    2006-12-01

    The power of maximum likelihood tests of positive selection on protein-coding genes depends heavily on detecting and accounting for potential biases in the studied data set. Although the influence of transition:transversion and codon biases have been investigated in detail, little is known about how inaccuracy in the phylogeny used during the calculations affects the performance of these tests. In this study, 3 empirical data sets are analyzed using sets of simulated topologies corresponding to low, intermediate, and high levels of phylogenetic uncertainty. The detection of positive selection was largely unaffected by errors in the underlying phylogeny. However, the number of sites identified as being under positive selection tended to be overestimated.

  1. Transcriptome Sequencing of Lima Bean (Phaseolus lunatus) to Identify Putative Positive Selection in Phaseolus and Legumes

    PubMed Central

    Li, Fengqi; Cao, Depan; Liu, Yang; Yang, Ting; Wang, Guirong

    2015-01-01

    The identification of genes under positive selection is a central goal of evolutionary biology. Many legume species, including Phaseolus vulgaris (common bean) and Phaseolus lunatus (lima bean), have important ecological and economic value. In this study, we sequenced and assembled the transcriptome of one Phaseolus species, lima bean. A comparison with the genomes of six other legume species, including the common bean, Medicago, lotus, soybean, chickpea, and pigeonpea, revealed 15 and 4 orthologous groups with signatures of positive selection among the two Phaseolus species and among the seven legume species, respectively. Characterization of these positively selected genes using Non redundant (nr) annotation, gene ontology (GO) classification, GO term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these genes are mostly involved in thylakoids, photosynthesis and metabolism. This study identified genes that may be related to the divergence of the Phaseolus and legume species. These detected genes are particularly good candidates for subsequent functional studies. PMID:26151849

  2. SAR studies on carboxylic acid series M(1) selective positive allosteric modulators (PAMs).

    PubMed

    Kuduk, Scott D; Beshore, Douglas C

    2014-01-01

    There is mounting evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M1 muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD). A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M2 to M5 sub-types. Thus, there is a need to identify selective activators of the M1 receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M1 is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. BQCA has been identified as a highly selective carboxylic acid M1 PAM and this review focuses on an extensive lead optimization campaign undertaken on this compound.

  3. Tuning transport selectivity of ionic species by phosphoric acid gradient in positively charged nanochannel membranes.

    PubMed

    Yang, Meng; Yang, Xiaohai; Wang, Kemin; Wang, Qing; Fan, Xin; Liu, Wei; Liu, Xizhen; Liu, Jianbo; Huang, Jin

    2015-02-03

    The transport of ionic species through a nanochannel plays important roles in fundamental research and practical applications of the nanofluidic device. Here, we demonstrated that ionic transport selectivity of a positively charged nanochannel membrane can be tuned under a phosphoric acid gradient. When phosphoric acid solution and analyte solution were connected by the positively charged nanochannel membrane, the faster-moving analyte through the positively charged nanochannel membrane was the positively charged dye (methylviologen, MV(2+)) instead of the negatively charged dye (1,5-naphthalene disulfonate, NDS(2-)). In other words, a reversed ion selectivity of the nanochannel membranes can be found. It can be explained as a result of the combination of diffusion, induced electroosmosis, and induced electrophoresis. In addition, the influencing factors of transport selectivity, including concentration of phosphoric acid, penetration time, and volume of feed solution, were also investigated. The results showed that the transport selectivity can further be tuned by adjusting these factors. As a method of tuning ionic transport selectivity by establishing phosphoric acid gradient, it will be conducive to improving the separation of ionic species.

  4. Positive selection sites in tertiary structure of Leguminosae chalcone isomerase 1.

    PubMed

    Wang, R K; Zhan, S F; Zhao, T J; Zhou, X L; Wang, C E

    2015-03-20

    Isoflavonoids and the related synthesis enzyme, chalcone isomerase 1 (CHI1), are unique in the Leguminosae, with diverse biological functions. Among the Leguminosae, the soybean is an important oil, protein crop, and model plant. In this study, we aimed to detect the generation pattern of Leguminosae CHI1. Genome-wide sequence analysis of CHI in 3 Leguminosae and 3 other closely related model plants was performed; the expression levels of soybean chalcone isomerases were also analyzed. By comparing positively selected sites and their protein structures, we retrieved the evolution patterns for Leguminosae CHI1. A total of 28 CHI and 7 FAP3 (CHI4) genes were identified and separated into 4 clades: CHI1, CHI2, CHI3, and FAP3. Soybean genes belonging to the same chalcone isomerase subfamily had similar expression patterns. CHI1, the unique chalcone isomerase subfamily in Leguminosae, showed signs of significant positive selection as well as special expression characteristics, indicating an accelerated evolution throughout its divergence. Eight sites were identified as undergoing positive selection with high confidence. When mapped onto the tertiary structure of CHI1, these 8 sites were observed surrounding the enzyme substrate only; some of them connected to the catalytic core of CHI. Thus, we inferred that the generation of Leguminosae CHI1 is dependent on the positively selected amino acids surrounding its catalytic substrate. In other words, the evolution of CHI1 was driven by specific selection or processing conditions within the substrate.

  5. Positioning.

    ERIC Educational Resources Information Center

    Conone, Ruth M.

    The key to positioning is the creation of a clear benefit image in the consumer's mind. One positioning strategy is creating in the prospect's mind a position that takes into consideration the company's or agency's strengths and weaknesses as well as those of its competitors. Another strategy is to gain entry into a position ladder owned by…

  6. Positive Selection or Free to Vary? Assessing the Functional Significance of Sequence Change Using Molecular Dynamics

    PubMed Central

    Allison, Jane R.; Lechner, Marcus; Hoeppner, Marc P.; Poole, Anthony M.

    2016-01-01

    Evolutionary arms races between pathogens and their hosts may be manifested as selection for rapid evolutionary change of key genes, and are sometimes detectable through sequence-level analyses. In the case of protein-coding genes, such analyses frequently predict that specific codons are under positive selection. However, detecting positive selection can be non-trivial, and false positive predictions are a common concern in such analyses. It is therefore helpful to place such predictions within a structural and functional context. Here, we focus on the p19 protein from tombusviruses. P19 is a homodimer that sequesters siRNAs, thereby preventing the host RNAi machinery from shutting down viral infection. Sequence analysis of the p19 gene is complicated by the fact that it is constrained at the sequence level by overprinting of a viral movement protein gene. Using homology modeling, in silico mutation and molecular dynamics simulations, we assess how non-synonymous changes to two residues involved in forming the dimer interface—one invariant, and one predicted to be under positive selection—impact molecular function. Interestingly, we find that both observed variation and potential variation (where a non-synonymous change to p19 would be synonymous for the overprinted movement protein) does not significantly impact protein structure or RNA binding. Consequently, while several methods identify residues at the dimer interface as being under positive selection, MD results suggest they are functionally indistinguishable from a site that is free to vary. Our analyses serve as a caveat to using sequence-level analyses in isolation to detect and assess positive selection, and emphasize the importance of also accounting for how non-synonymous changes impact structure and function. PMID:26871901

  7. Evidence of Positive Selection in Mitochondrial Complexes I and V of the African Elephant

    PubMed Central

    Finch, Tabitha M.; Zhao, Nan; Korkin, Dmitry; Frederick, Katy H.; Eggert, Lori S.

    2014-01-01

    As species evolve, they become adapted to their local environments. Detecting the genetic signature of selection and connecting that to the phenotype of the organism, however, is challenging. Here we report using an integrative approach that combines DNA sequencing with structural biology analyses to assess the effect of selection on residues in the mitochondrial DNA of the two species of African elephants. We detected evidence of positive selection acting on residues in complexes I and V, and we used homology protein structure modeling to assess the effect of the biochemical properties of the selected residues on the enzyme structure. Given the role these enzymes play in oxidative phosphorylation, we propose that the selected residues may contribute to the metabolic adaptation of forest and savanna elephants to their unique habitats. PMID:24695069

  8. Evidence of positive selection in mitochondrial complexes I and V of the African elephant.

    PubMed

    Finch, Tabitha M; Zhao, Nan; Korkin, Dmitry; Frederick, Katy H; Eggert, Lori S

    2014-01-01

    As species evolve, they become adapted to their local environments. Detecting the genetic signature of selection and connecting that to the phenotype of the organism, however, is challenging. Here we report using an integrative approach that combines DNA sequencing with structural biology analyses to assess the effect of selection on residues in the mitochondrial DNA of the two species of African elephants. We detected evidence of positive selection acting on residues in complexes I and V, and we used homology protein structure modeling to assess the effect of the biochemical properties of the selected residues on the enzyme structure. Given the role these enzymes play in oxidative phosphorylation, we propose that the selected residues may contribute to the metabolic adaptation of forest and savanna elephants to their unique habitats.

  9. Thinking too positive? Revisiting current methods of population genetic selection inference.

    PubMed

    Bank, Claudia; Ewing, Gregory B; Ferrer-Admettla, Anna; Foll, Matthieu; Jensen, Jeffrey D

    2014-12-01

    In the age of next-generation sequencing, the availability of increasing amounts and improved quality of data at decreasing cost ought to allow for a better understanding of how natural selection is shaping the genome than ever before. However, alternative forces, such as demography and background selection (BGS), obscure the footprints of positive selection that we would like to identify. In this review, we illustrate recent developments in this area, and outline a roadmap for improved selection inference. We argue (i) that the development and obligatory use of advanced simulation tools is necessary for improved identification of selected loci, (ii) that genomic information from multiple time points will enhance the power of inference, and (iii) that results from experimental evolution should be utilized to better inform population genomic studies.

  10. Multifunctionalized iron oxide nanoparticles for selective drug delivery to CD44-positive cancer cells

    NASA Astrophysics Data System (ADS)

    Aires, Antonio; Ocampo, Sandra M.; Simões, Bruno M.; Josefa Rodríguez, María; Cadenas, Jael F.; Couleaud, Pierre; Spence, Katherine; Latorre, Alfonso; Miranda, Rodolfo; Somoza, Álvaro; Clarke, Robert B.; Carrascosa, José L.; Cortajarena, Aitziber L.

    2016-02-01

    Nanomedicine nowadays offers novel solutions in cancer therapy and diagnosis by introducing multimodal treatments and imaging tools in one single formulation. Nanoparticles acting as nanocarriers change the solubility, biodistribution and efficiency of therapeutic molecules, reducing their side effects. In order to successfully apply these novel therapeutic approaches, efforts are focused on the biological functionalization of the nanoparticles to improve the selectivity towards cancer cells. In this work, we present the synthesis and characterization of novel multifunctionalized iron oxide magnetic nanoparticles (MNPs) with antiCD44 antibody and gemcitabine derivatives, and their application for the selective treatment of CD44-positive cancer cells. The lymphocyte homing receptor CD44 is overexpressed in a large variety of cancer cells, but also in cancer stem cells (CSCs) and circulating tumor cells (CTCs). Therefore, targeting CD44-overexpressing cells is a challenging and promising anticancer strategy. Firstly, we demonstrate the targeting of antiCD44 functionalized MNPs to different CD44-positive cancer cell lines using a CD44-negative non-tumorigenic cell line as a control, and verify the specificity by ultrastructural characterization and downregulation of CD44 expression. Finally, we show the selective drug delivery potential of the MNPs by the killing of CD44-positive cancer cells using a CD44-negative non-tumorigenic cell line as a control. In conclusion, the proposed multifunctionalized MNPs represent an excellent biocompatible nanoplatform for selective CD44-positive cancer therapy in vitro.

  11. Signatures of positive selection in East African Shorthorn Zebu: a genome-wide SNP analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The small East African Shorthorn Zebu is the main indigenous cattle across East Africa. A recent genome wide SNPs analysis has revealed their ancient stable African taurine x Asian zebu admixture. Here, we assess the presence of candidate signature of positive selection in their genome, with the aim...

  12. A powerful score test to detect positive selection in genome-wide scans

    PubMed Central

    Zhong, Ming; Lange, Kenneth; Papp, Jeanette C; Fan, Ruzong

    2010-01-01

    One of the surest signatures of recent positive selection is a local elevation of advantageous allele frequency and linkage disequilibrium (LD). We proposed to detect such hitchhiking effects by using extended stretches of homozygosity as a surrogate indicator of recent positive selection. An extended haplotype-based homozygosity score test (EHHST) was developed to detect excess homozygosity. The EHHST conditioned on existing LD and it tested the haplotype version of the Hardy–Weinberg equilibrium. Compared with existing popular tests, which usually lack clear distribution, the EHHST is asymptotically normal, which makes analysis and applications easier. In particular, the EHHST facilitates the computation of an asymptotic P-value instead of an empirical P-value, using simulations. We evaluated by simulation that the EHHST led to appropriate false-positive rates, and it had higher or similar power as the existing popular methods. The method was applied to HapMap Phase II data. We were able to replicate previous findings of strong positive selection in 17 autosome genomic regions out of 20 reported candidates. On the basis of high EHHST values and population differentiations, we identified 15 new candidate regions that could undergo recent selection. PMID:20461112

  13. Genome-wide detection and characterization of positive selection in human populations

    PubMed Central

    Sabeti, Pardis C.; Varilly, Patrick; Fry, Ben; Lohmueller, Jason; Hostetter, Elizabeth; Cotsapas, Chris; Xie, Xiaohui; Byrne, Elizabeth H.; McCarroll, Steven A.; Gaudet, Rachelle; Schaffner, Stephen F.; Lander, Eric S.

    2009-01-01

    With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2)1. We used ‘long-range haplotype’ methods, which were developed to identify alleles segregating in a population that have undergone recent selection2, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population: LARGE and DMD, both related to infection by the Lassa virus3, in West Africa; SLC24A5 and SLC45A2, both involved in skin pigmentation4,5, in Europe; and EDAR and EDA2R, both involved in development of hair follicles6, in Asia. PMID:17943131

  14. Genome-wide detection and characterization of positive selection in human populations.

    PubMed

    Sabeti, Pardis C; Varilly, Patrick; Fry, Ben; Lohmueller, Jason; Hostetter, Elizabeth; Cotsapas, Chris; Xie, Xiaohui; Byrne, Elizabeth H; McCarroll, Steven A; Gaudet, Rachelle; Schaffner, Stephen F; Lander, Eric S; Frazer, Kelly A; Ballinger, Dennis G; Cox, David R; Hinds, David A; Stuve, Laura L; Gibbs, Richard A; Belmont, John W; Boudreau, Andrew; Hardenbol, Paul; Leal, Suzanne M; Pasternak, Shiran; Wheeler, David A; Willis, Thomas D; Yu, Fuli; Yang, Huanming; Zeng, Changqing; Gao, Yang; Hu, Haoran; Hu, Weitao; Li, Chaohua; Lin, Wei; Liu, Siqi; Pan, Hao; Tang, Xiaoli; Wang, Jian; Wang, Wei; Yu, Jun; Zhang, Bo; Zhang, Qingrun; Zhao, Hongbin; Zhao, Hui; Zhou, Jun; Gabriel, Stacey B; Barry, Rachel; Blumenstiel, Brendan; Camargo, Amy; Defelice, Matthew; Faggart, Maura; Goyette, Mary; Gupta, Supriya; Moore, Jamie; Nguyen, Huy; Onofrio, Robert C; Parkin, Melissa; Roy, Jessica; Stahl, Erich; Winchester, Ellen; Ziaugra, Liuda; Altshuler, David; Shen, Yan; Yao, Zhijian; Huang, Wei; Chu, Xun; He, Yungang; Jin, Li; Liu, Yangfan; Shen, Yayun; Sun, Weiwei; Wang, Haifeng; Wang, Yi; Wang, Ying; Xiong, Xiaoyan; Xu, Liang; Waye, Mary M Y; Tsui, Stephen K W; Xue, Hong; Wong, J Tze-Fei; Galver, Luana M; Fan, Jian-Bing; Gunderson, Kevin; Murray, Sarah S; Oliphant, Arnold R; Chee, Mark S; Montpetit, Alexandre; Chagnon, Fanny; Ferretti, Vincent; Leboeuf, Martin; Olivier, Jean-François; Phillips, Michael S; Roumy, Stéphanie; Sallée, Clémentine; Verner, Andrei; Hudson, Thomas J; Kwok, Pui-Yan; Cai, Dongmei; Koboldt, Daniel C; Miller, Raymond D; Pawlikowska, Ludmila; Taillon-Miller, Patricia; Xiao, Ming; Tsui, Lap-Chee; Mak, William; Song, You Qiang; Tam, Paul K H; Nakamura, Yusuke; Kawaguchi, Takahisa; Kitamoto, Takuya; Morizono, Takashi; Nagashima, Atsushi; Ohnishi, Yozo; Sekine, Akihiro; Tanaka, Toshihiro; Tsunoda, Tatsuhiko; Deloukas, Panos; Bird, Christine P; Delgado, Marcos; Dermitzakis, Emmanouil T; Gwilliam, Rhian; Hunt, Sarah; Morrison, Jonathan; Powell, Don; Stranger, Barbara E; Whittaker, Pamela; Bentley, David R; Daly, Mark J; de Bakker, Paul I W; Barrett, Jeff; Chretien, Yves R; Maller, Julian; McCarroll, Steve; Patterson, Nick; Pe'er, Itsik; Price, Alkes; Purcell, Shaun; Richter, Daniel J; Sabeti, Pardis; Saxena, Richa; Schaffner, Stephen F; Sham, Pak C; Varilly, Patrick; Altshuler, David; Stein, Lincoln D; Krishnan, Lalitha; Smith, Albert Vernon; Tello-Ruiz, Marcela K; Thorisson, Gudmundur A; Chakravarti, Aravinda; Chen, Peter E; Cutler, David J; Kashuk, Carl S; Lin, Shin; Abecasis, Gonçalo R; Guan, Weihua; Li, Yun; Munro, Heather M; Qin, Zhaohui Steve; Thomas, Daryl J; McVean, Gilean; Auton, Adam; Bottolo, Leonardo; Cardin, Niall; Eyheramendy, Susana; Freeman, Colin; Marchini, Jonathan; Myers, Simon; Spencer, Chris; Stephens, Matthew; Donnelly, Peter; Cardon, Lon R; Clarke, Geraldine; Evans, David M; Morris, Andrew P; Weir, Bruce S; Tsunoda, Tatsuhiko; Johnson, Todd A; Mullikin, James C; Sherry, Stephen T; Feolo, Michael; Skol, Andrew; Zhang, Houcan; Zeng, Changqing; Zhao, Hui; Matsuda, Ichiro; Fukushima, Yoshimitsu; Macer, Darryl R; Suda, Eiko; Rotimi, Charles N; Adebamowo, Clement A; Ajayi, Ike; Aniagwu, Toyin; Marshall, Patricia A; Nkwodimmah, Chibuzor; Royal, Charmaine D M; Leppert, Mark F; Dixon, Missy; Peiffer, Andy; Qiu, Renzong; Kent, Alastair; Kato, Kazuto; Niikawa, Norio; Adewole, Isaac F; Knoppers, Bartha M; Foster, Morris W; Clayton, Ellen Wright; Watkin, Jessica; Gibbs, Richard A; Belmont, John W; Muzny, Donna; Nazareth, Lynne; Sodergren, Erica; Weinstock, George M; Wheeler, David A; Yakub, Imtaz; Gabriel, Stacey B; Onofrio, Robert C; Richter, Daniel J; Ziaugra, Liuda; Birren, Bruce W; Daly, Mark J; Altshuler, David; Wilson, Richard K; Fulton, Lucinda L; Rogers, Jane; Burton, John; Carter, Nigel P; Clee, Christopher M; Griffiths, Mark; Jones, Matthew C; McLay, Kirsten; Plumb, Robert W; Ross, Mark T; Sims, Sarah K; Willey, David L; Chen, Zhu; Han, Hua; Kang, Le; Godbout, Martin; Wallenburg, John C; L'Archevêque, Paul; Bellemare, Guy; Saeki, Koji; Wang, Hongguang; An, Daochang; Fu, Hongbo; Li, Qing; Wang, Zhen; Wang, Renwu; Holden, Arthur L; Brooks, Lisa D; McEwen, Jean E; Guyer, Mark S; Wang, Vivian Ota; Peterson, Jane L; Shi, Michael; Spiegel, Jack; Sung, Lawrence M; Zacharia, Lynn F; Collins, Francis S; Kennedy, Karen; Jamieson, Ruth; Stewart, John

    2007-10-18

    With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

  15. Genomic Analysis Identifies Targets of Convergent Positive Selection in Drug Resistant Mycobacterium tuberculosis

    PubMed Central

    Farhat, Maha R; Shapiro, B Jesse; Kieser, Karen J; Sultana, Razvan; Jacobson, Karen R; Victor, Thomas C; Warren, Robin M; Streicher, Elizabeth M; Calver, Alistair; Sloutsky, Alex; Kaur, Devinder; Posey, Jamie E; Plikaytis, Bonnie; Oggioni, Marco R; Gardy, Jennifer L; Johnston, James C; Rodrigues, Mabel; Tang, Patrick K C; Kato-Maeda, Midori; Borowsky, Mark L; Muddukrishna, Bhavana; Kreiswirth, Barry N; Kurepina, Natalia; Galagan, James; Gagneux, Sebastien; Birren, Bruce; Rubin, Eric J; Lander, Eric S; Sabeti, Pardis C; Murray, Megan

    2013-01-01

    Mycobacterium tuberculosis is successfully evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including the genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly and 7 previously sequenced M. tuberculosis genomes, we identified genomewide signatures of positive selection specific to the 47 resistant genomes. By searching for convergent evolution, the independent fixation of mutations at the same nucleotide site or gene, we recovered 100% of a set of known resistance markers. We also found evidence of positive selection in an additional 39 genomic regions in resistant isolates. These regions encode pathways of cell wall biosynthesis, transcriptional regulation and DNA repair. Mutations in these regions could directly confer resistance or compensate for fitness costs associated with resistance. Functional genetic analysis of mutations in one gene, ponA1, demonstrated an in vitro growth advantage in the presence of the drug rifampicin. PMID:23995135

  16. Ongoing Progress in Spacecraft Controls

    NASA Technical Reports Server (NTRS)

    Ghosh, Dave (Editor)

    1992-01-01

    This publication is a collection of papers presented at the Mars Mission Research Center workshop on Ongoing Progress in Spacecraft Controls. The technical program addressed additional Mars mission control problems that currently exist in robotic missions in addition to human missions. Topics include control systems design in the presence of large time delays, fuel-optimal propulsive control, and adaptive control to handle a variety of unknown conditions.

  17. Positive Selection Underlies Faster-Z Evolution of Gene Expression in Birds

    PubMed Central

    Dean, Rebecca; Harrison, Peter W.; Wright, Alison E.; Zimmer, Fabian; Mank, Judith E.

    2015-01-01

    The elevated rate of evolution for genes on sex chromosomes compared with autosomes (Fast-X or Fast-Z evolution) can result either from positive selection in the heterogametic sex or from nonadaptive consequences of reduced relative effective population size. Recent work in birds suggests that Fast-Z of coding sequence is primarily due to relaxed purifying selection resulting from reduced relative effective population size. However, gene sequence and gene expression are often subject to distinct evolutionary pressures; therefore, we tested for Fast-Z in gene expression using next-generation RNA-sequencing data from multiple avian species. Similar to studies of Fast-Z in coding sequence, we recover clear signatures of Fast-Z in gene expression; however, in contrast to coding sequence, our data indicate that Fast-Z in expression is due to positive selection acting primarily in females. In the soma, where gene expression is highly correlated between the sexes, we detected Fast-Z in both sexes, although at a higher rate in females, suggesting that many positively selected expression changes in females are also expressed in males. In the gonad, where intersexual correlations in expression are much lower, we detected Fast-Z for female gene expression, but crucially, not males. This suggests that a large amount of expression variation is sex-specific in its effects within the gonad. Taken together, our results indicate that Fast-Z evolution of gene expression is the product of positive selection acting on recessive beneficial alleles in the heterogametic sex. More broadly, our analysis suggests that the adaptive potential of Z chromosome gene expression may be much greater than that of gene sequence, results which have important implications for the role of sex chromosomes in speciation and sexual selection. PMID:26067773

  18. Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection

    PubMed Central

    Xing, Yan; Jameson, Stephen C.; Hogquist, Kristin A.

    2013-01-01

    Cortical thymic epithelial cells (cTECs) express a unique thymoproteasome subunit-β5T that plays an essential role in the development of CD8 T cells. In contrast, the immunoproteasome subunit-β5i is expressed in other thymic antigen-presenting cells (APCs). The thymoproteasome may generate peptides that are specialized for positive selection, or it may simply serve to generate peptides that are distinct from other APCs that cause negative selection, thereby promoting an overall larger number of surviving clones to mature and function in the immune system. To distinguish these models, we genetically engineered mice to express distinct peptide repertoires in cTECs vs. other APCs without expressing β5T, by generating β5t5i knockin mice, in which β5i replaced β5T in cTECs. When such animals were crossed to β5i−/− mice, β5i was exclusively expressed in cTECs, whereas β5 was expressed in other cells. However, this mouse did not support normal positive selection, suggesting that β5T generates peptides that are intrinsically better for positive selection (i.e., β5i could not replace β5T) and not merely because these peptides are distinct from peptides presented by other APCs. Finally, using an Nur77GFP reporter, we show that the T cells generated in the absence of β5T have higher reactivity to self, generating predominantly CD44hi memory phenotype peripheral CD8+ T cells. Altogether, our results suggest that the thymoproteasome supports positive selection by generating peptides that are optimized for the selection of weakly self-reactive, naïve T-cell clones. PMID:23569244

  19. Pervasive, genome-wide positive selection leading to functional divergence in the bacterial genus Campylobacter

    PubMed Central

    Lefébure, Tristan; Stanhope, Michael J.

    2009-01-01

    An open question in bacterial genomics is the role that adaptive evolution of the core genome plays in diversification and adaptation of bacterial species, and how this might differ between groups of bacteria occupying different environmental circumstances. The genus Campylobacter encompasses several important human and animal enteric pathogens, with genome sequence data available for eight species. We estimate the Campylobacter core genome at 647 genes, with 92.5% of the nonrecombinant core genome loci under positive selection in at least one lineage and the same gene frequently under positive selection in multiple lineages. Tests are provided that reject recombination, saturation, and variation in codon usage bias as factors contributing to this high level of selection. We suggest this genome-wide adaptive evolution may result from a Red Queen macroevolutionary dynamic, in which species are involved in competition for resources within the mammalian and/or vertebrate gastrointestinal tract. Much reduced levels of positive selection evident in Streptococcus, as reported by the authors in an earlier work, may be a consequence of these taxa inhabiting less species-rich habitats, and more unique niches. Despite many common loci under positive selection in multiple Campylobacter lineages, we found no evidence for molecular adaptive convergence at the level of the same or adjacent codons, or even protein domains. Taken collectively, these results describe the diversification of a bacterial genus that involves pervasive natural selection pressure across virtually the entire genome, with this adaptation occurring in different ways in different lineages, despite the species tendency toward a common gastrointestinal habitat. PMID:19304960

  20. Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever.

    PubMed

    Andersen, Kristian G; Shylakhter, Ilya; Tabrizi, Shervin; Grossman, Sharon R; Happi, Christian T; Sabeti, Pardis C

    2012-03-19

    Rapidly evolving viruses and other pathogens can have an immense impact on human evolution as natural selection acts to increase the prevalence of genetic variants providing resistance to disease. With the emergence of large datasets of human genetic variation, we can search for signatures of natural selection in the human genome driven by such disease-causing microorganisms. Based on this approach, we have previously hypothesized that Lassa virus (LASV) may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. In this study, we provide further evidence for this notion. By applying tests for selection to genome-wide data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, we demonstrate evidence for positive selection in LARGE and interleukin 21 (IL21), two genes implicated in LASV infectivity and immunity. We further localized the signals of selection, using the recently developed composite of multiple signals method, to introns and putative regulatory regions of those genes. Our results suggest that natural selection may have targeted variants giving rise to alternative splicing or differential gene expression of LARGE and IL21. Overall, our study supports the hypothesis that selective pressures imposed by LASV may have led to the emergence of particular alleles conferring resistance to Lassa fever, and opens up new avenues of research pursuit.

  1. The effects of alignment error and alignment filtering on the sitewise detection of positive selection.

    PubMed

    Jordan, Gregory; Goldman, Nick

    2012-04-01

    When detecting positive selection in proteins, the prevalence of errors resulting from misalignment and the ability of alignment filters to mitigate such errors are not well understood, but filters are commonly applied to try to avoid false positive results. Focusing on the sitewise detection of positive selection across a wide range of divergence levels and indel rates, we performed simulation experiments to quantify the false positives and false negatives introduced by alignment error and the ability of alignment filters to improve performance. We found that some aligners led to many false positives, whereas others resulted in very few. False negatives were a problem for all aligners, increasing with sequence divergence. Of the aligners tested, PRANK's codon-based alignments consistently performed the best and ClustalW performed the worst. Of the filters tested, GUIDANCE performed the best and Gblocks performed the worst. Although some filters showed good ability to reduce the error rates from ClustalW and MAFFT alignments, none were found to substantially improve the performance of PRANK alignments under most conditions. Our results revealed distinct trends in error rates and power levels for aligners and filters within a biologically plausible parameter space. With the best aligner, a low false positive rate was maintained even with extremely divergent indel-prone sequences. Controls using the true alignment and an optimal filtering method suggested that performance improvements could be gained by improving aligners or filters to reduce the prevalence of false negatives, especially at higher divergence levels and indel rates.

  2. Signatures of positive selection in Toll-like receptor (TLR) genes in mammals

    PubMed Central

    2011-01-01

    Background Toll-like receptors (TLRs) are a major class of pattern recognition receptors (PRRs) expressed in the cell surface or membrane compartments of immune and non-immune cells. TLRs are encoded by a multigene family and represent the first line of defense against pathogens by detecting foreigner microbial molecular motifs, the pathogen-associated molecular patterns (PAMPs). TLRs are also important by triggering the adaptive immunity in vertebrates. They are characterized by the presence of leucine-rich repeats (LRRs) in the ectodomain, which are associated with the PAMPs recognition. The direct recognition of different pathogens by TLRs might result in different evolutionary adaptations important to understand the dynamics of the host-pathogen interplay. Ten mammal TLR genes, viral (TLR3, 7, 8, 9) and non-viral (TLR1-6, 10), were selected to identify signatures of positive selection that might have been imposed by interacting pathogens and to clarify if viral and non-viral TLRs might display different patterns of molecular evolution. Results By using Maximum Likelihood approaches, evidence of positive selection was found in all the TLRs studied. The number of positively selected codons (PSC) ranged between 2-26 codons (0.25%-2.65%) with the non-viral TLR4 as the receptor with higher percentage of positively selected codons (2.65%), followed by the viral TLR8 (2.50%). The results indicated that viral and non-viral TLRs are similarly under positive selection. Almost all TLRs have at least one PSC located in the LRR ectodomain which underlies the importance of the pathogen recognition by this region. Conclusions Our results are not in line with previous studies on primates and birds that identified more codons under positive selection in non-viral TLRs. This might be explained by the fact that both primates and birds are homogeneous groups probably being affected by only a restricted number of related viruses with equivalent motifs to be recognized. The analyses

  3. Structural and functional implications of positive selection at the primate angiogenin gene

    PubMed Central

    Osorio, Daniel S; Antunes, Agostinho; Ramos, Maria J

    2007-01-01

    Background Angiogenesis, the formation of new blood vessels, is a primordial process in development and its dysregulation has a central role in the pathogenesis of many diseases. Angiogenin (ANG), a peculiar member of the RNase A superfamily, is a potent inducer of angiogenesis involved in many different types of cancer, amyotrophic lateral sclerosis and also with a possible role in the innate immune defense. The evolutionary path of this family has been a highly dynamic one, where positive selection has played a strong role. In this work we used a combined gene and protein level approach to determine the main sites under diversifying selection on the primate ANG gene and analyze its structural and functional implications. Results We obtained evidence for positive selection in the primate ANG gene. Site specific analysis pointed out 15 sites under positive selection, most of which also exhibited drastic changes in amino acid properties. The mapping of these sites in the ANG 3D-structure described five clusters, four of which were located in functional regions: two in the active site region, one in the nucleolar location signal and one in the cell-binding site. Eight of the 15 sites under selection in the primate ANG gene were highly or moderately conserved in the RNase A family, suggesting a directed event and not a simple consequence of local structural or functional permissiveness. Moreover, 11 sites were exposed to the surface of the protein indicating that they may influence the interactions performed by ANG. Conclusion Using a maximum likelihood gene level analysis we identified 15 sites under positive selection in the primate ANG genes, that were further corroborated through a protein level analysis of radical changes in amino acid properties. These sites mapped onto the main functional regions of the ANG protein. The fact that evidence for positive selection is present in all ANG regions required for angiogenesis may be a good indication that angiogenesis is

  4. Three-dimensional window analysis for detecting positive selection at structural regions of proteins.

    PubMed

    Suzuki, Yoshiyuki

    2004-12-01

    Detection of natural selection operating at the amino acid sequence level is important in the study of molecular evolution. Single-site analysis and one-dimensional window analysis can be used to detect selection when the biological functions of amino acid sites are unknown. Single-site analysis is useful when selection operates more or less constantly over evolutionary time, but less so when selection operates temporarily. One-dimensional window analysis is more sensitive than single-site analysis when the functions of amino acid sites in close proximity in the linear sequence are similar, although this is not always the case. Here I present a three-dimensional window analysis method for detecting selection given the three-dimensional structure of the protein of interest. In the three-dimensional structure, the window is defined as the sphere centered on the alpha-carbon of an amino acid site. The window size is the radius of the sphere. The sites whose alpha-carbons are included in the window are grouped for the neutrality test. The window is moved within the three-dimensional structure by sequentially moving the central site along the primary amino acid sequence. To detect positive selection, it may also be useful to group the surface-exposed sites in the window separately. Three-dimensional window analysis appears not only to be more sensitive than single-site analysis and one-dimensional window analysis but also to provide similar specificity for inferring positive selection in the analyses of the hemagglutinin and neuraminidase genes of human influenza A viruses. This method, however, may fail to detect selection when it operates only on a particular site, in which case single-site analysis may be preferred, although a large number of sequences is required.

  5. Detecting signatures of positive selection associated with musical aptitude in the human genome.

    PubMed

    Liu, Xuanyao; Kanduri, Chakravarthi; Oikkonen, Jaana; Karma, Kai; Raijas, Pirre; Ukkola-Vuoti, Liisa; Teo, Yik-Ying; Järvelä, Irma

    2016-02-16

    Abilities related to musical aptitude appear to have a long history in human evolution. To elucidate the molecular and evolutionary background of musical aptitude, we compared genome-wide genotyping data (641 K SNPs) of 148 Finnish individuals characterized for musical aptitude. We assigned signatures of positive selection in a case-control setting using three selection methods: haploPS, XP-EHH and FST. Gene ontology classification revealed that the positive selection regions contained genes affecting inner-ear development. Additionally, literature survey has shown that several of the identified genes were known to be involved in auditory perception (e.g. GPR98, USH2A), cognition and memory (e.g. GRIN2B, IL1A, IL1B, RAPGEF5), reward mechanisms (RGS9), and song perception and production of songbirds (e.g. FOXP1, RGS9, GPR98, GRIN2B). Interestingly, genes related to inner-ear development and cognition were also detected in a previous genome-wide association study of musical aptitude. However, the candidate genes detected in this study were not reported earlier in studies of musical abilities. Identification of genes related to language development (FOXP1 and VLDLR) support the popular hypothesis that music and language share a common genetic and evolutionary background. The findings are consistent with the evolutionary conservation of genes related to auditory processes in other species and provide first empirical evidence for signatures of positive selection for abilities that contribute to musical aptitude.

  6. Detecting signatures of positive selection associated with musical aptitude in the human genome

    PubMed Central

    Liu, Xuanyao; Kanduri, Chakravarthi; Oikkonen, Jaana; Karma, Kai; Raijas, Pirre; Ukkola-Vuoti, Liisa; Teo, Yik-Ying; Järvelä, Irma

    2016-01-01

    Abilities related to musical aptitude appear to have a long history in human evolution. To elucidate the molecular and evolutionary background of musical aptitude, we compared genome-wide genotyping data (641 K SNPs) of 148 Finnish individuals characterized for musical aptitude. We assigned signatures of positive selection in a case-control setting using three selection methods: haploPS, XP-EHH and FST. Gene ontology classification revealed that the positive selection regions contained genes affecting inner-ear development. Additionally, literature survey has shown that several of the identified genes were known to be involved in auditory perception (e.g. GPR98, USH2A), cognition and memory (e.g. GRIN2B, IL1A, IL1B, RAPGEF5), reward mechanisms (RGS9), and song perception and production of songbirds (e.g. FOXP1, RGS9, GPR98, GRIN2B). Interestingly, genes related to inner-ear development and cognition were also detected in a previous genome-wide association study of musical aptitude. However, the candidate genes detected in this study were not reported earlier in studies of musical abilities. Identification of genes related to language development (FOXP1 and VLDLR) support the popular hypothesis that music and language share a common genetic and evolutionary background. The findings are consistent with the evolutionary conservation of genes related to auditory processes in other species and provide first empirical evidence for signatures of positive selection for abilities that contribute to musical aptitude. PMID:26879527

  7. Colour polymorphism torn apart by opposing positive frequency-dependent selection, yet maintained in space.

    PubMed

    Gordon, Swanne P; Kokko, Hanna; Rojas, Bibiana; Nokelainen, Ossi; Mappes, Johanna

    2015-11-01

    Polymorphic warning signals in aposematic species are enigmatic because predator learning and discrimination should select for the most common coloration, resulting in positive frequency-dependent survival selection. Here, we investigated whether differential mating success could create sufficiently strong negative frequency-dependent selection for rare morphs to explain polymorphic (white and yellow) warning coloration in male wood tiger moths (Parasemia plantaginis). We conducted an experiment in semi-natural conditions where we estimated mating success for both white and yellow male moths under three different morph frequencies. Contrary to expectations, mating success was positively frequency-dependent: white morph males had high relative fitness when common, likewise yellow morph males had high relative fitness when instead they were common. We hence built a model parameterized with our data to examine whether polymorphism can be maintained despite two sources of positive frequency dependence. The model includes known spatial variation in the survival advantage enjoyed by the yellow morph and assumes that relative mating success follows our experimentally derived values. It predicts that polymorphism is possible under migration for up to approximately 20% exchange of individuals between subpopulations in each generation. Our results suggest that differential mating success combined with spatial variation in predator communities may operate as a selection mosaic that prevents complete fixation of either morph.

  8. Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers.

    PubMed

    Borgland, Stephanie L; Chang, Shao-Ju; Bowers, M Scott; Thompson, Jennifer L; Vittoz, Nicole; Floresco, Stan B; Chou, Jonathan; Chen, Billy T; Bonci, Antonello

    2009-09-09

    Orexin A/hypocretin-1 (oxA/hcrt-1) is known to be a modulator of dopamine-dependent neuronal activity and behaviors. However, the role of this system in driving motivated behaviors remains poorly understood. Here, we show that orexin/hypocretin receptor-1 (ox/hcrt-1R) signaling is important for motivation for highly salient, positive reinforcement. Blockade of ox/hcrt-1R selectively reduced work to self-administer cocaine or high fat food pellets. Moreover, oxA/hcrt-1 strengthened presynaptic glutamatergic inputs to the ventral tegmental area (VTA) only in cocaine or high fat self-administering rats. Finally, oxA/hcrt-1-mediated excitatory synaptic transmission onto VTA neurons was not potentiated following an arousing, aversive stimulus, suggesting that oxA/hcrt-1-mediated glutamatergic synaptic transmission was potentiated selectively with highly salient positive reinforcers. These experiments provide evidence for a selective role of oxA/hcrt-1 signaling in motivation for highly salient reinforcers and may represent a unique opportunity to design novel therapies that selectively reduce excessive drive to consume positive reinforcers of high salience.

  9. Evidence for the fixation of gene duplications by positive selection in Drosophila

    PubMed Central

    Cardoso-Moreira, Margarida; Arguello, J. Roman; Gottipati, Srikanth; Harshman, L.G.; Grenier, Jennifer K.; Clark, Andrew G.

    2016-01-01

    Gene duplications play a key role in the emergence of novel traits and in adaptation. But despite their centrality to evolutionary processes, it is still largely unknown how new gene duplicates are initially fixed within populations and later maintained in genomes. Long-standing debates on the evolution of gene duplications could be settled by determining the relative importance of genetic drift vs. positive selection in the fixation of new gene duplicates. Using the Drosophila Global Diversity Lines (GDL), we have combined genome-wide SNP polymorphism data with a novel set of copy number variant calls and gene expression profiles to characterize the polymorphic phase of new genes. We found that approximately half of the roughly 500 new complete gene duplications segregating in the GDL lead to significant increases in the expression levels of the duplicated genes and that these duplications are more likely to be found at lower frequencies, suggesting a negative impact on fitness. However, we also found that six of the nine gene duplications that are fixed or close to fixation in at least one of the five populations in our study show signs of being under positive selection, and that these duplications are likely beneficial because of dosage effects, with a possible role for additional mutations in two duplications. Our work suggests that in Drosophila, theoretical models that posit that gene duplications are immediately beneficial and fixed by positive selection are most relevant to explain the long-term evolution of gene duplications in this species. PMID:27197209

  10. Evidence for positive selection on the leptin gene in Cetacea and Pinnipedia.

    PubMed

    Yu, Li; Jin, Wei; Zhang, Xin; Wang, Ding; Zheng, Jin-song; Yang, Guang; Xu, Shi-xia; Cho, Soochin; Zhang, Ya-ping

    2011-01-01

    The leptin gene has received intensive attention and scientific investigation for its importance in energy homeostasis and reproductive regulation in mammals. Furthermore, study of the leptin gene is of crucial importance for public health, particularly for its role in obesity, as well as for other numerous physiological roles that it plays in mammals. In the present work, we report the identification of novel leptin genes in 4 species of Cetacea, and a comparison with 55 publicly available leptin sequences from mammalian genome assemblies and previous studies. Our study provides evidence for positive selection in the suborder Odontoceti (toothed whales) of the Cetacea and the family Phocidae (earless seals) of the Pinnipedia. We also detected positive selection in several leptin gene residues in these two lineages. To test whether leptin and its receptor evolved in a coordinated manner, we analyzed 24 leptin receptor gene (LPR) sequences from available mammalian genome assemblies and other published data. Unlike the case of leptin, our analyses did not find evidence of positive selection for LPR across the Cetacea and Pinnipedia lineages. In line with this, positively selected sites identified in the leptin genes of these two lineages were located outside of leptin receptor binding sites, which at least partially explains why co-evolution of leptin and its receptor was not observed in the present study. Our study provides interesting insights into current understanding of the evolution of mammalian leptin genes in response to selective pressures from life in an aquatic environment, and leads to a hypothesis that new tissue specificity or novel physiologic functions of leptin genes may have arisen in both odontocetes and phocids. Additional data from other species encompassing varying life histories and functional tests of the adaptive role of the amino acid changes identified in this study will help determine the factors that promote the adaptive evolution of the

  11. Positive selection in the SLC11A1 gene in the family Equidae.

    PubMed

    Bayerova, Zuzana; Janova, Eva; Matiasovic, Jan; Orlando, Ludovic; Horin, Petr

    2016-05-01

    Immunity-related genes are a suitable model for studying effects of selection at the genomic level. Some of them are highly conserved due to functional constraints and purifying selection, while others are variable and change quickly to cope with the variation of pathogens. The SLC11A1 gene encodes a transporter protein mediating antimicrobial activity of macrophages. Little is known about the patterns of selection shaping this gene during evolution. Although it is a typical evolutionarily conserved gene, functionally important polymorphisms associated with various diseases were identified in humans and other species. We analyzed the genomic organization, genetic variation, and evolution of the SLC11A1 gene in the family Equidae to identify patterns of selection within this important gene. Nucleotide SLC11A1 sequences were shown to be highly conserved in ten equid species, with more than 97 % sequence identity across the family. Single nucleotide polymorphisms (SNPs) were found in the coding and noncoding regions of the gene. Seven codon sites were identified to be under strong purifying selection. Codons located in three regions, including the glycosylated extracellular loop, were shown to be under diversifying selection. A 3-bp indel resulting in a deletion of the amino acid 321 in the predicted protein was observed in all horses, while it has been maintained in all other equid species. This codon comprised in an N-glycosylation site was found to be under positive selection. Interspecific variation in the presence of predicted N-glycosylation sites was observed.

  12. Evidence of Positive Selection of Aquaporins Genes from Pontoporia blainvillei during the Evolutionary Process of Cetaceans

    PubMed Central

    São Pedro, Simone Lima; Alves, João Marcelo Pereira; Barreto, André Silva; Lima, André Oliveira de Souza

    2015-01-01

    Background Marine mammals are well adapted to their hyperosmotic environment. Several morphological and physiological adaptations for water conservation and salt excretion are known to be present in cetaceans, being responsible for regulating salt balance. However, most previous studies have focused on the unique renal physiology of marine mammals, but the molecular bases of these mechanisms remain poorly explored. Many genes have been identified to be involved in osmotic regulation, including the aquaporins. Considering that aquaporin genes were potentially subject to strong selective pressure, the aim of this study was to analyze the molecular evolution of seven aquaporin genes (AQP1, AQP2, AQP3, AQP4, AQP6, AQP7, and AQP9) comparing the lineages of cetaceans and terrestrial mammals. Results Our results demonstrated strong positive selection in cetacean-specific lineages acting only in the gene for AQP2 (amino acids 23, 83, 107,179, 180, 181, 182), whereas no selection was observed in terrestrial mammalian lineages. We also analyzed the changes in the 3D structure of the aquaporin 2 protein. Signs of strong positive selection in AQP2 sites 179, 180, 181, and 182 were unexpectedly identified only in the baiji lineage, which was the only river dolphin examined in this study. Positive selection in aquaporins AQP1 (45), AQP4 (74), AQP7 (342, 343, 356) was detected in cetaceans and artiodactyls, suggesting that these events are not related to maintaining water and electrolyte homeostasis in seawater. Conclusions Our results suggest that the AQP2 gene might reflect different selective pressures in maintaining water balance in cetaceans, contributing to the passage from the terrestrial environment to the aquatic. Further studies are necessary, especially those including other freshwater dolphins, who exhibit osmoregulatory mechanisms different from those of marine cetaceans for the same essential task of maintaining serum electrolyte balance. PMID:26226365

  13. Detecting recent positive selection with high accuracy and reliability by conditional coalescent tree.

    PubMed

    Wang, Minxian; Huang, Xin; Li, Ran; Xu, Hongyang; Jin, Li; He, Yungang

    2014-11-01

    Studies of natural selection, followed by functional validation, are shedding light on understanding of genetic mechanisms underlying human evolution and adaptation. Classic methods for detecting selection, such as the integrated haplotype score (iHS) and Fay and Wu's H statistic, are useful for candidate gene searching underlying positive selection. These methods, however, have limited capability to localize causal variants in selection target regions. In this study, we developed a novel method based on conditional coalescent tree to detect recent positive selection by counting unbalanced mutations on coalescent gene genealogies. Extensive simulation studies revealed that our method is more robust than many other approaches against biases due to various demographic effects, including population bottleneck, expansion, or stratification, while not sacrificing its power. Furthermore, our method demonstrated its superiority in localizing causal variants from massive linked genetic variants. The rate of successful localization was about 20-40% higher than that of other state-of-the-art methods on simulated data sets. On empirical data, validated functional causal variants of four well-known positive selected genes were all successfully localized by our method, such as ADH1B, MCM6, APOL1, and HBB. Finally, the computational efficiency of this new method was much higher than that of iHS implementations, that is, 24-66 times faster than the REHH package, and more than 10,000 times faster than the original iHS implementation. These magnitudes make our method suitable for applying on large sequencing data sets. Software can be downloaded from https://github.com/wavefancy/scct.

  14. FOXP2 targets show evidence of positive selection in European populations.

    PubMed

    Ayub, Qasim; Yngvadottir, Bryndis; Chen, Yuan; Xue, Yali; Hu, Min; Vernes, Sonja C; Fisher, Simon E; Tyler-Smith, Chris

    2013-05-02

    Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction.

  15. Positive Selection Pressure Drives Variation on the Surface-Exposed Variable Proteins of the Pathogenic Neisseria

    PubMed Central

    Hill, Stuart

    2016-01-01

    Pathogenic species of Neisseria utilize variable outer membrane proteins to facilitate infection and proliferation within the human host. However, the mechanisms behind the evolution of these variable alleles remain largely unknown due to analysis of previously limited datasets. In this study, we have expanded upon the previous analyses to substantially increase the number of analyzed sequences by including multiple diverse strains, from various geographic locations, to determine whether positive selective pressure is exerted on the evolution of these variable genes. Although Neisseria are naturally competent, this analysis indicates that only intrastrain horizontal gene transfer among the pathogenic Neisseria principally account for these genes exhibiting linkage equilibrium which drives the polymorphisms evidenced within these alleles. As the majority of polymorphisms occur across species, the divergence of these variable genes is dependent upon the species and is independent of geographical location, disease severity, or serogroup. Tests of neutrality were able to detect strong selection pressures acting upon both the opa and pil gene families, and were able to locate the majority of these sites within the exposed variable regions of the encoded proteins. Evidence of positive selection acting upon the hypervariable domains of Opa contradicts previous beliefs and provides evidence for selection of receptor binding. As the pathogenic Neisseria reside exclusively within the human host, the strong selection pressures acting upon both the opa and pil gene families provide support for host immune system pressure driving sequence polymorphisms within these variable genes. PMID:27532335

  16. Positive Selection Pressure Drives Variation on the Surface-Exposed Variable Proteins of the Pathogenic Neisseria.

    PubMed

    Wachter, Jenny; Hill, Stuart

    2016-01-01

    Pathogenic species of Neisseria utilize variable outer membrane proteins to facilitate infection and proliferation within the human host. However, the mechanisms behind the evolution of these variable alleles remain largely unknown due to analysis of previously limited datasets. In this study, we have expanded upon the previous analyses to substantially increase the number of analyzed sequences by including multiple diverse strains, from various geographic locations, to determine whether positive selective pressure is exerted on the evolution of these variable genes. Although Neisseria are naturally competent, this analysis indicates that only intrastrain horizontal gene transfer among the pathogenic Neisseria principally account for these genes exhibiting linkage equilibrium which drives the polymorphisms evidenced within these alleles. As the majority of polymorphisms occur across species, the divergence of these variable genes is dependent upon the species and is independent of geographical location, disease severity, or serogroup. Tests of neutrality were able to detect strong selection pressures acting upon both the opa and pil gene families, and were able to locate the majority of these sites within the exposed variable regions of the encoded proteins. Evidence of positive selection acting upon the hypervariable domains of Opa contradicts previous beliefs and provides evidence for selection of receptor binding. As the pathogenic Neisseria reside exclusively within the human host, the strong selection pressures acting upon both the opa and pil gene families provide support for host immune system pressure driving sequence polymorphisms within these variable genes.

  17. Positive and purifying selection in mitochondrial genomes of a bird with mitonuclear discordance.

    PubMed

    Morales, Hernán E; Pavlova, Alexandra; Joseph, Leo; Sunnucks, Paul

    2015-06-01

    Diversifying selection on metabolic pathways can reduce intraspecific gene flow and promote population divergence. An opportunity to explore this arises from mitonuclear discordance observed in an Australian bird Eopsaltria australis. Across >1500 km, nuclear differentiation is low and latitudinally structured by isolation by distance, whereas two highly divergent, parapatric mitochondrial lineages (>6.6% in ND2) show a discordant longitudinal geographic pattern and experience different climates. Vicariance, incomplete lineage sorting and sex-biased dispersal were shown earlier to be unlikely drivers of the mitonuclear discordance; instead, natural selection on a female-linked trait was the preferred hypothesis. Accordingly, here we tested for signals of positive, divergent selection on mitochondrial genes in E. australis. We used codon models and physicochemical profiles of amino acid replacements to analyse complete mitochondrial genomes of the two mitochondrial lineages in E. australis, its sister species Eopsaltria griseogularis, and outgroups. We found evidence of positive selection on at least five amino acids, encoded by genes of two oxidative phosphorylation pathway complexes NADH dehydrogenase (ND4 and ND4L) and cytochrome bc1 (cyt-b) against a background of widespread purifying selection on all mitochondrial genes. Three of these amino acid replacements were fixed in ND4 of the geographically most widespread E. australis lineage. The other two replacements were fixed in ND4L and cyt-b of the geographically more restricted E. australis lineage. We discuss whether this selection may reflect local environmental adaptation, a by-product of other selective processes, or genetic incompatibilities, and propose how these hypotheses can be tested in future.

  18. Positive selection moments identify potential functional residues in human olfactory receptors

    NASA Technical Reports Server (NTRS)

    Singer, M. S.; Weisinger-Lewin, Y.; Lancet, D.; Shepherd, G. M.

    1996-01-01

    Correlated mutation analysis and molecular models of olfactory receptors have provided evidence that residues in the transmembrane domains form a binding pocket for odor ligands. As an independent test of these results, we have calculated positive selection moments for the alpha-helical sixth transmembrane domain (TM6) of human olfactory receptors. The moments can be used to identify residues that have been preferentially affected by positive selection and are thus likely to interact with odor ligands. The results suggest that residue 622, which is commonly a serine or threonine, could form critical H-bonds. In some receptors a dual-serine subsite, formed by residues 622 and 625, could bind hydroxyl determinants on odor ligands. The potential importance of these residues is further supported by site-directed mutagenesis in the beta-adrenergic receptor. The findings should be of practical value for future physiological studies, binding assays, and site-directed mutagenesis.

  19. Evolutionary analysis of TLR9 genes reveals the positive selection of extant teleosts in Perciformes.

    PubMed

    Zhu, Zhihuang; Sun, Yuena; Wang, Rixin; Xu, Tianjun

    2013-08-01

    The innate immune system can recognize non-self through pattern recognition receptors. Toll-like receptors were the best-known members of these receptors, and they could sense, recognize, and bind pathogen-associated molecular patterns. TLRs played an important role in innate immune system and were conserved in both invertebrate and vertebrate lineages. Thereinto, TLR9 could detect unmethylated CpG motifs in dsDNA and was expected to undergo coevolution with its microbial ligands. It was known that aquatic and terrestrial organisms dwelled in different environments which contained different pathogens, and they had to adapt to their local environmental conditions. Therefore, we collected TLR9 genes from invertebrate to vertebrate to further explore whether the huge differences between aquatic and terrestrial environments affected the TLR9s evolution between aquatic and terrestrial organisms. Molecular evolution analysis detected positively selected sites in the ancestral lineages of vertebrates, teleosts, and Perciformes but not in the ancestral lineage of mammals. In PAML, site model revealed that extant mammalian TLR9 genes underwent positive selection. However, the positive selection of extant teleosts appeared primarily in Perciformes in which there were 14 positively selected sites. Among these sites, two of them were located on the amino acid insertions of the leucine-rich repeats which could create DNA binding sites, three were found on the convex surface which might possibly affect the flexibility of the TLR solenoids, and six were located on the β-face of concave surface which contained the ligand-binding sites of the TLR solenoids. In other ML methods, we also found three sites under selection that coincided with the codons identified by M8 and these sites were all located in LRRs. The diverse aquatic and terrestrial environments might possess different pathogens to make the living organisms adapt to their local environmental conditions. The positive

  20. Relation between flexibility and positively selected HIV-1 protease mutants against inhibitors.

    PubMed

    Braz, Antônio S K; Tufanetto, Patrícia; Perahia, David; Scott, Luis P B

    2012-12-01

    The antiretroviral chemotherapy helps to reduce the mortality of HIVs infected patients. However, RNA dependant virus replication has a high mutation rate. Human immunodeficiency virus Type 1 protease plays an essential role in viral replication cycle. This protein is an important target for therapy with viral protein inhibitors. There are few works using normal mode analysis to investigate this problem from the structural changes viewpoint. The investigation of protein flexibility may be important for the study of processes associated with conformational changes and state transitions. The normal mode analysis allowed us to investigate structural changes in the protease (such as flexibility) in a straightforward way and try to associate these changes with the increase of fitness for each positively selected HIV-1 mutant protease of patients treated with several protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, lopinavir, fosamprenavir, atazanavir, darunavir, and tripanavir) in combination or separately. These positively selected mutations introduce significant flexibility in important regions such as the active site cavity and flaps. These mutations were also able to cause changes in accessible solvent area. This study showed that the majority of HIV-1 protease mutants can be grouped into two main classes of protein flexibility behavior. We presented a new approach to study structural changes caused by positively selected mutations in a pathogen protein, for instance the HIV-1 protease and their relationship with their resistance mechanism against known inhibitors. The method can be applied to any pharmaceutically relevant pathogen proteins and could be very useful to understand the effects of positively selected mutations in the context of structural changes.

  1. Positive selection is the main driving force for evolution of citrus canker-causing Xanthomonas.

    PubMed

    Zhang, Yunzeng; Jalan, Neha; Zhou, Xiaofeng; Goss, Erica; Jones, Jeffrey B; Setubal, João C; Deng, Xiaoling; Wang, Nian

    2015-10-01

    Understanding the evolutionary history and potential of bacterial pathogens is critical to prevent the emergence of new infectious bacterial diseases. Xanthomonas axonopodis subsp. citri (Xac) (synonym X. citri subsp. citri), which causes citrus canker, is one of the hardest-fought plant bacterial pathogens in US history. Here, we sequenced 21 Xac strains (14 XacA, 3 XacA* and 4 XacA(w)) with different host ranges from North America and Asia and conducted comparative genomic and evolutionary analyses. Our analyses suggest that acquisition of beneficial genes and loss of detrimental genes most likely allowed XacA to infect a broader range of hosts as compared with XacA(w) and XacA*. Recombination was found to have occurred frequently on the relative ancient branches, but rarely on the young branches of the clonal genealogy. The ratio of recombination/mutation ρ/θ was 0.0790±0.0005, implying that the Xac population was clonal in structure. Positive selection has affected 14% (395 out of 2822) of core genes of the citrus canker-causing Xanthomonas. The genes affected are enriched in 'carbohydrate transport and metabolism' and 'DNA replication, recombination and repair' genes (P<0.05). Many genes related to virulence, especially genes involved in the type III secretion system and effectors, are affected by positive selection, further highlighting the contribution of positive selection to the evolution of citrus canker-causing Xanthomonas. Our results suggest that both metabolism and virulence genes provide advantages to endow XacA with higher virulence and a wider host range. Our analysis advances our understanding of the genomic basis of specialization by positive selection in bacterial evolution.

  2. High amino acid diversity and positive selection at a putative coral immunity gene (tachylectin-2)

    PubMed Central

    2010-01-01

    Background Genes involved in immune functions, including pathogen recognition and the activation of innate defense pathways, are among the most genetically variable known, and the proteins that they encode are often characterized by high rates of amino acid substitutions, a hallmark of positive selection. The high levels of variation characteristic of immunity genes make them useful tools for conservation genetics. To date, highly variable immunity genes have yet to be found in corals, keystone organisms of the world's most diverse marine ecosystem, the coral reef. Here, we examine variation in and selection on a putative innate immunity gene from Oculina, a coral genus previously used as a model for studies of coral disease and bleaching. Results In a survey of 244 Oculina alleles, we find high nonsynonymous variation and a signature of positive selection, consistent with a putative role in immunity. Using computational protein structure prediction, we generate a structural model of the Oculina protein that closely matches the known structure of tachylectin-2 from the Japanese horseshoe crab (Tachypleus tridentatus), a protein with demonstrated function in microbial recognition and agglutination. We also demonstrate that at least three other genera of anthozoan cnidarians (Acropora, Montastrea and Nematostella) possess proteins structurally similar to tachylectin-2. Conclusions Taken together, the evidence of high amino acid diversity, positive selection and structural correspondence to the horseshoe crab tachylectin-2 suggests that this protein is 1) part of Oculina's innate immunity repertoire, and 2) evolving adaptively, possibly under selective pressure from coral-associated microorganisms. Tachylectin-2 may serve as a candidate locus to screen coral populations for their capacity to respond adaptively to future environmental change. PMID:20482872

  3. Evolutionary Dynamics of MERS-CoV: Potential Recombination, Positive Selection and Transmission

    PubMed Central

    Zhang, Zhao; Shen, Libing; Gu, Xun

    2016-01-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) belongs to beta group of coronavirus and was first discovered in 2012. MERS-CoV can infect multiple host species and cause severe diseases in human. We conducted a series of phylogenetic and bioinformatic analyses to study the evolution dynamics of MERS-CoV among different host species with genomic data. Our analyses show: 1) 28 potential recombinant sequences were detected and they can be classified into seven potential recombinant types; 2) The spike (S) protein of MERS-CoV was under strong positive selection when MERS-CoV transmitted from their natural host to human; 3) Six out of nine positive selection sites detected in spike (S) protein are located in its receptor-binding domain which is in direct contact with host cells; 4) MERS-CoV frequently transmitted back and forth between human and camel after it had acquired the human-camel infection capability. Together, these results suggest that potential recombination events might have happened frequently during MERS-CoV’s evolutionary history and the positive selection sites in MERS-CoV’s S protein might enable it to infect human. PMID:27142087

  4. Warning signals are under positive frequency-dependent selection in nature

    PubMed Central

    Chouteau, Mathieu; Arias, Mónica; Joron, Mathieu

    2016-01-01

    Positive frequency-dependent selection (FDS) is a selection regime where the fitness of a phenotype increases with its frequency, and it is thought to underlie important adaptive strategies resting on signaling and communication. However, whether and how positive FDS truly operates in nature remains unknown, which hampers our understanding of signal diversity. Here, we test for positive FDS operating on the warning color patterns of chemically defended butterflies forming multiple coexisting mimicry assemblages in the Amazon. Using malleable prey models placed in localities showing differences in the relative frequencies of warningly colored prey, we demonstrate that the efficiency of a warning signal increases steadily with its local frequency in the natural community, up to a threshold where protection stabilizes. The shape of this relationship is consistent with the direct effect of the local abundance of each warning signal on the corresponding avoidance knowledge of the local predator community. This relationship, which differs from purifying selection acting on each mimetic pattern, indicates that predator knowledge, integrated over the entire community, is saturated only for the most common warning signals. In contrast, among the well-established warning signals present in local prey assemblages, most are incompletely known to local predators and enjoy incomplete protection. This incomplete predator knowledge should generate strong benefits to life history traits that enhance warning efficiency by increasing the effective frequency of prey visible to predators. Strategies such as gregariousness or niche convergence between comimics may therefore readily evolve through their effects on predator knowledge and warning efficiency. PMID:26858416

  5. Warning signals are under positive frequency-dependent selection in nature.

    PubMed

    Chouteau, Mathieu; Arias, Mónica; Joron, Mathieu

    2016-02-23

    Positive frequency-dependent selection (FDS) is a selection regime where the fitness of a phenotype increases with its frequency, and it is thought to underlie important adaptive strategies resting on signaling and communication. However, whether and how positive FDS truly operates in nature remains unknown, which hampers our understanding of signal diversity. Here, we test for positive FDS operating on the warning color patterns of chemically defended butterflies forming multiple coexisting mimicry assemblages in the Amazon. Using malleable prey models placed in localities showing differences in the relative frequencies of warningly colored prey, we demonstrate that the efficiency of a warning signal increases steadily with its local frequency in the natural community, up to a threshold where protection stabilizes. The shape of this relationship is consistent with the direct effect of the local abundance of each warning signal on the corresponding avoidance knowledge of the local predator community. This relationship, which differs from purifying selection acting on each mimetic pattern, indicates that predator knowledge, integrated over the entire community, is saturated only for the most common warning signals. In contrast, among the well-established warning signals present in local prey assemblages, most are incompletely known to local predators and enjoy incomplete protection. This incomplete predator knowledge should generate strong benefits to life history traits that enhance warning efficiency by increasing the effective frequency of prey visible to predators. Strategies such as gregariousness or niche convergence between comimics may therefore readily evolve through their effects on predator knowledge and warning efficiency.

  6. Positive and strongly relaxed purifying selection drive the evolution of repeats in proteins

    PubMed Central

    Persi, Erez; Wolf, Yuri I.; Koonin, Eugene V

    2016-01-01

    Protein repeats are considered hotspots of protein evolution, associated with acquisition of new functions and novel phenotypic traits, including disease. Paradoxically, however, repeats are often strongly conserved through long spans of evolution. To resolve this conundrum, it is necessary to directly compare paralogous (horizontal) evolution of repeats within proteins with their orthologous (vertical) evolution through speciation. Here we develop a rigorous methodology to identify highly periodic repeats with significant sequence similarity, for which evolutionary rates and selection (dN/dS) can be estimated, and systematically characterize their evolution. We show that horizontal evolution of repeats is markedly accelerated compared with their divergence from orthologues in closely related species. This observation is universal across the diversity of life forms and implies a biphasic evolutionary regime whereby new copies experience rapid functional divergence under combined effects of strongly relaxed purifying selection and positive selection, followed by fixation and conservation of each individual repeat. PMID:27857066

  7. A Novel Positive Selection for Identifying Cold-Sensitive Myosin II Mutants in Dictyostelium

    PubMed Central

    Patterson, B.; Spudich, J. A.

    1995-01-01

    We developed a positive selection for myosin heavy chain mutants in Dictyostelium. This selection is based on the fact that brief exposure to azide causes wild-type cells to release from the substrate, whereas myosin null cells remain adherent. This procedure assays myosin function on a time scale of minutes and has therefore allowed us to select rapid-onset cold-sensitive mutants after random chemical mutagenesis of Dictyostelium cells. We developed a rapid technique for determining which mutations lie in sequences of the myosin gene that encode the head (motor) domain and localized 27 of 34 mutants to this domain. We recovered the appropriate sequences from five of the mutants and demonstrated that they retain their cold-sensitive properties when expressed from extrachromosomal plasmids. PMID:7498732

  8. Phylogenetic analysis and positive-selection site detecting of vascular endothelial growth factor family in vertebrates.

    PubMed

    He, Wenwu; Tang, Yanyan; Qi, Bin; Lu, Chuansen; Qin, Chao; Wei, Yunfei; Yi, Jiachao; Chen, Mingwu

    2014-02-10

    Vascular endothelial growth factor (VEGF), known to play an important role in vascular homeostasis, vascular integrity and angiogenesis, is little known about the evolutionary relationship of its five members especially the role of gene duplication and natural selection in the evolution of the VEGF family. In this study, seventy-five full-length cDNA sequences from 33 vertebrate species were extracted from the NCBI's GenBank, UniProt protein database and the Ensembl database. By phylogenetic analyses, we investigated the origin, conservation, and evolution of the VEGFs. Five VEGF family members in vertebrates might be formed by gene duplication. The inferred evolutionary transitions that separate members which belong to different gene clusters correlated with changes in functional properties. Selection analysis and protein structure analysis were combined to explain the relationship of the site-specific evolution in the vertebrate VEGF family. Eleven positive selection sites, one transmembrane region and the active sites were detected in this process.

  9. Detecting and characterizing genomic signatures of positive selection in global populations.

    PubMed

    Liu, Xuanyao; Ong, Rick Twee-Hee; Pillai, Esakimuthu Nisha; Elzein, Abier M; Small, Kerrin S; Clark, Taane G; Kwiatkowski, Dominic P; Teo, Yik-Ying

    2013-06-06

    Natural selection is a significant force that shapes the architecture of the human genome and introduces diversity across global populations. The question of whether advantageous mutations have arisen in the human genome as a result of single or multiple mutation events remains unanswered except for the fact that there exist a handful of genes such as those that confer lactase persistence, affect skin pigmentation, or cause sickle cell anemia. We have developed a long-range-haplotype method for identifying genomic signatures of positive selection to complement existing methods, such as the integrated haplotype score (iHS) or cross-population extended haplotype homozygosity (XP-EHH), for locating signals across the entire allele frequency spectrum. Our method also locates the founder haplotypes that carry the advantageous variants and infers their corresponding population frequencies. This presents an opportunity to systematically interrogate the whole human genome whether a selection signal shared across different populations is the consequence of a single mutation process followed subsequently by gene flow between populations or of convergent evolution due to the occurrence of multiple independent mutation events either at the same variant or within the same gene. The application of our method to data from 14 populations across the world revealed that positive-selection events tend to cluster in populations of the same ancestry. Comparing the founder haplotypes for events that are present across different populations revealed that convergent evolution is a rare occurrence and that the majority of shared signals stem from the same evolutionary event.

  10. Signatures of purifying and local positive selection in human miRNAs.

    PubMed

    Quach, Hélène; Barreiro, Luis B; Laval, Guillaume; Zidane, Nora; Patin, Etienne; Kidd, Kenneth K; Kidd, Judith R; Bouchier, Christiane; Veuille, Michel; Antoniewski, Christophe; Quintana-Murci, Lluís

    2009-03-01

    MicroRNAs (miRNAs) are noncoding RNAs involved in posttranscriptional gene repression, and their role in diverse physiological processes is increasingly recognized. Yet, few efforts have been devoted to evolutionary studies of human miRNAs. Knowledge about the way in which natural selection has targeted miRNAs should provide insight into their functional relevance as well as their mechanisms of action. Here we used miRNAs as a model system for investigating the influence of natural selection on gene regulation by characterizing the full spectrum of naturally occurring sequence variation of 117 human miRNAs from different populations worldwide. We found that purifying selection has globally constrained the diversity of miRNA-containing regions and has strongly targeted the mature miRNA. This observation emphasizes that mutations in these molecules are likely to be deleterious, and therefore they can have severe phenotypic consequences on human health. More importantly, we obtained evidence of population-specific events of positive selection acting on a number of miRNA-containing regions. Notably, our analysis revealed that positive selection has targeted a "small-RNA-rich island" on chromosome 14, harboring both miRNAs and small nucleolar RNAs, in Europeans and East Asians. These observations support the notion that the tuning of gene expression contributes to the processes by which populations adapt to specific environments. These findings will fuel future investigations exploring how genetic and functional variation of miRNAs under selection affects the repression of their mRNA targets, increasing our understanding of the role of gene regulation in population adaptation and human disease.

  11. Species-Specific Activity of HIV-1 Vpu and Positive Selection of Tetherin Transmembrane Domain Variants

    PubMed Central

    McNatt, Matthew W.; Zang, Trinity; Hatziioannou, Theodora; Bartlett, Mackenzie; Fofana, Ismael Ben; Johnson, Welkin E.; Neil, Stuart J. D.; Bieniasz, Paul D.

    2009-01-01

    Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1 Vpu appears to have specifically adapted to antagonize variants of tetherin found in humans and chimpanzees. Tetherin variants found in rhesus macaques (rh), African green monkeys (agm) and mice were able to inhibit HIV-1 particle release, but were resistant to antagonism by HIV-1 Vpu. Notably, reciprocal exchange of transmembrane domains between human and monkey tetherins conferred sensitivity and resistance to Vpu, identifying this protein domain as a critical determinant of Vpu function. Indeed, differences between hu-tetherin and rh-tetherin at several positions in the transmembrane domain affected sensitivity to antagonism by Vpu. Two alterations in the hu-tetherin transmembrane domain, that correspond to differences found in rh- and agm-tetherin proteins, were sufficient to render hu-tetherin completely resistant to HIV-1 Vpu. Interestingly, transmembrane and cytoplasmic domain sequences in primate tetherins exhibit variation at numerous codons that is likely the result of positive selection, and some of these changes coincide with determinants of HIV-1 Vpu sensitivity. Overall, these data indicate that tetherin could impose a barrier to viral zoonosis as a consequence of positive selection that has been driven by ancient viral antagonists, and that the HIV-1 Vpu protein has specialized to target the transmembrane domains found in human/chimpanzee tetherin proteins. PMID:19214216

  12. Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants.

    PubMed

    McNatt, Matthew W; Zang, Trinity; Hatziioannou, Theodora; Bartlett, Mackenzie; Fofana, Ismael Ben; Johnson, Welkin E; Neil, Stuart J D; Bieniasz, Paul D

    2009-02-01

    Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1 Vpu appears to have specifically adapted to antagonize variants of tetherin found in humans and chimpanzees. Tetherin variants found in rhesus macaques (rh), African green monkeys (agm) and mice were able to inhibit HIV-1 particle release, but were resistant to antagonism by HIV-1 Vpu. Notably, reciprocal exchange of transmembrane domains between human and monkey tetherins conferred sensitivity and resistance to Vpu, identifying this protein domain as a critical determinant of Vpu function. Indeed, differences between hu-tetherin and rh-tetherin at several positions in the transmembrane domain affected sensitivity to antagonism by Vpu. Two alterations in the hu-tetherin transmembrane domain, that correspond to differences found in rh- and agm-tetherin proteins, were sufficient to render hu-tetherin completely resistant to HIV-1 Vpu. Interestingly, transmembrane and cytoplasmic domain sequences in primate tetherins exhibit variation at numerous codons that is likely the result of positive selection, and some of these changes coincide with determinants of HIV-1 Vpu sensitivity. Overall, these data indicate that tetherin could impose a barrier to viral zoonosis as a consequence of positive selection that has been driven by ancient viral antagonists, and that the HIV-1 Vpu protein has specialized to target the transmembrane domains found in human/chimpanzee tetherin proteins.

  13. Suppressors of RNAi from plant viruses are subject to episodic positive selection

    PubMed Central

    Murray, Gemma G. R.; Kosakovsky Pond, Sergei L.; Obbard, Darren J.

    2013-01-01

    Viral suppressors of RNAi (VSRs) are proteins that actively inhibit the antiviral RNA interference (RNAi) immune response, providing an immune evasion route for viruses. It has been hypothesized that VSRs are engaged in a molecular ‘arms race’ with RNAi pathway genes. Two lines of evidence support this. First, VSRs from plant viruses display high sequence diversity, and are frequently gained and lost over evolutionary time scales. Second, Drosophila antiviral RNAi genes show high rates of adaptive evolution. Here, we investigate whether VSRs diversify faster than other genes and, if so, whether this is a result of positive selection, as might be expected in an arms race. By analysis of 12 plant RNA viruses, we show that the relative rate of protein evolution is higher for VSRs than for other genes, but that this is not attributable to pervasive positive selection. We argue that, because evolutionary time scales are extremely different for viruses and eukaryotes, it is improbable that viral adaptation (as measured by the ratio of non-synonymous to synonymous change) will be dominated by one-to-one coevolution with eukaryotes. Instead, for plant virus VSRs, we find strong evidence of episodic selection—diversifying selection that acts on a subset of lineages—which might be attributable to frequent shifts between different host genotypes or species. PMID:23804618

  14. Cytosine deaminase MX cassettes as positive/negative selectable markers in Saccharomyces cerevisiae.

    PubMed

    Hartzog, Phillip E; Nicholson, Bradly P; McCusker, John H

    2005-07-30

    We describe positive/negative selectable cytosine deaminase MX cassettes for use in Saccharomyces cerevisiae. The basis of positive selection for cytosine deaminase (Fcy1) activity is that (a) fcy1 strains are unable to grow on medium containing cytosine as a sole nitrogen source and (b) fcy1 ura3 strains are unable to grow on medium containing cytosine as the sole pyrimidine source. Conversely, as 5-fluorocytosine (5FC) is toxic to cytosine deaminase-producing cells, fcy1 strains are resistant to 5FC. FCY1MX and FCA1MX cassettes, containing open reading frames (ORFs) of S. cerevisiae FCY1 and Candida albicans FCA1, respectively, were constructed and used to disrupt targeted genes in S. cerevisiae fcy1 strains. In addition, new direct repeat cassettes, kanPR, FCA1PR, FCY1PR and CaURA3PR, were developed to allow efficient deletion of target genes in cells containing MX3 repeats. Finally, the FCY1- and FCA1MX3 or PR direct repeat cassettes can be readily recycled after 5FC counter-selection on both synthetic and rich media.

  15. Widespread Positive Selection Drives Differentiation of Centromeric Proteins in the Drosophila melanogaster subgroup

    PubMed Central

    Beck, Emily A.; Llopart, Ana

    2015-01-01

    Rapid evolution of centromeric satellite repeats is thought to cause compensatory amino acid evolution in interacting centromere-associated kinetochore proteins. Cid, a protein that mediates kinetochore/centromere interactions, displays particularly high amino acid turnover. Rapid evolution of both Cid and centromeric satellite repeats led us to hypothesize that the apparent compensatory evolution may extend to interacting partners in the Condensin I complex (i.e., SMC2, SMC4, Cap-H, Cap-D2, and Cap-G) and HP1s. Missense mutations in these proteins often result in improper centromere formation and aberrant chromosome segregation, thus selection for maintained function and coevolution among proteins of the complex is likely strong. Here, we report evidence of rapid evolution and recurrent positive selection in seven centromere-associated proteins in species of the Drosophila melanogaster subgroup, and further postulate that positive selection on these proteins could be a result of centromere drive and compensatory changes, with kinetochore proteins competing for optimal spindle attachment. PMID:26603658

  16. Widespread Positive Selection Drives Differentiation of Centromeric Proteins in the Drosophila melanogaster subgroup.

    PubMed

    Beck, Emily A; Llopart, Ana

    2015-11-25

    Rapid evolution of centromeric satellite repeats is thought to cause compensatory amino acid evolution in interacting centromere-associated kinetochore proteins. Cid, a protein that mediates kinetochore/centromere interactions, displays particularly high amino acid turnover. Rapid evolution of both Cid and centromeric satellite repeats led us to hypothesize that the apparent compensatory evolution may extend to interacting partners in the Condensin I complex (i.e., SMC2, SMC4, Cap-H, Cap-D2, and Cap-G) and HP1s. Missense mutations in these proteins often result in improper centromere formation and aberrant chromosome segregation, thus selection for maintained function and coevolution among proteins of the complex is likely strong. Here, we report evidence of rapid evolution and recurrent positive selection in seven centromere-associated proteins in species of the Drosophila melanogaster subgroup, and further postulate that positive selection on these proteins could be a result of centromere drive and compensatory changes, with kinetochore proteins competing for optimal spindle attachment.

  17. Characterization of two paralogous myostatin genes and evidence for positive selection in Tibet fish: Gymnocypris przewalskii.

    PubMed

    Tong, Chao; Zhang, Cunfang; Shi, Jianquan; Qi, Hongfang; Zhang, Renyi; Tang, Yongtao; Li, Guogang; Feng, Chenguang; Zhao, Kai

    2015-07-10

    Myostatin (mstn) is an important member of TGF-β superfamily, a muscle growth inhibitor. Though mstn has been identified in many organisms, little is known about this gene in highland fish, Gymnocypris przewalskii endemic to the Qinghai-Tibetan Plateau. In this study, we first cloned two paralogous mstn genes (mstn1 and mstn2) from G. przewalskii through homologue cloning. The 3D structures of both Mstn proteins varied in the numbers of β-sheets and conformations of α-helices. The branch-site model showed that mstn1 has undergone positive selection, and two positively selected sites (107M and 181T) were located on the random coils of the 3D protein structure. Expression patterns indicated that the mstn1 expressed widely, while the mstn2 only expressed in the muscle and brain. During the early stage of embryo development, the expression levels of both mstn paralogous genes showed different increasing trends. These results suggest that it is diverging in two mstn paralogues of G. przewalskii via specific differences in gene structure, protein structure, selection pressure and gene expression patterns. Taken together, this study provides novel contribution on the research topics of growth related gene function and mechanism of highland fish in extreme aquatic environment on the Qinghai-Tibetan Plateau.

  18. Using the CRISPR-Cas System to Positively Select Mutants in Genes Essential for Its Function.

    PubMed

    Yosef, Ido; Goren, Moran G; Edgar, Rotem; Qimron, Udi

    2015-01-01

    The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated proteins (Cas) comprise a prokaryotic adaptive defense system against foreign nucleic acids. This defense is mediated by Cas proteins, which are guided by sequences flanked by the repeats, called spacers, to target nucleic acids. Spacers designed against the prokaryotic self chromosome are lethal to the prokaryotic cell. This self-killing of the bacterium by its own CRISPR-Cas system can be used to positively select genes that participate in this killing, as their absence will result in viable cells. Here we describe a positive selection assay that uses this feature to identify E. coli mutants encoding an inactive CRISPR-Cas system. The procedure includes establishment of an assay that detects this self-killing, generation of transposon insertion mutants in random genes, and selection of viable mutants, suspected as required for this lethal activity. This procedure enabled us to identify a novel gene, htpG, that is required for the activity of the CRISPR-Cas system. The procedures described here can be adjusted to various organisms to identify genes required for their CRISPR-Cas activity.

  19. Positive selection of a gene family during the emergence of humans and African apes.

    PubMed

    Johnson, M E; Viggiano, L; Bailey, J A; Abdul-Rauf, M; Goodwin, G; Rocchi, M; Eichler, E E

    2001-10-04

    Gene duplication followed by adaptive evolution is one of the primary forces for the emergence of new gene function. Here we describe the recent proliferation, transposition and selection of a 20-kilobase (kb) duplicated segment throughout 15 Mb of the short arm of human chromosome 16. The dispersal of this segment was accompanied by considerable variation in chromosomal-map location and copy number among hominoid species. In humans, we identified a gene family (morpheus) within the duplicated segment. Comparison of putative protein-encoding exons revealed the most extreme case of positive selection among hominoids. The major episode of enhanced amino-acid replacement occurred after the separation of human and great-ape lineages from the orangutan. Positive selection continued to alter amino-acid composition after the divergence of human and chimpanzee lineages. The rapidity and bias for amino-acid-altering nucleotide changes suggest adaptive evolution of the morpheus gene family during the emergence of humans and African apes. Moreover, some genes emerge and evolve very rapidly, generating copies that bear little similarity to their ancestral precursors. Consequently, a small fraction of human genes may not possess discernible orthologues within the genomes of model organisms.

  20. Mitogenomic analyses propose positive selection in mitochondrial genes for high-altitude adaptation in galliform birds.

    PubMed

    Zhou, Taicheng; Shen, Xuejuan; Irwin, David M; Shen, Yongyi; Zhang, Yaping

    2014-09-01

    Galliform birds inhabit very diverse habitats, including plateaus that are above 3000 m in altitude. At high altitude, lower temperature and hypoxia are two important factors influencing survival. Mitochondria, as the ultimate oxygen transductor, play an important role in aerobic respiration through oxidative phosphorylation (OXPHOS). We analyzed the mitochondrial genomes of six high-altitude phasianidae birds and sixteen low-altitude relatives in an attempt to determine the role of mitochondrial genes in high-altitude adaptation. We reconstructed the phylogenetic relationships of these phasianidae birds and relatives and found at least four lineages that independently occupied this high-altitude habitat. Selective analyses revealed significant evidence for positive selection in the genes ND2, ND4, and ATP6 in three of the high-altitude lineages. This result strongly suggests that adaptive evolution of mitochondrial genes played a critical role during the independent acclimatization to high altitude by galliform birds.

  1. Area-Selective Atomic Layer Deposition: Conformal Coating, Subnanometer Thickness Control, and Smart Positioning.

    PubMed

    Fang, Ming; Ho, Johnny C

    2015-09-22

    Transistors have already been made three-dimensional (3D), with device channels (i.e., fins in trigate field-effect transistor (FinFET) technology) that are taller, thinner, and closer together in order to enhance device performance and lower active power consumption. As device scaling continues, these transistors will require more advanced, fabrication-enabling technologies for the conformal deposition of high-κ dielectric layers on their 3D channels with accurate position alignment and thickness control down to the subnanometer scale. Among many competing techniques, area-selective atomic layer deposition (AS-ALD) is a promising method that is well suited to the requirements without the use of complicated, complementary metal-oxide semiconductor (CMOS)-incompatible processes. However, further progress is limited by poor area selectivity for thicker films formed via a higher number of ALD cycles as well as the prolonged processing time. In this issue of ACS Nano, Professor Stacy Bent and her research group demonstrate a straightforward self-correcting ALD approach, combining selective deposition with a postprocess mild chemical etching, which enables selective deposition of dielectric films with thicknesses and processing times at least 10 times larger and 48 times shorter, respectively, than those obtained by conventional AS-ALD processes. These advances present an important technological breakthrough that may drive the AS-ALD technique a step closer toward industrial applications in electronics, catalysis, and photonics, etc. where more efficient device fabrication processes are needed.

  2. Delineation of plant caleosin residues critical for functional divergence, positive selection and coevolution

    PubMed Central

    2014-01-01

    Background The caleosin genes encode proteins with a single conserved EF hand calcium-binding domain and comprise small gene families found in a wide range of plant species. These proteins may be involved in many cellular and biological processes coupled closely to the synthesis, degradation, or stability of oil bodies. Although previous studies of this protein family have been reported for Arabidopsis and other species, understanding of the evolution of the caleosin gene family in plants remains inadequate. Results In this study, comparative genomic analysis was performed to investigate the phylogenetic relationships, evolutionary history, functional divergence, positive selection, and coevolution of caleosins. First, 84 caleosin genes were identified from five main lineages that included 15 species. Phylogenetic analysis placed these caleosins into five distinct subfamilies (sub I–V), including two subfamilies that have not been previously identified. Among these subfamilies, sub II coincided with the distinct P-caleosin isoform recently identified in the pollen oil bodies of lily; caleosin genes from the same lineage tended to be clustered together in the phylogenetic tree. A special motif was determined to be related with the classification of caleosins, which may have resulted from a deletion in sub I and sub III occurring after the evolutionary divergence of monocot and dicot species. Additionally, several segmentally and tandem-duplicated gene pairs were identified from seven species, and further analysis revealed that caleosins of different species did not share a common expansion model. The ages of each pair of duplications were calculated, and most were consistent with the time of genome-wide duplication events in each species. Functional divergence analysis showed that changes in functional constraints have occurred between subfamilies I/IV, II/IV, and II/V, and some critical amino acid sites were identified during the functional divergence. Additional

  3. Non-gated laser-induced breakdown spectroscopy in bulk water by position-selective detection

    SciTech Connect

    Tian, Ye; Xue, Boyang; Song, Jiaojian; Lu, Yuan; Zheng, Ronger

    2015-09-14

    Temporal and spatial evolutions of the laser-induced plasma in bulk water are investigated using fast imaging and emission spectroscopic techniques. By tightly focusing a single-pulse nanosecond Nd: YAG laser beam into the bulk water, we generate a strongly expanded plasma with high reproducibility. Such a strong expanding plasma enables us to obtain well-resolved spectral lines by means of position-selective detection; hence, the time-gated detector becomes abdicable. The present results suggest not only a possible non-gated approach for underwater laser-induced breakdown spectroscopy but also give an insight into the plasma generation and expansion in bulk water.

  4. Ongoing hydrothermal activities within Enceladus.

    PubMed

    Hsu, Hsiang-Wen; Postberg, Frank; Sekine, Yasuhito; Shibuya, Takazo; Kempf, Sascha; Horányi, Mihály; Juhász, Antal; Altobelli, Nicolas; Suzuki, Katsuhiko; Masaki, Yuka; Kuwatani, Tatsu; Tachibana, Shogo; Sirono, Sin-iti; Moragas-Klostermeyer, Georg; Srama, Ralf

    2015-03-12

    Detection of sodium-salt-rich ice grains emitted from the plume of the Saturnian moon Enceladus suggests that the grains formed as frozen droplets from a liquid water reservoir that is, or has been, in contact with rock. Gravitational field measurements suggest a regional south polar subsurface ocean of about 10 kilometres thickness located beneath an ice crust 30 to 40 kilometres thick. These findings imply rock-water interactions in regions surrounding the core of Enceladus. The resulting chemical 'footprints' are expected to be preserved in the liquid and subsequently transported upwards to the near-surface plume sources, where they eventually would be ejected and could be measured by a spacecraft. Here we report an analysis of silicon-rich, nanometre-sized dust particles (so-called stream particles) that stand out from the water-ice-dominated objects characteristic of Saturn. We interpret these grains as nanometre-sized SiO2 (silica) particles, initially embedded in icy grains emitted from Enceladus' subsurface waters and released by sputter erosion in Saturn's E ring. The composition and the limited size range (2 to 8 nanometres in radius) of stream particles indicate ongoing high-temperature (>90 °C) hydrothermal reactions associated with global-scale geothermal activity that quickly transports hydrothermal products from the ocean floor at a depth of at least 40 kilometres up to the plume of Enceladus.

  5. New Positive Ca2+-Activated K+ Channel Gating Modulators with Selectivity for KCa3.1

    PubMed Central

    Coleman, Nichole; Brown, Brandon M.; Oliván-Viguera, Aida; Singh, Vikrant; Olmstead, Marilyn M.; Valero, Marta Sofia; Köhler, Ralf

    2014-01-01

    Small-conductance (KCa2) and intermediate-conductance (KCa3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate KCa2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV1.5, and NaV1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1−/− mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation. PMID:24958817

  6. Investigation of some selected strategies for multi-GNSS instantaneous RTK positioning

    NASA Astrophysics Data System (ADS)

    Paziewski, Jacek; Wielgosz, Pawel

    2017-01-01

    It is clear that we can benefit from multi-constellation GNSS in precise relative positioning. On the other hand, it is still an open problem how to combine multi-GNSS signals in a single functional model. This study presents methodology and quality assessment of selected methods allowing for multi-GNSS observations combining in relative kinematic positioning using baselines up to tens of kilometers. In specific, this paper characterizes loose and tight integration strategies applied to the ionosphere and troposphere weighted model. Performance assessment of the established strategies was based on the analyses of the integer ambiguity resolution and rover coordinates' repeatability obtained in the medium range instantaneous RTK positioning with the use of full constellation dual frequency GPS and Galileo signals. Since full constellation of Galileo satellites is not yet available, the observational data were obtained from a hardware GNSS signal simulator using regular geodetic GNSS receivers. The results indicate on similar and high performance of the loose, and tight integration with calibrated receiver ISBs strategies. These approaches have undeniable advantage over single system positioning in terms of reliability of the integer ambiguity resolution as well as rover coordinate repeatability.

  7. Oligopolyphenylenevinylene-Conjugated Oligoelectrolyte Membrane Insertion Molecules Selectively Disrupt Cell Envelopes of Gram-Positive Bacteria

    PubMed Central

    Poh, Wee Han; Chu, Justin Jang Hann; Loo, Joachim Say Chye; Bazan, Guillermo C.; Hancock, Lynn E.

    2015-01-01

    The modification of microbial membranes to achieve biotechnological strain improvement with exogenous small molecules, such as oligopolyphenylenevinylene-conjugated oligoelectrolyte (OPV-COE) membrane insertion molecules (MIMs), is an emerging biotechnological field. Little is known about the interactions of OPV-COEs with their target, the bacterial envelope. We studied the toxicity of three previously reported OPV-COEs with a selection of Gram-negative and Gram-positive organisms and demonstrated that Gram-positive bacteria are more sensitive to OPV-COEs than Gram-negative bacteria. Transmission electron microscopy demonstrated that these MIMs disrupt microbial membranes and that this occurred to a much greater degree in Gram-positive organisms. We used a number of mutants to probe the nature of MIM interactions with the microbial envelope but were unable to align the membrane perturbation effects of these compounds to previously reported membrane disruption mechanisms of, for example, cationic antimicrobial peptides. Instead, the data support the notion that OPV-COEs disrupt microbial membranes through a suspected interaction with diphosphatidylglycerol (DPG), a major component of Gram-positive membranes. The integrity of model membranes containing elevated amounts of DPG was disrupted to a greater extent by MIMs than those prepared from Escherichia coli total lipid extracts alone. PMID:25576607

  8. Oligopolyphenylenevinylene-conjugated oligoelectrolyte membrane insertion molecules selectively disrupt cell envelopes of Gram-positive bacteria.

    PubMed

    Hinks, Jamie; Poh, Wee Han; Chu, Justin Jang Hann; Loo, Joachim Say Chye; Bazan, Guillermo C; Hancock, Lynn E; Wuertz, Stefan

    2015-03-01

    The modification of microbial membranes to achieve biotechnological strain improvement with exogenous small molecules, such as oligopolyphenylenevinylene-conjugated oligoelectrolyte (OPV-COE) membrane insertion molecules (MIMs), is an emerging biotechnological field. Little is known about the interactions of OPV-COEs with their target, the bacterial envelope. We studied the toxicity of three previously reported OPV-COEs with a selection of Gram-negative and Gram-positive organisms and demonstrated that Gram-positive bacteria are more sensitive to OPV-COEs than Gram-negative bacteria. Transmission electron microscopy demonstrated that these MIMs disrupt microbial membranes and that this occurred to a much greater degree in Gram-positive organisms. We used a number of mutants to probe the nature of MIM interactions with the microbial envelope but were unable to align the membrane perturbation effects of these compounds to previously reported membrane disruption mechanisms of, for example, cationic antimicrobial peptides. Instead, the data support the notion that OPV-COEs disrupt microbial membranes through a suspected interaction with diphosphatidylglycerol (DPG), a major component of Gram-positive membranes. The integrity of model membranes containing elevated amounts of DPG was disrupted to a greater extent by MIMs than those prepared from Escherichia coli total lipid extracts alone.

  9. School Discipline: The Ongoing Crisis

    ERIC Educational Resources Information Center

    Whiteside, Marilyn

    1975-01-01

    The positive and negative aspects of classroom punishment were compared and the characteristics of teachers who did not experience discipline problems with their students were discussed. Additionally, programs for overcoming discipline difficulties were presented. (RK)

  10. Rapid positive selection of stable integrants following transfection of Plasmodium falciparum.

    PubMed

    Wang, Ping; Wang, Qi; Sims, Paul F G; Hyde, John E

    2002-08-07

    With the near-completion of the genome sequence of Plasmodium falciparum, further understanding of this major human pathogen urgently requires more effective genetic tools. These must include faster and more reliable gene replacement or gene knockout techniques, essential for the analysis of gene function. We describe a serial system which uses the blasticidin S deaminase (bsd) gene of Aspergillus and the neomycin phosphotransferase II (neo) gene from transposon Tn5 as selectable markers for, respectively, transient transfection of malaria parasites and the selection of stable integrants. Challenge with blasticidin S (BS) enriches the parasite population transiently expressing the bsd gene, laying the foundation for the subsequent, much less frequent, integration event. Positive selection for this rare event is enormously facilitated by fusing the neo gene in frame to the replacement or knockout targeting gene. The sequence employed for the targeting (the polymorphic pppk-dhps gene of P. falciparum, as a model system) is truncated at the 5' end with no promoter located upstream, therefore neo cannot be expressed without specifically integrating within the genomic copy of the target gene. After BS selection, the culture is immediately exposed to geneticin (G418), leading to an apparently homogenous population of mutant parasites. As well as excluding spurious integrants at non-targeted sequences, this system greatly reduces the lengthy selection period for obtaining the desired mutants by eliminating the drug-on and drug-off cycles for the production of stable integrants, which are normally required by the single marker systems currently in use for transfection of malaria parasites.

  11. Ongoing incestuous abuse during adulthood.

    PubMed

    Middleton, Warwick

    2013-01-01

    Individual cases of adult incestuous abuse have surfaced repeatedly in the lay and professional literature of the past 1.5 centuries without it occasioning systematic investigation, such as the reporting of a case series of individuals subjected to such extreme abuse. Yet substantial numbers of patients with dissociative identity disorder at the time of presentation report incestuous abuse continuing into the adult years, and for many the abuse is ongoing. Data relating to a series of 10 such incestuously abused women are presented. These patients were sexually abused from a very early age (typically from before age 3), with the manipulation of their sexual response a key component in conditioning an enduring sexualized attachment. Shame and fear were also used to ensure compliance and silence. The women, when able to speak of it, describe the induction by their paternal abuser of orgasm at an early age, typically around the age of 6. The women have high indices of self-harm and suicidality and are prone to placing themselves in dangerous reenactment scenarios. The average duration of incestuous abuse for this group of women was 31 years, and the average estimate of total episodes of sexual abuse was 3,320. Most women do not feel that they own their body and experience being "fused" to their father. Their mother was reported as an active participant in the sexual abuse or as having done nothing to protect their daughter despite seeing obvious evidence of incest. The fathers, despite a propensity to use or threaten violence, were generally outwardly productively employed, financially comfortable, and stably married and half had close church involvement. However, suicide and murder occurred within the 1st- or 2nd-degree relatives of these women at a high frequency. All 10 had been sexually abused by various groupings of individuals connected to their fathers.

  12. Imbalanced positive selection maintains the functional divergence of duplicated DIHYDROKAEMPFEROL 4-REDUCTASE genes

    PubMed Central

    Huang, Bing-Hong; Chen, Yi-Wen; Huang, Chia-Lung; Gao, Jian; Liao, Pei-Chun

    2016-01-01

    Gene duplication could be beneficial by functional division but might increase the risk of genetic load. The dynamics of duplicated paralogs number could involve recombination, positive selection, and functional divergence. Duplication of DIHYDROFLAVONOL 4-REDUCTASE (DFR) has been reported in several organisms and may have been retained by escape from adaptive conflict (EAC). In this study, we screened the angiosperm DFR gene focusing on a diversified genus Scutellaria to investigate how these duplicated genes are retained. We deduced that gene duplication involved multiple independent events in angiosperms, but the duplication of DFR was before the divergence of Scutellaria. Asymmetric positive selective pressures resulted in different evolutionary rates between the duplicates. Different numbers of regulatory elements, differential codon usages, radical amino acid changes, and differential gene expressions provide evidences of functional divergence between the two DFR duplicates in Scutellaria, implying adaptive subfunctionalization between duplicates. The discovery of pseudogenes accompanying a reduced replacement rate in one DFR paralogous gene suggested possibly leading to “loss of function” due to dosage imbalance after the transient adaptive subfunctionalization in the early stage of duplication. Notwithstanding, episodic gene duplication and functional divergence may be relevant to the diversification of ecological function of DFR gene in Scutellaria. PMID:27966614

  13. High burden and pervasive positive selection of somatic mutations in normal human skin

    PubMed Central

    Martincorena, Iñigo; Roshan, Amit; Gerstung, Moritz; Ellis, Peter; Van Loo, Peter; McLaren, Stuart; Wedge, David C.; Fullam, Anthony; Alexandrov, Ludmil B.; Tubio, Jose M.; Stebbings, Lucy; Menzies, Andrew; Widaa, Sara; Stratton, Michael R.; Jones, Philip H.; Campbell, Peter J.

    2015-01-01

    How somatic mutations accumulate in normal cells is central to understanding cancer development, but is poorly understood. We performed ultra-deep sequencing of 74 cancer genes in small (0.8-4.7mm2) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged 2-6 mutations/megabase/cell, similar to many cancers, and exhibited characteristic signatures of ultraviolet light exposure. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected ‘driver’ mutations were found in 18-32% of normal skin cells at a density of ~140/cm2. We observed variability in the driver landscape among individuals and variability in sizes of clonal expansions across genes. Thus, aged, sun-exposed skin is a patchwork of thousands of evolving clones, with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis. PMID:25999502

  14. Selective nucleolus organizer inactivation in Arabidopsis is a chromosome position-effect phenomenon

    PubMed Central

    Mohannath, Gireesha; Pontvianne, Frederic

    2016-01-01

    Nucleolus organizer regions (NORs) are chromosomal loci where hundreds of rRNA genes are clustered. Despite being nearly identical in sequence, specific rRNA genes are selected for silencing during development via choice mechanism(s) that remain unclear. In Arabidopsis thaliana, rRNA gene subtypes that are silenced during development were recently mapped to the NOR on chromosome 2, NOR2, whereas active rRNA genes map to NOR4, on chromosome 4. In a mutant line deficient for ATXR5 or ATXR6-dependent histone H3 lysine 27 (H3K27) monomethylation, we show that millions of base pairs of chromosome 4, including the telomere, TEL4N, and much of NOR4, have been converted to the corresponding sequences of chromosome 2. This genomic change places rRNA genes of NOR2, which are normally silenced, at the position on chromosome 4 where active rRNA genes are normally located. At their new location, NOR2-derived rRNA genes escape silencing, independent of the atxr mutations, indicating that selective rRNA gene silencing is chromosome 2-specific. The chromosome 2 position effect is not explained by the NOR2-associated telomere, TEL2N, which remains linked to the translocated NOR, implicating centromere-proximal sequences in silencing. PMID:27821753

  15. Increased mitochondrial mutation frequency after an island colonization: positive selection or accumulation of slightly deleterious mutations?

    PubMed

    Hardouin, Emilie A; Tautz, Diethard

    2013-04-23

    Island colonizations are excellent models for studying early processes of evolution. We found in a previous study on mice that had colonized the sub-Antarctic Kerguelen Archipelago about 200 years ago that they were derived from a single founder lineage and that this showed an unexpectedly large number of new mutations in the mitochondrial D-loop. To assess whether positive selection has played a role in the emergence of these variants, we have obtained 16 full mitochondrial genome sequences from these mice. For comparison, we have compiled 57 mitochondrial genome sequences from laboratory inbred lines that became established about 100 years ago, also starting from a single founder lineage. We find that the island mice and the laboratory lines show very similar mutation frequencies and patterns. None of the patterns in the Kerguelen mice provides evidence for positive selection. We conclude that nearly neutral evolutionary processes that assume the presence of slightly deleterious variants can fully explain the patterns. This supports the notion of time-dependency of molecular evolution and provides a new calibration point. Based on the observed mutation frequency, we calculate an average evolutionary rate of 0.23 substitutions per site per Myr for the earliest time frame of divergence, which is about six times higher than the long-term rate of 0.037 substitutions per site per Myr.

  16. Positive Diversifying Selection on the Plasmodium falciparum surf4.1 Gene in Thailand

    PubMed Central

    Xangsayarath, Phonepadith; Kaewthamasorn, Morakot; Yahata, Kazuhide; Nakazawa, Shusuke; Sattabongkot, Jetsumon; Udomsangpetch, Rachanee; Kaneko, Osamu

    2012-01-01

    Plasmodium falciparum SURFIN4.1 is a type I transmembrane protein thought to locate on the merozoite surface and to be responsible for a reversible adherence to the erythrocyte before invasion. In this study, we evaluated surf4.1 gene segment encoding extracellular region for polymorphism, the signature of positive selection, the degree of linkage disequilibrium, and temporal change in allele frequency distribution in P. falciparum isolates from Thailand in 1988–89, 2003, and 2005. We found that SURFIN4.1 is highly polymorphic, particularly at the C-terminal side of the variable region located just before a predicted transmembrane region. A signature of positive diversifying selection on the variable region was detected by multiple tests and, to a lesser extent, on conserved N-terminally located cysteine-rich domain by Tajima’s D test. Linkage disequilibrium between sites over a long distance (> 1.5 kb) was detected, and multiple SURFIN4.1 haplotype sequences detected in 1988/89 still circulated in 2003. Few of the single amino acid polymorphism allele frequency distributions were significantly different between the 1988/89 and 2003 groups, suggesting that the frequency distribution of SURFIN4.1 extracellular region remained stable over 14 years. PMID:23264727

  17. A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells.

    PubMed

    Lo, Wan-Lin; Donermeyer, David L; Allen, Paul M

    2012-09-01

    The sustained entry of Ca(2+) into CD4(+)CD8(+) double-positive thymocytes is required for positive selection. Here we identified a voltage-gated Na(+) channel (VGSC) that was essential for positive selection of CD4(+) T cells. Pharmacological inhibition of VGSC activity inhibited the sustained Ca(2+) influx induced by positively selecting ligands and the in vitro positive selection of CD4(+) but not CD8(+) T cells. In vivo short hairpin RNA (shRNA)-mediated knockdown of the gene encoding a regulatory β-subunit of a VGSC specifically inhibited the positive selection of CD4(+) T cells. Ectopic expression of VGSC in peripheral AND CD4(+) T cells bestowed the ability to respond to a positively selecting ligand, which directly demonstrated that VGSC expression was responsible for the enhanced sensitivity. Thus, active VGSCs in thymocytes provide a mechanism by which a weak positive selection signal can induce the sustained Ca(2+) signals required for CD4(+) T cell development.

  18. Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry

    PubMed Central

    2013-01-01

    Background Currently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima’s D, Fay and Wu’s H and Fu and Li’s D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution. Results Our tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies. Conclusions We identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a

  19. Technical note: immunomagnetic procedure for positive selection of macrophages in ovine milk.

    PubMed

    Caroprese, M; Marzano, A; Schena, L; Sevi, A

    2008-05-01

    A simple immunomagnetic procedure was developed to select macrophages from ovine milk by using a non-specific magnetic positive separation technique. Samples of ewe bulk milk were collected during early, mid, and late lactation; milk samples were centrifuged at 2,000 x g for 30 min at 4 degrees C; the fatty fraction and supernatant were removed, and each pellet was dissolved in 500 microL of pH 7.4 phosphate buffered saline + 0.02% NaN(3). Cells were targeted for selection by using mouse-IgG anti-ovine macrophages. Several trials, testing 2 different fluorochrome-conjugated antibodies [i.e., mouse anti-human CD14:R-Phycoerythrin (RPE) (MCA1568PE, Serotec) and F(ab')2 rabbit anti-mouse IgG:RPE (STAR12A, Serotec)] and 3 different labeling procedures, were performed to evaluate the purity of samples by flow cytometry. A morphological test was carried out by direct microscopic count in enriched fraction smears stained with May-Grünwald-Giemsa stain to confirm the presence of macrophages. The method described in the present technical note can be considered an innovative application to obtain a single-cell population of high purity selected from all the somatic cells in milk.

  20. Positive selection of AS3MT to arsenic water in Andean populations

    PubMed Central

    Eichstaedt, Christina A.; Antao, Tiago; Cardona, Alexia; Pagani, Luca; Kivisild, Toomas; Mormina, Maru

    2016-01-01

    Arsenic is a carcinogen associated with skin lesions and cardiovascular diseases. The Colla population from the Puna region in Northwest Argentinean is exposed to levels of arsenic in drinking water exceeding the recommended maximum by a factor of 20. Yet, they thrive in this challenging environment since thousands of years and therefore we hypothesize strong selection signatures in genes involved in arsenic metabolism. We analyzed genome-wide genotype data for 730,000 loci in 25 Collas, considering 24 individuals of the neighbouring Calchaquíes and 24 Wichí from the Gran Chaco region in the Argentine province of Salta as control groups. We identified a strong signal of positive selection in the main arsenic methyltransferase AS3MT gene, which has been previously associated with lower concentrations of the most toxic product of arsenic metabolism monomethylarsonic acid. This study confirms recent studies reporting selection signals in the AS3MT gene albeit using different samples, tests and control populations. PMID:26366667

  1. Histidine substitution identifies a surface position and confers Cs+ selectivity on a K+ pore.

    PubMed Central

    De Biasi, M; Drewe, J A; Kirsch, G E; Brown, A M

    1993-01-01

    The amino acid located at position 369 is a key determinant of the ion conduction pathway or pore of the voltage-gated K+ channels, Kv2.1 and a chimeric channel, CHM, constructed by replacing the pore region of Kv2.1 with that of Kv3.1. To determine the orientation of residue 369 with respect to the aqueous lumen of the pore, the nonpolar Ile at 369 in Kv2.1 was replaced with a basic His. This substitution produced a Cs(+)-selective channel with Cs+:K+ permeability ratio of 4 compared to 0.1 in the wild type. Block by external tetraethylammonium (TEA) was reduced about 20-fold, while block by internal TEA was unaffected. External protons and Zn2+, that are known to interact with the imidazole ring of His, blocked the mutant channel much more effectively than the wild type channel. The blockade by Zn2+ and protons was voltage-independent, and the proton blockade had a pKa of about 6.5, consistent with the pKa for His in solution. The histidyl-specific reagent diethylpyrocarbonate produced greatly exaggerated blockade of the mutated channel compared to the wild type. The residue at position 369 appears to form part of the binding site for external TEA and to influence the selectivity for monovalent cations. We suggest that the imidazole side-chain of His369 is exposed to the aqueous lumen at a surface position near the external mouth of the pore. PMID:8241404

  2. Selective Population of Unbound Positive Parity States in 25F and 26F

    NASA Astrophysics Data System (ADS)

    Frank, Nathan; Herman, Jacob; Rabeh, Ali; Tuttle-Timm, Matthew; MoNA Collaboration

    2017-01-01

    Unbound Positive Parity States in 25F and 26F were populated in the one-proton removal reaction from a radioactive 27Ne beam. The experiment was performed at the National Superconducting Cyclotron Laboratory (NSCL), where a 101.3 MeV/u 27Ne ion beam impinged on a liquid deuterium target populating states in 26F. States above the one- and two- neutron separation energies lead to 24F and 25F, respectively. The MoNA/LISA setup at NSCL was used to detect the fragments in coincidence with neutrons and the decay energy spectra of 25F and 26F were reconstructed by invariant mass spectroscopy. Resonance energies of approximately 0.35 MeV and 0.5 MeV for 25F* and 26F*, respectively, were extracted. Based on the calculated spectroscopic strength distribution of negative and positive parity states in 26F and the selectivity of one proton-removal reactions both states were assigned positive parity. NSF Grant #1404236.

  3. Evidence for positive selection and recombination hotspots in Deformed wing virus (DWV)

    PubMed Central

    Dalmon, A.; Desbiez, C.; Coulon, M.; Thomasson, M.; Le Conte, Y.; Alaux, C.; Vallon, J.; Moury, B.

    2017-01-01

    Deformed wing virus (DWV) is considered one of the most damaging pests in honey bees since the spread of its vector, Varroa destructor. In this study, we sequenced the whole genomes of two virus isolates and studied the evolutionary forces that act on DWV genomes. The isolate from a Varroa-tolerant bee colony was characterized by three recombination breakpoints between DWV and the closely related Varroa destructor virus-1 (VDV-1), whereas the variant from the colony using conventional Varroa management was similar to the originally described DWV. From the complete sequence dataset, nine independent DWV-VDV-1 recombination breakpoints were detected, and recombination hotspots were found in the 5′ untranslated region (5′ UTR) and the conserved region encoding the helicase. Partial sequencing of the 5′ UTR and helicase-encoding region in 41 virus isolates suggested that most of the French isolates were recombinants. By applying different methods based on the ratio between non-synonymous (dN) and synonymous (dS) substitution rates, we identified four positions that showed evidence of positive selection. Three of these positions were in the putative leader protein (Lp), and one was in the polymerase. These findings raise the question of the putative role of the Lp in viral evolution. PMID:28120868

  4. Genes Regulated by Vitamin D in Bone Cells Are Positively Selected in East Asians

    PubMed Central

    Chen, Yuan; Xue, Yali; Luiselli, Donata; Tyler-Smith, Chris; Pagani, Luca; Ayub, Qasim

    2015-01-01

    Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20–60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting. PMID:26719974

  5. Ongoing Recovery Basic Information Tool (ORBIT)

    NASA Technical Reports Server (NTRS)

    Oberg, Donald

    1993-01-01

    The Federal Drug Free Work Place Program (DFWP) has now matured to the point of being able to return employees to sensitive testing designated positions (TDP) after completion of treatment of their addiction. The known tendency of addicted individuals to suffer multiple relapses prior to their final recovery has resulted in several positive urine tests (relapses) occurring among those Federal employees who have already completed treatment and who have been returned to TDP's. The very real potential for further relapses occurring after additional employees return to TDP's will be a critical factor in the ultimate success of the DFWP and in the public's impression of the program's effectiveness. In response to this concern, NASA has begun development of its Ongoing Recovery Basic Information Tool (ORBIT) instrument. The aim of the NASA ORBIT is to provide Employee Assistance Program (EAP) professionals with an advanced clinical tool which will be helpful in supporting recovery from substance abuse and which will allow more accurate determinations of when clients may be successfully returned to sensitive positions.

  6. High sensitivity to aligner and high rate of false positives in the estimates of positive selection in the 12 Drosophila genomes

    PubMed Central

    Markova-Raina, Penka; Petrov, Dmitri

    2011-01-01

    We investigate the effect of aligner choice on inferences of positive selection using site-specific models of molecular evolution. We find that independently of the choice of aligner, the rate of false positives is unacceptably high. Our study is a whole-genome analysis of all protein-coding genes in 12 Drosophila genomes annotated in either all 12 species (∼6690 genes) or in the six melanogaster group species. We compare six popular aligners: PRANK, T-Coffee, ClustalW, ProbCons, AMAP, and MUSCLE, and find that the aligner choice strongly influences the estimates of positive selection. Differences persist when we use (1) different stringency cutoffs, (2) different selection inference models, (3) alignments with or without gaps, and/or additional masking, (4) per-site versus per-gene statistics, (5) closely related melanogaster group species versus more distant 12 Drosophila genomes. Furthermore, we find that these differences are consequential for downstream analyses such as determination of over/under-represented GO terms associated with positive selection. Visual analysis indicates that most sites inferred as positively selected are, in fact, misaligned at the codon level, resulting in false positive rates of 48%–82%. PRANK, which has been reported to outperform other aligners in simulations, performed best in our empirical study as well. Unfortunately, PRANK still had a high, and unacceptable for most applications, false positives rate of 50%–55%. We identify misannotations and indels, many of which appear to be located in disordered protein regions, as primary culprits for the high misalignment-related error levels and discuss possible workaround approaches to this apparently pervasive problem in genome-wide evolutionary analyses. PMID:21393387

  7. Analysis of complexity measures and information planes of selected molecules in position and momentum spaces.

    PubMed

    Esquivel, Rodolfo O; Angulo, Juan Carlos; Antolín, Juan; Dehesa, Jesús S; López-Rosa, Sheila; Flores-Gallegos, Nelson

    2010-07-14

    The Fisher-Shannon and LMC shape complexities and the Shannon-disequilibrium, Fisher-Shannon and Fisher-disequilibrium information planes, which consist of two localization-delocalization factors, are computed in both position and momentum spaces for the one-particle densities of 90 selected molecules of various chemical types, at the CISD/6-311++G(3df,2p) level of theory. We found that while the two measures of complexity show general trends only, the localization-delocalization planes clearly exhibit chemically significant patterns. Several molecular properties (energy, ionization potential, total dipole moment, hardness, electrophilicity) are analyzed and used to interpret and understand the chemical nature of the composite information-theoretic measures above mentioned. Our results show that these measures detect not only randomness or localization but also pattern and organization.

  8. Species specific exome probes reveal new insights in positively selected genes in nonhuman primates

    PubMed Central

    Su, Zheng; Zhang, Junjie; Kumar, Chanchal; Molony, Cliona; Lu, Hongchao; Chen, Ronghua; Stone, David J.; Ling, Fei; Liu, Xiao

    2016-01-01

    Nonhuman primates (NHP) are important biomedical animal models for the study of human disease. Of these, the most widely used models in biomedical research currently are from the genus Macaca. However, evolutionary genetic divergence between human and NHP species makes human-based probes inefficient for the capture of genomic regions of NHP for sequencing and study. Here we introduce a new method to resequence the exome of NHP species by a designed capture approach specifically targeted to the NHP, and demonstrate its superior performance on four NHP species or subspecies. Detailed investigation on biomedically relevant genes demonstrated superior capture by the new approach. We identified 28 genes that appeared to be pseudogenized and inactivated in macaque. Finally, we identified 187 genes showing strong evidence for positive selection across all branches of the primate phylogeny including many novel findings. PMID:27659771

  9. Cross-linked block copolymer templated assembly of nanoparticle arrays with high density and position selectivity

    NASA Astrophysics Data System (ADS)

    Liu, Zhicheng; Chang, Tongxin; Huang, Haiying; Bai, Lu

    2016-10-01

    Patterning ordered nanoparticle arrays is crucial for the fascinating collective properties of nanoparticles. Block copolymer template provides us a platform for the simple and efficient assembly of nanoparticle arrays. In this work, cylinder-forming poly(styrene-block-2-vinylpyridine) thin film was firstly plasma-etched to expose poly(2-vinylpyridine) cylinders. Then the templates were cross-linked by small molecules so as to access gold nanoparticle arrays with both high density and excellent position selectivity. The cross-linking process significantly restrains the unfavorable surface reconstruction of the thin film. It is demonstrated that the quality of the nanoparticle array was affected by the degree of the cross-linking and the immersion time in nanoparticle solution. The highly ordered gold nanoparticle arrays are promising in several fields such as optics and surface enhanced Raman scattering (SERS).

  10. Trans genomic capture and sequencing of primate exomes reveals new targets of positive selection.

    PubMed

    George, Renee D; McVicker, Graham; Diederich, Rachel; Ng, Sarah B; MacKenzie, Alexandra P; Swanson, Willie J; Shendure, Jay; Thomas, James H

    2011-10-01

    Comparison of protein-coding DNA sequences from diverse primates can provide insight into these species' evolutionary history and uncover the molecular basis for their phenotypic differences. Currently, the number of available primate reference genomes limits these genome-wide comparisons. Here we use targeted capture methods designed for human to sequence the protein-coding regions, or exomes, of four non-human primate species (three Old World monkeys and one New World monkey). Despite average sequence divergence of up to 4% from the human sequence probes, we are able to capture ~96% of coding sequences. Using a combination of mapping and assembly techniques, we generated high-quality full-length coding sequences for each species. Both the number of nucleotide differences and the distribution of insertion and deletion (indel) lengths indicate that the quality of the assembled sequences is very high and exceeds that of most reference genomes. Using this expanded set of primate coding sequences, we performed a genome-wide scan for genes experiencing positive selection and identified a novel class of adaptively evolving genes involved in the conversion of epithelial cells in skin, hair, and nails to keratin. Interestingly, the genes we identify under positive selection also exhibit significantly increased allele frequency differences among human populations, suggesting that they play a role in both recent and long-term adaptation. We also identify several genes that have been lost on specific primate lineages, which illustrate the broad utility of this data set for other evolutionary analyses. These results demonstrate the power of second-generation sequencing in comparative genomics and greatly expand the repertoire of available primate coding sequences.

  11. Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor.

    PubMed

    Burford, Neil T; Livingston, Kathryn E; Canals, Meritxell; Ryan, Molly R; Budenholzer, Lauren M L; Han, Ying; Shang, Yi; Herbst, John J; O'Connell, Jonathan; Banks, Martyn; Zhang, Litao; Filizola, Marta; Bassoni, Daniel L; Wehrman, Tom S; Christopoulos, Arthur; Traynor, John R; Gerritz, Samuel W; Alt, Andrew

    2015-05-28

    Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.

  12. Augmenting the Genetic Toolbox for Sulfolobus islandicus with a Stringent Positive Selectable Marker for Agmatine Prototrophy

    PubMed Central

    Cooper, Tara E.; Krause, David J.

    2013-01-01

    Sulfolobus species have become the model organisms for studying the unique biology of the crenarchaeal division of the archaeal domain. In particular, Sulfolobus islandicus provides a powerful opportunity to explore natural variation via experimental functional genomics. To support these efforts, we further expanded genetic tools for S. islandicus by developing a stringent positive selection for agmatine prototrophs in strains in which the argD gene, encoding arginine decarboxylase, has been deleted. Strains with deletions in argD were shown to be auxotrophic for agmatine even in nutrient-rich medium, but growth could be restored by either supplementation of exogenous agmatine or reintroduction of a functional copy of the argD gene from S. solfataricus P2 into the ΔargD host. Using this stringent selection, a robust targeted gene knockout system was established via an improved next generation of the MID (marker insertion and unmarked target gene deletion) method. Application of this novel system was validated by targeted knockout of the upsEF genes involved in UV-inducible cell aggregation formation. PMID:23835176

  13. Serial position functions following selective hippocampal lesions in monkeys: Effects of delays and interference✩

    PubMed Central

    Bachevalier, Jocelyne; Wright, Anthony A.; Katz, Jeffrey S.

    2013-01-01

    We examined the role of the hippocampus in list-memory processing. Three rhesus monkeys that had extensive experience in this task and had demonstrated full abstract-concept learning and excellent list memory performance (Katz et al., 2002; Wright et al., 2003) received bilateral neurotoxic hippocampal lesions and were re-tested in the serial list memory task. Effects of delays on memory performance were measured in all monkeys, whereas the effects of proactive interference were assessed in only one. Despite a slight change in performance of one of the three animals during re-learning of the same/different task, selective hippocampal damage had little or no effects on list memory accuracy. In addition, the hippocampal damage did not impact serial list position functions (SPFs) but slightly altered the dynamic of the SPF curves. Finally, even more remarkable was that accurate memory performance of one animal remained intact despite the use of small set size of 8 items that created high proactive interference across lists thereby eliminating any use of familiarity judgments to support performance. Together the findings indicate that, with short list items and extensive training in the task (i.e., reference memory), monkeys with selective hippocampal lesions may be able to use alternative memory processes (i.e., working memory) that are mediated by structures other than the hippocampus. PMID:23246643

  14. Development of a screen for ongoing intimate partner violence.

    PubMed

    Weiss, Steve J; Ernst, Amy A; Cham, Elaine; Nick, Todd G

    2003-04-01

    A five-question Ongoing Abuse Screen (OAS) was developed to evaluate ongoing intimate partner violence. Our hypothesis was that the OAS was more accurate and more likely to reflect ongoing intimate partner violence than the AAS when compared to the Index of Spouse Abuse (ISA). The survey included the ISA, the OAS, and the AAS. During the busiest emergency department hours, a sampling of 856 patients completed all aspects of the survey tool. Comparisons were made between the two scales and the ISA. The accuracy, positive predictive value, and positive likelihood ratio were 84%, 58%, and 6.0 for the OAS and 59%, 33%, and 2.0 for the AAS. The OAS was more accurate, had a better positive predictive value, and was three times more likely to detect victims of ongoing intimate partner violence than the AAS. Because the OAS was still not accurate enough, we developed a new screen, based on the ISA, titled the Ongoing Violence Assessment Tool (OVAT).

  15. Recurrent positive selection and heterogeneous codon usage bias events leading to coexistence of divergent pigeon circoviruses.

    PubMed

    Liao, Pei-Chun; Wang, Kung-Kai; Tsai, Shinn-Shyong; Liu, Hung-Jen; Huang, Bing-Hong; Chuang, Kuo-Pin

    2015-08-01

    The capsid genes from 14 pigeon circovirus (PiCV) sequences, collected from Taiwan between 2009 and 2010, were sequenced and compared with 14 PiCV capsid gene sequences from GenBank. Based on pairwise comparison, PiCV strains from Taiwan shared 73.9-100% nucleotide identity and 72-100% amino acid identity with those of the 14 reported PiCV sequences. Phylogenetic analyses revealed that Taiwanese PiCV isolates can be grouped into two clades: clade 1 comprising isolates from Belgium, Australia, USA, Italy and China, and clade 2 showing close relation to isolates from Germany and France. Recurrent positive selection was detected in clade 1 PiCV lineages, which may contribute to the diversification of predominant PiCV sequences in Taiwan. Further observations suggest that synonymous codon usage variations between PiCV clade 1 and clade 2 may reflect the adaptive divergence on translation efficiency of capsid genes in infectious hosts. Variation in selective pressures acting on the evolutionary divergence and codon usage bias of both clades explains the regional coexistence of virus sequences congeners prevented from competitive exclusion within an island such as Taiwan. Our genotyping results also provide insight into the aetiological agents of PiCV outbreak in Taiwan and we present a comparative analysis of the central coding region of PiCV genome. From the sequence comparison results of 28 PiCVs which differs in regard to the geographical origin and columbid species, we identified conserved regions within the capsid gene that are likely to be suitable for primer selection and vaccine development.

  16. An Abdominal CT may be Safe in Selected Hypotensive Trauma Patients with Positive FAST Exam

    PubMed Central

    Cook, Mackenzie R.; Holcomb, John B.; Rahbar, Mohammad H.; Alarcon, Louis H.; Bulger, Eileen M.; Brasel, Karen J.; Schreiber, Martin A.

    2016-01-01

    Background Positive Focused Assessment with Sonography in Trauma (FAST) and hypotension often indicates urgent surgery. An abdomen/pelvis CT (apCT) may allow less invasive management but the delay may be associated with adverse outcomes. Methods Patients in the Prospective Observational Multicenter Major Trauma Transfusion study with hypotension and a positive FAST (HF+) who underwent a CT (apCT+) were compared to those who did not. Results Of the 92 HF+ identified, 32(35%) underwent apCT during initial evaluation and apCT was associated with decreased odds of an emergency operation, OR 0.11 95% CI (0.001–0.116) and increased odds of angiographic intervention, OR 14.3 95% CI (1.5–135). There was no significant difference in 30 day mortality or need for dialysis. Conclusion An apCt in HF+ patients is associated with reduced odds of emergency surgery, but not mortality. Select HF+ patients can safely undergo apCT to obtain clinically useful information. PMID:25805456

  17. Symmetrically Substituted Xanthone Amphiphiles Combat Gram-Positive Bacterial Resistance with Enhanced Membrane Selectivity.

    PubMed

    Lin, Shuimu; Koh, Jun-Jie; Aung, Thet Tun; Lim, Fanghui; Li, Jianguo; Zou, Hanxun; Wang, Lin; Lakshminarayanan, Rajamani; Verma, Chandra; Wang, Yingjun; Tan, Donald T H; Cao, Derong; Beuerman, Roger W; Ren, Li; Liu, Shouping

    2017-02-23

    This is the first report of the design of a new series of symmetric xanthone derivatives that mimic antimicrobial peptides using a total synthesis approach. This novel design is advantageous because of its low cost, synthetic simplicity and versatility, and easy tuning of amphiphilicity by controlling the incorporated cationic and hydrophobic moieties. Two water-soluble optimized compounds, 6 and 18, showed potent activities against Gram-positive bacteria, including MRSA and VRE (MICs = 0.78-6.25 μg/mL) with a rapid bactericidal effect, low toxicity, and no emergence of drug resistance. Both compounds demonstrated enhanced membrane selectivity that was higher than those of most membrane-active antimicrobials in clinical trials or previous reports. The compounds appear to kill bacteria by disrupting their membranes. Significantly, 6 was effective in vivo using a mouse model of corneal infection. These results provide compelling evidence that these compounds have therapeutic potential as novel antimicrobials for multidrug-resistant Gram-positive infections.

  18. Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution

    PubMed Central

    2014-01-01

    Background Cytochrome P450 CYP2C19 metabolizes a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated. We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese + Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models. Results Bifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19*2 and *3). REHH was high around CYP2C19*2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at −29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity < = 0.037, p <0.001. Conclusions We found some evidence that the slow metabolizing allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices. PMID:24690327

  19. Recent Positive Selection Has Acted on Genes Encoding Proteins with More Interactions within the Whole Human Interactome

    PubMed Central

    Pybus, Marc; Fares, Mario A.; Bertranpetit, Jaume; Laayouni, Hafid

    2015-01-01

    Genes vary in their likelihood to undergo adaptive evolution. The genomic factors that determine adaptability, however, remain poorly understood. Genes function in the context of molecular networks, with some occupying more important positions than others and thus being likely to be under stronger selective pressures. However, how positive selection distributes across the different parts of molecular networks is still not fully understood. Here, we inferred positive selection using comparative genomics and population genetics approaches through the comparison of 10 mammalian and 270 human genomes, respectively. In agreement with previous results, we found that genes with lower network centralities are more likely to evolve under positive selection (as inferred from divergence data). Surprisingly, polymorphism data yield results in the opposite direction than divergence data: Genes with higher centralities are more likely to have been targeted by recent positive selection during recent human evolution. Our results indicate that the relationship between centrality and the impact of adaptive evolution highly depends on the mode of positive selection and/or the evolutionary time-scale. PMID:25840415

  20. Recent positive selection has acted on genes encoding proteins with more interactions within the whole human interactome.

    PubMed

    Luisi, Pierre; Alvarez-Ponce, David; Pybus, Marc; Fares, Mario A; Bertranpetit, Jaume; Laayouni, Hafid

    2015-04-02

    Genes vary in their likelihood to undergo adaptive evolution. The genomic factors that determine adaptability, however, remain poorly understood. Genes function in the context of molecular networks, with some occupying more important positions than others and thus being likely to be under stronger selective pressures. However, how positive selection distributes across the different parts of molecular networks is still not fully understood. Here, we inferred positive selection using comparative genomics and population genetics approaches through the comparison of 10 mammalian and 270 human genomes, respectively. In agreement with previous results, we found that genes with lower network centralities are more likely to evolve under positive selection (as inferred from divergence data). Surprisingly, polymorphism data yield results in the opposite direction than divergence data: Genes with higher centralities are more likely to have been targeted by recent positive selection during recent human evolution. Our results indicate that the relationship between centrality and the impact of adaptive evolution highly depends on the mode of positive selection and/or the evolutionary time-scale.

  1. Positive association between ethanol consumption and anxiety-related behaviors in two selected rat lines.

    PubMed

    Izídio, Geison Souza; Ramos, André

    2007-11-01

    The Floripa H and L rat lines were selectively bred, respectively, for high and low scores of locomotion in the central aversive area of an open field (OF), which is a putative index of experimental anxiety. In the present study, we used these lines to examine the relationship between anxiety-related behaviors and ethanol intake through the use of three animal tests used to investigate anxiety (OF, elevated plus maze, and black/white box) and one oral ethanol consumption procedure. Males and females of the Floripa L line were more anxious-like than their counterparts in the three behavioral tests. No line differences in the tests of taste control solutions (saccharin and quinine) and forced ethanol (10%) were found. However, Floripa L female rats consumed more ethanol than their Floripa H counterparts at concentrations of 6 and 10% in a two-bottle choice protocol. Moreover, Floripa L females showed a higher ratio of ethanol to total fluids consumed, regardless of the concentration offered, than all other subgroups (males of both lines and Floripa H females). Males showed no line differences for ethanol consumption. Taken together, the results of this study confirm that there are important sex differences in both anxiety-related behaviors and ethanol consumption. Accordingly, these data suggest a positive genetic relationship between anxiety-related behaviors and ethanol intake, at concentrations of 6 and 10%, in females but not in males. This supports the use of both sexes in animal experiments involving anxiety- and ethanol-related behaviors. Finally, the results and the existing literature indicate that selectively bred laboratory animals constitute a useful tool in the search for genes influencing both anxiety and ethanol consummatory behavior.

  2. Possible Positive Selection for an Arsenic-Protective Haplotype in Humans

    PubMed Central

    Schlebusch, Carina M.; Lewis, Cecil M.; Vahter, Marie; Engström, Karin; Tito, Raúl Y.; Obregón-Tito, Alexandra J.; Huerta, Doris; Polo, Susan I.; Medina, Ángel C.; Brutsaert, Tom D.; Concha, Gabriela; Jakobsson, Mattias

    2012-01-01

    Background: Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite. Objectives: We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups. Methods: Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic. Results: We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared). Conclusions: Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis. PMID:23070617

  3. Ozone-induced dissociation: elucidation of double bond position within mass-selected lipid ions.

    PubMed

    Thomas, Michael C; Mitchell, Todd W; Harman, David G; Deeley, Jane M; Nealon, Jessica R; Blanksby, Stephen J

    2008-01-01

    Ions formed from lipids during electrospray ionization of crude lipid extracts have been mass-selected within a quadrupole linear ion trap mass spectrometer and allowed to react with ozone vapor. Gas-phase ion-molecule reactions between unsaturated lipid ions and ozone are found to yield two primary product ions for each carbon-carbon double bond within the molecule. The mass-to-charge ratios of these chemically induced fragments are diagnostic of the position of unsaturation within the precursor ion. This novel analytical technique, dubbed ozone-induced dissociation (OzID), can be applied both in series and in parallel with conventional collision-induced dissociation (CID) to provide near-complete structural assignment of unknown lipids within complex mixtures without prior fractionation or derivatization. In this study, OzID is applied to a suite of complex lipid extracts from sources including human lens, bovine kidney, and commercial olive oil, thus demonstrating the technique to be applicable to a broad range of lipid classes including both neutral and acidic glycerophospholipids, sphingomyelins, and triacylglycerols. Gas-phase ozonolysis reactions are also observed with different types of precursor ions including [M+H]+, [M+Li]+, [M+Na]+, and [M-H]-: in each case yielding fragmentation data that allow double bond position to be unambiguously assigned. Within the human lens lipid extract, three sphingomyelin regioisomers, namely SM(d18:0/15Z-24:1), SM(d18:0/17Z-24:1), and SM(d18:0/19Z-24:1), and a novel phosphatidylethanolamine alkyl ether, GPEtn(11Z-18:1e/9Z-18:1), are identified using a combination of CID and OzID. These discoveries demonstrate that lipid identification based on CID alone belies the natural structural diversity in lipid biochemistry and illustrate the potential of OzID as a complementary approach within automated, high-throughput lipid analysis protocols.

  4. A Novel Selectable Islet 1 Positive Progenitor Cell Reprogrammed to Expandable and Functional Smooth Muscle Cells.

    PubMed

    Turner, Elizabeth C; Huang, Chien-Ling; Sawhney, Neha; Govindarajan, Kalaimathi; Clover, Anthony J P; Martin, Kenneth; Browne, Tara C; Whelan, Derek; Kumar, Arun H S; Mackrill, John J; Wang, Shaohua; Schmeckpeper, Jeffrey; Stocca, Alessia; Pierce, William G; Leblond, Anne-Laure; Cai, Liquan; O'Sullivan, Donnchadh M; Buneker, Chirlei K; Choi, Janet; MacSharry, John; Ikeda, Yasuhiro; Russell, Stephen J; Caplice, Noel M

    2016-05-01

    Disorders affecting smooth muscle structure/function may require technologies that can generate large scale, differentiated and contractile smooth muscle cells (SMC) suitable for cell therapy. To date no clonal precursor population that provides large numbers of differentiated SMC in culture has been identified in a rodent. Identification of such cells may also enhance insight into progenitor cell fate decisions and the relationship between smooth muscle precursors and disease states that implicate differentiated SMC.  In this study, we used classic clonal expansion techniques to identify novel self-renewing Islet 1 (Isl-1) positive primitive progenitor cells (PPC) within rat bone marrow that exhibited canonical stem cell markers and preferential differentiation towards a smooth muscle-like fate. We subsequently used molecular tagging to select Isl-1 positive clonal populations from expanded and de novo marrow cell populations. We refer to these previously undescribed cells as the PPC given its stem cell marker profile, and robust self-renewal capacity. PPC could be directly converted into induced smooth muscle cells (iSMC) using single transcription factor (Kruppel-like factor 4) knockdown or transactivator (myocardin) overexpression in contrast to three control cells (HEK 293, endothelial cells and mesenchymal stem cells) where such induction was not possible. iSMC exhibited immuno- and cytoskeletal-phenotype, calcium signaling profile and contractile responses similar to bona fide SMC. Passaged iSMC could be expanded to a scale sufficient for large scale tissue replacement.  PPC and reprogramed iSMC so derived may offer future opportunities to investigate molecular, structure/function and cell-based replacement therapy approaches to diverse cardiovascular, respiratory, gastrointestinal, and genitourinary diseases that have as their basis smooth muscle cell functional aberrancy or numerical loss. Stem Cells 2016;34:1354-1368.

  5. Ongoing dengue epidemic - Angola, June 2013.

    PubMed

    2013-06-21

    On April 1, 2013, the Public Health Directorate of Angola announced that six cases of dengue had been reported to the Ministry of Health of Angola (MHA). As of May 31, a total of 517 suspected dengue cases had been reported and tested for dengue with a rapid diagnostic test (RDT). A total of 313 (60.5%) specimens tested positive for dengue, including one from a patient who died. All suspected cases were reported from Luanda Province, except for two from Malanje Province. Confirmatory diagnostic testing of 49 specimens (43 RDT-positive and six RDT-negative) at the CDC Dengue Branch confirmed dengue virus (DENV) infection in 100% of the RDT-positive specimens and 50% of the RDT-negative specimens. Only DENV-1 was detected by molecular diagnostic testing. Phylogenetic analysis indicated this virus has been circulating in the region since at least 1968, strongly suggesting that dengue is endemic in Angola. Health-care professionals throughout Angola should be aware of the ongoing epidemic, the recommended practices for clinical management of dengue patients, and the need to report cases to MHA. Persons in Angola should seek medical care for acute febrile illness to reduce the risk for developing complications. Laboratory-confirmed dengue also has been reported from seven countries on four continents among persons who had recently traveled to Luanda, including 79 persons from Portugal. Angola is the third of four African countries to report a dengue outbreak in 2013. Persons returning from Africa with acute febrile illness should seek medical care, including testing for DENV infection, and suspected cases should be reported to public health authorities.

  6. An epitope tagged mammalian/prokaryotic expression vector with positive selection of cloned inserts.

    PubMed

    Schneider, S; Georgiev, O; Buchert, M; Adams, M T; Moelling, K; Hovens, C M

    1997-09-15

    A dual eukaryotic/prokaryotic expression vector has been developed which combines the features of positive selection for cloned inserts along with the production of an epitope-tagged cDNA insert by transient transfection in mammalian cells as well as high level induced expression in E. coli cells harbouring T7 RNA polymerase. This vector, pZilch, has two MCSs flanking a mutant E. coli phenylalanyl-tRNA synthetase gene, pheS, which when expressed in combination with the phenylalanine analog p-CI-Phe, results in termination of host cell protein synthesis. Cloning of inserts using unique sites in the flanking MCS regions results in loss of the pZilch pheS allele and hence permits growth of colonies harbouring recombinants on p-Cl-Phe plates. Additional features of the vector include an optimal Kozak consensus sequence for high level eukaryotic cell expression and an efficient prokaryotic translation initiation site in frame and downstream from the eukaryotic initiation site. Recombinant proteins can be produced with an N-terminal FLAG epitope which can be removed via a specific protease cleavage site. Flanking T7 and SP6 RNA polymerase promoter sites permit in vitro transcription and translation of cloned inserts. A derivative of the vector has also been constructed enabling nuclear accumulation of the tagged proteins via an SV40 nuclear localisation signal upstream of the 5' MCS.

  7. Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia.

    PubMed

    Liu, Xuanyao; Yunus, Yushimah; Lu, Dongsheng; Aghakhanian, Farhang; Saw, Woei-Yuh; Deng, Lian; Ali, Mohammad; Wang, Xu; Nor, Fadzilah Mohd; Ghazali, Fadzilah; Rahman, Thuhairah Abdul; Shaari, Shahrul Azlin; Salleh, Mohd Zaki; Phipps, Maude E; Ong, Rick Twee-Hee; Xu, Shuhua; Teo, Yik-Ying; Hoh, Boon-Peng

    2015-04-01

    The indigenous populations from Peninsular Malaysia, locally known as Orang Asli, continue to adopt an agro-subsistence nomadic lifestyle, residing primarily within natural jungle habitats. Leading a hunter-gatherer lifestyle in a tropical jungle environment, the Orang Asli are routinely exposed to malaria. Here we surveyed the genetic architecture of individuals from four Orang Asli tribes with high-density genotyping across more than 2.5 million polymorphisms. These tribes reside in different geographical locations in Peninsular Malaysia and belong to three main ethno-linguistic groups, where there is minimal interaction between the tribes. We first dissect the genetic diversity and admixture between the tribes and with neighboring urban populations. Later, by implementing five metrics, we investigated the genome-wide signatures for positive natural selection of these Orang Asli, respectively. Finally, we searched for evidence of genomic adaptation to the pressure of malaria infection. We observed that different evolutionary responses might have emerged in the different Orang Asli communities to mitigate malaria infection.

  8. Antibacterial properties of biosurfactants against selected Gram-positive and -negative bacteria.

    PubMed

    Díaz De Rienzo, Mayri A; Stevenson, Paul; Marchant, Roger; Banat, Ibrahim M

    2016-01-01

    The antibacterial properties and ability to disrupt biofilms of biosurfactants (rhamnolipids, sophorolipids) and sodium dodecyl sulphate (SDS) in the presence and absence of selected organic acids were investigated. Pseudomonas aeruginosa PAO1 was inhibited by sophorolipids and SDS at concentrations >5% v/v, and the growth of Escherichia coli NCTC 10418 was also inhibited by sophorolipids and SDS at concentrations >5% and 0.1% v/v, respectively. Bacillus subtilis NCTC 10400 was inhibited by rhamnolipids, sophorolipids and SDS at concentrations >0.5% v/v of all three; the same effect was observed with Staphylococcus aureus ATCC 9144. The ability to attach to surfaces and biofilm formation of P. aeruginosa PAO1, E. coli NCTC 10418 and B. subtilis NCTC 10400 was inhibited by sophorolipids (1% v/v) in the presence of caprylic acid (0.8% v/v). In the case of S. aureus ATCC 9144, the best results were obtained using caprylic acid on its own. It was concluded that sophorolipids are promising compounds for the inhibition/disruption of biofilms formed by Gram-positive and Gram-negative microorganisms and this activity can be enhanced by the presence of booster compounds such as caprylic acid.

  9. Epilepsy Surgery: Current Status and Ongoing Challenges

    PubMed Central

    KAWAI, Kensuke

    2015-01-01

    This article reviews the current status of surgical treatment of epilepsy and introduces the ongoing challenges. Seizure outcome of resective surgery for focal seizures associated with focal lesions is satisfactory. Particularly for mesial temporal lobe epilepsy, surgical treatment should be considered from the earlier stage of the disease. Meanwhile, surgical outcome in nonlesional extratemporal lobe epilepsy is still to be improved using various approaches. Disconnective surgeries reduce surgical complications of extensive resections while achieving equivalent or better seizure outcomes. Multiple subpial transection is still being modified expecting a better outcome by transection to the vertical cortices along the sulci- and multi-directional transection from a single entry point. Hippocampal transection is expected to preserve memory function while interrupting the abnormal epileptic synchronization. Proper selection or combination of subdural and depth electrodes and a wide-band analysis of electroencephalography may improve the accurate localization of epileptogenic region. Patients for whom curative resective surgery is not indicated because of generalized or bilateral multiple nature of their epilepsies, neuromodulation therapies are options of treatment which palliate their seizures. PMID:25925752

  10. Positive Selection Drives Rapid Evolution of the meq Oncogene of Marek’s Disease Virus

    PubMed Central

    Padhi, Abinash

    2016-01-01

    Marek’s disease (MD), caused by Marek’s disease virus (MDV), a poultry-borne alphaherpesvirus, is a devastating disease of poultry causing an estimated annual loss of one billion dollars to poultry producers, worldwide. Despite decades of control through vaccination, MDV field strains continue to emerge having increased virulence. The evolutionary mechanism driving the emergence of this continuum of strains to increased MDV virulence, however, remains largely enigmatic. Increase in MDV virulence has been associated with specific amino acid changes within the C-terminus domain of Mareks’s EcoRI-Q (meq)-encoded oncoprotein. In this study, we sought to determine whether the meq gene has evolved adaptively and whether past vaccination efforts have had any significant effect on the reduction or increase of MDV diversity over time. Our analysis suggests that meq is estimated to be evolving at a much faster rate than most dsDNA viruses, and is comparable with the evolutionary rate of RNA viruses. Interestingly, most of the polymorphisms in meq gene appear to have evolved under positive selection and the time of divergence at the meq locus coincides with the period during which the poultry industry had undergone transitions in management practices including the introduction and widespread use of live attenuated vaccines. Our study has revealed that the decades-long use of vaccines did not reduce MDV diversity, but rather had a stimulating effect on the emergence of field strains with increased genetic diversity until the early 2000s. During the years 2004–2005, there was an abrupt decline in the genetic diversity of field isolates followed by a recovery from this bottleneck in the year 2010. Collectively, these data suggest that vaccination seems to not have had any effect on MDV eradication, but rather had a stimulating effect on MDV emergence through adaptation. PMID:27662574

  11. A Mixed Approach to Similarity Metric Selection in Affinity Propagation-Based WiFi Fingerprinting Indoor Positioning.

    PubMed

    Caso, Giuseppe; de Nardis, Luca; di Benedetto, Maria-Gabriella

    2015-10-30

    The weighted k-nearest neighbors (WkNN) algorithm is by far the most popular choice in the design of fingerprinting indoor positioning systems based on WiFi received signal strength (RSS). WkNN estimates the position of a target device by selecting k reference points (RPs) based on the similarity of their fingerprints with the measured RSS values. The position of the target device is then obtained as a weighted sum of the positions of the k RPs. Two-step WkNN positioning algorithms were recently proposed, in which RPs are divided into clusters using the affinity propagation clustering algorithm, and one representative for each cluster is selected. Only cluster representatives are then considered during the position estimation, leading to a significant computational complexity reduction compared to traditional, flat WkNN. Flat and two-step WkNN share the issue of properly selecting the similarity metric so as to guarantee good positioning accuracy: in two-step WkNN, in particular, the metric impacts three different steps in the position estimation, that is cluster formation, cluster selection and RP selection and weighting. So far, however, the only similarity metric considered in the literature was the one proposed in the original formulation of the affinity propagation algorithm. This paper fills this gap by comparing different metrics and, based on this comparison, proposes a novel mixed approach in which different metrics are adopted in the different steps of the position estimation procedure. The analysis is supported by an extensive experimental campaign carried out in a multi-floor 3D indoor positioning testbed. The impact of similarity metrics and their combinations on the structure and size of the resulting clusters, 3D positioning accuracy and computational complexity are investigated. Results show that the adoption of metrics different from the one proposed in the original affinity propagation algorithm and, in particular, the combination of different

  12. Evidence for increased levels of positive and negative selection on the X chromosome versus autosomes in humans.

    PubMed

    Veeramah, Krishna R; Gutenkunst, Ryan N; Woerner, August E; Watkins, Joseph C; Hammer, Michael F

    2014-09-01

    Partially recessive variants under positive selection are expected to go to fixation more quickly on the X chromosome as a result of hemizygosity, an effect known as faster-X. Conversely, purifying selection is expected to reduce substitution rates more effectively on the X chromosome. Previous work in humans contrasted divergence on the autosomes and X chromosome, with results tending to support the faster-X effect. However, no study has yet incorporated both divergence and polymorphism to quantify the effects of both purifying and positive selection, which are opposing forces with respect to divergence. In this study, we develop a framework that integrates previously developed theory addressing differential rates of X and autosomal evolution with methods that jointly estimate the level of purifying and positive selection via modeling of the distribution of fitness effects (DFE). We then utilize this framework to estimate the proportion of nonsynonymous substitutions fixed by positive selection (α) using exome sequence data from a West African population. We find that varying the female to male breeding ratio (β) has minimal impact on the DFE for the X chromosome, especially when compared with the effect of varying the dominance coefficient of deleterious alleles (h). Estimates of α range from 46% to 51% and from 4% to 24% for the X chromosome and autosomes, respectively. While dependent on h, the magnitude of the difference between α values estimated for these two systems is highly statistically significant over a range of biologically realistic parameter values, suggesting faster-X has been operating in humans.

  13. The Evaluation and Selection of a Fifth Ground Antenna Site for the Global Positioning System.

    DTIC Science & Technology

    1987-12-07

    selection was the region between Australia and South America and north of the Antartic . Using the performance results of this study, further study...indicated that the best region for selection was between Australia and South America and north of the Antartic . Using the performance results of this

  14. Distinct quasispecies characteristics and positive selection within the core gene in chronic hepatitis B virus infected child and adult patients.

    PubMed

    Haijun, Deng; Yong, Huang; Ailong, Huang; Quanxin, Long

    2015-05-01

    There are significant differences in clinical characteristics between chronic hepatitis B virus infected (CHB) child and adult patients. Viral quasispecies characteristics are associated with its pathogenic properties. For hepatitis B virus (HBV), its core region is the main immune recognition region for its enriched epitopes. In our study, we discuss the quasispecies characteristics and positive selection within core gene within chronic HBV infected child and adult patients. By analyzing 170 core gene sequences from child CHB patients and 121 core genes sequences from adult CHB patients, quasispecies characteristics were described by sequence complexity, diversity, non-synonymous substitution ratio (dN) and synonymous substitution ratios (dS). In addition, positive selection sites were also determined by bioinformatics tools. Then, all these parameters were compared between child and adult CHB patient groups. Compared with child patients, adult patients with CHB showed distinct quasispecies characteristics within the core region, had a higher sequence complexity and diversity and more positive selection sites, suggesting that the adult CHB patients had a higher immune selection pressure on the HBV core gene. Reduced selection pressure on the HBV core gene in hepatitis B e antigen (HBeAg)-positive CHB patients than HBeAg negative CHB patients were observed in both adult and child patient groups. The majority of the screened positive selection sites lay within human leukocyte antigens (HLA)-restricted epitopes. In conclusion, this study analyzed the quasispecies characteristics discrepancy between child and adult patients with CHB, and revealed the possible reason for the distinct clinical characteristics in the perspective of population genetics.

  15. Whole-genome analysis revealed the positively selected genes during the differentiation of indica and temperate japonica rice.

    PubMed

    Sun, Xinli; Jia, Qi; Guo, Yuchun; Zheng, Xiujuan; Liang, Kangjing

    2015-01-01

    To investigate the selective pressures acting on the protein-coding genes during the differentiation of indica and japonica, all of the possible orthologous genes between the Nipponbare and 93-11 genomes were identified and compared with each other. Among these genes, 8,530 pairs had identical sequences, and 27,384 pairs shared more than 90% sequence identity. Only 2,678 pairs of genes displaying a Ka/Ks ratio significantly greater than one were revealed, and most of these genes contained only nonsynonymous sites. The genes without synonymous site were further analyzed with the SNP data of 1529 O. sativa and O. rufipogon accessions, and 1068 genes were identified to be under positive selection during the differentiation of indica and temperate japonica. The positively selected genes (PSGs) are unevenly distributed on 12 chromosomes, and the proteins encoded by the PSGs are dominant with binding, transferase and hydrolase activities, and especially enriched in the plant responses to stimuli, biological regulations, and transport processes. Meanwhile, the most PSGs of the known function and/or expression were involved in the regulation of biotic/abiotic stresses. The evidence of pervasive positive selection suggested that many factors drove the differentiation of indica and japonica, which has already started in wild rice but is much lower than in cultivated rice. Lower differentiation and less PSGs revealed between the Or-It and Or-IIIt wild rice groups implied that artificial selection provides greater contribution on the differentiation than natural selection. In addition, the phylogenetic tree constructed with positively selected sites showed that the japonica varieties exhibited more diversity than indica on differentiation, and Or-III of O. rufipogon exhibited more than Or-I.

  16. Whole-genome positive selection and habitat-driven evolution in a shallow and a deep-sea urchin.

    PubMed

    Oliver, Thomas A; Garfield, David A; Manier, Mollie K; Haygood, Ralph; Wray, Gregory A; Palumbi, Stephen R

    2010-01-01

    Comparisons of genomic sequence between divergent species can provide insight into the action of natural selection across many distinct classes of proteins. Here, we examine the extent of positive selection as a function of tissue-specific and stage-specific gene expression in two closely-related sea urchins, the shallow-water Strongylocentrotus purpuratus and the deep-sea Allocentrotus fragilis, which have diverged greatly in their adult but not larval habitats. Genes that are expressed specifically in adult somatic tissue have significantly higher dN/dS ratios than the genome-wide average, whereas those in larvae are indistinguishable from the genome-wide average. Testis-specific genes have the highest dN/dS values, whereas ovary-specific have the lowest. Branch-site models involving the outgroup S. franciscanus indicate greater selection (ω(FG)) along the A. fragilis branch than along the S. purpuratus branch. The A. fragilis branch also shows a higher proportion of genes under positive selection, including those involved in skeletal development, endocytosis, and sulfur metabolism. Both lineages are approximately equal in enrichment for positive selection of genes involved in immunity, development, and cell-cell communication. The branch-site models further suggest that adult-specific genes have experienced greater positive selection than those expressed in larvae and that ovary-specific genes are more conserved (i.e., experienced greater negative selection) than those expressed specifically in adult somatic tissues and testis. Our results chart the patterns of protein change that have occurred after habitat divergence in these two species and show that the developmental or functional context in which a gene acts can play an important role in how divergent species adapt to new environments.

  17. Detecting Loci under recent positive selection in dairy and beef cattle by combining different genome-wide scan methods

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As the methodologies available for the detection of positive selection from genomic data vary in terms of assumptions and execution, weak correlations are expected among them. However, if there is any given signal that is consistently supported across different tests, it might be a strong evidence o...

  18. Positive selection and ancient duplications in the evolution of class B floral homeotic genes of orchids and grasses

    PubMed Central

    Mondragón-Palomino, Mariana; Hiese, Luisa; Härter, Andrea; Koch, Marcus A; Theißen, Günter

    2009-01-01

    Background Positive selection is recognized as the prevalence of nonsynonymous over synonymous substitutions in a gene. Models of the functional evolution of duplicated genes consider neofunctionalization as key to the retention of paralogues. For instance, duplicate transcription factors are specifically retained in plant and animal genomes and both positive selection and transcriptional divergence appear to have played a role in their diversification. However, the relative impact of these two factors has not been systematically evaluated. Class B MADS-box genes, comprising DEF-like and GLO-like genes, encode developmental transcription factors essential for establishment of perianth and male organ identity in the flowers of angiosperms. Here, we contrast the role of positive selection and the known divergence in expression patterns of genes encoding class B-like MADS-box transcription factors from monocots, with emphasis on the family Orchidaceae and the order Poales. Although in the monocots these two groups are highly diverse and have a strongly canalized floral morphology, there is no information on the role of positive selection in the evolution of their distinctive flower morphologies. Published research shows that in Poales, class B-like genes are expressed in stamens and in lodicules, the perianth organs whose identity might also be specified by class B-like genes, like the identity of the inner tepals of their lily-like relatives. In orchids, however, the number and pattern of expression of class B-like genes have greatly diverged. Results The DEF-like genes from Orchidaceae form four well-supported, ancient clades of orthologues. In contrast, orchid GLO-like genes form a single clade of ancient orthologues and recent paralogues. DEF-like genes from orchid clade 2 (OMADS3-like genes) are under less stringent purifying selection than the other orchid DEF-like and GLO-like genes. In comparison with orchids, purifying selection was less stringent in DEF

  19. Positive frequency-dependent selection on warning color in Alpine leaf beetles.

    PubMed

    Borer, Matthias; Van Noort, Tom; Rahier, Martine; Naisbit, Russell E

    2010-12-01

    Müller's theory of warning color and mimicry, despite forming a textbook example of frequency-dependent selection, has rarely been demonstrated in the wild. This may be largely due to the practical and statistical difficulties of measuring natural selection on mobile prey species. Here we demonstrate that this selection acts in alpine beetle communities by using tethered beetles exposed to natural predators. Oreina gloriosa leaf beetles (Coleoptera: Chrysomelidae) possess chemical defense in the form of cardenolides, accompanied by what appears to be warning color in bright metallic blues and greens. Individuals that match the locally predominant color morph have increased survival, with odds of week-long survival increased by a factor of 1.67 over those that do not match. This corresponds to selection of 13% against foreign morphs. Such selection, acting in concert with variation in community composition, could be responsible for geographic variation in warning color. However, in the face of this purifying selection, the within-population polymorphism seen in many Oreina species remains paradoxical.

  20. Evaluation of a new dipslide with a selective medium for the rapid detection of beta-glucuronidase-positive Escherichia coli.

    PubMed

    Larinkari, U; Rautio, M

    1995-07-01

    A selective medium was incorporated into a new three-media dipslide (Uricult Trio, Orion Diagnostica) to allow rapid identification of Escherichia coli. The medium is supplemented with a recently described chromogenic substrate, hydroxyquinoline-beta-D-glucuronide, for beta-glucuronidase enzyme. The performance of the medium was compared to that of three other beta-glucuronidase detection methods in tests of 602 routine urine samples. Of 324 Escherichia coli strains isolated, 92% grew brown colonies on dipslide, thus being beta-glucuronidase positive. The proportion of beta-glucuronidase-positive Escherichia coli detected by the three methods was 93% for BGA II agar plates (Tammer-Tutka), 91% for PGUA tablets (Rosco) and 84% for Fluorocult Brolacin agar plates (Merck). No false-positive reactions were seen in the case of 209 significant isolates of species other than Escherichia coli grown on the selective medium.

  1. Cloning, expression of, and evidence of positive selection for, the prolactin receptor gene in Chinese giant salamander (Andrias davidianus).

    PubMed

    Hu, Qiaomu; Meng, Yan; Tian, Haifeng; Chen, Songlin; Xiao, Hanbing

    2015-12-01

    Prolactin receptor (PRLR) is a protein associated with reproduction in mammals and with osmoregulation in fish. In this study, the complete length of Chinese giant salamander Andrias davidianus prolactin receptor (AD-prlr) was cloned. Andrias davidianus prlr expression was high in the kidney, pituitary, and ovary and low in other examined tissues. The AD-prlr levels were higher in ovary than in testis, and increased in ovaries with age from 1 to 6 years. To determine effect of exogenous androgen and aromatase inhibitor on AD-prlr expression, methyltestosterone (MT) and letrozole (LE) were injected, resulting in decreased AD-prlr in both brain and ovary, with MT repressing prlr transcription more rapidly than did LE. The molecular evolution of prlr was assessed, and found to have undergone a complex evolution process. The obranch-site test detected four positively selected sites in ancestral lineages prior to the separation of mammals and birds. Fourteen sites underwent positive selection in ancestral lineages of birds and six were positively selected in amphibians. The site model showed that 16, 7, and 30 sites underwent positive selection in extant mammals, amphibians, and birds, respectively. The positively selected sites in amphibians were located outside the transmembrane domain, with four in the extracellular and three in the intracellular domain, indicating that the transmembrane region might be conserved and essential for protein function. Our findings provide a basis for further studies of AD-prlr function and molecular evolution in Chinese giant salamander. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 707-719, 2015. © 2015 Wiley Periodicals, Inc.

  2. Inference of purifying and positive selection in three subspecies of chimpanzees (Pan troglodytes) from exome sequencing.

    PubMed

    Bataillon, Thomas; Duan, Jinjie; Hvilsom, Christina; Jin, Xin; Li, Yingrui; Skov, Laurits; Glemin, Sylvain; Munch, Kasper; Jiang, Tao; Qian, Yu; Hobolth, Asger; Wang, Jun; Mailund, Thomas; Siegismund, Hans R; Schierup, Mikkel H

    2015-03-30

    We study genome-wide nucleotide diversity in three subspecies of extant chimpanzees using exome capture. After strict filtering, Single Nucleotide Polymorphisms and indels were called and genotyped for greater than 50% of exons at a mean coverage of 35× per individual. Central chimpanzees (Pan troglodytes troglodytes) are the most polymorphic (nucleotide diversity, θw = 0.0023 per site) followed by Eastern (P. t. schweinfurthii) chimpanzees (θw = 0.0016) and Western (P. t. verus) chimpanzees (θw = 0.0008). A demographic scenario of divergence without gene flow fits the patterns of autosomal synonymous nucleotide diversity well except for a signal of recent gene flow from Western into Eastern chimpanzees. The striking contrast in X-linked versus autosomal polymorphism and divergence previously reported in Central chimpanzees is also found in Eastern and Western chimpanzees. We show that the direction of selection statistic exhibits a strong nonmonotonic relationship with the strength of purifying selection S, making it inappropriate for estimating S. We instead use counts in synonymous versus nonsynonymous frequency classes to infer the distribution of S coefficients acting on nonsynonymous mutations in each subspecies. The strength of purifying selection we infer is congruent with the differences in effective sizes of each subspecies: Central chimpanzees are undergoing the strongest purifying selection followed by Eastern and Western chimpanzees. Coding indels show stronger selection against indels changing the reading frame than observed in human populations.

  3. Genome-wide scans to detect positive selection in Large White and Tongcheng pigs.

    PubMed

    Li, Xiuling; Yang, Songbai; Tang, Zhonglin; Li, Kui; Rothschild, Max F; Liu, Bang; Fan, Bin

    2014-06-01

    Due to the direction, intensity, duration and consistency of genetic selection, especially recent artificial selection, the production performance of domestic pigs has been greatly changed. Therefore, we reasoned that there must be footprints or selection signatures that had been left during domestication. In this study, with porcine 60K BeadChip genotyping data from both commercial Large White and local Chinese Tongcheng pigs, we calculated the extended haplotype homozygosity values of the two breeds using the long-range haplotype method to detect selection signatures. We found 34 candidate regions, including 61 known genes, from Large White pigs and 25 regions comprising 57 known genes from Tongcheng pigs. Many selection signatures were found on SSC1, SSC4, SSC7 and SSC14 regions in both populations. According to quantitative trait loci and network pathway analyses, most of the regions and genes were linked to growth, reproduction and immune responses. In addition, the average genetic differentiation coefficient FST was 0.254, which means that there had already been a significant differentiation between the breeds. The findings from this study can contribute to further research on molecular mechanisms of pig evolution and domestication and also provide valuable references for improvement of their breeding and cultivation.

  4. Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus

    PubMed Central

    Heise, Christopher; Schroeder, Jan C.; Schoen, Michael; Halbedl, Sonja; Reim, Dominik; Woelfle, Sarah; Kreutz, Michael R.; Schmeisser, Michael J.; Boeckers, Tobias M.

    2016-01-01

    Members of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3) are core components of the postsynaptic density (PSD) of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies. PMID:27199660

  5. Analysis of C3 Suggests Three Periods of Positive Selection Events and Different Evolutionary Patterns between Fish and Mammals

    PubMed Central

    Meng, Fanxing; Sun, Yuena; Liu, Xuezhu; Wang, Jianxin; Xu, Tianjun; Wang, Rixin

    2012-01-01

    Background The third complement component (C3) is a central protein of the complement system conserved from fish to mammals. It also showed distinct characteristics in different animal groups. Striking features of the fish complement system were unveiled, including prominent levels of extrahepatic expression and isotypic diversity of the complement components. The evidences of the involvement of complement system in the enhancement of B and T cell responses found in mammals indicated that the complement system also serves as a bridge between the innate and adaptive responses. For the reasons mentioned above, it is interesting to explore the evolutionary process of C3 genes and to investigate whether the huge differences between aquatic and terrestrial environments affected the C3 evolution between fish and mammals. Methodology/Principal Findings Analysis revealed that these two groups of animals had experienced different evolution patterns. The mammalian C3 genes were under purifying selection pressure while the positive selection pressure was detected in fish C3 genes. Three periods of positive selection events of C3 genes were also detected. Two happened on the ancestral lineages to all vertebrates and mammals, respectively, one happened on early period of fish evolutionary history. Conclusions/Significance Three periods of positive selection events had happened on C3 genes during history and the fish and mammals C3 genes experience different evolutionary patterns for their distinct living environments. PMID:22624039

  6. Positive selection drives adaptive diversification of the 4-coumarate: CoA ligase (4CL) gene in angiosperms

    PubMed Central

    Sun, Haiyan; Guo, Kai; Feng, Shengqiu; Zou, Weihua; Li, Ying; Fan, Chunfen; Peng, Liangcai

    2015-01-01

    Lignin and flavonoids play a vital role in the adaption of plants to a terrestrial environment. 4-Coumarate: coenzyme A ligase (4CL) is a key enzyme of general phenylpropanoid metabolism which provides the precursors for both lignin and flavonoids biosynthesis. However, very little is known about how such essential enzymatic functions evolve and diversify. Here, we analyze 4CL sequence variation patterns in a phylogenetic framework to further identify the evolutionary forces that lead to functional divergence. The results reveal that lignin-biosynthetic 4CLs are under positive selection. The majority of the positively selected sites are located in the substrate-binding pocket and the catalytic center, indicating that nonsynonymous substitutions might contribute to the functional evolution of 4CLs for lignin biosynthesis. The evolution of 4CLs involved in flavonoid biosynthesis is constrained by purifying selection and maintains the ancestral role of the protein in response to biotic and abiotic factors. Overall, our results demonstrate that protein sequence evolution via positive selection is an important evolutionary force driving adaptive diversification in 4CL proteins in angiosperms. This diversification is associated with adaption to a terrestrial environment. PMID:26380674

  7. ‘Obesity’ is healthy for cetaceans? Evidence from pervasive positive selection in genes related to triacylglycerol metabolism

    PubMed Central

    Wang, Zhengfei; Chen, Zhuo; Xu, Shixia; Ren, Wenhua; Zhou, Kaiya; Yang, Guang

    2015-01-01

    Cetaceans are a group of secondarily adapted marine mammals with an enigmatic history of transition from terrestrial to fully aquatic habitat and subsequent adaptive radiation in waters around the world. Numerous physiological and morphological cetacean characteristics have been acquired in response to this drastic habitat transition; for example, the thickened blubber is one of the most striking changes that increases their buoyancy, supports locomotion, and provides thermal insulation. However, the genetic basis underlying the blubber thickening in cetaceans remains poorly explored. Here, 88 candidate genes associated with triacylglycerol metabolism were investigated in representative cetaceans and other mammals to test whether the thickened blubber matched adaptive evolution of triacylglycerol metabolism-related genes. Positive selection was detected in 41 of the 88 candidate genes, and functional characterization of these genes indicated that these are involved mainly in triacylglycerol synthesis and lipolysis processes. In addition, some essential regulatory genes underwent significant positive selection in cetacean-specific lineages, whereas no selection signal was detected in the counterpart terrestrial mammals. The extensive occurrence of positive selection in triacylglycerol metabolism-related genes is suggestive of their essential role in secondary adaptation to an aquatic life, and further implying that ‘obesity’ might be an indicator of good health for cetaceans. PMID:26381091

  8. Detecting Positive Selection of Korean Native Goat Populations Using Next-Generation Sequencing

    PubMed Central

    Lee, Wonseok; Ahn, Sojin; Taye, Mengistie; Sung, Samsun; Lee, Hyun-Jeong; Cho, Seoae; Kim, Heebal

    2016-01-01

    Goats (Capra hircus) are one of the oldest species of domesticated animals. Native Korean goats are a particularly interesting group, as they are indigenous to the area and were raised in the Korean peninsula almost 2,000 years ago. Although they have a small body size and produce low volumes of milk and meat, they are quite resistant to lumbar paralysis. Our study aimed to reveal the distinct genetic features and patterns of selection in native Korean goats by comparing the genomes of native Korean goat and crossbred goat populations. We sequenced the whole genome of 15 native Korean goats and 11 crossbred goats using next-generation sequencing (Illumina platform) to compare the genomes of the two populations. We found decreased nucleotide diversity in the native Korean goats compared to the crossbred goats. Genetic structural analysis demonstrated that the native Korean goat and crossbred goat populations shared a common ancestry, but were clearly distinct. Finally, to reveal the native Korean goat’s selective sweep region, selective sweep signals were identified in the native Korean goat genome using cross-population extended haplotype homozygosity (XP-EHH) and a cross-population composite likelihood ratio test (XP-CLR). As a result, we were able to identify candidate genes for recent selection, such as the CCR3 gene, which is related to lumbar paralysis resistance. Combined with future studies and recent goat genome information, this study will contribute to a thorough understanding of the native Korean goat genome. PMID:27989103

  9. Detecting Positive Selection of Korean Native Goat Populations Using Next-Generation Sequencing.

    PubMed

    Lee, Wonseok; Ahn, Sojin; Taye, Mengistie; Sung, Samsun; Lee, Hyun-Jeong; Cho, Seoae; Kim, Heebal

    2016-12-01

    Goats (Capra hircus) are one of the oldest species of domesticated animals. Native Korean goats are a particularly interesting group, as they are indigenous to the area and were raised in the Korean peninsula almost 2,000 years ago. Although they have a small body size and produce low volumes of milk and meat, they are quite resistant to lumbar paralysis. Our study aimed to reveal the distinct genetic features and patterns of selection in native Korean goats by comparing the genomes of native Korean goat and crossbred goat populations. We sequenced the whole genome of 15 native Korean goats and 11 crossbred goats using next-generation sequencing (Illumina platform) to compare the genomes of the two populations. We found decreased nucleotide diversity in the native Korean goats compared to the crossbred goats. Genetic structural analysis demonstrated that the native Korean goat and crossbred goat populations shared a common ancestry, but were clearly distinct. Finally, to reveal the native Korean goat's selective sweep region, selective sweep signals were identified in the native Korean goat genome using cross-population extended haplotype homozygosity (XP-EHH) and a cross-population composite likelihood ratio test (XP-CLR). As a result, we were able to identify candidate genes for recent selection, such as the CCR3 gene, which is related to lumbar paralysis resistance. Combined with future studies and recent goat genome information, this study will contribute to a thorough understanding of the native Korean goat genome.

  10. Selecting Children's Picture Books with Positive Native American Fathers and Father Figures.

    ERIC Educational Resources Information Center

    Heller, Craig; Cunningham, Bruce; Heller, Hannah M.

    2003-01-01

    Explores images of Native American fathers and father figures in children's picture books, offering background information about Native American cultures, traditional ways of culture and family, and the past and present role of fathers and father figures. Presents distinctive children's books along with guidelines for selecting and evaluating…

  11. A genome-wide signature of positive selection in ancient and recent invasive expansions of the honey bee Apis mellifera

    PubMed Central

    Zayed, Amro; Whitfield, Charles W.

    2008-01-01

    Apis mellifera originated in Africa and extended its range into Eurasia in two or more ancient expansions. In 1956, honey bees of African origin were introduced into South America, their descendents admixing with previously introduced European bees, giving rise to the highly invasive and economically devastating “Africanized” honey bee. Here we ask whether the honey bee's out-of-Africa expansions, both ancient and recent (invasive), were associated with a genome-wide signature of positive selection, detected by contrasting genetic differentiation estimates (FST) between coding and noncoding SNPs. In native populations, SNPs in protein-coding regions had significantly higher FST estimates than those in noncoding regions, indicating adaptive evolution in the genome driven by positive selection. This signal of selection was associated with the expansion of honey bees from Africa into Western and Northern Europe, perhaps reflecting adaptation to temperate environments. We estimate that positive selection acted on a minimum of 852–1,371 genes or ≈10% of the bee's coding genome. We also detected positive selection associated with the invasion of African-derived honey bees in the New World. We found that introgression of European-derived alleles into Africanized bees was significantly greater for coding than noncoding regions. Our findings demonstrate that Africanized bees exploited the genetic diversity present from preexisting introductions in an adaptive way. Finally, we found a significant negative correlation between FST estimates and the local GC content surrounding coding SNPs, suggesting that AT-rich genes play an important role in adaptive evolution in the honey bee. PMID:18299560

  12. Identifying positive selection candidate loci for high-altitude adaptation in Andean populations

    PubMed Central

    2009-01-01

    High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude. PMID:20038496

  13. Positive selection during the evolution of the blood coagulation factors in the context of their disease-causing mutations.

    PubMed

    Rallapalli, Pavithra M; Orengo, Christine A; Studer, Romain A; Perkins, Stephen J

    2014-11-01

    Blood coagulation occurs through a cascade of enzymes and cofactors that produces a fibrin clot, while otherwise maintaining hemostasis. The 11 human coagulation factors (FG, FII-FXIII) have been identified across all vertebrates, suggesting that they emerged with the first vertebrates around 500 Ma. Human FVIII, FIX, and FXI are associated with thousands of disease-causing mutations. Here, we evaluated the strength of selective pressures on the 14 genes coding for the 11 factors during vertebrate evolution, and compared these with human mutations in FVIII, FIX, and FXI. Positive selection was identified for fibrinogen (FG), FIII, FVIII, FIX, and FX in the mammalian Primates and Laurasiatheria and the Sauropsida (reptiles and birds). This showed that the coagulation system in vertebrates was under strong selective pressures, perhaps to adapt against blood-invading pathogens. The comparison of these results with disease-causing mutations reported in FVIII, FIX, and FXI showed that the number of disease-causing mutations, and the probability of positive selection were inversely related to each other. It was concluded that when a site was under positive selection, it was less likely to be associated with disease-causing mutations. In contrast, sites under negative selection were more likely to be associated with disease-causing mutations and be destabilizing. A residue-by-residue comparison of the FVIII, FIX, and FXI sequence alignments confirmed this. This improved understanding of evolutionary changes in FVIII, FIX, and FXI provided greater insight into disease-causing mutations, and better assessments of the codon sites that may be mutated in applications of gene therapy.

  14. Positive Selection during the Evolution of the Blood Coagulation Factors in the Context of Their Disease-Causing Mutations

    PubMed Central

    Rallapalli, Pavithra M.; Orengo, Christine A.; Studer, Romain A.; Perkins, Stephen J.

    2014-01-01

    Blood coagulation occurs through a cascade of enzymes and cofactors that produces a fibrin clot, while otherwise maintaining hemostasis. The 11 human coagulation factors (FG, FII–FXIII) have been identified across all vertebrates, suggesting that they emerged with the first vertebrates around 500 Ma. Human FVIII, FIX, and FXI are associated with thousands of disease-causing mutations. Here, we evaluated the strength of selective pressures on the 14 genes coding for the 11 factors during vertebrate evolution, and compared these with human mutations in FVIII, FIX, and FXI. Positive selection was identified for fibrinogen (FG), FIII, FVIII, FIX, and FX in the mammalian Primates and Laurasiatheria and the Sauropsida (reptiles and birds). This showed that the coagulation system in vertebrates was under strong selective pressures, perhaps to adapt against blood-invading pathogens. The comparison of these results with disease-causing mutations reported in FVIII, FIX, and FXI showed that the number of disease-causing mutations, and the probability of positive selection were inversely related to each other. It was concluded that when a site was under positive selection, it was less likely to be associated with disease-causing mutations. In contrast, sites under negative selection were more likely to be associated with disease-causing mutations and be destabilizing. A residue-by-residue comparison of the FVIII, FIX, and FXI sequence alignments confirmed this. This improved understanding of evolutionary changes in FVIII, FIX, and FXI provided greater insight into disease-causing mutations, and better assessments of the codon sites that may be mutated in applications of gene therapy. PMID:25158795

  15. Genomic organization and differential signature of positive selection in the alpha and beta globin gene clusters in two cetacean species.

    PubMed

    Nery, Mariana F; Arroyo, José Ignacio; Opazo, Juan C

    2013-01-01

    The hemoglobin of jawed vertebrates is a heterotetramer protein that contains two α- and two β-chains, which are encoded by members of α- and β-globin gene families. Given the hemoglobin role in mediating an adaptive response to chronic hypoxia, it is likely that this molecule may have experienced a selective pressure during the evolution of cetaceans, which have to deal with hypoxia tolerance during prolonged diving. This selective pressure could have generated a complex history of gene turnover in these clusters and/or changes in protein structure themselves. Accordingly, we aimed to characterize the genomic organization of α- and β-globin gene clusters in two cetacean species and to detect a possible role of positive selection on them using a phylogenetic framework. Maximum likelihood and Bayesian phylogeny reconstructions revealed that both cetacean species had retained a similar complement of putatively functional genes. For the α-globin gene cluster, the killer whale presents a complement of genes composed of HBZ, HBK, and two functional copies of HBA and HBQ genes, whereas the dolphin possesses HBZ, HBK, HBA and HBQ genes, and one HBA pseudogene. For the β-globin gene cluster, both species retained a complement of four genes, two early expressed genes-HBE and HBH-and two adult expressed genes-HBD and HBB. Our natural selection analysis detected two positively selected sites in the HBB gene (56 and 62) and four in HBA (15, 21, 49, 120). Interestingly, only the genes that are expressed during the adulthood showed the signature of positive selection.

  16. The Efficacy of an Outdoor Adventure Education Curriculum on Selected Aspects of Positive Psychological Development

    ERIC Educational Resources Information Center

    Sheard, Michael; Golby, Jim

    2006-01-01

    To date, little empirical research has been conducted to support the claim that outdoor adventure education (OAE) develops desirable psychological characteristics in participants. This study examined the effects of an OAE foundation degree curriculum on positive psychological development. Fifty-two students (26 OAE students, 26 controls on an…

  17. Sexual Orientation and Spatial Position Effects on Selective Forms of Object Location Memory

    ERIC Educational Resources Information Center

    Rahman, Qazi; Newland, Cherie; Smyth, Beatrice Mary

    2011-01-01

    Prior research has demonstrated robust sex and sexual orientation-related differences in object location memory in humans. Here we show that this sexual variation may depend on the spatial position of target objects and the task-specific nature of the spatial array. We tested the recovery of object locations in three object arrays (object…

  18. The thuggacins, novel antibacterial macrolides from Sorangium cellulosum acting against selected Gram-positive bacteria.

    PubMed

    Irschik, Herbert; Reichenbach, Hans; Höfle, Gerhard; Jansen, Rolf

    2007-12-01

    In our screening program we found an activity against some Gram-positive bacteria, including mycobacteria in the culture supernatant of Sorangium cellulosum strain So ce895. The antibiotic responsible for this activity was isolated and named thuggacin. Initial studies towards the mechanism of action showed that thuggacin A inhibits a late step of the respiratory chain of some bacteria.

  19. Croatian Meteor Network: ongoing work 2014 - 2015

    NASA Astrophysics Data System (ADS)

    Šegon, D.; Andreić, Ž.; Korlević, K.; Vida, D.

    2015-01-01

    Ongoing work mainly between 2014-2015 International Meteor Conferences (IMC) has been presented. Current sky coverage, software updates, orbit catalogues updates, shower search updates, international collaboration as well as new fields of research and educational efforts made by the Croatian Meteor Network are described.

  20. Croatian Meteor Network: Ongoing work 2015 - 2016

    NASA Astrophysics Data System (ADS)

    Šegon, D.; Vida, D.; Korlević, K.; Andreić, Ž.

    2016-01-01

    Ongoing work of the Croatian Meteor Network (CMN) between the 2015 and 2016 International Meteor Conferences is presented. The current sky coverage is considered, software updates and updates of orbit catalogues are described. Furthermore, the work done on meteor shower searches, international collaborations as well as new fields of research are discussed. Finally, the educational efforts made by the CMN are described.

  1. Simultaneous purifying selection on the ancestral MC1R allele and positive selection on the melanoma-risk allele V60L in south Europeans.

    PubMed

    Martínez-Cadenas, Conrado; López, Saioa; Ribas, Gloria; Flores, Carlos; García, Oscar; Sevilla, Arrate; Smith-Zubiaga, Isabel; Ibarrola-Villaba, Maider; Pino-Yanes, Maria del Mar; Gardeazabal, Jesús; Boyano, Dolores; García de Galdeano, Alicia; Izagirre, Neskuts; de la Rúa, Concepción; Alonso, Santos

    2013-12-01

    In humans, the geographical apportionment of the coding diversity of the pigmentary locus melanocortin-1 receptor (MC1R) is, unusually, higher in Eurasians than in Africans. This atypical observation has been interpreted as the result of purifying selection due to functional constraint on MC1R in high UV-B radiation environments. By analyzing 3,142 human MC1R alleles from different regions of Spain in the context of additional haplotypic information from the 1000 Genomes (1000G) Project data, we show that purifying selection is also strong in southern Europe, but not so in northern Europe. Furthermore, we show that purifying and positive selection act simultaneously on MC1R. Thus, at least in Spain, regions at opposite ends of the incident UV-B radiation distribution show significantly different frequencies for the melanoma-risk allele V60L (a mutation also associated to red hair and fair skin and even blonde hair), with higher frequency of V60L at those regions of lower incident UV-B radiation. Besides, using the 1000G south European data, we show that the V60L haplogroup is also characterized by an extended haplotype homozygosity (EHH) pattern indicative of positive selection. We, thus, provide evidence for an adaptive value of human skin depigmentation in Europe and illustrate how an adaptive process can simultaneously help to maintain a disease-risk allele. In addition, our data support the hypothesis proposed by Jablonski and Chaplin (Human skin pigmentation as an adaptation to UVB radiation. Proc Natl Acad Sci U S A. 2010;107:8962-8968), which posits that habitation of middle latitudes involved the evolution of partially depigmented phenotypes that are still capable of suitable tanning.

  2. Selective stabilization of the chorismate mutase transition state by a positively charged hydrogen bond donor.

    PubMed

    Kienhöfer, Alexander; Kast, Peter; Hilvert, Donald

    2003-03-19

    Citrulline was incorporated via chemical semisynthesis at position 90 in the active site of the AroH chorismate mutase from Bacillus subtilis. The wild-type arginine at this position makes hydrogen-bonding interactions with the ether oxygen of chorismate. Replacement of the positively charged guanidinium group with the isosteric but neutral urea has a dramatic effect on the ability of the enzyme to convert chorismate into prephenate. The Arg90Cit variant exhibits a >104-fold decrease in the catalytic rate constant kcat with a 2.7-fold increase in the Michaelis constant Km. In contrast, its affinity for a conformationally constrained inhibitor molecule that effectively mimics the geometry but not the dissociative character of the transition state is only reduced by a factor of approximately 6. These results show that an active site merely complementary to the reactive conformation of chorismate is insufficient for catalysis of the mutase reaction. Instead, electrostatic stabilization of the polarized transition state by provision of a cationic hydrogen bond donor proximal to the oxygen in the breaking C-O bond is essential for high catalytic efficiency.

  3. Positive Selection in Bone Morphogenetic Protein 15 Targets a Natural Mutation Associated with Primary Ovarian Insufficiency in Human

    PubMed Central

    Meslin, Camille; Monestier, Olivier; Di Pasquale, Elisa; Pascal, Géraldine; Persani, Luca; Fabre, Stéphane

    2013-01-01

    Bone Morphogenetic Protein 15 (BMP15) is a TGFβ-like oocyte-derived growth factor involved in ovarian folliculogenesis as a critical regulator of many granulosa cell processes. Alterations of the BMP15 gene have been found associated with different ovarian phenotypic effects depending on the species, from sterility to increased prolificacy in sheep, slight subfertility in mouse or associated with primary ovarian insufficiency (POI) in women. To investigate the evolving role of BMP15, a phylogenetic analysis of this particular TGFβ family member was performed. A maximum likelihood phylogenetic tree of several TGFβ/BMP family members expressed by the ovary showed that BMP15 has a very strong divergence and a rapid evolution compared to others. Moreover, among 24 mammalian species, we detected signals of positive selection in the hominidae clade corresponding to F146, L189 and Y235 residues in human BMP15. The biological importance of these residues was tested functionally after site directed-mutagenesis in a COV434 cells luciferase assay. By replacing the positively selected amino acid either by alanine or the most represented residue in other studied species, only L189A, Y235A and Y235C mutants showed a significant increase of BMP15 signaling when compared to wild type. Additionally, the Y235C mutant was more potent than wild type in inhibiting progesterone secretion of ovine granulosa cells in primary culture. Interestingly, the Y235C mutation was previously identified in association with POI in women. In conclusion, this study evidences that the BMP15 gene has evolved faster than other members of the TGFß family and was submitted to a positive selection pressure in the hominidae clade. Some residues under positive selection are of great importance for the normal function of the protein and thus for female fertility. Y235 represents a critical residue in the determination of BMP15 biological activity, thus indirectly confirming its role in the onset of POI in

  4. Positive selection on the Plasmodium falciparum clag2 gene encoding a component of the erythrocyte-binding rhoptry protein complex

    PubMed Central

    Alexandre, Jean SF; Kaewthamasorn, Morakot; Yahata, Kazuhide; Nakazawa, Shusuke; Kaneko, Osamu

    2011-01-01

    A protein complex of high-molecular-mass proteins (PfRhopH) of the human malaria parasite Plasmodium falciparum induces host protective immunity and therefore is a candidate for vaccine development. Clarification of the level of polymorphism and the evolutionary processes is important both for vaccine design and for a better understanding of the evolution of cell invasion in this parasite. In a previous study on 5 genes encoding RhopH1/Clag proteins, positive diversifying selection was detected in clag8 and clag9 but not in the paralogous clag2, clag3.1 and clag3.2. In this study, to extend the analysis of clag polymorphism, we obtained sequences surrounding the most polymorphic regions of clag2, clag8, and clag9 from parasites collected in Thailand. Using sequence data obtained newly in this study and reported previously, we classified clag2 sequences into 5 groups based on the similarity of the deduced amino acid sequences and number of insertions/deletions. By the sliding window method, an excess of nonsynonymous substitutions over synonymous substitutions was detected in the group 1 and group 2 clag2 and clag8 sequences. Population-based analyses also detected a significant departure from the neutral expectation for group 1 clag2 and clag8. Thus, two independent approaches suggest that clag2 is subject to a positive diversifying selection. The previously suggested positive selection on clag8 was also supported by population-based analyses. However, the positive selection on clag9, which was detected by comparing the 5 sequences, was not detected using the additional 34 sequences obtained in this study. PMID:22028613

  5. Evidence of positive selection at codon sites localized in extracellular domains of mammalian CC motif chemokine receptor proteins

    PubMed Central

    2010-01-01

    Background CC chemokine receptor proteins (CCR1 through CCR10) are seven-transmembrane G-protein coupled receptors whose signaling pathways are known for their important roles coordinating immune system responses through targeted trafficking of white blood cells. In addition, some of these receptors have been identified as fusion proteins for viral pathogens: for example, HIV-1 strains utilize CCR5, CCR2 and CCR3 proteins to obtain cellular entry in humans. The extracellular domains of these receptor proteins are involved in ligand-binding specificity as well as pathogen recognition interactions. In mammals, the majority of chemokine receptor genes are clustered together; in humans, seven of the ten genes are clustered in the 3p21-24 chromosome region. Gene conversion events, or exchange of DNA sequence between genes, have been reported in chemokine receptor paralogs in various mammalian lineages, especially between the cytogenetically closely located pairs CCR2/5 and CCR1/3. Datasets of mammalian orthologs for each gene were analyzed separately to minimize the potential confounding impact of analyzing highly similar sequences resulting from gene conversion events. Molecular evolution approaches and the software package Phylogenetic Analyses by Maximum Likelihood (PAML) were utilized to investigate the signature of selection that has acted on the mammalian CC chemokine receptor (CCR) gene family. The results of neutral vs. adaptive evolution (positive selection) hypothesis testing using Site Models are reported. In general, positive selection is defined by a ratio of nonsynonymous/synonymous nucleotide changes (dN/dS, or ω) >1. Results Of the ten mammalian CC motif chemokine receptor sequence datasets analyzed, only CCR2 and CCR3 contain amino acid codon sites that exhibit evidence of positive selection using site based hypothesis testing in PAML. Nineteen of the twenty codon sites putatively indentified as likely to be under positive selection code for amino acid

  6. Position-Related Differences in Selected Morphological Body Characteristics of Top-Level Female Handball Players.

    PubMed

    Bon, Marta; Pori, Primoz; Sibila, Marko

    2015-09-01

    The study aimed to establish the main morphological characteristics of Slovenian junior and senior female national handball team players. Morphological characteristics of various player subgroups (goalkeepers, wings, back players and pivots) were also determined so as to establish whether they had distinct profiles. The subjects were 87 handball players who were members of the Slovenian junior and senior female national teams in the period from 2003 to 2009. A standardised anthropometric protocol was used to assess the subjects' morphological characteristics. The measurements included 23 different anthropometric measures. First, basic statistical characteristics of anthropometric measures were obtained for all subjects together and then for each group separately. Somatotypes were determined using Heath-Carter's method. Endomorphic, mesomorphic and ectomorphic components were calculated by computer on the basis of formulas. In order to determine differences in the body composition and anthropometric data of the subjects playing in different positions, a one-way analysis of variance was employed. The results show that, on average, the wings differed the most from the other player groups in terms of their morphological body characteristics. The wings differed most prominently from the other player groups in terms of their morphological body parameters as they were significantly smaller and had a statistically significantly lower body mass than the other groups. In terms of transversal measures of the skeleton and the circumferences, the wings significantly differed mainly from the pivots and goalkeepers and less from the backs. The goalkeepers were the tallest, with high values of body mass and low values of transversal measures compared to P. Their skin folds were the most pronounced among all the groups on average and their share of subcutaneous fat in total body mass was the highest. Consequently, their endomorphic component of the somatotype was pronounced

  7. Molecular cloning, characterization and positively selected sites of the glutathione S-transferase family from Locusta migratoria.

    PubMed

    Zhang, Xueyao; Wang, Jianxin; Zhang, Min; Qin, Guohua; Li, Daqi; Zhu, Kun Yan; Ma, Enbo; Zhang, Jianzhen

    2014-01-01

    Glutathione S-transferases (GSTs) are multifunctional enzymes that are involved in the metabolism of endogenous and exogenous compounds and are related to insecticide resistance. The purpose of this study was to provide new information on the molecular characteristics and the positive selection of locust GSTs. Based on the transcriptome database, we sequenced 28 cytosolic GSTs and 4 microsomal GSTs from the migratory locust (Locusta migratoria). We assigned the 28 cytosolic GSTs into 6 classes--sigma, epsilon, delta, theta, omega and zeta, and the 4 microsomal GSTs into 2 subclasses--insect and MGST3. The tissue- and stage-expression patterns of the GSTs differed at the mRNA level. Further, the substrate specificities and kinetic constants of the cytosolic GSTs differed markedly at the protein level. The results of likelihood ratio tests provided strong evidence for positive selection in the delta class. The result of Bayes Empirical Bayes analysis identified 4 amino acid sites in the delta class as positive selection sites. These sites were located on the protein surface. Our findings will facilitate the elucidation of the molecular characteristics and evolutionary aspects of insect GST superfamily.

  8. No evidence for strong recent positive selection favoring the 7 repeat allele of VNTR in the DRD4 gene.

    PubMed

    Naka, Izumi; Nishida, Nao; Ohashi, Jun

    2011-01-01

    The human dopamine receptor D4 (DRD4) gene contains a 48-bp variable number of tandem repeat (VNTR) in exon 3, encoding the third intracellular loop of this dopamine receptor. The DRD4 7R allele, which seems to have a single origin, is commonly observed in various human populations and the nucleotide diversity of the DRD4 7R haplotype at the DRD4 locus is reduced compared to the most common DRD4 4R haplotype. Based on these observations, previous studies have hypothesized that positive selection has acted on the DRD4 7R allele. However, the degrees of linkage disequilibrium (LD) of the DRD4 7R allele with single nucleotide polymorphisms (SNPs) outside the DRD4 locus have not been evaluated. In this study, to re-examine the possibility of recent positive selection favoring the DRD4 7R allele, we genotyped HapMap subjects for DRD4 VNTR, and conducted several neutrality tests including long range haplotype test and iHS test based on the extended haplotype homozygosity. Our results indicated that LD of the DRD4 7R allele was not extended compared to SNP alleles with the similar frequency. Thus, we conclude that the DRD4 7R allele has not been subjected to strong recent positive selection.

  9. Molecular Cloning, Characterization and Positively Selected Sites of the Glutathione S-Transferase Family from Locusta migratoria

    PubMed Central

    Zhang, Min; Qin, Guohua; Li, Daqi; Zhu, Kun Yan; Ma, Enbo; Zhang, Jianzhen

    2014-01-01

    Glutathione S-transferases (GSTs) are multifunctional enzymes that are involved in the metabolism of endogenous and exogenous compounds and are related to insecticide resistance. The purpose of this study was to provide new information on the molecular characteristics and the positive selection of locust GSTs. Based on the transcriptome database, we sequenced 28 cytosolic GSTs and 4 microsomal GSTs from the migratory locust (Locusta migratoria). We assigned the 28 cytosolic GSTs into 6 classes—sigma, epsilon, delta, theta, omega and zeta, and the 4 microsomal GSTs into 2 subclasses—insect and MGST3. The tissue- and stage-expression patterns of the GSTs differed at the mRNA level. Further, the substrate specificities and kinetic constants of the cytosolic GSTs differed markedly at the protein level. The results of likelihood ratio tests provided strong evidence for positive selection in the delta class. The result of Bayes Empirical Bayes analysis identified 4 amino acid sites in the delta class as positive selection sites. These sites were located on the protein surface. Our findings will facilitate the elucidation of the molecular characteristics and evolutionary aspects of insect GST superfamily. PMID:25486043

  10. Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression.

    PubMed Central

    Brändle, D; Müller, C; Rülicke, T; Hengartner, H; Pircher, H

    1992-01-01

    We have examined the expression of the recombination activating gene RAG-1 by in situ hybridization to thymi from mice bearing transgenes for the T-cell receptor (TCR) alpha chain, TCR beta chain, or both TCR alpha and beta chains. RAG-1 transcription was found in the thymic cortex of transgenic mice carrying a single TCR alpha- or TCR beta-chain transgene, comparable to normal mice. However, RAG-1 transcription was strikingly reduced in the thymic cortex from transgenic mice carrying both TCR alpha- and beta-chain genes and expressing major histocompatibility complex (MHC) class I (H-2b) molecules necessary for positive selection of the transgenic TCR. In contrast, thymi of transgenic mice also carrying both TCR alpha- and beta-chain genes but expressing MHC molecules (H-2d) that did not positively select the transgenic TCR displayed high levels of RAG-1 transcription. The low thymic RAG-1 expression coincided with high transgenic TCR alpha-chain surface expression and with inhibition of endogenous TCR alpha-chain rearrangement. Our findings suggest that binding of the TCR to self MHC molecules during positive selection down-regulates RAG-1 transcription in cortical thymocytes and thereby prevents further TCR alpha-chain rearrangements. Images PMID:1329099

  11. Strong and widespread action of site-specific positive selection in the snake venom Kunitz/BPTI protein family

    PubMed Central

    Župunski, Vera; Kordiš, Dušan

    2016-01-01

    S1 family of serine peptidases is the largest family of peptidases. They are specifically inhibited by the Kunitz/BPTI inhibitors. Kunitz domain is characterized by the compact 3D structure with the most important inhibitory loops for the inhibition of S1 peptidases. In the present study we analysed the action of site-specific positive selection and its impact on the structurally and functionally important parts of the snake venom Kunitz/BPTI family of proteins. By using numerous models we demonstrated the presence of large numbers of site-specific positively selected sites that can reach between 30–50% of the Kunitz domain. The mapping of the positively selected sites on the 3D model of Kunitz/BPTI inhibitors has shown that these sites are located in the inhibitory loops 1 and 2, but also in the Kunitz scaffold. Amino acid replacements have been found exclusively on the surface, and the vast majority of replacements are causing the change of the charge. The consequence of these replacements is the change in the electrostatic potential on the surface of the Kunitz/BPTI proteins that may play an important role in the precise targeting of these inhibitors into the active site of S1 family of serine peptidases. PMID:27841308

  12. Neanderthal introgression at chromosome 3p21.31 was under positive natural selection in East Asians.

    PubMed

    Ding, Qiliang; Hu, Ya; Xu, Shuhua; Wang, Jiucun; Jin, Li

    2014-03-01

    Studies of the Neanderthal and Denisovan genomes demonstrate archaic hominin introgression in Eurasians. Here, we present evidence of Neanderthal introgression within the chromosome 3p21.31 region, occurring with a high frequency in East Asians (ranging from 49.4% to 66.5%) and at a low frequency in Europeans. We also detected a signal of strong positive selection in this region only in East Asians. Our data indicate that likely candidate targets of selection include rs12488302-T and its associated alleles--among which four are nonsynonymous, including rs35455589-G in HYAL2, a gene related to the cellular response to ultraviolet-B irradiation. Furthermore, suggestive evidence supports latitude-dependent selection, implicating a role of ultraviolet-B. Interestingly, the distribution of rs35455589-G suggests that this allele was lost during the exodus of ancestors of modern Eurasians from Africa and reintroduced to Eurasians from Neanderthals.

  13. Characterization of 40 full-length MHC class IIA functional alleles in miiuy croaker: Polymorphism and positive selection.

    PubMed

    Xu, Tianjun; Liu, Jiang; Sun, Yueyan; Zhu, Zhihuang; Liu, Tianxing

    2016-02-01

    The major histocompatibility complex is a highly polymorphic gene superfamily in vertebrates that plays an important role in adaptive immune response. In the present study, we identified 40 full-length miiuy croaker MHC class IIA (Mimi-DAA) functional alleles from 26 miiuy croaker individuals and found that the alleles encode 30 amino acid sequences. A high level of polymorphism in Mimi-DAA was detected in miiuy croaker. The rate of non-synonymous substitutions (d(N)) occurred at a significantly higher frequency than that of synonymous substitutions (d(S)) in the peptide-binding region (PBR) and non-PBR. This result suggests that balancing selection maintains polymorphisms at the Mimi-DAA locus. Phylogenetic analysis based on the full-length sequences showed that the Mimi-DAA alleles clustered into three groups. However, the phylogenetic tree constructed using the exon 2 sequences indicated that the Mimi-DAA alleles clustered into two groups. A total of 22 positively selected sites were identified on the Mimi-DAA alleles after testing for positive selection, and five sites were predicted to be associated with the binding of peptide antigen, suggesting that a few selected residues may play a significant role in immune function.

  14. Likelihood analysis of the chalcone synthase genes suggests the role of positive selection in morning glories (Ipomoea).

    PubMed

    Yang, Ji; Gu, Hongya; Yang, Ziheng

    2004-01-01

    Chalcone synthase (CHS) is a key enzyme in the biosynthesis of flavonoides, which are important for the pigmentation of flowers and act as attractants to pollinators. Genes encoding CHS constitute a multigene family in which the copy number varies among plant species and functional divergence appears to have occurred repeatedly. In morning glories (Ipomoea), five functional CHS genes (A-E) have been described. Phylogenetic analysis of the Ipomoea CHS gene family revealed that CHS A, B, and C experienced accelerated rates of amino acid substitution relative to CHS D and E. To examine whether the CHS genes of the morning glories underwent adaptive evolution, maximum-likelihood models of codon substitution were used to analyze the functional sequences in the Ipomoea CHS gene family. These models used the nonsynonymous/synonymous rate ratio (omega = d(N)/ d(S)) as an indicator of selective pressure and allowed the ratio to vary among lineages or sites. Likelihood ratio test suggested significant variation in selection pressure among amino acid sites, with a small proportion of them detected to be under positive selection along the branches ancestral to CHS A, B, and C. Positive Darwinian selection appears to have promoted the divergence of subfamily ABC and subfamily DE and is at least partially responsible for a rate increase following gene duplication.

  15. Positive selection drives the evolution of a major histocompatibility complex gene in an endangered Mexican salamander species complex.

    PubMed

    Tracy, Karen E; Kiemnec-Tyburczy, Karen M; DeWoody, J Andrew; Parra-Olea, Gabriela; Zamudio, Kelly R

    2015-06-01

    Immune gene evolution can be critical to species survival in the face of infectious disease. In particular, polymorphism in the genes of the major histocompatibility complex (MHC) helps vertebrates combat novel and diverse pathogens by increasing the number of pathogen-derived proteins that can initiate the host's acquired immune response. In this study, we used a combination of presumably adaptive and neutral markers to investigate MHC evolution in populations of five salamander species within the Ambystoma velasci complex, a group consisting of 15 recently diverged species, several of which are endangered. We isolated 31 unique MHC class II β alleles from 75 total individuals from five species in this complex. MHC heterozygosity was significantly lower than expected for all five species, and we found no clear relationship between number of MHC alleles and species range, life history, or level of heterozygosity. We inferred a phylogeny representing the evolutionary history of Ambystoma MHC, with which we found signatures of positive selection on the overall gene, putative peptide-binding residues, and allelic lineages. We identified several instances of trans-species polymorphism, a hallmark of balancing selection observed in other groups of closely related species. In contrast, we did not detect comparable allelic diversity or signatures of selection on neutral loci. Additionally, we identified 17 supertypes among the 44 unique Ambystoma alleles, indicating that these sequences may encode functionally distinct MHC variants. We therefore have strong evidence that positive selection is a major evolutionary force driving patterns of MHC polymorphism in this recently radiated species complex.

  16. Does Positive Selection Drive Transcription Factor Binding Site Turnover? A Test with Drosophila Cis-Regulatory Modules

    PubMed Central

    He, Bin Z.; Holloway, Alisha K.; Maerkl, Sebastian J.; Kreitman, Martin

    2011-01-01

    Transcription factor binding site(s) (TFBS) gain and loss (i.e., turnover) is a well-documented feature of cis-regulatory module (CRM) evolution, yet little attention has been paid to the evolutionary force(s) driving this turnover process. The predominant view, motivated by its widespread occurrence, emphasizes the importance of compensatory mutation and genetic drift. Positive selection, in contrast, although it has been invoked in specific instances of adaptive gene expression evolution, has not been considered as a general alternative to neutral compensatory evolution. In this study we evaluate the two hypotheses by analyzing patterns of single nucleotide polymorphism in the TFBS of well-characterized CRM in two closely related Drosophila species, Drosophila melanogaster and Drosophila simulans. An important feature of the analysis is classification of TFBS mutations according to the direction of their predicted effect on binding affinity, which allows gains and losses to be evaluated independently along the two phylogenetic lineages. The observed patterns of polymorphism and divergence are not compatible with neutral evolution for either class of mutations. Instead, multiple lines of evidence are consistent with contributions of positive selection to TFBS gain and loss as well as purifying selection in its maintenance. In discussion, we propose a model to reconcile the finding of selection driving TFBS turnover with constrained CRM function over long evolutionary time. PMID:21572512

  17. Evolution of the pygmy phenotype: evidence of positive selection fro genome-wide scans in African, Asian, and Melanesian pygmies.

    PubMed

    Migliano, Andrea Bamberg; Romero, Irene Gallego; Metspalu, Mait; Leavesley, Matthew; Pagani, Luca; Antao, Tiago; Huang, Da-Wei; Sherman, Brad T; Siddle, Katharine; Scholes, Clarissa; Hudjashov, Georgi; Kaitokai, Elton; Babalu, Avis; Belatti, Maggie; Cagan, Alex; Hopkinshaw, Byrony; Shaw, Colin; Nelis, Mari; Metspalu, Ene; Mägi, Reedik; Lempicki, Richard A; Villems, Richard; Lahr, Marta Mirazon; Kivisild, Toomas

    2013-01-01

    Human pygmy populations inhabit different regions of the world, from Africa to Melanesia. In Asia, short-statured populations are often referred to as "negritos." Their short stature has been interpreted as a consequence of thermoregulatory, nutritional, and/or locomotory adaptations to life in tropical forests. A more recent hypothesis proposes that their stature is the outcome of a life history trade-off in high-mortality environments, where early reproduction is favored and, consequently, early sexual maturation and early growth cessation have coevolved. Some serological evidence of deficiencies in the growth hormone/insulin-like growth factor axis have been previously associated with pygmies' short stature. Using genome-wide single-nucleotide polymorphism genotype data, we first tested whether different negrito groups living in the Philippines and Papua New Guinea are closely related and then investigated genomic signals of recent positive selection in African, Asian, and Papuan pygmy populations. We found that negritos in the Philippines and Papua New Guinea are genetically more similar to their nonpygmy neighbors than to one another and have experienced positive selection at different genes. These results indicate that geographically distant pygmy groups are likely to have evolved their short stature independently. We also found that selection on common height variants is unlikely to explain their short stature and that different genes associated with growth, thyroid function, and sexual development are under selection in different pygmy groups.

  18. Glycerol monolaurate inhibits the effects of Gram-positive select agents on eukaryotic cells.

    PubMed

    Peterson, Marnie L; Schlievert, Patrick M

    2006-02-21

    Many exotoxins of Gram-positive bacteria, such as superantigens [staphylococcal enterotoxins, toxic shock syndrome toxin-1 (TSST-1), and streptococcal pyrogenic exotoxins] and anthrax toxin are bioterrorism agents that cause diseases by immunostimulation or cytotoxicity. Glycerol monolaurate (GML), a fatty acid monoester found naturally in humans, has been reported to prevent synthesis of Gram-positive bacterial exotoxins. This study explored the ability of GML to inhibit the effects of exotoxins on mammalian cells and prevent rabbit lethality from TSS. GML (>or=10 microg/mL) inhibited superantigen (5 microg/mL) immunoproliferation, as determined by inhibition of (3)H-thymidine incorporation into DNA of human peripheral blood mononuclear cells (1 x 10(6) cells/mL) as well as phospholipase Cgamma1, suggesting inhibition of signal transduction. The compound (20 microg/mL) prevented superantigen (100 microg/mL) induced cytokine secretion by human vaginal epithelial cells (HVECs) as measured by ELISA. GML (250 microg) inhibited rabbit lethality as a result of TSST-1 administered vaginally. GML (10 microg/mL) inhibited HVEC and macrophage cytotoxicity by anthrax toxin, prevented erythrocyte lysis by purified hemolysins (staphylococcal alpha and beta) and culture fluids containing streptococcal and Bacillus anthracis hemolysins, and was nontoxic to mammalian cells (up to 100 microg/mL) and rabbits (250 microg). GML stabilized mammalian cell membranes, because erythrocyte lysis was reduced in the presence of hypotonic aqueous solutions (0-0.05 M saline) or staphylococcal alpha- and beta-hemolysins when erythrocytes were pretreated with GML. GML may be useful in the management of Gram-positive exotoxin illnesses; its action appears to be membrane stabilization with inhibition of signal transduction.

  19. Positive selection on NIN, a gene involved in neurogenesis, and primate brain evolution.

    PubMed

    Montgomery, S H; Mundy, N I

    2012-11-01

    A long-held dogma in comparative neurobiology has been that the number of neurons under a given area of cortical surface is constant. As such, the attention of those seeking to understand the genetic basis of brain evolution has focused on genes with functions in the lateral expansion of the developing cerebral cortex. However, new data suggest that cortical cytoarchitecture is not constant across primates, raising the possibility that changes in radial cortical development played a role in primate brain evolution. We present the first analysis of a gene with functions relevant to this dimension of brain evolution. We show that NIN, a gene necessary for maintaining asymmetric, neurogenic divisions of radial glial cells (RGCs), evolved adaptively during anthropoid evolution. We explored how this selection relates to neural phenotypes and find a significant association between selection on NIN and neonatal brain size in catarrhines. Our analyses suggest a relationship with prenatal neurogenesis and identify the human data point as an outlier, possibly explained by postnatal changes in development on the human lineage. A similar pattern is found in platyrrhines, but the highly encephalized genus Cebus departs from the general trend. We further show that the evolution of NIN may be associated with variation in neuron number not explained by increases in surface area, a result consistent with NIN's role in neurogenic divisions of RGCs. Our combined results suggest a role for NIN in the evolution of cortical development.

  20. Positive selection systems for discovery of novel polyester biosynthesis genes based on fatty acid detoxification.

    PubMed Central

    Kranz, R G; Gabbert, K K; Madigan, M T

    1997-01-01

    The photosynthetic bacterium Rhodobacter capsulatus can grow with short- to long-chain fatty acids as the sole carbon source (R. G. Kranz, K. K. Gabbert, T. A. Locke, and M. T. Madigan, Appl. Environ. Microbiol. 63:3003-3009, 1997). Concomitant with growth on fatty acids is the production to high levels of the polyester storage compounds called polyhydroxyalkanoates (PHAs). Here, we describe colony screening and selection systems to analyze the production of PHAs in R. capsulatus. A screen with Nile red dissolved in acetone distinguishes between PHA producers and nonproducers. Unlike the wild type, an R. capsulatus PhaC- strain with the gene encoding PHA synthase deleted is unable to grow on solid media containing high concentrations of certain fatty acids. It is proposed that this deficiency is due to the inability of the PhaC- strain to detoxify the surrounding medium by consumption of fatty acids and their incorporation into PHAs. This fatty acid toxicity phenotype is used in selection for the cloning and characterization of heterologous phaC genes. PMID:9251190

  1. How the CCA-Adding Enzyme Selects Adenine over Cytosine at Position 76 of tRNA

    SciTech Connect

    Pan, Baocheng; Xiong, Yong; Steitz, Thomas A.

    2010-11-22

    CCA-adding enzymes [ATP(CTP):tRNA nucleotidyltransferases] add CCA onto the 3{prime} end of transfer RNA (tRNA) precursors without using a nucleic acid template. Although the mechanism by which cytosine (C) is selected at position 75 of tRNA has been established, the mechanism by which adenine (A) is selected at position 76 remains elusive. Here, we report five cocrystal structures of the enzyme complexed with both a tRNA mimic and nucleoside triphosphates under catalytically active conditions. These structures suggest that adenosine 5{prime}-monophosphate is incorporated onto the A76 position of the tRNA via a carboxylate-assisted, one-metal-ion mechanism with aspartate 110 functioning as a general base. The discrimination against incorporation of cytidine 5{prime}-triphosphate (CTP) at position 76 arises from improper placement of the {alpha} phosphate of the incoming CTP, which results from the interaction of C with arginine 224 and prevents the nucleophilic attack by the 3{prime} hydroxyl group of cytidine75.

  2. How the CCA-Adding Enzyme Selects Adenine over Cytosine at Position 76 of tRNA

    SciTech Connect

    B Pan; Y Xiong; T Steitz

    2011-12-31

    CCA-adding enzymes [ATP(CTP):tRNA nucleotidyltransferases] add CCA onto the 3' end of transfer RNA (tRNA) precursors without using a nucleic acid template. Although the mechanism by which cytosine (C) is selected at position 75 of tRNA has been established, the mechanism by which adenine (A) is selected at position 76 remains elusive. Here, we report five cocrystal structures of the enzyme complexed with both a tRNA mimic and nucleoside triphosphates under catalytically active conditions. These structures suggest that adenosine 5'-monophosphate is incorporated onto the A76 position of the tRNA via a carboxylate-assisted, one-metal-ion mechanism with aspartate 110 functioning as a general base. The discrimination against incorporation of cytidine 5'-triphosphate (CTP) at position 76 arises from improper placement of the {alpha} phosphate of the incoming CTP, which results from the interaction of C with arginine 224 and prevents the nucleophilic attack by the 3' hydroxyl group of cytidine75.

  3. Sexual orientation and spatial position effects on selective forms of object location memory.

    PubMed

    Rahman, Qazi; Newland, Cherie; Smyth, Beatrice Mary

    2011-04-01

    Prior research has demonstrated robust sex and sexual orientation-related differences in object location memory in humans. Here we show that this sexual variation may depend on the spatial position of target objects and the task-specific nature of the spatial array. We tested the recovery of object locations in three object arrays (object exchanges, object shifts, and novel objects) relative to veridical center (left compared to right side of the arrays) in a sample of 35 heterosexual men, 35 heterosexual women, and 35 homosexual men. Relative to heterosexual men, heterosexual women showed better location recovery in the right side of the array during object exchanges and homosexual men performed better in the right side during novel objects. However, the difference between heterosexual and homosexual men disappeared after controlling for IQ. Heterosexual women and homosexual men did not differ significantly from each other in location change detection with respect to task or side of array. These data suggest that visual space biases in processing categorical spatial positions may enhance aspects of object location memory in heterosexual women.

  4. Multi-scale textural feature extraction and particle swarm optimization based model selection for false positive reduction in mammography.

    PubMed

    Zyout, Imad; Czajkowska, Joanna; Grzegorzek, Marcin

    2015-12-01

    The high number of false positives and the resulting number of avoidable breast biopsies are the major problems faced by current mammography Computer Aided Detection (CAD) systems. False positive reduction is not only a requirement for mass but also for calcification CAD systems which are currently deployed for clinical use. This paper tackles two problems related to reducing the number of false positives in the detection of all lesions and masses, respectively. Firstly, textural patterns of breast tissue have been analyzed using several multi-scale textural descriptors based on wavelet and gray level co-occurrence matrix. The second problem addressed in this paper is the parameter selection and performance optimization. For this, we adopt a model selection procedure based on Particle Swarm Optimization (PSO) for selecting the most discriminative textural features and for strengthening the generalization capacity of the supervised learning stage based on a Support Vector Machine (SVM) classifier. For evaluating the proposed methods, two sets of suspicious mammogram regions have been used. The first one, obtained from Digital Database for Screening Mammography (DDSM), contains 1494 regions (1000 normal and 494 abnormal samples). The second set of suspicious regions was obtained from database of Mammographic Image Analysis Society (mini-MIAS) and contains 315 (207 normal and 108 abnormal) samples. Results from both datasets demonstrate the efficiency of using PSO based model selection for optimizing both classifier hyper-parameters and parameters, respectively. Furthermore, the obtained results indicate the promising performance of the proposed textural features and more specifically, those based on co-occurrence matrix of wavelet image representation technique.

  5. Selective internalization of self-assembled artificial oil bodies by HER2/neu-positive cells

    NASA Astrophysics Data System (ADS)

    Chiang, Chung-Jen; Lin, Li-Jen; Lin, Che-Chin; Chang, Chih-Hsiang; Chao, Yun-Peng

    2011-01-01

    A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent anti-HER2/neu affibody domain (ZH2) was fused with Ole at the C terminus. After overproduction in Escherichia coli, the fusion protein (Ole-ZH2) was recovered to assemble AOBs. The size of self-assembled AOBs was tailored by varying the oil/Ole-ZH2 ratio and pH to reach a nanoscale. Upon co-incubation with tumor cells, the nanoscale AOBs encapsulated with a hydrophobic fluorescence dye were selectively internalized by HER2/neu-overexpressing cells and displayed biocompatibility with the cells. In addition, the ZH2-mediated endosomal entry of AOBs occurred in a time- and AOB dose-dependent manner. The internalization efficiency was as high as 90%. The internalized AOBs disintegrated at the non-permissive pH (e.g. in acidic endosomes) and the cargo dye was released. Results of in vitro study revealed a sustained and prolonged release profile. Taken together, our findings indicate the potential of AOBs as a delivery carrier.

  6. Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2

    PubMed Central

    Rytelewski, Mateusz; Vareki, Saman Maleki; Mangala, Lingegowda S.; Romanow, Larissa; Jiang, Dahai; Pradeep, Sunila; Rodriguez-Aguayo, Christian; Lopez-Berestein, Gabriel; Figueredo, Rene; Ferguson, Peter J.; Vincent, Mark; Sood, Anil K.; Koropatnick, James D.

    2016-01-01

    Human tumor heterogeneity promotes therapeutic failure by increasing the likelihood of resistant cell subpopulations. The PARP-1 inhibitor olaparib is approved for use in BRCA-mutated ovarian cancers but BRCA2-reversion mutations lead to functional homologous recombination repair (HRR) and olaparib resistance. To overcome that resistance and expand use of PARP1 inhibition to cancers with functional HRR, we developed an antisense strategy to render the majority of tumor cells in a population BRCA2-deficient. We predicted that this strategy would render HRR-proficient tumor cells sensitive to olaparib and prevent emergence of resistance in a tumor cell population heterogeneous for HRR proficiency. We report that BRCA2 downregulation sensitized multiple human tumor cell lines (but not non-cancer human kidney cells) to olaparib and, combined with olaparib, increased aneuploidy and chromosomal translocations in human tumor cells. In a mixed HRR-proficient and HRR-deficient cell population, olaparib monotherapy allowed outgrowth of HRR-proficient cells resistant to subsequent olaparib treatment. Combined BRCA2 inhibition and olaparib treatment prevented selection of HRR-proficient cells and inhibited proliferation of the entire population. Treatment with BRCA2 siRNA and olaparib decreased ovarian xenograft growth in mice more effectively than either treatment alone. In vivo use of BRCA2 antisense oligonucleotides may be a viable option to expand clinical use of olaparib and prevent resistance. PMID:26959114

  7. Positive selection of co-opted mobile genetic elements in a mammalian gene

    PubMed Central

    Franchini, Lucia F.; de Souza, Flavio S.J.; Low, Malcolm J.; Rubinstein, Marcelo

    2012-01-01

    The proopiomelanocortin (Pomc) gene encodes a prepropeptide with essential functions in the response to stress and energy balance, which is expressed in the pituitary and hypothalamus of vertebrate animals. Neuronal expression of Pomc is controlled by two distal enhancers named nPE1 and nPE2. Using transgenic mice, we observed that both enhancers drive identical expression patterns in the mammalian hypothalamus, starting at embryonic day 10.5, when endogenous Pomc expression commences. This overlapping enhancer activity is maintained throughout hypothalamic development and into adulthood. We also found that nPE1 and nPE2 were exapted as neuronal enhancers into the POMC locus after the sequential insertion of two unrelated retroposons. Thus, nPE1 and nPE2 are functional analogs and represent an authentic first example of convergent molecular evolution of cell-specific transcriptional enhancers. In this Commentary we discuss the following questions that remain unanswered: (1) how does transcriptional control of POMC operate in hypothalamic neurons of non-mammalian vertebrates? (2) What evolutionary forces are maintaining two discrete neuronal POMC enhancers under purifying selection for the last ~100 million years in all placental mammals? (3) What is the contribution of MaLRs to genome evolution? PMID:22934245

  8. Positive selection of the TRIM family regulatory region in primate genomes.

    PubMed

    He, Dan-Dan; Lu, Yueer; Gittelman, Rachel; Jin, Yabin; Ling, Fei; Joshua, Akey

    2016-10-12

    Viral selection pressure has acted on restriction factors that play an important role in the innate immune system by inhibiting the replication of viruses during primate evolution. Tripartite motif-containing (TRIM) family members are some of these restriction factors. It is becoming increasingly clear that gene expression differences, rather than protein-coding regions changes, could play a vital role in the anti-retroviral immune mechanism. Increasingly, recent studies have created genome-scale catalogues of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To improve our understanding of the molecular evolution mechanism of antiviral differences between species, we leveraged 14 130 DHSs derived from 145 cell types to characterize the regulatory landscape of the TRIM region. Subsequently, we compared the alignments of the DHSs across six primates and found 375 DHSs that are conserved in non-human primates but exhibit significantly accelerated rates of evolution in the human lineage (haDHSs). Furthermore, we discovered 31 human-specific potential transcription factor motifs within haDHSs, including the KROX and SP1, that both interact with HIV-1 Importantly, the corresponding haDHS was correlated with antiviral factor TRIM23 Thus, our results suggested that some viruses may contribute, through regulatory DNA differences, to organismal evolution by mediating TRIM gene expression to escape immune surveillance.

  9. A design of a valid signal selecting and position decoding ASIC for PET using silicon photomultipliers

    NASA Astrophysics Data System (ADS)

    Cho, M.; Lim, K.-t.; Kim, H.; Yeom, J.-y.; Kim, J.; Lee, C.; Choi, H.; Cho, G.

    2017-01-01

    In most cases, a PET system has numerous electrical components and channel circuits and thus it would rather be a bulky product. Also, most existing systems receive analog signals from detectors which make them vulnerable to signal distortions. For these reasons, channel reduction techniques are important. In this work, an ASIC for PET module is being proposed. An ASIC chip for 16 PET detector channels, VSSPDC, has been designed and simulated. The main function of the chip is 16-to-1 channel reduction, i.e., finding the position of only the valid signals, signal timing, and magnitudes in all 16 channels at every recorded event. The ASIC comprises four of 4-channel modules and a 2nd 4-to-1 router. A single channel module comprises a transimpedance amplifier for the silicon photomultipliers, dual comparators with high and low level references, and a logic circuitry. While the high level reference was used to test the validity of the signal, the low level reference was used for the timing. The 1-channel module of the ASIC produced an energy pulse by time-over-threshold method and it also produced a time pulse with a fixed delayed time. Since the ASIC chip outputs only a few digital pulses and does not require an external clock, it has an advantage over noise properties. The cadence simulation showed the good performance of the chip as designed.

  10. Inhibition of caspases prevents ototoxic and ongoing hair cell death

    NASA Technical Reports Server (NTRS)

    Matsui, Jonathan I.; Ogilvie, Judith M.; Warchol, Mark E.

    2002-01-01

    Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

  11. Positive selection of a duplicated UV-sensitive visual pigment coincides with wing pigment evolution in Heliconius butterflies

    PubMed Central

    Briscoe, Adriana D.; Bybee, Seth M.; Bernard, Gary D.; Yuan, Furong; Sison-Mangus, Marilou P.; Reed, Robert D.; Warren, Andrew D.; Llorente-Bousquets, Jorge; Chiao, Chuan-Chin

    2010-01-01

    The butterfly Heliconius erato can see from the UV to the red part of the light spectrum with color vision proven from 440 to 640 nm. Its eye is known to contain three visual pigments, rhodopsins, produced by an 11-cis-3-hydroxyretinal chromophore together with long wavelength (LWRh), blue (BRh) and UV (UVRh1) opsins. We now find that H. erato has a second UV opsin mRNA (UVRh2)—a previously undescribed duplication of this gene among Lepidoptera. To investigate its evolutionary origin, we screened eye cDNAs from 14 butterfly species in the subfamily Heliconiinae and found both copies only among Heliconius. Phylogeny-based tests of selection indicate positive selection of UVRh2 following duplication, and some of the positively selected sites correspond to vertebrate visual pigment spectral tuning residues. Epi-microspectrophotometry reveals two UV-absorbing rhodopsins in the H. erato eye with λmax = 355 nm and 398 nm. Along with the additional UV opsin, Heliconius have also evolved 3-hydroxy-DL-kynurenine (3-OHK)-based yellow wing pigments not found in close relatives. Visual models of how butterflies perceive wing color variation indicate this has resulted in an expansion of the number of distinguishable yellow colors on Heliconius wings. Functional diversification of the UV-sensitive visual pigments may help explain why the yellow wing pigments of Heliconius are so colorful in the UV range compared to the yellow pigments of close relatives lacking the UV opsin duplicate. PMID:20133601

  12. Selection of HyspIRI optimal band positions for the earth compositional mapping using HyTES data

    NASA Astrophysics Data System (ADS)

    Ullah, Saleem; Khalid, Noora; Iqbal, Arshad

    2016-07-01

    In near future, NASA/JPL will orbit a new space-borne sensor called HyspIRI (Hyperspectral and Infrared Imager) which will cover the spectral range from 0.4 -14μm. Two instruments will be mounted on HyspIRI platform; one is hyperspectral instrument which can sense earth surface between 0.4-2.5μm with 10 nm intervals and a multispectral TIR sensor will acquire images between 3 to 14μm in 8 (1 in MIR and 7 in TIR) spectral bands. The TIR spectral wavebands will be positioned based on their importance in various applications. This study aimed to find HyspIRI optimal TIR wavebands position for earth compositional mapping. Genetic algorithms coupled with Spectral Angle Mapper (GA-SAM) were used as spectral bands selector. High dimensional HyTES (Hyperspectral Thermal Emission Spectrometer) data comprised of 256 spectral bands of Cuprite and Death Valley regions were used to select meaningful subsets of bands for earth compositional mapping. The GA-SAM was trained for eight mineral classes and the algorithms were run iteratively 40 times. High calibration (> 98 %) and validation (> 96 %) accuracies were achieved with limited numbers (seven) of spectral bands selected by GA-SAM. Knowing the important band positions will help scientist of HyspIRI group to place spectral bands at regions were accuracies of earth compositional mapping can be enhanced.

  13. The multigenic structure of the MHC locus contributes to positive selection efficiency: a role for MHC class II gene-specific restriction.

    PubMed

    Monteiro, Miguel Caetano; Couceiro, Sofia; Penha-Gonçalves, Carlos

    2005-12-01

    The study of T cell positive selection in the thymus has long been focused on the specificity of the MHC-TCR interactions, making use of genetically manipulated mice that display TCR specificities or selecting peptides of limited diversity. However, little is known on the role of the MHC molecules irrespective of the peptide specificity and the implications of MHC multigenic structure in thymic positive selection have not been addressed. Here, we investigated the effect of MHC class II genetic configuration on the positive selection efficiency of naturally generated pre-selection repertoires in the mouse thymus. Analysis of positively selected thymocyte populations in MHC-congenic and -transgenic mice revealed that expression of I-E molecule in the thymic cortex increases positive selection efficiency of CD4 cells by approximately 50%. We show that increments in positive selection attributable to either the I-A and I-E genes are not due to increased MHC class II expression in the thymic cortex and are not affected by the number of MHC alleles. Collectively, our findings imply that MHC class II gene-restricted TCR specificities significantly contribute to positive selection efficiency, introducing the notion that multigenic structure of the MHC locus serves to increase selection of non-overlapping TCR repertoires.

  14. Selective GABAA α5 Positive Allosteric Modulators Improve Cognitive Function in Aged Rats with Memory Impairment

    PubMed Central

    Koh, Ming Teng; Rosenzweig-Lipson, Sharon; Gallagher, Michela

    2012-01-01

    A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer’s disease. Compounds that act as positive allosteric modulators at GABAA α5 receptors might be useful in targeting this condition because GABAA α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABAA α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABAA α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 μg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. PMID:22732440

  15. Genomic resources and their influence on the detection of the signal of positive selection in genome scans.

    PubMed

    Manel, S; Perrier, C; Pratlong, M; Abi-Rached, L; Paganini, J; Pontarotti, P; Aurelle, D

    2016-01-01

    Genome scans represent powerful approaches to investigate the action of natural selection on the genetic variation of natural populations and to better understand local adaptation. This is very useful, for example, in the field of conservation biology and evolutionary biology. Thanks to Next Generation Sequencing, genomic resources are growing exponentially, improving genome scan analyses in non-model species. Thousands of SNPs called using Reduced Representation Sequencing are increasingly used in genome scans. Besides, genome sequences are also becoming increasingly available, allowing better processing of short-read data, offering physical localization of variants, and improving haplotype reconstruction and data imputation. Ultimately, genome sequences are also becoming the raw material for selection inferences. Here, we discuss how the increasing availability of such genomic resources, notably genome sequences, influences the detection of signals of selection. Mainly, increasing data density and having the information of physical linkage data expand genome scans by (i) improving the overall quality of the data, (ii) helping the reconstruction of demographic history for the population studied to decrease false-positive rates and (iii) improving the statistical power of methods to detect the signal of selection. Of particular importance, the availability of a high-quality reference genome can improve the detection of the signal of selection by (i) allowing matching the potential candidate loci to linked coding regions under selection, (ii) rapidly moving the investigation to the gene and function and (iii) ensuring that the highly variable regions of the genomes that include functional genes are also investigated. For all those reasons, using reference genomes in genome scan analyses is highly recommended.

  16. Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.

    PubMed

    Byun, Nellie E; Grannan, Michael; Bubser, Michael; Barry, Robert L; Thompson, Analisa; Rosanelli, John; Gowrishankar, Raajaram; Kelm, Nathaniel D; Damon, Stephen; Bridges, Thomas M; Melancon, Bruce J; Tarr, James C; Brogan, John T; Avison, Malcolm J; Deutch, Ariel Y; Wess, Jürgen; Wood, Michael R; Lindsley, Craig W; Gore, John C; Conn, P Jeffrey; Jones, Carrie K

    2014-06-01

    Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis

  17. Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

    PubMed Central

    Byun, Nellie E; Grannan, Michael; Bubser, Michael; Barry, Robert L; Thompson, Analisa; Rosanelli, John; Gowrishankar, Raajaram; Kelm, Nathaniel D; Damon, Stephen; Bridges, Thomas M; Melancon, Bruce J; Tarr, James C; Brogan, John T; Avison, Malcolm J; Deutch, Ariel Y; Wess, Jürgen; Wood, Michael R; Lindsley, Craig W; Gore, John C; Conn, P Jeffrey; Jones, Carrie K

    2014-01-01

    Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis

  18. Positive selection of Kranz and non-Kranz C4 phosphoenolpyruvate carboxylase amino acids in Suaedoideae (Chenopodiaceae).

    PubMed

    Rosnow, Josh J; Edwards, Gerald E; Roalson, Eric H

    2014-07-01

    In subfamily Suaedoideae, four independent gains of C4 photosynthesis are proposed, which includes two parallel origins of Kranz anatomy (sections Salsina and Schoberia) and two independent origins of single-cell C4 anatomy (Bienertia and Suaeda aralocaspica). Additional phylogenetic support for this hypothesis was generated from sequence data of the C-terminal portion of the phosphoenolpyruvate carboxylase (PEPC) gene used in C4 photosynthesis (ppc-1) in combination with previous sequence data. ppc-1 sequence was generated for 20 species in Suaedoideae and two outgroup Salsola species that included all types of C4 anatomies as well as two types of C3 anatomies. A branch-site test for positively selected codons was performed using the software package PAML. From labelling of the four branches where C4 is hypothesized to have developed (foreground branches), residue 733 (maize numbering) was identified to be under positive selection with a posterior probability >0.99 and residue 868 at the >0.95 interval using Bayes empirical Bayes (BEB). When labelling all the branches within C4 clades, the branch-site test identified 13 codons to be under selection with a posterior probability >0.95 by BEB; this is discussed considering current information on functional residues. The signature C4 substitution of an alanine for a serine at position 780 in the C-terminal end (which is considered a major determinant of affinity for PEP) was only found in four of the C4 species sampled, while eight of the C4 species and all the C3 species have an alanine residue; indicating that this substitution is not a requirement for C4 function.

  19. Positive Darwinian Selection in the Piston That Powers Proton Pumps in Complex I of the Mitochondria of Pacific Salmon

    PubMed Central

    Garvin, Michael R.; Bielawski, Joseph P.; Gharrett, Anthony J.

    2011-01-01

    The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm. PMID:21969854

  20. Ongoing Fixed Wing Research within the NASA Langley Aeroelasticity Branch

    NASA Technical Reports Server (NTRS)

    Bartels, Robert; Chwalowski, Pawel; Funk, Christie; Heeg, Jennifer; Hur, Jiyoung; Sanetrik, Mark; Scott, Robert; Silva, Walter; Stanford, Bret; Wiseman, Carol

    2015-01-01

    The NASA Langley Aeroelasticity Branch is involved in a number of research programs related to fixed wing aeroelasticity and aeroservoelasticity. These ongoing efforts are summarized here, and include aeroelastic tailoring of subsonic transport wing structures, experimental and numerical assessment of truss-braced wing flutter and limit cycle oscillations, and numerical modeling of high speed civil transport configurations. Efforts devoted to verification, validation, and uncertainty quantification of aeroelastic physics in a workshop setting are also discussed. The feasibility of certain future civil transport configurations will depend on the ability to understand and control complex aeroelastic phenomena, a goal that the Aeroelasticity Branch is well-positioned to contribute through these programs.

  1. Recent Positive Selection Drives the Expansion of a Schizophrenia Risk Nonsynonymous Variant at SLC39A8 in Europeans

    PubMed Central

    Li, Ming; Wu, Dong-Dong; Yao, Yong-Gang; Huo, Yong-Xia; Liu, Jie-Wei; Su, Bing; Chasman, Daniel I.; Chu, Audrey Y.; Huang, Tao; Qi, Lu; Zheng, Yan; Luo, Xiong-Jian

    2016-01-01

    Natural selection has played important roles in optimizing complex human adaptations. However, schizophrenia poses an evolutionary paradox during human evolution, as the illness has strongly negative effects on fitness, but persists with a prevalence of ~0.5% across global populations. Recent studies have identified numerous risk variations in diverse populations, which might be able to explain the stable and high rate of schizophrenia morbidity in different cultures and regions, but the questions about why the risk alleles derived and maintained in human gene pool still remain unsolved. Here, we studied the evolutionary pattern of a schizophrenia risk variant rs13107325 (P < 5.0×10−8 in Europeans) in the SLC39A8 gene. We found the SNP is monomorphic in Asians and Africans with risk (derived) T-allele totally absent, and further evolutionary analyses showed the T-allele has experienced recent positive selection in Europeans. Subsequent exploratory analyses implicated that the colder environment in Europe was the likely selective pressures, ie, when modern humans migrated “out of Africa” and moved to Europe mainland (a colder and cooler continent than Africa), new alleles derived due to positive selection and protected humans from risk of hypertension and also helped them adapt to the cold environment. The hypothesis was supported by our pleiotropic analyses with hypertension and energy intake as well as obesity in Europeans. Our data thus provides an intriguing example to illustrate a possible mechanism for maintaining schizophrenia risk alleles in the human gene pool, and further supported that schizophrenia is likely a product caused by pleiotropic effect during human evolution. PMID:26006263

  2. Selective Anti-Proliferation of HER2-Positive Breast Cancer Cells by Anthocyanins Identified by High-Throughput Screening

    PubMed Central

    Liu, Weihua; Xu, Jinmei; Wu, Shaoping; Liu, Yilun; Yu, Xiaoping; Chen, Juan; Tang, Xi; Wang, Zhi; Zhu, Xiaohu; Li, Xin

    2013-01-01

    Overexpressed Human epidermal growth factor receptor 2 (HER2) drives the biology of 20% breast cancer and is a prediction of a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients. Traditional Chinese herbs/medicines have been used to treat breast cancer patients including HER2-positive patients in Asia for decades. Although the traditional medicines demonstrate efficacy in clinics for HER2-positive patients, the mechanism is largely unknown. In this article, we screened a 10,000 natural product library in 6 different cell lines representing breast cancer, and assessed the ability of each drug to cause cytotoxicity through a high-throughput screening approach. We have identified eight natural compounds that selectively inhibit the proliferation of HER2-positive cells. Two of the hit compounds, peonidin-3-glucoside and cyaniding-3-glucoside, are both extracts from black rice. They inhibit the phospho-HER2 and phospho-AKT and were confirmed to induce HER2-psotive breast cancer cells apoptosis both in vitro and in vivo. Peonidin-3-glucoside and cyaniding-3-glucoside treatments significantly reduced the tumor size and volume in vivo compared to the control group. There is no significant difference of antitumorgenic effects between peonidin-3-glucoside and cyaniding-3-glucoside treatments. PMID:24312561

  3. Evidence of positive selection and concerted evolution in the rapidly evolving PRDM9 zinc finger domain in goats and sheep.

    PubMed

    Ahlawat, S; Sharma, P; Sharma, R; Arora, R; Verma, N K; Brahma, B; Mishra, P; De, S

    2016-12-01

    Meiotic recombination contributes to augmentation of genetic diversity, exclusion of deleterious alleles and proper segregation of chromatids. PRDM9 has been identified as the gene responsible for specifying the location of recombination hotspots during meiosis and is also the only known vertebrate gene associated with reproductive isolation between species. PRDM9 encodes a protein with a highly variable zinc finger (ZF) domain that varies between as well as within species. In the present study, the ZF domain of PRDM9 on chromosome 1 was characterized for the first time in 15 goat breeds and 25 sheep breeds of India. A remarkable variation in the number and sequence of ZF domains was observed. The number of ZF repeats in the ZF array varied from eight to 12 yielding five homozygous and 10 heterozygous genotypes. The number of different ZF domains was 84 and 52 producing 36 and 26 unique alleles in goats and sheep respectively. The posterior mean of dN/dS or omega values were calculated using the codeml tool of pamlx to identify amino acids that are evolving positively in goats and sheep, as positions -1, +3 and +6 in the ZF domain have been reported to experience strong positive selection across different lineages. Our study identified sites -5, -1, +3, +4 and +6 to be experiencing positive selection. Small ruminant zinc fingers were also found to be evolving under concerted evolution. Our results demonstrate the existence of a vast diversity of PRDM9 in goats and sheep, which is in concert with reports in many metazoans.

  4. Different positively selected sites at the gametophytic self-incompatibility pistil S-RNase gene in the Solanaceae and Rosaceae (Prunus, Pyrus, and Malus).

    PubMed

    Vieira, Jorge; Morales-Hojas, Ramiro; Santos, Raquel A M; Vieira, Cristina P

    2007-08-01

    In this work we perform a comparative study on the location of positively selected sites (those likely responsible for defining specificity differences) at the S-RNase gene, the pistil component of the gametophytic self-incompatibility system. For Plantaginaceae and Rosaceae (Prunus and Pyrus/Malus) this is the first study of this kind. A clear sign of positive selection was observed for 13, 17, and 27 amino acid sites in Solanaceae, Prunus, and Pyrus/Malus, respectively, using two different methodologies. In Plantaginaceae no clear positively selected sites were identified. Possible reasons for this result are discussed. Indirect experimental evidence suggests that the identified positively selected amino acid sites play a role in specificity determination. The percentage of positively selected sites is similar in Solanaceae and Rosaceae but the location of those sites is different.

  5. Natural resistance to experimental feline infectious peritonitis virus infection is decreased rather than increased by positive genetic selection.

    PubMed

    Pedersen, Niels C; Liu, Hongwei; Durden, Monica; Lyons, Leslie A

    2016-03-01

    A previous study demonstrated the existence of a natural resistance to feline infectious peritonitis virus (FIPV) among 36% of randomly bred laboratory cats. A genome wide association study (GWAS) on this population suggested that resistance was polygenic but failed to identify any strong specific associations. In order to enhance the power of GWAS or whole genome sequencing to identify strong genetic associations, a decision was made to positively select for resistance over three generations. The inbreeding experiment began with a genetically related parental (P) population consisting of three toms and four queens identified from among the survivors of the earlier study and belonging to a closely related subgroup (B). The subsequent effects of inbreeding were measured using 42 genome-wide STR markers. P generation cats produced 57 first filial (F1) kittens, only five of which (9.0%) demonstrated a natural resistance to FIPV infection. One of these five F1 survivors was then used to produce six F1/P-backcrosses kittens, only one of which proved resistant to FIP. Six of eight of the F1 and F1/P survivors succumbed to a secondary exposure 4-12 months later. Therefore, survival after both primary and secondary infection was decreased rather than increased by positive selection for resistance. The common genetic factor associated with this diminished resistance was a loss of heterozygosity.

  6. Positive selection, molecular recombination structure and phylogenetic reconstruction of members of the family Tombusviridae: Implication in virus taxonomy.

    PubMed

    Boulila, Moncef

    2011-10-01

    A detailed study of putative recombination events and their evolution frequency in the whole genome of the currently known members of the family Tombusviridae, comprising 79 accessions retrieved from the international databases, was carried out by using the RECCO and RDP version 3.31β algorithms. The first program allowed the detection of potential recombination sites in seven out of eight virus genera (Aureusvirus, Avenavirus, Carmovirus, Dianthovirus, Necrovirus, Panicovirus, and Tombusvirus), the second program provided the same results except for genus Dianthovirus. On the other hand, both methods failed to detect recombination breakpoints in the genome of members of genus Machlomovirus. Furthermore, based on Fisher's Exact Test of Neutrality, positive selection exerted on protein-coding genes was detected in 17 accession pairs involving 15 different lineages. Except genera Machlomovirus, and Panicovirus along with unclassified Tombusviridae, all the other taxonomical genera and the unassigned Tombusviridae encompassed representatives under positive selection. The evolutionary history of all members of the Tombusviridae family showed that they segregated into eight distinct groups corresponding to the eight genera which constitute this family. The inferred phylogeny reshuffled the classification currently adopted by the International Committee on Taxonomy of Viruses. A reclassification was proposed.

  7. Physiological and anthropometric characteristics of young soccer players according to their playing position: relevance for the selection process.

    PubMed

    Gil, Susana M; Gil, Javier; Ruiz, Fátima; Irazusta, Amaia; Irazusta, Jon

    2007-05-01

    The aim of this study was to establish the anthropometric and physiological profiles of young nonelite soccer players according to their playing position, and to determine their relevance for the selection process. Two hundred forty-one male soccer players who were members of the Getxo Arenas Club (Bizkaia) participated in this study. Players, age 17.31 (+/- 2.64) years, range 14-21 years, were classified into the following groups: forwards (n = 56), midfielders (n = 79), defenders (n = 77), and goalkeepers (n = 29). Anthropometric variables of participants (height, weight, body mass index, 6 skinfolds, 4 diameters, and 3 perimeters) were measured. Also, their somatotype and body composition (weights and percentages of fat, bone, and muscle) were calculated. Participants performed the Astrand test to estimate their absolute and relative VO2max, an endurance test, sprint tests (30 meters flat and 30 meters with 10 cones) and 3 jump tests (squat jump, counter movement jump and drop jump). Forwards were the leanest, presenting the highest percentage of muscle. They were the best performers in all the physiological tests, including endurance, velocity, agility, and power. In contrast, goalkeepers were found to be the tallest and the heaviest players. They also had the largest fat skinfolds and the highest fat percentage, but their aerobic capacity was the lowest. In the selection process, agility and the jump tests were the most discriminating for forwards. In contrast, agility, height, and endurance were the key factors for midfielders. The defenders group was characterized by a lower quantity of fat. Thus, we may conclude that anthropometric and physiological differences exist among soccer players who play in different positions. These differences fit with their different workload in a game. Therefore, training programs should include specific sessions for each positional role.

  8. A qualitative analysis of partner selection, HIV serostatus disclosure, and sexual behaviors among HIV-positive urban men.

    PubMed

    Relf, Michael V; Bishop, Tammi L; Lachat, Maryanne F; Schiavone, Deborah B; Pawlowski, Lora; Bialko, Matthew F; Boozer, Diedre L; Dekker, Debra

    2009-06-01

    Using grounded theory, 18 interviews with HIV-positive urban men were conducted to understand their sexual relationships. Analysis of the verbatim transcripts revealed that regardless of age, sexual orientation or race/ethnicity, the participants were "making choices" related to their sexual relationships. Some men were "avoiding sex" whereas others were engaging in "just sex" or having sex in a relationship that was "going somewhere." However, dependent upon the type of sexual relationship, these HIV-positive urban men struggled with issues associated with "disclosure" of serostatus, the sexual "behaviors" in which they engaged, and selecting sexual "partners." Health care providers can facilitate sexual health and well-being among HIV-positive urban men by recognizing that men may be seeking sexual intimacy for different purposes, in different types of relationships, or avoiding it entirely. By exploring these decision-making processes, it is possible to facilitate sexual relationships that prevent new infections as well as manage the dissonance associated with this decision-making associated with disclosure, behaviors and their sexual partners.

  9. Meta-analysis of age and skill effects on recalling chess positions and selecting the best move.

    PubMed

    Moxley, Jerad H; Charness, Neil

    2013-10-01

    A meta-analysis was conducted of studies that measured the effects of both age and skill in chess on the tasks of selecting the best move for chess positions (the best move task) as well as recalling chess game positions (the recall task). Despite a small sample of studies, we demonstrated that there are age and skill effects on both tasks: age being negatively associated with performance on both tasks and skill being positively associated with performance on both tasks. On the best move task, we found that skill was the dominant effect, while on the recall task, skill and age were approximately equally strong effects. We also found that skill was best measured by the best move task. In the case of the best move task, this result is consistent with the argument that it accurately replicates expert performance (Ericsson & Smith, 1991). Results for the recall task argue that this task captures effects related to skill, but also effects likely due to a general aging process. Implications for our understanding of aging in skilled domains are also discussed.

  10. HIV-positive patients’ perceptions of care received at a selected antiretroviral therapy clinic in Vhembe district, South Africa

    PubMed Central

    Ndou, Tshifhiwa V.; Risenga, Patrone R.

    2016-01-01

    Background Patients’ experiences are a reflection of what has happened during the care process and, therefore, provide information about the performance of health care professional workers. They refer to the process of care provision at the antiretroviral therapy (ART) sites. Aim and setting This article explored the perceptions of HIV-positive patients of care received at the Gateway Clinic of the regional hospital that provides antiretroviral treatment in the Vhembe district. Methods A qualitative, explorative and descriptive design was used. A non-probability, convenient sampling method was used to select 20 HIV-positive patients who were above 18 years of age. In-depth individual interviews were used to collect data. Data were analysed through Tech’s open coding method. Results One theme and two sub-themes emerged, namely positive experiences related to the environment and attitudes of health professionals, and negative experiences concerning the practices by health care providers. Conclusion Patients’ perceptions of quality of, and satisfaction with, health care may affect health outcomes. Recommendations are made to consider, practice and strengthen the protocols, the standard operating procedures and the principles of infection control in the health facilities. PMID:27380841

  11. Anencephaly: An Ongoing Investigation in Washington State.

    PubMed

    Barron, Sara

    2016-03-01

    : In the spring of 2012, a nurse in Washington State detected a cluster of babies born with anencephaly-a fatal condition in which infants are born without parts of the brain or skull. The resulting investigation initially confirmed a rate of anencephaly between January 2010 and January 2013 of 8.4 per 10,000 live births-more than four times the national average. As of November 2015, cases of anencephaly in Washington State have continued to increase, with the current rate estimated at 9.5 per 10,000 live births. While no distinct cause has yet been determined, neural tube defects-including anencephaly-are known to have multiple causes, including folic acid deficit, genetic variants in the folate pathway, and exposure to a variety of environmental and occupational toxins. This article describes many of these risk factors and explores the findings of Washington's ongoing investigation.

  12. The Fukushima nuclear disaster is ongoing

    PubMed Central

    Marks, Andrew R.

    2016-01-01

    The 5th anniversary of the Fukushima disaster and the 30th anniversary of the Chernobyl disaster, the two most catastrophic nuclear accidents in history, both occurred recently. Images of Chernobyl are replete with the international sign of radioactive contamination (a circle with three broad spokes radiating outward in a yellow sign). In contrast, ongoing decontamination efforts at Fukushima lack international warnings about radioactivity. Decontamination workers at Fukushima appear to be poorly protected against radiation. It is almost as if the effort is to make the Fukushima problem disappear. A more useful response would be to openly acknowledge the monumental problems inherent in managing a nuclear plant disaster. Lessons from Chernobyl are the best predictors of what the Fukushima region of Japan is coping with in terms of health and environmental problems following a nuclear catastrophe. PMID:27214552

  13. Ongoing challenges in the management of malaria

    PubMed Central

    Kokwaro, Gilbert

    2009-01-01

    This article gives an overview of some of the ongoing challenges that are faced in the prevention, diagnosis and treatment of malaria. Malaria causes approximately 881,000 deaths every year, with nine out of ten deaths occurring in sub-Saharan Africa. In addition to the human burden of malaria, the economic burden is vast. It is thought to cost African countries more than US$12 billion every year in direct losses. However, great progress in malaria control has been made in some highly endemic countries. Vector control is assuming a new importance with the significant reductions in malaria burden achieved using combined malaria control interventions in countries such as Zanzibar, Zambia and Rwanda. The proportion of patients treated for malaria who have a confirmed diagnosis is low in Africa compared with other regions of the world, with the result that anti-malarials could be used to treat patients without malaria, especially in areas where progress has been made in reducing the malaria burden and malaria epidemiology is changing. Inappropriate administration of anti-malarials could contribute to the spread of resistance and incurs unnecessary costs. Parasite resistance to almost all commonly used anti-malarials has been observed in the most lethal parasite species, Plasmodium falciparum. This has presented a major barrier to successful disease management in malaria-endemic areas. ACT (artemisinin-based combination therapy) has made a significant contribution to malaria control and to reducing disease transmission through reducing gametocyte carriage. Administering ACT to infants and small children can be difficult and time consuming. Specially formulating anti-malarials for this vulnerable population is vital to ease administration and help ensure that an accurate dose is received. Education of healthworkers and communities about malaria prevention, diagnosis and treatment is a vital component of effective case management, especially as diagnostic policies change

  14. Constraints on the richness-mass relation and the optical-SZE positional offset distribution for SZE-selected clusters

    DOE PAGES

    Saro, A.

    2015-10-12

    In this study, we cross-match galaxy cluster candidates selected via their Sunyaev–Zel'dovich effect (SZE) signatures in 129.1 deg2 of the South Pole Telescope 2500d SPT-SZ survey with optically identified clusters selected from the Dark Energy Survey science verification data. We identify 25 clusters between 0.1 ≲ z ≲ 0.8 in the union of the SPT-SZ and redMaPPer (RM) samples. RM is an optical cluster finding algorithm that also returns a richness estimate for each cluster. We model the richness λ-mass relation with the following function 500> ∝ Bλln M500 + Cλln E(z) and use SPT-SZ cluster masses and RM richnessesmore » λ to constrain the parameters. We find Bλ=1.14+0.21–0.18 and Cλ=0.73+0.77–0.75. The associated scatter in mass at fixed richness is σlnM|λ = 0.18+0.08–0.05 at a characteristic richness λ = 70. We demonstrate that our model provides an adequate description of the matched sample, showing that the fraction of SPT-SZ-selected clusters with RM counterparts is consistent with expectations and that the fraction of RM-selected clusters with SPT-SZ counterparts is in mild tension with expectation. We model the optical-SZE cluster positional offset distribution with the sum of two Gaussians, showing that it is consistent with a dominant, centrally peaked population and a subdominant population characterized by larger offsets. We also cross-match the RM catalogue with SPT-SZ candidates below the official catalogue threshold significance ξ = 4.5, using the RM catalogue to provide optical confirmation and redshifts for 15 additional clusters with ξ ε [4, 4.5].« less

  15. Evaluation of five selective media for isolation of catalase-negative gram-positive cocci from bulk tank milk.

    PubMed

    Sawant, Ashish A; Pillai, Shreekumar R; Jayarao, Bhushan M

    2002-05-01

    Five selective media including Edwards modified medium, Edwards modified medium supplemented with colistin sulfate (5 mg/L) and oxolinic acid (2.5 mg/L), Streptococcus selective medium, Streptosel agar, and thallium-crystal violet-toxin-ferric citrate medium were evaluated for the isolation of streptococci and streptococci-like organisms from raw milk. The sensitivity and specificity of these selective media for streptococci and streptococci-like organisms were determined by using American Type Culture Collection reference strains. Under experimental conditions Edwards modified medium with colistin sulfate (5 mg/L) and oxolinic acid (2.5 mg/L) showed the highest sensitivity (100%) and specificity (100%) for streptococci and streptococci-like organisms followed by thallium-crystal violettoxin-ferric citrate medium, Edwards modified medium, Streptococcus selective medium, and Streptosel agar. Edwards modified medium supplemented with colistin sulfate (5 mg/L) and oxolinic acid (2.5 mg/L) allowed growth of all streptococci and streptococci-like organisms, while inhibiting growth of the staphylococci and gram-negative reference strains. Bulk tank milk samples from 114 dairy herds were spiral plated onto Edwards modified medium with colistin sulfate (5 mg/L) and oxolinic acid (2.5 mg/L). A total of 344 isolates (at least three isolates from each sample) were randomly selected and identified to their species. This medium permitted growth of 328 streptococci and streptococci-like organisms belonging to genera Aerococcus, Enterococcus, Gemella, Lactococcus, Streptococcus, and Vagococcus. When Edwards modified medium supplemented with colistin sulfate (5 mg/L) and oxolinic acid (2.5 mg/L) was evaluated using bulk tank milk samples, the sensitivity and specificity of this medium for streptococci and streptococci-like organisms were observed to be 100 and 87.5%, respectively. The positive predictive value for streptococci and streptococci-like organisms was observed to be 99

  16. Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns

    PubMed Central

    Ross, Jenny O.; Melichar, Heather J.; Au-Yeung, Byron B.; Herzmark, Paul; Weiss, Arthur; Robey, Ellen A.

    2014-01-01

    Positive selection of CD8 T cells in the thymus is thought to be a multistep process lasting 3–4 d; however, the discrete steps involved are poorly understood. Here, we examine phenotypic changes, calcium signaling, and intrathymic migration in a synchronized cohort of MHC class I-specific thymocytes undergoing positive selection in situ. Transient elevations in intracellular calcium concentration ([Ca2+]i) and migratory pauses occurred throughout the first 24 h of positive selection, becoming progressively briefer and accompanied by a gradual shift in basal [Ca2+]i over time. Changes in chemokine-receptor expression and relocalization from the cortex to medulla occurred between 12 and 24 h after the initial encounter with positive-selecting ligands, a time frame at which the majority of thymocytes retain CD4 and CD8 expression and still require T-cell receptor (TCR) signaling to efficiently complete positive selection. Our results identify distinct phases in the positive selection of MHC class I-specific thymocytes that are distinguished by their TCR-signaling pattern and intrathymic location and provide a framework for understanding the multistep process of positive selection in the thymus. PMID:24927565

  17. Functional assignment to positively selected sites in the core type III effector RipG7 from Ralstonia solanacearum.

    PubMed

    Wang, Keke; Remigi, Philippe; Anisimova, Maria; Lonjon, Fabien; Kars, Ilona; Kajava, Andrey; Li, Chien-Hui; Cheng, Chiu-Ping; Vailleau, Fabienne; Genin, Stéphane; Peeters, Nemo

    2016-05-01

    The soil-borne pathogen Ralstonia solanacearum causes bacterial wilt in a broad range of plants. The main virulence determinants of R. solanacearum are the type III secretion system (T3SS) and its associated type III effectors (T3Es), translocated into the host cells. Of the conserved T3Es among R. solanacearum strains, the Fbox protein RipG7 is required for R. solanacearum pathogenesis on Medicago truncatula. In this work, we describe the natural ripG7 variability existing in the R. solanacearum species complex. We show that eight representative ripG7 orthologues have different contributions to pathogenicity on M. truncatula: only ripG7 from Asian or African strains can complement the absence of ripG7 in GMI1000 (Asian reference strain). Nonetheless, RipG7 proteins from American and Indonesian strains can still interact with M. truncatula SKP1-like/MSKa protein, essential for the function of RipG7 in virulence. This indicates that the absence of complementation is most likely a result of the variability in the leucine-rich repeat (LRR) domain of RipG7. We identified 11 sites under positive selection in the LRR domains of RipG7. By studying the functional impact of these 11 sites, we show the contribution of five positively selected sites for the function of RipG7CMR15 in M. truncatula colonization. This work reveals the genetic and functional variation of the essential core T3E RipG7 from R. solanacearum. This analysis is the first of its kind on an essential disease-controlling T3E, and sheds light on the co-evolutionary arms race between the bacterium and its hosts.

  18. Ongoing Mars Missions: Extended Mission Plans

    NASA Astrophysics Data System (ADS)

    Zurek, Richard; Diniega, Serina; Crisp, Joy; Fraeman, Abigail; Golombek, Matt; Jakosky, Bruce; Plaut, Jeff; Senske, David A.; Tamppari, Leslie; Thompson, Thomas W.; Vasavada, Ashwin R.

    2016-10-01

    Many key scientific discoveries in planetary science have been made during extended missions. This is certainly true for the Mars missions both in orbit and on the planet's surface. Every two years, ongoing NASA planetary missions propose investigations for the next two years. This year, as part of the 2016 Planetary Sciences Division (PSD) Mission Senior Review, the Mars Odyssey (ODY) orbiter project submitted a proposal for its 7th extended mission, the Mars Exploration Rover (MER-B) Opportunity submitted for its 10th, the Mars Reconnaissance Orbiter (MRO) for its 4th, and the Mars Science Laboratory (MSL) Curiosity rover and the Mars Atmosphere and Volatile Evolution (MVN) orbiter for their 2nd extended missions, respectively. Continued US participation in the ongoing Mars Express Mission (MEX) was also proposed. These missions arrived at Mars in 2001, 2004, 2006, 2012, 2014, and 2003, respectively. Highlights of proposed activities include systematic observations of the surface and atmosphere in twilight (early morning and late evening), building on a 13-year record of global mapping (ODY); exploration of a crater rim gully and interior of Endeavour Crater, while continuing to test what can and cannot be seen from orbit (MER-B); refocused observations of ancient aqueous deposits and polar cap interiors, while adding a 6th Mars year of change detection in the atmosphere and the surface (MRO); exploration and sampling by a rover of mineralogically diverse strata of Mt. Sharp and of atmospheric methane in Gale Crater (MSL); and further characterization of atmospheric escape under different solar conditions (MVN). As proposed, these activities follow up on previous discoveries (e.g., recurring slope lineae, habitable environments), while expanding spatial and temporal coverage to guide new detailed observations. An independent review panel evaluated these proposals, met with project representatives in May, and made recommendations to NASA in June 2016. In this

  19. Gene flow, recombination, and positive selection in Stenotrophomonas maltophilia: mechanisms underlying the diversity of the widespread opportunistic pathogen.

    PubMed

    Yu, Dong; Yin, Zhiqiu; Li, Beiping; Jin, Yuan; Ren, Hongguang; Zhou, Jing; Zhou, Wei; Liang, Long; Yue, Junjie

    2016-12-01

    Stenotrophomonas maltophilia is a global multidrug-resistant human opportunistic pathogen in clinical environments. Stenotrophomonas maltophilia is also ubiquitous in aqueous environments, soil, and plants. Various molecular typing methods have revealed that S. maltophilia exhibits high levels of phenotypic and genotypic diversity. However, information regarding the genomic diversity within S. maltophilia and the corresponding genetic mechanisms resulting in said diversity remain scarce. The genome sequences of 17 S. maltophilia strains were selected to investigate the mechanisms contributing to genetic diversity at the genome level. The core and large pan-genomes of the species were first estimated, resulting in a large, open pan-genome. A species phylogeny was also reconstructed based on 344 orthologous genes with one copy per genome, and the contribution of four evolutionary mechanisms to the species genome diversity was quantified: 15%-35% of the genes showed evidence for recombination, 0%-25% of the genes in one genome were likely gained, 0%-44% of the genes in some genomes were likely lost, and less than 0.3% of the genes in a genome were under positive selection pressures. We observed that, among the four main mechanisms, homologous recombination plays a key role in maintaining diversity in S. maltophilia. In this study, we provide an overview of evolution in S. maltophilia to provide a better understanding of its evolutionary dynamics and its relationship with genome diversity.

  20. A high efficiency gene disruption strategy using a positive-negative split selection marker and electroporation for Fusarium oxysporum.

    PubMed

    Liang, Liqin; Li, Jianqiang; Cheng, Lin; Ling, Jian; Luo, Zhongqin; Bai, Miao; Xie, Bingyan

    2014-11-01

    The Fusarium oxysporum species complex consists of fungal pathogens that cause serial vascular wilt disease on more than 100 cultivated species throughout the world. Gene function analysis is rapidly becoming more and more important as the whole-genome sequences of various F. oxysporum strains are being completed. Gene-disruption techniques are a common molecular tool for studying gene function, yet are often a limiting step in gene function identification. In this study we have developed a F. oxysporum high-efficiency gene-disruption strategy based on split-marker homologous recombination cassettes with dual selection and electroporation transformation. The method was efficiently used to delete three RNA-dependent RNA polymerase (RdRP) genes. The gene-disruption cassettes of three genes can be constructed simultaneously within a short time using this technique. The optimal condition for electroporation is 10μF capacitance, 300Ω resistance, 4kV/cm field strength, with 1μg of DNA (gene-disruption cassettes). Under these optimal conditions, we were able to obtain 95 transformants per μg DNA. And after positive-negative selection, the transformants were efficiently screened by PCR, screening efficiency averaged 85%: 90% (RdRP1), 85% (RdRP2) and 77% (RdRP3). This gene-disruption strategy should pave the way for high throughout genetic analysis in F. oxysporum.

  1. Selective agonists and antagonists of formylpeptide receptors: duplex flow cytometry and mixture-based positional scanning libraries.

    PubMed

    Pinilla, Clemencia; Edwards, Bruce S; Appel, Jon R; Yates-Gibbins, Tina; Giulianotti, Marc A; Medina-Franco, Jose L; Young, Susan M; Santos, Radleigh G; Sklar, Larry A; Houghten, Richard A

    2013-09-01

    The formylpeptide receptor (FPR1) and formylpeptide-like 1 receptor (FPR2) are G protein-coupled receptors that are linked to acute inflammatory responses, malignant glioma stem cell metastasis, and chronic inflammation. Although several N-formyl peptides are known to bind to these receptors, more selective small-molecule, high-affinity ligands are needed for a better understanding of the physiologic roles played by these receptors. High-throughput assays using mixture-based combinatorial libraries represent a unique, highly efficient approach for rapid data acquisition and ligand identification. We report the superiority of this approach in the context of the simultaneous screening of a diverse set of mixture-based small-molecule libraries. We used a single cross-reactive peptide ligand for a duplex flow cytometric screen of FPR1 and FPR2 in color-coded cell lines. Screening 37 different mixture-based combinatorial libraries totaling more than five million small molecules (contained in 5,261 mixture samples) resulted in seven libraries that significantly inhibited activity at the receptors. Using positional scanning deconvolution, selective high-affinity (low nM K(i)) individual compounds were identified from two separate libraries, namely, pyrrolidine bis-diketopiperazine and polyphenyl urea. The most active individual compounds were characterized for their functional activities as agonists or antagonists with the most potent FPR1 agonist and FPR2 antagonist identified to date with an EC₅₀ of 131 nM (4 nM K(i)) and an IC₅₀ of 81 nM (1 nM K(i)), respectively, in intracellular Ca²⁺ response determinations. Comparative analyses of other previous screening approaches clearly illustrate the efficiency of identifying receptor selective, individual compounds from mixture-based combinatorial libraries.

  2. Positive selection on sperm ion channels in a brooding brittle star: consequence of life-history traits evolution.

    PubMed

    Weber, A A-T; Abi-Rached, L; Galtier, N; Bernard, A; Montoya-Burgos, J I; Chenuil, A

    2017-01-18

    Closely related species are key models to investigate mechanisms leading to reproductive isolation and early stages of diversification, also at the genomic level. The brittle star cryptic species complex Ophioderma longicauda encompasses the sympatric broadcast-spawning species C3 and the internal brooding species C5. Here, we used de novo transcriptome sequencing and assembly in two closely related species displaying contrasting reproductive modes to compare their genetic diversity and to investigate the role of natural selection in reproductive isolation. We reconstructed 20 146 and 22 123 genes for C3 and C5, respectively, and characterized a set of 12 229 orthologs. Genetic diversity was 1.5-2 times higher in C3 compared to C5, confirming that species with low parental investment display higher levels of genetic diversity. Forty-eight genes were the targets of positive diversifying selection during the evolution of the two species. Notably, two genes (NHE and TetraKCNG) are sperm-specific ion channels involved in sperm motility. Ancestral sequence reconstructions show that natural selection targeted the two genes in the brooding species. This may result from an adaptation to the novel environmental conditions surrounding sperm in the brooding species, either directly affecting sperm or via an increase in male/female conflict. This phenomenon could have promoted prezygotic reproductive isolation between C3 and C5. Finally, the sperm receptors to egg chemoattractants differed between C3 and C5 in the ligand-binding region. We propose that mechanisms of species-specific gamete recognition in brittle stars occur during sperm chemotaxis (sperm attraction towards the eggs), contrary to other marine invertebrates where prezygotic barriers to interspecific hybridization typically occur before sperm-egg fusion.

  3. Spectral Tuning of Killer Whale (Orcinus orca) Rhodopsin: Evidence for Positive Selection and Functional Adaptation in a Cetacean Visual Pigment.

    PubMed

    Dungan, Sarah Z; Kosyakov, Alexander; Chang, Belinda S W

    2016-02-01

    Cetaceans have undergone a remarkable evolutionary transition that was accompanied by many sensory adaptations, including modification of the visual system for underwater environments. Recent sequencing of cetacean genomes has made it possible to begin exploring the molecular basis of these adaptations. In this study we use in vitro expression methods to experimentally characterize the first step of the visual transduction cascade, the light activation of rhodopsin, for the killer whale. To investigate the spectral effects of amino acid substitutions thought to correspond with absorbance shifts relative to terrestrial mammals, we used the orca gene as a background for the first site-directed mutagenesis experiments in a cetacean rhodopsin. The S292A mutation had the largest effect, and was responsible for the majority of the spectral difference between killer whale and bovine (terrestrial) rhodopsin. Using codon-based likelihood models, we also found significant evidence for positive selection in cetacean rhodopsin sequences, including on spectral tuning sites we experimentally mutated. We then investigated patterns of ecological divergence that may be correlated with rhodopsin functional variation by using a series of clade models that partitioned the data set according to phylogeny, habitat, and foraging depth zone. Only the model partitioning according to depth was significant. This suggests that foraging dives might be a selective regime influencing cetacean rhodopsin divergence, and our experimental results indicate that spectral tuning may be playing an adaptive role in this process. Our study demonstrates that combining computational and experimental methods is crucial for gaining insight into the selection pressures underlying molecular evolution.

  4. The Landscape of A-to-I RNA Editome Is Shaped by Both Positive and Purifying Selection

    PubMed Central

    Kong, Yimeng; Pan, Bohu; Chen, Longxian; Wang, Hongbing; Hao, Pei; Li, Xuan

    2016-01-01

    The hydrolytic deamination of adenosine to inosine (A-to-I editing) in precursor mRNA induces variable gene products at the post-transcription level. How and to what extent A-to-I RNA editing diversifies transcriptome is not fully characterized in the evolution, and very little is known about the selective constraints that drive the evolution of RNA editing events. Here we present a study on A-to-I RNA editing, by generating a global profile of A-to-I editing for a phylogeny of seven Drosophila species, a model system spanning an evolutionary timeframe of approximately 45 million years. Of totally 9281 editing events identified, 5150 (55.5%) are located in the coding sequences (CDS) of 2734 genes. Phylogenetic analysis places these genes into 1,526 homologous families, about 5% of total gene families in the fly lineages. Based on conservation of the editing sites, the editing events in CDS are categorized into three distinct types, representing events on singleton genes (type I), and events not conserved (type II) or conserved (type III) within multi-gene families. While both type I and II events are subject to purifying selection, notably type III events are positively selected, and highly enriched in the components and functions of the nervous system. The tissue profiles are documented for three editing types, and their critical roles are further implicated by their shifting patterns during holometabolous development and in post-mating response. In conclusion, three A-to-I RNA editing types are found to have distinct evolutionary dynamics. It appears that nervous system functions are mainly tested to determine if an A-to-I editing is beneficial for an organism. The coding plasticity enabled by A-to-I editing creates a new class of binary variations, which is a superior alternative to maintain heterozygosity of expressed genes in a diploid mating system. PMID:27467689

  5. Extensive Evolutionary Changes in Regulatory Element Activity during Human Origins Are Associated with Altered Gene Expression and Positive Selection

    PubMed Central

    Fedrigo, Olivier; Babbitt, Courtney C.; Wortham, Matthew; Tewari, Alok K.; London, Darin; Song, Lingyun; Lee, Bum-Kyu; Iyer, Vishwanath R.; Parker, Stephen C. J.; Margulies, Elliott H.; Wray, Gregory A.; Furey, Terrence S.; Crawford, Gregory E.

    2012-01-01

    Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differential gene expression analyses in general, but not by the identification of specific regulatory elements responsible for changes in transcription and phenotype. To identify the genetic source of regulatory differences, we mapped DNaseI hypersensitive (DHS) sites, which mark all types of active gene regulatory elements, genome-wide in the same cell type isolated from human, chimpanzee, and macaque. Most DHS sites were conserved among all three species, as expected based on their central role in regulating transcription. However, we found evidence that several hundred DHS sites were gained or lost on the lineages leading to modern human and chimpanzee. Species-specific DHS site gains are enriched near differentially expressed genes, are positively correlated with increased transcription, show evidence of branch-specific positive selection, and overlap with active chromatin marks. Species-specific sequence differences in transcription factor motifs found within these DHS sites are linked with species-specific changes in chromatin accessibility. Together, these indicate that the regulatory elements identified here are genetic contributors to transcriptional and phenotypic differences among primate species. PMID:22761590

  6. Evaluation of ongoing oxycodone abuse among methadone-maintained patients.

    PubMed

    Dunn, Kelly E; Sigmon, Stacey C; McGee, Mark R; Heil, Sarah H; Higgins, Stephen T

    2008-12-01

    Prevalence of prescription opioid abuse has increased dramatically in recent years in the United States generally, and a similar pattern of increasing prescription opioid use has also been noted among patients seeking treatment for opioid dependence. This study presents results from an internal quality assurance project conducted by an outpatient methadone maintenance (MM) treatment clinic which sought to examine the extent of ongoing oxycodone abuse among patients that might be going undetected with current urinalysis-testing methods. One hundred five MM patients provided 437 urine samples over a 6-week period. Samples were analyzed using the clinic's usual enzyme multiplied immunoassay test (EMIT) opiate assay (300 ng/ml opiate cutpoint) and a supplemental oxycodone test strip (100 ng/ml oxycodone cutpoint). The EMIT assay identified only 6% (20/437) of samples as positive for oxycodone, whereas the oxycodone test strip indicated that 19% (83/437) tested positive for recent oxycodone use. Inspection of patient characteristics revealed that oxycodone users were more likely to report a prescription opioid as their primary drug at intake, be in MM treatment for a significantly shorter duration, and provide significantly more opioid- and cocaine-positive urine samples. Overall, these data illustrate the potential importance of monitoring for ongoing oxycodone use in MM clinics. Although future efforts should examine this question using more rigorous experimental methods, findings from this initial project have implications for clinical issues such as evaluating patient stability in treatment, making medication-dosing decisions, and determining patient eligibility for methadone take-home privileges.

  7. Vascular Reactivity Profile of Novel KCa 3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed.

    PubMed

    Oliván-Viguera, Aida; Valero, Marta Sofía; Pinilla, Estéfano; Amor, Sara; García-Villalón, Ángel Luis; Coleman, Nichole; Laría, Celia; Calvín-Tienza, Víctor; García-Otín, Ángel-Luis; Fernández-Fernández, José M; Murillo, M Divina; Gálvez, José A; Díaz-de-Villegas, María D; Badorrey, Ramón; Simonsen, Ulf; Rivera, Luis; Wulff, Heike; Köhler, Ralf

    2016-08-01

    Opening of intermediate-conductance calcium-activated potassium channels (KC a 3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KC a 3.1-selective positive-gating modulators, SKA-111 and SKA-121, to (1) evoke porcine endothelial cell KC a 3.1 membrane hyperpolarization, (2) induce endothelium-dependent and, particularly, endothelium-derived hyperpolarization (EDH)-type relaxation in porcine coronary arteries (PCA) and (3) influence coronary artery tone in isolated rat hearts. In whole-cell patch-clamp experiments on endothelial cells of PCA (PCAEC), KC a currents evoked by bradykinin (BK) were potentiated ≈7-fold by either SKA-111 or SKA-121 (both at 1 μM) and were blocked by a KC a 3.1 blocker, TRAM-34. In membrane potential measurements, SKA-111 and SKA-121 augmented bradykinin-induced hyperpolarization. Isometric tension measurements in large- and small-calibre PCA showed that SKA-111 and SKA-121 potentiated endothelium-dependent relaxation with intact NO synthesis and EDH-type relaxation to BK by ≈2-fold. Potentiation of the BK response was prevented by KC a 3.1 inhibition. In Langendorff-perfused rat hearts, SKA-111 potentiated coronary vasodilation elicited by BK. In conclusion, our data show that positive-gating modulation of KC a 3.1 channels improves BK-induced membrane hyperpolarization and endothelium-dependent relaxation in small and large PCA as well as in the coronary circulation of rats. Positive-gating modulators of KC a 3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in cardiovascular disease.

  8. Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking, but not from somatostatin-positive interneurons

    PubMed Central

    Gibson, Jay R.; Huber, Kimberly M.; Südhof, Thomas C.

    2009-01-01

    Neuroligins are cell-adhesion molecules involved in synapse formation and/or function. Neurons express four neuroligins (NL1–NL4), of which NL1 is specific to excitatory, and NL2 to inhibitory synapses. Excitatory and inhibitory synapses include numerous subtypes. However, it is unknown whether NL1 performs similar functions in all excitatory and NL2 in all inhibitory synapses, or whether they regulate the formation and/or function of specific subsets of synapses. To address this central question, we performed paired recordings in primary somatosensory cortex of mice lacking NL1 or NL2. Using this system, we examined neocortical microcircuits formed by reciprocal synapses between excitatory neurons and two subtypes of inhibitory interneurons, namely fast-spiking and somatostatin-positive interneurons. We find that the NL1 deletion had little effect on inhibitory synapses, whereas the NL2 deletion decreased (40–50%) the unitary (cell-to-cell) IPSC amplitude evoked from single fast-spiking interneurons. Strikingly, the NL2 deletion had no effect on IPSC amplitude evoked from single somatostatin-positive inhibitory interneurons. Moreover, the frequency of unitary synaptic connections between individual fast-spiking and somatostatin-positive interneurons and excitatory neurons was unchanged. The decrease in unitary IPSC amplitude originating from fast-spiking interneurons in NL2-deficient mice was due to a multiplicative and uniform down-scaling of the amplitude distribution, which in turn was mediated by a decrease in both synaptic quantal amplitude and quantal content – the latter inferred from an increase in the coefficient of variation. Thus, NL2 is not necessary for establishing unitary inhibitory synaptic connections, but is selectively required for “scaling up” unitary connections originating from a subset of interneurons. PMID:19889999

  9. The effects of two different arm positions and weight status on select kinematic variables during the bodyweight squat.

    PubMed

    Glave, A Page; Olson, Jacilyn M; Applegate, Danika K; Brezzo, Ro Di

    2012-11-01

    The bodyweight squat is a common movement and is safe and effective. There are many variations and techniques, but little research has explored alterations of the movement. The purpose of this study was to examine the effects of 2 arm positions on select kinematic variables during the bodyweight squat. The participants were classified as normal-weight (NW: n = 17, height: 1.67 ± 0.06 m, weight: 61.25 ± 6.90 kg, body mass index [BMI]: 21.92 ± 1.68) or overweight (OW: n = 11, height: 1.68 ± 0.06 m, weight: 88.91 ± 16.86 kg, BMI: 31.64 ± 6.06) according to BMI. The participants completed a bodyweight squat with the arms held at the sides (AP1) followed by a bodyweight squat with the arms held at shoulder level (AP2). Reflective markers were placed on the shoulder, hip, knee, base of the fifth toe, and heel. Data were recorded and analyzed using Peak 9. Trunk and knee flexion was analyzed using separate repeated measures analyses of variance. Overweight participants exhibited reduced knee (OW: 75.56 ± 17.94°; NW: 83.73 ± 13.03°; p < 0.05) and trunk flexion (OW: -78.18 ± 17.72°; NW: -90.65 ± 17.57°; p = 0.05). Holding the arms at shoulder level resulted in greater knee flexion (AP1: 80.81 ± 15.17°; AP2: 86.31 ± 15.21°; p < 0.01). Both weight status and arm position affected the range of motion in the bodyweight squat. Using an arms-up position should be considered, especially for the OW population, to increase the benefits of the bodyweight squat by increasing the range of motion.

  10. Sandia's mentoring program : an ongoing success.

    SciTech Connect

    Brewer, Soila

    2003-12-01

    This report summarizes the Mentoring Program at Sandia National Laboratories (SNL), which has been an on-going success since its inception in 1995. The Mentoring Program provides a mechanism to develop a workforce able to respond to changing requirements and complex customer needs. The program objectives are to enhance employee contributions through increased knowledge of SNL culture, strategies, and programmatic direction. Mentoring is a proven mechanism for attracting new employees, retaining employees, and developing leadership. It helps to prevent the loss of corporate knowledge from attrition and retirement, and it increases the rate and level of contributions of new managers and employees, also spurring cross-organizational teaming. The Mentoring Program is structured as a one-year partnership between an experienced staff member or leader and a less experienced one. Mentors and mentees are paired according to mutual objectives and interests. Support is provided to the matched pairs from their management as well as division program coordinators in both New Mexico and California locations. In addition, bi-monthly large-group training sessions are held.

  11. Dry needling versus acupuncture: the ongoing debate.

    PubMed

    Zhou, Kehua; Ma, Yan; Brogan, Michael S

    2015-12-01

    Although Western medical acupuncture (WMA) is commonly practised in the UK, a particular approach called dry needling (DN) is becoming increasingly popular in other countries. The legitimacy of the use of DN by conventional non-physician healthcare professionals is questioned by acupuncturists. This article describes the ongoing debate over the practice of DN between physical therapists and acupuncturists, with a particular emphasis on the USA. DN and acupuncture share many similarities but may differ in certain aspects. Currently, little information is available from the literature regarding the relationship between the two needling techniques. Through reviewing their origins, theory, and practice, we found that DN and acupuncture overlap in terms of needling technique with solid filiform needles as well as some fundamental theories. Both WMA and DN are based on modern biomedical understandings of the human body, although DN arguably represents only one subcategory of WMA. The increasing volume of research into needling therapy explains its growing popularity in the musculoskeletal field including sports medicine. To resolve the debate over DN practice, we call for the establishment of a regulatory body to accredit DN courses and a formal, comprehensive educational component and training for healthcare professionals who are not physicians or acupuncturists. Because of the close relationship between DN and acupuncture, collaboration rather than dispute between acupuncturists and other healthcare professionals should be encouraged with respect to education, research, and practice for the benefit of patients with musculoskeletal conditions who require needling therapy.

  12. Improved methods in Agrobacterium-mediated transformation of almond using positive (mannose/pmi) or negative (kanamycin resistance) selection-based protocols.

    PubMed

    Ramesh, Sunita A; Kaiser, Brent N; Franks, Tricia; Collins, Graham; Sedgley, Margaret

    2006-08-01

    A protocol for Agrobacterium-mediated transformation with either kanamycin or mannose selection was developed for leaf explants of the cultivar Prunus dulcis cv. Ne Plus Ultra. Regenerating shoots were selected on medium containing 15 muM kanamycin (negative selection), while in the positive selection strategy, shoots were selected on 2.5 g/l mannose supplemented with 15 g/l sucrose. Transformation efficiencies based on PCR analysis of individual putative transformed shoots from independent lines relative to the initial numbers of leaf explants tested were 5.6% for kanamycin/nptII and 6.8% for mannose/pmi selection, respectively. Southern blot analysis on six randomly chosen PCR-positive shoots confirmed the presence of the nptII transgene in each, and five randomly chosen lines identified to contain the pmi transgene by PCR showed positive hybridisation to a pmi DNA probe. The positive (mannose/pmi) and the negative (kanamycin) selection protocols used in this study have greatly improved transformation efficiency in almond, which were confirmed with PCR and Southern blot. This study also demonstrates that in almond the mannose/pmi selection protocol is appropriate and can result in higher transformation efficiencies over that of kanamycin/nptII selection protocols.

  13. Constraints on the richness-mass relation and the optical-SZE positional offset distribution for SZE-selected clusters

    SciTech Connect

    Saro, A.

    2015-10-12

    In this study, we cross-match galaxy cluster candidates selected via their Sunyaev–Zel'dovich effect (SZE) signatures in 129.1 deg2 of the South Pole Telescope 2500d SPT-SZ survey with optically identified clusters selected from the Dark Energy Survey science verification data. We identify 25 clusters between 0.1 ≲ z ≲ 0.8 in the union of the SPT-SZ and redMaPPer (RM) samples. RM is an optical cluster finding algorithm that also returns a richness estimate for each cluster. We model the richness λ-mass relation with the following function 500> ∝ Bλln M500 + Cλln E(z) and use SPT-SZ cluster masses and RM richnesses λ to constrain the parameters. We find Bλ=1.14+0.21–0.18 and Cλ=0.73+0.77–0.75. The associated scatter in mass at fixed richness is σlnM|λ = 0.18+0.08–0.05 at a characteristic richness λ = 70. We demonstrate that our model provides an adequate description of the matched sample, showing that the fraction of SPT-SZ-selected clusters with RM counterparts is consistent with expectations and that the fraction of RM-selected clusters with SPT-SZ counterparts is in mild tension with expectation. We model the optical-SZE cluster positional offset distribution with the sum of two Gaussians, showing that it is consistent with a dominant, centrally peaked population and a subdominant population characterized by larger offsets. We also cross-match the RM catalogue with SPT-SZ candidates below the official catalogue threshold significance ξ = 4.5, using the RM catalogue to provide optical confirmation and redshifts for 15 additional clusters with ξ ε [4, 4.5].

  14. On-Going Temperature Extremes in Siberia

    NASA Astrophysics Data System (ADS)

    Shulgina, T. M.; Gordov, E. P.

    2014-12-01

    Ongoing global climate changes accompanied by the restructuring of global processes in the atmosphere and biosphere are strongly pronounced in the Northern Eurasia regions, especially in Siberia. Temperature trends (grows up to 0.5 °C per decade), more frequent occurrence of temperature extremes provoked serious natural disasters (2010 heat waves in Russia, 2013 flood in Russia's Far East) led to socio-economical impact (crop damages, infrastructure failures, respectively). To get reliable knowledge on location, frequency and magnitude of observed extremes we have studied daily max/min temperature trends based on ECMWF ERA Interim Reanalysis data (0,25°×0,25°). This dataset is most accurately reproduces observed temperature behavior in the region. Statistical analysis of daily temperature time series (1979-2012) indicates the asymmetric changes in distribution tails of such extreme indices as warm/cold days/nights. Namely, the warming during winter cold nights is stronger than during warm nights, especially over the north of Siberia. Increases in minimum temperatures are more significant than in maximum temperatures. Warming determined at the high latitudes of the region is achieved mostly due to winter temperature changes. South area of Siberia has slightly cooling during winter and summer. Results obtained provide regional decision-makers with detailed high spatial and temporal resolution climatic information required for adaptation and mitigation measures development. Calculations presented have been realized using information-computational web-GIS system "Climate" (http://climate.scert.ru/) which automatically generates the archive of calculated fields ready for multidisciplinary studies of regional climate change impacts. The authors acknowledge partial financial support for this research from the RFBR (13-05-12034, 14-05-00502), SB RAS 131 and VIII.80.2.1.) and grant of the President of RF (№ 181).

  15. A Universal Positive-Negative Selection System for Gene Targeting in Plants Combining an Antibiotic Resistance Gene and Its Antisense RNA.

    PubMed

    Nishizawa-Yokoi, Ayako; Nonaka, Satoko; Osakabe, Keishi; Saika, Hiroaki; Toki, Seiichi

    2015-09-01

    Gene targeting (GT) is a useful technology for accurate genome engineering in plants. A reproducible approach based on a positive-negative selection system using hygromycin resistance and the diphtheria toxin A subunit gene as positive and negative selection markers, respectively, is now available. However, to date, this selection system has been applied exclusively in rice (Oryza sativa). To establish a universally applicable positive-negative GT system in plants, we designed a selection system using a combination of neomycin phosphotransferaseII (nptII) and an antisense nptII construct. The concomitant transcription of both sense and antisense nptII suppresses significantly the level of expression of the sense nptII gene, and transgenic calli and plants become sensitive to the antibiotic geneticin. In addition, we were able to utilize the sense nptII gene as a positive selection marker and the antisense nptII construct as a negative selection marker for knockout of the endogenous rice genes Waxy and 33-kD globulin through GT, although negative selection with this system is relatively less efficient compared with diphtheria toxin A subunit. The approach developed here, with some additional improvements, could be applied as a universal selection system for the enrichment of GT cells in several plant species.

  16. "Smartening Up": Ongoing Challenges for Australia's Outback

    ERIC Educational Resources Information Center

    Cradduck, Lucy

    2016-01-01

    As the international community moves inexorably towards a "smart" future, the position of Australia's non-urban areas in that future is less certain. The (re-elected) Australian federal government made a commitment to moving Australian cities forward as part of the international "smart city" movement. However, the effectiveness…

  17. Ongoing climatic extreme dynamics in Siberia

    NASA Astrophysics Data System (ADS)

    Gordov, E. P.; Shulgina, T. M.; Okladnikov, I. G.; Titov, A. G.

    2013-12-01

    Ongoing global climate changes accompanied by the restructuring of global processes in the atmosphere and biosphere are strongly pronounced in the Northern Eurasia regions, especially in Siberia. Recent investigations indicate not only large changes in averaged climatic characteristics (Kabanov and Lykosov, 2006, IPCC, 2007; Groisman and Gutman, 2012), but more frequent occurrence and stronger impacts of climatic extremes are reported as well (Bulygina et al., 2007; IPCC, 2012: Climate Extremes, 2012; Oldenborh et al., 2013). This paper provides the results of daily temperature and precipitation extreme dynamics in Siberia for the last three decades (1979 - 2012). Their seasonal dynamics is assessed using 10th and 90th percentile-based threshold indices that characterize frequency, intensity and duration of climatic extremes. To obtain the geographical pattern of these variations with high spatial resolution, the sub-daily temperature data from ECMWF ERA-Interim reanalysis and daily precipitation amounts from APHRODITE JMA dataset were used. All extreme indices and linear trend coefficients have been calculated using web-GIS information-computational platform Climate (http://climate.scert.ru/) developed to support collaborative multidisciplinary investigations of regional climatic changes and their impacts (Gordov et al., 2012). Obtained results show that seasonal dynamics of daily temperature extremes is asymmetric for tails of cold and warm temperature extreme distributions. Namely, the intensity of warming during cold nights is higher than during warm nights, especially at high latitudes of Siberia. The similar dynamics is observed for cold and warm day-time temperatures. Slight summer cooling was observed in the central part of Siberia. It is associated with decrease in warm temperature extremes. In the southern Siberia in winter, we also observe some cooling mostly due to strengthening of the cold temperature extremes. Changes in daily precipitation extremes

  18. Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels

    PubMed Central

    Hougaard, C; Eriksen, B L; Jørgensen, S; Johansen, T H; Dyhring, T; Madsen, L S; Strøbæk, D; Christophersen, P

    2007-01-01

    Background and purpose: Positive modulators of small conductance Ca2+-activated K+ channels (SK1, SK2, and SK3) exert hyperpolarizing effects that influence the activity of excitable and non-excitable cells. The prototype compound 1-EBIO or the more potent compound NS309, do not distinguish between the SK subtypes and they also activate the related intermediate conductance Ca2+-activated K+ channel (IK). This paper demonstrates, for the first time, subtype-selective positive modulation of SK channels. Experimental approach: Using patch clamp and fluorescence techniques we studied the effect of the compound cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) on recombinant hSK1-3 and hIK channels expressed in HEK293 cells. CyPPA was also tested on SK3 and IK channels endogenously expressed in TE671 and HeLa cells. Key results: CyPPA was found to be a positive modulator of hSK3 (EC50 = 5.6 ± 1.6 μM, efficacy 90 ± 1.8 %) and hSK2 (EC50 = 14 ± 4 μM, efficacy 71 ± 1.8 %) when measured in inside-out patch clamp experiments. CyPPA was inactive on both hSK1 and hIK channels. At hSK3 channels, CyPPA induced a concentration-dependent increase in the apparent Ca2+-sensitivity of channel activation, changing the EC50(Ca2+) from 429 nM to 59 nM. Conclusions and implications: As a pharmacological tool, CyPPA may be used in parallel with the IK/SK openers 1-EBIO and NS309 to distinguish SK3/SK2- from SK1/IK-mediated pharmacological responses. This is important for the SK2 and SK1 subtypes, since they have overlapping expression patterns in the neocortical and hippocampal regions, and for SK3 and IK channels, since they co-express in certain peripheral tissues. PMID:17486140

  19. Duplications and positive selection drive the evolution of parasitism associated gene families in the nematode Strongyloides papillosus.

    PubMed

    Baskaran, Praveen; Jaleta, Tegegn G; Streit, Adrian; Rödelsperger, Christian

    2017-03-02

    Gene duplication is one major mechanism playing a role in the evolution of phenotypic complexity and in the generation of novel traits. By comparing parasitic and nonparasitic nematodes, a recent study found that the evolution of parasitism in Strongyloididae is associated with a large expansion in the Astacin and CAP gene families.To gain novel insights into the developmental processes in the sheep parasite Strongyloides papillosus, we sequenced transcriptomes of different developmental stages and sexes. Overall, we found that the majority of genes are developmentally regulated and have one-to-one orthologs in the diverged S. ratti genome. Together with the finding of similar expression profiles between S. papillosus and S. ratti, these results indicate a strong evolutionary constraint acting against change at sequence and expression levels. However, the comparison between parasitic and free-living females demonstrates a quite divergent pattern that is mostly due to the previously mentioned expansion in the Astacin and CAP gene families. More detailed phylogenetic analysis of both gene families shows that most members date back to single expansion events early in the Strongyloides lineage and have undergone subfunctionalization resulting in clusters that are highly expressed either in infective larvae or in parasitic females. Finally, we found increased evidence for positive selection in both gene families relative to the genome-wide expectation.In summary, our study reveals first insights into the developmental transcriptomes of S. papillosus and provides a detailed analysis of sequence and expression evolution in parasitism associated gene families.

  20. Resampling Images to a Regular Grid From a Non-Regular Subset of Pixel Positions Using Frequency Selective Reconstruction.

    PubMed

    Seiler, Jurgen; Jonscher, Markus; Schöberl, Michael; Kaup, André

    2015-11-01

    Even though image signals are typically defined on a regular 2D grid, there also exist many scenarios where this is not the case and the amplitude of the image signal only is available for a non-regular subset of pixel positions. In such a case, a resampling of the image to a regular grid has to be carried out. This is necessary since almost all algorithms and technologies for processing, transmitting or displaying image signals rely on the samples being available on a regular grid. Thus, it is of great importance to reconstruct the image on this regular grid, so that the reconstruction comes closest to the case that the signal has been originally acquired on the regular grid. In this paper, Frequency Selective Reconstruction is introduced for solving this challenging task. This algorithm reconstructs image signals by exploiting the property that small areas of images can be represented sparsely in the Fourier domain. By further considering the basic properties of the optical transfer function of imaging systems, a sparse model of the signal is iteratively generated. In doing so, the proposed algorithm is able to achieve a very high reconstruction quality, in terms of peak signal-to-noise ratio (PSNR) and structural similarity measure as well as in terms of visual quality. The simulation results show that the proposed algorithm is able to outperform state-of-the-art reconstruction algorithms and gains of more than 1 dB PSNR are possible.

  1. Duplications and Positive Selection Drive the Evolution of Parasitism-Associated Gene Families in the Nematode Strongyloides papillosus

    PubMed Central

    Baskaran, Praveen; Jaleta, Tegegn G.; Streit, Adrian

    2017-01-01

    Gene duplication is a major mechanism playing a role in the evolution of phenotypic complexity and in the generation of novel traits. By comparing parasitic and nonparasitic nematodes, a recent study found that the evolution of parasitism in Strongyloididae is associated with a large expansion in the Astacin and CAP gene families. To gain novel insights into the developmental processes in the sheep parasite Strongyloides papillosus, we sequenced transcriptomes of different developmental stages and sexes. Overall, we found that the majority of genes are developmentally regulated and have one-to-one orthologs in the diverged S. ratti genome. Together with the finding of similar expression profiles between S. papillosus and S. ratti, these results indicate a strong evolutionary constraint acting against change at sequence and expression levels. However, the comparison between parasitic and free-living females demonstrates a quite divergent pattern that is mostly due to the previously mentioned expansion in the Astacin and CAP gene families. More detailed phylogenetic analysis of both gene families shows that most members date back to single expansion events early in the Strongyloides lineage and have undergone subfunctionalization resulting in clusters that are highly expressed either in infective larvae or in parasitic females. Finally, we found increased evidence for positive selection in both gene families relative to the genome-wide expectation. In summary, our study reveals first insights into the developmental transcriptomes of S. papillosus and provides a detailed analysis of sequence and expression evolution in parasitism-associated gene families. PMID:28338804

  2. A haplotype at STAT2 Introgressed from neanderthals and serves as a candidate of positive selection in Papua New Guinea.

    PubMed

    Mendez, Fernando L; Watkins, Joseph C; Hammer, Michael F

    2012-08-10

    Signals of archaic admixture have been identified through comparisons of the draft Neanderthal and Denisova genomes with those of living humans. Studies of individual loci contributing to these genome-wide average signals are required for characterization of the introgression process and investigation of whether archaic variants conferred an adaptive advantage to the ancestors of contemporary human populations. However, no definitive case of adaptive introgression has yet been described. Here we provide a DNA sequence analysis of the innate immune gene STAT2 and show that a haplotype carried by many Eurasians (but not sub-Saharan Africans) has a sequence that closely matches that of the Neanderthal STAT2. This haplotype, referred to as N, was discovered through a resequencing survey of the entire coding region of STAT2 in a global sample of 90 individuals. Analyses of publicly available complete genome sequence data show that haplotype N shares a recent common ancestor with the Neanderthal sequence (~80 thousand years ago) and is found throughout Eurasia at an average frequency of ~5%. Interestingly, N is found in Melanesian populations at ~10-fold higher frequency (~54%) than in Eurasian populations. A neutrality test that controls for demography rejects the hypothesis that a variant of N rose to high frequency in Melanesia by genetic drift alone. Although we are not able to pinpoint the precise target of positive selection, we identify nonsynonymous mutations in ERBB3, ESYT1, and STAT2-all of which are part of the same 250 kb introgressive haplotype-as good candidates.

  3. Hydrothermal conditions of South Eastern Siberia under the ongoing warming

    NASA Astrophysics Data System (ADS)

    Voropay, N. N.; Maksyutova, E. V.; Riazanova, A. A.

    2016-11-01

    A great increase in air temperature has been observed since 1976. Siberia is a region with most severe ongoing climate change. To monitor the extreme weather events is important. To evaluate moisture conditions we used the D.A. Ped index (Si). Monthly air temperature and precipitation data from 19 weather stations of South Eastern Siberia (50-60° N 90-120° E) were used for the index calculation during the vegetation period. During 1976-2010 the number of droughts in the study region was more than the number of excessive moisture periods. The maximal statistically significant trend (0.4-0.6 per 10 years) in Eastern Siberia was observed in May. The characteristics of the winter-spring period preceding the vegetation season were analyzed. Significant positive trends exist in the study area for the May temperature (0.5-0.9 °C per 10 years) and the May sum of positive temperatures (14-28 °C per 10 years). There are tendencies to increase the number of days with temperatures above zero in March (1-3 days per 10 years) and the sum of positive temperatures in April (5-16 °C per 10 years). The stable transition of air temperature over 0 °C shifts into early dates by 1-7 days every 10 years.

  4. Positive selection pressure on the B/C domains of the E2-gene of classical swine fever virus in endemic areas under C-strain vaccination.

    PubMed

    Pérez, Lester Josué; Díaz de Arce, Heidy; Perera, Carmen Laura; Rosell, Rosa; Frías, Maria T; Percedo, Maria I; Tarradas, Joan; Dominguez, Patricia; Núñez, Jose I; Ganges, Llilianne

    2012-10-01

    In Cuba, classical swine fever (CSF) has become an endemic disease with several outbreaks each year, despite the implemented vaccination program. Interestingly, a trend towards a milder presentation of the disease has been observed among the animals during the last years. This study aimed to assess positive selection pressure acting on partial E2 gene of CSF viruses to gain insights into the mechanisms governing virulence and the driving forces of classical swine fever virus (CSFV) evolution in swine populations under regular vaccination. Selection pressure analysis were performed to detect positive selection acting on a particular lineage as well as among sites of the E2-B/C-domain of CSFV nucleotide sequences, reported in a previous study and in the present work, several models, available in the CODEML module of PAML 4.3, were used. In addition, a representative Cuban CSF isolate was assessed in an experimental infection trial for their clinical virulence in order to expand the knowledge regarding CSF viruses circulating in pig populations. The viral genomes sequenced in this study were grouped in a defined cluster within the genotype 1.2, as it has been reported previously for Cuban CSF viruses. The selection pressure analysis didn't find evidence of positive selection (dN/dS of>1) along any branch. The positive selective pressure analysis estimated six new sites under positive selection on E2 partial gene analysed. Besides, the clinical manifestations of the CSF-disease were related mainly to a mild course of the illness. The high number of positively selected sites suggests that these changes could be associated to viral evasion of the host-immune response. These observations highlight a possible association between escape viral variants and the alterations observed in the virulence and pathogenesis of the virus. Therefore, while the vaccination programs have not led to a genotype change, alterations in virulence were suggested to arise.

  5. EIDA Next Generation: ongoing and future developments

    NASA Astrophysics Data System (ADS)

    Strollo, Angelo; Quinteros, Javier; Sleeman, Reinoud; Trani, Luca; Clinton, John; Stammler, Klaus; Danecek, Peter; Pedersen, Helle; Ionescu, Constantin

    2015-04-01

    The European Integrated Data Archive (EIDA; http://www.orfeus-eu.org/eida/eida.html) is the distributed Data Centre system within ORFEUS, providing transparent access and services to high quality, seismic data across (currently) 9 large data archives in Europe. EIDA is growing, in terms of the number of participating data centres, the size of the archives, the variability of the data in the archives, the number of users, and the volume of downloads. The on-going success of EIDA is thus providing challenges that are the driving force behind the design of the next generation (NG) of EIDA, which is expected to be implemented within EPOS IP. EIDA ORFEUS must cope with further expansion of the system and more complex user requirements by developing new techniques and extended services. The EIDA NG is being designed to work on standard FDSN web services and two additional new web services: Routing Service and QC (quality controlled) service. This presentation highlights the challenges EIDA needs to address during the EPOS IP and focuses on these 2 new services. The Routing Service can be considered as the core of EIDA NG. It was designed to assist users and clients to locate data within a federated, decentralized data centre (e.g. EIDA). A detailed, FDSN-compliant specification of the service has been developed. Our implementation of this service will run at every EIDA node, but is also capable of running on a user's computer, allowing anyone to define virtual or integrate existing data centres. This (meta)service needs to be queried in order to locate the data. Some smart clients (in a beta status) have been also provided to offer the user an integrated view of the whole EIDA, hiding the complexity of its internal structure. The service is open and able to be queried by anyone without the need of credentials or authentication. The QC Service is developed to cope with user requirements to query for relevant data only. The web service provides detailed information on the

  6. Distinction of Gram-positive and -negative bacteria using a colorimetric microbial viability assay based on the reduction of water-soluble tetrazolium salts with a selection medium.

    PubMed

    Tsukatani, Tadayuki; Suenaga, Hikaru; Higuchi, Tomoko; Shiga, Masanobu; Noguchi, Katsuya; Matsumoto, Kiyoshi

    2011-01-01

    Bacteria are fundamentally divided into two groups: Gram-positive and Gram-negative. Although the Gram stain and other techniques can be used to differentiate these groups, some issues exist with traditional approaches. In this study, we developed a method for differentiating Gram-positive and -negative bacteria using a colorimetric microbial viability assay based on the reduction of the tetrazolium salt {2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt} (WST-8) via 2-methyl-1,4-napthoquinone with a selection medium. We optimized the composition of the selection medium to allow the growth of Gram-negative bacteria while inhibiting the growth of Gram-positive bacteria. When the colorimetric viability assay was carried out in a selection medium containing 0.5µg/ml crystal violet, 5.0 µg/ml daptomycin, and 5.0µg/ml vancomycin, the reduction in WST-8 by Gram-positive bacteria was inhibited. On the other hand, Gram-negative bacteria produced WST-8-formazan in the selection medium. The proposed method was also applied to determine the Gram staining characteristics of bacteria isolated from various foodstuffs. There was good agreement between the results obtained using the present method and those obtained using a conventional staining method. These results suggest that the WST-8 colorimetric assay with selection medium is a useful technique for accurately differentiating Gram-positive and -negative bacteria.

  7. Enzyme-like specificity in zeolites: a unique site position in mordenite for selective carbonylation of methanol and dimethyl ether with CO.

    PubMed

    Boronat, Mercedes; Martínez-Sánchez, Cristina; Law, David; Corma, Avelino

    2008-12-03

    The mechanism of methanol carbonylation at different positions of zeolite MOR is investigated by quantum-chemical methods in order to discover which are the active sites that can selectively catalyze the desired reaction. It is shown that when methanol carbonylation competes with hydrocarbon formation, the first reaction occurs preferentially within 8MR channels. However, the unique selectivity for the carbonylation of methanol and dimethyl ether in mordenite is not only due to the size of the 8MR channel: neither process occurs equally at the two T3-O31 and T3-O33 positions. We show that only the T3-O33 positions are selective and that this selectivity is due to the unusual orientation of the methoxy group in relation to the 8MR channel (parallel to the cylinder axis). Only in this situation does the transition state for the attack of CO fit perfectly in the 8MR channel, while the reaction with methanol or DME is sterically impeded. This result explains why T3-O31, while also located in the 8MR channel of mordenite, is not as selective as the T3-O33 position and why ferrierite, although it contains 8MR channels, is less selective than mordenite. The competing effect of water is explained at the molecular level, and the molecular microkinetic reaction model has been established.

  8. Positive Changes in Perceptions and Selections of Healthful Foods by College Students after a Short-Term Point-of-Selection Intervention at a Dining Hall

    ERIC Educational Resources Information Center

    Peterson, Sharon; Duncan, Diana Poovey; Null, Dawn Bloyd; Roth, Sara Long; Gill, Lynn

    2010-01-01

    Objective: Determine the effects of a short-term, multi-faceted, point-of-selection intervention on college students' perceptions and selection of 10 targeted healthful foods in a university dining hall and changes in their self-reported overall eating behaviors. Participants: 104 college students, (age 18-23) completed pre-I and post-I surveys.…

  9. Positive Selection on a Regulatory Insertion–Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid

    PubMed Central

    Kothapalli, Kumar S. D.; Ye, , Kaixiong; Gadgil, Maithili S.; Carlson, Susan E.; O’Brien, Kimberly O.; Zhang, Ji Yao; Park, Hui Gyu; Ojukwu, Kinsley; Zou, James; Hyon, Stephanie S.; Joshi, Kalpana S.; Gu, Zhenglong; Keinan, Alon; Brenna, J.Thomas

    2016-01-01

    Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion–deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product–precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice. PMID:27188529

  10. Positive Selection on a Regulatory Insertion-Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid.

    PubMed

    Kothapalli, Kumar S D; Ye, Kaixiong; Gadgil, Maithili S; Carlson, Susan E; O'Brien, Kimberly O; Zhang, Ji Yao; Park, Hui Gyu; Ojukwu, Kinsley; Zou, James; Hyon, Stephanie S; Joshi, Kalpana S; Gu, Zhenglong; Keinan, Alon; Brenna, J Thomas

    2016-07-01

    Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product-precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.

  11. Positive selection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia.

    PubMed

    Ségurel, Laure; Austerlitz, Frederic; Toupance, Bruno; Gautier, Mathieu; Kelley, Joanna L; Pasquet, Patrick; Lonjou, Christine; Georges, Myriam; Voisin, Sarah; Cruaud, Corinne; Couloux, Arnaud; Hegay, Tatyana; Aldashev, Almaz; Vitalis, Renaud; Heyer, Evelyne

    2013-10-01

    The high prevalence of type 2 diabetes and its uneven distribution among human populations is both a major public health concern and a puzzle in evolutionary biology. Why is this deleterious disease so common, while the associated genetic variants should be removed by natural selection? The 'thrifty genotype' hypothesis proposed that the causal genetic variants were advantageous and selected for during the majority of human evolution. It remains, however, unclear whether genetic data support this scenario. In this study, we characterized patterns of selection at 10 variants associated with type 2 diabetes, contrasting one herder and one farmer population from Central Asia. We aimed at identifying which alleles (risk or protective) are under selection, dating the timing of selective events, and investigating the effect of lifestyle on selective patterns. We did not find any evidence of selection on risk variants, as predicted by the thrifty genotype hypothesis. Instead, we identified clear signatures of selection on protective variants, in both populations, dating from the beginning of the Neolithic, which suggests that this major transition was accompanied by a selective advantage for non-thrifty variants. Combining our results with worldwide data further suggests that East Asia was particularly prone to such recent selection of protective haplotypes. As much effort has been devoted so far to searching for thrifty variants, we argue that more attention should be paid to the evolution of non-thrifty variants.

  12. Ongoing Climatic Changes in Northern Eurasia

    NASA Astrophysics Data System (ADS)

    Groisman, P. Ya.; Bulygina, O. N.; Razuvaev, V. N.; Meshcherskaya, A. V.; Ivanov, S. V.; Akhmadiyeva, Zh. K.; Speranskaya, N. A.; Zhai, P.; Shein, K.

    2009-04-01

    Northern Eurasia is the region where the contemporary warming and associated climatic and environmental changes are among the most pronounced globally, with winter temperature increased by more than 2K and summer temperature by 1.35K during the period of instrumental observations since 1881. The summer warming is a new phenomenon observed during the past several decades. Summer temperature controls most of vegetation in the polar region, where surface radiation balance (SRB) is positive only for a short period of the year. But, in the middle of this period, it exceeds the SRB values in Sahara or southern California. North of the Eurasian coast, the Arctic Ocean is moving to perennial ice-free conditions and has already lost nearly half of its end-of-summer extent since the late 1970s. This changes the regional albedo and dramatically affects the cold season heat fluxes from the ocean to the atmosphere. Thus, Northern Eurasia and, particularly, its Arctic part is being affected by global and regional factors that are contributing to these observed changes and the positive feedbacks to this forcing may further exaggerate the situation. Climatic changes over Northern Eurasia during the 20th century have been reflected in many atmospheric and terrestrial variables. These include various snow cover, agricultural and phenological characteristics, temperature and precipitation changes, as well as changes in derived variables of economic, social and ecological interest. Among these variables are the frequency of extremes in precipitation and temperature; frequency and duration of no-rain periods; agricultural and hydrological droughts; frequency of thaws and days with severe fire danger; heating degree days; growing season duration; sum of temperatures above/below a given threshold; days without frost; day-to-day temperature variability; precipitation frequency; and precipitation type fraction. We shall systematically present these changes observed during the past 50 to

  13. Single substitutions to closely related amino acids contribute to the functional diversification of an insect-inducible, positively selected plant cystatin.

    PubMed

    Rasoolizadeh, Asieh; Goulet, Marie-Claire; Sainsbury, Frank; Cloutier, Conrad; Michaud, Dominique

    2016-04-01

    A causal link has been reported between positively selected amino acids in plant cystatins and the inhibitory range of these proteins against insect digestive cysteine (Cys) proteases. Here we assessed the impact of single substitutions to closely related amino acids on the contribution of positive selection to cystatin diversification. Cystatin sequence alignments, while confirming hypervariability, indicated a preference for related amino acids at positively selected sites. For example, the non-polar residues leucine (Leu), isoleucine (Ile) and valine (Val) were shown to predominate at positively selected site 2 in the N-terminal region, unlike selected sites 6 and 10, where polar residues are preferred. The model cystatin SlCYS8 and single variants with Leu, Ile or Val at position 2 were compared with regard to their ability to bind digestive proteases of the coleopteran pest Leptinotarsa decemlineata and to induce compensatory responses in this insect. A functional proteomics procedure to capture target Cys proteases in midgut extracts allowed confirmation of distinct binding profiles for the cystatin variants. A shotgun proteomics procedure to monitor whole Cys protease complements revealed protease family specific compensatory responses in the insect, dependent on the variant ingested. Our data confirm the contribution of closely related amino acids to the functional diversity of positively selected plant cystatins in a broader structure/function context imposing physicochemical constraints to primary structure alterations. They also underline the complexity of protease/inhibitor interactions in plant-insect systems, and the challenges still to be met in order to harness the full potential of ectopically expressed protease inhibitors in crop protection.

  14. Position effects in encoding briefly exposed item matrices: evidence for a reading bias or merely a matter of the selection criterion?

    PubMed

    Lass, Uta; Yan, Song; Chen, Guopeng; Becker, Dietrich; Lüer, Gerd

    2008-11-01

    Position effects are frequently reported in experiments that investigate the recognition of items from briefly exposed stimulus matrices. A reliable finding is the ability to report items from the first row of the matrix more accurately than from the second row. The present experiments explore whether this position effect depends upon the selection criterion used to indicate the subgroup of items that has to be reported in a given trial. In Experiment 1, German and Chinese participants were presented with language-specific items which had to be selected by column. In Experiment 2, Germans were presented with Latin letters and the selection criterion was letter color. A strong row effect was evident in both experiments although the selection criteria did not prompt a line-by-line grouping of the items. The row effect is seen as a manifestation of top-down processing that is derived from reading habits.

  15. Evolutionary analysis of classical HLA class I and II genes suggests that recent positive selection acted on DPB1*04:01 in Japanese population.

    PubMed

    Kawashima, Minae; Ohashi, Jun; Nishida, Nao; Tokunaga, Katsushi

    2012-01-01

    The human leukocyte antigen (HLA) genes exhibit the highest degree of polymorphism in the human genome. This high degree of variation at classical HLA class I and class II loci has been maintained by balancing selection for a long evolutionary time. However, little is known about recent positive selection acting on specific HLA alleles in a local population. To detect the signature of recent positive selection, we genotyped six HLA loci, HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 in 418 Japanese subjects, and then assessed the haplotype homozygosity (HH) of each HLA allele. There were 120 HLA alleles across the six loci. Among the 80 HLA alleles with frequencies of more than 1%, DPB1*04∶01, which had a frequency of 6.1%, showed exceptionally high HH (0.53). This finding raises the possibility that recent positive selection has acted on DPB1*04∶01. The DPB1*04∶01 allele, which was present in the most common 6-locus HLA haplotype (4.4%), A*33∶03-C*14∶03-B*44∶03-DRB1*13∶02-DQB1*06∶04-DPB1*04∶01, seems to have flowed from the Korean peninsula to the Japanese archipelago in the Yayoi period. A stochastic simulation approach indicated that the strong linkage disequilibrium between DQB1*06∶04 and DPB1*04∶01 observed in Japanese cannot be explained without positive selection favoring DPB1*04∶01. The selection coefficient of DPB1*04∶01 was estimated as 0.041 (95% credible interval 0.021-0.077). Our results suggest that DPB1*04∶01 has recently undergone strong positive selection in Japanese population.

  16. Social gating of sensory information during ongoing communication.

    PubMed

    Anders, Silke; Heussen, Yana; Sprenger, Andreas; Haynes, John-Dylan; Ethofer, Thomas

    2015-01-01

    Social context plays an important role in human communication. Depending on the nature of the source, the same communication signal might be processed in fundamentally different ways. However, the selective modulation (or "gating") of the flow of neural information during communication is not fully understood. Here, we use multivoxel pattern analysis (MVPA) and multivoxel connectivity analysis (MVCA), a novel technique that allows to analyse context-dependent changes of the strength interregional coupling between ensembles of voxels, to examine how the human brain differentially gates content-specific sensory information during ongoing perception of communication signals. In a simulated electronic communication experiment, participants received two alternative text messages during fMRI ("happy" or "sad") which they believed had been sent either by their real-life friend outside the scanner or by a computer. A region in the dorsal medial prefrontal cortex (dmPFC) selectively increased its functional coupling with sensory-content encoding regions in the visual cortex when a text message was perceived as being sent by the participant's friend, and decreased its functional coupling with these regions when a text message was perceived as being sent by the computer. Furthermore, the strength of neural encoding of content-specific information of text messages in the dmPFC was modulated by the social tie between the participant and her friend: the more of her spare time a participant reported to spend with her friend the stronger was the neural encoding. This suggests that the human brain selectively gates sensory information into the relevant network for processing the mental states of others, depending on the source of the communication signal.

  17. Mutation at positively selected positions in the binding site for HLA-C shows that KIR2DL1 is a more refined but less adaptable NK cell receptor than KIR2DL3.

    PubMed

    Hilton, Hugo G; Vago, Luca; Older Aguilar, Anastazia M; Moesta, Achim K; Graef, Thorsten; Abi-Rached, Laurent; Norman, Paul J; Guethlein, Lisbeth A; Fleischhauer, Katharina; Parham, Peter

    2012-08-01

    Through recognition of HLA class I, killer cell Ig-like receptors (KIR) modulate NK cell functions in human immunity and reproduction. Although a minority of HLA-A and -B allotypes are KIR ligands, HLA-C allotypes dominate this regulation, because they all carry either the C1 epitope recognized by KIR2DL2/3 or the C2 epitope recognized by KIR2DL1. The C1 epitope and C1-specific KIR evolved first, followed several million years later by the C2 epitope and C2-specific KIR. Strong, varying selection pressure on NK cell functions drove the diversification and divergence of hominid KIR, with six positions in the HLA class I binding site of KIR being targets for positive diversifying selection. Introducing each naturally occurring residue at these positions into KIR2DL1 and KIR2DL3 produced 38 point mutants that were tested for binding to 95 HLA- A, -B, and -C allotypes. Modulating specificity for HLA-C is position 44, whereas positions 71 and 131 control cross-reactivity with HLA-A*11:02. Dominating avidity modulation is position 70, with lesser contributions from positions 68 and 182. KIR2DL3 has lower avidity and broader specificity than KIR2DL1. Mutation could increase the avidity and change the specificity of KIR2DL3, whereas KIR2DL1 specificity was resistant to mutation, and its avidity could only be lowered. The contrasting inflexibility of KIR2DL1 and adaptability of KIR2DL3 fit with C2-specific KIR having evolved from C1-specific KIR, and not vice versa. Substitutions restricted to activating KIR all reduced the avidity of KIR2DL1 and KIR2DL3, further evidence that activating KIR function often becomes subject to selective attenuation.

  18. Selective lesion of cholinergic neurons in the medial septum by 192 IgG-saporin impairs learning in a delayed matching to position T-maze paradigm.

    PubMed

    Johnson, David A; Zambon, Natalie J; Gibbs, Robert B

    2002-07-05

    This study examined whether selective destruction of cholinergic neurons in the medial septum impairs acquisition of a delayed matching-to-position (DMP) spatial memory task. Either the selective immunotoxin 192 IgG-saporin (SAP; 0.22 or 1.0 microg) or the non-selective excitatory neurotoxin ibotenate (IBO; 5 microg), was infused directly into the medial septum of rats. Both doses of SAP, but not IBO, significantly impaired acquisition of the DMP task and blunted the initial alternating behavior of the rats in the T-maze. Histochemical staining revealed that both doses of SAP produced a near complete depletion of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Some loss of parvalbumin staining was observed following administration of the higher dose, but not the lower dose, of SAP. In contrast, IBO produced a nearly complete depletion of parvalbumin-positive staining throughout the medial septum. IBO also produced a loss of ChAT-positive neurons and considerable local damage in the medial septum around the area of injection; however, many ChAT-positive neurons in the medial septum distal to the injection remained. A significant correlation between the number of days to reach criterion and ChAT activity in the frontal cortex and hippocampus was observed. The results suggest that low doses of SAP can be used to selectively destroy cholinergic neurons in the medial septum, and that selective destruction of these neurons significantly impairs acquisition of the DMP task. We propose that acquisition of the DMP task is a sensitive behavioral assay for the selective loss of basal forebrain cholinergic projections.

  19. An Investigation of the Relationship between Forms of Positive Interdependence, Social Support, and Selected Aspects of Classroom Climate

    ERIC Educational Resources Information Center

    Ghaith, Ghazi M.; Shaaban, Kassim A.; Harkous, Samar A.

    2007-01-01

    Studies on the effect of cooperative learning have demonstrated its efficacy in improving the cognitive and non-cognitive outcomes of schooling. However, it remains unclear what forms of cooperation are especially effective in multilingual contexts. This research examines the connection between positive goal interdependence and positive resource…

  20. 42 CFR 460.192 - Ongoing monitoring after trial period.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 4 2010-10-01 2010-10-01 false Ongoing monitoring after trial period. 460.192 Section 460.192 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN... FOR THE ELDERLY (PACE) Federal/State Monitoring § 460.192 Ongoing monitoring after trial period....

  1. 10 CFR 1045.20 - Ongoing call for declassification proposals.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Ongoing call for declassification proposals. 1045.20 Section 1045.20 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) NUCLEAR CLASSIFICATION AND DECLASSIFICATION Identification of Restricted Data and Formerly Restricted Data Information § 1045.20 Ongoing...

  2. A Case Study of the Progressive Impact of School-Wide Positive Behavior Support on Five Selected Student Performance Factors in a Missouri K-12 Alternative Public School

    ERIC Educational Resources Information Center

    Becker, Colleen Gilday

    2013-01-01

    The purpose of this case study was to examine the School-Wide Positive Behavior Support (SWPBS) impact on five selected student performance factors. A literature review revealed there have been many SWPBS research studies regarding traditional public schools. However, there have not been any published empirical SWPBS studies involving K-12…

  3. Positive selection and functional divergence of R2R3-MYB paralogous genes expressed in inflorescence buds of Scutellaria species (Labiatae).

    PubMed

    Huang, Bing-Hong; Pang, Erli; Chen, Yi-Wen; Cao, Huifen; Ruan, Yu; Liao, Pei-Chun

    2015-03-13

    Anthocyanin is the main pigment forming floral diversity. Several transcription factors that regulate the expression of anthocyanin biosynthetic genes belong to the R2R3-MYB family. Here we examined the transcriptomes of inflorescence buds of Scutellaria species (skullcaps), identified the expression R2R3-MYBs, and detected the genetic signatures of positive selection for adaptive divergence across the rapidly evolving skullcaps. In the inflorescence buds, seven R2R3-MYBs were identified. MYB11 and MYB16 were detected to be positively selected. The signature of positive selection on MYB genes indicated that species diversification could be affected by transcriptional regulation, rather than at the translational level. When comparing among the background lineages of Arabidopsis, tomato, rice, and Amborella, heterogeneous evolutionary rates were detected among MYB paralogs, especially between MYB13 and MYB19. Significantly different evolutionary rates were also evidenced by type-I functional divergence between MYB13 and MYB19, and the accelerated evolutionary rates in MYB19, implied the acquisition of novel functions. Another paralogous pair, MYB2/7 and MYB11, revealed significant radical amino acid changes, indicating divergence in the regulation of different anthocyanin-biosynthetic enzymes. Our findings not only showed that Scutellaria R2R3-MYBs are functionally divergent and positively selected, but also indicated the adaptive relevance of regulatory genes in floral diversification.

  4. Conserved hypothetical protein Rv1977 in Mycobacterium tuberculosis strains contains sequence polymorphisms and might be involved in ongoing immune evasion.

    PubMed

    Jiang, Yi; Liu, Haican; Wang, Xuezhi; Li, Guilian; Qiu, Yan; Dou, Xiangfeng; Wan, Kanglin

    2015-01-01

    Host immune pressure and associated parasite immune evasion are key features of host-pathogen co-evolution. A previous study showed that human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved and thus it was deduced that M. tuberculosis lacks antigenic variation and immune evasion. Here, we selected 151 clinical Mycobacterium tuberculosis isolates from China, amplified gene encoding Rv1977 and compared the sequences. The results showed that Rv1977, a conserved hypothetical protein, is not conserved in M. tuberculosis strains and there are polymorphisms existed in the protein. Some mutations, especially one frameshift mutation, occurred in the antigen Rv1977, which is uncommon in M.tb strains and may lead to the protein function altering. Mutations and deletion in the gene all affect one of three T cell epitopes and the changed T cell epitope contained more than one variable position, which may suggest ongoing immune evasion.

  5. Selective and Nonselective Cleavages in Positive and Negative CID of the Fragments Generated from In-Source Decay of Intact Proteins in MALDI-MS

    NASA Astrophysics Data System (ADS)

    Takayama, Mitsuo; Sekiya, Sadanori; Iimuro, Ryunosuke; Iwamoto, Shinichi; Tanaka, Koichi

    2014-01-01

    Selective and nonselective cleavages in ion trap low-energy collision-induced dissociation (CID) experiments of the fragments generated from in-source decay (ISD) with matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) of intact proteins are described in both positive and negative ion modes. The MALDI-ISD spectra of the proteins demonstrate common, discontinuous, abundant c- and z'-ions originating from cleavage at the N-Cα bond of Xxx-Asp/Asn and Gly-Xxx residues in both positive- and negative-ion modes. The positive ion CID of the c- and z'-ions resulted in product ions originating from selective cleavage at Asp-Xxx, Glu-Xxx and Cys-Xxx residues. Nonselective cleavage product ions rationalized by the mechanism of a "mobile proton" are also observed in positive ion CID spectra. Negative ion CID of the ISD fragments results in complex product ions accompanied by the loss of neutrals from b-, c-, and y-ions. The most characteristic feature of negative ion CID is selective cleavage of the peptide bonds of acidic residues, Xxx-Asp/Glu/Cys. A definite influence of α-helix on the CID product ions was not obtained. However, the results from positive ion and negative ion CID of the MALDI-ISD fragments that may have long α-helical domains suggest that acidic residues in helix-free regions tend to degrade more than those in helical regions.

  6. Morphological stasis in an ongoing gastropod radiation from Lake Malawi

    PubMed Central

    Van Bocxlaer, Bert; Hunt, Gene

    2013-01-01

    Evolutionary processes leading to adaptive radiation regularly occur too fast to be accurately recorded in the fossil record but too slowly to be readily observed in living biota. The study of evolutionary radiations is thereby confronted with an epistemological gap between the timescales and approaches used by neontologists and paleontologists. Here we report on an ongoing radiation of extant Bellamya species (n = 4) from the African Rift Lake Malawi that provides an unusual opportunity to bridge this gap. The substantial molecular differentiation in this monophyletic Bellamya clade has arisen since Late Pleistocene megadroughts in the Malawi Basin caused by climate change. Morphological time-series analysis of a high-resolution, radiocarbon-dated sequence of 22 faunas spanning the Holocene documents stasis up to the middle Holocene in all traits studied (shell height, number of whorls, and two variables obtained from geometric morphometrics). Between deposition of the last fossil fauna (∼5 ka) and the present day, a drastic increase in morphological disparity was observed (3.7–5.8 times) associated with an increase in species diversity. Comparison of the rates of morphological evolution obtained from the paleontological time-series with phylogenetic rates indicates that the divergence in two traits could be reconstructed with the slow rates documented in the fossils, that one trait required a rate reduction (stabilizing selection), and the other faster rates (divergent selection). The combined paleontological and comparative approach taken here allows recognition that morphological stasis can be the dominant evolutionary pattern within species lineages, even in very young and radiating clades. PMID:23924610

  7. Trauma-Focused CBT for Youth who Experience Ongoing Traumas

    PubMed Central

    Cohen, Judith A.; Mannarino, Anthony P.; Murray, Laura A.

    2011-01-01

    Many youth experience ongoing trauma exposure, such as domestic or community violence. Clinicians often ask whether evidence-based treatments containing exposure components to reduce learned fear responses to historical trauma are appropriate for these youth. Essentially the question is, if youth are desensitized to their trauma experiences, will this in some way impair their responding to current or ongoing trauma? The paper addresses practical strategies for implementing one evidence-based treatment, Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) for youth with ongoing traumas. Collaboration with local therapists and families participating in TF-CBT community and international programs elucidated effective strategies for applying TF-CBT with these youth. These strategies included: 1) enhancing safety early in treatment; 2) effectively engaging parents who experience personal ongoing trauma; and 3) during the trauma narrative and processing component focusing on a) increasing parental awareness and acceptance of the extent of the youths’ ongoing trauma experiences; b) addressing youths’ maladaptive cognitions about ongoing traumas; and c) helping youth differentiate between real danger and generalized trauma reminders. Case examples illustrate how to use these strategies in diverse clinical situations. Through these strategies TF-CBT clinicians can effectively improve outcomes for youth experiencing ongoing traumas. PMID:21855140

  8. Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y

    PubMed Central

    Wilde, Sandra; Timpson, Adrian; Kirsanow, Karola; Kaiser, Elke; Kayser, Manfred; Unterländer, Martina; Hollfelder, Nina; Potekhina, Inna D.; Schier, Wolfram; Thomas, Mark G.; Burger, Joachim

    2014-01-01

    Pigmentation is a polygenic trait encompassing some of the most visible phenotypic variation observed in humans. Here we present direct estimates of selection acting on functional alleles in three key genes known to be involved in human pigmentation pathways—HERC2, SLC45A2, and TYR—using allele frequency estimates from Eneolithic, Bronze Age, and modern Eastern European samples and forward simulations. Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2–10% per generation. Our results provide direct evidence that strong selection favoring lighter skin, hair, and eye pigmentation has been operating in European populations over the last 5,000 y. PMID:24616518

  9. Relation of Landscape Position and Irrigation to Concentrations of Alachlor, Atrazine, and Selected Degradates in Regolith in Northeastern Nebraska

    USGS Publications Warehouse

    Verstraeten, Ingrid M.; Lewis, D.T.; McCallister, D.L.; Parkhurst, A.; Thurman, E.M.

    1996-01-01

    Concentrations of alachlor, its ethanesulfonic acid degradate, atrazine and its degradates, deethylatrazine and deisopropylatrazine, in the upper regolith and associated shallow aquifers were determined in relation to landscape position (floodplains, terraces, and uplands) and irrigation (nonirrigated and irrigated corn cropland) in 1992. Irrigated and nonirrigated sites were located on each landscape position. Samples were collected from three depths. Canonical discriminant and multivariate analyses were used to interpret data. Herbicides and their degradation products tended to be present in soils with high percent organic matter, low pH, and low sand content. Atrazine was present more frequently on the floodplain at all depths than the other compounds. Atrazine (maximum 17.5 ??g/kg) and ethanesulfonic acid (maximum 10 ??g/kg) were associated with landscape position, but not with irrigation. Alachlor (maximum 24 ??g/kg), deethylatrazine (maximum 1.5 ??g/kg), and deisopropylatrazine (maximum 3.5 ??g/kg) were not significantly associated with either landscape position or irrigation. Ground-water analytical results suggested that concentrations of these herbicides and degradates in ground water did not differ among landscape position or between irrigated and nonirrigated corn cropland.

  10. The self-study: an ongoing evaluative process.

    PubMed

    Scott, E

    1986-01-01

    The benefits from an ongoing evaluation process cannot be overstated for programs in radiologic technology. The importance of an ongoing evaluation is heightened because of the relationship of accreditation. Problems may be detected early in their development and appropriate solutions found before a crisis stage is reached. Additionally, ongoing evaluations would give us a body of information to contribute to our professional literature. A values-oriented approach to evaluation should be used as these evaluations provide information on the worth of a project and solutions for improvement. The CIPP model lends itself perfectly to our needs in radiologic technology.

  11. Selecting Children's Picture Books with Positive Chinese, Japanese, and Other Asian and Asian-American Fathers and Father Figures.

    ERIC Educational Resources Information Center

    Heller, Craig; Cunningham, Bruce; Lee, Ginny; Heller, Hannah M.

    2000-01-01

    Discusses distinctive children's picture books that depict Asian fathers and other men who play significant roles in the lives of children. Books are grouped by theme, such as fairly tale versus real life, Asian immigration to North America, and discipline. Includes guidelines for selecting and evaluating books and appropriate classroom teaching…

  12. Production of marker-free disease-resistant potato using isopentenyl transferase gene as a positive selection marker.

    PubMed

    Khan, Raham Sher; Ntui, Valentine Otang; Chin, Dong Poh; Nakamura, Ikuo; Mii, Masahiro

    2011-04-01

    The use of antibiotic or herbicide resistant genes as selection markers for production of transgenic plants and their continuous presence in the final transgenics has been a serious problem for their public acceptance and commercialization. MAT (multi-auto-transformation) vector system has been one of the different strategies to excise the selection marker gene and produce marker-free transgenic plants. In the present study, ipt (isopentenyl transferase) gene was used as a selection marker gene. A chitinase gene, ChiC (isolated from Streptomyces griseus strain HUT 6037) was used as a gene of interest. ChiC gene was cloned from the binary vector, pEKH1 to an ipt-type MAT vector, pMAT21 by gateway cloning and transferred to Agrobacterium tumefaciens strain EHA105. The infected tuber discs of potato were cultured on hormone- and antibiotic-free MS medium. Seven of the 35 explants infected with the pMAT21/ChiC produced shoots. The same antibiotic- and hormones-free MS medium was used in subcultures of the shoots (ipt like and normal shoots). Molecular analyses of genomic DNA from transgenic plants confirmed the integration of gene of interest and excision of the selection marker in 3 of the 7 clones. Expression of ChiC gene was confirmed by Northern blot and western blot analyses. Disease-resistant assay of the marker-free transgenic, in vitro and greenhouse-grown plants exhibited enhanced resistance against Alternaria solani (early blight), Botrytis cinerea (gray mold) and Fusarium oxysporum (Fusarium wilt). From these results it could be concluded that ipt gene can be used as a selection marker to produce marker-free disease-resistant transgenic potato plants on PGR- and antibiotic-free MS medium.

  13. Ion channels of N-terminally linked alamethicin dimers: enhancement of cation-selectivity by substitution of Glu for Gln at position 7.

    PubMed

    Okazaki, Takashi; Nagaoka, Yasuo; Asami, Koji

    2007-05-01

    Alamethicin forms voltage-gated ion channels that have moderate cation-selectivity. The enhancement of the cation-selectivity by introducing negatively charged residues at positions 7 and 18 has been studied using the tethered homodimers of alamethicin with Q7 and E18 (di-alm-Q7E18) and its analog with E7 and Q18 (di-alm-E7Q18). In the dimeric peptides, monomer peptides are linked at the N-termini by a disulfide bond. Both the peptides formed long lasting ion channels at cis-positive voltages when added to the cis-side membrane. Their long open duration enabled us to obtain current-voltage (I-V(m)) relations and reversal potentials at the single-channel level by applying a voltage ramp during the channel opening. The reversal potentials measured in asymmetric KCl solutions indicated that ionized E7 provided strong cation-selectivity, whereas ionized E18 little influenced the charge selectivity. This was also the case for the macroscopic charge selectivity determined from the reversal potentials obtained by the macroscopic I-V(m) measurements. The results are accounted for by stronger electrostatic interactions between permeant ions and negatively charged residues at the narrowest part of the pore than at the pore mouth.

  14. Competition between "Meta Effect" Photochemical Reactions of Selected Benzophenone Compounds Having Two Different Substituents at Meta Positions.

    PubMed

    Ma, Jiani; Li, Huai; Zhang, Xiting; Tang, Wen-Jian; Li, Mingde; Phillips, David Lee

    2016-10-21

    Recent studies conducted on some "meta effect" photochemical reactions focused on aromatic carbonyls having a substitution on one meta position of the benzophenone (BP) and anthraquinone parent compound. In this paper, two different substitutions were introduced with one at each meta position of the BP parent compound to investigate possible competition between different types of meta effect photochemistry observed in acidic solutions containing water. The photochemical pathways of 3-hydroxymethyl-3'-fluorobenzophenone (1) and 3-fluoro-3'-methylbenzophenone (2) were explored in several solvents, including acidic water-containing solutions, using time-resolved spectroscopic experiments and density functional theory computations. It is observed that 1 can undergo a photoredox reaction and 2 can undergo a meta-methyl deprotonation reaction in acidic water-containing solutions. Comparison of these results to those previously reported for the analogous BP derivatives that contain only one substituent at a meta position indicates the introduction of electron-donating (such as hydroxyl) and electron-withdrawing groups (such as F) on the meta positions of BP can influence the meta effect photochemical reactions. It was found that involvement of an electron-donating moiety facilitates the meta effect photochemical reactions by stabilizing the crucial reactive biradical intermediate associated with the meta effect photochemical reactions.

  15. Selective loss of parvalbumin-positive GABAergic interneurons in the cerebral cortex of maternally stressed Gad1-heterozygous mouse offspring.

    PubMed

    Uchida, T; Furukawa, T; Iwata, S; Yanagawa, Y; Fukuda, A

    2014-03-11

    Exposure to maternal stress (MS) and mutations in GAD1, which encodes the γ-aminobutyric acid (GABA) synthesizing enzyme glutamate decarboxylase (GAD) 67, are both risk factors for psychiatric disorders. However, the relationship between these risk factors remains unclear. Interestingly, the critical period of MS for psychiatric disorders in offspring corresponds to the period of GABAergic neuron neurogenesis and migration in the fetal brain, that is, in the late stage of gestation. Indeed, decrement of parvalbumin (PV)-positive GABAergic interneurons in the medial prefrontal cortex (mPFC) and hippocampus (HIP) has often been observed in schizophrenia patients. In the present study, we used GAD67-green fluorescent protein (GFP) knock-in mice (that is, mice in which the Gad1 gene is heterozygously deleted; GAD67(+/GFP)) that underwent prenatal stress from embryonic day 15.0 to 17.5 and monitored PV-positive GABAergic neurons to address the interaction between Gad1 disruption and stress. Administration of 5-bromo-2-deoxyuridine revealed that neurogenesis of GFP-positive GABAergic neurons, but not cortical plate cells, was significantly diminished in fetal brains during MS. Differential expression of glucocorticoid receptors by different progenitor cell types may underlie this differential outcome. Postnatally, the density of PV-positive, but not PV-negative, GABAergic neurons was significantly decreased in the mPFC, HIP and somatosensory cortex but not in the motor cortex of GAD67(+/GFP) mice. By contrast, these findings were not observed in wild-type (GAD67(+/+)) offspring. These results suggest that prenatal stress, in addition to heterozygous deletion of Gad1, could specifically disturb the proliferation of neurons destined to be PV-positive GABAergic interneurons.

  16. Versatile protein-based bifunctional nano-systems (encapsulation and directed assembly): Selective nanoscale positioning of gold nanoparticle-viral protein hybrids

    NASA Astrophysics Data System (ADS)

    Zheng, Bin; Zettsu, Nobuyuki; Fukuta, Megumi; Uenuma, Mutsunori; Hashimoto, Tatsuya; Gamo, Kentaro; Uraoka, Yukiharu; Yamashita, Ichiro; Watanabe, Heiji

    2011-04-01

    We demonstrate a selective nanoscale positioning of targeted Au nanoparticles (NPs) through a bifunctional protein-based encapsulation/delivery system. The newly designed recombinant bifunctional protein, appended with both gold-binding peptide (GBP) and Ti/Si-binding peptide (TBP) at the C- and N-termini efficiently encapsulated 15-20 nm-diameter Au NPs during the pH-controlled reversible reassembly process, and showed the ability of the internalized Au NPs in selective binding to nanometer-scale Ti islands without overshooting. This highly controlled placement of the Au NPs on substrates can be employed to make both large scale devices and point-contact devices.

  17. Positive Selection in CD8+ T-Cell Epitopes of Influenza Virus Nucleoprotein Revealed by a Comparative Analysis of Human and Swine Viral Lineages

    PubMed Central

    Machkovech, Heather M.; Bedford, Trevor; Suchard, Marc A.

    2015-01-01

    ABSTRACT Numerous experimental studies have demonstrated that CD8+ T cells contribute to immunity against influenza by limiting viral replication. It is therefore surprising that rigorous statistical tests have failed to find evidence of positive selection in the epitopes targeted by CD8+ T cells. Here we use a novel computational approach to test for selection in CD8+ T-cell epitopes. We define all epitopes in the nucleoprotein (NP) and matrix protein (M1) with experimentally identified human CD8+ T-cell responses and then compare the evolution of these epitopes in parallel lineages of human and swine influenza viruses that have been diverging since roughly 1918. We find a significant enrichment of substitutions that alter human CD8+ T-cell epitopes in NP of human versus swine influenza virus, consistent with the idea that these epitopes are under positive selection. Furthermore, we show that epitope-altering substitutions in human influenza virus NP are enriched on the trunk versus the branches of the phylogenetic tree, indicating that viruses that acquire these mutations have a selective advantage. However, even in human influenza virus NP, sites in T-cell epitopes evolve more slowly than do nonepitope sites, presumably because these epitopes are under stronger inherent functional constraint. Overall, our work demonstrates that there is clear selection from CD8+ T cells in human influenza virus NP and illustrates how comparative analyses of viral lineages from different hosts can identify positive selection that is otherwise obscured by strong functional constraint. IMPORTANCE There is a strong interest in correlates of anti-influenza immunity that are protective against diverse virus strains. CD8+ T cells provide such broad immunity, since they target conserved viral proteins. An important question is whether T-cell immunity is sufficiently strong to drive influenza virus evolution. Although many studies have shown that T cells limit viral replication in animal

  18. 42 CFR 460.192 - Ongoing monitoring after trial period.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICES (CONTINUED) PROGRAMS OF ALL-INCLUSIVE CARE FOR THE ELDERLY (PACE) PROGRAMS OF ALL-INCLUSIVE CARE FOR THE ELDERLY (PACE) Federal/State Monitoring § 460.192 Ongoing monitoring after trial period....

  19. 42 CFR 460.192 - Ongoing monitoring after trial period.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... SERVICES (CONTINUED) PROGRAMS OF ALL-INCLUSIVE CARE FOR THE ELDERLY (PACE) PROGRAMS OF ALL-INCLUSIVE CARE FOR THE ELDERLY (PACE) Federal/State Monitoring § 460.192 Ongoing monitoring after trial period....

  20. Using ArcMap, Google Earth, and Global Positioning Systems to select and locate random households in rural Haiti

    PubMed Central

    2013-01-01

    Background A remote sensing technique was developed which combines a Geographic Information System (GIS); Google Earth, and Microsoft Excel to identify home locations for a random sample of households in rural Haiti. The method was used to select homes for ethnographic and water quality research in a region of rural Haiti located within 9 km of a local hospital and source of health education in Deschapelles, Haiti. The technique does not require access to governmental records or ground based surveys to collect household location data and can be performed in a rapid, cost-effective manner. Methods The random selection of households and the location of these households during field surveys were accomplished using GIS, Google Earth, Microsoft Excel, and handheld Garmin GPSmap 76CSx GPS units. Homes were identified and mapped in Google Earth, exported to ArcMap 10.0, and a random list of homes was generated using Microsoft Excel which was then loaded onto handheld GPS units for field location. The development and use of a remote sensing method was essential to the selection and location of random households. Results A total of 537 homes initially were mapped and a randomized subset of 96 was identified as potential survey locations. Over 96% of the homes mapped using Google Earth imagery were correctly identified as occupied dwellings. Only 3.6% of the occupants of mapped homes visited declined to be interviewed. 16.4% of the homes visited were not occupied at the time of the visit due to work away from the home or market days. A total of 55 households were located using this method during the 10 days of fieldwork in May and June of 2012. Conclusions The method used to generate and field locate random homes for surveys and water sampling was an effective means of selecting random households in a rural environment lacking geolocation infrastructure. The success rate for locating households using a handheld GPS was excellent and only rarely was local knowledge

  1. Multiyear measurements of Position Angle and Separation of selected binary stars from the Washington Double Star Catalog

    NASA Astrophysics Data System (ADS)

    Muller, Rafael J.; Cersosimo, Juan C.; Lopez, Andy J.; Vergara, Nelson; Torres, Brian; Mendoza, Lizyan; Ortiz, Deliris; Del Valle, Yashira; Espinosa, Gabriela; Reyes, Marjory

    2016-01-01

    We present here the multiyear data sets on separation and position angle of binary stars obtained at the NURO telescope, located east of Flagstaff Arizona at an elevation of 7200 feet. The data was analyzed at the Humacao University Observatory of the University of Puerto Rico and will be submitted for publication at the Journal of Double Star Observations. We describe the methodology for the analysis of the images we obtained.

  2. A sensitive dual-fluorescence reporter system enables positive selection of ras suppressors by suppression of ras-induced apoptosis.

    PubMed

    Dolnikov, Alla; Shen, Sylvie; Millington, Michelle; Passioura, Toby; Pedler, Michelle; Rasko, John Edward Joshua; Symonds, Geoff

    2003-10-01

    We have developed a novel dual-fluorescence reporter system incorporating green (GFP) and red (RFP) fluorescent proteins to monitor expression of the N-ras(m) gene and an N-ras(m) suppressor, respectively. Retroviral vectors were produced in which human N-ras(m) (codon 13 mutation) was coexpressed with GFP, and a ribozyme specifically targeting N-ras(m) was coexpressed with RFP. N-Ras(m) suppression was monitored by measurement of GFP fluorescence in dual-fluorescent (GFP and RFP) cells. We demonstrated that the degree of N-ras(m) suppression was dependent on the ribozyme dose, proportional to red fluorescence, in dual-fluorescent cells. We further showed that ribozyme-mediated N-ras(m)suppression inhibited growth of NIH3T3 and CD34-positive TF-1 cells. In these cultures, ras suppressor activity resulted in the depletion of suppressor-positive cells due to inhibition of cell growth. In contrast, N-ras(m) suppression produced a growth advantage to human leukemic K562 cells, presumably by inhibiting N-ras(m)-induced apoptosis. In K562 cells, ras suppression resulted in the outgrowth of suppressor-positive cells. This provides a platform to identify suppressors of ras that is based on function.

  3. Positive Selection of Deleterious Alleles through Interaction with a Sex-Ratio Suppressor Gene in African Buffalo: A Plausible New Mechanism for a High Frequency Anomaly

    PubMed Central

    van Hooft, Pim; Greyling, Ben J.; Getz, Wayne M.; van Helden, Paul D.; Zwaan, Bas J.; Bastos, Armanda D. S.

    2014-01-01

    Although generally rare, deleterious alleles can become common through genetic drift, hitchhiking or reductions in selective constraints. Here we present a possible new mechanism that explains the attainment of high frequencies of deleterious alleles in the African buffalo (Syncerus caffer) population of Kruger National Park, through positive selection of these alleles that is ultimately driven by a sex-ratio suppressor. We have previously shown that one in four Kruger buffalo has a Y-chromosome profile that, despite being associated with low body condition, appears to impart a relative reproductive advantage, and which is stably maintained through a sex-ratio suppressor. Apparently, this sex-ratio suppressor prevents fertility reduction that generally accompanies sex-ratio distortion. We hypothesize that this body-condition-associated reproductive advantage increases the fitness of alleles that negatively affect male body condition, causing genome-wide positive selection of these alleles. To investigate this we genotyped 459 buffalo using 17 autosomal microsatellites. By correlating heterozygosity with body condition (heterozygosity-fitness correlations), we found that most microsatellites were associated with one of two gene types: one with elevated frequencies of deleterious alleles that have a negative effect on body condition, irrespective of sex; the other with elevated frequencies of sexually antagonistic alleles that are negative for male body condition but positive for female body condition. Positive selection and a direct association with a Y-chromosomal sex-ratio suppressor are indicated, respectively, by allele clines and by relatively high numbers of homozygous deleterious alleles among sex-ratio suppressor carriers. This study, which employs novel statistical techniques to analyse heterozygosity-fitness correlations, is the first to demonstrate the abundance of sexually-antagonistic genes in a natural mammal population. It also has important

  4. Position-controlled III-V compound semiconductor nanowire solar cells by selective-area metal-organic vapor phase epitaxy.

    PubMed

    Fukui, Takashi; Yoshimura, Masatoshi; Nakai, Eiji; Tomioka, Katsuhiro

    2012-01-01

    We demonstrate position-controlled III-V semiconductor nanowires (NWs) by using selective-area metal-organic vapor phase epitaxy and their application to solar cells. Efficiency of 4.23% is achieved for InP core-shell NW solar cells. We form a 'flexible NW array' without a substrate, which has the advantage of saving natural resources over conventional thin film photovoltaic devices. Four junction NW solar cells with over 50% efficiency are proposed and discussed.

  5. Positive selection of deleterious alleles through interaction with a sex-ratio suppressor gene in African Buffalo: a plausible new mechanism for a high frequency anomaly.

    PubMed

    van Hooft, Pim; Greyling, Ben J; Getz, Wayne M; van Helden, Paul D; Zwaan, Bas J; Bastos, Armanda D S

    2014-01-01

    Although generally rare, deleterious alleles can become common through genetic drift, hitchhiking or reductions in selective constraints. Here we present a possible new mechanism that explains the attainment of high frequencies of deleterious alleles in the African buffalo (Syncerus caffer) population of Kruger National Park, through positive selection of these alleles that is ultimately driven by a sex-ratio suppressor. We have previously shown that one in four Kruger buffalo has a Y-chromosome profile that, despite being associated with low body condition, appears to impart a relative reproductive advantage, and which is stably maintained through a sex-ratio suppressor. Apparently, this sex-ratio suppressor prevents fertility reduction that generally accompanies sex-ratio distortion. We hypothesize that this body-condition-associated reproductive advantage increases the fitness of alleles that negatively affect male body condition, causing genome-wide positive selection of these alleles. To investigate this we genotyped 459 buffalo using 17 autosomal microsatellites. By correlating heterozygosity with body condition (heterozygosity-fitness correlations), we found that most microsatellites were associated with one of two gene types: one with elevated frequencies of deleterious alleles that have a negative effect on body condition, irrespective of sex; the other with elevated frequencies of sexually antagonistic alleles that are negative for male body condition but positive for female body condition. Positive selection and a direct association with a Y-chromosomal sex-ratio suppressor are indicated, respectively, by allele clines and by relatively high numbers of homozygous deleterious alleles among sex-ratio suppressor carriers. This study, which employs novel statistical techniques to analyse heterozygosity-fitness correlations, is the first to demonstrate the abundance of sexually-antagonistic genes in a natural mammal population. It also has important

  6. Identification of selective agonists and positive allosteric modulators for µ- and δ-opioid receptors from a single high-throughput screen.

    PubMed

    Burford, Neil T; Wehrman, Tom; Bassoni, Daniel; O'Connell, Jonathan; Banks, Martyn; Zhang, Litao; Alt, Andrew

    2014-10-01

    Hetero-oligomeric complexes of G protein-coupled receptors (GPCRs) may represent novel therapeutic targets exhibiting different pharmacology and tissue- or cell-specific site of action compared with receptor monomers or homo-oligomers. An ideal tool for validating this concept pharmacologically would be a hetero-oligomer selective ligand. We set out to develop and execute a 1536-well high-throughput screen of over 1 million compounds to detect potential hetero-oligomer selective ligands using a β-arrestin recruitment assay in U2OS cells coexpressing recombinant µ- and δ-opioid receptors. Hetero-oligomer selective ligands may bind to orthosteric or allosteric sites, and we might anticipate that the formation of hetero-oligomers may provide novel allosteric binding pockets for ligand binding. Therefore, our goal was to execute the screen in such a way as to identify positive allosteric modulators (PAMs) as well as agonists for µ, δ, and hetero-oligomeric receptors. While no hetero-oligomer selective ligands were identified (based on our selection criteria), this single screen did identify numerous µ- and δ-selective agonists and PAMs as well as nonselective agonists and PAMs. To our knowledge, these are the first µ- and δ-opioid receptor PAMs described in the literature.

  7. Socially selected ornaments and fitness: Signals of fighting ability in paper wasps are positively associated with survival, reproductive success, and rank.

    PubMed

    Tibbetts, Elizabeth A; Forrest, Taylor; Vernier, Cassondra; Jinn, Judy; Madagame, Andrew

    2015-11-01

    Many animals have ornaments that mediate choice and competition in social and sexual contexts. Individuals with elaborate sexual ornaments typically have higher fitness than those with less elaborate ornaments, but less is known about whether socially selected ornaments are associated with fitness. Here, we test the relationship between fitness and facial patterns that are a socially selected signal of fighting ability in Polistes dominula wasps. We found wasps that signal higher fighting ability have larger nests, are more likely to survive harsh winters, and obtain higher dominance rank than wasps that signal lower fighting ability. In comparison, body weight was not associated with fitness. Larger wasps were dominant over smaller wasps, but showed no difference in nest size or survival. Overall, the positive relationship between wasp facial patterns and fitness indicates that receivers can obtain diverse information about a signaler's phenotypic quality by paying attention to socially selected ornaments. Therefore, there are surprisingly strong parallels between the information conveyed by socially and sexually selected signals. Similar fitness relationships in social and sexually selected signals may be one reason it can be difficult to distinguish the role of social versus sexual selection in ornament evolution.

  8. Coreceptor signal strength regulates positive selection but does not determine CD4/CD8 lineage choice in a physiologic in vivo model.

    PubMed

    Erman, Batu; Alag, Amala S; Dahle, Oyvind; van Laethem, François; Sarafova, Sophia D; Guinter, Terry I; Sharrow, Susan O; Grinberg, Alexander; Love, Paul E; Singer, Alfred

    2006-11-15

    TCR signals drive thymocyte development, but it remains controversial what impact, if any, the intensity of those signals have on T cell differentiation in the thymus. In this study, we assess the impact of CD8 coreceptor signal strength on positive selection and CD4/CD8 lineage choice using novel gene knockin mice in which the endogenous CD8alpha gene has been re-engineered to encode the stronger signaling cytoplasmic tail of CD4, with the re-engineered CD8alpha gene referred to as CD8.4. We found that stronger signaling CD8.4 coreceptors specifically improved the efficiency of CD8-dependent positive selection and quantitatively increased the number of MHC class I (MHC-I)-specific thymocytes signaled to differentiate into CD8+ T cells, even for thymocytes expressing a single, transgenic TCR. Importantly, however, stronger signaling CD8.4 coreceptors did not alter the CD8 lineage choice of any MHC-I-specific thymocytes, even MHC-I-specific thymocytes expressing the high-affinity F5 transgenic TCR. This study documents in a physiologic in vivo model that coreceptor signal strength alters TCR-signaling thresholds for positive selection and so is a major determinant of the CD4:CD8 ratio, but it does not influence CD4/CD8 lineage choice.

  9. Effects of Gene Duplication, Positive Selection, and Shifts in Gene Expression on the Evolution of the Venom Gland Transcriptome in Widow Spiders

    PubMed Central

    Haney, Robert A.; Clarke, Thomas H.; Gadgil, Rujuta; Fitzpatrick, Ryan; Hayashi, Cheryl Y.; Ayoub, Nadia A.; Garb, Jessica E.

    2016-01-01

    Gene duplication and positive selection can be important determinants of the evolution of venom, a protein-rich secretion used in prey capture and defense. In a typical model of venom evolution, gene duplicates switch to venom gland expression and change function under the action of positive selection, which together with further duplication produces large gene families encoding diverse toxins. Although these processes have been demonstrated for individual toxin families, high-throughput multitissue sequencing of closely related venomous species can provide insights into evolutionary dynamics at the scale of the entire venom gland transcriptome. By assembling and analyzing multitissue transcriptomes from the Western black widow spider and two closely related species with distinct venom toxicity phenotypes, we do not find that gene duplication and duplicate retention is greater in gene families with venom gland biased expression in comparison with broadly expressed families. Positive selection has acted on some venom toxin families, but does not appear to be in excess for families with venom gland biased expression. Moreover, we find 309 distinct gene families that have single transcripts with venom gland biased expression, suggesting that the switching of genes to venom gland expression in numerous unrelated gene families has been a dominant mode of evolution. We also find ample variation in protein sequences of venom gland–specific transcripts, lineage-specific family sizes, and ortholog expression among species. This variation might contribute to the variable venom toxicity of these species. PMID:26733576

  10. Effects of Gene Duplication, Positive Selection, and Shifts in Gene Expression on the Evolution of the Venom Gland Transcriptome in Widow Spiders.

    PubMed

    Haney, Robert A; Clarke, Thomas H; Gadgil, Rujuta; Fitzpatrick, Ryan; Hayashi, Cheryl Y; Ayoub, Nadia A; Garb, Jessica E

    2016-01-05

    Gene duplication and positive selection can be important determinants of the evolution of venom, a protein-rich secretion used in prey capture and defense. In a typical model of venom evolution, gene duplicates switch to venom gland expression and change function under the action of positive selection, which together with further duplication produces large gene families encoding diverse toxins. Although these processes have been demonstrated for individual toxin families, high-throughput multitissue sequencing of closely related venomous species can provide insights into evolutionary dynamics at the scale of the entire venom gland transcriptome. By assembling and analyzing multitissue transcriptomes from the Western black widow spider and two closely related species with distinct venom toxicity phenotypes, we do not find that gene duplication and duplicate retention is greater in gene families with venom gland biased expression in comparison with broadly expressed families. Positive selection has acted on some venom toxin families, but does not appear to be in excess for families with venom gland biased expression. Moreover, we find 309 distinct gene families that have single transcripts with venom gland biased expression, suggesting that the switching of genes to venom gland expression in numerous unrelated gene families has been a dominant mode of evolution. We also find ample variation in protein sequences of venom gland-specific transcripts, lineage-specific family sizes, and ortholog expression among species. This variation might contribute to the variable venom toxicity of these species.

  11. Avionics Architectures for Exploration: Ongoing Efforts in Human Spaceflight

    NASA Technical Reports Server (NTRS)

    Goforth, Montgomery B.; Ratliff, James E.; Hames, Kevin L.; Vitalpur, Sharada V.; Woodman, Keith L.

    2014-01-01

    The field of Avionics is advancing far more rapidly in terrestrial applications than in spaceflight applications. Spaceflight Avionics are not keeping pace with expectations set by terrestrial experience, nor are they keeping pace with the need for increasingly complex automation and crew interfaces as we move beyond Low Earth Orbit. NASA must take advantage of the strides being made by both space-related and terrestrial industries to drive our development and sustaining costs down. This paper describes ongoing efforts by the Avionics Architectures for Exploration (AAE) project chartered by NASA's Advanced Exploration Systems (AES) Program to evaluate new avionic architectures and technologies, provide objective comparisons of them, and mature selected technologies for flight and for use by other AES projects. The AAE project team includes members from most NASA centers, and from industry. It is our intent to develop a common core avionic system that has standard capabilities and interfaces, and contains the basic elements and functionality needed for any spacecraft. This common core will be scalable and tailored to specific missions. It will incorporate hardware and software from multiple vendors, and be upgradeable in order to infuse incremental capabilities and new technologies. It will maximize the use of reconfigurable open source software (e.g., Goddard Space Flight Center's (GSFC's) Core Flight Software (CFS)). Our long-term focus is on improving functionality, reliability, and autonomy, while reducing size, weight, and power. Where possible, we will leverage terrestrial commercial capabilities to drive down development and sustaining costs. We will select promising technologies for evaluation, compare them in an objective manner, and mature them to be available for future programs. The remainder of this paper describes our approach, technical areas of emphasis, integrated test experience and results as of mid-2014, and future plans. As a part of the AES

  12. Cloning and characterization of wnt4a gene and evidence for positive selection in half-smooth tongue sole (Cynoglossus semilaevis)

    NASA Astrophysics Data System (ADS)

    Hu, Qiaomu; Zhu, Ying; Liu, Yang; Wang, Na; Chen, Songlin

    2014-11-01

    Wnt4 gene plays a role in developmental processes in mammals. However, little is known regarding its function in teleosts. We cloned and characterized the full-length half-smooth tongue sole (Cynoglossus semilaevis) wnt4a gene (CS-wnt4a). CS-wnt4a cDNA was 1746 bp in length encoding 353aa. CS-wnt4a expression level was highest in the testis, and gradually increased in the developing gonads until 1 year of age. In situ hybridization revealed that CS-wnt4a expression level was highest in stage II oocytes and sperm in the adult ovary and testis, respectively. CS-wnt4a expression level was significantly up-regulated in the gonads after exposure to high temperature. The level of methylation of the CS-wnt4a first exon was negatively correlated with the expression of CS-wnt4a. The branch-site model suggested that vertebrate wnt4a differed significantly from that of wnt4b, and that the selective pressures differed between ancestral aquatic and terrestrial organisms. Two positively selected sites were found in the ancestral lineages of teleost fish, but none in the ancestral lineages of mammals. One positively selected site was located on the α-helices of the 3D structure, the other on the random coil. Our results are of value for further study of the function of wnt4 and the mechanism of selection.

  13. Cloning and characterization of wnt4a gene and evidence for positive selection in half-smooth tongue sole (Cynoglossus semilaevis).

    PubMed

    Hu, Qiaomu; Zhu, Ying; Liu, Yang; Wang, Na; Chen, Songlin

    2014-11-24

    Wnt4 gene plays a role in developmental processes in mammals. However, little is known regarding its function in teleosts. We cloned and characterized the full-length half-smooth tongue sole (Cynoglossus semilaevis) wnt4a gene (CS-wnt4a). CS-wnt4a cDNA was 1746 bp in length encoding 353aa. CS-wnt4a expression level was highest in the testis, and gradually increased in the developing gonads until 1 year of age. In situ hybridization revealed that CS-wnt4a expression level was highest in stage II oocytes and sperm in the adult ovary and testis, respectively. CS-wnt4a expression level was significantly up-regulated in the gonads after exposure to high temperature. The level of methylation of the CS-wnt4a first exon was negatively correlated with the expression of CS-wnt4a. The branch-site model suggested that vertebrate wnt4a differed significantly from that of wnt4b, and that the selective pressures differed between ancestral aquatic and terrestrial organisms. Two positively selected sites were found in the ancestral lineages of teleost fish, but none in the ancestral lineages of mammals. One positively selected site was located on the α-helices of the 3D structure, the other on the random coil. Our results are of value for further study of the function of wnt4 and the mechanism of selection.

  14. Ethanol-dispersed and antibody-conjugated polymer nanofibers for the selective capture and 3-dimensional culture of EpCAM-positive cells.

    PubMed

    Yoon, Junghyo; Yoon, Hee-Sook; Shin, Yoojin; Kim, Sanghyun; Ju, Youngjun; Kim, Jungbae; Chung, Seok

    2017-03-08

    Electrospun and ethanol-dispersed polystyrene-poly(styrene-co-maleic anhydride) (PS-PSMA) nanofibers (NFs) were used as a platform for the selective capture and three-dimensional culture of EpCAM-positive cells in cell culture medium and whole blood. The NFs were treated with streptavidin to facilitate bond formation between the amino groups of streptavidin and the maleic anhydride groups of the NFs. A biotinylated anti-EpCAM monoclonal antibody (mAb) was attached to the streptavidin-conjugated NFs via the selective binding of streptavidin and biotin. Upon simple mixing and shaking with EpCAM-positive cancer cells in a wide concentration range from 10 to 1000,000 cells per 10mL, the mAb-attached NFs (mAb-NFs) captured the Ep-CAM positive cells in an efficiency of 59%-67% depending on initial cell concentrations, with minor mechanical capture of 14%-36%. Captured cells were directly cultured, forming cell aggregates, in the NF matrix, which ensures the cell proliferation and follow-up analysis. Furthermore, the capture capacity of mAb-NFs was assessed in the presence of whole blood and blood lysates, indicating cluster formation that captured target cells. It is anticipated that the antibody-attached NFs can be employed for the capture and analysis of very rare EpCAM positive circulating cancer cells.

  15. Improvement of mannitol lysine crystal violet brilliant green agar for the selective isolation of H2S-positive Salmonella.

    PubMed

    Kodaka, H; Mizuochi, S; Honda, T; Yamaguchi, K

    2000-12-01

    Mannitol lysine crystal violet brilliant green agar (MLCB) is widely used in Japan for Salmonella isolation because the medium has been commercially available. Colonies of Salmonella on MLCB appear colorless with black centers due to H2S gas production; however, most Citrobacter freundii also produce H2S gas. In order to distinguish H2S-positive Salmonella from C. freundii we have improved MLCB. To MLCB was added 1% lactose (L-MLCB). The relation for pH and black center colony formation was examined. The pH of MLCB and L-MLCB inoculated with Salmonella species was slightly acid after 7 h, but the pH of L-MLCB inoculated with C. freundii did not become acid for 24 h. The colony of C. freundii did not have a black center because the production of acid from lactose lowers the pH below 10 where it is needed for H2S to react with iron to produce black pigments. Of 99 Salmonella strains including 13 serotypes tested, all strains had the same colony morphologies on MLCB and L-MLCB. When MLCB and L-MLCB were evaluated with 36 C. freundii strains isolated from foods, only colonies on MLCB had black centers. We conclude that L-MLCB is useful for detection of nonlactose-fermenting, H2S-positive Salmonella in food samples.

  16. Alu-miRNA interactions modulate transcript isoform diversity in stress response and reveal signatures of positive selection

    NASA Astrophysics Data System (ADS)

    Pandey, Rajesh; Bhattacharya, Aniket; Bhardwaj, Vivek; Jha, Vineet; Mandal, Amit K.; Mukerji, Mitali

    2016-09-01

    Primate-specific Alus harbor different regulatory features, including miRNA targets. In this study, we provide evidence for miRNA-mediated modulation of transcript isoform levels during heat-shock response through exaptation of Alu-miRNA sites in mature mRNA. We performed genome-wide expression profiling coupled with functional validation of miRNA target sites within exonized Alus, and analyzed conservation of these targets across primates. We observed that two miRNAs (miR-15a-3p and miR-302d-3p) elevated in stress response, target RAD1, GTSE1, NR2C1, FKBP9 and UBE2I exclusively within Alu. These genes map onto the p53 regulatory network. Ectopic overexpression of miR-15a-3p downregulates GTSE1 and RAD1 at the protein level and enhances cell survival. This Alu-mediated fine-tuning seems to be unique to humans as evident from the absence of orthologous sites in other primate lineages. We further analyzed signatures of selection on Alu-miRNA targets in the genome, using 1000 Genomes Phase-I data. We found that 198 out of 3177 Alu-exonized genes exhibit signatures of selection within Alu-miRNA sites, with 60 of them containing SNPs supported by multiple evidences (global-FST > 0.3, pair-wise-FST > 0.5, Fay-Wu’s H < ‑20, iHS > 2.0, high ΔDAF) and implicated in p53 network. We propose that by affecting multiple genes, Alu-miRNA interactions have the potential to facilitate population-level adaptations in response to environmental challenges.

  17. Alu-miRNA interactions modulate transcript isoform diversity in stress response and reveal signatures of positive selection

    PubMed Central

    Pandey, Rajesh; Bhattacharya, Aniket; Bhardwaj, Vivek; Jha, Vineet; Mandal, Amit K.; Mukerji, Mitali

    2016-01-01

    Primate-specific Alus harbor different regulatory features, including miRNA targets. In this study, we provide evidence for miRNA-mediated modulation of transcript isoform levels during heat-shock response through exaptation of Alu-miRNA sites in mature mRNA. We performed genome-wide expression profiling coupled with functional validation of miRNA target sites within exonized Alus, and analyzed conservation of these targets across primates. We observed that two miRNAs (miR-15a-3p and miR-302d-3p) elevated in stress response, target RAD1, GTSE1, NR2C1, FKBP9 and UBE2I exclusively within Alu. These genes map onto the p53 regulatory network. Ectopic overexpression of miR-15a-3p downregulates GTSE1 and RAD1 at the protein level and enhances cell survival. This Alu-mediated fine-tuning seems to be unique to humans as evident from the absence of orthologous sites in other primate lineages. We further analyzed signatures of selection on Alu-miRNA targets in the genome, using 1000 Genomes Phase-I data. We found that 198 out of 3177 Alu-exonized genes exhibit signatures of selection within Alu-miRNA sites, with 60 of them containing SNPs supported by multiple evidences (global-FST > 0.3, pair-wise-FST > 0.5, Fay-Wu’s H < −20, iHS > 2.0, high ΔDAF) and implicated in p53 network. We propose that by affecting multiple genes, Alu-miRNA interactions have the potential to facilitate population-level adaptations in response to environmental challenges. PMID:27586304

  18. Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery

    SciTech Connect

    Brown, Nicole; Nagarkatti, Mitzi; Nagarkatti, Prakash S. . E-mail: pnagark@hsc.vcu.edu

    2006-04-15

    Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effects of DES on T-cell differentiation in the thymus using the HY-TCR transgenic (Tg) mouse model in which the female mice exhibit positive selection of T cells bearing the Tg TCR, while the male mice show negative selection of such T cells. In female HY-TCR-Tg mice, exposure to DES showed more pronounced decrease in thymic cellularity when compared to male mice. Additionally, female mice also showed a significant decrease in the proportion of double-positive (DP) T cells in the thymus and HY-TCR-specific CD8{sup +} T cells in the periphery. Male mice exhibiting negative selection also showed decreased thymic cellularity following DES exposure. Moreover, the male mice showed increased proportion of double-negative (DN) T cells in the thymus and decreased proportion of CD8{sup +} T cells. The density of expression of HY-TCR on CD8{sup +} cells was increased following DES exposure in both females and males. Finally, the proliferative response of thymocytes to mitogens and peripheral lymph node T cells to male H-Y antigen was significantly altered in female and male mice following DES treatment. Taken together, these data suggest that DES alters T-cell differentiation in the thymus by interfering with positive and negative selection processes, which in turn modulates the T-cell repertoire in the periphery.

  19. The roles of gene duplication, gene conversion and positive selection in rodent Esp and Mup pheromone gene families with comparison to the Abp family.

    PubMed

    Karn, Robert C; Laukaitis, Christina M

    2012-01-01

    Three proteinaceous pheromone families, the androgen-binding proteins (ABPs), the exocrine-gland secreting peptides (ESPs) and the major urinary proteins (MUPs) are encoded by large gene families in the genomes of Mus musculus and Rattus norvegicus. We studied the evolutionary histories of the Mup and Esp genes and compared them with what is known about the Abp genes. Apparently gene conversion has played little if any role in the expansion of the mouse Class A and Class B Mup genes and pseudogenes, and the rat Mups. By contrast, we found evidence of extensive gene conversion in many Esp genes although not in all of them. Our studies of selection identified at least two amino acid sites in β-sheets as having evolved under positive selection in the mouse Class A and Class B MUPs and in rat MUPs. We show that selection may have acted on the ESPs by determining K(a)/K(s) for Exon 3 sequences with and without the converted sequence segment. While it appears that purifying selection acted on the ESP signal peptides, the secreted portions of the ESPs probably have undergone much more rapid evolution. When the inner gene converted fragment sequences were removed, eleven Esp paralogs were present in two or more pairs with K(a)/K(s) >1.0 and thus we propose that positive selection is detectable by this means in at least some mouse Esp paralogs. We compare and contrast the evolutionary histories of all three mouse pheromone gene families in light of their proposed functions in mouse communication.

  20. A new method with flexible and balanced control of false negatives and false positives for hit selection in RNA interference high-throughput screening assays.

    PubMed

    Zhang, Xiaohua Douglas

    2007-08-01

    The z-score method and its variants for testing mean difference are commonly used for hit selection in high-throughput screening (HTS) assays. Strictly standardized mean difference (SSMD) offers a way to measure and classify the short interfering RNA (siRNA) effects. In this article, based on SSMD, the authors propose a new testing method for hit selection in RNA interference (RNAi) HTS assays. This SSMD-based method allows the differentiation between siRNAs with large and small effects on the assay output and maintains flexible and balanced control of both the false-negative rate, in which the siRNAs with strong effects are not selected as hits, and the restricted false-positive rate, in which the siRNAs with weak or no effects are selected as hits. This method directly addresses the size of siRNA effects represented by the strength of difference between an siRNA and a negative reference, whereas the classic z-score method and t-test of testing no mean difference address whether the mean of an siRNA is exactly the same as the mean of a negative reference. This method can readily control the false-negative rate, whereas it is nontrivial for the classic z-score method and t-test to control the false-negative rate. Therefore, theoretically, the SSMD-based method offers better control of the sizes of siRNA effects and the associated false-positive and false-negative rates than the commonly used z-score method and t-test for hit selection in HTS assays. The SSMD-based method should generally be applicable to any assay in which the end point is a difference in signal compared to a reference sample, including those for RNAi, receptor, enzyme, and cellular function.

  1. Evidence for Positive Selection on a Number of MicroRNA Regulatory Interactions during Recent Human Evolution

    PubMed Central

    Xin, Xiaofeng; Kim, Taehyung Simon; Cabeza, Eduardo Aguiar; Ren, Jie; Nielsen, Rasmus; Wrana, Jeffrey L.; Zhang, Zhaolei

    2012-01-01

    MicroRNA (miRNA)–mediated gene regulation is of critical functional importance in animals and is thought to be largely constrained during evolution. However, little is known regarding evolutionary changes of the miRNA network and their role in human evolution. Here we show that a number of miRNA binding sites display high levels of population differentiation in humans and thus are likely targets of local adaptation. In a subset we demonstrate that allelic differences modulate miRNA regulation in mammalian cells, including an interaction between miR-155 and TYRP1, an important melanosomal enzyme associated with human pigmentary differences. We identify alternate alleles of TYRP1 that induce or disrupt miR-155 regulation and demonstrate that these alleles are selected with different modes among human populations, causing a strong negative correlation between the frequency of miR-155 regulation of TYRP1 in human populations and their latitude of residence. We propose that local adaptation of microRNA regulation acts as a rheostat to optimize TYRP1 expression in response to differential UV radiation. Our findings illustrate the evolutionary plasticity of the microRNA regulatory network in recent human evolution. PMID:22457636

  2. Artificial selection on relative brain size reveals a positive genetic correlation between brain size and proactive personality in the guppy.

    PubMed

    Kotrschal, Alexander; Lievens, Eva J P; Dahlbom, Josefin; Bundsen, Andreas; Semenova, Svetlana; Sundvik, Maria; Maklakov, Alexei A; Winberg, Svante; Panula, Pertti; Kolm, Niclas

    2014-04-01

    Animal personalities range from individuals that are shy, cautious, and easily stressed (a "reactive" personality type) to individuals that are bold, innovative, and quick to learn novel tasks, but also prone to routine formation (a "proactive" personality type). Although personality differences should have important consequences for fitness, their underlying mechanisms remain poorly understood. Here, we investigated how genetic variation in brain size affects personality. We put selection lines of large- and small-brained guppies (Poecilia reticulata), with known differences in cognitive ability, through three standard personality assays. First, we found that large-brained animals were faster to habituate to, and more exploratory in, open field tests. Large-brained females were also bolder. Second, large-brained animals excreted less cortisol in a stressful situation (confinement). Third, large-brained animals were slower to feed from a novel food source, which we interpret as being caused by reduced behavioral flexibility rather than lack of innovation in the large-brained lines. Overall, the results point toward a more proactive personality type in large-brained animals. Thus, this study provides the first experimental evidence linking brain size and personality, an interaction that may affect important fitness-related aspects of ecology such as dispersal and niche exploration.

  3. Improving hospital mass casualty preparedness through ongoing readiness evaluation.

    PubMed

    Adini, Bruria; Laor, Daniel; Hornik-Lurie, Tzipora; Schwartz, Dagan; Aharonson-Daniel, Limor

    2012-01-01

    The objective of this study was to investigate the effect of ongoing use of an evaluation tool on hospitals' emergency preparedness for mass casualty events (MCEs). Two cycles of evaluation of emergency preparedness were conducted based on measurable parameters. A significant increase was found in mean total scores between the 2 cycles (from 77.1 to 88.5). An increase was found in scores for standard operating procedures, training, and equipment, but the change was significant only in the training category. Relative increase was highest for hospitals that did not experience real MCEs. This study offers a structured and practical approach for ongoing improvement of emergency preparedness, based on validated, measurable benchmarks. Ongoing assessment of emergency preparedness motivates hospitals to improve capabilities and results in a more effective emergency response mechanism. Use of predetermined and measurable benchmarks allows the institutions being assessed to improve their level of performance in the areas evaluated.

  4. Ongoing Slow Fluctuations in V1 Impact on Visual Perception

    PubMed Central

    Wohlschläger, Afra M.; Glim, Sarah; Shao, Junming; Draheim, Johanna; Köhler, Lina; Lourenço, Susana; Riedl, Valentin; Sorg, Christian

    2016-01-01

    The human brain’s ongoing activity is characterized by intrinsic networks of coherent fluctuations, measured for example with correlated functional magnetic resonance imaging signals. So far, however, the brain processes underlying this ongoing blood oxygenation level dependent (BOLD) signal orchestration and their direct relevance for human behavior are not sufficiently understood. In this study, we address the question of whether and how ongoing BOLD activity within intrinsic occipital networks impacts on conscious visual perception. To this end, backwardly masked targets were presented in participants’ left visual field only, leaving the ipsi-lateral occipital areas entirely free from direct effects of task throughout the experiment. Signal time courses of ipsi-lateral BOLD fluctuations in visual areas V1 and V2 were then used as proxies for the ongoing contra-lateral BOLD activity within the bilateral networks. Magnitude and phase of these fluctuations were compared in trials with and without conscious visual perception, operationalized by means of subjective confidence ratings. Our results show that ipsi-lateral BOLD magnitudes in V1 were significantly higher at times of peak response when the target was perceived consciously. A significant difference between conscious and non-conscious perception with regard to the pre-target phase of an intrinsic-frequency regime suggests that ongoing V1 fluctuations exert a decisive impact on the access to consciousness already before stimulation. Both effects were absent in V2. These results thus support the notion that ongoing slow BOLD activity within intrinsic networks covering V1 represents localized processes that modulate the degree of readiness for the emergence of visual consciousness. PMID:27601986

  5. Lateralization of noise-burst trains based on onset and ongoing interaural delays.

    PubMed

    Freyman, Richard L; Balakrishnan, Uma; Zurek, Patrick M

    2010-07-01

    The lateralization of 250-ms trains of brief noise bursts was measured using an acoustic pointing technique. Stimuli were designed to assess the contribution of the interaural time delay (ITD) of the onset binaural burst relative to that of the ITDs in the ongoing part of the train. Lateralization was measured by listeners' adjustments of the ITD of a pointer stimulus, a 50-ms burst of noise, to match the lateral position of the target train. Results confirmed previous reports of lateralization dominance by the onset burst under conditions in which the train is composed of frozen tokens and the ongoing part contains multiple ambiguous interaural delays. In contrast, lateralization of ongoing trains in which fresh noise tokens were used for each set of two alternating (left-leading/right-leading) binaural pairs followed the ITD of the first pair in each set, regardless of the ITD of the onset burst of the entire stimulus and even when the onset burst was removed by gradual gating. This clear lateralization of a long-duration stimulus with ambiguous interaural delay cues suggests precedence mechanisms that involve not only the interaural cues at the beginning of a sound, but also the pattern of cues within an ongoing sound.

  6. Purine salvage in the apicomplexan Sarcocystis neurona, and generation of hypoxanthine-xanthine-guanine phosphoribosyltransferase-deficient clones for positive-negative selection of transgenic parasites.

    PubMed

    Dangoudoubiyam, Sriveny; Zhang, Zijing; Howe, Daniel K

    2014-09-01

    Sarcocystis neurona is an apicomplexan parasite that causes severe neurological disease in horses and marine mammals. The Apicomplexa are all obligate intracellular parasites that lack purine biosynthesis pathways and rely on the host cell for their purine requirements. Hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) and adenosine kinase (AK) are key enzymes that function in two complementary purine salvage pathways in apicomplexans. Bioinformatic searches of the S. neurona genome revealed genes encoding HXGPRT, AK and all of the major purine salvage enzymes except purine nucleoside phosphorylase. Wild-type S. neurona were able to grow in the presence of mycophenolic acid (MPA) but were inhibited by 6-thioxanthine (6-TX), suggesting that the pathways involving either HXGPRT or AK are functional in this parasite. Prior work with Toxoplasma gondii demonstrated the utility of HXGPRT as a positive-negative selection marker. To enable the use of HXGPRT in S. neurona, the SnHXGPRT gene sequence was determined and a gene-targeting plasmid was transfected into S. neurona. SnHXGPRT-deficient mutants were selected with 6-TX, and single-cell clones were obtained. These Sn∆HXG parasites were susceptible to MPA and could be complemented using the heterologous T. gondii HXGPRT gene. In summary, S. neurona possesses both purine salvage pathways described in apicomplexans, thus allowing the use of HXGPRT as a positive-negative drug selection marker in this parasite.

  7. Selective Toxicity of NSC 73306 in MDR1-positive cells as a New Strategy to Circumvent Multidrug Resistance in Cancer

    PubMed Central

    Ludwig, Joseph A.; Martin, Scott E.; Chu, Benjamin F.; Cardarelli, Carol; Sauna, Zuben E.; Caplen, Natasha J.; Fales, Henry M.; Ambudkar, Suresh V.; Weinstein, John N.

    2006-01-01

    ATP-binding cassette (ABC) proteins include the best known mediators of resistance to anticancer drugs. In particular, ABCB1 (MDR1/P-gp) extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. Attempts to overcome P-gp-mediated drug resistance using specific inhibitors of P-gp has had limited success, and has faced many therapeutic challenges. As an alternative approach to using P-gp inhibitors, we characterize a thiosemicarbazone derivative (NSC73306) identified in a generic screen as a compound that exploits, rather than suppresses, P-gp function to induce cytotoxicity. Cytotoxic activity of NSC73306 was evaluated in vitro using human epidermoid, ovarian, and colon cancer cell lines expressing various levels of P-gp. Our findings suggest that cells become hypersensitive to NSC73306 in proportion to the increased P-gp function and multidrug resistance (MDR). Abrogation of both sensitivity to NSC73306 and resistance to P-gp substrate anticancer agents occurred with specific inhibition of P-gp function using either a P-gp inhibitor (PSC833, XR9576) or RNA interference (RNAi), suggesting that cytotoxicity was linked to MDR1 function, not to other, nonspecific factors arising during the generation of resistant or transfected cells. Molecular characterization of cells selected for resistance to NSC73306 revealed loss of P-gp expression and consequent loss of the MDR phenotype. Although hypersensitivity to NSC73306 required functional expression of P-gp, biochemical assays revealed no direct interaction between NSC73306 and P-gp. This work demonstrates that NSC73306 kills cells with intrinsic or acquired P-gp-induced MDR and indirectly acts to eliminate resistance to MDR1 substrates. PMID:16651436

  8. Selective Activation Around the Left Occipito-Temporal Sulcus for Words Relative to Pictures: Individual Variability or False Positives?

    PubMed Central

    Wright, Nicholas D; Mechelli, Andrea; Noppeney, Uta; Veltman, Dick J; Rombouts, Serge ARB; Glensman, Janice; Haynes, John-Dylan; Price, Cathy J

    2008-01-01

    We used high-resolution fMRI to investigate claims that learning to read results in greater left occipito-temporal (OT) activation for written words relative to pictures of objects. In the first experiment, 9/16 subjects performing a one-back task showed activation in ≥1 left OT voxel for words relative to pictures (P < 0.05 uncorrected). In a second experiment, another 9/15 subjects performing a semantic decision task activated ≥1 left OT voxel for words relative to pictures. However, at this low statistical threshold false positives need to be excluded. The semantic decision paradigm was therefore repeated, within subject, in two different scanners (1.5 and 3 T). Both scanners consistently localised left OT activation for words relative to fixation and pictures relative to words, but there were no consistent effects for words relative to pictures. Finally, in a third experiment, we minimised the voxel size (1.5 × 1.5 × 1.5 mm3) and demonstrated a striking concordance between the voxels activated for words and pictures, irrespective of task (naming vs. one-back) or script (English vs. Hebrew). In summary, although we detected differential activation for words relative to pictures, these effects: (i) do not withstand statistical rigour; (ii) do not replicate within or between subjects; and (iii) are observed in voxels that also respond to pictures of objects. Our findings have implications for the role of left OT activation during reading. More generally, they show that studies using low statistical thresholds in single subject analyses should correct the statistical threshold for the number of comparisons made or replicate effects within subject. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc. PMID:17712786

  9. Can Autonomy Be Imposed? Examining Teacher (Re)positioning during the Ongoing Curriculum Change in Cyprus

    ERIC Educational Resources Information Center

    Philippou, Stavroula; Kontovourki, Stavroula; Theodorou, Eleni

    2014-01-01

    For the past few years, the Republic of Cyprus has been pursuing a major educational reform across all levels of mandatory education, focusing especially on curriculum change, for the implementation of which in-service teachers have undergone a series of professional development seminars. Individual and focus group interviews with in-service…

  10. Hepatic Tissue Environment in NEMO-Deficient Mice Critically Regulates Positive Selection of Donor Cells after Hepatocyte Transplantation

    PubMed Central

    Kaldenbach, Michaela; Cubero, Francisco Javier; Erschfeld, Stephanie; Liedtke, Christian; Trautwein, Christian; Streetz, Konrad

    2014-01-01

    Background Hepatocyte transplantation (HT) is a promising alternative treatment strategy for end-stage liver diseases compared with orthotopic liver transplantation. A limitation for this approach is the low engraftment of donor cells. The deletion of the I-kappa B kinase-regulatory subunit IKKγ/NEMO in hepatocytes prevents nuclear factor (NF)-kB activation and triggers spontaneous liver apoptosis, chronic hepatitis and the development of liver fibrosis and hepatocellular carcinoma. We hypothesized that NEMOΔhepa mice may therefore serve as an experimental model to study HT. Methods Pre-conditioned NEMOΔhepa mice were transplanted with donor-hepatocytes from wildtype (WT) and mice deficient for the pro-apoptotic mediator Caspase-8 (Casp8Δhepa). Results Transplantation of isolated WT-hepatocytes into pre-conditioned NEMOΔhepa mice resulted in a 6-7 fold increase of donor cells 12 weeks after HT, while WT-recipients showed no liver repopulation. The use of apoptosis-resistant Casp8Δhepa-derived donor cells further enhanced the selection 3-fold after 12-weeks and up to 10-fold increase after 52 weeks compared with WT donors. While analysis of NEMOΔhepa mice revealed strong liver injury, HT-recipient NEMOΔhepa mice showed improved liver morphology and decrease in serum transaminases. Concomitant with these findings, the histological examination elicited an improved liver tissue architecture associated with significantly lower levels of apoptosis, decreased proliferation and a lesser amount of liver fibrogenesis. Altogether, our data clearly support the therapeutic benefit of the HT procedure into NEMOΔhepa mice. Conclusion This study demonstrates the feasibility of the NEMOΔhepa mouse as an in vivo tool to study liver repopulation after HT. The improvement of the characteristic phenotype of chronic liver injury in NEMOΔhepa mice after HT suggests the therapeutic potential of HT in liver diseases with a chronic inflammatory phenotype and opens a new door for

  11. Selectable marker elimination in the T0 generation by Agrobacterium-mediated co-transformation involving Mungbean yellow mosaic virus TrAP as a non-conditional negative selectable marker and bar for transient positive selection.

    PubMed

    RamanaRao, Mangu Venkata; Veluthambi, Karuppannan

    2010-05-01

    Transient selection involving the bar gene and non-conditional negative selection against stable T-DNA integration through the use of the Mungbean yellow mosaic virus (MYMV) transcriptional activator protein gene (TrAP) were used in a novel co-transformation strategy to generate selectable marker gene (SMG)-eliminated transgenic tobacco plants in the T(0) generation itself. Two compatible binary plasmids, pCam-bar-TrAP-gus harbouring bar as an SMG and the MYMV TrAP gene as a non-conditional negative selectable marker, and pGA472 with the nptII gene as an unselected experimental gene of interest (GOI) were placed in the Agrobacterium tumefaciens strain EHA105 and used for co-transformation. Transient selection with 5 mg l(-1) phosphinothricin (PPT) for 2-4 weeks and subsequent establishment in a PPT-minus medium yielded 114 plants from 200 leaf discs. The unselected nptII gene was detected by Southern blot analysis in 13 plants, revealing a co-transformation efficiency of 11.5%. Five of these plants harboured only the nptII gene (GOI) and not the bar gene (SMG). Thus, SMG elimination was achieved in the T(0) generation itself in 4.4% (5/114) of plants, which were transiently selected for 2-4 weeks on PPT. MYMV TrAP, a non-conditional negative selectable marker, effectively reduced the recovery of plants with stable integration of the SMG (bar).

  12. Investigation for improving Global Positioning System (GPS) orbits using a discrete sequential estimator and stochastic models of selected physical processes

    NASA Technical Reports Server (NTRS)

    Goad, Clyde C.; Chadwell, C. David

    1993-01-01

    GEODYNII is a conventional batch least-squares differential corrector computer program with deterministic models of the physical environment. Conventional algorithms were used to process differenced phase and pseudorange data to determine eight-day Global Positioning system (GPS) orbits with several meter accuracy. However, random physical processes drive the errors whose magnitudes prevent improving the GPS orbit accuracy. To improve the orbit accuracy, these random processes should be modeled stochastically. The conventional batch least-squares algorithm cannot accommodate stochastic models, only a stochastic estimation algorithm is suitable, such as a sequential filter/smoother. Also, GEODYNII cannot currently model the correlation among data values. Differenced pseudorange, and especially differenced phase, are precise data types that can be used to improve the GPS orbit precision. To overcome these limitations and improve the accuracy of GPS orbits computed using GEODYNII, we proposed to develop a sequential stochastic filter/smoother processor by using GEODYNII as a type of trajectory preprocessor. Our proposed processor is now completed. It contains a correlated double difference range processing capability, first order Gauss Markov models for the solar radiation pressure scale coefficient and y-bias acceleration, and a random walk model for the tropospheric refraction correction. The development approach was to interface the standard GEODYNII output files (measurement partials and variationals) with software modules containing the stochastic estimator, the stochastic models, and a double differenced phase range processing routine. Thus, no modifications to the original GEODYNII software were required. A schematic of the development is shown. The observational data are edited in the preprocessor and the data are passed to GEODYNII as one of its standard data types. A reference orbit is determined using GEODYNII as a batch least-squares processor and the

  13. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.

    PubMed

    Choi, Soo-Kyung; Yoon, Song-Ro; Calabrese, Peter; Arnheim, Norman

    2012-01-01

    Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot) or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36-68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19-23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75-80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.

  14. Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2.

    PubMed

    Kasumu, Adebimpe W; Hougaard, Charlotte; Rode, Frederik; Jacobsen, Thomas A; Sabatier, Jean Marc; Eriksen, Birgitte L; Strøbæk, Dorte; Liang, Xia; Egorova, Polina; Vorontsova, Dasha; Christophersen, Palle; Rønn, Lars Christian B; Bezprozvanny, Ilya

    2012-10-26

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from transgenic SCA2 mice we demonstrate that SK channel modulators restore regular pacemaker activity of SCA2 PCs. Furthermore, we also show that oral delivery of a more selective positive modulator of SK2/3 channels (NS13001) alleviates behavioral and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a therapeutic target for SCA2 treatment and that the developed selective SK2/3 modulator NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias.

  15. Filter-based feature selection and support vector machine for false positive reduction in computer-aided mass detection in mammograms

    NASA Astrophysics Data System (ADS)

    Nguyen, V. D.; Nguyen, D. T.; Nguyen, T. D.; Phan, V. A.; Truong, Q. D.

    2015-02-01

    In this paper, a method for reducing false positive in computer-aided mass detection in screening mammograms is proposed. A set of 32 features, including First Order Statistics (FOS) features, Gray-Level Occurrence Matrix (GLCM) features, Block Difference Inverse Probability (BDIP) features, and Block Variation of Local Correlation coefficients (BVLC) are extracted from detected Regions-Of-Interest (ROIs). An optimal subset of 8 features is selected from the full feature set by mean of a filter-based Sequential Backward Selection (SBS). Then, Support Vector Machine (SVM) is utilized to classify the ROIs into massive regions or normal regions. The method's performance is evaluated using the area under the Receiver Operating Characteristic (ROC) curve (AUC or AZ). On a dataset consisting about 2700 ROIs detected from mini-MIAS database of mammograms, the proposed method achieves AZ=0.938.

  16. Strong positive selection and habitat-specific amino acid substitution patterns in MHC from an estuarine fish under intense pollution stress.

    PubMed

    Cohen, Sarah

    2002-11-01

    Population-level studies using the major histocompatibility complex (Mhc) have linked specific alleles with specific diseases, but data requirements are high and the power to detect disease association is low. A novel use of Mhc population surveys involves mapping allelic substitutions onto the inferred structural molecular model to show functional differentiation related to local selective pressures. In the estuarine fish Fundulus heteroclitus, populations experiencing strong differences in antigenic challenges show significant differences in amino acid substitution patterns that are reflected as variation in the structural location of changes between populations. Fish from a population genetically adapted to severe chemical pollution also show novel patterns of DNA substitution at a highly variable Mhc class II B locus including strong signals of positive selection at inferred antigen-binding sites and population-specific signatures of amino acid substitution. Heavily parasitized fish from an extreme PCB-contaminated (U.S. Environmental Protection Agency Superfund) site show enhanced population-specific substitutions in the a-helix portion of the inferred antigen-binding region. In contrast, fish from an unpolluted site show a significantly different pattern focused on the first strand of the B-pleated sheet. Whether Mhc population profile differences represent the direct effects of chemical toxicants or indirect parasite-mediated selection, the result is a composite habitat-specific signature of strong selection and evolution affecting the genetic repertoire of the major histocompatibility complex.

  17. One-pot enzymatic synthesis of docosahexaenoic acid-rich triacylglycerols at the sn-1(3) position using by-product from selective hydrolysis of tuna oil.

    PubMed

    Nagao, Toshihiro; Watanabe, Yomi; Maruyama, Kazuaki; Momokawa, Yuusuke; Kishimoto, Noriaki; Shimada, Yuji

    2011-01-31

    Docosahexaenoic acid (DHA)-rich oil has been industrially produced by selective hydrolysis of tuna oil with a lipase that acts weakly on DHA. The free fatty acids (FFAs) generated in this process as by-products contain a high DHA concentration (46wt%) but are treated as industrial waste. This study attempted to reuse these by-product FFAs using a one-pot process, and succeeded in producing triacylglycerols (TAGs) through the esterification of the by-product FFAs with glycerol using immobilized Rhizomucor miehei lipase. Regiospecific analysis of the resulting TAGs showed that the content of DHA at the sn-1(3) position (51.7mol%) was higher than the content of DHA at the sn-2 position (17.3mol%). The DHA distribution in TAGs synthesized in this study was similar to the DHA distribution in TAGs from seal oil.

  18. Benzyloxycarbonyl-D-Phe-Pro-methoxypropylboroglycine: a novel inhibitor of thrombin with high selectivity containing a neutral side chain at the P1 position.

    PubMed Central

    Claeson, G; Philipp, M; Agner, E; Scully, M F; Metternich, R; Kakkar, V V; DeSoyza, T; Niu, L H

    1993-01-01

    Thrombin, the blood-clotting enzyme, is a serine proteinase with trypsin-like specificity and is able to cleave Arg-Xaa peptide bonds but only in a very limited number of substrates (and sites therein). For the prevention and treatment of thrombosis the control of thrombin activity is a key target, and a variety of synthetic inhibitors have been introduced recently, all of which have a positive charge at the P1 site. We report the synthesis of the first example of a new class of inhibitor containing a neutral side chain at the P1 site, the peptide benzyloxycarbonyl-D-Phe-Pro- methoxypropylboroglycine. The peptide is a potent inhibitor of thrombin [Ki (limiting) = 7 nM] and is highly selective for its target enzyme in respect of other serine proteinases. This may be expected to confer considerable advantage in terms of specificity of action and reduced toxicity over conventional, positively charged, inhibitors. PMID:8452516

  19. EMERGING CONTAMINANTS: AN OVERVIEW OF ON-GOING RESEARCH

    EPA Science Inventory

    This presentation covers an overview of research on emerging contaminants on-going at

    U.S. EPA's National Exposure Research Laboratory in Las Vegas. Due to the

    improvements and sophistication of recent analytical instruments, increasing numbers of

    chemicals a...

  20. Trauma-Focused CBT for Youth Who Experience Ongoing Traumas

    ERIC Educational Resources Information Center

    Cohen, Judith A.; Mannarino, Anthony P.; Murray, Laura K.

    2011-01-01

    Many youth experience ongoing trauma exposure, such as domestic or community violence. Clinicians often ask whether evidence-based treatments containing exposure components to reduce learned fear responses to historical trauma are appropriate for these youth. Essentially the question is, if youth are desensitized to their trauma experiences, will…

  1. DIESEL EXHAUST EXPOSURE INCREASES SEVERITY OF AN ONGOING INFLUENZA INFECTION

    EPA Science Inventory

    Numerous studies have shown that air pollutants including diesel exhaust (DE) alter host defense responses, resulting in decreased resistance to respiratory infection. The purpose of this study was to evaluate the effects of DE exposure on the severity of an ongoing influenza in...

  2. [Patient safety, – a current and ongoing problem].

    PubMed

    Díaz, Carlos Alberto; Braem, Virginia; Giuliani, Amalia; Restelli, Emilio

    2014-04-22

    Patient safety is a current and ongoing problem of increasing importance in healthcare. The implementation of a safety culture leads to behavioral change in all processes and responsibility centers. It means a long, slow, arduous path and requires effort, persistence and commitment, but it is increasingly necessary and indispensable in hospital management.

  3. Defining and Assessing Generic Competencies in Australian Universities: Ongoing Challenges

    ERIC Educational Resources Information Center

    Chapman, Elaine; O'Neill, Marnie

    2010-01-01

    In this paper, we discuss ongoing challenges in defining and assessing generic competencies in Australian universities. The paper begins with a discussion of factors that led to, and later fuelled, the focus on generic competencies in Australian higher education. Broad constructs that have underpinned research and practice in the field are then…

  4. Central sensitization and neuropathic features of ongoing pain in a rat model of advanced osteoarthritis

    PubMed Central

    Havelin, Joshua; Imbert, Ian; Cormier, Jennifer; Allen, Joshua; Porreca, Frank; King, Tamara

    2015-01-01

    Osteoarthritis (OA) pain is most commonly characterized by movement-triggered joint pain. However, in advanced disease, OA pain becomes persistent, ongoing and resistant to treatment with NSAIDs. The mechanisms underlying ongoing pain in advanced OA are poorly understood. We recently showed that intra-articular (i.a.) injection of monosodium iodoacetate (MIA) into the rat knee joint produces concentration-dependent outcomes. Thus, a low dose of i.a. MIA produces NSAID-sensitive weight asymmetry without evidence of ongoing pain while a high i.a. MIA dose produces weight asymmetry and NSAID-resistant ongoing pain. In the present studies, palpation of the ipsilateral hindlimb of rats treated 14 days previously with high, but not low, doses of i.a. MIA produced FOS expression in the spinal dorsal horn. Inactivation of descending pain facilitatory pathways by microinjection of lidocaine within the rostral ventromedial medulla (RVM) induced conditioned place preference (CPP) selectively in rats treated with the high dose of MIA. CPP to intra-articular lidocaine was blocked by pretreatment with duloxetine (30 mg/kg, i.p. at −30 min). These observations are consistent with the likelihood of a neuropathic component of OA that elicits ongoing, NSAID resistant pain and central sensitization that is mediated, in part, by descending modulatory mechanisms. This model provides a basis for exploration of underlying mechanisms promoting neuropathic components of OA pain and for the identification of mechanisms that may guide drug discovery for treatment of advanced OA pain without the need for joint replacement. PMID:26694132

  5. Behavioral and neurochemical analysis of ongoing bone cancer pain in rats.

    PubMed

    Remeniuk, Bethany; Sukhtankar, Devki; Okun, Alec; Navratilova, Edita; Xie, Jennifer Y; King, Tamara; Porreca, Frank

    2015-10-01

    Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized after intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching. Conditioned place preference (CPP) and enhanced dopamine (DA) release in the nucleus accumbens (NAc) shell was observed after peripheral nerve block (PNB) selectively in tumor-bearing rats revealing nociceptive-driven ongoing pain. Oral diclofenac reversed tumor-induced tactile hypersensitivity but did not block PNB-induced CPP or NAc DA release. Tumor-induced tactile hypersensitivity, and PNB-induced CPP and NAc DA release, was blocked by prior subcutaneous implantation of a morphine pellet. In sham rats, morphine produced a modest but sustained increase in NAc DA release. In contrast, morphine produced a transient 5-fold higher NAc DA release in tumor bearing rats compared with sham morphine rats. The possibility that this increased NAc DA release reflected the reward of pain relief was tested by irreversible blockade of rostral anterior cingulate cortex (rACC) μ-opioid receptors (MORs). The rACC MOR blockade prevented the morphine-induced transient increased NAc DA release in tumor bearing rats but did not affect morphine-induced effects in sham-operated animals. Consistent with clinical experience, ongoing cancer pain was controlled by morphine but not by a dose of diclofenac that reversed evoked hypersensitivity. Additionally, the intrinsic reward of morphine can be dissociated from the reward of relief of cancer pain by blockade of rACC MOR. This approach allows mechanistic and therapeutic assessment of ongoing cancer pain with likely translation relevance.

  6. Control of HIV-1 in Elite Suppressors despite Ongoing Replication and Evolution in Plasma Virus▿

    PubMed Central

    O'Connell, Karen A.; Brennan, Timothy P.; Bailey, Justin R.; Ray, Stuart C.; Siliciano, Robert F.; Blankson, Joel N.

    2010-01-01

    A subset of HIV-1-infected patients known as elite controllers or suppressors (ES) control the virus naturally. We have previously demonstrated sequence discordance between proviral and plasma gag clones in ES, much of which can be attributed to selective pressure from the host (J. R. Bailey, T. M. Williams, R. F. Siliciano, and J. N. Blankson, J. Exp. Med. 203:1357-1369, 2006). However, it is not clear whether ongoing viral replication continues in ES once the control of viremia has been established or whether selective pressure impacts this evolution. The cytotoxic T-lymphocyte (CTL) response in ES often targets Gag and frequently is superior to that of HIV-1 progressors, partially due to the HLA class I alleles B*57/5801 and B*27, which are overrepresented in ES. We therefore examined longitudinal plasma and proviral gag sequences from HLA-B*57/5801 and -B*27 ES. Despite the highly conserved nature of gag, we observed clear evidence of evolution in the plasma virus, largely due to synonymous substitutions. In contrast, evolution was rare in proviral clones, suggesting that ongoing replication in ES does not permit the significant reseeding of the latent reservoir. Interestingly, there was little continual evolution in CTL epitopes, and we detected de novo CTL responses to autologous viral mutants. Thus, some ES control viremia despite ongoing replication and evolution. PMID:20444904

  7. Phylogenomic analyses of nuclear genes reveal the evolutionary relationships within the BEP clade and the evidence of positive selection in Poaceae.

    PubMed

    Zhao, Lei; Zhang, Ning; Ma, Peng-Fei; Liu, Qi; Li, De-Zhu; Guo, Zhen-Hua

    2013-01-01

    BEP clade of the grass family (Poaceae) is composed of three subfamilies, i.e. Bambusoideae, Ehrhartoideae, and Pooideae. Controversies on the phylogenetic relationships among three subfamilies still persist in spite of great efforts. However, previous evidence was mainly provided from plastid genes with only a few nuclear genes utilized. Given different evolutionary histories recorded by plastid and nuclear genes, it is indispensable to uncover their relationships based on nuclear genes. Here, eleven species with whole-sequenced genome and six species with transcriptomic data were included in this study. A total of 121 one-to-one orthologous groups (OGs) were identified and phylogenetic trees were reconstructed by different tree-building methods. Genes which might have undergone positive selection and played important roles in adaptive evolution were also investigated from 314 and 173 one-to-one OGs in two bamboo species and 14 grass species, respectively. Our results support the ((B, P) E) topology with high supporting values. Besides, our findings also indicate that 24 and nine orthologs with statistically significant evidence of positive selection are mainly involved in abiotic and biotic stress response, reproduction and development, plant metabolism and enzyme etc. from two bamboo species and 14 grass species, respectively. In summary, this study demonstrates the power of phylogenomic approach to shed lights on the evolutionary relationships within the BEP clade, and offers valuable insights into adaptive evolution of the grass family.

  8. Phylogenomic Analyses of Nuclear Genes Reveal the Evolutionary Relationships within the BEP Clade and the Evidence of Positive Selection in Poaceae

    PubMed Central

    Zhao, Lei; Zhang, Ning; Ma, Peng-Fei; Liu, Qi; Li, De-Zhu; Guo, Zhen-Hua

    2013-01-01

    BEP clade of the grass family (Poaceae) is composed of three subfamilies, i.e. Bambusoideae, Ehrhartoideae, and Pooideae. Controversies on the phylogenetic relationships among three subfamilies still persist in spite of great efforts. However, previous evidence was mainly provided from plastid genes with only a few nuclear genes utilized. Given different evolutionary histories recorded by plastid and nuclear genes, it is indispensable to uncover their relationships based on nuclear genes. Here, eleven species with whole-sequenced genome and six species with transcriptomic data were included in this study. A total of 121 one-to-one orthologous groups (OGs) were identified and phylogenetic trees were reconstructed by different tree-building methods. Genes which might have undergone positive selection and played important roles in adaptive evolution were also investigated from 314 and 173 one-to-one OGs in two bamboo species and 14 grass species, respectively. Our results support the ((B, P) E) topology with high supporting values. Besides, our findings also indicate that 24 and nine orthologs with statistically significant evidence of positive selection are mainly involved in abiotic and biotic stress response, reproduction and development, plant metabolism and enzyme etc. from two bamboo species and 14 grass species, respectively. In summary, this study demonstrates the power of phylogenomic approach to shed lights on the evolutionary relationships within the BEP clade, and offers valuable insights into adaptive evolution of the grass family. PMID:23734211

  9. Myopia as a latent phenotype of a pleiotropic gene positively selected for facilitating neurocognitive development, and the effects of environmental factors in its expression.

    PubMed

    Mak, W; Kwan, M W M; Cheng, T S; Chan, K H; Cheung, R T F; Ho, S L

    2006-01-01

    Myopia has become an almost pandemic problem in many populations. There are compelling evidence to suggest that myopia is a hereditary condition. However, myopia would constitute a definite selection disadvantage during most stages of human evolution, which is incompatible with its moderate to high prevalence in most modern populations. The rapid upsurge of myopia over just a few decades also implies that its inheritance does not follow any of the usual patterns, and environmental factors may have an important role in precipitating its occurrence in those who are genetically predisposed. Previous studies showed that myopes were, on average, more intelligent than non-myopes, and this association had been attributed to a biological link between eye growth and brain development. We propose a pleiotropic genetic model to explain the atypical epidemiologic and inheritance pattern of myopia and its relationship with neurocognitive development. This pleiotropic gene was positively selected for its facilitation of human intelligence. The myopic component is a latent phenotype; myopia will not be expressed unless some novel external factors are encountered (i.e. a "quirk" phenomenon). Therefore, the myopic component was selectively neutral in our ancestral environment. The net gain in Darwinian fitness enables the pleiotropic gene to attain a high frequency in the human population, as reflected by our current prevalence of myopia.

  10. Lgals6, a 2-Million-Year-Old Gene in Mice: A Case of Positive Darwinian Selection and Presence/Absence Polymorphism

    PubMed Central

    Houzelstein, Denis; Gonçalves, Isabelle R.; Orth, Annie; Bonhomme, François; Netter, Pierre

    2008-01-01

    Duplications of genes are widely considered to be a driving force in the evolutionary process. The fate of such duplicated genes (paralogs) depends mainly on the early stages of their evolution. Therefore, the study of duplications that have already started to diverge is useful to better understand their evolution. We present here the example of a 2-million-year-old segmental duplication at the origin of the Lgals4 and Lgals6 genes in the mouse genome. We analyzed the distribution of these genes in samples from 110 wild individuals and wild-derived inbred strains belonging to eight mouse species from Mus (Coelomys) pahari to M. musculus and 28 laboratory strains. Using a maximum-likelihood method, we show that the sequence of the Lgals6 gene has evolved under the influence of strong positive selection that is likely to result in its neofunctionalization. Surprisingly, despite this selection pressure, the Lgals6 gene is present in some mouse species, but not all. Furthermore, even within the species and populations where it is present, the Lgals6 gene is never fixed. To explain this paradox, we propose different hypotheses such as balanced selection and neutral retention of ancient polymophism and we discuss this unexpected result with regard to known galectin properties and response to infections by pathogens. PMID:18385114

  11. Development of a positive genetic selection system for inhibition of protein splicing using mycobacterial inteins in Escherichia coli DNA gyrase subunit A.

    PubMed

    Adam, Eric; Perler, Francine B

    2002-09-01

    An intein-based positive genetic selection system was developed to study protein splicing and to provide a selection system with the potential for finding splicing inhibitors. Inteins can be novel antimicrobial targets when present in essential proteins since blocking splicing would kill the organism. For example, pathogenic mycobacteria encode inteins that interrupt DNA gyrase. The gyrase selection system exploits (1) splicing of inteins out of Gyrase A and (2) the dominant lethal effect of quinolone poisoning of DNA gyrase, which in turn blocks replication. The system was adapted for whole-cell high-throughput screening using green fluorescent protein as an automatable readout of viability. To demonstrate the efficacy of this system, mutations that blocked splicing of the Mycobacterium xenopi Gyrase A intein were isolated. Splicing was then assayed at a second temperature to identify inteins with a temperature-sensitive splicing phenotype. Mutations were mapped onto a structure-based sequence alignment, which led to the rational prediction of a temperature-sensitive splicing mutation. GyrA intein subdomain relationships also provided insight into intein evolution.

  12. Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.

    PubMed

    Volgraf, Matthew; Sellers, Benjamin D; Jiang, Yu; Wu, Guosheng; Ly, Cuong Q; Villemure, Elisia; Pastor, Richard M; Yuen, Po-wai; Lu, Aijun; Luo, Xifeng; Liu, Mingcui; Zhang, Shun; Sun, Liang; Fu, Yuhong; Lupardus, Patrick J; Wallweber, Heidi J A; Liederer, Bianca M; Deshmukh, Gauri; Plise, Emile; Tay, Suzanne; Reynen, Paul; Herrington, James; Gustafson, Amy; Liu, Yichin; Dirksen, Akim; Dietz, Matthias G A; Liu, Yanzhou; Wang, Tzu-Ming; Hanson, Jesse E; Hackos, David; Scearce-Levie, Kimberly; Schwarz, Jacob B

    2016-03-24

    The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer's disease. Herein we describe the discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from a high-throughput screening hit. Using structure-based design, we sought to increase potency at the GluN2A subtype, while improving selectivity against related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The structure-activity relationship of channel deactivation kinetics was studied using a combination of electrophysiology and protein crystallography. Effective incorporation of these strategies resulted in the discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for in vivo characterization.

  13. Lgals6, a 2-million-year-old gene in mice: a case of positive Darwinian selection and presence/absence polymorphism.

    PubMed

    Houzelstein, Denis; Gonçalves, Isabelle R; Orth, Annie; Bonhomme, François; Netter, Pierre

    2008-03-01

    Duplications of genes are widely considered to be a driving force in the evolutionary process. The fate of such duplicated genes (paralogs) depends mainly on the early stages of their evolution. Therefore, the study of duplications that have already started to diverge is useful to better understand their evolution. We present here the example of a 2-million-year-old segmental duplication at the origin of the Lgals4 and Lgals6 genes in the mouse genome. We analyzed the distribution of these genes in samples from 110 wild individuals and wild-derived inbred strains belonging to eight mouse species from Mus (Coelomys) pahari to M. musculus and 28 laboratory strains. Using a maximum-likelihood method, we show that the sequence of the Lgals6 gene has evolved under the influence of strong positive selection that is likely to result in its neofunctionalization. Surprisingly, despite this selection pressure, the Lgals6 gene is present in some mouse species, but not all. Furthermore, even within the species and populations where it is present, the Lgals6 gene is never fixed. To explain this paradox, we propose different hypotheses such as balanced selection and neutral retention of ancient polymophism and we discuss this unexpected result with regard to known galectin properties and response to infections by pathogens.

  14. Oxidative stress-mediated selective antimicrobial ability of nano-VO2 against Gram-positive bacteria for environmental and biomedical applications.

    PubMed

    Li, Jinhua; Zhou, Huaijuan; Wang, Jiaxing; Wang, Donghui; Shen, Ruxiang; Zhang, Xianlong; Jin, Ping; Liu, Xuanyong

    2016-06-09

    Vanadium dioxide (VO2) is a unique thermochromic material as a result of its semiconductor-metal transition, holding great promise for energy-saving intelligent windows. Herein, pure nano-VO2 from discrete nanoparticles to continuous films were successfully deposited on quartz glass by controlling the sputtering parameters. It was demonstrated that, for Gram-positive S. aureus and S. epidermidis, the nano-VO2 could effectively disrupt bacteria morphology and membrane integrity, and eventually cause death. By contrast, the nano-VO2 did not exhibit significant toxicity towards Gram-negative E. coli and P. aeruginosa. To our knowledge, this is the first report on a selective antimicrobial effect of nano-VO2 materials on Gram-positive bacteria. Based on the experimental results, a plausible mechanism was proposed for the antimicrobial selectivity, which might originate from the different sensitivity of Gram-positive and Gram-negative bacteria to intracellular reactive oxygen species (ROS) level. Elevated intracellular ROS levels exceed the threshold that bacteria can self-regulate to maintain cellular redox homeostasis and thus cause oxidative stress, which can be alleviated by the intervention of glutathione (GSH) antioxidant. In addition, nano-VO2 did not produce significant cytotoxicity (hemolysis) against human erythrocytes within 12 h. Meanwhile, potential cytotoxicity against HIBEpiC revealed a time- and dose-dependent behavior that might be controlled and balanced by careful design. The findings in the present work may contribute to understanding the antimicrobial behavior of nano-VO2, and to expanding the new applications of VO2-based nanomaterials in environmental and biomedical fields.

  15. Oxidative stress-mediated selective antimicrobial ability of nano-VO2 against Gram-positive bacteria for environmental and biomedical applications

    NASA Astrophysics Data System (ADS)

    Li, Jinhua; Zhou, Huaijuan; Wang, Jiaxing; Wang, Donghui; Shen, Ruxiang; Zhang, Xianlong; Jin, Ping; Liu, Xuanyong

    2016-06-01

    Vanadium dioxide (VO2) is a unique thermochromic material as a result of its semiconductor-metal transition, holding great promise for energy-saving intelligent windows. Herein, pure nano-VO2 from discrete nanoparticles to continuous films were successfully deposited on quartz glass by controlling the sputtering parameters. It was demonstrated that, for Gram-positive S. aureus and S. epidermidis, the nano-VO2 could effectively disrupt bacteria morphology and membrane integrity, and eventually cause death. By contrast, the nano-VO2 did not exhibit significant toxicity towards Gram-negative E. coli and P. aeruginosa. To our knowledge, this is the first report on a selective antimicrobial effect of nano-VO2 materials on Gram-positive bacteria. Based on the experimental results, a plausible mechanism was proposed for the antimicrobial selectivity, which might originate from the different sensitivity of Gram-positive and Gram-negative bacteria to intracellular reactive oxygen species (ROS) level. Elevated intracellular ROS levels exceed the threshold that bacteria can self-regulate to maintain cellular redox homeostasis and thus cause oxidative stress, which can be alleviated by the intervention of glutathione (GSH) antioxidant. In addition, nano-VO2 did not produce significant cytotoxicity (hemolysis) against human erythrocytes within 12 h. Meanwhile, potential cytotoxicity against HIBEpiC revealed a time- and dose-dependent behavior that might be controlled and balanced by careful design. The findings in the present work may contribute to understanding the antimicrobial behavior of nano-VO2, and to expanding the new applications of VO2-based nanomaterials in environmental and biomedical fields.

  16. Ongoing Clinical Trials of the Pleiotropic Effects of Statins

    PubMed Central

    Davignon, Jean; Leiter, Lawrence A

    2005-01-01

    Background The multiple effects (ie, pleiotropic effects of statins) have received increasing recognition and may have clinical applicability across a broad range of cardiovascular and noncardiovascular conditions. Objective To determine the relevance and significance of ongoing clinical trials of the pleiotropic effects of statins, focusing on nonlipid effects. Method Ongoing trials were identified through personal communication, reports presented at scientific meetings (2000–2004), and queries made to AstraZeneca, Bristol-Myers Squibb Co, Merck & Co, Novartis, and Pfizer, manufacturers of the currently marketed statins. Published trials and other source material were identified through electronic searches on MEDLINE (1990–2003), abstract books, and references identified from bibliographies of pertinent articles. Eligible studies were the clinical trials of statins currently under way in which primary or secondary outcomes included the statins' nonlipid (ie, pleiotropic) effect(s). Data were extracted and trial quality was assessed by the authors. Results Of the 22 ongoing trials of the nonlipid effects of statins identified, 10 assessed inflammatory markers and plaque stabilization, 4 assessed oxidized low density lipoprotein/vascular oxidant stress, 3 assessed end-stage renal disease, 3 assessed fibrinogen/viscosity, 2 assessed endothelial function, 2 assessed acute coronary syndrome, 2 assessed aortic stenosis progression, and 1 each assessed hypertension, osteoporosis, ischemic burden, Alzheimer's disease, multiple sclerosis, and stroke (outcomes often overlapped). Conclusion Given the excellent safety and tolerability of statins as a class, full exploration of their pleiotropic effects has the potential to provide additional benefits to many patients. PMID:17319096

  17. The phase of ongoing EEG oscillations predicts visual perception.

    PubMed

    Busch, Niko A; Dubois, Julien; VanRullen, Rufin

    2009-06-17

    Oscillations are ubiquitous in electrical recordings of brain activity. While the amplitude of ongoing oscillatory activity is known to correlate with various aspects of perception, the influence of oscillatory phase on perception remains unknown. In particular, since phase varies on a much faster timescale than the more sluggish amplitude fluctuations, phase effects could reveal the fine-grained neural mechanisms underlying perception. We presented brief flashes of light at the individual luminance threshold while EEG was recorded. Although the stimulus on each trial was identical, subjects detected approximately half of the flashes (hits) and entirely missed the other half (misses). Phase distributions across trials were compared between hits and misses. We found that shortly before stimulus onset, each of the two distributions exhibited significant phase concentration, but at different phase angles. This effect was strongest in the theta and alpha frequency bands. In this time-frequency range, oscillatory phase accounted for at least 16% of variability in detection performance and allowed the prediction of performance on the single-trial level. This finding indicates that the visual detection threshold fluctuates over time along with the phase of ongoing EEG activity. The results support the notion that ongoing oscillations shape our perception, possibly by providing a temporal reference frame for neural codes that rely on precise spike timing.

  18. Whole-genome sequence analyses of Western Central African Pygmy hunter-gatherers reveal a complex demographic history and identify candidate genes under positive natural selection

    PubMed Central

    Hsieh, PingHsun; Veeramah, Krishna R.; Lachance, Joseph; Tishkoff, Sarah A.; Wall, Jeffrey D.; Hammer, Michael F.; Gutenkunst, Ryan N.

    2016-01-01

    African Pygmies practicing a mobile hunter-gatherer lifestyle are phenotypically and genetically diverged from other anatomically modern humans, and they likely experienced strong selective pressures due to their unique lifestyle in the Central African rainforest. To identify genomic targets of adaptation, we sequenced the genomes of four Biaka Pygmies from the Central African Republic and jointly analyzed these data with the genome sequences of three Baka Pygmies from Cameroon and nine Yoruba famers. To account for the complex demographic history of these populations that includes both isolation and gene flow, we fit models using the joint allele frequency spectrum and validated them using independent approaches. Our two best-fit models both suggest ancient divergence between the ancestors of the farmers and Pygmies, 90,000 or 150,000 yr ago. We also find that bidirectional asymmetric gene flow is statistically better supported than a single pulse of unidirectional gene flow from farmers to Pygmies, as previously suggested. We then applied complementary statistics to scan the genome for evidence of selective sweeps and polygenic selection. We found that conventional statistical outlier approaches were biased toward identifying candidates in regions of high mutation or low recombination rate. To avoid this bias, we assigned P-values for candidates using whole-genome simulations incorporating demography and variation in both recombination and mutation rates. We found that genes and gene sets involved in muscle development, bone synthesis, immunity, reproduction, cell signaling and development, and energy metabolism are likely to be targets of positive natural selection in Western African Pygmies or their recent ancestors. PMID:26888263

  19. Altered Ca2+ kinetics associated with α-actinin-3 deficiency may explain positive selection for ACTN3 null allele in human evolution.

    PubMed

    Head, Stewart I; Chan, Stephen; Houweling, Peter J; Quinlan, Kate G R; Murphy, Robyn; Wagner, Sören; Friedrich, Oliver; North, Kathryn N

    2015-01-01

    Over 1.5 billion people lack the skeletal muscle fast-twitch fibre protein α-actinin-3 due to homozygosity for a common null polymorphism (R577X) in the ACTN3 gene. α-Actinin-3 deficiency is detrimental to sprint performance in elite athletes and beneficial to endurance activities. In the human genome, it is very difficult to find single-gene loss-of-function variants that bear signatures of positive selection, yet intriguingly, the ACTN3 null variant has undergone strong positive selection during recent evolution, appearing to provide a survival advantage where food resources are scarce and climate is cold. We have previously demonstrated that α-actinin-3 deficiency in the Actn3 KO mouse results in a shift in fast-twitch fibres towards oxidative metabolism, which would be more "energy efficient" in famine, and beneficial to endurance performance. Prolonged exposure to cold can also induce changes in skeletal muscle similar to those observed with endurance training, and changes in Ca2+ handling by the sarcoplasmic reticulum (SR) are a key factor underlying these adaptations. On this basis, we explored the effects of α-actinin-3 deficiency on Ca2+ kinetics in single flexor digitorum brevis muscle fibres from Actn3 KO mice, using the Ca2+-sensitive dye fura-2. Compared to wild-type, fibres of Actn3 KO mice showed: (i) an increased rate of decay of the twitch transient; (ii) a fourfold increase in the rate of SR Ca2+ leak; (iii) a threefold increase in the rate of SR Ca2+ pumping; and (iv) enhanced maintenance of tetanic Ca2+ during fatigue. The SR Ca2+ pump, SERCA1, and the Ca2+-binding proteins, calsequestrin and sarcalumenin, showed markedly increased expression in muscles of KO mice. Together, these changes in Ca2+ handling in the absence of α-actinin-3 are consistent with cold acclimatisation and thermogenesis, and offer an additional explanation for the positive selection of the ACTN3 577X null allele in populations living in cold environments during recent

  20. Rejection positivity predicts trial-to-trial reaction times in an auditory selective attention task: a computational analysis of inhibitory control

    PubMed Central

    Chen, Sufen; Melara, Robert D.

    2014-01-01

    A series of computer simulations using variants of a formal model of attention (Melara and Algom, 2003) probed the role of rejection positivity (RP), a slow-wave electroencephalographic (EEG) component, in the inhibitory control of distraction. Behavioral and EEG data were recorded as participants performed auditory selective attention tasks. Simulations that modulated processes of distractor inhibition accounted well for reaction-time (RT) performance, whereas those that modulated target excitation did not. A model that incorporated RP from actual EEG recordings in estimating distractor inhibition was superior in predicting changes in RT as a function of distractor salience across conditions. A model that additionally incorporated momentary fluctuations in EEG as the source of trial-to-trial variation in performance precisely predicted individual RTs within each condition. The results lend support to the linking proposition that RP controls the speed of responding to targets through the inhibitory control of distractors. PMID:25191244

  1. Selectively catalytic activity of metal-organic frameworks depending on the N-position within the pyridine ring of their building blocks

    NASA Astrophysics Data System (ADS)

    Xu, Haitao; Gou, Yongxia; Ye, Jing; Xu, Zhen-liang; Wang, Zixuan

    2016-05-01

    Iron metal-organic frameworks (MOFs) [Fe(L)2(SCN)2]∝ (L1: 4-bpdh=2,5-bis(4-pyridyl)-3,4-diaza-2,4-hexadiene for 1Fe; and L2: 3-bpdh=2,5-bis(3-pyridyl)-3,4-diaza-2,4-hexadiene for 2Fe) were assembled in a MeOH-H2O solvent system. 1Fe exhibits a two-dimensional extended-grid network, whereas 2Fe exhibits a stair-like double-chain; the N-position within the pyridine ring of the complexes was observed to regulate the MOF structure as layers or chains. Furthermore, selectively catalytic activity was observed for the layered MOF but not the chain-structured MOF; micro/nanoparticles of the layered MOF were therefore investigated for new potential applications of micro/nano MOFs.

  2. Contribution of Temperature and Precipitation Anomalies to the Ongoing California Drought

    NASA Astrophysics Data System (ADS)

    Luo, L.; Apps, D.; Arcand, S. E.

    2015-12-01

    The ongoing multiyear drought over California is a major concern for the residents of the golden state as it brings water restrictions in preparing for water shortages and wild fires due to dry and hot conditions. Both positive temperature and negative precipitation anomalies can contribute to drought developments, but how important are these anomalies for the ongoing California drought? Using the VIC hydrological model, this study investigated the relative contribution of temperature and precipitation anomalies to the ongoing 2011-2015 drought in comparison with another multiyear drought between 1987 and 1992 over the same region. By swapping the observed temperature and precipitation anomalies between two drought events, the study was able to show how temperature and precipitation anomalies and their spatial variability affect other elements of the hydrological cycle including evapotranspiration, soil moisture and streamflow, thus the severity of the drought. The comparison between these two events helps to reveal the unique characteristics of the current drought and provides useful insights for drought prediction and mitigation.

  3. Can Evidence from Genome-Wide Association Studies and Positive Natural Selection Surveys Be Used to Evaluate the Thrifty Gene Hypothesis in East Asians?

    PubMed Central

    Koh, Xuan-Han; Liu, Xuanyao; Teo, Yik-Ying

    2014-01-01

    Body fat deposition and distribution differ between East Asians and Europeans, and for the same level of obesity, East Asians are at higher risks of Type 2 diabetes (T2D) and other metabolic disorders. This observation has prompted the reclassifications of body mass index thresholds for the definitions of “overweight” and “obese” in East Asians. However, the question remains over what evolutionary mechanisms have driven the differences in adiposity morphology between two population groups that shared a common ancestor less than 80,000 years ago. The Thrifty Gene hypothesis has been suggested as a possible explanation, where genetic factors that allowed for efficient food-energy conversion and storage are evolutionarily favoured by conferring increased chances of survival and fertility. Here, we leveraged on the existing findings from genome-wide association studies and large-scale surveys of positive natural selection to evaluate whether there is currently any evidence to support the Thrifty Gene hypothesis. We first assess whether the existing genetic associations with obesity and T2D are located in genomic regions that are reported to be under positive selection, and if so, whether the risk alleles sit on the extended haplotype forms. In addition, we interrogate whether these risk alleles are the derived forms that differ from the ancestral alleles, and whether there is significant evidence of population differentiation at these SNPs between East Asian and European populations. Our systematic survey did not yield conclusive evidence to support the Thrifty Gene hypothesis as a possible explanation for the differences observed between East Asians and Europeans. PMID:25337808

  4. Evolution of the Transmission-Blocking Vaccine Candidates Pvs28 and Pvs25 in Plasmodium vivax: Geographic Differentiation and Evidence of Positive Selection

    PubMed Central

    Cornejo, Omar E.; Durrego, Ester; Stanley, Craig E.; Castillo, Andreína I.; Herrera, Sócrates; Escalante, Ananias A.

    2016-01-01

    Transmission-blocking (TB) vaccines are considered an important tool for malaria control and elimination. Among all the antigens characterized as TB vaccines against Plasmodium vivax, the ookinete surface proteins Pvs28 and Pvs25 are leading candidates. These proteins likely originated by a gene duplication event that took place before the radiation of the known Plasmodium species to primates. We report an evolutionary genetic analysis of a worldwide sample of pvs28 and pvs25 alleles. Our results show that both genes display low levels of genetic polymorphism when compared to the merozoite surface antigens AMA-1 and MSP-1; however, both ookinete antigens can be as polymorphic as other merozoite antigens such as MSP-8 and MSP-10. We found that parasite populations in Asia and the Americas are geographically differentiated with comparable levels of genetic diversity and specific amino acid replacements found only in the Americas. Furthermore, the observed variation was mainly accumulated in the EGF2- and EGF3-like domains for P. vivax in both proteins. This pattern was shared by other closely related non-human primate parasites such as Plasmodium cynomolgi, suggesting that it could be functionally important. In addition, examination with a suite of evolutionary genetic analyses indicated that the observed patterns are consistent with positive natural selection acting on Pvs28 and Pvs25 polymorphisms. The geographic pattern of genetic differentiation and the evidence for positive selection strongly suggest that the functional consequences of the observed polymorphism should be evaluated during development of TBVs that include Pvs25 and Pvs28. PMID:27347876

  5. Analysis of HLA class II haplotypes in the Cayapa Indians of Ecuador: a novel DRB1 allele reveals evidence for convergent evolution and balancing selection at position 86.

    PubMed Central

    Titus-Trachtenberg, E. A.; Rickards, O.; De Stefano, G. F.; Erlich, H. A.

    1994-01-01

    PCR amplification, oligonucleotide probe typing, and sequencing were used to analyze the HLA class II loci (DRB1, DQA1, DQB1, and DPB1) of an isolated South Amerindian tribe. Here we report HLA class II variation, including the identification of a new DRB1 allele, several novel DR/DQ haplotypes, and an unusual distribution of DPB1 alleles, among the Cayapa Indians (N = 100) of Ecuador. A general reduction of HLA class II allelic variation in the Cayapa is consistent with a population bottle-neck during the colonization of the Americas. The new Cayapa DRB1 allele, DRB1*08042, which arose by a G-->T point mutation in the parental DRB1*0802, contains a novel Val codon (GTT) at position 86. The generation of DRB1*08042 (Val-86) from DRB1*0802 (Gly-86) in the Cayapa, by a different mechanism than the (GT-->TG) change in the creation of DRB1*08041 (Val-86) from DRB1*0802 in Africa, implicates selection in the convergent evolution of position 86 DR beta variants. The DRB1*08042 allele has not been found in > 1,800 Amerindian haplotypes and thus presumably arose after the Cayapa separated from other South American Amerindians. Selection pressure for increased haplotype diversity can be inferred in the generation and maintenance of three new DRB1*08042 haplotypes and several novel DR/DQ haplotypes in this population. The DPB1 allelic distribution in the Cayapa is also extraordinary, with two alleles, DPB1*1401, a very rare allele in North American Amerindian populations, and DPB1*0402, the most common Amerindian DPB1 allele, constituting 89% of the Cayapa DPB1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8023844

  6. A high-throughput venom-gland transcriptome for the Eastern Diamondback Rattlesnake (Crotalus adamanteus) and evidence for pervasive positive selection across toxin classes.

    PubMed

    Rokyta, Darin R; Wray, Kenneth P; Lemmon, Alan R; Lemmon, Emily Moriarty; Caudle, S Brian

    2011-04-01

    Despite causing considerable human mortality and morbidity, animal toxins represent a valuable source of pharmacologically active macromolecules, a unique system for studying molecular adaptation, and a powerful framework for examining structure-function relationships in proteins. Snake venoms are particularly useful in the latter regard as they consist primarily of a moderate number of proteins and peptides that have been found to belong to just a handful of protein families. As these proteins and peptides are produced in dedicated glands, transcriptome sequencing has proven to be an effective approach to identifying the expressed toxin genes. We generated a venom-gland transcriptome for the Eastern Diamondback Rattlesnake (Crotalus adamanteus) using Roche 454 sequencing technology. In the current work, we focus on transcripts encoding toxins. We identified 40 unique toxin transcripts, 30 of which have full-length coding sequences, and 10 have only partial coding sequences. These toxins account for 24% of the total sequencing reads. We found toxins from 11 previously described families of snake-venom toxins and have discovered two putative, previously undescribed toxin classes. The most diverse and highly expressed toxin classes in the C. adamanteus venom-gland transcriptome are the serine proteinases, metalloproteinases, and C-type lectins. The serine proteinases are the most abundant class, accounting for 35% of the toxin sequencing reads. Metalloproteinases are the most diverse; 11 different forms have been identified. Using our sequences and those available in public databases, we detected positive selection in seven of the eight toxin families for which sufficient sequences were available for the analysis. We find that the vast majority of the genes that contribute directly to this vertebrate trait show evidence for a role for positive selection in their evolutionary history.

  7. A Functional polymorphism under positive evolutionary selection in ADRB2 is associated with human intelligence with opposite effects in the young and the elderly.

    PubMed

    Bochdanovits, Zoltán; Gosso, Florencia M; van den Berg, Linda; Rizzu, Patrizia; Polderman, Tinca J C; Pardo, Luba M; Houlihan, Lorna M; Luciano, Michelle; Starr, John M; Harris, Sarah E; Deary, Ian J; de Geus, Eco J C; Boomsma, Dorret I; Heutink, Peter; Posthuma, Danielle

    2009-01-01

    Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior.

  8. Selective versus comprehensive neck dissection in the treatment of patients with a pathologically node-positive neck with or without microscopic extracapsular spread in oral squamous cell carcinoma.

    PubMed

    Feng, Z; Gao, Y; Niu, L X; Peng, X; Guo, C B

    2014-10-01

    The objective of this study was to compare the prognosis and complications between selective neck dissection (SND) and comprehensive neck dissection (CND) for patients with a pathologically node-positive neck in squamous cell carcinoma of the tongue and the floor of the mouth. This was a retrospective cohort study. There was no significant difference between the SND group and the CND group in 3-year neck control rate (86.2% vs. 85.9%, P=0.797) or disease-specific survival (DSS) rate (64.6% vs. 61.9%, P=0.646). Further analyses of the respective 3-year DSS rates in the SND and CND subgroups were as follows: pN1 without extracapsular spread (ECS), 67.7% vs. 72.2%, P=0.851; pN2b without ECS, 64.7% vs. 68.8%, P=0.797; and pN+ with ECS, 57.1% vs. 60.0%, P=0.939. Of note, there were significantly fewer complications in the SND group compared with the CND group (7.3% vs. 20.0%, P=0.032). Multivariate analysis showed that the modality of neck treatment, pN+ status, and microscopic ECS did not serve as independent prognostic factors. SND plus adjuvant radiotherapy is a management strategy of high efficiency and minor morbidity for selected oral cancer patients with a pN+ neck with or without microscopic ECS.

  9. Growth kinetics in position-controlled and catalyst-free InAs nanowire arrays on Si(111) grown by selective area molecular beam epitaxy

    NASA Astrophysics Data System (ADS)

    Hertenberger, S.; Rudolph, D.; Bichler, M.; Finley, J. J.; Abstreiter, G.; Koblmüller, G.

    2010-12-01

    We investigated the interwire distance dependence on the growth kinetics of vertical, high-yield InAs nanowire arrays on Si(111) grown by catalyst-free selective area molecular beam epitaxy (MBE). Utilizing lithographically defined SiO2 nanomasks on Si(111) with regular hole patterns, catalyst-free and site-selective growth of vertically (111)-oriented InAs nanowires was achieved with very high yields of ˜90 percent. Interestingly, the yield of vertically ordered nanowires was independent of the interwire distance and the initial growth stages. Significant size variation in the nanowires was found to depend critically on the interwire distance and growth time. Two growth regimes were identified—(i) a competitive growth regime with shorter and thinner nanowires for narrow interwire distances and (ii) a diffusion-limited growth regime for wider distances, providing good estimates for the surface diffusion lengths. Surprisingly, despite these size-dependent effects the nanowire geometries remained unaltered with uniform, almost nontapered morphologies even over large variation in nanowire density (˜mid-106-109 cm-2 range). X-ray diffraction further confirmed the vertical (111) directionality with low crystal tilt by rocking curve widths (ω scans) as low as ˜0.6°. These findings demonstrate the capability to precisely tailor the position and size of well-oriented III-V semiconductor nanowires through noncatalytic MBE selective area growth and provide an important step toward fully integrated, uniform vertical III-V nanowire array-on-Si devices.

  10. Selective determination of tobacco-specific nitrosamines in mainstream cigarette smoke by GC coupled to positive chemical ionization triple quadrupole MS.

    PubMed

    Wu, Da; Lu, Yifeng; Lin, Huaqing; Zhou, Wanhong; Gu, Wenbo

    2013-08-01

    A rapid method for the selective determination of four kinds of tobacco-specific nitrosamines, N-nitrosonornicotine, N-nitrosoanatabine, N-nitrosoanabasine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in mainstream cigarette smoke was developed by GC coupled to positive chemical ionization triple-quadrupole MS. After mainstream cigarette smoke was collected on a cambridge filter pad, the particulate matter was extracted with 0.1 M HCL aqueous solution, cleaned by positive cation-exchange solid extraction, and finally injected into GC-MS/MS using isotopically labeled analogues as internal standards. Excellent linearity was obtained over the concentration range of 0.5-200.0 ng mL(-1) for all tobacco-specific nitrosamines with values for correlation coefficient between 0.9996-0.9999. Limits of detection of each tobacco specific nitrosamine varied from 0.023-0.028 ng cig(-1), and lower limits of quantification varied from 0.077-0.093 ng cig(-1). The recovery of each tobacco specific nitrosamine was from 90.0-109.0%. The relative standard deviations of the intra-day and inter-day precisions were 3.1-5.8 and 3.9-6.6, respectively. This method was applied to reference and domestic cigarettes. The result showed that the method was consistent with traditional methods and can be used as an effective approach for the routine analysis of tobacco-specific nitrosamines.

  11. The Role of Glutamic or Aspartic Acid in Position Four of the Epitope Binding Motif and Thyrotropin Receptor-Extracellular Domain Epitope Selection in Graves' Disease

    PubMed Central

    Inaba, Hidefumi; Martin, William; Ardito, Matt; De Groot, Anne Searls; De Groot, Leslie J.

    2010-01-01

    Context: Development of Graves' disease (GD) is related to HLA-DRB1*0301 (DR3),and more specifically to arginine at position 74 of the DRB1 molecule. The extracellular domain (ECD) of human TSH receptor (hTSH-R) contains the target antigen. Objective and Design: We analyzed the relation between hTSH-R-ECD peptides and DR molecules to determine whether aspartic acid (D) or glutamic acid (E) at position four in the binding motif influenced selection of functional epitopes. Results: Peptide epitopes from TSH-R-ECD with D or E in position four (D/E+) had higher affinity for binding to DR3 than peptides without D/E (D/E−) (IC50 29.3 vs. 61.4, P = 0.0024). HLA-DR7, negatively correlated with GD, and DRB1*0302 (HLA-DR18), not associated with GD, had different profiles of epitope binding. Toxic GD patients who are DR3+ had higher responses to D/E+ peptides than D/E− peptides (stimulation index 1.42 vs. 1.22, P = 0.028). All DR3+ GD patients (toxic + euthyroid) had higher responses, with borderline significance (Sl; 1.32 vs. 1.18, P = 0.051). Splenocytes of DR3 transgenic mice immunized to TSH-R-ECD responded to D/E+ peptides more than D/E− peptides (stimulation index 1.95 vs. 1.69, P = 0.036). Seven of nine hTSH-R-ECD peptide epitopes reported to be reactive with GD patients' peripheral blood mononuclear cells contain binding motifs with D/E at position four. Conclusions: TSH-R-ECD epitopes with D/E in position four of the binding motif bind more strongly to DRB1*0301 than epitopes that are D/E− and are more stimulatory to GD patients' peripheral blood mononuclear cells and to splenocytes from mice immunized to hTSH-R. These epitopes appear important in immunogenicity to TSH-R due to their favored binding to HLA-DR3, thus increasing presentation to T cells. PMID:20392871

  12. Offsetting Ongoing Methane Emissions --- An Alternative to Emission Equivalence Metrics

    NASA Astrophysics Data System (ADS)

    Clisby, N.; Enting, I. G.; Lauder, A.; Carter, J.; Cowie, A.; Henry, B.; Raupach, M. R.

    2012-12-01

    The Global Warming Potential (GWP) has been widely adopted as a metric for comparing the climate impact of different greenhouse gases. As has been frequently noted, there are many problems with using GWPs to define emission equivalence in spite of the use of GWPs for this purpose in contexts such as the Kyoto Protocol. We propose that for methane, rather than define emission equivalence, the appropriate comparison is between ongoing emissions of 0.9 to 1.0 kg of CH4 per year and one-off emissions of 1 tonne of carbon. This approach represents an approximate solution to the inverse problem of defining a forcing equivalent index (FEI) that gives exact equivalence of radiative forcing over a range of timescales. In our approach, if ongoing methane emissions are offset by a one-off carbon removal that is built up with 40-year e-folding time, then the result is close to radiatively neutral over periods from years to centuries. In contrast, the GWP provides radiative equivalence (in integrated terms) only at a single time, with large discrepancies at other times. Our approach also follows from consideration of greenhouse gas stabilisation, since stabilising atmospheric CO2 requires an approximate cap on total emissions, while stabilising methane requires stabilisation of ongoing emissions. Our quantitative treatment recognises that, on time scales of centuries, removal of 1 tonne of carbon only lowers the atmospheric carbon content by 0.3 to 0.35 tonnes. We discuss the implications for rangeland grazing systems. In the absence of effective mitigation techniques for methane from rangeland systems, this approach may provide an attractive offset mechanism in spite of requiring that woody vegetation be established and maintained over about 15% of the landscape, or an equivalent amount of carbon storage in soil.

  13. Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

    PubMed Central

    Gastambide, Francois; Cotel, Marie-Caroline; Gilmour, Gary; O'Neill, Michael J; Robbins, Trevor W; Tricklebank, Mark D

    2012-01-01

    Based on the glutamatergic hypothesis of schizophrenia we assessed the effects of a novel mGlu5 positive allosteric modulator, LSN2463359 [N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide] on deficits in cognitive flexibility in two distinct rodent models of schizophrenia, the neurodevelopmental MAM E17 model and the acute PCP model. Cognitive flexibility was measured with the intra-dimensional and extra-dimensional set-shifting and reversal learning digging paradigm. Regional effects of MAM on the expression of parvalbumin-positive cells (PV) and mGlu5 receptors were also examined, to further characterize the model. Results showed that LSN2463359 selectively attenuated reversal learning deficits in the MAM but not acute PCP model. Whilst both models led to deficits in reversal learning and extra-dimensional set-shifting, the reversal impairments were qualitatively distinct, with MAM increasing perseverative responding, whereas the PCP deficit was mainly due to the inability of rats to maintain reinforced choice behavior. Reduction of PV and mGlu5 expression was found in the MAM model in several regions of importance in schizophrenia, such as the orbitofrontal and medial prefrontal cortex, which also mediate reversal learning and extra-dimensional set-shifting. The present findings confirm that the positive modulation of mGlu5 receptors may have beneficial effects in the treatment of certain aspects of cognitive impairment associated with schizophrenia. This study also illustrates the importance of studying putative cognitive enhancing drug effects in a number of models which may have implications for the future development of the compound. PMID:22129780

  14. Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator.

    PubMed

    Gastambide, Francois; Cotel, Marie-Caroline; Gilmour, Gary; O'Neill, Michael J; Robbins, Trevor W; Tricklebank, Mark D

    2012-03-01

    Based on the glutamatergic hypothesis of schizophrenia we assessed the effects of a novel mGlu5 positive allosteric modulator, LSN2463359 [N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide] on deficits in cognitive flexibility in two distinct rodent models of schizophrenia, the neurodevelopmental MAM E17 model and the acute PCP model. Cognitive flexibility was measured with the intra-dimensional and extra-dimensional set-shifting and reversal learning digging paradigm. Regional effects of MAM on the expression of parvalbumin-positive cells (PV) and mGlu5 receptors were also examined, to further characterize the model. Results showed that LSN2463359 selectively attenuated reversal learning deficits in the MAM but not acute PCP model. Whilst both models led to deficits in reversal learning and extra-dimensional set-shifting, the reversal impairments were qualitatively distinct, with MAM increasing perseverative responding, whereas the PCP deficit was mainly due to the inability of rats to maintain reinforced choice behavior. Reduction of PV and mGlu5 expression was found in the MAM model in several regions of importance in schizophrenia, such as the orbitofrontal and medial prefrontal cortex, which also mediate reversal learning and extra-dimensional set-shifting. The present findings confirm that the positive modulation of mGlu5 receptors may have beneficial effects in the treatment of certain aspects of cognitive impairment associated with schizophrenia. This study also illustrates the importance of studying putative cognitive enhancing drug effects in a number of models which may have implications for the future development of the compound.

  15. Overview of ongoing cohort and dietary studies in the Arctic

    PubMed Central

    Weihe, Pál; Bjerregaard, Peter; Bonefeld-Jørgensen, Eva; Dudarev, Alexey; Halling, Jónrit; Hansen, Solrunn; Muckle, Gina; Nøst, Therese; Odland, Jon Øyvind; Petersen, Maria Skaalum; Rautio, Arja; Veyhe, Anna Sofía; Wennberg, Maria; Bergdahl, Ingvar

    2016-01-01

    This article gives an overview of the ongoing cohort and dietary studies underlying the assessment of population health in the Arctic. The emphasis here is on a description of the material, methods and results or preliminary results for each study. Detailed exposure information is available in an article in this journal, whereas another paper describes the effects associated with contaminant exposure in the Arctic. The cohort descriptions have been arranged geographically, beginning in Norway and moving east to Finland, Sweden, Russia and the other Arctic countries and ultimately to the Faroe Islands. No cohort studies have been reported for Alaska or Iceland. PMID:27974135

  16. Ongoing collapse of coral-reef shark populations.

    PubMed

    Robbins, William D; Hisano, Mizue; Connolly, Sean R; Choat, J Howard

    2006-12-05

    Marine ecosystems are suffering severe depletion of apex predators worldwide; shark declines are principally due to conservative life-histories and fisheries overexploitation. On coral reefs, sharks are strongly interacting apex predators and play a key role in maintaining healthy reef ecosystems. Despite increasing fishing pressure, reef shark catches are rarely subject to specific limits, with management approaches typically depending upon no-take marine reserves to maintain populations. Here, we reveal that this approach is failing by documenting an ongoing collapse in two of the most abundant reef shark species on the Great Barrier Reef (Australia). We find an order of magnitude fewer sharks on fished reefs compared to no-entry management zones that encompass only 1% of reefs. No-take zones, which are more difficult to enforce than no-entry zones, offer almost no protection for shark populations. Population viability models of whitetip and gray reef sharks project ongoing steep declines in abundance of 7% and 17% per annum, respectively. These findings indicate that current management of no-take areas is inadequate for protecting reef sharks, even in one of the world's most-well-managed reef ecosystems. Further steps are urgently required for protecting this critical functional group from ecological extinction.

  17. Diverse thalamocortical short-term plasticity elicited by ongoing stimulation.

    PubMed

    Díaz-Quesada, Marta; Martini, Francisco J; Ferrati, Giovanni; Bureau, Ingrid; Maravall, Miguel

    2014-01-08

    To produce sensation, neuronal pathways must transmit and process stimulus patterns that unfold over time. This behavior is determined by short-term synaptic plasticity (STP), which shapes the temporal filtering properties of synapses in a pathway. We explored STP variability across thalamocortical (TC) synapses, measuring whole-cell responses to stimulation of TC fibers in layer 4 neurons of mouse barrel cortex in vitro. As expected, STP during stimulation from rest was dominated by depression. However, STP during ongoing stimulation was strikingly diverse across TC connections. Diversity took the form of variable tuning to the latest interstimulus interval: some connections responded weakly to shorter intervals, while other connections were facilitated. These behaviors did not cluster into categories but formed a continuum. Diverse tuning did not require disynaptic inhibition. Hence, monosynaptic excitatory lemniscal TC connections onto layer 4 do not behave uniformly during ongoing stimulation. Each connection responds differentially to particular stimulation intervals, enriching the ability of the pathway to convey complex, temporally fluctuating information.

  18. Positive Selection and Multiple Losses of the LINE-1-Derived L1TD1 Gene in Mammals Suggest a Dual Role in Genome Defense and Pluripotency

    PubMed Central

    Yang, Lei; Neme, Rafik; Wichman, Holly A.; Malik, Harmit S.

    2014-01-01

    Mammalian genomes comprise many active and fossilized retroelements. The obligate requirement for retroelement integration affords host genomes an opportunity to ‘domesticate’ retroelement genes for their own purpose, leading to important innovations in genome defense and placentation. While many such exaptations involve retroviruses, the L1TD1 gene is the only known domesticated gene whose protein-coding sequence is almost entirely derived from a LINE-1 (L1) retroelement. Human L1TD1 has been shown to play an important role in pluripotency maintenance. To investigate how this role was acquired, we traced the origin and evolution of L1TD1. We find that L1TD1 originated in the common ancestor of eutherian mammals, but was lost or pseudogenized multiple times during mammalian evolution. We also find that L1TD1 has evolved under positive selection during primate and mouse evolution, and that one prosimian L1TD1 has ‘replenished’ itself with a more recent L1 ORF1 from the prosimian genome. These data suggest that L1TD1 has been recurrently selected for functional novelty, perhaps for a role in genome defense. L1TD1 loss is associated with L1 extinction in several megabat lineages, but not in sigmodontine rodents. We hypothesize that L1TD1 could have originally evolved for genome defense against L1 elements. Later, L1TD1 may have become incorporated into pluripotency maintenance in some lineages. Our study highlights the role of retroelement gene domestication in fundamental aspects of mammalian biology, and that such domesticated genes can adopt different functions in different lineages. PMID:25211013

  19. The Avian XPR1 Gammaretrovirus Receptor Is under Positive Selection and Is Disabled in Bird Species in Contact with Virus-Infected Wild Mice

    PubMed Central

    Martin, Carrie; Buckler-White, Alicia; Wollenberg, Kurt

    2013-01-01

    Xenotropic mouse leukemia viruses (X-MLVs) are broadly infectious for mammals except most of the classical strains of laboratory mice. These gammaretroviruses rely on the XPR1 receptor for entry, and the unique resistance of laboratory mice is due to two mutations in different putative XPR1 extracellular loops. Cells from avian species differ in susceptibility to X-MLVs, and 2 replacement mutations in the virus-resistant chicken XPR1 (K496Q and Q579E) distinguish it from the more permissive duck and quail receptors. These substitutions align with the two mutations that disable the laboratory mouse XPR1. Mutagenesis of the chicken and duck genes confirms that residues at both sites are critical for virus entry. Among 32 avian species, the 2 disabling XPR1 mutations are found together only in the chicken, an omnivorous, ground-dwelling fowl that was domesticated in India and/or Southeast Asia, which is also where X-MLV-infected house mice evolved. The receptor-disabling mutations are also present separately in 5 additional fowl and raptor species, all of which are native to areas of Asia populated by the virus-infected subspecies Mus musculus castaneus. Phylogenetic analysis showed that the avian XPR1 gene is under positive selection at sites implicated in receptor function, suggesting a defensive role for XPR1 in the avian lineage. Contact between bird species and virus-infected mice may thus have favored selection of mouse virus-resistant receptor orthologs in the birds, and our data suggest that similar receptor-disabling mutations were fixed in mammalian and avian species exposed to similar virus challenges. PMID:23843647

  20. The avian XPR1 gammaretrovirus receptor is under positive selection and is disabled in bird species in contact with virus-infected wild mice.

    PubMed

    Martin, Carrie; Buckler-White, Alicia; Wollenberg, Kurt; Kozak, Christine A

    2013-09-01

    Xenotropic mouse leukemia viruses (X-MLVs) are broadly infectious for mammals except most of the classical strains of laboratory mice. These gammaretroviruses rely on the XPR1 receptor for entry, and the unique resistance of laboratory mice is due to two mutations in different putative XPR1 extracellular loops. Cells from avian species differ in susceptibility to X-MLVs, and 2 replacement mutations in the virus-resistant chicken XPR1 (K496Q and Q579E) distinguish it from the more permissive duck and quail receptors. These substitutions align with the two mutations that disable the laboratory mouse XPR1. Mutagenesis of the chicken and duck genes confirms that residues at both sites are critical for virus entry. Among 32 avian species, the 2 disabling XPR1 mutations are found together only in the chicken, an omnivorous, ground-dwelling fowl that was domesticated in India and/or Southeast Asia, which is also where X-MLV-infected house mice evolved. The receptor-disabling mutations are also present separately in 5 additional fowl and raptor species, all of which are native to areas of Asia populated by the virus-infected subspecies Mus musculus castaneus. Phylogenetic analysis showed that the avian XPR1 gene is under positive selection at sites implicated in receptor function, suggesting a defensive role for XPR1 in the avian lineage. Contact between bird species and virus-infected mice may thus have favored selection of mouse virus-resistant receptor orthologs in the birds, and our data suggest that similar receptor-disabling mutations were fixed in mammalian and avian species exposed to similar virus challenges.

  1. CoMFA analyses of C-2 position salvinorin A analogs at the kappa-opioid receptor provides insights into epimer selectivity.

    PubMed

    McGovern, Donna L; Mosier, Philip D; Roth, Bryan L; Westkaemper, Richard B

    2010-04-01

    The highly potent and kappa-opioid (KOP) receptor-selective hallucinogen Salvinorin A and selected analogs have been analyzed using the 3D quantitative structure-affinity relationship technique Comparative Molecular Field Analysis (CoMFA) in an effort to derive a statistically significant and predictive model of salvinorin affinity at the KOP receptor and to provide additional statistical support for the validity of previously proposed structure-based interaction models. Two CoMFA models of Salvinorin A analogs substituted at the C-2 position are presented. Separate models were developed based on the radioligand used in the kappa-opioid binding assay, [(3)H]diprenorphine or [(125)I]6 beta-iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan ([(125)I]IOXY). For each dataset, three methods of alignment were employed: a receptor-docked alignment derived from the structure-based docking algorithm GOLD, another from the ligand-based alignment algorithm FlexS, and a rigid realignment of the poses from the receptor-docked alignment. The receptor-docked alignment produced statistically superior results compared to either the FlexS alignment or the realignment in both datasets. The [(125)I]IOXY set (Model 1) and [(3)H]diprenorphine set (Model 2) gave q(2) values of 0.592 and 0.620, respectively, using the receptor-docked alignment, and both models produced similar CoMFA contour maps that reflected the stereoelectronic features of the receptor model from which they were derived. Each model gave significantly predictive CoMFA statistics (Model 1 PSET r(2)=0.833; Model 2 PSET r(2)=0.813). Based on the CoMFA contour maps, a binding mode was proposed for amine-containing Salvinorin A analogs that provides a rationale for the observation that the beta-epimers (R-configuration) of protonated amines at the C-2 position have a higher affinity than the corresponding alpha-epimers (S-configuration).

  2. CoMFA Analyses of C-2 Position Salvinorin A Analogs at the Kappa-Opioid Receptor Provides Insights into Epimer Selectivity

    PubMed Central

    McGovern, Donna L.; Mosier, Philip D.; Roth, Bryan L.; Westkaemper, Richard B.

    2010-01-01

    The highly potent and kappa-opioid receptor (KOR)-selective hallucinogen salvinorin A and selected analogs have been analyzed using the 3D quantitative structure-affinity relationship technique Comparative Molecular Field Analysis (CoMFA) in an effort to derive a statistically significant and predictive model of salvinorin affinity at the KOR and to provide additional statistical support for the validity of previously proposed structure-based interaction models. Two CoMFA models of salvinorin A analogs substituted at the C-2 position are presented. Separate models were developed based on the radioligand used in the kappa-opioid binding assay, [3H]diprenorphine or [125I]6β-iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5α-epoxymorphinan ([125I]IOXY). For each dataset, three methods of alignment were employed: a receptor-docked alignment derived from the structure-based docking algorithm GOLD, another from the ligand-based alignment algorithm FlexS, and a rigid realignment of the poses from the receptor-docked alignment. The receptor-docked alignment produced statistically superior results compared to either the FlexS alignment or the realignment in both datasets. The [125I]IOXY set (Model 1) and [3H]diprenorphine set (Model 2) gave q2 values of 0.592 and 0.620, respectively, using the receptor-docked alignment, and both models produced similar CoMFA contour maps that reflected the stereoelectronic features of the receptor model from which they were derived. Each model gave significantly predictive CoMFA statistics (Model 1 PSET r2 = 0.833; Model 2 PSET r2 = 0.813). Based on the CoMFA contour maps, a binding mode was proposed for amine-containing salvinorin A analogs that provides a rationale for the observation that the β-epimers (R-configuration) of protonated amines at the C-2 position have a higher affinity than the corresponding β-epimers (S-configuration). PMID:20083418

  3. Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia.

    PubMed

    Stansfield, K H; Ruby, K N; Soares, B D; McGlothan, J L; Liu, X; Guilarte, T R

    2015-03-10

    Environmental factors have been associated with psychiatric disorders and recent epidemiological studies suggest an association between prenatal lead (Pb(2+)) exposure and schizophrenia (SZ). Pb(2+) is a potent antagonist of the N-methyl-D-aspartate receptor (NMDAR) and converging evidence indicates that NMDAR hypofunction has a key role in the pathophysiology of SZ. The glutamatergic hypothesis of SZ posits that NMDAR hypofunction results in the loss of parvalbumin (PV)-positive GABAergic interneurons (PVGI) in the brain. Loss of PVGI inhibitory control to pyramidal cells alters the excitatory drive to midbrain dopamine neurons increasing subcortical dopaminergic activity. We hypothesized that if Pb(2+) exposure in early life is an environmental risk factor for SZ, it should recapitulate the loss of PVGI and reproduce subcortical dopaminergic hyperactivity. We report that on postnatal day 50 (PN50), adolescence rats chronically exposed to Pb(2+) from gestation through adolescence exhibit loss of PVGI in SZ-relevant brain regions. PV and glutamic acid decarboxylase 67 kDa (GAD67) protein were significantly decreased in Pb(2+) exposed rats with no apparent change in calretinin or calbindin protein levels suggesting a selective effect on the PV phenotype of GABAergic interneurons. We also show that Pb(2+) animals exhibit a heightened locomotor response to cocaine and express significantly higher levels of dopamine metabolites and D2-dopamine receptors relative to controls indicative of subcortical dopaminergic hyperactivity. Our results show that developmental Pb(2+) exposure reproduces specific neuropathology and functional dopamine system changes present in SZ. We propose that exposure to environmental toxins that produce NMDAR hypofunction during critical periods of brain development may contribute significantly to the etiology of mental disorders.

  4. Incongruent Nuclear and Mitochondrial Genetic Structure of New World Screwworm Fly Populations Due to Positive Selection of Mutations Associated with Dimethyl- and Diethyl-Organophosphates Resistance

    PubMed Central

    Bergamo, Luana Walravens; Fresia, Pablo; Azeredo-Espin, Ana Maria L.

    2015-01-01

    that these mutations evolved under positive selection. PMID:26030866

  5. Ongoing Development of NASA's Global Land Data Assimilation System

    NASA Technical Reports Server (NTRS)

    Rodell, Matthew; Kato, Hiroko; Zaitchik, Ben

    2008-01-01

    NASA's Global Land Data Assimilation System (GLDAS) produces global fields of land surface states (e.g., soil moisture and temperature) and fluxes (e.g., latent heat flux and runoff) by driving offline land surface models with observation-based inputs, using the Land Information System (LIS) software. Since production began in 2001, GLDAS has supported more than 100 scientific investigations and applications. Some examples are GEWEX and NASA Energy and Water Cycle Study (NEWS) global water and energy budget analyses, interpretations of hydrologic data derived from the Gravity Recovery and Climate Experiment (GRACE) satellite mission, and forecast model initiation studies at NOAA and NASA. At the same time, the GLDAS team has continued improve results through the development of new modeling and data assimilation techniques. Here we describe several recent and ongoing innovations. These include global implementation of a runoff routing procedure, GRACE data assimilation, advanced snow cover assimilation, and irrigation modeling.

  6. BASS2000: on-going projects and results

    NASA Astrophysics Data System (ADS)

    Meunier, N.; Lafon, M.; Maeght, P.; Grimaud, F.; Roudier, Th.

    2006-06-01

    We review the current status of the services proposed by the database BASS2000. Then we describe our main on-going project, i.e. the implementation of the processing, by the BASS2000 team, of a large data set (several Terabytes) of solar multi-line spectropolarimetric data (MTR mode) obtained by many observers at the THEMIS telescope in Tenerife. The implementation of this data processing and the data products are described as well as the future services associated to this processing: data sets of magnetograms, dopplergrams, vector magnetic field maps, organization of workshops. The other projects we are involved in are also briefly described, and concerns the Pic du Midi Coronagraph (HACO, as well as the future new version CLIMSO), the Lunette Jean Rösch of the Pic du Midi (mostly imagery data) and the implications in the Virtual Observatory.

  7. Ongoing Space Nuclear Systems Development in the United States

    SciTech Connect

    S. Bragg-Sitton; J. Werner; S. Johnson; Michael G. Houts; Donald T. Palac; Lee S. Mason; David I. Poston; A. Lou Qualls

    2011-10-01

    Reliable, long-life power systems are required for ambitious space exploration missions. Nuclear power and propulsion options can enable a bold, new set of missions and introduce propulsion capabilities to achieve access to science destinations that are not possible with more conventional systems. Space nuclear power options can be divided into three main categories: radioisotope power for heating or low power applications; fission power systems for non-terrestrial surface application or for spacecraft power; and fission power systems for electric propulsion or direct thermal propulsion. Each of these areas has been investigated in the United States since the 1950s, achieving various stages of development. While some nuclear systems have achieved flight deployment, others continue to be researched today. This paper will provide a brief overview of historical space nuclear programs in the U.S. and will provide a summary of the ongoing space nuclear systems research, development, and deployment in the United States.

  8. Ongoing Analysis of Jupiter's Equatorial Hotspots and Plumes from Cassini

    NASA Technical Reports Server (NTRS)

    Choi, D. S.; Showmwn, A. P.; Vasavada, A. R.; Simon-Miller, A. A.

    2012-01-01

    We present updated results from our ongoing analysis of Cassini observations of Jupiter's equatorial meteorology. For two months preceding the spacecraft's closest approach of the planet, the ISS instrument onboard Cassini regularly imaged the atmosphere of Jupiter. We created time-lapse movies from this period that show the complex activity and interactions of the equatorial atmosphere. During this period, hot spots exhibited significant variations in size and shape over timescales of days and weeks. Some of these changes appear to be a result of interactions with passing vortex systems in adjacent latitudes. Strong anticyclonic gyres to the southeast of the dark areas converge with flow from the west and appear to circulate into a hot spot at its southwestern corner.

  9. Ongoing geographical spread of Tomato yellow leaf curl virus.

    PubMed

    Mabvakure, Batsirai; Martin, Darren P; Kraberger, Simona; Cloete, Leendert; van Brunschot, Sharon; Geering, Andrew D W; Thomas, John E; Bananej, Kaveh; Lett, Jean-Michel; Lefeuvre, Pierre; Varsani, Arvind; Harkins, Gordon W

    2016-11-01

    Tomato yellow leaf curl virus (TYLCV) seriously impacts tomato production throughout tropical and sub-tropical regions of the world. It has a broad geographical distribution and continues to spread to new regions in the Indian and Pacific Oceans including Australia, New Caledonia and Mauritius. We undertook a temporally-scaled, phylogeographic analysis of all publicly available, full genome sequences of TYLCV, together with 70 new genome sequences from Australia, Iran and Mauritius. This revealed that whereas epidemics in Australia and China likely originated through multiple independent viral introductions from the East-Asian region around Japan and Korea, the New Caledonian epidemic was seeded by a variant from the Western Mediterranean region and the Mauritian epidemic by a variant from the neighbouring island of Reunion. Finally, we show that inter-continental scale movements of TYLCV to East Asia have, at least temporarily, ceased, whereas long-distance movements to the Americas and Australia are probably still ongoing.

  10. Phylogenic analysis of adhesion related genes Mad1 revealed a positive selection for the evolution of trapping devices of nematode-trapping fungi.

    PubMed

    Li, Juan; Liu, Yue; Zhu, Hongyan; Zhang, Ke-Qin

    2016-03-04

    Adhesions, the major components of the extracellular fibrillar polymers which accumulate on the outer surface of adhesive traps of nematode-trapping fungi, are thought to have played important roles during the evolution of trapping devices. Phylogenetic analyses based on the genes related to adhesive materials can be of great importance for understanding the evolution of trapping devices. Recently, AoMad1, one homologous gene of the entomopathogenic fungus Metarhizium anisopliae cell wall protein MAD1, has been functionally characterized as involved in the production of adhesions in the nematode-trapping fungus Arthrobotrys oligospora. In this study, we cloned Mad1 homologous genes from nematode-trapping fungi with various trapping devices. Phylogenetic analyses suggested that species which formed nonadhesive constricting ring (CR) traps more basally placed and species with adhesive traps evolved along two lineages. Likelihood ratio tests (LRT) revealed that significant positive selective pressure likely acted on the ancestral trapping devices including both adhesive and mechanical traps, indicating that the Mad1 genes likely played important roles during the evolution of nematode-trapping fungi. Our study provides new insights into the evolution of trapping devices of nematode-trapping fungi and also contributes to understanding the importance of adhesions during the evolution of nematode-trapping fungi.

  11. Independent variation and positive selection in env V1 and V2 domains within maternal-infant strains of human immunodeficiency virus type 1 in vivo.

    PubMed Central

    Lamers, S L; Sleasman, J W; She, J X; Barrie, K A; Pomeroy, S M; Barrett, D J; Goodenow, M M

    1993-01-01

    Multiple targets for immune recognition and cellular tropism are localized to the V1 and V2 hypervariable regions in the amino portion of human immunodeficiency virus type 1 (HIV-1) gp120env. We have assessed genetic diversity in env V1 and V2 hypervariable domains in vivo within epidemiologically related strains of HIV-1. Our strategy was to analyze longitudinal samples from two seropositive mothers and multiple children infected by perinatal transmission. Although the V1 and V2 domains are closely linked in the HIV-1 genome, nucleotide sequences in V1 and in V2 evolved independently in maternal-infant viruses in vivo. A high proportion of the nucleotide substitutions would introduce amino acid diversity in V1 and in V2. A significant excess of nonsynonymous over synonymous substitutions was identified in HIV-1 env V1 and V2 peptides in the mothers and in two older children but was not generally apparent in HIV-1 sequences in infants. An excess of nonsynonymous over synonymous substitutions indicated that there is positive selection for independent genetic variation in the V1 and V2 domains in vivo. It is likely that there are host responses to complex determinants in the V1 or V2 hypervariable domain of HIV-1 gp120. PMID:8510212

  12. Utilization of leukapheresis and CD4 positive selection in Treg isolation and the ex-vivo expansion for a clinical application in transplantation and autoimmune disorders

    PubMed Central

    Gołąb, Karolina; Grose, Randall; Trzonkowski, Piotr; Wickrema, Amittha; Tibudan, Martin; Marek-Trzonkowska, Natalia; Matosz, Sabrina; Solomina, Julia; Ostrega, Diane; Millis, J. Michael; Witkowski, Piotr

    2016-01-01

    Adoptive transfer of T regulatory cells (Tregs) is of great interest as a novel immunosuppressive therapy in autoimmune disorders and transplantation. Obtaining a sufficient number of stable and functional Tregs generated according to current Good Manufacturing Practice (cGMP) requirements has been a major challenge in introducing Tregs as a clinical therapy. Here, we present a protocol involving leukapheresis and CD4+ cell pre-enrichment prior to Treg sorting, which allows a sufficient number of Tregs for a clinical application to be obtained. With this method there is a decreased requirement for ex-vivo expansion. The protocol was validated in cGMP conditions. Our final Treg product passed all release criteria set for clinical applications. Moreover, during expansion Tregs presented their stable phenotype: percentage of CD4+CD25hiCD127− and CD4+FoxP3+ Tregs was > 95% and > 80%, respectively, and Tregs maintained proper immune suppressive function in vitro. Our results suggest that utilization of leukapheresis and CD4 positive selection during Treg isolation improves the likelihood of obtaining a sufficient number of high quality Treg cells during subsequent ex-vivo expansion and they can be applied clinically. PMID:27821811

  13. Phylogenic analysis of adhesion related genes Mad1 revealed a positive selection for the evolution of trapping devices of nematode-trapping fungi

    PubMed Central

    Li, Juan; Liu, Yue; Zhu, Hongyan; Zhang, Ke-Qin

    2016-01-01

    Adhesions, the major components of the extracellular fibrillar polymers which accumulate on the outer surface of adhesive traps of nematode-trapping fungi, are thought to have played important roles during the evolution of trapping devices. Phylogenetic analyses based on the genes related to adhesive materials can be of great importance for understanding the evolution of trapping devices. Recently, AoMad1, one homologous gene of the entomopathogenic fungus Metarhizium anisopliae cell wall protein MAD1, has been functionally characterized as involved in the production of adhesions in the nematode-trapping fungus Arthrobotrys oligospora. In this study, we cloned Mad1 homologous genes from nematode-trapping fungi with various trapping devices. Phylogenetic analyses suggested that species which formed nonadhesive constricting ring (CR) traps more basally placed and species with adhesive traps evolved along two lineages. Likelihood ratio tests (LRT) revealed that significant positive selective pressure likely acted on the ancestral trapping devices including both adhesive and mechanical traps, indicating that the Mad1 genes likely played important roles during the evolution of nematode-trapping fungi. Our study provides new insights into the evolution of trapping devices of nematode-trapping fungi and also contributes to understanding the importance of adhesions during the evolution of nematode-trapping fungi. PMID:26941065

  14. Selective photochemical synthesis of Ag nanoparticles on position-controlled ZnO nanorods for the enhancement of yellow-green light emission.

    PubMed

    Park, Hyeong-Ho; Zhang, Xin; Lee, Keun Woo; Sohn, Ahrum; Kim, Dong-Wook; Kim, Joondong; Song, Jin-Won; Choi, Young Su; Lee, Hee Kwan; Jung, Sang Hyun; Lee, In-Geun; Cho, Young-Dae; Shin, Hyun-Beom; Sung, Ho Kun; Park, Kyung Ho; Kang, Ho Kwan; Park, Won-Kyu; Park, Hyung-Ho

    2015-12-28

    A novel technique for the selective photochemical synthesis of silver (Ag) nanoparticles (NPs) on ZnO nanorod arrays is established by combining ultraviolet-assisted nanoimprint lithography (UV-NIL) for the definition of growth sites, hydrothermal reaction for the position-controlled growth of ZnO nanorods, and photochemical reduction for the decoration of Ag NPs on the ZnO nanorods. During photochemical reduction, the size distribution and loading of Ag NPs on ZnO nanorods can be tuned by varying the UV-irradiation time. The photochemical reduction is hypothesized to facilitate the adsorbed citrate ions on the surface of ZnO, allowing Ag ions to preferentially form Ag NPs on ZnO nanorods. The ratio of visible emission to ultraviolet (UV) emission for the Ag NP-decorated ZnO nanorod arrays, synthesized for 30 min, is 20.5 times that for the ZnO nanorod arrays without Ag NPs. The enhancement of the visible emission is believed to associate with the surface plasmon (SP) effect of Ag NPs. The Ag NP-decorated ZnO nanorod arrays show significant SP-induced enhancement of yellow-green light emission, which could be useful in optoelectronic applications. The technique developed here requires low processing temperatures (120 °C and lower) and no high-vacuum deposition tools, suitable for applications such as flexible electronics.

  15. First study on antimicriobial activity and synergy between isothiocyanates and antibiotics against selected Gram-negative and Gram-positive pathogenic bacteria from clinical and animal source.

    PubMed

    Dias, Carla; Aires, Alfredo; Bennett, Richard N; Rosa, Eduardo A S; Saavedra, Maria J

    2012-05-01

    The emergence of new diseases and the resurgence of several infections that were controlled in the past, associated with recent increase of bacterial resistance have created the necessity for more studies towards to the development of new antimicrobials and new treatment strategies. The aim of the present study was to evaluate the in vitro synergy between different classes of important glucosinolates hydrolysis products-isothiocyanates with antibiotics (gentamycin and vancomycin), against important pathogenic bacteria: Escherichia coli, Enterococcus faecalis, Listeria monocytogenes, Pseudomonas aeruginosa and Staphylococcus aureus. A disc diffusion method was used to evaluate the antibacterial activity. The antimicrobial activity of phytochemicals and combinations between gentamycin, vancomycin and phytochemicals were quantitatively assessed by measuring the inhibitory halos. The results showed a selective antimicrobial effect of isothiocyanates, and this effect was strictly related with their chemical structure. In general the benzylisothiocyanate was the most effective compound against both Gram-positive and Gram-negative bacteria. The Listeria monocytogenes and Staphylococcus aureus were the bacteria most affected either by the phytochemicals alone or by the combination phytochemical-antibiotic. The bacteria Pseudomonas aeruginosa was the less affected pathogen. The most important synergism detected occurred between the commercial antibiotics with benzylisothiocyanate and 2-phenylethylisothiocyanate. In conclusion, some isothiocyanates are effective inhibitors of in vitro bacterial growth, and they can act synergistically with antibiotics.

  16. Leadership Succession Planning in Catholic Education: An Ongoing Plan for Leadership Development, Identification, and Selection

    ERIC Educational Resources Information Center

    Fitzgerald, Mary; Sabatino, Anthony

    2014-01-01

    The fundamental elements of successful leadership succession in any organization are recognizing the inevitability of leadership change and the necessity of a plan for leadership succession. This book provides a rationale and planning guideline for board chairs, superintendents, and superiors of religious communities to use when the need arises to…

  17. Immune reconstitution following allogeneic peripheral blood progenitor cell transplantation: comparison of recipients of positive CD34+ selected grafts with recipients of unmanipulated grafts.

    PubMed

    Martínez, C; Urbano-Ispizua, A; Rozman, C; Marín, P; Rovira, M; Sierra, J; Montfort, N; Carreras, E; Montserrat, E

    1999-03-01

    We compared the kinetic recovery of lymphocytes and their subsets in two groups of patients submitted to allogeneic peripheral blood progenitor cell transplantation (allo-PBT): those receiving lymphocyte-depleted leukaphereses by positive selection of CD34+ cells (group 1, n = 18) and those receiving unmanipulated leukaphereses (group 2, n = 15). Patients were conditioned with cyclophosphamide (120 mg/kg) and fractioned total body irradiation (13 Gy, group 1; 12 Gy, group 2). The mean number (x 10(6)/kg) of CD34+ and CD3+ cells infused was 4.0 and 0.67, respectively, in group 1 patients, and 4.7 and 274, respectively, for group 2 patients. Graft-versus-host disease prophylaxis consisted of cyclosporin A + methylprednisolone for group 1 and cyclosporin A + methotrexate for group 2. Median follow-up was 7 months (range 2-8 months) for both groups. During the first 6 months post-transplant, CD4+ cell counts were lower in group 1 as compared with group 2 (p = 0.014, 0.010, 0.011, 0.0003, and 0.052 at 0.5, 1, 2, 3, and 6 months, respectively), whereas there was no difference at 8 months. The number of CD4+CD45RA+ cells was very low throughout the study in both groups, being lower in group 1 than in group 2, especially during the first 3 months post-transplant (p = 0.007 and 0.0006 at 1 and 3 months). Normal levels of CD8+ cells were reached by 1 month post-transplant in both groups. TCR gamma delta + cell counts were lower in group 1 than in group 2 during the first 4 months post-transplant (p = 0.001, 0.004, and 0.04 at 1, 3, and 4 months). A normal number of natural killer cells (CD3-CD56+) was achieved 1 month post-transplant in both groups. B lymphocytes (CD19+) showed low or undetectable counts throughout the first 4 months in both groups, achieving the normal range at 8 months. These results show that, during the first 6 months following allo-PBT with CD34+ selected grafts, the number of CD4+, CD4+CD45RA+, and TCR gamma delta + cells is significantly lower than

  18. [The study of selecting sample detecting position and lead plate inner material in thin film method X-ray fluorescence measurement].

    PubMed

    Gan, Ting-ting; Zhang, Yu-jun; Zhao, Nan-jing; Yin, Gao-fang; Dong, Xin-xin; Wang, Ya-ping; Liu Jian-guo; Liu, Wen-qing

    2015-01-01

    (1) In this paper type 316 stainless steel metal plate as the research object, the selection of sample detecting position was studied when thin film method X-ray fluorescence measurement was conducted. The study showed that the optimal location for the sample detection was sample distance X-ray tube and detector baseline 1cm with the baseline into a 16°angle. (2) Heavy metal pollutants of Pb, Cd and Cr in industrial ambient air as the main analysis object, when thin film method X-ray fluorescence conducted with lead plate protection, X-rays will penetrate the membrane and continuely stimulate the protective lead plate. Therefore there is lead spectral line interference in the filter membrane background spectrum, which will affect the detection of lead element in real samples. Studies show that when a layer of isolating material was applied between the thin sample and the protective lead plate, the interference of lead line can effectively be avoided. (3) Several rigid insulating material of type 316 stainless steel, brass, aluminum, red copper and PTEE as lead inner material were selected and studied. The study results showed that compared with X-ray fluorescence spectra of other lead inner materials, the X-ray fluorescence spectrum of red copper contained the least element spectral lines. There were not Cr, Cd and Pb spectrum peaks in the X-ray fluorescence spectrum of red copper. And the target timber scattering spectrum intensity in the high energy part was weaker compared to other X-ray fluorescence spectrum. The above analysis shows that red copper has the minimal disturbance to the actual measurement of heavy metals Cr, Cd and Pb. At the same time, red copper as lead inner materials can effectively avoid the interference of lead spectrum line in lead plate. So red copper is the best lead plate inner materials in thin film method X-ray fluorescence spectroscopy measurement. This study provides an important theoretical basis for the assembling and setting

  19. Continuously on-going hindcast simulations for impact applications

    NASA Astrophysics Data System (ADS)

    Anders, Ivonne; Geyer, Beate

    2016-04-01

    Observations for e.g. temperature, precipitation, radiation, or wind are often used as meteorological forcing for different impact models, like e.g. crop models, urban models, economic models and energy system models. To assess a climate signal, the time period covered by the observation is often too short, they have gaps in between, and are inhomogeneous over time, due to changes in the measurements itself or in the near surrounding. Thus output from global and regional climate models can close the gap and provide homogeneous and physically consistent time series of meteorological parameters. CORDEX evaluation runs performed for the IPCC-AR5 provide a good base for the regional scale. However, with respect to climate services, continuously on-going hindcast simulations are required for regularly updated applications. In this study two projects are presented where hindcast-simulations optimized for a region of interest are performed continuously. The hindcast simulation performed by HZG covering Europe includes the EURO-CORDEX domain with a wider extend to the north to cover the ice edge. The simulation under consideration of the coastDat-experiences is available for the period of 1979 - 2015, prolonged ongoing and fulfills the customer's needs with respect of output variables, levels, intervals and statistical measures. CoastDat - customers are dealing e.g. with naval architecture, renewable energies, offshore wind farming, shipping emissions, coastal flood risk and others. The evaluation of the hindcast is done for Europe by using the EVAL-tool of the CCLM community and by comparison with HYRAS - data for Germany and neighbouring countries. The Climate Research group at the national Austrian weather service, ZAMG, is focusing on high mountain regions and, especially on the Alps. The hindcast-simulation is forced by ERA-interim and optimized for the Alpine Region. One of the main tasks is to capture strong precipitation events which often occur during summer when

  20. Selective photochemical synthesis of Ag nanoparticles on position-controlled ZnO nanorods for the enhancement of yellow-green light emission

    NASA Astrophysics Data System (ADS)

    Park, Hyeong-Ho; Zhang, Xin; Lee, Keun Woo; Sohn, Ahrum; Kim, Dong-Wook; Kim, Joondong; Song, Jin-Won; Choi, Young Su; Lee, Hee Kwan; Jung, Sang Hyun; Lee, In-Geun; Cho, Young-Dae; Shin, Hyun-Beom; Sung, Ho Kun; Park, Kyung Ho; Kang, Ho Kwan; Park, Won-Kyu; Park, Hyung-Ho

    2015-12-01

    A novel technique for the selective photochemical synthesis of silver (Ag) nanoparticles (NPs) on ZnO nanorod arrays is established by combining ultraviolet-assisted nanoimprint lithography (UV-NIL) for the definition of growth sites, hydrothermal reaction for the position-controlled growth of ZnO nanorods, and photochemical reduction for the decoration of Ag NPs on the ZnO nanorods. During photochemical reduction, the size distribution and loading of Ag NPs on ZnO nanorods can be tuned by varying the UV-irradiation time. The photochemical reduction is hypothesized to facilitate the adsorbed citrate ions on the surface of ZnO, allowing Ag ions to preferentially form Ag NPs on ZnO nanorods. The ratio of visible emission to ultraviolet (UV) emission for the Ag NP-decorated ZnO nanorod arrays, synthesized for 30 min, is 20.5 times that for the ZnO nanorod arrays without Ag NPs. The enhancement of the visible emission is believed to associate with the surface plasmon (SP) effect of Ag NPs. The Ag NP-decorated ZnO nanorod arrays show significant SP-induced enhancement of yellow-green light emission, which could be useful in optoelectronic applications. The technique developed here requires low processing temperatures (120 °C and lower) and no high-vacuum deposition tools, suitable for applications such as flexible electronics.A novel technique for the selective photochemical synthesis of silver (Ag) nanoparticles (NPs) on ZnO nanorod arrays is established by combining ultraviolet-assisted nanoimprint lithography (UV-NIL) for the definition of growth sites, hydrothermal reaction for the position-controlled growth of ZnO nanorods, and photochemical reduction for the decoration of Ag NPs on the ZnO nanorods. During photochemical reduction, the size distribution and loading of Ag NPs on ZnO nanorods can be tuned by varying the UV-irradiation time. The photochemical reduction is hypothesized to facilitate the adsorbed citrate ions on the surface of ZnO, allowing Ag ions to

  1. A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.

    PubMed

    Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D; Granados-Silvestre, Ma de Angeles; Montufar-Robles, Isela; Tito-Alvarez, Ana M; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A; Lisker, Ruben; Moises, Regina S; Menjivar, Marta; Salzano, Francisco M; Knowler, William C; Bortolini, M Cátira; Hayden, Michael R; Baier, Leslie J; Canizales-Quinteros, Samuel

    2010-07-15

    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

  2. A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

    PubMed Central

    Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K.; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D.; de Ángeles Granados-Silvestre, Ma; Montufar-Robles, Isela; Tito-Alvarez, Ana M.; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P.; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L.; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Lisker, Ruben; Moises, Regina S.; Menjivar, Marta; Salzano, Francisco M.; Knowler, William C.; Bortolini, M. Cátira; Hayden, Michael R.; Baier, Leslie J.; Canizales-Quinteros, Samuel

    2010-01-01

    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive