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- ArticleJump AS, Peñuelas J.Proc Natl Acad Sci U S A. 2006 May 23;103(21):8096-100.Habitat fragmentation poses a serious threat to plants through genetic changes associated with increased isolation and reduced population size. However, the longevity of trees, combined with effective seed or pollen dispersal, can enhance their resistance to these effects. The European beech (Fagus sylvatica) dominates forest over large regions of Europe. We demonstrate that habitat fragmentation in this species has led to genetic bottlenecks and the disruption of the species' breeding system, leading to significantly elevated levels of inbreeding, population divergence, and reduced genetic diversity within populations. These results show that, in contrast with the findings of previous studies, forest fragmentation has a negative genetic impact, even in this widespread, wind-pollinated tree. The identification of significant effects of forest fragmentation in beech demonstrates that trees are not at reduced risk from environmental change. This should be accounted for in the management of remaining natural and seminatural forest throughout the world.
- ArticleLi Q, Fang X, Han H, Stamatoyannopoulos G.Proc Natl Acad Sci U S A. 2004 May 25;101(21):8096-101.The human gamma-globin gene and its orthologous galago gamma-globin gene evolved from an ancestral epsilon-globin gene. In galago, expression of the gamma-gene remained restricted to the embryonic stage of development, whereas in humans, expression of the gamma-gene was recruited to the fetal stage. To localize the cis-elements responsible for this developmentally distinct regulation, we studied the expression patterns of the human gamma-gene driven by either the human or the galago gamma-promoters in transgenic mice. gamma-gene transcription driven by either promoter reached similar levels in embryonic erythropoiesis. In adult erythropoiesis the gamma-gene was silenced when controlled by the galago gamma-promoter, but it was expressed at a high level when it was linked to the human gamma-promoter. By a series of gamma-promoter truncations the sequences required for the down-regulation of the galago gamma-globin gene were localized to the minimal promoter. Furthermore, by interchanging the TATA, CCAAT, and CACCC elements between the human and galago minimal promoters we found that whereas each box made a developmentally distinctive contribution to gamma-globin gene expression, the CACCC box was largely responsible for the down-regulation of the gamma-gene in adult erythropoiesis.
- ArticleGraves GR, Romanek CS, Rodriguez Navarro A.Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8096-100.Stable isotope analysis is widely promoted as a practical method for tracing the geographic origins of migratory birds. However, the extent to which geospatial patterns of isotope ratios in avian tissues are influenced by age-specific, altitudinal, and temporal factors remains largely unexplored. We measured carbon ((13)C/(12)C) and nitrogen ((15)N/(14)N) isotope ratios in feathers of black-throated blue warblers (Dendroica caerulescens) breeding along a relatively steep altitudinal gradient in the Appalachian Mountains to evaluate the effects of altitude and year on the isotopic signatures of yearling (first breeding season) and older males (>2 years). Breeding males (n = 302) collected during 7 consecutive years exhibited significant age-specific and altitudinal effects in delta(13)C values and age-specific and temporal effects in delta(15)N values. The delta(13)C values of older males increased with altitude at the rate of approximately 1.3 per thousand per 1,000 m, suggesting a high degree of year-to-year philopatry to narrow altitudinal zones, if not to breeding territories. In contrast, absence of altitudinal patterns in yearlings most likely reflects natal dispersal. Carbon isotope variation (delta(13)C = -26.07 to -20.86 per thousand) observed along a single altitudinal transect (755 m) nearly brackets the range of delta(13)C values recorded in feathers across the North American breeding range of the warbler from Georgia to New Brunswick (11 degrees of latitude) and from New Brunswick to Michigan (22 degrees of longitude). These data indicate that age-specific and altitudinal effects must be considered when using delta(13)C values to delineate the geographic origin of avian species with large altitudinal and latitudinal ranges.
- ArticleSharmeen L, Bass B, Sonenberg N, Weintraub H, Groudine M.Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8096-100.Tat is a potent activator of gene expression in human immunodeficiency virus type 1 (HIV-1). Activation by Tat requires a cis-acting element, the transactivation response (TAR) site, located in the viral long terminal repeat and the 5' end of all viral mRNAs. Sequences in TAR RNA can fold into a specific stem-loop structure, and certain features of the stem-loop are essential for Tat-mediated transactivation. In Xenopus oocytes, TAR sequences can inhibit the translation of 3' cis-linked mRNAs. However, coinjection of Tat and the TAR-containing RNA into oocyte nuclei relieves this translational inhibition [Braddock, M., Chambers, A., Wilson, W., Esnout, M. A., Adams, S.E. & Kingsman, S.M. (1989) Cell 58, 269-279]. We report here that the intramolecular TAR stem-loop structure is a substrate for the double-stranded RNA (dsRNA)-modifying activity, which converts adenosines to inosines. This activity is located in the nuclei of Xenopus oocytes. The specificity and extent of modification of adenosines in TAR is dependent on Tat. We propose that the dsRNA-modifying activity may be one of the cellular proteins that interacts with TAR in the nucleus. The possible role of TAR RNA modification in the expression of HIV-1 is discussed.
- ArticleMcCormick M.Proc Natl Acad Sci U S A. 2019 04 23;116(17):8096-8098.
- ArticleKnoch E, Sugawara S, Mori T, Poulsen C, Fukushima A, Harholt J, Fujimoto Y, Umemoto N, Saito K.Proc Natl Acad Sci U S A. 2018 08 21;115(34):E8096-E8103.A large part of chemodiversity of plant triterpenes is due to the modification of their side chains. Reduction or isomerization of double bonds in the side chains is often an important step for the diversification of triterpenes, although the enzymes involved are not fully understood. Withanolides are a large group of structurally diverse C28 steroidal lactones derived from 24-methylenecholesterol. These compounds are found in the Indian medicinal plant Withania somnifera, also known as ashwagandha, and other members of the Solanaceae. The pathway for withanolide biosynthesis is unknown, preventing sustainable production via white biotechnology and downstream pharmaceutical usages. In the present study, based on genome and transcriptome data we have identified a key enzyme in the biosynthesis of withanolides: a DWF1 paralog encoding a sterol Δ24-isomerase (24ISO). 24ISO originated from DWF1 after two subsequent duplication events in Solanoideae plants. Withanolides and 24ISO appear only in the medicinal plants in the Solanoideae, not in crop plants such as potato and tomato, indicating negative selection during domestication. 24ISO is a unique isomerase enzyme evolved from a reductase and as such has maintained the FAD-binding oxidoreductase structure and requirement for NADPH. Using phylogenetic, metabolomic, and gene expression analysis in combination with heterologous expression and virus-induced gene silencing, we showed that 24ISO catalyzes the conversion of 24-methylenecholesterol to 24-methyldesmosterol. We propose that this catalytic step is the committing step in withanolide biosynthesis, opening up elucidation of the whole pathway and future larger-scale sustainable production of withanolides and related compounds with pharmacological properties.
- ArticleParobek CM, Lin JT, Saunders DL, Barnett EJ, Lon C, Lanteri CA, Balasubramanian S, Brazeau N, DeConti DK, Garba DL, Meshnick SR, Spring MD, Chuor CM, Bailey JA, Juliano JJ.Proc Natl Acad Sci U S A. 2016 12 13;113(50):E8096-E8105.Cambodia, in which both Plasmodium vivax and Plasmodium falciparum are endemic, has been the focus of numerous malaria-control interventions, resulting in a marked decline in overall malaria incidence. Despite this decline, the number of P vivax cases has actually increased. To understand better the factors underlying this resilience, we compared the genetic responses of the two species to recent selective pressures. We sequenced and studied the genomes of 70 P vivax and 80 P falciparum isolates collected between 2009 and 2013. We found that although P falciparum has undergone population fracturing, the coendemic P vivax population has grown undisrupted, resulting in a larger effective population size, no discernable population structure, and frequent multiclonal infections. Signatures of selection suggest recent, species-specific evolutionary differences. Particularly, in contrast to P falciparum, P vivax transcription factors, chromatin modifiers, and histone deacetylases have undergone strong directional selection, including a particularly strong selective sweep at an AP2 transcription factor. Together, our findings point to different population-level adaptive mechanisms used by P vivax and P falciparum parasites. Although population substructuring in P falciparum has resulted in clonal outgrowths of resistant parasites, P vivax may use a nuanced transcriptional regulatory approach to population maintenance, enabling it to preserve a larger, more diverse population better suited to facing selective threats. We conclude that transcriptional control may underlie P vivax's resilience to malaria control measures. Novel strategies to target such processes are likely required to eradicate P vivax and achieve malaria elimination.
- ArticleMaiti A, Noon MS, MacKerell AD, Pozharski E, Drohat AC.Proc Natl Acad Sci U S A. 2012 May 22;109(21):8091-6.DNA base excision repair is essential for maintaining genomic integrity and for active DNA demethylation, a central element of epigenetic regulation. A key player is thymine DNA glycosylase (TDG), which excises thymine from mutagenic G·T mispairs that arise by deamination of 5-methylcytosine (mC). TDG also removes 5-formylcytosine and 5-carboxylcytosine, oxidized forms of mC produced by Tet enzymes. Recent studies show that the glycosylase activity of TDG is essential for active DNA demethylation and for embryonic development. Our understanding of how repair enzymes excise modified bases without acting on undamaged DNA remains incomplete, particularly for mismatch glycosylases such as TDG. We solved a crystal structure of TDG (catalytic domain) bound to a substrate analog and characterized active-site residues by mutagenesis, kinetics, and molecular dynamics simulations. The studies reveal how TDG binds and positions the nucleophile (water) and uncover a previously unrecognized catalytic residue (Thr197). Remarkably, mutation of two active-site residues (Ala145 and His151) causes a dramatic enhancement in G·T glycosylase activity but confers even greater increases in the aberrant removal of thymine from normal A·T base pairs. The strict conservation of these residues may reflect a mechanism used to strike a tolerable balance between the requirement for efficient repair of G·T lesions and the need to minimize aberrant action on undamaged DNA, which can be mutagenic and cytotoxic. Such a compromise in G·T activity can account in part for the relatively weak G·T activity of TDG, a trait that could potentially contribute to the hypermutability of CpG sites in cancer and genetic disease.
- ArticleMoxey D, Barkley D.Proc Natl Acad Sci U S A. 2010 May 04;107(18):8091-6.When fluid flows through a channel, pipe, or duct, there are two basic forms of motion: smooth laminar motion and complex turbulent motion. The discontinuous transition between these states is a fundamental problem that has been studied for more than 100 yr. What has received far less attention is the large-scale nature of the turbulent flows near transition once they are established. We have carried out extensive numerical computations in pipes of variable lengths up to 125 diameters to investigate the nature of transitional turbulence in pipe flow. We show the existence of three fundamentally different turbulent states separated by two distinct Reynolds numbers. Below Re (1) approximately equal 2,300, turbulence takes the form of familiar equilibrium (or longtime transient) puffs that are spatially localized and keep their size independent of pipe length. At Re (1) the flow makes a striking transition to a spatio-temporally intermittent flow that fills the pipe. Irregular alternation of turbulent and laminar regions is inherent and does not result from random disturbances. The fraction of turbulence increases with Re until Re (2) approximately equal 2,600 where there is a continuous transition to a state of uniform turbulence along the pipe. We relate these observations to directed percolation and argue that Re (1) marks the onset of infinite-lifetime turbulence.
- ArticleZheng BJ, Chan KW, Lin YP, Zhao GY, Chan C, Zhang HJ, Chen HL, Wong SS, Lau SK, Woo PC, Chan KH, Jin DY, Yuen KY.Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8091-6.The mortality of human infection by influenza A/H5N1 virus can exceed 80%. The high mortality and its poor response to the neuraminidase inhibitor oseltamivir have been attributed to uncontrolled virus-induced cytokine storm. We challenged BALB/c mice with 1,000 LD50 of influenza A/Vietnam/1194/04. Survival, body weight, histopathology, inflammatory markers, viral loads, T lymphocyte counts, and neutralizing antibody response were documented in infected mice treated individually or in combination with zanamvir, celecoxib, gemfibrozil, and mesalazine. To imitate the real-life scenario, treatment was initiated at 48 h after viral challenge. There were significant improvements in survival rate (P = 0.02), survival time (P < 0.02), and inflammatory markers (P < 0.01) in the group treated with a triple combination of zanamivir, celecoxib, and mesalazine when compared with zanamivir alone. Zanamivir with or without immunomodulators reduced viral load to a similar extent. Insignificant prolongation of survival was observed when individual agents were used alone. Significantly higher levels of CD4+ and CD8+ T lymphocytes and less pulmonary inflammation were also found in the group receiving triple therapy. Zanamivir alone reduced viral load but not inflammation and mortality. The survival benefits of adding celecoxib and mesalazine to zanamivir could be caused by their synergistic effects in reducing cytokine dysfunction and preventing apoptosis. Combinations of a neuraminidase inhibitor with these immunomodulators should be considered in randomized controlled treatment trials of patients suffering from H5N1 infection.
- ArticleFridman A.Proc Natl Acad Sci U S A. 2003 Jul 08;100(14):8092-6.Markov random fields can encode complex probabilistic relationships involving multiple variables and admit efficient procedures for probabilistic inference. However, from a knowledge engineering point of view, these models suffer from a serious limitation. The graph of a Markov field must connect all pairs of variables that are conditionally dependent even for a single choice of values of the other variables. This makes it hard to encode interactions that occur only in a certain context and are absent in all others. Furthermore, the requirement that two variables be connected unless always conditionally independent may lead to excessively dense graphs, obscuring the independencies present among the variables and leading to computationally prohibitive inference algorithms. Mumford [Mumford, D. (1996) in ICIAM 95, eds. Kirchgassner, K., Marenholtz, O. & Mennicken, R. (Akademie Verlag, Berlin), pp. -->233-256-->] proposed an alternative modeling framework where the graph need not be rigid and completely determined a priori. Mixed Markov models contain node-valued random variables that, when instantiated, augment the graph by a set of transient edges. A single joint probability distribution relates the values of regular and node-valued variables. In this article, we study the analytical and computational properties of mixed Markov models. In particular, we show that positive mixed models have a local Markov property that is equivalent to their global factorization. We also describe a computationally efficient procedure for answering probabilistic queries in mixed Markov models.
- ArticleVeres Z, Stadtman TC.Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8092-6.A tRNA-modifying enzyme tentatively termed tRNA 2-selenouridine synthase was purified by a five-step procedure that resulted in 50-60% pure preparations. This enzyme catalyzes the conversion of a 5-methylaminomethyl-2-thiouridine residue in the tRNA substrate to 5-methylaminomethyl-2-selenouridine. The selenium donor substrate for this reaction is shown to be selenophosphate which is formed from ATP and selenide by selenophosphate synthetase. Replacement of sulfur with selenium in tRNAs catalyzed by tRNA 2-selenouridine synthase occurs in the absence of ATP. The dependence of reaction velocity on selenophosphate concentration obeys Michaelis-Menten kinetics indicating an apparent Km value of 17.1 microM. Bulk thio-tRNA preparations from Escherichia coli and Salmonella typhimurium are equally effective as substrates for the selenium incorporation reaction. An intact 3' end of the tRNA molecule does not seem to be essential for selenium incorporation. Identity of the product of the reaction was confirmed by HPLC analysis of digests of [75Se]seleno-tRNAs labeled by incubation with the purified enzyme. A labeled compound in the nucleoside mixture was coeluted with authentic 5-methylaminomethyl-2-selenouridine.
- ArticleInoue K, Hoshijima K, Higuchi I, Sakamoto H, Shimura Y.Proc Natl Acad Sci U S A. 1992 Sep 01;89(17):8092-6.Sex-specific alternative processing of double-sex (dsx) precursor messenger RNA (pre-mRNA) is one of the key steps that regulates somatic sexual differentiation in Drosophila melanogaster. By transfection analyses using dsx minigene constructs, we identified six copies of the 13-nucleotide sequences TC(T/A)(T/A)C(A/G)ATCAACA in the female-specific fourth exon that act as the cis elements for the female-specific splicing of dsx pre-mRNA. UV-crosslinking experiments revealed that both female-specific transformer (tra) and transformer-2 (tra-2) products bind to the 13-nucleotide sequences of dsx pre-mRNA. These results strongly suggest that the female-specific splicing of dsx pre-mRNA is activated by binding of these proteins to the 13-nucleotide sequences.
- ArticlePeerce BE, Wright EM.Proc Natl Acad Sci U S A. 1986 Nov;83(21):8092-6.Covalent fluorescent probes were used to label the rabbit intestinal brush border Na+-glucose cotransporter at the putative glucose and Na+ binding sites, and a steady-state fluorescence energy transfer technique was used to measure the distance between the two binding sites. In both intact brush border membrane vesicles and partially purified soluble protein, the distance (R2/3) between the Na+ and glucose sites was approximately equal to 35 A. This distance was the same with four different donor/acceptor pairs with different transfer efficiencies, by donor quantum yield measurements, or sensitized acceptor fluorescence. The fact that the Na+ site and glucose site probes bind to a 75-kDa polypeptide, copurify with the same isoelectric point (pI 5.3) and retain function, and exhibit energy transfer indicates that the sites are on the same 75-kDa polypeptide. The large distance between the Na+ and glucose site probes raises questions about simple models of frictional interactions between the two substrates during the transport cycle.