WorldWideScience

Sample records for underlying molecular basis

  1. Molecular Ecological Basis of Grasshopper (Oedaleus asiaticus) Phenotypic Plasticity under Environmental Selection

    Science.gov (United States)

    Qin, Xinghu; Hao, Kun; Ma, Jingchuan; Huang, Xunbing; Tu, Xiongbing; Ali, Md. Panna; Pittendrigh, Barry R.; Cao, Guangchun; Wang, Guangjun; Nong, Xiangqun; Whitman, Douglas W.; Zhang, Zehua

    2017-01-01

    While ecological adaptation in insects can be reflected by plasticity of phenotype, determining the causes and molecular mechanisms for phenotypic plasticity (PP) remains a crucial and still difficult question in ecology, especially where control of insect pests is involved. Oedaleus asiaticus is one of the most dominant pests in the Inner Mongolia steppe and represents an excellent system to study phenotypic plasticity. To better understand ecological factors affecting grasshopper phenotypic plasticity and its molecular control, we conducted a full transcriptional screening of O. asiaticus grasshoppers reared in four different grassland patches in Inner Mongolia. Grasshoppers showed different degrees of PP associated with unique gene expressions and different habitat plant community compositions. Grasshopper performance variables were susceptible to habitat environment conditions and closely associated with plant architectures. Intriguingly, eco-transcriptome analysis revealed five potential candidate genes playing important roles in grasshopper performance, with gene expression closely relating to PP and plant community factors. By linking the grasshopper performances to gene profiles and ecological factors using canonical regression, we first demonstrated the eco-transcriptomic architecture (ETA) of grasshopper phenotypic traits (ETAGPTs). ETAGPTs revealed plant food type, plant density, coverage, and height were the main ecological factors influencing PP, while insect cuticle protein (ICP), negative elongation factor A (NELFA), and lactase-phlorizin hydrolase (LCT) were the key genes associated with PP. Our study gives a clear picture of gene-environment interaction in the formation and maintenance of PP and enriches our understanding of the transcriptional events underlying molecular control of rapid phenotypic plasticity associated with environmental variability. The findings of this study may also provide new targets for pest control and highlight the

  2. Molecular Ecological Basis of Grasshopper (Oedaleus asiaticus Phenotypic Plasticity under Environmental Selection

    Directory of Open Access Journals (Sweden)

    Xinghu Qin

    2017-10-01

    Full Text Available While ecological adaptation in insects can be reflected by plasticity of phenotype, determining the causes and molecular mechanisms for phenotypic plasticity (PP remains a crucial and still difficult question in ecology, especially where control of insect pests is involved. Oedaleus asiaticus is one of the most dominant pests in the Inner Mongolia steppe and represents an excellent system to study phenotypic plasticity. To better understand ecological factors affecting grasshopper phenotypic plasticity and its molecular control, we conducted a full transcriptional screening of O. asiaticus grasshoppers reared in four different grassland patches in Inner Mongolia. Grasshoppers showed different degrees of PP associated with unique gene expressions and different habitat plant community compositions. Grasshopper performance variables were susceptible to habitat environment conditions and closely associated with plant architectures. Intriguingly, eco-transcriptome analysis revealed five potential candidate genes playing important roles in grasshopper performance, with gene expression closely relating to PP and plant community factors. By linking the grasshopper performances to gene profiles and ecological factors using canonical regression, we first demonstrated the eco-transcriptomic architecture (ETA of grasshopper phenotypic traits (ETAGPTs. ETAGPTs revealed plant food type, plant density, coverage, and height were the main ecological factors influencing PP, while insect cuticle protein (ICP, negative elongation factor A (NELFA, and lactase-phlorizin hydrolase (LCT were the key genes associated with PP. Our study gives a clear picture of gene-environment interaction in the formation and maintenance of PP and enriches our understanding of the transcriptional events underlying molecular control of rapid phenotypic plasticity associated with environmental variability. The findings of this study may also provide new targets for pest control and

  3. Molecular basis of alcoholism.

    Science.gov (United States)

    Most, Dana; Ferguson, Laura; Harris, R Adron

    2014-01-01

    Acute alcohol intoxication causes cellular changes in the brain that last for hours, while chronic alcohol use induces widespread neuroadaptations in the nervous system that can last a lifetime. Chronic alcohol use and the progression into dependence involve the remodeling of synapses caused by changes in gene expression produced by alcohol. The progression of alcohol use, abuse, and dependence can be divided into stages, which include intoxication, withdrawal, and craving. Each stage is associated with specific changes in gene expression, cellular function, brain circuits, and ultimately behavior. What are the molecular mechanisms underlying the transition from recreational use (acute) to dependence (chronic)? What cellular adaptations result in drug memory retention, leading to the persistence of addictive behaviors, even after prolonged drug abstinence? Research into the neurobiology of alcoholism aims to answer these questions. This chapter will describe the molecular adaptations caused by alcohol use and dependence, and will outline key neurochemical participants in alcoholism at the molecular level, which are also potential targets for therapy. © 2014 Elsevier B.V. All rights reserved.

  4. Molecular basis of familial hypercholesterolemia

    NARCIS (Netherlands)

    Bruikman, Caroline S.; Hovingh, Gerard K.; Kastelein, John J. P.

    2017-01-01

    Purpose of review To provide an overview about the molecular basis of familial hypercholesterolemia. Recent findings Familial hypercholesterolemia is a common hereditary cause of premature coronary heart disease. It has been estimated that 1 in every 250 individuals has heterozygous familial

  5. Molecular basis for mitochondrial signaling

    CERN Document Server

    2017-01-01

    This book covers recent advances in the study of structure, function, and regulation of metabolite, protein and ion translocating channels, and transporters in mitochondria. A wide array of cutting-edge methods are covered, ranging from electrophysiology and cell biology to bioinformatics, as well as structural, systems, and computational biology. At last, the molecular identity of two important channels in the mitochondrial inner membrane, the mitochondrial calcium uniporter and the mitochondrial permeability transition pore have been established. After years of work on the physiology and structure of VDAC channels in the mitochondrial outer membrane, there have been multiple discoveries on VDAC permeation and regulation by cytosolic proteins. Recent breakthroughs in structural studies of the mitochondrial cholesterol translocator reveal a set of novel unexpected features and provide essential clues for defining therapeutic strategies. Molecular Basis for Mitochondrial Signaling covers these and many more re...

  6. Molecular basis of photochromism of a fluorescent protein revealed by direct 13C detection under laser illumination

    International Nuclear Information System (INIS)

    Mizuno, Hideaki; Mal, Tapas Kumar; Waelchli, Markus; Fukano, Takashi; Ikura, Mitsuhiko; Miyawaki, Atsushi

    2010-01-01

    Dronpa is a green fluorescent protein homologue with a photochromic property. A green laser illumination reversibly converts Dronpa from a green-emissive bright state to a non-emissive dark state, and ultraviolet illumination converts it to the bright state. We have employed solution NMR to understand the underlying molecular mechanism of the photochromism. The detail characterization of Dronpa is hindered as it is metastable in the dark state and spontaneously converts to the bright state. To circumvent this issue, we have designed in magnet laser illumination device. By combining the device with a 150-mW argon laser at 514.5 nm, we have successfully converted and maintained Dronpa in the dark state in the NMR tube by continuous illumination during the NMR experiments. We have employed direct-detection of 13 C nuclei from the carbon skeleton of the chromophore for detailed characterization of chromophore in both states of Dronpa by using the Bruker TCI cryoprobe. The results from NMR data have provided direct evidence of the double bond formation between C α and C β of Y63 in the chromophore, the β-barrel structure in solution, and the ionized and protonated state of Y63 hydroxyl group in the bright and dark states, respectively. These studies have also revealed that a part of β-barrel around the chromophore becomes polymorphic only in the dark state, which may be critical to make the fluorescence dim by increasing the contribution of non-emissive vibrational relaxation pathways.

  7. Molecular basis of cadmium toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Nath, R; Prasad, R; Palinal, V K; Chopra, R K

    1984-01-01

    Cadmium has been shown to manifest its toxicity in human and animals by mainly accumulating in almost all of the organs. The kidney is the main target organ where it is concentrated mainly in the cortex. Environmental exposure of cadmium occurs via food, occupational industries, terrestrial and aquatic ecosystem. At molecular level, cadmium interferes with the utilization of essential metals e.g. Ca, Zn, Se, Cr and Fe and deficiencies of these essential metals including protein and vitamins, exaggerate cadmium toxicity, due to its increased absorption through the gut and greater retention in different organs as metallothionein (Cd-Mt). Cadmium transport, across the intestinal and renal brush border membrane vesicles, is carrier mediated and it competes with zinc and calcium. It has been postulated that cadmium shares the same transport system. Cadmium inhibits protein synthesis, carbohydrate metabolism and drug metabolizing enzymes in liver of animals. Chronic environmental exposure of cadmium produces hypertension in experimental animals. Functional changes accompanying cadmium nephropathy include low molecular weight proteinuria which is of tubular origin associated with excess excretion of proteins such as beta 2 microglobulin, metallothionein and high molecular weight proteinuria of glomerular origin (excretion of proteins such as albumin IgG, transferrin etc.). Recent data has shown that metallothionein is more nephrotoxic to animals. Cadmium is also toxic to central nervous system. It causes an alterations of cellular functions in lungs. Cadmium affects both humoral and cell mediated immune response in animals. Cadmium induces metallothionein in liver and kidney but under certain nutritional deficiencies like protein-calorie malnutrition and calcium deficiency, enhanced induction and greater accumulation of cadmium metallothionein has been observed.

  8. The molecular basis of radiosensitivity

    International Nuclear Information System (INIS)

    McMillan, T.J.

    1989-01-01

    This paper considers how DNA damage induced by ionising radiation is processed within the cell. The current view of radiobiology is discussed. The author explains the molecular processes that underlie the differences in radiosensitivity

  9. Molecular Basis for Mucolytic Therapy

    Directory of Open Access Journals (Sweden)

    Bonnie Dasgupta

    1995-01-01

    Full Text Available Airway mucus is a complex, viscoelastic gel that has a three-dimensional structure. It is composed of water, mucous glycoproteins, low molecular weight ions, proteins and lipids. The three-dimensional structure of the mucous gel depends on a number of forms of bonding, such as ionic bonds and disulphide bridges. Airway obstruction in cystic fibrosis (CF lung disease is accompanied by the accumulation of thick and viscous secretions resulting from chronic infection and inflammation, promoting recurrent exacerbations. The normal, free-flow ing airway mucus becomes thick and purulent in patients suffering from CF lung disease. Therefore, current approaches to the treatment of CF include strategics for changing the physical properties of pulmonary secretions with the goal of improving airway clearance. Some of the same strategies may be applicable in the larger group of patients with chronic obstructive airway diseases, including bronchiectasis and chronic obstructive pulmonary disease. This paper reviews various approaches to mucolysis based on the molecular nature of crosslinking and bonding in mucin gels. A brief review of the structure and biochemistry of airway mucus is followed by a discussion of the various physical and biochemical approaches to mucolysis. Seven representative mucotropic modalities are presented: N-acetylcysteine; urea; hypertonic saline; recombinant human DNase; gelsolin; oscillation; and surfactants. Each of these mucotropic modalities acts on a different component within the mucous gel. Finally, the possibilities of mucolytic synergism among these various agents are conside red.

  10. [Molecular basis of Fanconi's anemia].

    Science.gov (United States)

    Digweed, M

    1999-01-01

    Fanconi anaemia (FA) is an autosomal recessive genetic disorder characterised clinically by progressive bone marrow failure, skeletal deformities and a predisposition to neoplasia. Patient cells manifest an extreme chromosomal instability and hypersensitivity to polyfunctional alkylating agents. It is assumed that the basic defect is related to the repair of DNA damage, in particular that of so-called DNA crosslinks. Currently there are eight complementation groups in FA (FA-A-FA-H) which indicates that at least eight independent genes can lead to FA. Three of these genes have been identified: FANCA, FANCC and FANCG. In this review, the molecular biology and genetics of FA are presented and possible functions of the FANC proteins are discussed.

  11. The Molecular Basis of Hypopituitarism

    Science.gov (United States)

    Romero, Christopher J; Nesi-França, Suzana; Radovick, Sally

    2009-01-01

    Hypopituitarism is defined as the deficiency of one or more of the hormones secreted by the pituitary gland. Several developmental factors necessary for pituitary embryogenesis and hormone secretion have been described, and mutations of these genes in humans provide a molecular understanding of hypopituitarism. Genetic studies of affected patients and their families provide insights into possible mechanisms of abnormal pituitary development, however, mutations are rare. This review characterizes several of these developmental proteins and their role in the pathogenesis of hypopituitarism. Continuing research is required to better understand the complexities and interplay between these pituitary factors and to make improvements in genetic diagnosis that may lead to early detection and provide a future cure. PMID:19854060

  12. Molecular basis of androgen insensitivity

    NARCIS (Netherlands)

    Brinkmann, A.; Jenster, G.; Ris-Stalpers, C.; van der Korput, H.; Brüggenwirth, H.; Boehmer, A.; Trapman, J.

    1996-01-01

    Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the

  13. COXIELLA BURNETII PATHOGENICITY MOLECULAR BASIS

    Directory of Open Access Journals (Sweden)

    Yu. A. Panferova

    2016-01-01

    characterization of novel virulence factors it is now possible through axenic media for C. burnetii cultivation and development of site-specific mutagenesis and other genetic technics, which is important for research of C. burnetii molecular pathogenesis.

  14. The molecular basis of peanut allergy

    Science.gov (United States)

    Peanut allergens can trigger a potent and sometimes dangerous immune response in an increasing number of people. The molecular structures of these allergens form the basis for understanding this response. This review describes the currently known peanut allergen structures, and discusses how modif...

  15. Cellular and Molecular Basis of Cerebellar Development

    Directory of Open Access Journals (Sweden)

    Salvador eMartinez

    2013-06-01

    Full Text Available Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function.

  16. The molecular basis of lactose intolerance.

    Science.gov (United States)

    Campbell, Anthony K; Waud, Jonathan P; Matthews, Stephanie B

    2009-01-01

    A staggering 4000 million people cannot digest lactose, the sugar in milk, properly. All mammals, apart from white Northern Europeans and few tribes in Africa and Asia, lose most of their lactase, the enzyme that cleaves lactose into galactose and glucose, after weaning. Lactose intolerance causes gut and a range of systemic symptoms, though the threshold to lactose varies considerably between ethnic groups and individuals within a group. The molecular basis of inherited hypolactasia has yet to be identified, though two polymorphisms in the introns of a helicase upstream from the lactase gene correlate closely with hypolactasia, and thus lactose intolerance. The symptoms of lactose intolerance are caused by gases and toxins produced by anaerobic bacteria in the large intestine. Bacterial toxins may play a key role in several other diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis and some cancers. The problem of lactose intolerance has been exacerbated because of the addition of products containing lactose to various foods and drinks without being on the label. Lactose intolerance fits exactly the illness that Charles Darwin suffered from for over 40 years, and yet was never diagnosed. Darwin missed something else--the key to our own evolution--the Rubicon some 300 million years ago that produced lactose and lactase in sufficient amounts to be susceptible to natural selection.

  17. Molecular Basis for Saccharomyces cerevisiae Biofilm Development

    DEFF Research Database (Denmark)

    Andersen, Kaj Scherz

    In this study, I sought to identify genes regulating the global molecular program for development of sessile multicellular communities, also known as biofilm, of the eukaryotic microorganism, Saccharomyces cerevisiae (yeast). Yeast biofilm has a clinical interest, as biofilms can cause chronic...... infections in humans. Biofilm is also interesting from an evolutionary standpoint, as an example of primitive multicellularity. By using a genome-wide screen of yeast deletion mutants, I show that 71 genes are essential for biofilm formation. Two-thirds of these genes are required for transcription of FLO11......, but only a small subset is previously described as regulators of FLO11. These results reveal that the regulation of biofilm formation and FLO11 is even more complex than what has previously been described. I find that the molecular program for biofilm formation shares many essential components with two...

  18. Molecular basis of angiosperm tree architecture.

    Science.gov (United States)

    Hollender, Courtney A; Dardick, Chris

    2015-04-01

    The architecture of trees greatly impacts the productivity of orchards and forestry plantations. Amassing greater knowledge on the molecular genetics that underlie tree form can benefit these industries, as well as contribute to basic knowledge of plant developmental biology. This review describes the fundamental components of branch architecture, a prominent aspect of tree structure, as well as genetic and hormonal influences inferred from studies in model plant systems and from trees with non-standard architectures. The bulk of the molecular and genetic data described here is from studies of fruit trees and poplar, as these species have been the primary subjects of investigation in this field of science. No claim to original US Government works. New Phytologist © 2014 New Phytologist Trust.

  19. The molecular basis of radiation action

    International Nuclear Information System (INIS)

    Smith, K.C.

    1985-01-01

    Before turning his full attention to research on oncogenic viruses, Henry S. Kaplan made seminal contributions to the field of molecular radiobiology during the years from 1960 to 1975. One of his first areas of interest in microbial radiobiology was the radiation sensitization of cells by the incorporation into DNA of analogs of the natural purines and pyrimidines. This fundamental work ultimately led to clinical trials using halogenated pyrimidines in conjunction with radiation therapy. Dr Kaplan published the first method for assaying for the formation and repair of DNA double-strand breaks, and made other major contributions to our understanding of the biological importance of X-ray-induced DNA strand breaks, and the modulation of their repair. The specifics of Dr. Kaplan's discoveries in these areas are discussed, as well as some recent work from the author's laboratory that unifies some of the earlier work of Dr. Kaplan on the repair of DNA strand breaks

  20. Molecular basis of HFE-hemochromatosis

    Directory of Open Access Journals (Sweden)

    Maja eVujic Spasic

    2014-03-01

    Full Text Available Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH. The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-hemochromatosis as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH associated pathologies.

  1. Molecular basis of HFE-hemochromatosis.

    Science.gov (United States)

    Vujić, Maja

    2014-01-01

    Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies.

  2. Metabolic syndrome: clinical concept and molecular basis.

    Science.gov (United States)

    Funahashi, Tohru; Matsuzawa, Yuji

    2007-01-01

    The metabolic syndrome is a cluster of insulin resistance, elevated blood pressure, and atherogenic dyslipidemia and is a common basis of cardiovascular diseases (CVD). Although the precise mechanism remains to be elucidated, a practical definition is needed. A worldwide definition that considers increased waist circumference as an essential component has been settled. Visceral fat locates upstream of the liver. Free fatty acids and glycerol derived from visceral fat reach the liver and stimulate lipoprotein synthesis and gluconeogenesis, respectively. The adipose tissue produces a variety of bioactive substances conceptualized as 'adipocytokines'. Overproduction of plasminogen activator inhibitor-1 and tumor necrosis factor- seems to relate to the thrombotic and inflammatory tendency. On the other hand, adiponectin, which has antiatherogenic and antidiabetic activities, is reduced in subjects with metabolic syndrome. In Japan, the waist circumference criterion based on visceral fat accumulation has been adopted. The concept of this syndrome has been widely publicized, and health promotion programs based on the concept have commenced in various areas of the country. Such 'Adipo-Do-It' movement is an incentive to encourage physical exercise to reduce visceral fat and is a big challenge to prevent life-style-related diseases and CVD.

  3. Molecular and Genetic Basis of Stress

    Directory of Open Access Journals (Sweden)

    Bakir Mehić

    2012-05-01

    Full Text Available A person’s reaction to trauma depends on the traumatic situation itself, personality characteristics of the person exposed to trauma, and posttraumatic social environment. Stressor must be extreme event that is extremely dangerous or fatal nature, and which is outside normal human experience [1].Studies investigating psychological consequences of military and civil trauma confirmed the correlation between the nature and intensity of trauma, previous traumatic experience, and psychological consequences. Stress causes the autonomic nervous system hyperactivity. If the stress is extreme or constant symptoms of hyperactivity, increased heart rate, increased respiration, sweating, muscle tension, insomnia and increased anxiety are becoming significant for the prolonging the symptoms of PTSD. Our cells are well adapted to exposure to a mild stress for a short time. In contrast there are potentially serious consequences of exposure to the prolonged stress[2].Various damages arising from the war in Bosnia (1992 - 1995 are almost undetectable, and the consequences for the mental health of the population of Bosnia and Herzegovina are long and painful. It is estimated that in Bosnia and Herzegovina there are 1.75 million people who have some stress-related mental disorders, of which 1 million in the Federation.PTSD may be represented by mutations that must be carried by many genes. There may even be epigenetic reasons for the disorder that have nothing to do with heritable mutations per se. Epigenetic means related to functional changes in the genome that can be regulated by external environmental events that do not involve alterations in the genetic code. One epigenetic mechanism is called “methylation,” a molecular process that affects the activity of a large percentage of genes. Epigenetic investigations say that methylation may be involved in the development of stress regulation in early life[3].A number of longitudinal studies have looked at

  4. Molecular basis and regulation of OTULIN-LUBAC interaction

    DEFF Research Database (Denmark)

    Elliott, Paul R.; Al-Saoudi, Sofie Vincents; Marco-Casanova, Paola

    2014-01-01

    Ub. Now, we show that OTULIN binds via a conserved PUB-interacting motif (PIM) to the PUB domain of the LUBAC component HOIP. Crystal structures and nuclear magnetic resonance experiments reveal the molecular basis for the high-affinity interaction and explain why OTULIN binds the HOIP PUB domain...

  5. The molecular genetic basis of age-related macular degeneration ...

    Indian Academy of Sciences (India)

    2009-12-10

    Dec 10, 2009 ... this review, we have provided an overview on the underlying molecular genetic mechanisms in AMD worldwide and highlight ..... eases like diabetes (Scott et al. ...... 2006 Systematic review and meta-analysis of.

  6. Molecular basis for dominantly inherited inclusion body β-thalassemia

    International Nuclear Information System (INIS)

    Thein, S.L.; Hesketh, C.; Wood, W.G.; Clegg, J.B.; Old, J.M.; Weatherall, D.J.; Taylor, P.; Temperley, I.J.; Hutchinson, R.M.

    1990-01-01

    Analysis of the molecular basis of dominantly inherited β-thalassemia in four families has revealed different mutations involving exon 3 of the β-globin gene. It is suggested that the phenotypic difference between this condition and the more common recessive forms of β-thalassemia lies mainly in the length and stability of the abnormal translation products that are synthesized and, in particular, whether they are capable of binding heme and producing aggregations that are relatively resistant to proteolytic degradation

  7. Changing pulse-shape basis for molecular learning control

    International Nuclear Information System (INIS)

    Cardoza, David; Langhojer, Florian; Trallero-Herrero, Carlos; Weinacht, Thomas; Monti, Oliver L.A.

    2004-01-01

    We interpret the results of a molecular fragmentation learning control experiment. We show that in the case of a system where control can be related to the structure of the optimal pulse matching the vibrational dynamics of the molecule, a simple change of pulse-shape basis in which the learning algorithm performs the search can reduce the dimensionality of the search space to one or two degrees of freedom

  8. Molecular basis of antifungal drug resistance in yeasts

    DEFF Research Database (Denmark)

    Morio, Florent; Jensen, Rasmus Hare; Le Pape, Patrice

    2017-01-01

    Besides inherent differences in in vitro susceptibilities, clinically-relevant yeast species may acquire resistance upon exposure to most antifungal drugs used in the clinic. In recent years, major fundamental research studies have been conducted to improve our understanding of the molecular basis...... of antifungal resistance. This topic is of major interest as antifungal resistance in yeast is clearly evolving and is correlated with clinical failure. This minireview is an overview of the most recent findings about key molecular mechanisms evolving in human pathogenic yeasts, particularly Candida spp......., in the context of antifungal drug resistance. Also included are the methods currently available for in vitro antifungal susceptibility testing and for molecular detection of mutations associated with resistance. Finally, the genetic drivers of antifungal resistance are discussed in light of the spectra...

  9. The molecular basis of hereditary enamel defects in humans.

    Science.gov (United States)

    Wright, J T; Carrion, I A; Morris, C

    2015-01-01

    The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel. © International & American Associations for

  10. The Molecular Basis of Hereditary Enamel Defects in Humans

    Science.gov (United States)

    Carrion, I.A.; Morris, C.

    2015-01-01

    The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel. PMID:25389004

  11. Molecular basis of the triple negative breast cancer

    Directory of Open Access Journals (Sweden)

    Ayse Feyda Nursal

    2015-06-01

    Full Text Available Breast cancer is the most common type of cancer in women and more than 1 million breast cancer cases are diagnosed each year all over the world. Breast cancer is a complex and heterogeneous disease in terms of its molecular structure, mutation type, metastase properties, clinical course and therapeutic response. Breast cancer is divided into subtypes based on expression properties of molecular markers as estrogen receptor, progestron receptor, human epidermal growth factor receptor 2. Triple-negative breast cancer is characterized by the lack of tumors that estrogen receptor, progestron receptor, human epidermal growth factor receptor 2 gene expression. These type of tumors lead to agressive clinical course due to unresponsiveness to systemic endocrine therapy and poor prognosis. Triple negative breast cancer constitutes 10-20% of all breast cancers. It affects generally young and African-American women. Triple negative breast cancer have several subtypes based on the gene expression properties. The majority of them are basal-like breast cancers. In this review, current literature is revised and summarized with respect to the molecular basis of triple negative cancers. [Archives Medical Review Journal 2015; 24(2.000: 251-259

  12. Complex basis functions for molecular resonances: Methodology and applications

    Science.gov (United States)

    White, Alec; McCurdy, C. William; Head-Gordon, Martin

    The computation of positions and widths of metastable electronic states is a challenge for molecular electronic structure theory because, in addition to the difficulty of the many-body problem, such states obey scattering boundary conditions. These resonances cannot be addressed with naïve application of traditional bound state electronic structure theory. Non-Hermitian electronic structure methods employing complex basis functions is one way that we may rigorously treat resonances within the framework of traditional electronic structure theory. In this talk, I will discuss our recent work in this area including the methodological extension from single determinant SCF-based approaches to highly correlated levels of wavefunction-based theory such as equation of motion coupled cluster and many-body perturbation theory. These approaches provide a hierarchy of theoretical methods for the computation of positions and widths of molecular resonances. Within this framework, we may also examine properties of resonances including the dependence of these parameters on molecular geometry. Some applications of these methods to temporary anions and dianions will also be discussed.

  13. Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition

    Science.gov (United States)

    Limongelli, Vittorio; Bonomi, Massimiliano; Marinelli, Luciana; Gervasio, Francesco Luigi; Cavalli, Andrea; Novellino, Ettore; Parrinello, Michele

    2010-01-01

    The widely used nonsteroidal anti-inflammatory drugs block the cyclooxygenase enzymes (COXs) and are clinically used for the treatment of inflammation, pain, and cancers. A selective inhibition of the different isoforms, particularly COX-2, is desirable, and consequently a deeper understanding of the molecular basis of selective inhibition is of great demand. Using an advanced computational technique we have simulated the full dissociation process of a highly potent and selective inhibitor, SC-558, in both COX-1 and COX-2. We have found a previously unreported alternative binding mode in COX-2 explaining the time-dependent inhibition exhibited by this class of inhibitors and consequently their long residence time inside this isoform. Our metadynamics-based approach allows us to illuminate the highly dynamical character of the ligand/protein recognition process, thus explaining a wealth of experimental data and paving the way to an innovative strategy for designing new COX inhibitors with tuned selectivity. PMID:20215464

  14. Molecular basis of pathogenesis of emerging viruses infecting aquatic animals

    Directory of Open Access Journals (Sweden)

    Lang Gui

    2018-01-01

    Full Text Available Aquatic vertebrates are very abundant in the world, and they are of tremendous importance in providing global food security and nutrition. However, emergent and resurgent viruses, such as ranavirus (e.g., Rana grylio virus, RGV and Andriasd avidianus ranavirus, ADRV, herpesvirus (e.g., Carassius carassius herpesvirus, CaHV, reovirus (e.g., grass carp reovirus 109, GCRV-109, Scophthal musmaximus reovirus, SMReV and Micropterus salmoides reovirus, MsReV, and rhabdovirus (e.g., Siniper cachuatsi rhabdovirus, SCRV and Scophthal musmaximus rhabdovirus, SMRV can cause severe diseases in aquaculture animals and wild lower vertebrates, such as frogs, giant salamanders, fish, and so on. Here, we will briefly describe the symptoms produced by the aforementioned viruses and the molecular basis of the virus–host interactions. This manuscript aims to provide an overview of viral diseases in lower vertebrates with an emphasis on visible symptomatic manifestations and pathogenesis.

  15. The molecular basis of retinal ganglion cell death in glaucoma.

    Science.gov (United States)

    Almasieh, Mohammadali; Wilson, Ariel M; Morquette, Barbara; Cueva Vargas, Jorge Luis; Di Polo, Adriana

    2012-03-01

    Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs), a population of CNS neurons with their soma in the inner retina and axons in the optic nerve. Strategies that delay or halt RGC loss have been recognized as potentially beneficial to preserve vision in glaucoma; however, the success of these approaches depends on an in-depth understanding of the mechanisms that lead to RGC dysfunction and death. In recent years, there has been an exponential increase in valuable information regarding the molecular basis of RGC death stemming from animal models of acute and chronic optic nerve injury as well as experimental glaucoma. The emerging landscape is complex and points at a variety of molecular signals - acting alone or in cooperation - to promote RGC death. These include: axonal transport failure, neurotrophic factor deprivation, toxic pro-neurotrophins, activation of intrinsic and extrinsic apoptotic signals, mitochondrial dysfunction, excitotoxic damage, oxidative stress, misbehaving reactive glia and loss of synaptic connectivity. Collectively, this body of work has considerably updated and expanded our view of how RGCs might die in glaucoma and has revealed novel, potential targets for neuroprotection. Copyright © 2011. Published by Elsevier Ltd.

  16. Structural and molecular basis of starch viscosity in hexaploid wheat.

    Science.gov (United States)

    Ral, J-P; Cavanagh, C R; Larroque, O; Regina, A; Morell, M K

    2008-06-11

    Wheat starch is considered to have a low paste viscosity relative to other starches. Consequently, wheat starch is not preferred for many applications as compared to other high paste viscosity starches. Increasing the viscosity of wheat starch is expected to increase the functionality of a range of wheat flour-based products in which the texture is an important aspect of consumer acceptance (e.g., pasta, and instant and yellow alkaline noodles). To understand the molecular basis of starch viscosity, we have undertaken a comprehensive structural and rheological analysis of starches from a genetically diverse set of wheat genotypes, which revealed significant variation in starch traits including starch granule protein content, starch-associated lipid content and composition, phosphate content, and the structures of the amylose and amylopectin fractions. Statistical analysis highlighted the association between amylopectin chains of 18-25 glucose residues and starch pasting properties. Principal component analysis also identified an association between monoesterified phosphate and starch pasting properties in wheat despite the low starch-phosphate level in wheat as compared to tuber starches. We also found a strong negative correlation between the phosphate ester content and the starch content in flour. Previously observed associations between internal starch granule fatty acids and the swelling peak time and pasting temperature have been confirmed. This study has highlighted a range of parameters associated with increased starch viscosity that could be used in prebreeding/breeding programs to modify wheat starch pasting properties.

  17. Molecular Basis for Drug Resistance in HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Celia A. Schiffer

    2010-11-01

    Full Text Available HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.

  18. Microbial biotransformation of DON: molecular basis for reduced toxicity

    Science.gov (United States)

    Pierron, Alix; Mimoun, Sabria; Murate, Leticia S.; Loiseau, Nicolas; Lippi, Yannick; Bracarense, Ana-Paula F. L.; Schatzmayr, Gerd; He, Jian Wei; Zhou, Ting; Moll, Wulf-Dieter; Oswald, Isabelle P.

    2016-07-01

    Bacteria are able to de-epoxidize or epimerize deoxynivalenol (DON), a mycotoxin, to deepoxy-deoxynivalenol (deepoxy-DON or DOM-1) or 3-epi-deoxynivalenol (3-epi-DON), respectively. Using different approaches, the intestinal toxicity of 3 molecules was compared and the molecular basis for the reduced toxicity investigated. In human intestinal epithelial cells, deepoxy-DON and 3-epi-DON were not cytotoxic, did not change the oxygen consumption or impair the barrier function. In intestinal explants, exposure for 4 hours to 10 μM DON induced intestinal lesions not seen in explants treated with deepoxy-DON and 3-epi-DON. A pan-genomic transcriptomic analysis was performed on intestinal explants. 747 probes, representing 323 genes, were differentially expressed, between DON-treated and control explants. By contrast, no differentially expressed genes were observed between control, deepoxy-DON and 3-epi-DON treated explants. Both DON and its biotransformation products were able to fit into the pockets of the A-site of the ribosome peptidyl transferase center. DON forms three hydrogen bonds with the A site and activates MAPKinases (mitogen-activated protein kinases). By contrast deepoxy-DON and 3-epi-DON only form two hydrogen bonds and do not activate MAPKinases. Our data demonstrate that bacterial de-epoxidation or epimerization of DON altered their interaction with the ribosome, leading to an absence of MAPKinase activation and a reduced toxicity.

  19. Molecular basis of colorectal cancer: Towards an individualized management?

    Directory of Open Access Journals (Sweden)

    J. Perea

    Full Text Available Colorectal cancer (CRC has become a highly relevant condition nowadays. In this respect, advances in the understanding of its molecular basis are key for an adequate management. From the time when the adenoma-carcinoma sequence was formulated as a carcinogenesis model to this day, when, among other things, three major carcinogenic pathways have been identified, the CRC concept has evolved from that of a single disease to the notion that each CRC is a differentiated condition in itself. The suppressor or chromosome instability pathway, the mutator or microsatellite instability pathway, and the methylator or CpG island methylation pathway allow various phenotypes to be identified within CRC. Similarly, the presence of different changes in certain genes confers several behaviors on CRC from both the prognostic and responsive standpoints to specific therapies. However, this apparent complexity does help develop the clinical management of this disease through the identification of novel, more specific therapy targets, and also markers for various behaviors within the condition, which will most likely lead us to an individualized management for these patients.

  20. Personalized skincare: from molecular basis to clinical and commercial applications

    Directory of Open Access Journals (Sweden)

    Markiewicz E

    2018-04-01

    Full Text Available Ewa Markiewicz, Olusola Clement Idowu Research & Development, Hexis Lab, Science Central, The Core, Bath Lane, Newcastle upon Tyne, UK Abstract: Individual responses of human skin to the environmental stress are determined by differences in the anatomy and physiology that are closely linked to the genetic characteristics such as pigmentation. Ethnic skin phenotypes can be distinguished based on defined genotypic traits, structural organization and compartmentalized sensitivity to distinct extrinsic aging factors. These differences are not only responsible for the variation in skin performance after exposure to damaging conditions, but can also affect the mechanisms of drug absorption, sensitization and other longer term effects. The unique characteristics of the individual skin function and, particularly, of the ethnic skin type are currently considered to shape the future of clinical and pharmacologic interventions as a basis for personalized skincare. Individual approaches to skincare render a novel and actively growing area with a range of biomedical and commercial applications within cosmetics industry. In this review, we summarize the aspects of the molecular and clinical manifestations of the environmental stress on human skin and proposed protective mechanisms that are linked to ethnic differences and pathophysiology of extrinsic skin aging. We subsequently discuss the possible applications and translation of this knowledge into personalized skincare. Keywords: pigmentation, gene polymorphism, photodamage, environmental stress, cosmetics

  1. Molecular basis of hypohidrotic ectodermal dysplasia: an update.

    Science.gov (United States)

    Trzeciak, Wieslaw H; Koczorowski, Ryszard

    2016-02-01

    Recent advances in understanding the molecular events underlying hypohidrotic ectodermal dysplasia (HED) caused by mutations of the genes encoding proteins of the tumor necrosis factor α (TNFα)-related signaling pathway have been presented. These proteins are involved in signal transduction from ectoderm to mesenchyme during development of the fetus and are indispensable for the differentiation of ectoderm-derived structures such as eccrine sweat glands, teeth, hair, skin, and/or nails. Novel data were reviewed and discussed on the structure and functions of the components of TNFα-related signaling pathway, the consequences of mutations of the genes encoding these proteins, and the prospect for further investigations, which might elucidate the origin of HED.

  2. Molecular investigations on grain filling rate under terminal heat ...

    African Journals Online (AJOL)

    Grain yield under post anthesis high temperature stress is largely influenced by grain filling rate (GFR). To investigate molecular basis of this trait, a set of 111 recombinant inbred lines (RILs) derived from Raj 4014, a heat sensitive genotype and WH 730, heat tolerant cultivar was phenotyped during 2009-2010 and ...

  3. Molecular basis of Bcl-X(L-p53 interaction: insights from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Nagakumar Bharatham

    Full Text Available Bcl-X(L, an antiapoptotic Bcl-2 family protein, plays a central role in the regulation of the apoptotic pathway. Heterodimerization of the antiapoptotic Bcl-2 family proteins with the proapoptotic family members such as Bad, Bak, Bim and Bid is a crucial step in the apoptotic regulation. In addition to these conventional binding partners, recent evidences reveal that the Bcl-2 family proteins also interact with noncanonical binding partners such as p53. Our previous NMR studies showed that Bcl-X(L: BH3 peptide and Bcl-X(L: SN15 peptide (a peptide derived from residues S15-N29 of p53 complex structures share similar modes of bindings. To further elucidate the molecular basis of the interactions, here we have employed molecular dynamics simulations coupled with MM/PBSA approach. Bcl-X(L and other Bcl-2 family proteins have 4 hydrophobic pockets (p1-p4, which are occupied by four systematically spaced hydrophobic residues (h1-h4 of the proapoptotic Bad and Bak BH3 peptides. We observed that three conserved hydrophobic residues (F19, W23 and L26 of p53 (SN15 peptide anchor into three hydrophobic pockets (p2-p4 of Bcl-X(L in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-X(L with p53.

  4. Learning and teaching the molecular basis of life

    NARCIS (Netherlands)

    van Mil, M.H.W.|info:eu-repo/dai/nl/33645659X

    2013-01-01

    Although learning about DNA, RNA and proteins is part of the upper-secondary biology curriculum in most countries, many studies report that that students fail to connect molecular knowledge to phenomena at the level of cells, organs and organisms. It is proposed that students are not sufficiently

  5. Molecular basis of development in petaloid monocot flowers

    DEFF Research Database (Denmark)

    Johansen, Bo; Frederiksen, Signe; Skipper, Martin

    2006-01-01

    -class genes apparently are expressed in meristems of both flower and inflorescence. Morphologically petaloid stamens and styles are well known within the petaloid monocots, whereas the phenomenon is rare in core eudicots. A simple model based on the extra copies of B-class genes can explain the molecular...

  6. The molecular basis of disease resistance in higher plants

    African Journals Online (AJOL)

    xxxxxx

    Therefore, manipulating a single transcription factor could have the same effect as manipulating a set of specific genes within the plant. As highlighted above, transgenic plants allow the targeted ... including molecular techniques and genetics will provide insights into pathogen-defense mechanism and subsequent disease ...

  7. Molecular basis of potassium channels in pancreatic duct epithelial cells

    DEFF Research Database (Denmark)

    Hayashi, M.; Novak, Ivana

    2013-01-01

    Potassium channels regulate excitability, epithelial ion transport, proliferation, and apoptosis. In pancreatic ducts, K channels hyperpolarize the membrane potential and provide the driving force for anion secretion. This review focuses on the molecular candidates of functional K channels...... and pancreatic pathologies, including pancreatitis, cystic fibrosis, and cancer, in which the dysregulation or altered expression of K channels may be of importance....

  8. Coulomb Sturmians as a basis for molecular calculations

    DEFF Research Database (Denmark)

    Avery, John Scales; Avery, James Emil

    2012-01-01

    mathematical difficulty of evaluating interelectron repulsion integrals when exponential-type orbitals (ETOs) are used. In this paper we show that when many-centre Coulomb Sturmian ETOs are used as a basis, the most important integrals can be evaluated rapidly and accurately by means of the theory...... of hyperspherical harmonics. For the remaining many-centre integrals, Coulomb Sturmians are shown to have advantages over other ETOs. Pilot calculations are performed on N-electron molecules using the Generalized Sturmian Method....

  9. Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

    Science.gov (United States)

    Lambers Heerspink, Hiddo J; Oberbauer, Rainer; Perco, Paul; Heinzel, Andreas; Heinze, Georg; Mayer, Gert; Mayer, Bernd

    2015-08-01

    Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients. © The Author 2015. Published by

  10. MOV motor and gearbox performance under design basis loads

    International Nuclear Information System (INIS)

    DeWall, K.G.; Watkins, J.C.

    1998-01-01

    This paper describes the results of valve testing sponsored by the US Nuclear Regulatory Commission, Office of Nuclear Regulatory Research and conducted at the Idaho National Engineering and Environmental Laboratory. The research objective was to evaluate the capabilities of specific actuator motor and gearbox assemblies under various design basis loading conditions. The testing was performed using the motor-operated valve load simulator, a test fixture that simulates the stem load profiles a valve actuator would experience when closing a valve against flow and pressure loadings. The authors tested five typical motors (four ac motors and one dc motor) with three gearbox assemblies at conditions a motor might experience in a power plant, including such off-normal conditions as operation at high temperature and reduced voltage. The authors also determined the efficiency of the actuator gearbox. The testing produced the following significant results: all five motors operated at or above their rated torque during tests at full voltage and ambient temperature; for all five motors (dc as well as ac), the actual torque loss due to voltage degradation was greater than the torque loss predicted using common methods; startup torques in locked rotor tests compared well with stall torques in dynamometer-type tests; the methods commonly used to predict torque losses due to elevated operating temperatures sometimes bounded the actual losses, but not in all cases; the greatest discrepancy involved the prediction for the dc motor; running efficiencies published by the manufacturer for actuator gearboxes were higher than the actual efficiencies determined from testing, in some instances, the published pullout efficiencies were also higher than the actual values; operation of the gearbox at elevated temperature did not affect the operating efficiency

  11. Molecular stress response pathways as the basis of hormesis

    DEFF Research Database (Denmark)

    Demirovic, Dino; de Toda, Irene Martinez; Rattan, Suresh

    2014-01-01

    There is now a large amount of data available for human beings showing positive hormetic effects of mild stresses from physical, chemical, nutritional and mental sources. However, these data are dispersed in the literature and not always interpreted as hormetic effects, thus restricting their full...... apprehension and application. A comprehensive discussion of the research, this book is composed of four sections: (1) History and terminology; (2) Evidence for hormesis in humans; (3) Molecular mechanisms of hormesis; and (4) Ethical and legal aspects, and risk assessment....

  12. Basis set construction for molecular electronic structure theory: natural orbital and Gauss-Slater basis for smooth pseudopotentials.

    Science.gov (United States)

    Petruzielo, F R; Toulouse, Julien; Umrigar, C J

    2011-02-14

    A simple yet general method for constructing basis sets for molecular electronic structure calculations is presented. These basis sets consist of atomic natural orbitals from a multiconfigurational self-consistent field calculation supplemented with primitive functions, chosen such that the asymptotics are appropriate for the potential of the system. Primitives are optimized for the homonuclear diatomic molecule to produce a balanced basis set. Two general features that facilitate this basis construction are demonstrated. First, weak coupling exists between the optimal exponents of primitives with different angular momenta. Second, the optimal primitive exponents for a chosen system depend weakly on the particular level of theory employed for optimization. The explicit case considered here is a basis set appropriate for the Burkatzki-Filippi-Dolg pseudopotentials. Since these pseudopotentials are finite at nuclei and have a Coulomb tail, the recently proposed Gauss-Slater functions are the appropriate primitives. Double- and triple-zeta bases are developed for elements hydrogen through argon. These new bases offer significant gains over the corresponding Burkatzki-Filippi-Dolg bases at various levels of theory. Using a Gaussian expansion of the basis functions, these bases can be employed in any electronic structure method. Quantum Monte Carlo provides an added benefit: expansions are unnecessary since the integrals are evaluated numerically.

  13. Genotoxicity of formaldehyde: Molecular basis of DNA damage and mutation

    Directory of Open Access Journals (Sweden)

    Masanobu eKawanishi

    2014-09-01

    Full Text Available Formaldehyde is commonly used in the chemical industry and is present in the environment, such as vehicle emissions, some building materials, food and tobacco smoke. It also occurs as a natural product in most organisms, the sources of which include a number of metabolic processes. It causes various acute and chronic adverse effects in humans if they inhale its fumes. Among the chronic effects on human health, we summarize data on genotoxicity and carcinogenicity in this review, and we particularly focus on the molecular mechanisms involved in the formaldehyde mutagenesis. Formaldehyde mainly induces N-hydroxymethyl mono-adducts on guanine, adenine and cytosine, and N-methylene crosslinks between adjacent purines in DNA. These crosslinks are types of DNA damage potentially fatal for cell survival if they are not removed by the nucleotide excision repair pathway. In the previous studies, we showed evidence that formaldehyde causes intra-strand crosslinks between purines in DNA using a unique method (Matsuda et al. Nucleic Acids Res. 26, 1769-1774,1998. Using shuttle vector plasmids, we also showed that formaldehyde as well as acetaldehyde induces tandem base substitutions, mainly at 5’-GG and 5’-GA sequences, which would arise from the intra-strand crosslinks. These mutation features are different from those of other aldehydes such as crotonaldehyde, acrolein, glyoxal and methylglyoxal. These findings provide molecular clues to improve our understanding of the genotoxicity and carcinogenicity of formaldehyde.

  14. Comparison of biomolecules on the basis of Molecular Interaction Potentials

    Directory of Open Access Journals (Sweden)

    Rodrigo Jordi

    2002-01-01

    Full Text Available Molecular Interaction Potentials (MIP are frequently used for the comparison of series of compounds displaying related biological behaviors. These potentials are interaction energies between the considered compounds and relevant probes. The interaction energies are computed in the nodes of grids defined around the compounds. There is a need of detailed and objective comparative analyses of MIP distributions in the framework of structure-activity studies. On the other hand, MIP-based studies do not have to be restricted to series of small ligands, since such studies present also interesting possibilities for the analysis and comparison of biological macromolecules. Such analyses can benefit from the application of new methods and computational approaches. The new software MIPSim (Molecular Interaction Potentials Similarity analysis has recently been introduced with the purpose of analyzing and comparing MIP distributions of series of biomolecules. This program is transparently integrated with other programs, like GAMESS or GRID, which can be used for the computation of the potentials to be analyzed or compared. MIPSim incorporates several definitions of similarity coefficients, and is capable of combining several similarity measures into a single one. On the other hand, MIPSim can perform automatic explorations of the maximum similarity alignments between pairs of molecules.

  15. A Molecular Genetic Basis Explaining Altered Bacterial Behavior in Space.

    Directory of Open Access Journals (Sweden)

    Luis Zea

    Full Text Available Bacteria behave differently in space, as indicated by reports of reduced lag phase, higher final cell counts, enhanced biofilm formation, increased virulence, and reduced susceptibility to antibiotics. These phenomena are theorized, at least in part, to result from reduced mass transport in the local extracellular environment, where movement of molecules consumed and excreted by the cell is limited to diffusion in the absence of gravity-dependent convection. However, to date neither empirical nor computational approaches have been able to provide sufficient evidence to confirm this explanation. Molecular genetic analysis findings, conducted as part of a recent spaceflight investigation, support the proposed model. This investigation indicated an overexpression of genes associated with starvation, the search for alternative energy sources, increased metabolism, enhanced acetate production, and other systematic responses to acidity-all of which can be associated with reduced extracellular mass transport.

  16. Molecular basis of glyphosate resistance: Different approaches through protein engineering

    Science.gov (United States)

    Pollegioni, Loredano; Schonbrunn, Ernst; Siehl, Daniel

    2011-01-01

    Glyphosate (N-phosphonomethyl-glycine) is the most-used herbicide in the world: glyphosate-based formulations exhibit broad-spectrum herbicidal activity with minimal human and environmental toxicity. The extraordinary success of this simple small molecule is mainly due to the high specificity of glyphosate towards the plant enzyme enolpyruvylshikimate-3-phosphate synthase in the shikimate pathway leading to biosynthesis of aromatic amino acids. Starting in 1996, transgenic glyphosate-resistant plants were introduced thus allowing the application of the herbicide to the crop (post-emergence) to remove emerged weeds without crop damage. This review focuses on the evolution of mechanisms of resistance to glyphosate as obtained through natural diversity, the gene shuffling approach to molecular evolution, and a rational, structure-based approach to protein engineering. In addition, we offer rationale for the means by which the modifications made have had their intended effect. PMID:21668647

  17. A Molecular Genetic Basis Explaining Altered Bacterial Behavior in Space

    Science.gov (United States)

    Prasad, Nripesh; Levy, Shawn E.; Stodieck, Louis; Jones, Angela; Shrestha, Shristi; Klaus, David

    2016-01-01

    Bacteria behave differently in space, as indicated by reports of reduced lag phase, higher final cell counts, enhanced biofilm formation, increased virulence, and reduced susceptibility to antibiotics. These phenomena are theorized, at least in part, to result from reduced mass transport in the local extracellular environment, where movement of molecules consumed and excreted by the cell is limited to diffusion in the absence of gravity-dependent convection. However, to date neither empirical nor computational approaches have been able to provide sufficient evidence to confirm this explanation. Molecular genetic analysis findings, conducted as part of a recent spaceflight investigation, support the proposed model. This investigation indicated an overexpression of genes associated with starvation, the search for alternative energy sources, increased metabolism, enhanced acetate production, and other systematic responses to acidity—all of which can be associated with reduced extracellular mass transport. PMID:27806055

  18. Functional histology of tumors as a basis of molecular imaging

    International Nuclear Information System (INIS)

    Ljungkvist, A.S.; Bussink, J.; Rijken, P.F.; Van Der Kogel, A.; Kaanders, J.H.

    2003-01-01

    The aim of this study was to characterize the various elements of the microenvironment and their interrelationships by quantitative image analysis. Tumor cell proliferation, hypoxia, and apoptosis are detected by immunohistochemical methods, and mapped in relation to the vasculature. This allows quantitative relationships to be measured in the context of tissue structure. Guided by e.g., gene expression profiles for hypoxia induced-genes, several molecular markers of tumor hypoxia were identified and are immunohistochemically detectable. We have thus far concentrated on the glucose transporters glut-1 and glut-3, as well as a pH-regulating enzyme, carbonic anhydrase IX. The extent and distribution of hypoxia is assessed by administering nitroimidazole-based markers such as pimonidazole, that can be detected immunohistochemically. Multiple hypoxia markers (CCI-103F, pimonidazole) can be used to study the effects of modifiers of perfusion or oxygenation on the distribution and dynamics of hypoxic cells in the same tumor. Proliferating cells are detected by thymidine analogues. Apoptotic cells are imaged by TUNEL and caspase-3 detection. In xenografted human tumors, examples of the use of quantitative imaging of hypoxia and proliferation are the study of reoxygenation after irradiation, or the investigation of the lifespan and dynamics of hypoxic cell populations over time. Perturbation of the microenvironment after cytotoxic treatments has been investigated by co-registration of the various markers, e.g. after treatment with the hypoxic cytotoxin tirapazamine. The combination of well-timed administration of external markers of hypoxia and proliferation with the detection of intrinsic molecular markers followed by quantitative image-registration yields a comprehensive view of the dynamics of the microenvironment in individual tumors

  19. Molecular basis sets - a general similarity-based approach for representing chemical spaces.

    Science.gov (United States)

    Raghavendra, Akshay S; Maggiora, Gerald M

    2007-01-01

    A new method, based on generalized Fourier analysis, is described that utilizes the concept of "molecular basis sets" to represent chemical space within an abstract vector space. The basis vectors in this space are abstract molecular vectors. Inner products among the basis vectors are determined using an ansatz that associates molecular similarities between pairs of molecules with their corresponding inner products. Moreover, the fact that similarities between pairs of molecules are, in essentially all cases, nonzero implies that the abstract molecular basis vectors are nonorthogonal, but since the similarity of a molecule with itself is unity, the molecular vectors are normalized to unity. A symmetric orthogonalization procedure, which optimally preserves the character of the original set of molecular basis vectors, is used to construct appropriate orthonormal basis sets. Molecules can then be represented, in general, by sets of orthonormal "molecule-like" basis vectors within a proper Euclidean vector space. However, the dimension of the space can become quite large. Thus, the work presented here assesses the effect of basis set size on a number of properties including the average squared error and average norm of molecular vectors represented in the space-the results clearly show the expected reduction in average squared error and increase in average norm as the basis set size is increased. Several distance-based statistics are also considered. These include the distribution of distances and their differences with respect to basis sets of differing size and several comparative distance measures such as Spearman rank correlation and Kruscal stress. All of the measures show that, even though the dimension can be high, the chemical spaces they represent, nonetheless, behave in a well-controlled and reasonable manner. Other abstract vector spaces analogous to that described here can also be constructed providing that the appropriate inner products can be directly

  20. Cellular and molecular pathology of HTS: basis for treatment.

    Science.gov (United States)

    Armour, Alexis; Scott, Paul G; Tredget, Edward E

    2007-01-01

    Hypertrophic scar and keloids are fibroproliferative disorders of the skin which occur often unpredictably, following trauma and inflammation that compromise cosmesis and function and commonly recur following surgical attempts for improvement. Despite decades of research in these fibrotic conditions, current non-surgical methods of treatment are slow, inconvenient and often only partially effective. Fibroblasts from these conditions are activated to produce extracellular matrix proteins such as collagen I and III, proteoglycans such as versican and biglycan and growth factors, including transforming growth factor-beta and insulin like growth factor I. However, more consistently these cells produce less remodeling enzymes including collagenase and other matrix metalloproteinases, as well as the small proteoglycan decorin which is important for normal collagen fibrillogenesis. Recently, the systemic response to injury appears to influence the local healing process whereby increases in Th2 and possibly Th3 cytokines such as IL-2, IL-4 and IL-10 and TGF-beta are present in the circulating lymphocytes in these fibrotic conditions. Finally, unique bone marrow derived cells including mesenchymal and endothelial stem cells as well as fibrocytes appear to traffic into healing wounds and influence the healing tissue. On this background, clinicians are faced with patients who require treatment and the pathophysiologic basis as currently understood is reviewed for a number of emerging modalities.

  1. The physical basis of biochemistry the foundations of molecular biophysics

    CERN Document Server

    Bergethon, Peter R

    1998-01-01

    The objective of this book is to provide a unifying approach to the study of biophysical chemistry for the advanced undergraduate who has had a year of physics, organic chem­ istry, calculus, and biology. This book began as a revised edition of Biophysical Chemistry: Molecules to Membranes, which Elizabeth Simons and I coauthored. That short volume was written in an attempt to provide a concise text for a one-semester course in biophysical chemistry at the graduate level. The experience of teaching biophysical chemistry to bi­ ologically oriented students over the last decade has made it clear that the subject requires a more fundamental text that unifies the many threads of modem science: physics, chem­ istry, biology, mathematics, and statistics. This book represents that effort. This volume is not a treatment of modem biophysical chemistry with its rich history and many contro­ versies, although a book on that topic is also needed. The Physical Basis of Biochemistry is an introduction to the philosophy...

  2. Basis for molecular diagnostics and immunotherapy for esophageal cancer.

    Science.gov (United States)

    Abdo, Joe; Agrawal, Devendra K; Mittal, Sumeet K

    2017-01-01

    Esophageal cancer (EC) is an extremely aggressive neoplasm, diagnosed in about 17,000 Americans every year with a mortality rate of more than 80% within five years and a median overall survival of just 13 months. For decades, the go-to regimen for esophageal cancer patients has been the use of taxane and platinum-based chemotherapy regimens, which has yielded the field's most dire survival statistics. Areas covered: Combination immunotherapy and a more robust molecular diagnostic platform for esophageal tumors could improve patient management strategies and potentially extend lives beyond the current survival figures. Analyzing a panel of biomarkers including those affiliated with taxane and platinum resistance (ERCC1 and TUBB3) as well as immunotherapy effectiveness (PD-L1) would provide oncologists more information on how to optimize first-line therapy for EC. Expert commentary: Of the 12 FDA-approved therapies in EC, zero target the genome. A majority of the approved drugs either target or are effected by proteomic expression. Therefore, a broader understanding of diagnostic biomarkers could give more clarity and direction in treating esophageal cancer in concert with a greater use of immunotherapy.

  3. The molecular basis of herpes simplex virus latency

    Science.gov (United States)

    Nicoll, Michael P; Proença, João T; Efstathiou, Stacey

    2012-01-01

    Herpes simplex virus type 1 is a neurotropic herpesvirus that establishes latency within sensory neurones. Following primary infection, the virus replicates productively within mucosal epithelial cells and enters sensory neurones via nerve termini. The virus is then transported to neuronal cell bodies where latency can be established. Periodically, the virus can reactivate to resume its normal lytic cycle gene expression programme and result in the generation of new virus progeny that are transported axonally back to the periphery. The ability to establish lifelong latency within the host and to periodically reactivate to facilitate dissemination is central to the survival strategy of this virus. Although incompletely understood, this review will focus on the mechanisms involved in the regulation of latency that centre on the functions of the virus-encoded latency-associated transcripts (LATs), epigenetic regulation of the latent virus genome and the molecular events that precipitate reactivation. This review considers current knowledge and hypotheses relating to the mechanisms involved in the establishment, maintenance and reactivation herpes simplex virus latency. PMID:22150699

  4. Uniqueness of thermodynamic projector and kinetic basis of molecular individualism

    Science.gov (United States)

    Gorban, Alexander N.; Karlin, Iliya V.

    2004-05-01

    Three results are presented: First, we solve the problem of persistence of dissipation for reduction of kinetic models. Kinetic equations with thermodynamic Lyapunov functions are studied. Uniqueness of the thermodynamic projector is proven: There exists only one projector which transforms any vector field equipped with the given Lyapunov function into a vector field with the same Lyapunov function for a given anzatz manifold which is not tangent to the Lyapunov function levels. Second, we use the thermodynamic projector for developing the short memory approximation and coarse-graining for general nonlinear dynamic systems. We prove that in this approximation the entropy production increases. ( The theorem about entropy overproduction.) In example, we apply the thermodynamic projector to derive the equations of reduced kinetics for the Fokker-Planck equation. A new class of closures is developed, the kinetic multipeak polyhedra. Distributions of this type are expected in kinetic models with multidimensional instability as universally as the Gaussian distribution appears for stable systems. The number of possible relatively stable states of a nonequilibrium system grows as 2 m, and the number of macroscopic parameters is in order mn, where n is the dimension of configuration space, and m is the number of independent unstable directions in this space. The elaborated class of closures and equations pretends to describe the effects of “molecular individualism”. This is the third result.

  5. On the basis of molecular orbitals for relativistic bound systems of many bodies

    International Nuclear Information System (INIS)

    Cook, A.H.

    1987-09-01

    The quasi-relativistic Hamiltonian for bound states of many bodies proposed in previous articles (Cook, 1986, 1987a) is shown to provide a basis for the molecular orbital scheme of constructing wavefunctions and calculating eigenenergies. (author). 5 refs

  6. Molecular basis for Duarte and Los Angeles variant galactosemia

    Energy Technology Data Exchange (ETDEWEB)

    Langley, S.D.; Lai, K.; Dembure, P.P. [Emory Univ. School of Medicine, Atlanta, GA (United States)] [and others

    1997-02-01

    Human erythrocytes that are homozygous for the Duarte enzyme variant of galactosemia (D/D) have a characteristic isoform on isoelectric focusing and 50% reduction in galactose-1-phosphate uridyltransferase (GALT) enzyme activity. The Duarte biochemical phenotype has a molecular genotype of N314D/N314D. The characteristic Duarte isoform is also associated with a variant called the {open_quotes}Los Angeles (LA) phenotype,{close_quotes} which has increased GALT enzyme activity. We evaluated GALT enzyme activity and screened the GALT genes of 145 patients with one or more N314D-containing alleles. We found seven with the LA biochemical phenotype, and all had a 1721C{r_arrow}T transition in exon 7 in cis with the N314D missense mutation. The 1721C{r_arrow}T transition is a neutral polymorphism for leucine at amino acid 218 (L218L). In pedigree analyses, this 1721C{r_arrow}T transition segregated with the LA phenotype of increased GALT activity in three different biochemical phenotypes (LA/N, LA/G, and LA/D). To determine the mechanism for increased activity of the LA variant, we compared GALT mRNA, protein abundance, and enzyme thermal stability in lymphoblast cell lines of D and LA phenotypes with comparable genotypes. GALT protein abundance was increased in LA compared to D alleles, but mRNA was similar among all genotypes. We conclude that the codon change N314D in cis with the base-pair transition 1721C{r_arrow}T produces the LA variant of galactosemia and that this nucleotide change increases GALT activity by increasing GALT protein abundance without increasing transcription or decreasing thermal lability. A favorable codon bias for the mutated codon with consequently increased translation rates is postulated as the mechanism. 23 refs., 3 figs., 4 tabs.

  7. Vitamin E-drug interactions: molecular basis and clinical relevance.

    Science.gov (United States)

    Podszun, Maren; Frank, Jan

    2014-12-01

    Vitamin E (α-, β-, γ- and δ-tocopherol and -tocotrienol) is an essential factor in the human diet and regularly taken as a dietary supplement by many people, who act under the assumption that it may be good for their health and can do no harm. With the publication of meta-analyses reporting increased mortality in persons taking vitamin E supplements, the safety of the micronutrient was questioned and interactions with prescription drugs were suggested as one potentially underlying mechanism. Here, we review the evidence in the scientific literature for adverse vitamin E-drug interactions and discuss the potential of each of the eight vitamin E congeners to alter the activity of drugs. In summary, there is no evidence from animal models or randomised controlled human trials to suggest that the intake of tocopherols and tocotrienols at nutritionally relevant doses may cause adverse nutrient-drug interactions. Consumption of high-dose vitamin E supplements ( ≥  300 mg/d), however, may lead to interactions with the drugs aspirin, warfarin, tamoxifen and cyclosporine A that may alter their activities. For the majority of drugs, however, interactions with vitamin E, even at high doses, have not been observed and are thus unlikely.

  8. Molecular basis of virulence in Staphylococcus aureus mastitis.

    Directory of Open Access Journals (Sweden)

    Caroline Le Maréchal

    Full Text Available S. aureus is one of the main pathogens involved in ruminant mastitis worldwide. The severity of staphylococcal infection is highly variable, ranging from subclinical to gangrenous mastitis. This work represents an in-depth characterization of S. aureus mastitis isolates to identify bacterial factors involved in severity of mastitis infection.We employed genomic, transcriptomic and proteomic approaches to comprehensively compare two clonally related S. aureus strains that reproducibly induce severe (strain O11 and milder (strain O46 mastitis in ewes. Variation in the content of mobile genetic elements, iron acquisition and metabolism, transcriptional regulation and exoprotein production was observed. In particular, O11 produced relatively high levels of exoproteins, including toxins and proteases known to be important in virulence. A characteristic we observed in other S. aureus strains isolated from clinical mastitis cases.Our data are consistent with a dose-dependant role of some staphylococcal factors in the hypervirulence of strains isolated from severe mastitis. Mobile genetic elements, transcriptional regulators, exoproteins and iron acquisition pathways constitute good targets for further research to define the underlying mechanisms of mastitis severity.

  9. Cellular and molecular basis of RV hypertrophy in congenital heart disease.

    Science.gov (United States)

    Iacobazzi, D; Suleiman, M-S; Ghorbel, M; George, S J; Caputo, M; Tulloh, R M

    2016-01-01

    RV hypertrophy (RVH) is one of the triggers of RV failure in congenital heart disease (CHD). Therefore, improving our understanding of the cellular and molecular basis of this pathology will help in developing strategic therapeutic interventions to enhance patient benefit in the future. This review describes the potential mechanisms that underlie the transition from RVH to RV failure. In particular, it addresses structural and functional remodelling that encompass contractile dysfunction, metabolic changes, shifts in gene expression and extracellular matrix remodelling. Both ischaemic stress and reactive oxygen species production are implicated in triggering these changes and will be discussed. Finally, RV remodelling in response to various CHDs as well as the potential role of biomarkers will be addressed. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  10. Biochemical basis of drought tolerance in hybrid Populus grown under field production conditions. CRADA final report

    Energy Technology Data Exchange (ETDEWEB)

    Tschaplinski, T.J.; Tuskan, G.A. [Oak Ridge National Lab., TN (United States); Wierman, C. [Boise Cascade Corp., Wallula, WA (United States)

    1997-04-01

    The purpose of this cooperative effort was to assess the use of osmotically active compounds as molecular selection criteria for drought tolerance in Populus in a large-scale field trial. It is known that some plant species, and individuals within a plant species, can tolerate increasing stress associated with reduced moisture availability by accumulating solutes. The biochemical matrix of such metabolites varies among species and among individuals. The ability of Populus clones to tolerate drought has equal value to other fiber producers, i.e., the wood products industry, where irrigation is used in combination with other cultural treatments to obtain high dry weight yields. The research initially involved an assessment of drought stress under field conditions and characterization of changes in osmotic constitution among the seven clones across the six moisture levels. The near-term goal was to provide a mechanistic basis for clonal differences in productivity under various irrigation treatments over time.

  11. Molecular Basis of Clay Mineral Structure and Dynamics in Subsurface Engineering Applications

    Science.gov (United States)

    Cygan, R. T.

    2015-12-01

    Clay minerals and their interfaces play an essential role in many geochemical, environmental, and subsurface engineering applications. Adsorption, dissolution, precipitation, nucleation, and growth mechanisms, in particular, are controlled by the interplay of structure, thermodynamics, kinetics, and transport at clay mineral-water interfaces. Molecular details of these processes are typically beyond the sensitivity of experimental and analytical methods, and therefore require accurate models and simulations. Also, basal surfaces and interlayers of clay minerals provide constrained interfacial environments to facilitate the evaluation of these complex processes. We have developed and used classical molecular and quantum methods to examine the complex behavior of clay mineral-water interfaces and dynamics of interlayer species. Bulk structures, swelling behavior, diffusion, and adsorption processes are evaluated and compared to experimental and spectroscopic findings. Analysis of adsorption mechanisms of radionuclides on clay minerals provides a scientific basis for predicting the suitability of engineered barriers associated with nuclear waste repositories and the fate of contaminants in the environment. Similarly, the injection of supercritical carbon dioxide into geological reservoirs—to mitigate the impact of climate change—is evaluated by molecular models of multi-fluid interactions with clay minerals. Molecular dynamics simulations provide insights into the wettability of different fluids—water, electrolyte solutions, and supercritical carbon dioxide—on clay surfaces, and which ultimately affects capillary fluid flow and the integrity of shale caprocks. This work is supported as part of Center for Frontiers of Subsurface Energy Security, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science and by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, Geosciences Research Program

  12. Reactor safety under design basis flood condition for inland sites

    International Nuclear Information System (INIS)

    Hajela, S.; Bajaj, S.S.; Samota, A.; Verma, U.S.P.; Warudkar, A.S.

    2002-01-01

    Full text: In June 1994, there was an incident of flooding at Kakrapar Atomic Power Station (KAPS) due to combination of heavy rains and mechanical failure in the operation of gates at the adjoining weir. An indepth review of the incident was carried out and a number of flood protection measures were recommended and were implemented at site. As part of this review, a safety analysis was also done to demonstrate reactor safety with a series of failures considered in the flood protection features. For each inland NPP site, as part of design, different flood scenarios are analysed to arrive at design basis flood (DBF) level. This level is estimated based on worst combination of heavy local precipitation, flooding in river, failure of upstream/downstream water control structures

  13. The Dirac Equation in the algebraic approximation. VII. A comparison of molecular finite difference and finite basis set calculations using distributed Gaussian basis sets

    NARCIS (Netherlands)

    Quiney, H. M.; Glushkov, V. N.; Wilson, S.; Sabin,; Brandas, E

    2001-01-01

    A comparison is made of the accuracy achieved in finite difference and finite basis set approximations to the Dirac equation for the ground state of the hydrogen molecular ion. The finite basis set calculations are carried out using a distributed basis set of Gaussian functions the exponents and

  14. Molecular basis of Acute Myelogenous Leukemia As bases moleculares da leucemia mielóide aguda

    Directory of Open Access Journals (Sweden)

    Eduardo M. Rego

    2002-01-01

    Full Text Available Acute Myelogenous Leukemia (AML is frequently associated with recurring chromosomal translocations, which lead to the fusion of two genes encoding transcription factors. As the moieties of these fusion proteins retain part of the functional domains of the wild-type proteins, they may interfere directly or indirectly with the transcriptional regulation of the leukemic cell, conferring survival advantage. The majority of the transcription factors commonly involved in recurring chromosomal translocations may be grouped in one of the following families: core binding factor (CBF, retinoic acid receptor alpha (RARalpha, homeobox (HOX family, and mixed lineage leukemia (MLL. In vivo analysis of the molecular basis of leukemogenesis through the generation of transgenic mouse models revealed that a common theme is the recruitment of transcriptional co-activators and co-repressors by these fusion proteins. However, the expression of the fusion protein is not sufficient to induce full blown leukemia, as evidenced in part by the long latencies required for disease development in the transgenic models of leukemia, and therefore, second mutagenic events may contribute to AML pathogenesis.A leucemia mielóide aguda (LMA está freqüentemente associada a translocações cromossômicas recorrentes. Em muitos casos, os genes presentes nos pontos de quebra cromossômica são conhecidos e, quase todos codificam para fatores de transcrição. O gene híbrido, resultante da justaposição de exons de genes distintos, codifica para proteínas de fusão. Como estas retêm a maior parte dos domínios funcionais das proteínas selvagens, elas interferem direta ou indiretamente com regulação da transcrição gênica, conferindo vantagem à sobrevivência das células leucêmicas. A maioria dos fatores de transcrição afetados pelas translocações cromossômicas associadas a LMA pode ser agrupada numa das seguintes famílias: dos core binding factors (CBF, do receptor

  15. Separation of both fibrous and globular proteins on the basis of molecular weight using high-performance size exclusion chromatography.

    Science.gov (United States)

    Barden, J A

    1983-11-01

    A high-performance size exclusion liquid chromatographic system has been used to separate proteins with different shapes solely on the basis of their molecular weights. After the effects of ionic and hydrophobic interactions with the stationary phase have been overcome, protein elution is normally governed by their effective size in solution. Conditions are described under which proteins, with isoelectric points within the normal operating pH range of the columns, are eluted independent of their Stokes' radii. Even fibrous proteins with axial ratios of 50 elute according to their known molecular weights over the range 2000-2,000,000.

  16. Molecular Basis of β-Thalassemia Intermedia in Erbil Province of Iraqi Kurdistan.

    Science.gov (United States)

    Shamoon, Rawand P; Al-Allawi, Nasir A S; Cappellini, Maria D; Di Pierro, Elena; Brancaleoni, Valentina; Granata, Francesca

    2015-01-01

    β-Thalassemia intermedia (β-TI) is a clinical term describing a range of clinical phenotypes that are intermediate in severity between the carrier state and β-thalassemia major (β-TM). To characterize the molecular basis of β-TI in Erbil Province, Northern Iraq, 83 unrelated patients were investigated. Detection of β-globin gene mutations was carried out by reverse hybridization assay and direct gene sequencing. All patients were screened for the XmnI polymorphism by direct sequencing of HBG2 ((G)γ promoter gene). Detection of α-globin gene deletions and triplication was carried out using the reverse hybridization assay. Four main molecular patterns were identified in association with the β-TI phenotype, namely: β(+)/β(+) (38.5%), β(+)/β(0) (21.6%), β(0)/β(0) (31.3%), and β(0)/wild type (8.4%). IVS-I-6 (T > C) was the most frequently encountered mutation (55 alleles, 34.6%), followed by IVS-II-1 (G > A) and codon 8 (-AA); furthermore, we report for the first time from Iraq two β(+) mutations, -87 (C > G) and 5' untranslated region (5'UTR) +22 (G > A). The XmnI polymorphism was detected in 47.0% of patients, mainly in association with the β(0)/β(0) genotype. The α-globin gene deletions were encountered in four cases, including one case with (- -(FIL)) double gene deletion, a report that is the first from our country. The α-globin gene triplication was detected in five of the seven heterozygous β-thalassemia (β-thal) patients. Similar to other Mediterranean countries, inheritance of mild β-globin mutations was the main molecular pattern underlying β-TI in our patients followed by the ameliorating effect of the XmnI polymorphism.

  17. Library of molecular associations: curating the complex molecular basis of liver diseases

    Directory of Open Access Journals (Sweden)

    Maass Thorsten

    2010-03-01

    Full Text Available Abstract Background Systems biology approaches offer novel insights into the development of chronic liver diseases. Current genomic databases supporting systems biology analyses are mostly based on microarray data. Although these data often cover genome wide expression, the validity of single microarray experiments remains questionable. However, for systems biology approaches addressing the interactions of molecular networks comprehensive but also highly validated data are necessary. Results We have therefore generated the first comprehensive database for published molecular associations in human liver diseases. It is based on PubMed published abstracts and aimed to close the gap between genome wide coverage of low validity from microarray data and individual highly validated data from PubMed. After an initial text mining process, the extracted abstracts were all manually validated to confirm content and potential genetic associations and may therefore be highly trusted. All data were stored in a publicly available database, Library of Molecular Associations http://www.medicalgenomics.org/databases/loma/news, currently holding approximately 1260 confirmed molecular associations for chronic liver diseases such as HCC, CCC, liver fibrosis, NASH/fatty liver disease, AIH, PBC, and PSC. We furthermore transformed these data into a powerful resource for molecular liver research by connecting them to multiple biomedical information resources. Conclusion Together, this database is the first available database providing a comprehensive view and analysis options for published molecular associations on multiple liver diseases.

  18. Systematic determination of extended atomic orbital basis sets and application to molecular SCF and MCSCF calculations

    Energy Technology Data Exchange (ETDEWEB)

    Feller, D.F.

    1979-01-01

    The behavior of the two exponential parameters in an even-tempered gaussian basis set is investigated as the set optimally approaches an integral transform representation of the radial portion of atomic and molecular orbitals. This approach permits a highly accurate assessment of the Hartree-Fock limit for atoms and molecules.

  19. Molecular basis of the mutagenic and lethal effects of ultraviolet irradiation

    International Nuclear Information System (INIS)

    Grossman, L.

    1982-01-01

    Using bacteria as a model, the molecular basis of the mutagenic and lethal effects of uv radiation is being studied. Attention is focused on the mechanism of action of uv-1 specific endonucleases in the repair of damaged DNA. The isolation and identification of similar enzymes in human cells are being conducted concurrently

  20. Localized orbitals vs. pseudopotential-plane waves basis sets: performances and accuracy for molecular magnetic systems

    International Nuclear Information System (INIS)

    Massobrio, C.; Ruiz, E.

    2003-01-01

    Density functional theory, in combination with a) a careful choice of the exchange-correlation part of the total energy and b) localized basis sets for the electronic orbital, has become the method of choice for calculating the exchange-couplings in magnetic molecular complexes. Orbital expansion on plane waves can be seen as an alternative basis set especially suited to allow optimization of newly synthesized materials of unknown geometries. However, little is known on the predictive power of this scheme to yield quantitative values for exchange coupling constants J as small as a few hundredths of eV (50-300 cm -1 ). We have used density functional theory and a plane waves basis set to calculate the exchange couplings J of three homodinuclear Cu-based molecular complexes with experimental values ranging from +40 cm -1 to -300 cm -1 . The plane waves basis set proves as accurate as the localized basis set, thereby suggesting that this approach can be reliably employed to predict and rationalize the magnetic properties of molecular-based materials. (author)

  1. Evolution of molecular phenotypes under stabilizing selection

    International Nuclear Information System (INIS)

    Nourmohammad, Armita; Schiffels, Stephan; Lässig, Michael

    2013-01-01

    Molecular phenotypes are important links between genomic information and organismic functions, fitness, and evolution. Complex phenotypes, which are also called quantitative traits, often depend on multiple genomic loci. Their evolution builds on genome evolution in a complicated way, which involves selection, genetic drift, mutations and recombination. Here we develop a coarse-grained evolutionary statistics for phenotypes, which decouples from details of the underlying genotypes. We derive approximate evolution equations for the distribution of phenotype values within and across populations. This dynamics covers evolutionary processes at high and low recombination rates, that is, it applies to sexual and asexual populations. In a fitness landscape with a single optimal phenotype value, the phenotypic diversity within populations and the divergence between populations reach evolutionary equilibria, which describe stabilizing selection. We compute the equilibrium distributions of both quantities analytically and we show that the ratio of mean divergence and diversity depends on the strength of selection in a universal way: it is largely independent of the phenotype’s genomic encoding and of the recombination rate. This establishes a new method for the inference of selection on molecular phenotypes beyond the genome level. We discuss the implications of our findings for the predictability of evolutionary processes. (paper)

  2. Homozygous deletion in MYL9 expands the molecular basis of megacystis-microcolon-intestinal hypoperistalsis syndrome.

    Science.gov (United States)

    Moreno, Carolina Araujo; Sobreira, Nara; Pugh, Elizabeth; Zhang, Peng; Steel, Gary; Torres, Fábio Rossi; Cavalcanti, Denise Pontes

    2018-05-01

    Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a severe disease characterized by functional obstruction in the urinary and gastrointestinal tract. The molecular basis of this condition started to be defined recently, and the genes related to the syndrome (ACTG2-heterozygous variant in sporadic cases; and MYH11 (myosin heavy chain 11), LMOD1 (leiomodin 1) and MYLK (myosin light chain (MLC) kinase)-autosomal recessive inheritance), encode proteins involved in the smooth muscle contraction, supporting a myopathic basis for the disease. In the present article, we described a family with two affected siblings with MMIHS born to consanguineous parents and the molecular investigation performed to define the genetic etiology. Previous whole exome sequencing of the affected child and parents did not identify a candidate gene for the disease in this family, but now we present a reanalysis of the data that led to the identification of a homozygous deletion encompassing the last exon of MYL9 (myosin regulatory light chain 9) in the affected individual. MYL9 gene encodes a regulatory myosin MLC and the phosphorylation of this protein is a crucial step in the contraction process of smooth muscle cell. Despite the absence of human or animal phenotype related to MYL9, a cause-effect relationship between MYL9 and the MMIHS seems biologically plausible. The present study reveals a strong candidate gene for autosomal recessive forms of MMIHS, expanding the molecular basis of this disease and reinforces the myopathic basis of this condition.

  3. Localized orbitals vs. pseudopotential-plane waves basis sets: performances and accuracy for molecular magnetic systems

    CERN Document Server

    Massobrio, C

    2003-01-01

    Density functional theory, in combination with a) a careful choice of the exchange-correlation part of the total energy and b) localized basis sets for the electronic orbital, has become the method of choice for calculating the exchange-couplings in magnetic molecular complexes. Orbital expansion on plane waves can be seen as an alternative basis set especially suited to allow optimization of newly synthesized materials of unknown geometries. However, little is known on the predictive power of this scheme to yield quantitative values for exchange coupling constants J as small as a few hundredths of eV (50-300 cm sup - sup 1). We have used density functional theory and a plane waves basis set to calculate the exchange couplings J of three homodinuclear Cu-based molecular complexes with experimental values ranging from +40 cm sup - sup 1 to -300 cm sup - sup 1. The plane waves basis set proves as accurate as the localized basis set, thereby suggesting that this approach can be reliably employed to predict and r...

  4. Are spontaneous conformational interconversions a molecular basis for long-period oscillations in enzyme activity?

    Science.gov (United States)

    Queiroz-Claret, C; Valon, C; Queiroz, O

    1988-01-01

    An unconventional hypothesis to the molecular basis of enzyme rhythms is that the intrinsic physical instability of the protein molecules which, in an aqueous medium, tend to move continuously from one conformational state to another could lead, in the population of enzyme molecules, to sizeable long-period oscillations in affinity for substrate and sensitivity to ligands and regulatory effects. To investigate this hypothesis, malate dehydrogenase was extracted and purified from leaves of the plant Kalanchoe blossfeldiana. The enzyme solutions were maintained under constant conditions and sampled at regular intervals for up to 40 or 70 h for measurements of activity as a function of substrate concentration, Km for oxaloacetic acid and sensitivity to the action of 2,3-butanedione, a modifier of active site arginyl residues. The results show that continuous slow oscillations in the catalytic capacity of the enzyme occur in all the extracts checked, together with fluctuations in Km. Apparent circadian periodicities were observed in accordance with previous data established during long run (100 h) experiments. The saturation curves for substrate showed multiple kinetic functions, with various pronounced intermediary plateaus and "bumps" depending on the time of sampling. Variation in the response to the effect of butanedione indicated fluctuation in the accessibility to the active site. Taken together, the results suggest that, under constant conditions, the enzyme in solution shifts continuously and reversibly between different configurations. This was confirmed by parallel studies on the proton-NMR spectrum of water aggregates in the enzyme solution and proton exchange rates.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Spectral properties of minimal-basis-set orbitals: Implications for molecular electronic continuum states

    Science.gov (United States)

    Langhoff, P. W.; Winstead, C. L.

    Early studies of the electronically excited states of molecules by John A. Pople and coworkers employing ab initio single-excitation configuration interaction (SECI) calculations helped to simulate related applications of these methods to the partial-channel photoionization cross sections of polyatomic molecules. The Gaussian representations of molecular orbitals adopted by Pople and coworkers can describe SECI continuum states when sufficiently large basis sets are employed. Minimal-basis virtual Fock orbitals stabilized in the continuous portions of such SECI spectra are generally associated with strong photoionization resonances. The spectral attributes of these resonance orbitals are illustrated here by revisiting previously reported experimental and theoretical studies of molecular formaldehyde (H2CO) in combination with recently calculated continuum orbital amplitudes.

  6. A quantum molecular similarity analysis of changes in molecular electron density caused by basis set flotation and electric field application

    Science.gov (United States)

    Simon, Sílvia; Duran, Miquel

    1997-08-01

    Quantum molecular similarity (QMS) techniques are used to assess the response of the electron density of various small molecules to application of a static, uniform electric field. Likewise, QMS is used to analyze the changes in electron density generated by the process of floating a basis set. The results obtained show an interrelation between the floating process, the optimum geometry, and the presence of an external field. Cases involving the Le Chatelier principle are discussed, and an insight on the changes of bond critical point properties, self-similarity values and density differences is performed.

  7. The Molecular Basis of Evolution and Disease: A Cold War Alliance.

    Science.gov (United States)

    Suárez-Díaz, Edna

    2017-03-28

    This paper extends previous arguments against the assumption that the study of variation at the molecular level was instigated with a view to solving an internal conflict between the balance and classical schools of population genetics. It does so by focusing on the intersection of basic research in protein chemistry and the molecular approach to disease with the enactment of global health campaigns during the Cold War period. The paper connects advances in research on protein structure and function as reflected in Christian Anfinsen's The molecular basis of evolution, with a political reading of Emilé Zuckerkandl and Linus Pauling's identification of molecular disease and evolution. Beyond atomic fallout, these advances constituted a rationale for the promotion of genetic surveys of human populations in the Third World, in connection with international health programs. Light is shed not only on the experimental roots of the molecular challenge but on the broader geopolitical context where the rising role of biomedicine and public health (particularly the malaria eradication campaigns) had an impact on evolutionary biology.

  8. Molecular basis of the functional heterogeneity of the muscarinic acetylcholine receptor

    International Nuclear Information System (INIS)

    Numa, S.; Fukuda, K.; Kubo, T.; Maeda, A.; Akiba, I.; Bujo, H.; Nakai, J.; Mishina, M.; Higashida, H.

    1988-01-01

    The muscarinic acetylcholine receptor (mAChR) mediates a variety of cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides, and modulation of potassium channels, through the action of guanine-nucleotide-binding regulatory proteins (G proteins). The question then arises as to whether multiple mAChR species exist that are responsible for the various biochemical and physiological effects. In fact, pharmacologically distinguishable forms of the mAChR occur in different tissues and have been provisionally classified into M 1 (I), M 2 cardiac (II), and M 2 glandular (III) subtypes on the basis of their difference in apparent affinity for antagonists. Here, the authors have made attempts to understand the molecular basis of the functional heterogeneity of the mAChR, using recombinant DNA technology

  9. Gaussian basis sets for use in correlated molecular calculations. IV. Calculation of static electrical response properties

    International Nuclear Information System (INIS)

    Woon, D.E.; Dunning, T.H. Jr.

    1994-01-01

    An accurate description of the electrical properties of atoms and molecules is critical for quantitative predictions of the nonlinear properties of molecules and of long-range atomic and molecular interactions between both neutral and charged species. We report a systematic study of the basis sets required to obtain accurate correlated values for the static dipole (α 1 ), quadrupole (α 2 ), and octopole (α 3 ) polarizabilities and the hyperpolarizability (γ) of the rare gas atoms He, Ne, and Ar. Several methods of correlation treatment were examined, including various orders of Moller--Plesset perturbation theory (MP2, MP3, MP4), coupled-cluster theory with and without perturbative treatment of triple excitations [CCSD, CCSD(T)], and singles and doubles configuration interaction (CISD). All of the basis sets considered here were constructed by adding even-tempered sets of diffuse functions to the correlation consistent basis sets of Dunning and co-workers. With multiply-augmented sets we find that the electrical properties of the rare gas atoms converge smoothly to values that are in excellent agreement with the available experimental data and/or previously computed results. As a further test of the basis sets presented here, the dipole polarizabilities of the F - and Cl - anions and of the HCl and N 2 molecules are also reported

  10. Membrane dynamics of γ-secretase provides a molecular basis for Aβ binding and processing

    DEFF Research Database (Denmark)

    Somavarapu, Arun Kumar; Kepp, Kasper Planeta

    2017-01-01

    and explicit dynamics relevant to substrate processing remain unknown. We report a modeled structure utilizing the optimal multi-template information available, including loops and missing side chains, account of maturation cleavage, and explicit all-atom molecular dynamics in the membrane. We observe three...... interactions and induces shorter residence time and by inference releases Aβ peptides of longer lengths. Our simulations thus provide a molecular basis for substrate processing and changes in the Aβ42/Aβ40 ratio. Accordingly, selective binding to protect the semi-open “innocent” conformation provides......γ-secretase produces β-amyloid (Aβ) within its presenilin (PS1) subunit, mutations in which cause Alzheimer’s disease, and current therapies thus seek to modulate its activity. While the general structure is known from recent electron microscopy studies, direct loop- and membrane-interactions...

  11. On the molecular basis of D-bifunctional protein deficiency type III.

    Directory of Open Access Journals (Sweden)

    Maija L Mehtälä

    Full Text Available Molecular basis of D-bifunctional protein (D-BP deficiency was studied with wild type and five disease-causing variants of 3R-hydroxyacyl-CoA dehydrogenase fragment of the human MFE-2 (multifunctional enzyme type 2 protein. Complementation analysis in vivo in yeast and in vitro enzyme kinetic and stability determinants as well as in silico stability and structural fluctuation calculations were correlated with clinical data of known patients. Despite variations not affecting the catalytic residues, enzyme kinetic performance (K(m, V(max and k(cat of the recombinant protein variants were compromised to a varying extent and this can be judged as the direct molecular cause for D-BP deficiency. Protein stability plays an additional role in producing non-functionality of MFE-2 in case structural variations affect cofactor or substrate binding sites. Structure-function considerations of the variant proteins matched well with the available data of the patients.

  12. Construction of the Fock Matrix on a Grid-Based Molecular Orbital Basis Using GPGPUs.

    Science.gov (United States)

    Losilla, Sergio A; Watson, Mark A; Aspuru-Guzik, Alán; Sundholm, Dage

    2015-05-12

    We present a GPGPU implementation of the construction of the Fock matrix in the molecular orbital basis using the fully numerical, grid-based bubbles representation. For a test set of molecules containing up to 90 electrons, the total Hartree-Fock energies obtained from reference GTO-based calculations are reproduced within 10(-4) Eh to 10(-8) Eh for most of the molecules studied. Despite the very large number of arithmetic operations involved, the high performance obtained made the calculations possible on a single Nvidia Tesla K40 GPGPU card.

  13. Molecular basis of the apolipoprotein H (beta 2-glycoprotein I) protein polymorphism

    DEFF Research Database (Denmark)

    Sanghera, Dharambir K; Kristensen, Torsten; Hamman, Richard F

    1997-01-01

    Apolipoprotein H (apoH, protein; APOH, gene) is considered to be an essential cofactor for the binding of certain antiphospholipid autoantibodies to anionic phospholipids. APOH exhibits a genetically determined structural polymorphism due to the presence of three common alleles (APOH*1, APOH*2...... was observed sporadically in blacks (0.008), it was present at a polymorphic frequency in Hispanics (0.027) and non-Hispanic whites (0.059). The identification of the molecular basis of the APOH protein polymorphism will help to elucidate the structural – functional relationship of apoH in the production...

  14. Venom Resistance as a Model for Understanding the Molecular Basis of Complex Coevolutionary Adaptations.

    Science.gov (United States)

    Holding, Matthew L; Drabeck, Danielle H; Jansa, Sharon A; Gibbs, H Lisle

    2016-11-01

    SynopsisVenom and venom resistance are molecular phenotypes widely considered to have diversified through coevolution between predators and prey. However, while evolutionary and functional studies on venom have been extensive, little is known about the molecular basis, variation, and complexity of venom resistance. We review known mechanisms of venom resistance and relate these mechanisms to their predicted impact on coevolutionary dynamics with venomous enemies. We then describe two conceptual approaches which can be used to examine venom/resistance systems. At the intraspecific level, tests of local adaptation in venom and resistance phenotypes can identify the functional mechanisms governing the outcomes of coevolution. At deeper evolutionary timescales, the combination of phylogenetically informed analyses of protein evolution coupled with studies of protein function promise to elucidate the mode and tempo of evolutionary change on potentially coevolving genes. We highlight case studies that use each approach to extend our knowledge of these systems as well as address larger questions about coevolutionary dynamics. We argue that resistance and venom are phenotypic traits which hold exceptional promise for investigating the mechanisms, dynamics, and outcomes of coevolution at the molecular level. Furthermore, extending the understanding of single gene-for-gene interactions to the whole resistance and venom phenotypes may provide a model system for examining the molecular and evolutionary dynamics of complex multi-gene interactions. © The Author 2016. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

  15. Many-body calculations of molecular electric polarizabilities in asymptotically complete basis sets

    Science.gov (United States)

    Monten, Ruben; Hajgató, Balázs; Deleuze, Michael S.

    2011-10-01

    The static dipole polarizabilities of Ne, CO, N2, F2, HF, H2O, HCN, and C2H2 (acetylene) have been determined close to the Full-CI limit along with an asymptotically complete basis set (CBS), according to the principles of a Focal Point Analysis. For this purpose the results of Finite Field calculations up to the level of Coupled Cluster theory including Single, Double, Triple, Quadruple and perturbative Pentuple excitations [CCSDTQ(P)] were used, in conjunction with suited extrapolations of energies obtained using augmented and doubly-augmented Dunning's correlation consistent polarized valence basis sets of improving quality. The polarizability characteristics of C2H4 (ethylene) and C2H6 (ethane) have been determined on the same grounds at the CCSDTQ level in the CBS limit. Comparison is made with results obtained using lower levels in electronic correlation, or taking into account the relaxation of the molecular structure due to an adiabatic polarization process. Vibrational corrections to electronic polarizabilities have been empirically estimated according to Born-Oppenheimer Molecular Dynamical simulations employing Density Functional Theory. Confrontation with experiment ultimately indicates relative accuracies of the order of 1 to 2%.

  16. An in silico study of the molecular basis of B-RAF activation and conformational stability

    Directory of Open Access Journals (Sweden)

    Jónsdóttir Svava

    2009-07-01

    Full Text Available Abstract Background B-RAF kinase plays an important role both in tumour induction and maintenance in several cancers and it is an attractive new drug target. However, the structural basis of the B-RAF activation is still not well understood. Results In this study we suggest a novel molecular basis of B-RAF activation based on molecular dynamics (MD simulations of B-RAFWT and the B-RAFV600E, B-RAFK601E and B-RAFD594V mutants. A strong hydrogen bond network was identified in B-RAFWT in which the interactions between Lys601 and the well known catalytic residues Lys483, Glu501 and Asp594 play an important role. It was found that several mutations, which directly or indirectly destabilized the interactions between these residues within this network, contributed to the changes in B-RAF activity. Conclusion Our results showed that the above mechanisms lead to the disruption of the electrostatic interactions between the A-loop and the αC-helix in the activating mutants, which presumably contribute to the flipping of the activation segment to an active form. Conversely, in the B-RAFD594V mutant that has impaired kinase activity, and in B-RAFWT these interactions were strong and stabilized the kinase inactive form.

  17. An in silico study of the molecular basis of B-RAF activation and conformational stability

    DEFF Research Database (Denmark)

    Fratev, Filip Filipov; Jonsdottir, Svava Osk

    2009-01-01

    B-RAF kinase plays an important role both in tumour induction and maintenance in several cancers and it is an attractive new drug target. However, the structural basis of the B-RAF activation is still not well understood. RESULTS: In this study we suggest a novel molecular basis of B-RAF activation...... based on molecular dynamics (MD) simulations of B-RAFWT and the B-RAFV600E, B-RAFK601E and B-RAFD594V mutants. A strong hydrogen bond network was identified in B-RAFWT in which the interactions between Lys601 and the well known catalytic residues Lys483, Glu501 and Asp594 play an important role...... the A-loop and the alphaC-helix in the activating mutants, which presumably contribute to the flipping of the activation segment to an active form. Conversely, in the B-RAFD594V mutant that has impaired kinase activity, and in B-RAFWT these interactions were strong and stabilized the kinase inactive...

  18. Auxiliary-field quantum Monte Carlo calculations of molecular systems with a Gaussian basis

    International Nuclear Information System (INIS)

    Al-Saidi, W.A.; Zhang Shiwei; Krakauer, Henry

    2006-01-01

    We extend the recently introduced phaseless auxiliary-field quantum Monte Carlo (QMC) approach to any single-particle basis and apply it to molecular systems with Gaussian basis sets. QMC methods in general scale favorably with the system size as a low power. A QMC approach with auxiliary fields, in principle, allows an exact solution of the Schroedinger equation in the chosen basis. However, the well-known sign/phase problem causes the statistical noise to increase exponentially. The phaseless method controls this problem by constraining the paths in the auxiliary-field path integrals with an approximate phase condition that depends on a trial wave function. In the present calculations, the trial wave function is a single Slater determinant from a Hartree-Fock calculation. The calculated all-electron total energies show typical systematic errors of no more than a few millihartrees compared to exact results. At equilibrium geometries in the molecules we studied, this accuracy is roughly comparable to that of coupled cluster with single and double excitations and with noniterative triples [CCSD(T)]. For stretched bonds in H 2 O, our method exhibits a better overall accuracy and a more uniform behavior than CCSD(T)

  19. Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

    Science.gov (United States)

    Pamenter, Matthew E.; Powell, Frank L.

    2016-01-01

    Ventilatory responses to hypoxia vary widely depending on the pattern and length of hypoxic exposure. Acute, prolonged, or intermittent hypoxic episodes can increase or decrease breathing for seconds to years, both during the hypoxic stimulus, and also after its removal. These myriad effects are the result of a complicated web of molecular interactions that underlie plasticity in the respiratory control reflex circuits and ultimately control the physiology of breathing in hypoxia. Since the time domains of the physiological hypoxic ventilatory response (HVR) were identified, considerable research effort has gone toward elucidating the underlying molecular mechanisms that mediate these varied responses. This research has begun to describe complicated and plastic interactions in the relay circuits between the peripheral chemoreceptors and the ventilatory control circuits within the central nervous system. Intriguingly, many of these molecular pathways seem to share key components between the different time domains, suggesting that varied physiological HVRs are the result of specific modifications to overlapping pathways. This review highlights what has been discovered regarding the cell and molecular level control of the time domains of the HVR, and highlights key areas where further research is required. Understanding the molecular control of ventilation in hypoxia has important implications for basic physiology and is emerging as an important component of several clinical fields. PMID:27347896

  20. Laplace-transformed multi-reference second-order perturbation theories in the atomic and active molecular orbital basis

    NARCIS (Netherlands)

    Helmich-Paris, B.; Knecht, Stefan

    2017-01-01

    In the present article, we show how to formulate the partially contracted n-electron valence second-order perturbation theory (NEVPT2) energies in the atomic and active molecular orbital basis by employing the Laplace transformation of orbital-energy denominators (OEDs). As atomic-orbital (AO) basis

  1. Characterization of hairless (Hr) and FGF5 genes provides insights into the molecular basis of hair loss in cetaceans.

    Science.gov (United States)

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

    2013-02-09

    Hair is one of the main distinguishing characteristics of mammals and it has many important biological functions. Cetaceans originated from terrestrial mammals and they have evolved a series of adaptations to aquatic environments, which are of evolutionary significance. However, the molecular mechanisms underlying their aquatic adaptations have not been well explored. This study provided insights into the evolution of hair loss during the transition from land to water by investigating and comparing two essential regulators of hair follicle development and hair follicle cycling, i.e., the Hairless (Hr) and FGF5 genes, in representative cetaceans and their terrestrial relatives. The full open reading frame sequences of the Hr and FGF5 genes were characterized in seven cetaceans. The sequence characteristics and evolutionary analyses suggested the functional loss of the Hr gene in cetaceans, which supports the loss of hair during their full adaptation to aquatic habitats. By contrast, positive selection for the FGF5 gene was found in cetaceans where a series of positively selected amino acid residues were identified. This is the first study to investigate the molecular basis of the hair loss in cetaceans. Our investigation of Hr and FGF5, two indispensable regulators of the hair cycle, provide some new insights into the molecular basis of hair loss in cetaceans. The results suggest that positive selection for the FGF5 gene might have promoted the termination of hair growth and early entry into the catagen stage of hair follicle cycling. Consequently, the hair follicle cycle was disrupted and the hair was lost completely due to the loss of the Hr gene function in cetaceans. This suggests that cetaceans have evolved an effective and complex mechanism for hair loss.

  2. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancer

    NARCIS (Netherlands)

    Heger, Michal; van Golen, Rowan F.; Broekgaarden, Mans; Michel, Martin C.

    2014-01-01

    This review addresses the oncopharmacological properties of curcumin at the molecular level. First, the interactions between curcumin and its molecular targets are addressed on the basis of curcumin's distinct chemical properties, which include H-bond donating and accepting capacity of the

  3. "The molecular basis of aging": the Boehringer Ingelheim Fonds 95th International Titisee Conference.

    Science.gov (United States)

    Garinis, George A; Patil, Christopher K; Schumacher, Björn

    2007-01-01

    Nearly 20 years ago, researchers discovered that lifespan can be extended by single-gene mutations in the nematode worm Caenorhabditis elegans. Further studies revealed that the mechanisms governing aging in the smallest organisms have been evolutionarily conserved and may operate in human beings. Since then, the field of biogerontology has expanded considerably, learning from - and contributing to - such disparate fields as cell signaling, metabolism, endocrinology, and a wide range of human diseases including cancer. To date, newly discovered connections and novel interdisciplinary approaches gradually unify what once seemed unrelated observations between seemingly disparate research areas. While this unification is far from complete, several overlapping themes have clearly emerged. At the 95th International Titisee Conference, devoted to "The Molecular Basis of Aging," 60 of the world's pre-eminent biogerontologists shared their most recent findings in the biology of aging, and discussed interdisciplinary connections between diverse fields.

  4. Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments.

    Science.gov (United States)

    Barski, Michal; Brennan, Benjamin; Miller, Ona K; Potter, Jane A; Vijayakrishnan, Swetha; Bhella, David; Naismith, James H; Elliott, Richard M; Schwarz-Linek, Ulrich

    2017-09-15

    Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83-248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence.

  5. Molecular basis for the presence of glycosylated onco-foetal fibronectin in oral carcinomas

    DEFF Research Database (Denmark)

    Wandall, Hans H; Dabelsteen, Sally; Sørensen, Jens Ahm

    2007-01-01

    spliced IIICS region. Using cell culture experiments, immunohistochemical staining of primary tissue, and RT-PCR of tumour cells isolated by laser capture techniques we have examined the molecular basis for the production of GOF in oral carcinomas. Immuno-histochemical investigation confirmed the stromal......Glycosylated onco-foetal fibronectin (GOF) deposited in the stroma of oral squamous cell carcinomas correlates with survival. One of the two polypeptide GalNAc-transferases, GalNAc-T3 or GalNAc-T6, is required for the biosynthesis of GOF by the initiation of a unique O-glycan in the alternative...... deposition of GOF in oral carcinomas. However, neither GalNAc-T3 nor GalNAc-T6 could be detected in stromal fibroblasts. In contrast both transferases were present in the oral squamous carcinoma cells, suggesting that GOF is produced by the oral cancer cells and not only the stromal cells. RT-PCR analysis...

  6. Molecular basis of cellular localization of poly C binding protein 1 in neuronal cells

    International Nuclear Information System (INIS)

    Berry, Andrea M.; Flock, Kelly E.; Loh, Horace H.; Ko, Jane L.

    2006-01-01

    Poly C binding protein 1 (PCBP) is involved in the transcriptional regulation of neuronal mu-opioid receptor gene. In this study, we examined the molecular basis of PCBP cellular/nuclear localization in neuronal cells using EGFP fusion protein. PCBP, containing three KH domains and a variable domain, distributed in cytoplasm and nucleus with a preferential nuclear expression. Domain-deletional analyses suggested the requirement of variable and KH3 domains for strong PCBP nuclear expression. Within the nucleus, a low nucleolar PCBP expression was observed, and PCBP variable domain contributed to this restricted nucleolar expression. Furthermore, the punctate nuclear pattern of PCBP was correlated to its single-stranded (ss) DNA binding ability, with both requiring cooperativity of at least three sequential domains. Collectively, certain PCBP domains thus govern its nuclear distribution and transcriptional regulatory activity in the nucleus of neurons, whereas the low nucleolar expression implicates the disengagement of PCBP in the ribosomal RNA synthesis

  7. Molecular basis of hepatic fibrosis and current status of its diagnosis and treatment

    Directory of Open Access Journals (Sweden)

    LI Yan

    2018-01-01

    Full Text Available During the process of acute or chronic liver injury, hepatic stellate cells interact with various types of cells such as hepatic parenchymal cells, Kupffer cells, and liver sinusoidal endothelial cells to mediate extracellular matrix deposition and sinusoid capillarization and thus initiate the process of hepatic fibrosis. The nature of hepatic fibrosis is repair response after liver injury. Liver biopsy is regarded as the gold standard for the diagnosis of hepatic fibrosis; however, it is generally associated with the risk of bleeding and even death. Noninvasive diagnostic methods for liver fibrosis mainly include serum biomarkers, imaging techniques, and predictive statistical model, but such methods cannot completely replace liver biopsy. At present, the treatment of hepatic fibrosis focuses on the research and development of new drugs targeting primary disease, hepatic stellate cells, or balance of extracellular matrix synthesis/degradation. The research on the molecular mechanism of hepatic fibrosis provides a solid theoretical basis for exploring the treatment of hepatic fibrosis.

  8. Evaluation of molecular basis of cross reactivity between rye and Bermuda grass pollen allergens.

    Science.gov (United States)

    Tiwari, Ruby; Bhalla, Prem L; Singh, Mohan B

    2009-12-01

    Allergenic cross reactivity between the members of the Pooids (Lolium perenne, Phleum pratense, and Poa pratensis) and Chloridoids (Cynodon dactylon and Paspalum notatum) is well established. Studies using crude extracts in the past have demonstrated limited cross reactivity between the Pooids and the Chloridoids suggesting separate diagnosis and therapy. However, little is known regarding the molecular basis for the limited cross reactivity observed between the 2 groups of grasses. The present study was undertaken to gain insights into the molecular basis of cross allergenicity between the major allergens from rye and Bermuda grass pollens. Immunoblot inhibition tests were carried out to determine the specificity of the proteins involved in cross reactivity. Crude pollen extract and bacterially expressed and purified recombinant Lol p 1and Lol p 5 from rye grass were subjected to cross inhibition experiments with crude and purified recombinant Cyn d 1 from Bermuda grass using sera from patients allergic to rye grass pollen. The immunoblot inhibition studies revealed a high degree of cross inhibition between the group 1 allergens. In contrast, a complete lack of inhibition was observed between Bermuda grass group 1 allergen rCyn d 1, and rye grass group 5 allergen rLol p 5. Crude rye grass extract strongly inhibited IgE reactivity to Bermuda grass, whereas crude Bermuda grass pollen extract showed a weaker inhibition. Our data suggests that a possible explanation for the limited cross reactivity between the Pooids and Chloridoids may, in part, be due to the absence of group 5 allergen from Chloridoid grasses. This approach of using purified proteins may be applied to better characterize the cross allergenicity patterns between different grass pollen allergens.

  9. Molecular basis of differential B-pentamer stability of Shiga toxins 1 and 2.

    Directory of Open Access Journals (Sweden)

    Deborah G Conrady

    2010-12-01

    Full Text Available Escherichia coli strain O157:H7 is a major cause of food poisoning that can result in severe diarrhea and, in some cases, renal failure. The pathogenesis of E. coli O157:H7 is in large part due to the production of Shiga toxin (Stx, an AB(5 toxin that consists of a ribosomal RNA-cleaving A-subunit surrounded by a pentamer of receptor-binding B subunits. There are two major isoforms, Stx1 and Stx2, which differ dramatically in potency despite having 57% sequence identity. Animal studies and epidemiological studies show Stx2 is associated with more severe disease. Although the molecular basis of this difference is unknown, data suggest it is associated with the B-subunit. Mass spectrometry studies have suggested differential B-pentamer stability between Stx1 and Stx2. We have examined the relative stability of the B-pentamers in solution. Analytical ultracentrifugation using purified B-subunits demonstrates that Stx2B, the more deadly isoform, shows decreased pentamer stability compared to Stx1B (EC(50 = 2.3 µM vs. EC(50 = 0.043 µM for Stx1B. X-ray crystal structures of Stx1B and Stx2B identified a glutamine in Stx2 (versus leucine in Stx1 within the otherwise strongly hydrophobic interface between B-subunits. Interchanging these residues switches the stability phenotype of the B-pentamers of Stx1 and Stx2, as demonstrated by analytical ultracentrifugation and circular dichroism. These studies demonstrate a profound difference in stability of the B-pentamers in Stx1 and Stx2, illustrate the mechanistic basis for this differential stability, and provide novel reagents to test the basis for differential pathogenicity of these toxins.

  10. Molecular Basis for Converting (2S-Methylsuccinyl-CoA Dehydrogenase into an Oxidase

    Directory of Open Access Journals (Sweden)

    Simon Burgener

    2017-12-01

    Full Text Available Although flavoenzymes have been studied in detail, the molecular basis of their dioxygen reactivity is only partially understood. The members of the flavin adenosine dinucleotide (FAD-dependent acyl-CoA dehydrogenase and acyl-CoA oxidase families catalyze similar reactions and share common structural features. However, both enzyme families feature opposing reaction specificities in respect to dioxygen. Dehydrogenases react with electron transfer flavoproteins as terminal electron acceptors and do not show a considerable reactivity with dioxygen, whereas dioxygen serves as a bona fide substrate for oxidases. We recently engineered (2S-methylsuccinyl-CoA dehydrogenase towards oxidase activity by rational mutagenesis. Here we characterized the (2S-methylsuccinyl-CoA dehydrogenase wild-type, as well as the engineered (2S-methylsuccinyl-CoA oxidase, in detail. Using stopped-flow UV-spectroscopy and liquid chromatography-mass spectrometry (LC-MS based assays, we explain the molecular base for dioxygen reactivity in the engineered oxidase and show that the increased oxidase function of the engineered enzyme comes at a decreased dehydrogenase activity. Our findings add to the common notion that an increased activity for a specific substrate is achieved at the expense of reaction promiscuity and provide guidelines for rational engineering efforts of acyl-CoA dehydrogenases and oxidases.

  11. Peptide dynamics by molecular dynamics simulation and diffusion theory method with improved basis sets

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Po Jen; Lai, S. K., E-mail: sklai@coll.phy.ncu.edu.tw [Complex Liquids Laboratory, Department of Physics, National Central University, Chungli 320, Taiwan and Molecular Science and Technology Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan (China); Rapallo, Arnaldo [Istituto per lo Studio delle Macromolecole (ISMAC) Consiglio Nazionale delle Ricerche (CNR), via E. Bassini 15, C.A.P 20133 Milano (Italy)

    2014-03-14

    Improved basis sets for the study of polymer dynamics by means of the diffusion theory, and tests on a melt of cis-1,4-polyisoprene decamers, and a toluene solution of a 71-mer syndiotactic trans-1,2-polypentadiene were presented recently [R. Gaspari and A. Rapallo, J. Chem. Phys. 128, 244109 (2008)]. The proposed hybrid basis approach (HBA) combined two techniques, the long time sorting procedure and the maximum correlation approximation. The HBA takes advantage of the strength of these two techniques, and its basis sets proved to be very effective and computationally convenient in describing both local and global dynamics in cases of flexible synthetic polymers where the repeating unit is a unique type of monomer. The question then arises if the same efficacy continues when the HBA is applied to polymers of different monomers, variable local stiffness along the chain and with longer persistence length, which have different local and global dynamical properties against the above-mentioned systems. Important examples of this kind of molecular chains are the proteins, so that a fragment of the protein transthyretin is chosen as the system of the present study. This peptide corresponds to a sequence that is structured in β-sheets of the protein and is located on the surface of the channel with thyroxin. The protein transthyretin forms amyloid fibrils in vivo, whereas the peptide fragment has been shown [C. P. Jaroniec, C. E. MacPhee, N. S. Astrof, C. M. Dobson, and R. G. Griffin, Proc. Natl. Acad. Sci. U.S.A. 99, 16748 (2002)] to form amyloid fibrils in vitro in extended β-sheet conformations. For these reasons the latter is given considerable attention in the literature and studied also as an isolated fragment in water solution where both experimental and theoretical efforts have indicated the propensity of the system to form β turns or α helices, but is otherwise predominantly unstructured. Differing from previous computational studies that employed implicit

  12. Peptide dynamics by molecular dynamics simulation and diffusion theory method with improved basis sets

    International Nuclear Information System (INIS)

    Hsu, Po Jen; Lai, S. K.; Rapallo, Arnaldo

    2014-01-01

    Improved basis sets for the study of polymer dynamics by means of the diffusion theory, and tests on a melt of cis-1,4-polyisoprene decamers, and a toluene solution of a 71-mer syndiotactic trans-1,2-polypentadiene were presented recently [R. Gaspari and A. Rapallo, J. Chem. Phys. 128, 244109 (2008)]. The proposed hybrid basis approach (HBA) combined two techniques, the long time sorting procedure and the maximum correlation approximation. The HBA takes advantage of the strength of these two techniques, and its basis sets proved to be very effective and computationally convenient in describing both local and global dynamics in cases of flexible synthetic polymers where the repeating unit is a unique type of monomer. The question then arises if the same efficacy continues when the HBA is applied to polymers of different monomers, variable local stiffness along the chain and with longer persistence length, which have different local and global dynamical properties against the above-mentioned systems. Important examples of this kind of molecular chains are the proteins, so that a fragment of the protein transthyretin is chosen as the system of the present study. This peptide corresponds to a sequence that is structured in β-sheets of the protein and is located on the surface of the channel with thyroxin. The protein transthyretin forms amyloid fibrils in vivo, whereas the peptide fragment has been shown [C. P. Jaroniec, C. E. MacPhee, N. S. Astrof, C. M. Dobson, and R. G. Griffin, Proc. Natl. Acad. Sci. U.S.A. 99, 16748 (2002)] to form amyloid fibrils in vitro in extended β-sheet conformations. For these reasons the latter is given considerable attention in the literature and studied also as an isolated fragment in water solution where both experimental and theoretical efforts have indicated the propensity of the system to form β turns or α helices, but is otherwise predominantly unstructured. Differing from previous computational studies that employed implicit

  13. Study on effective prestressing effects on concrete containment under the design-basis pressure condition

    International Nuclear Information System (INIS)

    Sun Feng; Pan Rong; Wang Lu; Mao Huan; Yang Yu

    2013-01-01

    Prestressing technology is widely used in nuclear power plant containment building, and the durability of containment structure is affected directly by the distribution and loss of prestressing value under design-basis pressure. Containment structure and the distribution of prestressing system are introduced briefly. Furthermore, the calculating process of horizontal prestressing bunch loss near the equipment hatch hole is put forward in details, and the containment structure prestressing loss when 5-year pressure test is obtained. Based above analysis, the finite element model of the prestressed concrete containment structure is built by using ANSYS code, the prestressing effect on concrete containment is analysed. The results show that most of the design pressure is bore by the prestressing system under the design-basis pressure, so the containment structure is safe. These conclusions are consistent with prestressing containment system design concepts, which can provide reference to the engineering staff. (authors)

  14. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells.

    Science.gov (United States)

    Watanabe, Toshiki

    2017-03-02

    Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor-NF-κB signaling such as PLCG1 , PRKCB , and CARD11 and gain-of function mutations in CCR4 and CCR7 Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1-infected CD4 + T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated. © 2017 by The American Society of Hematology.

  15. Molecular basis for the regulation of hypoxia-inducible factor-1α levels by 2-deoxy-D-ribose.

    Science.gov (United States)

    Ikeda, Ryuji; Tabata, Sho; Tajitsu, Yusuke; Nishizawa, Yukihiko; Minami, Kentaro; Furukawa, Tatsuhiko; Yamamoto, Masatatsu; Shinsato, Yoshinari; Akiyama, Shin-Ichi; Yamada, Katsushi; Takeda, Yasuo

    2013-09-01

    The angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity, inhibits the upregulation of hypoxia-inducible factor (HIF) 1α, BNIP3 and caspase-3 induced by hypoxia. In the present study, we investigated the molecular basis for the suppressive effect of 2-deoxy-D-ribose on the upregulation of HIF-1α. 2-Deoxy-D-ribose enhanced the interaction of HIF-1α and the von Hippel-Lindau (VHL) protein under hypoxic conditions. It did not affect the expression of HIF-1α, prolyl hydroxylase (PHD)1/2/3 and VHL mRNA under normoxic or hypoxic conditions, but enhanced the interaction of HIF-1α and PHD2 under hypoxic conditions. 2-Deoxy-D-ribose also increased the amount of hydroxy-HIF-1α in the presence of the proteasome inhibitor MG-132. The expression levels of TP are elevated in many types of malignant solid tumors and, thus, 2-deoxy-D-ribose generated by TP in these tumors may play an important role in tumor progression by preventing hypoxia-induced apoptosis.

  16. Molecular processes as basis for plasmid-mediated bacterial UV-light resistance and mutagenesis

    International Nuclear Information System (INIS)

    Aleshkin, G.I.; Brukhanskij, G.V.; Skavronskaya, A.G.

    1985-01-01

    The increase of UV-resistance and UV-induced mutagenesis by lambda 1 pint intmid as well as molecular-genetic mechanisms of plasmid participation in reparation and DNA replication and its degradation after UV-irradiation in plasmid cells on pKM101 plasmid model have been investigated. Data testifying to the necessity of intmid integration in chromosome as obligatory stage of intmid participation in increasing UV-resistance of bacterial cells are obtained. It has been found that intmid raises UV-resistance of cells and increases respectively the UV-induced reverants efficiency. On the basis of the experiment data the conclusion is drawn that the intmid capacity to raise UV-resistance and, possibly, mutagenesis is bound not only with its integration into chromosome but also with pol A + chromosome replication by dependendent imtmid replication complex. It is shown that pKM101 plasmid ensures functioning in E coli cells of inducible, chloroamphenicol-resistant DNA replication, highly resistant to UV-light harmful effect and that the volume of excision reparation in E. coli cells carrying pKM101 plasmid is increased as compared with the volume of reparation in plasmid legs cells. The combination of the data obtained gives grounds to the authors to assume that inducible replication, inducible reparation of DNA and inducible decrease of DNA degradation determined by pKM101 plasmid may serve as recA + lexA + basis dependent increase of UV-resistance and mutagenesis and that these processes provide the possibility of functioning of integrative replication mechanism of plasmid participation in ensuring UV-resistance and mutagenesis of plants

  17. The molecular basis of low activity levels of coagulation factor VII: a Brazilian cohort.

    Science.gov (United States)

    Rabelo, F Y; Jardim, L L; Landau, M B; Gadelha, T; Corrêa, M F B; Pereira, I F M; Rezende, S M

    2015-09-01

    Inherited factor VII (FVII) deficiency is the most common among the rare bleeding disorders. It is transmitted as an autosomal recessive inheritance, due to mutations in the FVII gene (F7). Molecular studies of FVII deficiency are rare in non-Caucasian populations. The aim of the study was to evaluate the molecular basis behind low levels of FVII activity (FVII:C) levels in a cohort of Brazilian patients. A total of 34 patients with low FVII levels were clinically evaluated and submitted to laboratory tests, among these, prothrombin time and FVII:C, with different thromboplastins. All exons and intron/exon boundaries of F7 were amplified and sequenced. A total of 14 genetic alterations were identified, of which six were described previously, c.1091G>A, c.1151C>T, c.-323_-313insCCTATATCCT, c.285G>A, c.525C>T, c.1238G>A and eight (54.0%) and eight were new, c.128G>A, c.252C>T, c.348G>A, c.417G>A, c.426G>A, c.745_747delGTG, c.843G>A and c.805+52C>T. In addition to the mutation c.1091G>A, known as FVII Padua, the mutation c.1151C>T also presented discrepant FVII:C levels when tested with human and rabbit brain thromboplastin. There was no association between phenotype and genotype. Most of the identified genetic alterations found were polymorphisms. Low levels of FVII:C in this population were mostly related to polymorphisms in F7 and associated with a mild clinical phenotype. Mutation c.1151C>T was associated with discrepant levels of FVII:C using different thromboplastins, such as reported with FVII Padua. © 2015 John Wiley & Sons Ltd.

  18. The Burmese python genome reveals the molecular basis for extreme adaptation in snakes.

    Science.gov (United States)

    Castoe, Todd A; de Koning, A P Jason; Hall, Kathryn T; Card, Daren C; Schield, Drew R; Fujita, Matthew K; Ruggiero, Robert P; Degner, Jack F; Daza, Juan M; Gu, Wanjun; Reyes-Velasco, Jacobo; Shaney, Kyle J; Castoe, Jill M; Fox, Samuel E; Poole, Alex W; Polanco, Daniel; Dobry, Jason; Vandewege, Michael W; Li, Qing; Schott, Ryan K; Kapusta, Aurélie; Minx, Patrick; Feschotte, Cédric; Uetz, Peter; Ray, David A; Hoffmann, Federico G; Bogden, Robert; Smith, Eric N; Chang, Belinda S W; Vonk, Freek J; Casewell, Nicholas R; Henkel, Christiaan V; Richardson, Michael K; Mackessy, Stephen P; Bronikowski, Anne M; Bronikowsi, Anne M; Yandell, Mark; Warren, Wesley C; Secor, Stephen M; Pollock, David D

    2013-12-17

    Snakes possess many extreme morphological and physiological adaptations. Identification of the molecular basis of these traits can provide novel understanding for vertebrate biology and medicine. Here, we study snake biology using the genome sequence of the Burmese python (Python molurus bivittatus), a model of extreme physiological and metabolic adaptation. We compare the python and king cobra genomes along with genomic samples from other snakes and perform transcriptome analysis to gain insights into the extreme phenotypes of the python. We discovered rapid and massive transcriptional responses in multiple organ systems that occur on feeding and coordinate major changes in organ size and function. Intriguingly, the homologs of these genes in humans are associated with metabolism, development, and pathology. We also found that many snake metabolic genes have undergone positive selection, which together with the rapid evolution of mitochondrial proteins, provides evidence for extensive adaptive redesign of snake metabolic pathways. Additional evidence for molecular adaptation and gene family expansions and contractions is associated with major physiological and phenotypic adaptations in snakes; genes involved are related to cell cycle, development, lungs, eyes, heart, intestine, and skeletal structure, including GRB2-associated binding protein 1, SSH, WNT16, and bone morphogenetic protein 7. Finally, changes in repetitive DNA content, guanine-cytosine isochore structure, and nucleotide substitution rates indicate major shifts in the structure and evolution of snake genomes compared with other amniotes. Phenotypic and physiological novelty in snakes seems to be driven by system-wide coordination of protein adaptation, gene expression, and changes in the structure of the genome.

  19. Transcriptome analysis of Crossostephium chinensis provides insight into the molecular basis of salinity stress responses.

    Directory of Open Access Journals (Sweden)

    Haiyan Yang

    Full Text Available Soil salinization is becoming a limitation to the utilization of ornamental plants worldwide. Crossostephium chinensis (Linnaeus Makino is often cultivated along the southeast coast of China for its desirable ornamental qualities and high salt tolerance. However, little is known about the genomic background of the salt tolerance mechanism in C. chinensis. In the present study, we used Illumina paired-end sequencing to systematically investigate leaf transcriptomes derived from C. chinensis seedlings grown under normal conditions and under salt stress. A total of 105,473,004 bp of reads were assembled into 163,046 unigenes, of which 65,839 (40.38% of the total and 54,342 (33.32% of the total were aligned in Swiss-Prot and Nr protein, respectively. A total of 11,331 (6.95% differentially expressed genes (DEGs were identified among three comparisons, including 2,239 in 'ST3 vs ST0', 5,880 in 'ST9 vs ST3' and 9,718 in 'ST9 vs ST0', and they were generally classified into 26 Gene Ontology terms and 58 Kyoto Encyclopedia of Genes and Genomes (KEGG pathway terms. Many genes encoding important transcription factors (e.g., WRKY, MYB, and AP2/EREBP and proteins involved in starch and sucrose metabolism, arginine and proline metabolism, plant hormone signal transduction, amino acid biosynthesis, plant-pathogen interactions and carbohydrate metabolism, among others, were substantially up-regulated under salt stress. These genes represent important candidates for studying the salt-response mechanism and molecular biology of C. chinensis and its relatives. Our findings provide a genomic sequence resource for functional genetic assignments in C. chinensis. These transcriptome datasets will help elucidate the molecular mechanisms responsible for salt-stress tolerance in C. chinensis and facilitate the breeding of new stress-tolerant cultivars for high-saline areas using this valuable genetic resource.

  20. Adaptive local basis set for Kohn–Sham density functional theory in a discontinuous Galerkin framework II: Force, vibration, and molecular dynamics calculations

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Gaigong [Computational Research Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Lin, Lin, E-mail: linlin@math.berkeley.edu [Department of Mathematics, University of California, Berkeley, Berkeley, CA 94720 (United States); Computational Research Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Hu, Wei, E-mail: whu@lbl.gov [Computational Research Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Yang, Chao, E-mail: cyang@lbl.gov [Computational Research Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Pask, John E., E-mail: pask1@llnl.gov [Physics Division, Lawrence Livermore National Laboratory, Livermore, CA 94550 (United States)

    2017-04-15

    Recently, we have proposed the adaptive local basis set for electronic structure calculations based on Kohn–Sham density functional theory in a pseudopotential framework. The adaptive local basis set is efficient and systematically improvable for total energy calculations. In this paper, we present the calculation of atomic forces, which can be used for a range of applications such as geometry optimization and molecular dynamics simulation. We demonstrate that, under mild assumptions, the computation of atomic forces can scale nearly linearly with the number of atoms in the system using the adaptive local basis set. We quantify the accuracy of the Hellmann–Feynman forces for a range of physical systems, benchmarked against converged planewave calculations, and find that the adaptive local basis set is efficient for both force and energy calculations, requiring at most a few tens of basis functions per atom to attain accuracies required in practice. Since the adaptive local basis set has implicit dependence on atomic positions, Pulay forces are in general nonzero. However, we find that the Pulay force is numerically small and systematically decreasing with increasing basis completeness, so that the Hellmann–Feynman force is sufficient for basis sizes of a few tens of basis functions per atom. We verify the accuracy of the computed forces in static calculations of quasi-1D and 3D disordered Si systems, vibration calculation of a quasi-1D Si system, and molecular dynamics calculations of H{sub 2} and liquid Al–Si alloy systems, where we show systematic convergence to benchmark planewave results and results from the literature.

  1. The molecular basis for stability of heterochromatin-mediated silencing in mammals

    Directory of Open Access Journals (Sweden)

    Hiragami-Hamada Kyoko

    2009-11-01

    Full Text Available Abstract The archetypal epigenetic phenomenon of position effect variegation (PEV in Drosophila occurs when a gene is brought abnormally close to heterochromatin, resulting in stochastic silencing of the affected gene in a proportion of cells that would normally express it. PEV has been instrumental in unraveling epigenetic mechanisms. Using an in vivo mammalian model for PEV we have extensively investigated the molecular basis for heterochromatin-mediated gene silencing. Here we distinguish 'epigenetic effects' from other cellular differences by studying ex vivo cells that are identical, apart from the expression of the variegating gene which is silenced in a proportion of the cells. By separating cells according to transgene expression we show here that silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3, DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modifications. In contrast, histone H3 acetylation (H3Ac and lysine 4 di or tri methylation (H3K4me2/3 are the predominant modifications associated with expression where we see the gene in a euchromatic compartment. Interestingly, DNA methylation and inaccessibility, rather than H3K9me3, correlated most strongly with resistance to de-repression by cellular activation. These results have important implications for understanding the contribution of specific factors involved in the establishment and maintenance of gene silencing and activation in vivo.

  2. Molecular Basis of Cardioprotective Effect of Antioxidant Vitamins in Myocardial Infarction

    Science.gov (United States)

    Rodrigo, Ramón; Feliú, Felipe; Hasson, Daniel

    2013-01-01

    Acute myocardial infarction (AMI) is the leading cause of mortality worldwide. Major advances in the treatment of acute coronary syndromes and myocardial infarction, using cardiologic interventions, such as thrombolysis or percutaneous coronary angioplasty (PCA) have improved the clinical outcome of patients. Nevertheless, as a consequence of these procedures, the ischemic zone is reperfused, giving rise to a lethal reperfusion event accompanied by increased production of reactive oxygen species (oxidative stress). These reactive species attack biomolecules such as lipids, DNA, and proteins enhancing the previously established tissue damage, as well as triggering cell death pathways. Studies on animal models of AMI suggest that lethal reperfusion accounts for up to 50% of the final size of a myocardial infarct, a part of the damage likely to be prevented. Although a number of strategies have been aimed at to ameliorate lethal reperfusion injury, up to date the beneficial effects in clinical settings have been disappointing. The use of antioxidant vitamins could be a suitable strategy with this purpose. In this review, we propose a systematic approach to the molecular basis of the cardioprotective effect of antioxidant vitamins in myocardial ischemia-reperfusion injury that could offer a novel therapeutic opportunity against this oxidative tissue damage. PMID:23936799

  3. Molecular Basis of Cardioprotective Effect of Antioxidant Vitamins in Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Ramón Rodrigo

    2013-01-01

    Full Text Available Acute myocardial infarction (AMI is the leading cause of mortality worldwide. Major advances in the treatment of acute coronary syndromes and myocardial infarction, using cardiologic interventions, such as thrombolysis or percutaneous coronary angioplasty (PCA have improved the clinical outcome of patients. Nevertheless, as a consequence of these procedures, the ischemic zone is reperfused, giving rise to a lethal reperfusion event accompanied by increased production of reactive oxygen species (oxidative stress. These reactive species attack biomolecules such as lipids, DNA, and proteins enhancing the previously established tissue damage, as well as triggering cell death pathways. Studies on animal models of AMI suggest that lethal reperfusion accounts for up to 50% of the final size of a myocardial infarct, a part of the damage likely to be prevented. Although a number of strategies have been aimed at to ameliorate lethal reperfusion injury, up to date the beneficial effects in clinical settings have been disappointing. The use of antioxidant vitamins could be a suitable strategy with this purpose. In this review, we propose a systematic approach to the molecular basis of the cardioprotective effect of antioxidant vitamins in myocardial ischemia-reperfusion injury that could offer a novel therapeutic opportunity against this oxidative tissue damage.

  4. The molecular basis for stability of heterochromatin-mediated silencing in mammals.

    Science.gov (United States)

    Hiragami-Hamada, Kyoko; Xie, Sheila Q; Saveliev, Alexander; Uribe-Lewis, Santiago; Pombo, Ana; Festenstein, Richard

    2009-11-04

    The archetypal epigenetic phenomenon of position effect variegation (PEV) in Drosophila occurs when a gene is brought abnormally close to heterochromatin, resulting in stochastic silencing of the affected gene in a proportion of cells that would normally express it. PEV has been instrumental in unraveling epigenetic mechanisms. Using an in vivo mammalian model for PEV we have extensively investigated the molecular basis for heterochromatin-mediated gene silencing. Here we distinguish 'epigenetic effects' from other cellular differences by studying ex vivo cells that are identical, apart from the expression of the variegating gene which is silenced in a proportion of the cells. By separating cells according to transgene expression we show here that silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3), DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modifications. In contrast, histone H3 acetylation (H3Ac) and lysine 4 di or tri methylation (H3K4me2/3) are the predominant modifications associated with expression where we see the gene in a euchromatic compartment. Interestingly, DNA methylation and inaccessibility, rather than H3K9me3, correlated most strongly with resistance to de-repression by cellular activation. These results have important implications for understanding the contribution of specific factors involved in the establishment and maintenance of gene silencing and activation in vivo.

  5. 2004 Molecular Basis of Microbial One-Carbon Metabolism Gordon Conference - August 1-6, 2004

    Energy Technology Data Exchange (ETDEWEB)

    Joseph A. Krzycki

    2005-09-15

    The Gordon Research Conference (GRC) on 2004 Molecular Basis of Microbial One-Carbon Metabolism Gordon Conference - August 1-6, 2004 was held at Mount Holyoke College, South Hadley, MA from August 1-6, 2004. The Conference was well-attended with 117 participants (attendees list attached). The attendees represented the spectrum of endeavor in this field coming from academia, industry, and government laboratories, both U.S. and foreign scientists, senior researchers, young investigators, and students. In designing the formal speakers program, emphasis was placed on current unpublished research and discussion of the future target areas in this field. There was a conscious effort to stimulate lively discussion about the key issues in the field today. Time for formal presentations was limited in the interest of group discussions. In order that more scientists could communicate their most recent results, poster presentation time was scheduled. Attached is a copy of the formal schedule and speaker program and the poster program. In addition to these formal interactions, 'free time' was scheduled to allow informal discussions. Such discussions are fostering new collaborations and joint efforts in the field.

  6. MOLECULAR-GENETIC BASIS OF HIGHER PLANTS TOLERANCE TO, AND ACCUMULATION OF, CADMIUM

    Directory of Open Access Journals (Sweden)

    Olga A Kulaeva

    2010-09-01

    Full Text Available Cadmium (Cd is one of the most wide-ranged and dangerous pollutants for all living organisms, including plants. At present time the intensive studies of mechanisms of Cd accumulation in plant tissues and plant tolerance to its toxic influence are performed. Data about variation of Cd tolerance and accumulation traits in natural populations of hyperaccumulators species as well as important crops were obtained. A series of mutants with changed sensitivity to Cd was obtained. In recent decade several classes of proteins involving in cell responses to Cd ions were revealed. An important role of microRNA in plant adaptation to Cd was recently demonstrated. Studies of molecular-genetic mechanisms of Cd accumulation and plant tolerance to it are theoretical basis for development of phytoremediation technologies of soil contaminated with heavy metals and breeding of crop varieties with decreased Cd accumulation.

  7. Exploring the common molecular basis for the universal DNA mutation bias: Revival of Loewdin mutation model

    International Nuclear Information System (INIS)

    Fu, Liang-Yu; Wang, Guang-Zhong; Ma, Bin-Guang; Zhang, Hong-Yu

    2011-01-01

    Highlights: → There exists a universal G:C → A:T mutation bias in three domains of life. → This universal mutation bias has not been sufficiently explained. → A DNA mutation model proposed by Loewdin 40 years ago offers a common explanation. -- Abstract: Recently, numerous genome analyses revealed the existence of a universal G:C → A:T mutation bias in bacteria, fungi, plants and animals. To explore the molecular basis for this mutation bias, we examined the three well-known DNA mutation models, i.e., oxidative damage model, UV-radiation damage model and CpG hypermutation model. It was revealed that these models cannot provide a sufficient explanation to the universal mutation bias. Therefore, we resorted to a DNA mutation model proposed by Loewdin 40 years ago, which was based on inter-base double proton transfers (DPT). Since DPT is a fundamental and spontaneous chemical process and occurs much more frequently within GC pairs than AT pairs, Loewdin model offers a common explanation for the observed universal mutation bias and thus has broad biological implications.

  8. Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport.

    Directory of Open Access Journals (Sweden)

    Igor Arregi

    Full Text Available Nucleophosmin (NPM is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML, where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES. To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs, and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.

  9. Genomic analysis reveals the molecular basis for capsule loss in the group B Streptococcus population.

    Directory of Open Access Journals (Sweden)

    Roberto Rosini

    Full Text Available The human and bovine bacterial pathogen Streptococcus agalactiae (Group B Streptococcus, GBS expresses a thick polysaccharide capsule that constitutes a major virulence factor and vaccine target. GBS can be classified into ten distinct serotypes differing in the chemical composition of their capsular polysaccharide. However, non-typeable strains that do not react with anti-capsular sera are frequently isolated from colonized and infected humans and cattle. To gain a comprehensive insight into the molecular basis for the loss of capsule expression in GBS, a collection of well-characterized non-typeable strains was investigated by genome sequencing. Genome based phylogenetic analysis extended to a wide population of sequenced strains confirmed the recently observed high clonality among GBS lineages mainly containing human strains, and revealed a much higher degree of diversity in the bovine population. Remarkably, non-typeable strains were equally distributed in all lineages. A number of distinct mutations in the cps operon were identified that were apparently responsible for inactivation of capsule synthesis. The most frequent genetic alterations were point mutations leading to stop codons in the cps genes, and the main target was found to be cpsE encoding the portal glycosyl transferase of capsule biosynthesis. Complementation of strains carrying missense mutations in cpsE with a wild-type gene restored capsule expression allowing the identification of amino acid residues essential for enzyme activity.

  10. Molecular basis for genetic deficiency of the second component of human complement

    International Nuclear Information System (INIS)

    Cole, F.S.; Whitehead, A.S.; Auerbach, H.S.; Lint, T.; Zeitz, H.J.; Kilbridge, P.; Colten, H.R.

    1985-01-01

    Genetic deficiency of the second component of complement (C2) is the most common complement-deficiency state among Western Europeans and is frequently associated with autoimmune diseases. To examine the molecular basis of this deficiency, the authors established cultures of blood monocytes from four families with C2-deficient members. Using a hemolytic-plaque assay, [ 35 S]methionine metabolic labeling of proteins in tissue culture and immunoprecipitation, RNA extraction and Northern blot analysis, and DNA restriction-enzyme digestion and Southern blot analysis, the authors found that C2 deficiency is not due to a major gene deletion or rearrangement but is the result of a specific and selective pretranslational regulatory defect in C2 gene expression. This leads to a lack of detectable C2 mRNA and a lack of synthesis of C2 protein. The approach used in this study should prove useful in examination of other plasma protein deficiencies, especially those in which the deficient gene is normally expressed in peripheral-blood monocytes or tissue macrophages and in which ethical considerations preclude the use of liver or other tissue for study

  11. Angiotensin-I converting enzyme (ACE): structure, biological roles, and molecular basis for chloride ion dependence.

    Science.gov (United States)

    Masuyer, Geoffrey; Yates, Christopher J; Sturrock, Edward D; Acharya, K Ravi

    2014-10-01

    Somatic angiotensin-I converting enzyme (sACE) has an essential role in the regulation of blood pressure and electrolyte fluid homeostasis. It is a zinc protease that cleaves angiotensin-I (AngI), bradykinin, and a broad range of other signalling peptides. The enzyme activity is provided by two homologous domains (N- and C-), which display clear differences in substrate specificities and chloride activation. The presence of chloride ions in sACE and its unusual role in activity was identified early on in the characterisation of the enzyme. The molecular mechanisms of chloride activation have been investigated thoroughly through mutagenesis studies and shown to be substrate-dependent. Recent results from X-ray crystallography structural analysis have provided the basis for the intricate interactions between ACE, its substrate and chloride ions. Here we describe the role of chloride ions in human ACE and its physiological consequences. Insights into the chloride activation of the N- and C-domains could impact the design of improved domain-specific ACE inhibitors.

  12. The neuronal and molecular basis of quinine-dependent bitter taste signaling in Drosophila larvae

    Science.gov (United States)

    Apostolopoulou, Anthi A.; Mazija, Lorena; Wüst, Alexander; Thum, Andreas S.

    2014-01-01

    The sensation of bitter substances can alert an animal that a specific type of food is harmful and should not be consumed. However, not all bitter compounds are equally toxic and some may even be beneficial in certain contexts. Thus, taste systems in general may have a broader range of functions than just in alerting the animal. In this study we investigate bitter sensing and processing in Drosophila larvae using quinine, a substance perceived by humans as bitter. We show that behavioral choice, feeding, survival, and associative olfactory learning are all directly affected by quinine. On the cellular level, we show that 12 gustatory sensory receptor neurons that express both GR66a and GR33a are required for quinine-dependent choice and feeding behavior. Interestingly, these neurons are not necessary for quinine-dependent survival or associative learning. On the molecular receptor gene level, the GR33a receptor, but not GR66a, is required for quinine-dependent choice behavior. A screen for gustatory sensory receptor neurons that trigger quinine-dependent choice behavior revealed that a single GR97a receptor gene expressing neuron located in the peripheral terminal sense organ is partially necessary and sufficient. For the first time, we show that the elementary chemosensory system of the Drosophila larva can serve as a simple model to understand the neuronal basis of taste information processing on the single cell level with respect to different behavioral outputs. PMID:24478653

  13. Investigating the molecular basis for heterophylly in the aquatic plant Potamogeton octandrus (Potamogetonaceae with comparative transcriptomics

    Directory of Open Access Journals (Sweden)

    Dingxuan He

    2018-02-01

    Full Text Available Many plant species exhibit different leaf morphologies within a single plant, or heterophylly. The molecular mechanisms regulating this phenomenon, however, have remained elusive. In this study, the transcriptomes of submerged and floating leaves of an aquatic heterophyllous plant, Potamogeton octandrus Poir, at different stages of development, were sequenced using high-throughput sequencing (RNA-Seq, in order to aid gene discovery and functional studies of genes involved in heterophylly. A total of 81,103 unigenes were identified in submerged and floating leaves and 6,822 differentially expressed genes (DEGs were identified by comparing samples at differing time points of development. KEGG pathway enrichment analysis categorized these unigenes into 128 pathways. A total of 24,025 differentially expressed genes were involved in carbon metabolic pathways, biosynthesis of amino acids, ribosomal processes, and plant-pathogen interactions. In particular, KEGG pathway enrichment analysis categorized a total of 70 DEGs into plant hormone signal transduction pathways. The high-throughput transcriptomic results presented here highlight the potential for understanding the molecular mechanisms underlying heterophylly, which is still poorly understood. Further, these data provide a framework to better understand heterophyllous leaf development in P. octandrus via targeted studies utilizing gene cloning and functional analyses.

  14. Mass Spectrometry-based Approaches to Understand the Molecular Basis of Memory

    Directory of Open Access Journals (Sweden)

    Arthur Henriques Pontes

    2016-10-01

    Full Text Available The central nervous system is responsible for an array of cognitive functions such as memory, learning, language and attention. These processes tend to take place in distinct brain regions; yet, they need to be integrated to give rise to adaptive or meaningful behavior. Since cognitive processes result from underlying cellular and molecular changes, genomics and transcriptomics assays have been applied to human and animal models to understand such events. Nevertheless, genes and RNAs are not the end products of most biological functions. In order to gain further insights toward the understanding of brain processes, the field of proteomics has been of increasing importance in the past years. Advancements in liquid chromatography-tandem mass spectrometry (LC-MS/MS have enable the identification and quantification of thousand of proteins with high accuracy and sensitivity, fostering a revolution in the neurosciences. Herein, we review the molecular bases of explicit memory in the hippocampus. We outline the principles of mass spectrometry (MS-based proteomics, highlighting the use of this analytical tool to study memory formation. In addition, we discuss MS-based targeted approaches as the future of protein analysis.

  15. Tests of qualification of national components of nuclear power plants under design basis accident

    International Nuclear Information System (INIS)

    Mesquita, A.Z.

    1990-01-01

    With the purpose of qualifying national components of nuclear power plants, whose working must be maintained during and after an accident, the Thermohydraulic Division of CDTN have done tests to check the equipment stability, under Design Basis Accident conditions. Until this moment, the following components were tested: electrical junction boxes (connectors); coating systems for wall, inside cover and steel containment; hydraulics components of personnel and equipment airlock. This work describes the test instalation, the tests performed and its results. The components tested, in a general way, fulfil the specified requirements. (author) [pt

  16. Proteomic-Biostatistic Integrated Approach for Finding the Underlying Molecular Determinants of Hypertension in Human Plasma.

    Science.gov (United States)

    Gajjala, Prathibha R; Jankowski, Vera; Heinze, Georg; Bilo, Grzegorz; Zanchetti, Alberto; Noels, Heidi; Liehn, Elisa; Perco, Paul; Schulz, Anna; Delles, Christian; Kork, Felix; Biessen, Erik; Narkiewicz, Krzysztof; Kawecka-Jaszcz, Kalina; Floege, Juergen; Soranna, Davide; Zidek, Walter; Jankowski, Joachim

    2017-08-01

    Despite advancements in lowering blood pressure, the best approach to lower it remains controversial because of the lack of information on the molecular basis of hypertension. We, therefore, performed plasma proteomics of plasma from patients with hypertension to identify molecular determinants detectable in these subjects but not in controls and vice versa. Plasma samples from hypertensive subjects (cases; n=118) and controls (n=85) from the InGenious HyperCare cohort were used for this study and performed mass spectrometric analysis. Using biostatistical methods, plasma peptides specific for hypertension were identified, and a model was developed using least absolute shrinkage and selection operator logistic regression. The underlying peptides were identified and sequenced off-line using matrix-assisted laser desorption ionization orbitrap mass spectrometry. By comparison of the molecular composition of the plasma samples, 27 molecular determinants were identified differently expressed in cases from controls. Seventy percent of the molecular determinants selected were found to occur less likely in hypertensive patients. In cross-validation, the overall R 2 was 0.434, and the area under the curve was 0.891 with 95% confidence interval 0.8482 to 0.9349, P hypertensive patients were found to be -2.007±0.3568 and 3.383±0.2643, respectively, P hypertensives and normotensives. The identified molecular determinants may be the starting point for further studies to clarify the molecular causes of hypertension. © 2017 American Heart Association, Inc.

  17. Molecular basis of the evolution of alternative tyrosine biosynthetic routes in plants

    Energy Technology Data Exchange (ETDEWEB)

    Schenck, Craig A.; Holland, Cynthia K.; Schneider, Matthew R.; Men, Yusen; Lee, Soon Goo; Jez, Joseph M.; Maeda , Hiroshi A. (UW); (WU)

    2017-06-26

    L-Tyrosine (Tyr) is essential for protein synthesis and is a precursor of numerous specialized metabolites crucial for plant and human health. Tyr can be synthesized via two alternative routes by different key regulatory TyrA family enzymes, prephenate dehydrogenase (PDH, also known as TyrAp) or arogenate dehydrogenase (ADH, also known as TyrAa), representing a unique divergence of primary metabolic pathways. The molecular foundation underlying the evolution of these alternative Tyr pathways is currently unknown. Here we characterized recently diverged plant PDH and ADH enzymes, obtained the X-ray crystal structure of soybean PDH, and identified a single amino acid residue that defines TyrA substrate specificity and regulation. Structures of mutated PDHs co-crystallized with Tyr indicate that substitutions of Asn222 confer ADH activity and Tyr sensitivity. Reciprocal mutagenesis of the corresponding residue in divergent plant ADHs further introduced PDH activity and relaxed Tyr sensitivity, highlighting the critical role of this residue in TyrA substrate specificity that underlies the evolution of alternative Tyr biosynthetic pathways in plants.

  18. Molecular basis of usher pore gating in Escherichia coli pilus biogenesis.

    Science.gov (United States)

    Volkan, Ender; Kalas, Vasilios; Pinkner, Jerome S; Dodson, Karen W; Henderson, Nadine S; Pham, Thieng; Waksman, Gabriel; Delcour, Anne H; Thanassi, David G; Hultgren, Scott J

    2013-12-17

    Extracellular fibers called chaperone-usher pathway pili are critical virulence factors in a wide range of Gram-negative pathogenic bacteria that facilitate binding and invasion into host tissues and mediate biofilm formation. Chaperone-usher pathway ushers, which catalyze pilus assembly, contain five functional domains: a 24-stranded transmembrane β-barrel translocation domain (TD), a β-sandwich plug domain (PLUG), an N-terminal periplasmic domain, and two C-terminal periplasmic domains (CTD1 and 2). Pore gating occurs by a mechanism whereby the PLUG resides stably within the TD pore when the usher is inactive and then upon activation is translocated into the periplasmic space, where it functions in pilus assembly. Using antibiotic sensitivity and electrophysiology experiments, a single salt bridge was shown to function in maintaining the PLUG in the TD channel of the P pilus usher PapC, and a loop between the 12th and 13th beta strands of the TD (β12-13 loop) was found to facilitate pore opening. Mutation of the β12-13 loop resulted in a closed PapC pore, which was unable to efficiently mediate pilus assembly. Deletion of the PapH terminator/anchor resulted in increased OM permeability, suggesting a role for the proper anchoring of pili in retaining OM integrity. Further, we introduced cysteine residues in the PLUG and N-terminal periplasmic domains that resulted in a FimD usher with a greater propensity to exist in an open conformation, resulting in increased OM permeability but no loss in type 1 pilus assembly. These studies provide insights into the molecular basis of usher pore gating and its roles in pilus biogenesis and OM permeability.

  19. The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells

    Directory of Open Access Journals (Sweden)

    Joanna F. Flatt

    2018-04-01

    Full Text Available Normal human RBCs have a very low basal permeability (leak to cations, which is continuously corrected by the Na,K-ATPase. The leak is temperature-dependent, and this temperature dependence has been evaluated in the presence of inhibitors to exclude the activity of the Na,K-ATPase and NaK2Cl transporter. The severity of the RBC cation leak is altered in various conditions, most notably the hereditary stomatocytosis group of conditions. Pedigrees within this group have been classified into distinct phenotypes according to various factors, including the severity and temperature-dependence of the cation leak. As recent breakthroughs have provided more information regarding the molecular basis of hereditary stomatocytosis, it has become clear that these phenotypes elegantly segregate with distinct genetic backgrounds. The cryohydrocytosis phenotype, including South-east Asian Ovalocytosis, results from mutations in SLC4A1, and the very rare condition, stomatin-deficient cryohydrocytosis, is caused by mutations in SLC2A1. Mutations in RHAG cause the very leaky condition over-hydrated stomatocytosis, and mutations in ABCB6 result in familial pseudohyperkalemia. All of the above are large multi-spanning membrane proteins and the mutations may either modify the structure of these proteins, resulting in formation of a cation pore, or otherwise disrupt the membrane to allow unregulated cation movement across the membrane. More recently mutations have been found in two RBC cation channels, PIEZO1 and KCNN4, which result in dehydrated stomatocytosis. These mutations alter the activation and deactivation kinetics of these channels, leading to increased opening and allowing greater cation fluxes than in wild type.

  20. Molecular basis and drug sensitivity of the delayed rectifier (IKr) in the fish heart.

    Science.gov (United States)

    Hassinen, Minna; Haverinen, Jaakko; Vornanen, Matti

    2015-01-01

    Fishes are increasingly used as models for human cardiac diseases, creating a need for a better understanding of the molecular basis of fish cardiac ion currents. To this end we cloned KCNH6 channel of the crucian carp (Carassius carassius) that produces the rapid component of the delayed rectifier K(+) current (IKr), the main repolarising current of the fish heart. KCNH6 (ccErg2) was the main isoform of the Kv11 potassium channel family with relative transcript levels of 98.9% and 99.6% in crucian carp atrium and ventricle, respectively. KCNH2 (ccErg1), an orthologue to human cardiac Erg (Herg) channel, was only slightly expressed in the crucian carp heart. The native atrial IKr and the cloned ccErg2 were inhibited by similar concentrations of verapamil, terfenadine and KB-R7943 (P>0.05), while the atrial IKr was about an order of magnitude more sensitive to E-4031 than ccErg2 (P<0.05) suggesting that some accessory β-subunits may be involved. Sensitivity of the crucian carp atrial IKr to E-4031, terfenadine and KB-R7943 was similar to what has been reported for the Herg channel. In contrast, the sensitivity of the crucian carp IKr to verapamil was approximately 30 times higher than the previously reported values for the Herg current. In conclusion, the cardiac IKr is produced by non-orthologous gene products in fish (Erg2) and mammalian hearts (Erg1) and some marked differences exist in drug sensitivity between fish and mammalian Erg1/2 which need to be taken into account when using fish heart as a model for human heart. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Molecular Basis of Impaired Glycogen Metabolism during Ischemic Stroke and Hypoxia

    Science.gov (United States)

    Hossain, Mohammed Iqbal; Roulston, Carli Lorraine; Stapleton, David Ian

    2014-01-01

    Background Ischemic stroke is the combinatorial effect of many pathological processes including the loss of energy supplies, excessive intracellular calcium accumulation, oxidative stress, and inflammatory responses. The brain's ability to maintain energy demand through this process involves metabolism of glycogen, which is critical for release of stored glucose. However, regulation of glycogen metabolism in ischemic stroke remains unknown. In the present study, we investigate the role and regulation of glycogen metabolizing enzymes and their effects on the fate of glycogen during ischemic stroke. Results Ischemic stroke was induced in rats by peri-vascular application of the vasoconstrictor endothelin-1 and forebrains were collected at 1, 3, 6 and 24 hours post-stroke. Glycogen levels and the expression and activity of enzymes involved in glycogen metabolism were analyzed. We found elevated glycogen levels in the ipsilateral hemispheres compared with contralateral hemispheres at 6 and 24 hours (25% and 39% increase respectively; PGlycogen synthase activity and glycogen branching enzyme expression were found to be similar between the ipsilateral, contralateral, and sham control hemispheres. In contrast, the rate-limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 58% lower activity (Pglycogen debranching enzyme expression 24 hours post-stroke was 77% (Pglycogen phosphorylase activity and increased glycogen accumulation but did not alter glycogen synthase activity. Furthermore, elevated glycogen levels provided metabolic support to astrocytes during hypoxia. Conclusion Our study has identified that glycogen breakdown is impaired during ischemic stroke, the molecular basis of which includes reduced glycogen debranching enzyme expression level together with reduced glycogen phosphorylase and PKA activity. PMID:24858129

  2. Molecular time-course and the metabolic basis of entry into dauer in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Pan-Young Jeong

    Full Text Available When Caenorhabditis elegans senses dauer pheromone (daumone, signaling inadequate growth conditions, it enters the dauer state, which is capable of long-term survival. However, the molecular pathway of dauer entry in C. elegans has remained elusive. To systematically monitor changes in gene expression in dauer paths, we used a DNA microarray containing 22,625 gene probes corresponding to 22,150 unique genes from C. elegans. We employed two different paths: direct exposure to daumone (Path 1 and normal growth media plus liquid culture (Path 2. Our data reveal that entry into dauer is accomplished through the multi-step process, which appears to be compartmentalized in time and according to metabolic flux. That is, a time-course of dauer entry in Path 1 shows that dauer larvae formation begins at post-embryonic stage S4 (48 h and is complete at S6 (72 h. Our results also suggest the presence of a unique adaptive metabolic control mechanism that requires both stage-specific expression of specific genes and tight regulation of different modes of fuel metabolite utilization to sustain the energy balance in the context of prolonged survival under adverse growth conditions. It is apparent that worms entering dauer stage may rely heavily on carbohydrate-based energy reserves, whereas dauer larvae utilize fat or glyoxylate cycle-based energy sources. We created a comprehensive web-based dauer metabolic database for C. elegans (www.DauerDB.org that makes it possible to search any gene and compare its relative expression at a specific stage, or evaluate overall patterns of gene expression in both paths. This database can be accessed by the research community and could be widely applicable to other related nematodes as a molecular atlas.

  3. Medicinal Chemistry and Molecular Modeling: An Integration to Teach Drug Structure-Activity Relationship and the Molecular Basis of Drug Action

    Science.gov (United States)

    Carvalho, Ivone; Borges, Aurea D. L.; Bernardes, Lilian S. C.

    2005-01-01

    The use of computational chemistry and the protein data bank (PDB) to understand and predict the chemical and molecular basis involved in the drug-receptor interactions is discussed. A geometrical and chemical overview of the great structural similarity in the substrate and inhibitor is provided.

  4. Microarray Analysis Reveals the Molecular Basis of Antiarthritic Activity of Huo-Luo-Xiao-Ling Dan

    Directory of Open Access Journals (Sweden)

    Hua Yu

    2013-01-01

    Full Text Available Rheumatoid arthritis (RA is a chronic inflammatory disease of autoimmune origin. Huo-luo-xiao-ling dan (HLXL is an herbal mixture that has been used in traditional Chinese medicine over several decades to treat chronic inflammatory diseases including RA. However, the mechanism of the anti-arthritic action of this herbal remedy is poorly understood at the molecular level. In this study, we determined by microarray analysis the effects of HLXL on the global gene expression profile of the draining lymph node cells (LNC in the rat adjuvant arthritis (AA model of human RA. In LNC restimulated in vitro with the disease-related antigen mycobacterial heat-shock protein 65 (Bhsp65, 84 differentially expressed genes (DEG (64 upregulated and 20 downregulated versus 120 DEG (94 upregulated and 26 downregulated were identified in HLXL-treated versus vehicle (Water-treated rats, respectively, and 62 DEG (45 upregulated and 17 downregulated were shared between the two groups. The most affected pathways in response to HLXL treatment included immune response, inflammation, cellular proliferation and apoptosis, and metabolic processes, many of which are directly relevant to arthritis pathogenesis. These results would advance our understanding of the mechanisms underlying the anti-arthritic activity of HLXL.

  5. The molecular basis of the genesis of basal tone in internal anal sphincter

    Science.gov (United States)

    Zhang, Cheng-Hai; Wang, Pei; Liu, Dong-Hai; Chen, Cai-Ping; Zhao, Wei; Chen, Xin; Chen, Chen; He, Wei-Qi; Qiao, Yan-Ning; Tao, Tao; Sun, Jie; Peng, Ya-Jing; Lu, Ping; Zheng, Kaizhi; Craige, Siobhan M.; Lifshitz, Lawrence M.; Keaney Jr, John F.; Fogarty, Kevin E.; ZhuGe, Ronghua; Zhu, Min-Sheng

    2016-01-01

    Smooth muscle sphincters exhibit basal tone and control passage of contents through organs such as the gastrointestinal tract; loss of this tone leads to disorders such as faecal incontinence. However, the molecular mechanisms underlying this tone remain unknown. Here, we show that deletion of myosin light-chain kinases (MLCK) in the smooth muscle cells from internal anal sphincter (IAS-SMCs) abolishes basal tone, impairing defecation. Pharmacological regulation of ryanodine receptors (RyRs), L-type voltage-dependent Ca2+ channels (VDCCs) or TMEM16A Ca2+-activated Cl− channels significantly changes global cytosolic Ca2+ concentration ([Ca2+]i) and the tone. TMEM16A deletion in IAS-SMCs abolishes the effects of modulators for TMEM16A or VDCCs on a RyR-mediated rise in global [Ca2+]i and impairs the tone and defecation. Hence, MLCK activation in IAS-SMCs caused by a global rise in [Ca2+]i via a RyR-TMEM16A-VDCC signalling module sets the basal tone. Targeting this module may lead to new treatments for diseases like faecal incontinence. PMID:27101932

  6. Structural and molecular basis for resistance to aminoglycoside antibiotics by the adenylyltransferase ANT(2″)-Ia.

    Science.gov (United States)

    Cox, Georgina; Stogios, Peter J; Savchenko, Alexei; Wright, Gerard D

    2015-01-06

    problem among Gram-negative human pathogens, since there are very few therapeutic options for infections caused by these organisms. In order to successfully circumvent or inhibit the activity of aminoglycoside-modifying enzymes, and to thus rejuvenate the activity of the aminoglycoside antibiotics against Gram-negative pathogens, structural and mechanistic information is crucial. This study reveals the structure of a clinically prevalent aminoglycoside resistance enzyme [ANT(2″)-Ia] and depicts the molecular basis underlying modification of antibiotic substrates. Combined, these findings provide the groundwork for the development of broad-spectrum inhibitors against antibiotic nucleotidyltransferases. Copyright © 2015 Cox et al.

  7. Optical and electrical properties of semiconducting BaSi2 thin films on Si substrates grown by molecular beam epitaxy

    International Nuclear Information System (INIS)

    Morita, K.; Inomata, Y.; Suemasu, T.

    2006-01-01

    The electrical properties and optical absorption (OA) spectra of undoped BaSi 2 films grown by molecular beam epitaxy were investigated The electron density and mobility of BaSi 2 grown epitaxially on Si(111) were 5 x 10 15 cm -3 and 820 cm 2 /V.s at room temperature, respectively. The conduction-band discontinuity at the BaSi 2 /Si heterojunction was estimated to be 0.7 eV from the current-voltage characteristics of n-BaSi 2 /n-Si isotype diodes. OA spectra were measured on polycrystalline BaSi 2 films grown on transparent fused silica substrates with predeposited polycrystalline Si layer. The indirect absorption edge was derived to be 1.3 eV, and the optical absorption coefficient reached 10 5 cm -1 at 1.5 eV

  8. Molecular basis of proton uptake in single and double mutants of cytochrome c oxidase

    Energy Technology Data Exchange (ETDEWEB)

    Henry, Rowan M; Caplan, David; Pomes, Regis [Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, M5G 1X8 (Canada); Fadda, Elisa, E-mail: pomes@sickkids.ca [Department of Chemistry, University of Galway (Ireland)

    2011-06-15

    Cytochrome c oxidase, the terminal enzyme of the respiratory chain, utilizes the reduction of dioxygen into water to pump protons across the mitochondrial inner membrane. The principal pathway of proton uptake into the enzyme, the D channel, is a 2.5 nm long channel-like cavity named after a conserved, negatively charged aspartic acid (D) residue thought to help recruiting protons to its entrance (D132 in the first subunit of the S. sphaeroides enzyme). The single-point mutation of D132 to asparagine (N), a neutral residue, abolishes enzyme activity. Conversely, replacing conserved N139, one-third into the D channel, by D, induces a decoupled phenotype, whereby oxygen reduction proceeds but not proton pumping. Intriguingly, the double mutant D132N/N139D, which conserves the charge of the D channel, restores the wild-type phenotype. We use molecular dynamics simulations and electrostatic calculations to examine the structural and physical basis for the coupling of proton pumping and oxygen chemistry in single and double N139D mutants. The potential of mean force for the conformational isomerization of N139 and N139D side chains reveals the presence of three rotamers, one of which faces the channel entrance. This out-facing conformer is metastable in the wild-type and in the N139D single mutant, but predominant in the double mutant thanks to the loss of electrostatic repulsion with the carboxylate group of D132. The effects of mutations and conformational isomerization on the pKa of E286, an essential proton-shuttling residue located at the top of the D channel, are shown to be consistent with the electrostatic control of proton pumping proposed recently (Fadda et al 2008 Biochim. Biophys. Acta 1777 277-84). Taken together, these results suggest that preserving the spatial distribution of charges at the entrance of the D channel is necessary to guarantee both the uptake and the relay of protons to the active site of the enzyme. These findings highlight the interplay

  9. Molecular basis of proton uptake in single and double mutants of cytochrome c oxidase

    International Nuclear Information System (INIS)

    Henry, Rowan M; Caplan, David; Pomes, Regis; Fadda, Elisa

    2011-01-01

    Cytochrome c oxidase, the terminal enzyme of the respiratory chain, utilizes the reduction of dioxygen into water to pump protons across the mitochondrial inner membrane. The principal pathway of proton uptake into the enzyme, the D channel, is a 2.5 nm long channel-like cavity named after a conserved, negatively charged aspartic acid (D) residue thought to help recruiting protons to its entrance (D132 in the first subunit of the S. sphaeroides enzyme). The single-point mutation of D132 to asparagine (N), a neutral residue, abolishes enzyme activity. Conversely, replacing conserved N139, one-third into the D channel, by D, induces a decoupled phenotype, whereby oxygen reduction proceeds but not proton pumping. Intriguingly, the double mutant D132N/N139D, which conserves the charge of the D channel, restores the wild-type phenotype. We use molecular dynamics simulations and electrostatic calculations to examine the structural and physical basis for the coupling of proton pumping and oxygen chemistry in single and double N139D mutants. The potential of mean force for the conformational isomerization of N139 and N139D side chains reveals the presence of three rotamers, one of which faces the channel entrance. This out-facing conformer is metastable in the wild-type and in the N139D single mutant, but predominant in the double mutant thanks to the loss of electrostatic repulsion with the carboxylate group of D132. The effects of mutations and conformational isomerization on the pKa of E286, an essential proton-shuttling residue located at the top of the D channel, are shown to be consistent with the electrostatic control of proton pumping proposed recently (Fadda et al 2008 Biochim. Biophys. Acta 1777 277-84). Taken together, these results suggest that preserving the spatial distribution of charges at the entrance of the D channel is necessary to guarantee both the uptake and the relay of protons to the active site of the enzyme. These findings highlight the interplay

  10. Molecular basis of retinol anti-ageing properties in naturally aged human skin in vivo.

    Science.gov (United States)

    Shao, Y; He, T; Fisher, G J; Voorhees, J J; Quan, T

    2017-02-01

    Retinoic acid has been shown to improve the aged-appearing skin. However, less is known about the anti-ageing effects of retinol (ROL, vitamin A), a precursor of retinoic acid, in aged human skin in vivo. This study aimed to investigate the molecular basis of ROL anti-ageing properties in naturally aged human skin in vivo. Sun-protected buttock skin (76 ± 6 years old, n = 12) was topically treated with 0.4% ROL and its vehicle for 7 days. The effects of topical ROL on skin epidermis and dermis were evaluated by immunohistochemistry, in situ hybridization, Northern analysis, real-time RT-PCR and Western analysis. Collagen fibrils nanoscale structure and surface topology were analysed by atomic force microscopy. Topical ROL shows remarkable anti-ageing effects through three major types of skin cells: epidermal keratinocytes, dermal endothelial cells and fibroblasts. Topical ROL significantly increased epidermal thickness by stimulating keratinocytes proliferation and upregulation of c-Jun transcription factor. In addition to epidermal changes, topical ROL significantly improved dermal extracellular matrix (ECM) microenvironment; increasing dermal vascularity by stimulating endothelial cells proliferation and ECM production (type I collagen, fibronectin and elastin) by activating dermal fibroblasts. Topical ROL also stimulates TGF-β/CTGF pathway, the major regulator of ECM homeostasis, and thus enriched the deposition of ECM in aged human skin in vivo. 0.4% topical ROL achieved similar results as seen with topical retinoic acid, the biologically active form of ROL, without causing noticeable signs of retinoid side effects. 0.4% topical ROL shows remarkable anti-ageing effects through improvement of the homeostasis of epidermis and dermis by stimulating the proliferation of keratinocytes and endothelial cells, and activating dermal fibroblasts. These data provide evidence that 0.4% topical ROL is a promising and safe treatment to improve the naturally aged human skin

  11. Molecular basis of proton uptake in single and double mutants of cytochrome c oxidase

    Science.gov (United States)

    Henry, Rowan M.; Caplan, David; Fadda, Elisa; Pomès, Régis

    2011-06-01

    Cytochrome c oxidase, the terminal enzyme of the respiratory chain, utilizes the reduction of dioxygen into water to pump protons across the mitochondrial inner membrane. The principal pathway of proton uptake into the enzyme, the D channel, is a 2.5 nm long channel-like cavity named after a conserved, negatively charged aspartic acid (D) residue thought to help recruiting protons to its entrance (D132 in the first subunit of the S. sphaeroides enzyme). The single-point mutation of D132 to asparagine (N), a neutral residue, abolishes enzyme activity. Conversely, replacing conserved N139, one-third into the D channel, by D, induces a decoupled phenotype, whereby oxygen reduction proceeds but not proton pumping. Intriguingly, the double mutant D132N/N139D, which conserves the charge of the D channel, restores the wild-type phenotype. We use molecular dynamics simulations and electrostatic calculations to examine the structural and physical basis for the coupling of proton pumping and oxygen chemistry in single and double N139D mutants. The potential of mean force for the conformational isomerization of N139 and N139D side chains reveals the presence of three rotamers, one of which faces the channel entrance. This out-facing conformer is metastable in the wild-type and in the N139D single mutant, but predominant in the double mutant thanks to the loss of electrostatic repulsion with the carboxylate group of D132. The effects of mutations and conformational isomerization on the pKa of E286, an essential proton-shuttling residue located at the top of the D channel, are shown to be consistent with the electrostatic control of proton pumping proposed recently (Fadda et al 2008 Biochim. Biophys. Acta 1777 277-84). Taken together, these results suggest that preserving the spatial distribution of charges at the entrance of the D channel is necessary to guarantee both the uptake and the relay of protons to the active site of the enzyme. These findings highlight the interplay

  12. The molecular basis for cell cycle delays following ionizing radiation. A review

    International Nuclear Information System (INIS)

    Maity, A.; McKenna, W.G.; Muschel, R.J.

    1994-01-01

    Exposure of a wide variety of cells to ionizing (X- or γ-) irradiation results in a division delay which may have several components including a G 1 block, a G 2 arrest or an S phase delay. The G 1 arrest is absent in many cells lines, and the S phase delay is typically seen following relatively high doses (>5 Gy). In contrast, the G 2 arrest is seen in virtually all eukaryotic cells and occurs following high and low doses, even under 1 Gy. The mechanism underlying the G 2 arrest may involve suppression of cyclin B1 mRNA and/or protein in some cell lines and tyrosine phosphorylation of p34 cdc2 in others. Similar mechanisms are likely to be operative in the G 2 arrest induced by various chemotherapeutic agents including nitrogen mustard and etoposide. The upstream signal transduction pathways involved in the G 2 arrest following ionizing radiation remain obscure in mammalian cells; however, in the budding yeast the rad9 gene and in the fission yeast the chk1/rad27 gene are involved. There is evidence indicating that shortening of the G 2 arrest results in decreased survival which has led to the hypothesis that during this block, cells repair damaged DNA following exposure to genotoxic agents. In cell lines examined to date, wildtype p53 is required for the G 1 arrest following ionizing radiation. The gadd45 gene may also have a role in this arrest. Elimination of the G 1 arrest leads to no change in survival following radiation in some cell lines and increased radioresistance in others. It has been suggested that this induction of radioresistance in certain cell lines is due to loss of the ability to undergo apoptosis. Relatively little is known about the mechanism underlying the S phase delay. This delay is due to a depression in the rate of DNA synthesis and has both a slow and a fast component. In some cells the S phase delay can be abolished by staurosporine, suggesting involvement of a protein kinase. Understanding the molecular mechanisms behind these delays

  13. ANTHOCYANIN PIGMENTATION IN TRITICUM AESTIVUM L.: GENETIC BASIS AND ROLE UNDER ABIOTIC STRESS CONDITIONS

    Directory of Open Access Journals (Sweden)

    Tereshchenko O.Yu.

    2012-08-01

    Full Text Available Anthocyanins are secondary metabolites of plants. They have a wide range of biological activity such as antioxidant, photoprotection, osmoregulation, heavy metal ions chelation, antimicrobial and antifungal activities, which help plants to survive under different stress conditions. Bread wheat (T. aestivum L. can have purple pigmentation provided by anthocyanin compounds in different organs, such as grain pericarp, coleoptile, culm, leaf blades, leaf sheaths, glumes and anthers. However, the genetic mechanisms underlying formation of these traits as well as contribution of the pigmentation to stress tolerance have not been widely studied in wheat. The aim of the current study was to investigate molecular-genetic mechanisms underlying anthocyanin pigmentation in different wheat organs and to estimate the role of the pigmentation under different abiotic stress conditions in wheat seedlings. In the current study, near-isogenic lines (NILs: cv. ‘Saratovskaya 29’ (‘S29’ and lines i:S29Pp1Pp2PF and i:S29Pp1Pp3P developed on the ‘S29’ background but having grain pericarp coloration (genes Pp and more intense coleoptile (Rc, culm (Pc, leaf blade (Plb, leaf sheath (Pls pigmentation in comparison with ‘S29’, were used. Comparative transcriptional analysis of the five structural genes Chs, Chi, F3h, Dfr, Ans, encoding enzymes participating in the anthocyanin biosynthesis, was performed in different organs of NILs. It was shown that the presence of the Rc, Pc, Plb, Pls and Pp alleles conferring strong anthocyanin pigmentation induced more intense transcription of the structural genes, suggesting the genes Rc, Pc, Plb, Pls and Pp to play a regulatory role in anthocyanin biosynthesis network. To evaluate the role of anthocyanins in stress response at the seedling stage, growth ability of the NILs and anthocyanin content in their coleoptiles were assessed after treatments with NaCl (100 and 200 mM, CdCl2 (25 and 50 μM and 15% PEG 6000

  14. Molecular basis of immunogenicity to botulinum neurotoxins and uses of the defined antigenic regions.

    Science.gov (United States)

    Atassi, M Z

    2015-12-01

    Intensive research in this laboratory over the last 19 years has aimed at understanding the molecular bases for immune recognition of botulinum neurotoxin, types A and B and the role of anti-toxin immune responses in defense against the toxin. Using 92 synthetic 19-residue peptides that overlapped by 5 residues and comprised an entire toxin (A or B) we determined the peptides' ability to bind anti-toxin Abs of human, mouse, horse and chicken. We also localized the epitopes recognized by Abs of cervical dystonia patients who developed immunoresistance to correlate toxin during treatment with BoNT/A or BoNT/B. For BoNT/A, patients' blocking Abs bound to 13 regions (5 on L and 8 on H subunit) on the surface and the response to each region was under separate MHC control. The responses were defined by the structure of the antigen and by the MHC of the host. The antigenic regions coincided or overlapped with synaptosomes (SNPS) binding regions. Antibody binding blocked the toxin's ability to bind to neuronal cells. In fact selected synthetic peptides were able to inhibit the toxin's action in vivo. A combination of three synthetic strong antigenic peptides detected blocking Abs in 88% of immunoresistant patients' sera. Administration of selected epitopes, pre-linked at their N(α) group to monomethoxyployethylene glycol, into mice with ongoing blocking anti-toxin Abs, reduced blocking Ab levels in the recipients. This may be suitable for clinical applications. Defined epitopes should also be valuable in synthetic vaccines design. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Physiological basis of barley yield under near optimal and stress conditions

    Directory of Open Access Journals (Sweden)

    Pržulj Novo

    2004-01-01

    Full Text Available Average barley yield fall below its potential due to incidence of stresses. Water stress is the main environmental factor limiting yield. The component a priori more sensitive to most stresses is the amount of radiation absorbed. The effect of stresses influence on the total amount of radiation absorbed by barley crop during its vegetation and the photosynthetic efficiency of radiation conversion. Growth inhibition is accompanied by reductions in leaf and cell wall extensibility. Grain yield under drought conditions is source limited. Supply of assimilates to the developing inflorescence plays a critical role in establishing final grain number and grain size. Grain weight is negatively affected by drought, high temperature, and any other factors that may reduce grain filling duration and grain filling rate. Awns and glaucousness confer better performance of barley under drought stress conditions. Barley responds with an increased accumulation of a number of proteins when subjected to different stress inducing cell dehydration. Screening techniques that are able to identify desirable genotypes based on the evaluation of physiological traits related to stress evasion and stress resistance maybe useful in breeding barley for resistance to stress, particularly drought stress. Crop management and breeding can reduce the incidence of stress on yield. The effect of these practices is sustained by an understanding of their physiology. In this paper the physiological basis of the processes determining barley yield and the incidence of stresses on photosynthetic metabolism that determine grain yield of barley is discussed. .

  16. 29 CFR 778.313 - Computing overtime pay under the Act for employees compensated on task basis.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Computing overtime pay under the Act for employees compensated on task basis. 778.313 Section 778.313 Labor Regulations Relating to Labor (Continued) WAGE AND... TO REGULATIONS OVERTIME COMPENSATION Special Problems âtaskâ Basis of Payment § 778.313 Computing...

  17. Deciphering Molecular Mechanism Underlying Hypolipidemic Activity of Echinocystic Acid

    Directory of Open Access Journals (Sweden)

    Li Han

    2014-01-01

    Full Text Available Our previous study showed that a triterpene mixture, consisting of echinocystic acid (EA and oleanolic acid (OA at a ratio of 4 : 1, dose-dependently ameliorated the hyperlipidemia and atherosclerosis in rabbits fed with high fat/high cholesterol diets. This study was aimed at exploring the mechanisms underlying antihyperlipidemic effect of EA. Molecular docking simulation of EA was performed using Molegro Virtual Docker (version: 4.3.0 to investigate the potential targets related to lipid metabolism. Based on the molecular docking information, isotope labeling method or spectrophotometry was applied to examine the effect of EA on the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT, and diacylglycerol acyltransferase (DGAT in rat liver microsomes. Our results revealed a strong affinity of EA towards ACAT and DGAT in molecular docking analysis, while low binding affinity existed between EA and HMG-CoA reductase as well as between EA and cholesteryl ester transfer protein. Consistent with the results of molecular docking, in vitro enzyme activity assays showed that EA inhibited ACAT and DGAT, with IC50 values of 103 and 139 μM, respectively, and exhibited no significant effect on HMG-CoA reductase activity. The present findings suggest that EA may exert hypolipidemic effect by inhibiting the activity of ACAT and DGAT.

  18. Tracting the neural basis of music: Deficient structural connectivity underlying acquired amusia.

    Science.gov (United States)

    Sihvonen, Aleksi J; Ripollés, Pablo; Särkämö, Teppo; Leo, Vera; Rodríguez-Fornells, Antoni; Saunavaara, Jani; Parkkola, Riitta; Soinila, Seppo

    2017-12-01

    Acquired amusia provides a unique opportunity to investigate the fundamental neural architectures of musical processing due to the transition from a functioning to defective music processing system. Yet, the white matter (WM) deficits in amusia remain systematically unexplored. To evaluate which WM structures form the neural basis for acquired amusia and its recovery, we studied 42 stroke patients longitudinally at acute, 3-month, and 6-month post-stroke stages using DTI [tract-based spatial statistics (TBSS) and deterministic tractography (DT)] and the Scale and Rhythm subtests of the Montreal Battery of Evaluation of Amusia (MBEA). Non-recovered amusia was associated with structural damage and subsequent degeneration in multiple WM tracts including the right inferior fronto-occipital fasciculus (IFOF), arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and frontal aslant tract (FAT), as well as in the corpus callosum (CC) and its posterior part (tapetum). In a linear regression analysis, the volume of the right IFOF was the main predictor of MBEA performance across time. Overall, our results provide a comprehensive picture of the large-scale deficits in intra- and interhemispheric structural connectivity underlying amusia, and conversely highlight which pathways are crucial for normal music perception. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Graph theoretical ordering of structures as a basis for systematic searches for regularities in molecular data

    International Nuclear Information System (INIS)

    Randic, M.; Wilkins, C.L.

    1979-01-01

    Selected molecular data on alkanes have been reexamined in a search for general regularities in isomeric variations. In contrast to the prevailing approaches concerned with fitting data by searching for optimal parameterization, the present work is primarily aimed at established trends, i.e., searching for relative magnitudes and their regularities among the isomers. Such an approach is complementary to curve fitting or correlation seeking procedures. It is particularly useful when there are incomplete data which allow trends to be recognized but no quantitative correlation to be established. One proceeds by first ordering structures. One way is to consider molecular graphs and enumerate paths of different length as the basic graph invariant. It can be shown that, for several thermodynamic molecular properties, the number of paths of length two (p 2 ) and length three (p 3 ) are critical. Hence, an ordering based on p 2 and p 3 indicates possible trends and behavior for many molecular properties, some of which relate to others, some which do not. By considering a grid graph derived by attributing to each isomer coordinates (p 2 ,p 3 ) and connecting points along the coordinate axis, one obtains a simple presentation useful for isomer structural interrelations. This skeletal frame is one upon which possible trends for different molecular properties may be conveniently represented. The significance of the results and their conceptual value is discussed. 16 figures, 3 tables

  20. Can Coulomb Sturmians Be Used as a Basis for N-Electron Molecular Calculations?

    DEFF Research Database (Denmark)

    Avery, John Scales; Avery, James Emil

    2009-01-01

    A method is proposed for using isoenergetic configurations formed from many-center Coulomb Sturmians as a basis for calculations on N-electron molecules. Such configurations are solutions to an approximate N-electron Schrödinger equation with a weighted potential, and they are thus closely analog...

  1. [Molecular basis of the mutagenic and lethal effects of ultraviolet irradiation]: Progress report

    International Nuclear Information System (INIS)

    1988-01-01

    Studies on the molecular mechanisms by which Escherichia Coli and Micrococcus luteus repair pyrimidine dimers induced in their DNA by ultraviolet light are reported. The studies involve the isolation and enzymatic activity of the ucr system. The specific roles of ucr A and ucr B proteins are sought. In addition the expression of the ucr genes in mammalian cells is addressed. 35 refs. (DT)

  2. Identifying the molecular functions of electron transport proteins using radial basis function networks and biochemical properties.

    Science.gov (United States)

    Le, Nguyen-Quoc-Khanh; Nguyen, Trinh-Trung-Duong; Ou, Yu-Yen

    2017-05-01

    The electron transport proteins have an important role in storing and transferring electrons in cellular respiration, which is the most proficient process through which cells gather energy from consumed food. According to the molecular functions, the electron transport chain components could be formed with five complexes with several different electron carriers and functions. Therefore, identifying the molecular functions in the electron transport chain is vital for helping biologists understand the electron transport chain process and energy production in cells. This work includes two phases for discriminating electron transport proteins from transport proteins and classifying categories of five complexes in electron transport proteins. In the first phase, the performances from PSSM with AAIndex feature set were successful in identifying electron transport proteins in transport proteins with achieved sensitivity of 73.2%, specificity of 94.1%, and accuracy of 91.3%, with MCC of 0.64 for independent data set. With the second phase, our method can approach a precise model for identifying of five complexes with different molecular functions in electron transport proteins. The PSSM with AAIndex properties in five complexes achieved MCC of 0.51, 0.47, 0.42, 0.74, and 1.00 for independent data set, respectively. We suggest that our study could be a power model for determining new proteins that belongs into which molecular function of electron transport proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. the genetic and molecular basis of bacterial invasion of epithelial cells

    African Journals Online (AJOL)

    DR. AMINU

    The pathogenic species of bacteria are of great medical importance as causative agents of infectious diseases. Moreover, as the condition of human existence have changed, so have the bacterial species that produce diseases. It is against this background that molecular genetics have now entered the field of microbial ...

  4. Cellular and molecular basis of chronic constipation: Taking the functional/idiopathic label out

    OpenAIRE

    Bassotti, Gabrio; Villanacci, Vincenzo; Creƫoiu, Dragos; Creƫoiu, Sanda Maria; Becheanu, Gabriel

    2013-01-01

    In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called “functional” or “idiopathic” disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable a...

  5. Final Report: Molecular Basis for Microbial Adhesion and Geochemical Surface Reactions: A Study Across Scales

    Energy Technology Data Exchange (ETDEWEB)

    Dixon, David Adams [The University of Alabama

    2013-06-27

    Computational chemistry was used to help provide a molecular level description of the interactions of Gram-negative microbial membranes with subsurface materials. The goal is to develop a better understanding of the molecular processes involved in microbial metal binding, microbial attachment to mineral surfaces, and, eventually, oxidation/reduction reactions (electron transfer) that can occur at these surfaces and are mediated by the bacterial exterior surface. The project focused on the interaction of the outer microbial membrane, which is dominated by an exterior lipopolysaccharide (LPS) portion, of Pseudomonas aeruginosa with the mineral goethite and with solvated ions in the environment. This was originally a collaborative project with T.P. Straatsma and B. Lowery of the Pacific Northwest National Laboratory. The University of Alabama effort used electronic structure calculations to predict the molecular behavior of ions in solution and the behavior of the sugars which form a critical part of the LPS. The interactions of the sugars with metal ions are expected to dominate much of the microscopic structure and transport phenomena in the LPS. This work, in combination with the molecular dynamics simulations of Straatsma and the experimental electrochemistry and microscopy measurements of Lowry, both at PNNL, is providing new insights into the detailed molecular behavior of these membranes in geochemical environments. The effort at The University of Alabama has three components: solvation energies and structures of ions in solution, prediction of the acidity of the critical groups in the sugars in the LPS, and binding of metal ions to the sugar anions. An important aspect of the structure of the LPS membrane as well as ion transport in the LPS is the ability of the sugar side groups such as the carboxylic acids and the phosphates to bind positively charged ions. We are studying the acidity of the acidic side groups in order to better understand the ability of

  6. Current-voltage curves for molecular junctions computed using all-electron basis sets

    International Nuclear Information System (INIS)

    Bauschlicher, Charles W.; Lawson, John W.

    2006-01-01

    We present current-voltage (I-V) curves computed using all-electron basis sets on the conducting molecule. The all-electron results are very similar to previous results obtained using effective core potentials (ECP). A hybrid integration scheme is used that keeps the all-electron calculations cost competitive with respect to the ECP calculations. By neglecting the coupling of states to the contacts below a fixed energy cutoff, the density matrix for the core electrons can be evaluated analytically. The full density matrix is formed by adding this core contribution to the valence part that is evaluated numerically. Expanding the definition of the core in the all-electron calculations significantly reduces the computational effort and, up to biases of about 2 V, the results are very similar to those obtained using more rigorous approaches. The convergence of the I-V curves and transmission coefficients with respect to basis set is discussed. The addition of diffuse functions is critical in approaching basis set completeness

  7. Molecular Bases Underlying the Hepatoprotective Effects of Coffee

    Directory of Open Access Journals (Sweden)

    Federico Salomone

    2017-01-01

    Full Text Available Coffee is the most consumed beverage worldwide. Epidemiological studies with prospective cohorts showed that coffee intake is associated with reduced cardiovascular and all-cause mortality independently of caffeine content. Cohort and case-control studies reported an inverse association between coffee consumption and the degree of liver fibrosis as well as the development of liver cancer. Furthermore, the beneficial effects of coffee have been recently confirmed by large meta-analyses. In the last two decades, various in vitro and in vivo studies evaluated the molecular determinants for the hepatoprotective effects of coffee. In the present article, we aimed to critically review experimental evidence regarding the active components and the molecular bases underlying the beneficial role of coffee against chronic liver diseases. Almost all studies highlighted the beneficial effects of this beverage against liver fibrosis with the most solid results indicating a pivot role for both caffeine and chlorogenic acids. In particular, in experimental models of fibrosis, caffeine was shown to inhibit hepatic stellate cell activation by blocking adenosine receptors, and emerging evidence indicated that caffeine may also favorably impact angiogenesis and hepatic hemodynamics. On the other side, chlorogenic acids, potent phenolic antioxidants, suppress liver fibrogenesis and carcinogenesis by reducing oxidative stress and counteract steatogenesis through the modulation of glucose and lipid homeostasis in the liver. Overall, these molecular insights may have translational significance and suggest that coffee components need clinical evaluation.

  8. The hallmarks of premalignant conditions: a molecular basis for cancer prevention.

    Science.gov (United States)

    Ryan, Bríd M; Faupel-Badger, Jessica M

    2016-02-01

    The hallmarks of premalignant lesions were first described in the 1970s, a time when relatively little was known about the molecular underpinnings of cancer. Yet it was clear there must be opportunities to intervene early in carcinogenesis. A vast array of molecular information has since been uncovered, with much of this stemming from studies of existing cancer or cancer models. Here, examples of how an understanding of cancer biology has informed cancer prevention studies are highlighted and emerging areas that may have implications for the field of cancer prevention research are described. A note of caution accompanies these examples, in that while there are similarities, there are also fundamental differences between the biology of premalignant lesions or premalignant conditions and invasive cancer. These differences must be kept in mind, and indeed leveraged, when exploring potential cancer prevention measures. Published by Elsevier Inc.

  9. Plant Adaptation to Acid Soils: The Molecular Basis for Crop Aluminum Resistance.

    Science.gov (United States)

    Kochian, Leon V; Piñeros, Miguel A; Liu, Jiping; Magalhaes, Jurandir V

    2015-01-01

    Aluminum (Al) toxicity in acid soils is a significant limitation to crop production worldwide, as approximately 50% of the world's potentially arable soil is acidic. Because acid soils are such an important constraint to agriculture, understanding the mechanisms and genes conferring resistance to Al toxicity has been a focus of intense research interest in the decade since the last article on crop acid soil tolerance was published in this journal. An impressive amount of progress has been made during that time that has greatly increased our understanding of the diversity of Al resistance genes and mechanisms, how resistance gene expression is regulated and triggered by Al and Al-induced signals, and how the proteins encoded by these genes function and are regulated. This review examines the state of our understanding of the physiological, genetic, and molecular bases for crop Al tolerance, looking at the novel Al resistance genes and mechanisms that have been identified over the past ten years. Additionally, it examines how the integration of molecular and genetic analyses of crop Al resistance is starting to be exploited for the improvement of crop plants grown on acid soils via both molecular-assisted breeding and biotechnology approaches.

  10. Molecular mechanics of silk nanostructures under varied mechanical loading.

    Science.gov (United States)

    Bratzel, Graham; Buehler, Markus J

    2012-06-01

    Spider dragline silk is a self-assembling tunable protein composite fiber that rivals many engineering fibers in tensile strength, extensibility, and toughness, making it one of the most versatile biocompatible materials and most inviting for synthetic mimicry. While experimental studies have shown that the peptide sequence and molecular structure of silk have a direct influence on the stiffness, toughness, and failure strength of silk, few molecular-level analyses of the nanostructure of silk assemblies, in particular, under variations of genetic sequences have been reported. In this study, atomistic-level structures of wildtype as well as modified MaSp1 protein from the Nephila clavipes spider dragline silk sequences, obtained using an in silico approach based on replica exchange molecular dynamics and explicit water molecular dynamics, are subjected to simulated nanomechanical testing using different force-control loading conditions including stretch, pull-out, and peel. The authors have explored the effects of the poly-alanine length of the N. clavipes MaSp1 peptide sequence and identify differences in nanomechanical loading conditions on the behavior of a unit cell of 15 strands with 840-990 total residues used to represent a cross-linking β-sheet crystal node in the network within a fibril of the dragline silk thread. The specific loading condition used, representing concepts derived from the protein network connectivity at larger scales, have a significant effect on the mechanical behavior. Our analysis incorporates stretching, pull-out, and peel testing to connect biochemical features to mechanical behavior. The method used in this study could find broad applications in de novo design of silk-like tunable materials for an array of applications. Copyright © 2011 Wiley Periodicals, Inc.

  11. Molecular Basis of Ion Channels and Receptors Involved in Nerve Excitation, Synaptic Transmission and Muscle Contraction

    Science.gov (United States)

    1993-12-20

    R\\I) (CHARLES A SANDE[RS. Past Chairman {I IElNE 1. KAPLAN . General ,unsel (c-\\ itimol RODNEY W NI(HOI.S. Chief Fiveut,,, Officer [k.x fliui...MUSCARINIC ACETYLCHOLINE RECEPTOR 221 𔃼 -7 acca cr Y. x a ý . a; > -, -~ 2x 1 Ft. 4• ,1; S4" វ - ɜ:4+ 222 ANNALS NEW YORK ACADEMY OF SCIENCES with other...Physiol. 263: C267-C286. 22. KAPLAN , J, H. 1993. Molecular biology of carrier proteins. Cell 72: 13-18. 23. SOEJIMA, M. & A. NOMA. 1984. Mode of

  12. Molecular basis for convergent evolution of glutamate recognition by pentameric ligand-gated ion channels

    DEFF Research Database (Denmark)

    Lynagh, Timothy; Beech, Robin N.; Lalande, Maryline J.

    2015-01-01

    that glutamate recognition requires an arginine residue in the base of the binding site, which originated at least three distinct times according to phylogenetic analysis. Most remarkably, the arginine emerged on the principal face of the binding site in the Lophotrochozoan lineage, but 65 amino acids upstream......Glutamate is an indispensable neurotransmitter, triggering postsynaptic signals upon recognition by postsynaptic receptors. We questioned the phylogenetic position and the molecular details of when and where glutamate recognition arose in the glutamate-gated chloride channels. Experiments revealed......, on the complementary face, in the Ecdysozoan lineage. This combined experimental and computational approach throws new light on the evolution of synaptic signalling....

  13. PREFACE: International Symposium on Molecular Conductors: Novel Functions of Molecular Conductors under Extreme Conditions (ISMC 2008)

    Science.gov (United States)

    Takahashi, Toshihiro; Suzumura, Yoshikazu

    2008-02-01

    The International Symposium on Molecular Conductors 2008 (ISMC2008) was held as the second international symposium of the project entitled `Novel Functions of Molecular Conductors under Extreme Conditions', which was supported by the Grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology in Japan. The project lasted from September 2003 to March 2008, and was completed by this symposium held at Okazaki Conference Center, Institute for Molecular Science, Okazaki, Japan (23-25 July 2008), which about 100 scientists attended. During the symposium, five project teams gave summary talks and exciting talks were given on the topics developed recently not only by the members of the project but also by other scientists including invited speakers from abroad, who are doing active research on molecular conductors. It is expected that papers presented in the symposium will give valuable hints for the next step in the research of this field. Therefore the organizers of this symposium decided to publish this proceedings in order to demonstrate these activities, not only for the local community of the project, but also for the broad society of international scientists who are interested in molecular conductors. The editors, who are also the organizers of this symposium, believe that this proceedings provides a significant and relevant contribution to the field of molecular conductors since it is the first time we have published such a proceedings as an electronic journal. We note that all papers published in this volume of Journal of Physics: Conference Series have been peer reviewed by expert referees. Editors made every effort to satisfy the criterion of a proceedings journal published by IOP Publishing. Toshihiro Takahashi and Yoshikazu Suzumura Editors: Toshihiro Takahashi (Gakushuin University) (Chairman) Kazushi Kanoda (University of Tokyo) Seiichi Kagoshima (University of Tokyo) Takehiko Mori (Tokyo

  14. Molecular mechanisms of nematode-nematophagous microbe interactions: basis for biological control of plant-parasitic nematodes.

    Science.gov (United States)

    Li, Juan; Zou, Chenggang; Xu, Jianping; Ji, Xinglai; Niu, Xuemei; Yang, Jinkui; Huang, Xiaowei; Zhang, Ke-Qin

    2015-01-01

    Plant-parasitic nematodes cause significant damage to a broad range of vegetables and agricultural crops throughout the world. As the natural enemies of nematodes, nematophagous microorganisms offer a promising approach to control the nematode pests. Some of these microorganisms produce traps to capture and kill the worms from the outside. Others act as internal parasites to produce toxins and virulence factors to kill the nematodes from within. Understanding the molecular basis of microbe-nematode interactions provides crucial insights for developing effective biological control agents against plant-parasitic nematodes. Here, we review recent advances in our understanding of the interactions between nematodes and nematophagous microorganisms, with a focus on the molecular mechanisms by which nematophagous microorganisms infect nematodes and on the nematode defense against pathogenic attacks. We conclude by discussing several key areas for future research and development, including potential approaches to apply our recent understandings to develop effective biocontrol strategies.

  15. Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology.

    Science.gov (United States)

    Wu, Wei; Sanguinetti, Michael C

    2016-06-01

    Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

    Directory of Open Access Journals (Sweden)

    Adi Lahiani

    2017-03-01

    Full Text Available An understanding of the molecular mechanisms by which microbial, plant or animal-secreted toxins exert their action provides the most important element for assessment of human health risks and opens new insights into therapies addressing a plethora of pathologies, ranging from neurological disorders to cancer, using toxinomimetic agents. Recently, molecular and cellular biology dissecting tools have provided a wealth of information on the action of these diverse toxins, yet, an integrated framework to explain their selective toxicity is still lacking. In this review, specific examples of different toxins are emphasized to illustrate the fundamental mechanisms of toxicity at different biochemical, molecular and cellular- levels with particular consideration for the nervous system. The target of primary action has been highlighted and operationally classified into 13 sub-categories. Selected examples of toxins were assigned to each target category, denominated as portal, and the modulation of the different portal’s signaling was featured. The first portal encompasses the plasma membrane lipid domains, which give rise to pores when challenged for example with pardaxin, a fish toxin, or is subject to degradation when enzymes of lipid metabolism such as phospholipases A2 (PLA2 or phospholipase C (PLC act upon it. Several major portals consist of ion channels, pumps, transporters and ligand gated ionotropic receptors which many toxins act on, disturbing the intracellular ion homeostasis. Another group of portals consists of G-protein-coupled and tyrosine kinase receptors that, upon interaction with discrete toxins, alter second messengers towards pathological levels. Lastly, subcellular organelles such as mitochondria, nucleus, protein- and RNA-synthesis machineries, cytoskeletal networks and exocytic vesicles are also portals targeted and deregulated by other diverse group of toxins. A fundamental concept can be drawn from these seemingly different

  17. Molecular and Genetic Basis of Hereditary Connective-Tissue Diseases Accompanied by Frequent Fractures

    Directory of Open Access Journals (Sweden)

    G. T. Yakhyaeva

    2016-01-01

    Full Text Available Frequent bone fractures in infancy require the elimination of a large number (> 100 of genetic disorders. The modern diagnostic method of hereditary diseases characterized by debilitating course is a new generation sequencing. The article presents the results of molecular-genetic study conducted in 18 patients with clinical symptoms of connective tissue disorders. 10 (56% patients had mutations in the genes encoding type I collagen chains, leading to the development of osteogenesis imperfecta, 5 (28% — mutations in IV and V type collagen genes that are responsible for the development of Ehlers-Danlos syndrome. 3 (17% patients had mutations in the gene encoding fibrillin-1 protein, deficiency of which is manifested by Marfan syndrome. However, the correlation between patient's phenotype and discovered mutations in the investigated gene is established not in all cases.

  18. The Molecular Basis of Neural Memory. Part 7: Neural Intelligence (NI versus Artificial Intelligence (AI

    Directory of Open Access Journals (Sweden)

    Gerard Marx

    2017-07-01

    Full Text Available The link of memory to intelligence is incontestable, though the development of electronic artifacts with memory has confounded cognitive and computer scientists’ conception of memory and its relevance to “intelligence”. We propose two categories of “Intelligence”: (1 Logical (objective — mathematics, numbers, pattern recognition, games, programmable in binary format. (2 Emotive (subjective — sensations, feelings, perceptions, goals desires, sociability, sex, food, love. The 1st has been reduced to computational algorithms of which we are well versed, witness global technology and the internet. The 2nd relates to the mysterious process whereby (psychic emotive states are achieved by neural beings sensing, comprehending, remembering and dealing with their surroundings. Many theories and philosophies have been forwarded to rationalize this process, but as neuroscientists, we remain dissatisfied. Our own musings on universal neural memory, suggest a tripartite mechanism involving neurons interacting with their surroundings, notably the neural extracellular matrix (nECM with dopants [trace metals and neurotransmitters (NTs]. In particular, the NTs are the molecular encoders of emotive states. We have developed a chemographic representation of such a molecular code.To quote Longuet-Higgins, “Perhaps it is time for the term ‘artificial intelligence’ to be replaced by something more modest and less provisional”. We suggest “artifact intelligence” (ARTI or “machine intelligence” (MI, neither of which imply emulation of emotive neural processes, but simply refer to the ‘demotive’ (lacking emotive quality capability of electronic artifacts that employ a recall function, to calculate algorithms.

  19. 76 FR 36993 - Guidance Under Section 956 for Determining the Basis of Property Acquired in Certain...

    Science.gov (United States)

    2011-06-24

    ... the US2 stock from US2, the issuing corporation. Therefore, because CFC's adjusted basis in the US2... States property is stock of a domestic corporation described in section 956(c)(1)(B) or an obligation of... corporation from the domestic issuing corporation. Specified United States property does not include property...

  20. Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Jee Un Lee

    2017-01-01

    Full Text Available Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFα in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFα by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFα trimer. Additionally, the DE loop and the GH loop of TNFα play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFα. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFα-receptor interaction. A comprehensive comparison of the interactions of TNFα blockers with TNFα revealed the epitope diversity on the surface of TNFα, providing a better understanding of the molecular mechanism of TNFα blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFα.

  1. Natural emulsifiers - Biosurfactants, phospholipids, biopolymers, and colloidal particles: Molecular and physicochemical basis of functional performance.

    Science.gov (United States)

    McClements, David Julian; Gumus, Cansu Ekin

    2016-08-01

    There is increasing consumer pressure for commercial products that are more natural, sustainable, and environmentally friendly, including foods, cosmetics, detergents, and personal care products. Industry has responded by trying to identify natural alternatives to synthetic functional ingredients within these products. The focus of this review article is on the replacement of synthetic surfactants with natural emulsifiers, such as amphiphilic proteins, polysaccharides, biosurfactants, phospholipids, and bioparticles. In particular, the physicochemical basis of emulsion formation and stabilization by natural emulsifiers is discussed, and the benefits and limitations of different natural emulsifiers are compared. Surface-active polysaccharides typically have to be used at relatively high levels to produce small droplets, but the droplets formed are highly resistant to environmental changes. Conversely, surface-active proteins are typically utilized at low levels, but the droplets formed are highly sensitive to changes in pH, ionic strength, and temperature. Certain phospholipids are capable of producing small oil droplets during homogenization, but again the droplets formed are highly sensitive to changes in environmental conditions. Biosurfactants (saponins) can be utilized at low levels to form fine oil droplets that remain stable over a range of environmental conditions. Some nature-derived nanoparticles (e.g., cellulose, chitosan, and starch) are effective at stabilizing emulsions containing relatively large oil droplets. Future research is encouraged to identify, isolate, purify, and characterize new types of natural emulsifier, and to test their efficacy in food, cosmetic, detergent, personal care, and other products. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Molecular basis for the mutagenic and lethal effects of ultraviolet irradiation. Research accomplishments (1968 to present)

    International Nuclear Information System (INIS)

    Grossman, L.

    1978-01-01

    Earlier work on the chemical basis of mutagenesis led to certain chemical generalities sufficient to explain how certain mutagens such as uv light and hydroxylamine functioned in information transfer systems (replicative, transcriptive and translational). When such modifications were applied to biologically active DNA in a controlled manner biological expression was non-stoichiometric because much of the damage was removed from the DNA by repair systems. Our efforts were then directed to these systems which led to: (1) the isolation, purification and characterization of endonucleases responsible for the first and controlling step in DNA repair - referred to as incision in both M. luteus and E. coli. The biological role of these enzymes was inferred in appropriate mutants; (2) the isolation, purification and characterization of exonucleases responsible for the removal or excision of damaged nucleotides in M. luteus and human placental trophoblasts; (3) the repair of uv damaged biologically active transforming and transfecting DNAs by purified endonucleases, exonucleases, DNA polymerase I and polynucleotide ligase from M. luteus and E. coli; (4) the characterization of the dual gene control for incision phenomenon in M. luteus and E. coli; and (5) isolation, purification and characterization of repair enzymes from human placenta

  3. Cellular and molecular basis of chronic constipation: taking the functional/idiopathic label out.

    Science.gov (United States)

    Bassotti, Gabrio; Villanacci, Vincenzo; Creţoiu, Dragos; Creţoiu, Sanda Maria; Becheanu, Gabriel

    2013-07-14

    In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors' work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality.

  4. Molecular basis for the reproductive division of labour in a lower termite

    Directory of Open Access Journals (Sweden)

    Rehli Michael

    2007-06-01

    Full Text Available Abstract Background Polyphenism, the expression of different phenotypes with the same genetic background, is well known for social insects. The substantial physiological and morphological differences among the castes generally are the result of differential gene expression. In lower termites, workers are developmentally flexible to become neotenic replacement reproductives via a single moult after the death of the founding reproductives. Thus, both castes (neotenics and workers are expected to differ mainly in the expression of genes linked to reproductive division of labour, which constitutes the fundamental basis of insect societies. Results Representational difference analysis of cDNAs was used to study differential gene expression between neotenics and workers in the drywood termite Cryptotermes secundus (Kalotermitidae. We identified and, at least partially cloned five novel genes that were highly expressed in female neotenics. Quantitative real-time PCR analysis of all five genes in different castes (neotenics, founding reproductives, winged sexuals and workers of both sexes confirmed the differential expression patterns. In addition, the relative expression of these genes was determined in three body parts of female neotenics (head, thorax, and abdomen using quantitative real-time PCR. Conclusion The identified genes could be involved in the control and regulation of reproductive division of labour. Interestingly, this study revealed an expression pattern partly similar to social Hymenoptera indicating both common and species-specific regulatory mechanisms in hemimetabolous and holometabolous social insects.

  5. Molecular basis for PrimPol recruitment to replication forks by RPA.

    Science.gov (United States)

    Guilliam, Thomas A; Brissett, Nigel C; Ehlinger, Aaron; Keen, Benjamin A; Kolesar, Peter; Taylor, Elaine M; Bailey, Laura J; Lindsay, Howard D; Chazin, Walter J; Doherty, Aidan J

    2017-05-23

    DNA damage and secondary structures can stall the replication machinery. Cells possess numerous tolerance mechanisms to complete genome duplication in the presence of such impediments. In addition to translesion synthesis (TLS) polymerases, most eukaryotic cells contain a multifunctional replicative enzyme called primase-polymerase (PrimPol) that is capable of directly bypassing DNA damage by TLS, as well as repriming replication downstream of impediments. Here, we report that PrimPol is recruited to reprime through its interaction with RPA. Using biophysical and crystallographic approaches, we identify that PrimPol possesses two RPA-binding motifs and ascertained the key residues required for these interactions. We demonstrate that one of these motifs is critical for PrimPol's recruitment to stalled replication forks in vivo. In addition, biochemical analysis reveals that RPA serves to stimulate the primase activity of PrimPol. Together, these findings provide significant molecular insights into PrimPol's mode of recruitment to stalled forks to facilitate repriming and restart.

  6. Introduction to the molecular basis of cancer metabolism and the Warburg effect.

    Science.gov (United States)

    Ngo, Darleen C; Ververis, Katherine; Tortorella, Stephanie M; Karagiannis, Tom C

    2015-04-01

    In differentiated normal cells, the conventional route of glucose metabolism involves glycolysis, followed by the citric acid cycle and electron transport chain to generate usable energy in the form of adenosine triphosphate (ATP). This occurs in the presence of oxygen. In hypoxic conditions, normal cells undergo anaerobic glycolysis to yield significantly less energy producing lactate as a product. As first highlighted in the 1920s by Otto Warburg, the metabolism exhibited by tumor cells involves an increased rate of aerobic glycolysis, known as the Warburg effect. In aerobic glycolysis, pyruvate molecules yielded from glycolysis are converted into fewer molecules of ATP even in the presence of oxygen. Evidence indicates that the reasons as to why tumor cells undergo aerobic glycolysis include: (1) the shift in priority to accumulate biomass rather than energy production, (2) the evasion of apoptosis as fewer reactive oxygen species are released by the mitochondria and (3) the production of lactate to further fuel growth of tumors. In this mini-review we discuss emerging molecular aspects of cancer metabolism and the Warburg effect. Aspects of the Warburg effect are analyzed in the context of the established hallmarks of cancer including the role of oncogenes and tumor suppressor genes.

  7. The molecular basis of nutritional intervention in multiple sclerosis: a narrative review.

    Science.gov (United States)

    Riccio, P

    2011-08-01

    It is commonly accepted that nutrition is one of the possible environmental factors involved in the pathogenesis of multiple sclerosis (MS), but its role as complementary MS treatment is unclear and largely disregarded. At present, MS therapy is not associated to a particular diet, probably due to lack of information on the effects of nutrition on the disease. To overcome the distrust of the usefulness of dietary control in MS and to encourage nutritional interventions in the course of the disease, it is necessary to assess the nature and the role of bioactive dietary molecules and their targets, and establish how a dietary control can influence cell metabolism and improve the wellness of MS patients. The aim of this review is to provide a rationale for a nutritional intervention in MS by evaluating at the molecular level the effects of dietary molecules on the inflammatory and autoimmune processes involved in the disease. Present data reveal that healthy dietary molecules have a pleiotropic role and are able to change cell metabolism from anabolism to catabolism and down-regulate inflammation by interacting with enzymes, nuclear receptors and transcriptional factors. The control of gut dysbiosis and the combination of hypo-caloric, low-fat diets with specific vitamins, oligoelements and dietary integrators, including fish oil and polyphenols, may slow-down the progression of the disease and ameliorate the wellness of MS patients. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and -nonresponsive forms of gyrate atrophy

    International Nuclear Information System (INIS)

    Ramesh, V.; McClatchey, A.I.; Ramesh, N.; Benoit, L.A.; Berson, E.L.; Shih, V.E.; Gusella, J.F.

    1988-01-01

    Gyrate atrophy (GA), a recessive eye disease involving progressive loss of vision due to chorioretinal degeneration, is associated with a deficiency of the mitochondrial enzyme ornithine aminotransferase with consequent hyperornithinemia. Genetic heterogeneity of GA has been suggested by the demonstration that administration of pyridoxine to increase the level of pyridoxal phosphate, a cofactor of OATase, reduces hyperornithinemia in a subset of patients. The authors have cloned and sequences cDNAs for OATase from two GA patients, one responsive and one nonresponsive to pyridoxine treatment. The respective cDNAs contained different single missense mutations, which were sufficient to eliminate OATase activity when each cDNA was tested in a eukaryotic expression system. However, like the enzyme in fibroblasts from the pyridoxine-responsive patient, OATase encoded by the corresponding cDNA from this individual showed a significant increase in activity when assayed in the presence of an increased pyridoxal phosphate concentration. These data firmly establish that both pyridoxine responsive and nonresponsive forms of GA result from mutations in the OATase structural gene. Moreover, they provide a molecular characterization of the primary lesion in a pyridoxine-responsive genetic disorder

  9. The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel.

    Directory of Open Access Journals (Sweden)

    Samira Yazdi

    2016-01-01

    Full Text Available Voltage-gated potassium (KV channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs induce channel opening by modulating the voltage-sensitivity, which can provide effective treatment against refractory epilepsy by means of a ketogenic diet. While PUFAs have been reported to influence the gating mechanism by electrostatic interactions to the voltage-sensor domain (VSD, the exact PUFA-protein interactions are still elusive. In this study, we report on the interactions between the Shaker KV channel in open and closed states and a PUFA-enriched lipid bilayer using microsecond molecular dynamics simulations. We determined a putative PUFA binding site in the open state of the channel located at the protein-lipid interface in the vicinity of the extracellular halves of the S3 and S4 helices of the VSD. In particular, the lipophilic PUFA tail covered a wide range of non-specific hydrophobic interactions in the hydrophobic central core of the protein-lipid interface, while the carboxylic head group displayed more specific interactions to polar/charged residues at the extracellular regions of the S3 and S4 helices, encompassing the S3-S4 linker. Moreover, by studying the interactions between saturated fatty acids (SFA and the Shaker KV channel, our study confirmed an increased conformational flexibility in the polyunsaturated carbon tails compared to saturated carbon chains, which may explain the specificity of PUFA action on channel proteins.

  10. Structural and Molecular Basis for Coordination in a Viral DNA Packaging Motor.

    Science.gov (United States)

    Mao, Huzhang; Saha, Mitul; Reyes-Aldrete, Emilio; Sherman, Michael B; Woodson, Michael; Atz, Rockney; Grimes, Shelley; Jardine, Paul J; Morais, Marc C

    2016-03-01

    Ring NTPases are a class of ubiquitous molecular motors involved in basic biological partitioning processes. dsDNA viruses encode ring ATPases that translocate their genomes to near-crystalline densities within pre-assembled viral capsids. Here, X-ray crystallography, cryoEM, and biochemical analyses of the dsDNA packaging motor in bacteriophage phi29 show how individual subunits are arranged in a pentameric ATPase ring and suggest how their activities are coordinated to translocate dsDNA. The resulting pseudo-atomic structure of the motor and accompanying functional analyses show how ATP is bound in the ATPase active site; identify two DNA contacts, including a potential DNA translocating loop; demonstrate that a trans-acting arginine finger is involved in coordinating hydrolysis around the ring; and suggest a functional coupling between the arginine finger and the DNA translocating loop. The ability to visualize the motor in action illuminates how the different motor components interact with each other and with their DNA substrate. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Structural and Molecular Basis for Coordination in a Viral DNA Packaging Motor

    Directory of Open Access Journals (Sweden)

    Huzhang Mao

    2016-03-01

    Full Text Available Ring NTPases are a class of ubiquitous molecular motors involved in basic biological partitioning processes. dsDNA viruses encode ring ATPases that translocate their genomes to near-crystalline densities within pre-assembled viral capsids. Here, X-ray crystallography, cryoEM, and biochemical analyses of the dsDNA packaging motor in bacteriophage phi29 show how individual subunits are arranged in a pentameric ATPase ring and suggest how their activities are coordinated to translocate dsDNA. The resulting pseudo-atomic structure of the motor and accompanying functional analyses show how ATP is bound in the ATPase active site; identify two DNA contacts, including a potential DNA translocating loop; demonstrate that a trans-acting arginine finger is involved in coordinating hydrolysis around the ring; and suggest a functional coupling between the arginine finger and the DNA translocating loop. The ability to visualize the motor in action illuminates how the different motor components interact with each other and with their DNA substrate.

  12. The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors.

    Directory of Open Access Journals (Sweden)

    Keith P Romano

    Full Text Available Hepatitis C virus (HCV infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer resistance to nearly all inhibitors in clinical development. Thus, developing the next-generation of drugs that retain activity against a broader spectrum of resistant viral variants requires a comprehensive understanding of the molecular basis of drug resistance. In this study, 16 high-resolution crystal structures of four representative protease inhibitors--telaprevir, danoprevir, vaniprevir and MK-5172--in complex with the wild-type protease and three major drug-resistant variants R155K, A156T and D168A, reveal unique molecular underpinnings of resistance to each drug. The drugs exhibit differential susceptibilities to these protease variants in both enzymatic and antiviral assays. Telaprevir, danoprevir and vaniprevir interact directly with sites that confer resistance upon mutation, while MK-5172 interacts in a unique conformation with the catalytic triad. This novel mode of MK-5172 binding explains its retained potency against two multi-drug-resistant variants, R155K and D168A. These findings define the molecular basis of HCV N3/4A protease inhibitor resistance and provide potential strategies for designing robust therapies against this rapidly evolving virus.

  13. 75 FR 62120 - Notice of Availability of Draft Basis for Determination Under Section 3116 of the Ronald W...

    Science.gov (United States)

    2010-10-07

    ... DEPARTMENT OF ENERGY Notice of Availability of Draft Basis for Determination Under Section 3116 of the Ronald W. Reagan National Defense Authorization Act for Fiscal Year 2005 (NDAA) for Closure of the F-Tank Farm at the Savannah River Site AGENCY: U.S. Department of Energy. ACTION: Notice of...

  14. Molecular basis of a novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole

    Directory of Open Access Journals (Sweden)

    Bonaventura Joseph

    2010-07-01

    Full Text Available Abstract Background Elevated blood O2 affinity enhances survival at low O2 pressures, and is perhaps the best known and most broadly accepted evolutionary adjustment of terrestrial vertebrates to environmental hypoxia. This phenotype arises by increasing the intrinsic O2 affinity of the hemoglobin (Hb molecule, by decreasing the intracellular concentration of allosteric effectors (e.g., 2,3-diphosphoglycerate; DPG, or by suppressing the sensitivity of Hb to these physiological cofactors. Results Here we report that strictly fossorial eastern moles (Scalopus aquaticus have evolved a low O2 affinity, DPG-insensitive Hb - contrary to expectations for a mammalian species that is adapted to the chronic hypoxia and hypercapnia of subterranean burrow systems. Molecular modelling indicates that this functional shift is principally attributable to a single charge altering amino acid substitution in the β-type δ-globin chain (δ136Gly→Glu of this species that perturbs electrostatic interactions between the dimer subunits via formation of an intra-chain salt-bridge with δ82Lys. However, this replacement also abolishes key binding sites for the red blood cell effectors Cl-, lactate and DPG (the latter of which is virtually absent from the red cells of this species at δ82Lys, thereby markedly reducing competition for carbamate formation (CO2 binding at the δ-chain N-termini. Conclusions We propose this Hb phenotype illustrates a novel mechanism for adaptively elevating the CO2 carrying capacity of eastern mole blood during burst tunnelling activities associated with subterranean habitation.

  15. The molecular basis of simple relationships between exposure concentration and toxic effects with time.

    Science.gov (United States)

    Tennekes, Henk A; Sánchez-Bayo, Francisco

    2013-07-05

    Understanding the toxicity of chemicals to organisms requires considering the molecular mechanisms involved as well as the relationships between exposure concentration and toxic effects with time. Our current knowledge about such relationships is mainly explained from a toxicodynamic and toxicokinetic perspective. This paper re-introduces an old approach that takes into account the biochemical mode of action and their resulting biological effects over time of exposure. Empirical evidence demonstrates that the Druckrey-Küpfmüller toxicity model, which was validated for chemical carcinogens in the early 1960s, is also applicable to a wide range of toxic compounds in ecotoxicology. According to this model, the character of a poison is primarily determined by the reversibility of critical receptor binding. Chemicals showing irreversible or slowly reversible binding to specific receptors will produce cumulative effects with time of exposure, and whenever the effects are also irreversible (e.g. death) they are reinforced over time; these chemicals have time-cumulative toxicity. Compounds having non-specific receptor binding, or involving slowly reversible binding to some receptors that do not contribute to toxicity, may also be time-dependent; however, their effects depend primarily on the exposure concentration, with time playing a minor role. Consequently, the mechanism of toxic action has important implications for risk assessment. Traditional risk approaches cannot predict the impacts of toxicants with time-cumulative toxicity in the environment. New assessment procedures are needed to evaluate the risk that the latter chemicals pose on humans and the environment. An example is shown to explain how the risk of time-dependent toxicants is underestimated when using current risk assessment protocols. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. Molecular Basis of the Extracellular Ligands Mediated Signaling by the Calcium Sensing Receptor

    Directory of Open Access Journals (Sweden)

    Chen Zhang

    2016-09-01

    Full Text Available Ca2+-sensing receptors (CaSRs play a central role in regulating extracellular calcium concentration ([Ca2+]o homeostasis and many (pathophysiological processes in multiple organs. This regulation is orchestrated by a cooperative response to extracellular stimuli such as small changes in Ca2+, Mg2+, amino acids and other ligands. In addition, CaSR is a pleiotropic receptor regulating several intracellular signaling pathways, including calcium mobilization and intracellular calcium oscillation. Nearly 200 mutations and polymorphisms have been found in CaSR in relation to a variety of human disorders associated with abnormal Ca2+ homeostasis. In this review, we summarize efforts directed at identifying binding sites for calcium and amino acids. Both homotropic cooperativity among multiple calcium binding sites and heterotropic cooperativity between calcium and amino acid were revealed using computational modeling, predictions, and site-directed mutagenesis coupled with functional assays. The hinge region of the bilobed Venus flytrap (VFT domain of CaSR plays a pivotal role in coordinating multiple extracellular stimuli, leading to cooperative responses from the receptor. We further highlight the extensive number of disease-associated mutations that have also been shown to affect CaSR’s cooperative action via several types of mechanisms. These results provide insights into the molecular bases of the structure and functional cooperativity of this receptor and other members of family C of the G protein-coupled receptors (cGPCRs in health and disease states, and may assist in the prospective development of novel receptor-based therapeutics.

  17. Transport Deficiency Is the Molecular Basis of Candida albicans Resistance to Antifungal Oligopeptides

    Directory of Open Access Journals (Sweden)

    Marta Schielmann

    2017-11-01

    Full Text Available Oligopeptides incorporating N3-(4-methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP, an inhibitor of glucosamine-6-phosphate synthase, exhibited growth inhibitory activity against Candida albicans, with minimal inhibitory concentration values in the 0.05–50 μg mL-1 range. Uptake by the peptide permeases was found to be the main factor limiting an anticandidal activity of these compounds. Di- and tripeptide containing FMDP (F2 and F3 were transported by Ptr2p/Ptr22p peptide transporters (PTR and FMDP-containing hexa-, hepta-, and undecapeptide (F6, F7, and F11 were taken up by the oligopeptide transporters (OPT oligopeptide permeases, preferably by Opt2p/Opt3p. A phenotypic, apparent resistance of C. albicans to FMDP-oligopeptides transported by OPT permeases was triggered by the environmental factors, whereas resistance to those taken up by the PTR system had a genetic basis. Anticandidal activity of longer FMDP-oligopeptides was strongly diminished in minimal media containing easily assimilated ammonium sulfate or L-glutamine as the nitrogen source, both known to downregulate expression of the OPT genes. All FMDP-oligopeptides tested were more active at lower pH and this effect was slightly more remarkable for peptides F6, F7, and F11, compared to F2 and F3. Formation of isolated colonies was observed inside the growth inhibitory zones induced by F2 and F3 but not inside those induced by F6, F7, and F11. The vast majority (98% of those colonies did not originate from truly resistant cells. The true resistance of 2% of isolates was due to the impaired transport of di- and to a lower extent, tripeptides. The resistant cells did not exhibit a lower expression of PTR2, PTR22, or OPT1–3 genes, but mutations in the PTR2 gene resulting in T422H, A320S, D119V, and A320S substitutions in the amino acid sequence of Ptr2p were found.

  18. Microbes on building materials - Evaluation of DNA extraction protocols as common basis for molecular analysis

    Energy Technology Data Exchange (ETDEWEB)

    Ettenauer, Joerg D., E-mail: joerg.ettenauer@boku.ac.at [VIBT-BOKU, University of Natural Resources and Life Sciences, Department of Biotechnology, Muthgasse 11, A-1190 Vienna (Austria); Pinar, Guadalupe, E-mail: Guadalupe.Pinar@boku.ac.at [VIBT-BOKU, University of Natural Resources and Life Sciences, Department of Biotechnology, Muthgasse 11, A-1190 Vienna (Austria); Lopandic, Ksenija, E-mail: Ksenija.Lopandic@boku.ac.at [VIBT-BOKU, University of Natural Resources and Life Sciences, Department of Biotechnology, Muthgasse 11, A-1190 Vienna (Austria); Spangl, Bernhard, E-mail: Bernhard.Spangl@boku.ac.at [University of Natural Resources and Life Sciences, Department of Landscape, Spatial and Infrastructure Science, Institute of Applied Statistics and Computing (IASC), Gregor Mendel-Str. 33, A-1180 Vienna (Austria); Ellersdorfer, Guenther, E-mail: Guenther.Ellersdorfer@boku.ac.at [VIBT-BOKU, University of Natural Resources and Life Sciences, Department of Biotechnology, Muthgasse 11, A-1190 Vienna (Austria); Voitl, Christian, E-mail: Christian.Voitl@boku.ac.at [VIBT-BOKU, University of Natural Resources and Life Sciences, Department of Biotechnology, Muthgasse 11, A-1190 Vienna (Austria); Sterflinger, Katja, E-mail: Katja.Sterflinger@boku.ac.at [VIBT-BOKU, University of Natural Resources and Life Sciences, Department of Biotechnology, Muthgasse 11, A-1190 Vienna (Austria)

    2012-11-15

    The study of microbial life in building materials is an emerging topic concerning biodeterioration of materials as well as health risks in houses and at working places. Biodegradation and potential health implications associated with microbial growth in our residues claim for more precise methods for quantification and identification. To date, cultivation experiments are commonly used to gain insight into the microbial diversity. Nowadays, molecular techniques for the identification of microorganisms provide efficient methods that can be applied in this field. The efficiency of DNA extraction is decisive in order to perform a reliable and reproducible quantification of the microorganisms by qPCR or to characterize the structure of the microbial community. In this study we tested thirteen DNA extraction methods and evaluated their efficiency for identifying (1) the quantity of DNA, (2) the quality and purity of DNA and (3) the ability of the DNA to be amplified in a PCR reaction using three universal primer sets for the ITS region of fungi as well as one primer pair targeting the 16S rRNA of bacteria with three typical building materials - common plaster, red brick and gypsum cardboard. DNA concentration measurements showed strong variations among the tested methods and materials. Measurement of the DNA yield showed up to three orders of magnitude variation from the same samples, whereas A260/A280 ratios often prognosticated biases in the PCR amplifications. Visualization of the crude DNA extracts and the comparison of DGGE fingerprints showed additional drawbacks of some methods. The FastDNA Spin kit for soil showed to be the best DNA extraction method and could provide positive results for all tests with the three building materials. Therefore, we suggest this method as a gold standard for quantification of indoor fungi and bacteria in building materials. -- Highlights: Black-Right-Pointing-Pointer Up to thirteen extraction methods were evaluated with three

  19. Microbes on building materials — Evaluation of DNA extraction protocols as common basis for molecular analysis

    International Nuclear Information System (INIS)

    Ettenauer, Jörg D.; Piñar, Guadalupe; Lopandic, Ksenija; Spangl, Bernhard; Ellersdorfer, Günther; Voitl, Christian; Sterflinger, Katja

    2012-01-01

    The study of microbial life in building materials is an emerging topic concerning biodeterioration of materials as well as health risks in houses and at working places. Biodegradation and potential health implications associated with microbial growth in our residues claim for more precise methods for quantification and identification. To date, cultivation experiments are commonly used to gain insight into the microbial diversity. Nowadays, molecular techniques for the identification of microorganisms provide efficient methods that can be applied in this field. The efficiency of DNA extraction is decisive in order to perform a reliable and reproducible quantification of the microorganisms by qPCR or to characterize the structure of the microbial community. In this study we tested thirteen DNA extraction methods and evaluated their efficiency for identifying (1) the quantity of DNA, (2) the quality and purity of DNA and (3) the ability of the DNA to be amplified in a PCR reaction using three universal primer sets for the ITS region of fungi as well as one primer pair targeting the 16S rRNA of bacteria with three typical building materials — common plaster, red brick and gypsum cardboard. DNA concentration measurements showed strong variations among the tested methods and materials. Measurement of the DNA yield showed up to three orders of magnitude variation from the same samples, whereas A260/A280 ratios often prognosticated biases in the PCR amplifications. Visualization of the crude DNA extracts and the comparison of DGGE fingerprints showed additional drawbacks of some methods. The FastDNA Spin kit for soil showed to be the best DNA extraction method and could provide positive results for all tests with the three building materials. Therefore, we suggest this method as a gold standard for quantification of indoor fungi and bacteria in building materials. -- Highlights: ► Up to thirteen extraction methods were evaluated with three building materials.

  20. Investigating molecular basis of lambda-cyhalothrin resistance in an Anopheles funestus population from Senegal.

    Science.gov (United States)

    Samb, Badara; Konate, Lassana; Irving, Helen; Riveron, Jacob M; Dia, Ibrahima; Faye, Ousmane; Wondji, Charles S

    2016-08-12

    Anopheles funestus is one of the major malaria vectors in tropical Africa, notably in Senegal. The highly anthropophilic and endophilic behaviours of this mosquito make it a good target for vector control operations through the use of insecticide treated nets, long-lasting insecticide nets and indoor residual spraying. However, little is known about patterns of resistance to insecticides and the underlying resistance mechanisms in field populations of this vector in Senegal. Here, we assessed the susceptibility status of An. funestus populations from Gankette Balla, located in northern Senegal and investigated the potential resistance mechanisms. WHO bioassays indicated that An. funestus is resistant to lambda-cyhalothrin 0.05 % (74.64 % mortality), DDT 4 % (83.36 % mortality) and deltamethrin 0.05 % (88.53 % mortality). Suspected resistance was observed to permethrin 0.75 % (91.19 % mortality), bendiocarb 0.1 % (94.13 % mortality) and dieldrin 4 % (96.41 % mortality). However, this population is fully susceptible to malathion 5 % (100 % mortality) and fenitrothion 1 % (100 % mortality). The microarray and qRT-PCR analysis indicated that the lambda-cyhalothrin resistance in Gankette Balla is conferred by metabolic resistance mechanisms under the probable control of cytochrome P450 genes among which CYP6M7 is the most overexpressed. The absence of overexpression of the P450 gene, CYP6P9a, indicates that the resistance mechanism in Senegal is different to that observed in southern Africa. This study represents the first report of pyrethroid and DDT resistance in An. funestus from Senegal and shows that resistance to insecticides is not only confined to An. gambiae as previously thought. Therefore, urgent action should be taken to manage the resistance in this species to ensure the continued effectiveness of malaria control.

  1. The Hawaiian bobtail squid (Euprymna scolopes): a model to study the molecular basis of eukaryote-prokaryote mutualism and the development and evolution of morphological novelties in cephalopods.

    Science.gov (United States)

    Lee, Patricia N; McFall-Ngai, Margaret J; Callaerts, Patrick; de Couet, H Gert

    2009-11-01

    The Hawaiian bobtail squid, Euprymna scolopes, is a cephalopod whose small size, short lifespan, rapid growth, and year-round availability make it suitable as a model organism. E. scolopes is studied in three principal contexts: (1) as a model of cephalopod development; (2) as a model of animal-bacterial symbioses; and (3) as a system for studying adaptations of tissues that interact with light. E. scolopes embryos can be obtained continually and can be reared in the laboratory over an entire generation. The embryos and protective chorions are optically clear, facilitating in situ developmental observations, and can be manipulated experimentally. Many molecular protocols have been developed for studying E. scolopes development. This species is best known, however, for its symbiosis with the luminous marine bacterium Vibrio fischeri and has been used to study determinants of symbiont specificity, the influence of symbiosis on development of the squid light organ, and the mechanisms by which a stable association is achieved. Both partners can be grown independently under laboratory conditions, a feature that offers the unusual opportunity to manipulate the symbiosis experimentally. Molecular and genetic tools have been developed for V. fischeri, and a large expressed sequence tag (EST) database is available for the host symbiotic tissues. Additionally, comparisons between light organ form and function to those of the eye can be made. Both types of tissue interact with light, but have divergent embryonic development. As such, they offer an opportunity to study the molecular basis for the evolution of morphological novelties.

  2. Molecular Basis Underlying Leaf Variegation of a Moth Orchid Mutant (Phalaenopsis aphrodite subsp. formosana

    Directory of Open Access Journals (Sweden)

    Chi-Chu Tsai

    2017-07-01

    Full Text Available Leaf variegation is often the focus of plant breeding. Here, we studied a variegated mutant of Phalaenopsis aphrodite subsp. formosana, which is usually used as a parent of horticultural breeding, to understand its anatomic and genetic regulatory mechanisms in variegation. Chloroplasts with well-organized thylakoids and starch grains were found only in the mesophyll cells of green sectors but not of yellow sectors, confirming that the variegation belongs to the chlorophyll type. The two-dimensional electrophoresis and LC/MS/MS also reveal differential expressions of PsbP and PsbO between the green and yellow leaf sectors. Full-length cDNA sequencing revealed that mutant transcripts were caused by intron retention. When conditioning on the total RNA expression, we found that the functional transcript of PsbO and mutant transcript of PsbP are higher expressed in the yellow sector than in the green sector, suggesting that the post-transcriptional regulation of PsbO and PsbP differentiates the performance between green and yellow sectors. Because PsbP plays an important role in the stability of thylakoid folding, we suggest that the negative regulation of PsbP may inhibit thylakoid development in the yellow sectors. This causes chlorophyll deficiency in the yellow sectors and results in leaf variegation. We also provide evidence of the link of virus CymMV and the formation of variegation according to the differential expression of CymMV between green and yellow sectors.

  3. Myocardial contractility in the echo lab: molecular, cellular and pathophysiological basis

    Directory of Open Access Journals (Sweden)

    Bombardini Tonino

    2005-09-01

    Full Text Available Abstract In the standard accepted concept, contractility is the intrinsic ability of heart muscle to generate force and to shorten, independently of changes in the preload or afterload with fixed heart rates. At molecular level the crux of the contractile process lies in the changing concentrations of Ca2+ ions in the myocardial cytosol. Ca2+ ions enter through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca2+ ions "trigger" the release of more calcium from the sarcoplasmic reticulum (SR and thereby initiate a contraction-relaxation cycle. In the past, several attempts were made to transfer the pure physiological concept of contractility, expressed in the isolated myocardial fiber by the maximal velocity of contraction of unloaded muscle fiber (Vmax, to the in vivo beating heart. Suga and Sagawa achieved this aim by measuring pressure/volume loops in the intact heart: during a positive inotropic intervention, the pressure volume loop reflects a smaller end-systolic volume and a higher end-systolic pressure, so that the slope of the pressure volume relationship moves upward and to the left. The pressure volume relationship is the most reliable index for assessing myocardial contractility in the intact circulation and is almost insensitive to changes in preload and after load. This is widely used in animal studies and occasionally clinically. The limit of the pressure volume relationship is that it fails to take into account the frequency-dependent regulation of contractility: the frequency-dependent control of transmembrane Ca2+ entry via voltage-gated Ca2+ channels provides cardiac cells with a highly sophisticated short-term system for the regulation of intracellular Ca2+ homeostasis. An increased stimulation rate increases the force of contraction: the explanation is repetitive Ca2+ entry with each depolarization and, hence, an accumulation of cytosolic calcium. As the heart

  4. Current insights into the molecular genetic basis of dwarfism in livestock.

    Science.gov (United States)

    Boegheim, Iris J M; Leegwater, Peter A J; van Lith, Hein A; Back, Willem

    2017-06-01

    Impairment of bone growth at a young age leads to dwarfism in adulthood. Dwarfism can be categorised as either proportionate, an overall size reduction without changes in body proportions, or disproportionate, a size reduction in one or more limbs, with changes in body proportions. Many forms of dwarfism are inherited and result from structural disruptions or disrupted signalling pathways. Hormonal disruptions are evident in Brooksville miniature Brahman cattle and Z-linked dwarfism in chickens, caused by mutations in GH1 and GHR. Furthermore, mutations in IHH are the underlying cause of creeper achondroplasia in chickens. Belgian blue cattle display proportionate dwarfism caused by a mutation in RNF11, while American Angus cattle dwarfism is caused by a mutation in PRKG2. Mutations in EVC2 are associated with dwarfism in Japanese brown cattle and Tyrolean grey cattle. Fleckvieh dwarfism is caused by mutations in the GON4L gene. Mutations in COL10A1 and COL2A1 cause dwarfism in pigs and Holstein cattle, both associated with structural disruptions, while several mutations in ACAN are associated with bulldog-type dwarfism in Dexter cattle and dwarfism in American miniature horses. In other equine breeds, such as Shetland ponies and Friesian horses, dwarfism is caused by mutations in SHOX and B4GALT7. In Texel sheep, chondrodysplasia is associated with a deletion in SLC13A1. This review discusses genes known to be involved in these and other forms of dwarfism in livestock. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. A molecular basis behind heterophylly in an amphibious plant, Ranunculus trichophyllus.

    Science.gov (United States)

    Kim, Juhyun; Joo, Youngsung; Kyung, Jinseul; Jeon, Myeongjune; Park, Jong Yoon; Lee, Ho Gyun; Chung, Doo Soo; Lee, Eunju; Lee, Ilha

    2018-02-01

    Ranunculus trichophyllus is an amphibious plant that produces thin and cylindrical leaves if grown under water but thick and broad leaves if grown on land. We found that such heterophylly is widely controlled by two plant hormones, abscisic acid (ABA) and ethylene, which control terrestrial and aquatic leaf development respectively. Aquatic leaves produced higher levels of ethylene but lower levels of ABA than terrestrial leaves. In aquatic leaves, their distinct traits with narrow shape, lack of stomata, and reduced vessel development were caused by EIN3-mediated overactivation of abaxial genes, RtKANADIs, and accompanying with reductions of STOMAGEN and VASCULAR-RELATED NAC-DOMAIN7 (VDN7). In contrast, in terrestrial leaves, ABI3-mediated activation of the adaxial genes, RtHD-ZIPIIIs, and STOMAGEN and VDN7 established leaf polarity, and stomata and vessel developments. Heterophylly of R.trichophyllus could be also induced by external cues such as cold and hypoxia, which is accompanied with the changes in the expression of leaf polarity genes similar to aquatic response. A closely-related land plant R. sceleratus did not show such heterophyllic responses, suggesting that the changes in the ABA/ethylene signaling and leaf polarity are one of key evolutionary steps for aquatic adaptation.

  6. Molecular basis of adaptation to high soil boron in wheat landraces and elite cultivars.

    Science.gov (United States)

    Pallotta, Margaret; Schnurbusch, Thorsten; Hayes, Julie; Hay, Alison; Baumann, Ute; Paull, Jeff; Langridge, Peter; Sutton, Tim

    2014-10-02

    Environmental constraints severely restrict crop yields in most production environments, and expanding the use of variation will underpin future progress in breeding. In semi-arid environments boron toxicity constrains productivity, and genetic improvement is the only effective strategy for addressing the problem. Wheat breeders have sought and used available genetic diversity from landraces to maintain yield in these environments; however, the identity of the genes at the major tolerance loci was unknown. Here we describe the identification of near-identical, root-specific boron transporter genes underlying the two major-effect quantitative trait loci for boron tolerance in wheat, Bo1 and Bo4 (ref. 2). We show that tolerance to a high concentration of boron is associated with multiple genomic changes including tetraploid introgression, dispersed gene duplication, and variation in gene structure and transcript level. An allelic series was identified from a panel of bread and durum wheat cultivars and landraces originating from diverse agronomic zones. Our results demonstrate that, during selection, breeders have matched functionally different boron tolerance alleles to specific environments. The characterization of boron tolerance in wheat illustrates the power of the new wheat genomic resources to define key adaptive processes that have underpinned crop improvement.

  7. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann–Pick disease

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yan-Feng; Metcalf, Matthew C.; Garman, Scott C.; Edmunds, Tim; Qiu, Huawei; Wei, Ronnie R. (Sanofi Aventis); (UMASS, Amherst)

    2016-10-26

    Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann–Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients.

  8. Molecular Basis for Electron Flow Within Metal-and Electrode-Reducing Biofilms

    Energy Technology Data Exchange (ETDEWEB)

    Bond, Daniel R. [Univ. of Minnesota, Minneapolis, MN (United States)

    2016-11-01

    Electrochemical, spectral, genetic, and biochemical techniques were developed to reveal that a diverse suite of redox proteins and structural macromolecules outside the cell work together to move electrons long distances between Geobacter cells to metals and electrodes. In this project, we greatly expanded the known participants in the electron transfer pathway of Geobacter. For example, in addition to well-studied pili, polysaccharides contribute to anchoring, different cytochromes are required under different conditions, strategies change with redox potential, and the localization of these components can change depending on where cells are located in a biofilm. By inventing new electrodes compatible with real-time spectral measurements, we were able to visualize the redox status of biofilms in action, leading to a hypothesis that long-distance electron transfer is ultimately limiting in these systems and redox potentials change within biofilms. The goals of this project were met, as we were able to 1) identify new elements crucial to the expression, assembly and function of the extracellular electron transfer phenotype 2) expand spectral and electrochemical techniques to define the mechanism and route of electron transfer through the matrix, and 3) combine this knowledge to build the next generation of genetic tools for study of this complex process.

  9. Molecular biology of castration-resistant prostate cancer: basis for the novel therapeutic targets.

    Science.gov (United States)

    Mellado, Begoña; Marin Aguilera, Mercedes; Pereira, Maria Veronica

    2013-06-01

    Prostate cancer cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration-resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer (CRPC) stage is often mediated by AR signalling. Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients' survival. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated:(1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression,(3)increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer.

  10. The molecular basis for oat intolerance in patients with celiac disease.

    Directory of Open Access Journals (Sweden)

    Helene Arentz-Hansen

    2004-10-01

    Full Text Available BACKGROUND: Celiac disease is a small intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range of clinical manifestations. It is caused by an inappropriate immune response to dietary gluten and is treated with a gluten-free diet. Recent feeding studies have indicated oats to be safe for celiac disease patients, and oats are now often included in the celiac disease diet. This study aimed to investigate whether oat intolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance. METHODS AND FINDINGS: We selected for study nine adults with celiac disease who had a history of oats exposure. Four of the patients had clinical symptoms on an oats-containing diet, and three of these four patients had intestinal inflammation typical of celiac disease at the time of oats exposure. We established oats-avenin-specific and -reactive intestinal T-cell lines from these three patients, as well as from two other patients who appeared to tolerate oats. The avenin-reactive T-cell lines recognized avenin peptides in the context of HLA-DQ2. These peptides have sequences rich in proline and glutamine residues closely resembling wheat gluten epitopes. Deamidation (glutamine-->glutamic acid conversion by tissue transglutaminase was involved in the avenin epitope formation. CONCLUSIONS: We conclude that some celiac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation. Oat intolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who are eating oats but otherwise are adhering to a strict gluten-free diet. Clinical follow-up of celiac disease patients eating oats is advisable.

  11. Electron transfer in keV Li+-Na*(3p) collisions: Pt.2. Molecular basis model

    International Nuclear Information System (INIS)

    Machholm, M.; Courbin, C.

    1996-01-01

    The velocity dependence of state-to-state integral cross sections for electron transfer and excitation in Li + -Na(3s, 3p) collisions is studied in the 0.05-0.3 au velocity range using the impact parameter semi-classical method and a 28-state molecular orbital basis model including a common translation factor. The initial orbital alignment dependence of electron transfer is in fair agreement with recent experiments and with atomic orbital model calculations. The main electron transfer channel from Na*(3p) is to the Li*(2p) states. The integral cross sections from an aligned or oriented Na*(3p) state to an aligned or oriented Li*(2p) state and vice versa and the corresponding alignment and orientation parameters are presented as a function of the impact velocity. (author)

  12. Molecular basis of hereditary C1q deficiency-revisited: identification of several novel disease-causing mutations

    DEFF Research Database (Denmark)

    Schejbel, L; Skattum, L; Hagelberg, S

    2011-01-01

    C1q is the central pattern-recognition molecule in the classical pathway of the complement system and is known to have a key role in the crossroads between adaptive and innate immunity. Hereditary C1q deficiency is a rare genetic condition strongly associated with systemic lupus erythematosus...... and increased susceptibility to bacterial infections. However, the clinical symptoms may vary. For long, the molecular basis of C1q deficiency was ascribed to only six different mutations. In the present report, we describe five new patients with C1q deficiency, present the 12 causative mutations described till...... now and review the clinical spectrum of symptoms found in patients with C1q deficiency. With the results presented here, confirmed C1q deficiency is reported in 64 patients from at least 38 families....

  13. Post-learning molecular reactivation underlies taste memory consolidation

    Directory of Open Access Journals (Sweden)

    Kioko eGuzman-Ramos

    2011-09-01

    Full Text Available It is considered that memory consolidation is a progressive process that requires post-trial stabilization of the information. In this regard, it has been speculated that waves of receptors activation, expression of immediate early genes and replenishment of receptor subunit pools occur to induce functional or morphological changes to maintain the information for longer periods. In this paper, we will review data related to neuronal changes in the post-acquisition stage of taste aversion learning that could be involved in further stabilization of the memory trace. In order to achieve such stabilization, evidence suggests that the functional integrity of the insular cortex (IC and the amygdala (AMY is required. Particularly the increase of extracellular levels of glutamate and activation of N-methyl-D-aspartate (NMDA receptors within the IC shows a main role in the consolidation process. Additionally the modulatory actions of the dopaminergic system in the IC appear to be involved in the mechanisms that lead to taste aversion memory consolidation through the activation of pathways related to enhancement of protein synthesis such as the Protein Kinase A pathway. In summary, we suggest that post-acquisition molecular and neuronal changes underlying memory consolidation are dependent on the interactions between the AMY and the IC.

  14. Dynamic coherence in excitonic molecular complexes under various excitation conditions

    Energy Technology Data Exchange (ETDEWEB)

    Chenu, Aurélia; Malý, Pavel; Mančal, Tomáš, E-mail: mancal@karlov.mff.cuni.cz

    2014-08-17

    Highlights: • Dynamic coherence does not improve energy transfer efficiency in natural conditions. • Photo-induced quantum jumps are discussed in classical context. • Natural time scale of a light excitation event is identified. • Coherence in FMO complex averages out under excitation by neighboring antenna. • This result is valid even in absence of dissipation. - Abstract: We investigate the relevance of dynamic quantum coherence in the energy transfer efficiency of molecular aggregates. We derive the time evolution of the density matrix for an open quantum system excited by light or by a neighboring antenna. Unlike in the classical case, the quantum description does not allow for a formal decomposition of the dynamics into sudden jumps in an observable quantity – an expectation value. Rather, there is a natural finite time-scale associated with the excitation process. We propose a simple experiment to test the influence of this time scale on the yield of photosynthesis. We demonstrate, using typical parameters of the Fenna–Matthews–Olson (FMO) complex and a typical energy transfer rate from the chlorosome baseplate, that dynamic coherences are averaged out in the complex even when the FMO model is completely free of all dissipation and dephasing.

  15. Novel methods for the molecular discrimination of Fasciola spp. on the basis of nuclear protein-coding genes.

    Science.gov (United States)

    Shoriki, Takuya; Ichikawa-Seki, Madoka; Suganuma, Keisuke; Naito, Ikunori; Hayashi, Kei; Nakao, Minoru; Aita, Junya; Mohanta, Uday Kumar; Inoue, Noboru; Murakami, Kenji; Itagaki, Tadashi

    2016-06-01

    Fasciolosis is an economically important disease of livestock caused by Fasciola hepatica, Fasciola gigantica, and aspermic Fasciola flukes. The aspermic Fasciola flukes have been discriminated morphologically from the two other species by the absence of sperm in their seminal vesicles. To date, the molecular discrimination of F. hepatica and F. gigantica has relied on the nucleotide sequences of the internal transcribed spacer 1 (ITS1) region. However, ITS1 genotypes of aspermic Fasciola flukes cannot be clearly differentiated from those of F. hepatica and F. gigantica. Therefore, more precise and robust methods are required to discriminate Fasciola spp. In this study, we developed PCR restriction fragment length polymorphism and multiplex PCR methods to discriminate F. hepatica, F. gigantica, and aspermic Fasciola flukes on the basis of the nuclear protein-coding genes, phosphoenolpyruvate carboxykinase and DNA polymerase delta, which are single locus genes in most eukaryotes. All aspermic Fasciola flukes used in this study had mixed fragment pattern of F. hepatica and F. gigantica for both of these genes, suggesting that the flukes are descended through hybridization between the two species. These molecular methods will facilitate the identification of F. hepatica, F. gigantica, and aspermic Fasciola flukes, and will also prove useful in etiological studies of fasciolosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Computational Modelling of Dapsone Interaction With Dihydropteroate Synthase in Mycobacterium leprae; Insights Into Molecular Basis of Dapsone Resistance in Leprosy.

    Science.gov (United States)

    Chaitanya V, Sundeep; Das, Madhusmita; Bhat, Pritesh; Ebenezer, Mannam

    2015-10-01

    The molecular basis for determination of resistance to anti-leprosy drugs is the presence of point mutations within the genes of Mycobacterium leprae (M. leprae) that encode active drug targets. The downstream structural and functional implications of these point mutations on drug targets were scarcely studied. In this study, we utilized computational tools to develop native and mutant protein models for 5 point mutations at codon positions 53 and 55 in 6-hydroxymethyl-7, 8-dihydropteroate synthase (DHPS) of M. leprae, an active target for dapsone encoded by folp1 gene, that confer resistance to dapsone. Molecular docking was performed to identify variations in dapsone interaction with mutant DHPS in terms of hydrogen bonding, hydrophobic interactions, and energy changes. Schrodinger Suite 2014-3 was used to build homology models and in performing molecular docking. An increase in volume of the binding cavities of mutant structures was noted when compared to native form indicating a weakening in interaction (60.7 Å(3) in native vs. 233.6 Å(3) in Thr53Ala, 659.9 Å(3) in Thr53Ile, 400 Å(3) for Thr53Val, 385 Å(3) for Pro55Arg, and 210 Å(3) for Pro55Leu). This was also reflected by changes in hydrogen bonds and decrease in hydrophobic interactions in the mutant models. The total binding energy (ΔG) decreased significantly in mutant forms when compared to the native form (-51.92 Kcal/mol for native vs. -35.64, -35.24, -46.47, -47.69, and -41.36 Kcal/mol for mutations Thr53Ala, Thr53Ile, Thr53Val, Pro55Arg, and Pro55Leu, respectively. In brief, this analysis provided structural and mechanistic insights to the degree of dapsone resistance contributed by each of these DHPS mutants in leprosy. © 2015 Wiley Periodicals, Inc.

  17. Dynamic Fault Diagnosis for Semi-Batch Reactor under Closed-Loop Control via Independent Radial Basis Function Neural Network

    OpenAIRE

    Abdelkarim M. Ertiame; D. W. Yu; D. L. Yu; J. B. Gomm

    2015-01-01

    In this paper, a robust fault detection and isolation (FDI) scheme is developed to monitor a multivariable nonlinear chemical process called the Chylla-Haase polymerization reactor, when it is under the cascade PI control. The scheme employs a radial basis function neural network (RBFNN) in an independent mode to model the process dynamics, and using the weighted sum-squared prediction error as the residual. The Recursive Orthogonal Least Squares algorithm (ROLS) is emplo...

  18. Analysis of insulation material deterioration under the LOCA simulated environment on the basis of reaction kinetics

    Energy Technology Data Exchange (ETDEWEB)

    Okada, Sohei; Kusama, Yasuo; Ito, Masayuki; Yagi, Toshiaki; Yoshikawa, Masato (Japan Atomic Energy Research Inst., Takasaki, Gunma. Takasaki Radiation Chemistry Research Establishment)

    1982-12-01

    In the type test of the electric cables installed in reactor containment vessels, it is considerably difficult to perform the testing over a year once in a while to simulate the accidental environment containing radiation and high temperature steam. Two requirements which seem to be more realistic as compared with the above mentioned testing method are inconsistent with each other. To solve this problem, a general rule of deterioration or the expression by an equation is necessary, which enables the extrapolation to show that a short term testing stands on the safety side. The authors have tried to numerically analyze the change of mechanical characteristics of ethylene-propylene rubber (EPR) and Hypalon which are, important as the materials for PH cables (fire-retardant, EP rubber-insulated, chlorosulfonated polyethylene-sheathed cable), in a complex environment of radiation, steam and chemical spray simulating PWR LOCA conditions. In this report, a method is proposed to analyze and estimate the properties by the regression analysis technique on the basis of reaction kinetics, and the analyzed results are described in the order of experiment, analysis method and the results and consideration. The deterioration of the elongation P = e/esub(o) of EPR and Hypalon in the above described complex environment can be represented by the equation - dP/dt = KPsup(n). The exponent n varied in the cases when air is contained or not in that environment, suggesting that the different reactions are dominant in both conditions, respectively. For EPR, n was close to 2 if air was not contained and close to 1 if air was contained in the system.

  19. Revisiting the Neural Basis of Acquired Amusia: Lesion Patterns and Structural Changes Underlying Amusia Recovery.

    Science.gov (United States)

    Sihvonen, Aleksi J; Ripollés, Pablo; Rodríguez-Fornells, Antoni; Soinila, Seppo; Särkämö, Teppo

    2017-01-01

    Although, acquired amusia is a common deficit following stroke, relatively little is still known about its precise neural basis, let alone to its recovery. Recently, we performed a voxel-based lesion-symptom mapping (VLSM) and morphometry (VBM) study which revealed a right lateralized lesion pattern, and longitudinal gray matter volume (GMV) and white matter volume (WMV) changes that were specifically associated with acquired amusia after stroke. In the present study, using a larger sample of stroke patients ( N = 90), we aimed to replicate and extend the previous structural findings as well as to determine the lesion patterns and volumetric changes associated with amusia recovery. Structural MRIs were acquired at acute and 6-month post-stroke stages. Music perception was behaviorally assessed at acute and 3-month post-stroke stages using the Scale and Rhythm subtests of the Montreal Battery of Evaluation of Amusia (MBEA). Using these scores, the patients were classified as non-amusic, recovered amusic, and non-recovered amusic. The results of the acute stage VLSM analyses and the longitudinal VBM analyses converged to show that more severe and persistent (non-recovered) amusia was associated with an extensive pattern of lesions and GMV/WMV decrease in right temporal, frontal, parietal, striatal, and limbic areas. In contrast, less severe and transient (recovered) amusia was linked to lesions specifically in left inferior frontal gyrus as well as to a GMV decrease in right parietal areas. Separate continuous analyses of MBEA Scale and Rhythm scores showed extensively overlapping lesion pattern in right temporal, frontal, and subcortical structures as well as in the right insula. Interestingly, the recovered pitch amusia was related to smaller GMV decreases in the temporoparietal junction whereas the recovered rhythm amusia was associated to smaller GMV decreases in the inferior temporal pole. Overall, the results provide a more comprehensive picture of the lesions

  20. Revisiting the Neural Basis of Acquired Amusia: Lesion Patterns and Structural Changes Underlying Amusia Recovery

    Science.gov (United States)

    Sihvonen, Aleksi J.; Ripollés, Pablo; Rodríguez-Fornells, Antoni; Soinila, Seppo; Särkämö, Teppo

    2017-01-01

    Although, acquired amusia is a common deficit following stroke, relatively little is still known about its precise neural basis, let alone to its recovery. Recently, we performed a voxel-based lesion-symptom mapping (VLSM) and morphometry (VBM) study which revealed a right lateralized lesion pattern, and longitudinal gray matter volume (GMV) and white matter volume (WMV) changes that were specifically associated with acquired amusia after stroke. In the present study, using a larger sample of stroke patients (N = 90), we aimed to replicate and extend the previous structural findings as well as to determine the lesion patterns and volumetric changes associated with amusia recovery. Structural MRIs were acquired at acute and 6-month post-stroke stages. Music perception was behaviorally assessed at acute and 3-month post-stroke stages using the Scale and Rhythm subtests of the Montreal Battery of Evaluation of Amusia (MBEA). Using these scores, the patients were classified as non-amusic, recovered amusic, and non-recovered amusic. The results of the acute stage VLSM analyses and the longitudinal VBM analyses converged to show that more severe and persistent (non-recovered) amusia was associated with an extensive pattern of lesions and GMV/WMV decrease in right temporal, frontal, parietal, striatal, and limbic areas. In contrast, less severe and transient (recovered) amusia was linked to lesions specifically in left inferior frontal gyrus as well as to a GMV decrease in right parietal areas. Separate continuous analyses of MBEA Scale and Rhythm scores showed extensively overlapping lesion pattern in right temporal, frontal, and subcortical structures as well as in the right insula. Interestingly, the recovered pitch amusia was related to smaller GMV decreases in the temporoparietal junction whereas the recovered rhythm amusia was associated to smaller GMV decreases in the inferior temporal pole. Overall, the results provide a more comprehensive picture of the lesions

  1. Revisiting the Neural Basis of Acquired Amusia: Lesion Patterns and Structural Changes Underlying Amusia Recovery

    Directory of Open Access Journals (Sweden)

    Aleksi J. Sihvonen

    2017-07-01

    Full Text Available Although, acquired amusia is a common deficit following stroke, relatively little is still known about its precise neural basis, let alone to its recovery. Recently, we performed a voxel-based lesion-symptom mapping (VLSM and morphometry (VBM study which revealed a right lateralized lesion pattern, and longitudinal gray matter volume (GMV and white matter volume (WMV changes that were specifically associated with acquired amusia after stroke. In the present study, using a larger sample of stroke patients (N = 90, we aimed to replicate and extend the previous structural findings as well as to determine the lesion patterns and volumetric changes associated with amusia recovery. Structural MRIs were acquired at acute and 6-month post-stroke stages. Music perception was behaviorally assessed at acute and 3-month post-stroke stages using the Scale and Rhythm subtests of the Montreal Battery of Evaluation of Amusia (MBEA. Using these scores, the patients were classified as non-amusic, recovered amusic, and non-recovered amusic. The results of the acute stage VLSM analyses and the longitudinal VBM analyses converged to show that more severe and persistent (non-recovered amusia was associated with an extensive pattern of lesions and GMV/WMV decrease in right temporal, frontal, parietal, striatal, and limbic areas. In contrast, less severe and transient (recovered amusia was linked to lesions specifically in left inferior frontal gyrus as well as to a GMV decrease in right parietal areas. Separate continuous analyses of MBEA Scale and Rhythm scores showed extensively overlapping lesion pattern in right temporal, frontal, and subcortical structures as well as in the right insula. Interestingly, the recovered pitch amusia was related to smaller GMV decreases in the temporoparietal junction whereas the recovered rhythm amusia was associated to smaller GMV decreases in the inferior temporal pole. Overall, the results provide a more comprehensive picture of

  2. Morphological and ecological preadaptations as the basis of bird synanthropization under transformed environment conditions

    Science.gov (United States)

    Rakhimov, I. I.; Ibragimova, K. K.

    2018-01-01

    Bird synanthropization is connected with a thorough and serious reconstruction of their biology and is a demonstration of changes currently occurring in the biosphere due to human influence. Nutritional and nesting conditions as well as protection due to urban characteristics are advantage factors that affect their populations. Under these conditions, the adaptive potential of species can be realized. Adaptations to a new and in-distinctive environment appear due to preadaptations. The synanthropization process of species happens without speciation by expression of existing genetic variation of morphological and ecological characteristics.

  3. [Selection of occlusal scheme on the basis of pressure distribution on supporting structures under complete dentures].

    Science.gov (United States)

    Nagao, Kan; Kawano, Fumiaki; Ichikawa, Tetsuo

    2004-12-01

    In case of making complete dentures, we have to consider not only denture stability but also the restoration of aesthetics and function such as mastication and speech. However these are contradictory theoretically from the point of view of denture stability, and it is very difficult to satisfy both requirements in the case of a patient who has poor upper and lower alveolar ridges. We investigated the effect of artificial posterior teeth form and occlusal scheme on the distribution of pressure on supporting structures under complete dentures during mastication with upper and lower edentulous simulators. In this report, a guideline for the selection of occlusal scheme for complete dentures, based on our previous investigations, is described. The occlusal scheme remarkably affected the distribution of pressure under simulated complete dentures, as shown by comparing the distribution of pressure using two different occlusal schemes:fully balanced occlusion and lingualized occlusion. However other factors such as posterior teeth form and position affect the distribution of pressure as well, and are related to each other. Therefore, not only occlusal scheme but also posterior artificial teeth form has to be considered, and the form of posterior teeth should be carefully and comprehensively decided when making complete dentures.

  4. Elucidating the Molecular Basis and Regulation of Chromium (VI) Reduction by Shewanella oneidensis MR-1 Using Biochemical, Genomic, and Proteomic Approaches

    Energy Technology Data Exchange (ETDEWEB)

    Hettich, Robert L.

    2006-10-30

    Although microbial metal reduction has been investigated intensively from physiological and biochemical perspectives, little is known about the genetic basis and regulatory mechanisms underlying the ability of certain bacteria to transform, detoxify, or immobilize a wide array of heavy metals contaminating DOE-relevant environments. The major goal of this work is to elucidate the molecular components comprising the chromium(VI) response pathway, with an emphasis on components involved in Cr(VI) detoxification and the enzyme complex catalyzing the terminal step in Cr(VI) reduction by Shewanella oneidensis MR-1. We have identified and characterized (in the case of DNA-binding response regulator [SO2426] and a putative azoreductase [SO3585]) the genes and gene products involved in the molecular response of MR-1 to chromium(VI) stress using whole-genome sequence information for MR-1 and recently developed proteomic technology, in particular liquid chromatographymass spectrometry (LC-MS), in conjunction with conventional protein purification and characterization techniques. The proteome datasets were integrated with information from whole-genome expression arrays for S. oneidensis MR-1 (as illustrated in Figure 1). The genes and their encoded products identified in this study are of value in understanding metal reduction and bacterial resistance to metal toxicity and in developing effective metal immobilization strategies.

  5. Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in Gypsies.

    Science.gov (United States)

    Sivadorai, P; Cherninkova, S; Bouwer, S; Kamenarova, K; Angelicheva, D; Seeman, P; Hollingsworth, K; Mihaylova, V; Oscar, A; Dimitrova, G; Kaneva, R; Tournev, I; Kalaydjieva, L

    2008-07-01

    Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder of autosomal recessive inheritance, with mutations in the cytochrome P450 1B1 (CYP1B1) gene detected in an average of approximately 50% of cases worldwide. The Roma/Gypsies are considered to be a rare example of a single founder CYP1B1 mutation, E387K (identified in the Slovak Roma), accounting for 100% of disease alleles. Contrary to this concept, unusual genetic heterogeneity was revealed in this study of 21 Gypsy PCG patients from Bulgaria and 715 controls from the general Gypsy population. In our small sample of affected subjects, we identified five different CYP1B1 mutations - four known (E229K, R368H, E387K and R390C) and one novel and potentially pathogenic (F445I), which together accounted for approximately 30% of disease alleles. E387K was rare in both the patient and the control group, indicating that its high frequency in the Slovak Roma is the product of local founder effect not representative of the overall molecular pattern of PCG in the Gypsy population. Data on other Mendelian disorders and on the population genetics of the Gypsies suggest that a true founder mutation is likely to exist and has remained undetected. Our analysis of another candidate gene, MYOC, and the GLC3B and GLC3C loci did not provide support for their involvement. The molecular basis of PCG in the Gypsies is thus unresolved, and diagnostic analyses should be extended beyond the E387K mutation.

  6. Structural and biochemical studies of a fluoroacetyl-CoA-specific thioesterase reveal a molecular basis for fluorine selectivity.

    Science.gov (United States)

    Weeks, Amy M; Coyle, Scott M; Jinek, Martin; Doudna, Jennifer A; Chang, Michelle C Y

    2010-11-02

    We have initiated a broad-based program aimed at understanding the molecular basis of fluorine specificity in enzymatic systems, and in this context, we report crystallographic and biochemical studies on a fluoroacetyl-coenzyme A (CoA) specific thioesterase (FlK) from Streptomyces cattleya. Our data establish that FlK is competent to protect its host from fluoroacetate toxicity in vivo and demonstrate a 10(6)-fold discrimination between fluoroacetyl-CoA (k(cat)/K(M) = 5 × 10⁷ M⁻¹ s⁻¹) and acetyl-CoA (k(cat)/K(M) = 30 M⁻¹ s⁻¹) based on a single fluorine substitution that originates from differences in both substrate reactivity and binding. We show that Thr 42, Glu 50, and His 76 are key catalytic residues and identify several factors that influence substrate selectivity. We propose that FlK minimizes interaction with the thioester carbonyl, leading to selection against acetyl-CoA binding that can be recovered in part by new C═O interactions in the T42S and T42C mutants. We hypothesize that the loss of these interactions is compensated by the entropic driving force for fluorinated substrate binding in a hydrophobic binding pocket created by a lid structure, containing Val 23, Leu 26, Phe 33, and Phe 36, that is not found in other structurally characterized members of this superfamily. We further suggest that water plays a critical role in fluorine specificity based on biochemical and structural studies focused on the unique Phe 36 "gate" residue, which functions to exclude water from the active site. Taken together, the findings from these studies offer molecular insights into organofluorine recognition and design of fluorine-specific enzymes.

  7. Structure of the Regulator of G Protein Signaling 8 (RGS8)-Gαq Complex: MOLECULAR BASIS FOR Gα SELECTIVITY.

    Science.gov (United States)

    Taylor, Veronica G; Bommarito, Paige A; Tesmer, John J G

    2016-03-04

    Regulator of G protein signaling (RGS) proteins interact with activated Gα subunits via their RGS domains and accelerate the hydrolysis of GTP. Although the R4 subfamily of RGS proteins generally accepts both Gαi/o and Gαq/11 subunits as substrates, the R7 and R12 subfamilies select against Gαq/11. In contrast, only one RGS protein, RGS2, is known to be selective for Gαq/11. The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with Gαq revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the Gα subunit, or both. To resolve this ambiguity, the 2.6 Å crystal structure of RGS8, an R4 subfamily member, was determined in complex with Gαq. RGS8 adopts the same pose on Gαq as it does when bound to Gαi3, indicating that the non-canonical interaction of RGS2 with Gαq is due to unique features of RGS2. Based on the RGS8-Gαq structure, residues in RGS8 that contact a unique α-helical domain loop of Gαq were converted to those typically found in R12 subfamily members, and the reverse substitutions were introduced into RGS10, an R12 subfamily member. Although these substitutions perturbed their ability to stimulate GTP hydrolysis, they did not reverse selectivity. Instead, selectivity for Gαq seems more likely determined by whether strong contacts can be maintained between α6 of the RGS domain and Switch III of Gαq, regions of high sequence and conformational diversity in both protein families. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex

    Science.gov (United States)

    Goldstein, Rita Z.; Volkow, Nora D.

    2005-01-01

    Objective Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. Method An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. Results The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to track, update, and modulate the salience of a reinforcer as a function of context and expectation and the ability to control and inhibit prepotent responses. Conclusions These results imply that addiction connotes cortically regulated cognitive and emotional processes, which result in the overvaluing of drug reinforcers, the undervaluing of alternative reinforcers, and deficits in inhibitory control for drug responses. These changes in addiction, which the authors call I-RISA (impaired response inhibition and salience attribution), expand the traditional concepts of drug dependence that emphasize limbic-regulated responses to pleasure and reward. PMID:12359667

  9. Molecular basis for arsenic-Induced alteration in nitric oxide production and oxidative stress: implication of endothelial dysfunction

    International Nuclear Information System (INIS)

    Kumagai, Yoshito; Pi Jingbo

    2004-01-01

    Accumulated epidemiological studies have suggested that prolonged exposure of humans to arsenic in drinking water is associated with vascular diseases. The exact mechanism of how this occurs currently unknown. Nitric oxide (NO), formed by endothelial NO synthase (eNOS), plays a crucial role in the vascular system. Decreased availability of biologically active NO in the endothelium is implicated in the pathophysiology of several vascular diseases and inhibition of eNOS by arsenic is one of the proposed mechanism s for arsenic-induced vascular diseases. In addition, during exposure to arsenic, overproduction of reactive oxygen species (ROS) can occur, resulting in oxidative stress, which is another major risk factor for vascular dysfunction. The molecular basis for decreased NO levels and increased oxidative stress during arsenic exposure is poorly understood. In this article, evidence for arsenic-mediated alteration in NO production and oxidative stress is reviewed. The results of a cross-sectional study in an endemic area of chronic arsenic poisoning and experimental animal studies to elucidate a potential mechanism for the impairment of NO formation and oxidative stress caused by prolonged exposure to arsenate in the drinking water are also reviewed

  10. Molecular basis for the wide range of affinity found in Csr/Rsm protein-RNA recognition.

    Science.gov (United States)

    Duss, Olivier; Michel, Erich; Diarra dit Konté, Nana; Schubert, Mario; Allain, Frédéric H-T

    2014-04-01

    The carbon storage regulator/regulator of secondary metabolism (Csr/Rsm) type of small non-coding RNAs (sRNAs) is widespread throughout bacteria and acts by sequestering the global translation repressor protein CsrA/RsmE from the ribosome binding site of a subset of mRNAs. Although we have previously described the molecular basis of a high affinity RNA target bound to RsmE, it remains unknown how other lower affinity targets are recognized by the same protein. Here, we have determined the nuclear magnetic resonance solution structures of five separate GGA binding motifs of the sRNA RsmZ of Pseudomonas fluorescens in complex with RsmE. The structures explain how the variation of sequence and structural context of the GGA binding motifs modulate the binding affinity for RsmE by five orders of magnitude (∼10 nM to ∼3 mM, Kd). Furthermore, we see that conformational adaptation of protein side-chains and RNA enable recognition of different RNA sequences by the same protein contributing to binding affinity without conferring specificity. Overall, our findings illustrate how the variability in the Csr/Rsm protein-RNA recognition allows a fine-tuning of the competition between mRNAs and sRNAs for the CsrA/RsmE protein.

  11. Geometric Energy Derivatives at the Complete Basis Set Limit: Application to the Equilibrium Structure and Molecular Force Field of Formaldehyde.

    Science.gov (United States)

    Morgan, W James; Matthews, Devin A; Ringholm, Magnus; Agarwal, Jay; Gong, Justin Z; Ruud, Kenneth; Allen, Wesley D; Stanton, John F; Schaefer, Henry F

    2018-03-13

    Geometric energy derivatives which rely on core-corrected focal-point energies extrapolated to the complete basis set (CBS) limit of coupled cluster theory with iterative and noniterative quadruple excitations, CCSDTQ and CCSDT(Q), are used as elements of molecular gradients and, in the case of CCSDT(Q), expansion coefficients of an anharmonic force field. These gradients are used to determine the CCSDTQ/CBS and CCSDT(Q)/CBS equilibrium structure of the S 0 ground state of H 2 CO where excellent agreement is observed with previous work and experimentally derived results. A fourth-order expansion about this CCSDT(Q)/CBS reference geometry using the same level of theory produces an exceptional level of agreement to spectroscopically observed vibrational band origins with a MAE of 0.57 cm -1 . Second-order vibrational perturbation theory (VPT2) and variational discrete variable representation (DVR) results are contrasted and discussed. Vibration-rotation, anharmonicity, and centrifugal distortion constants from the VPT2 analysis are reported and compared to previous work. Additionally, an initial application of a sum-over-states fourth-order vibrational perturbation theory (VPT4) formalism is employed herein, utilizing quintic and sextic derivatives obtained with a recursive algorithmic approach for response theory.

  12. Insights into cellular and molecular basis for urinary tract infection in autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Gao, Chao; Zhang, Long; Zhang, Ye; Wallace, Darren P; Lopez-Soler, Reynold I; Higgins, Paul J; Zhang, Wenzheng

    2017-11-01

    Urinary tract infection (UTI) is a broad term referring to an infection of the kidneys, ureters, bladder, and/or urethra. Because of its prevalence, frequent recurrence, and rising resistance to antibiotics, UTI has become a challenge in clinical practice. Autosomal-dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder of the kidney and is characterized by the growth of fluid-filled cysts in both kidneys. Progressive cystic enlargement, inflammation, and interstitial fibrosis result in nephron loss with subsequent decline in kidney function. ADPKD patients frequently develop UTI; however, the cellular and molecular mechanisms responsible for the high UTI incidence in ADPKD patients remain virtually unaddressed. Emerging evidence suggests that α-intercalated cells (α-ICs) of the collecting ducts function in the innate immune defense against UTI. α-ICs inhibit bacterial growth by acidifying urine and secreting neutrophil gelatinase-associated lipocalin (NGAL) that chelates siderophore-containing iron. It is necessary to determine, therefore, if ADPKD patients with recurrent UTI have a reduced number and/or impaired function of α-ICs. Identification of the underlying cellular and molecular mechanisms may lead to the development of novel strategies to reduce UTI in ADPKD. Copyright © 2017 the American Physiological Society.

  13. Survival under stress: molecular mechanisms of metabolic rate ...

    African Journals Online (AJOL)

    Studies in my laboratory are analysing the molecular mechanisms and regulatory events that underlie transitions to and from hypometabolic states In systems including anoxia-tolerant turtles and molluscs, estivating snails and toads, hibernating small mammals, and freeze tolerant frogs and insects. Our newest research ...

  14. Understanding the molecular basis of plant growth promotional effect of Pseudomonas fluorescens on rice through protein profiling.

    Science.gov (United States)

    Kandasamy, Saveetha; Loganathan, Karthiba; Muthuraj, Raveendran; Duraisamy, Saravanakumar; Seetharaman, Suresh; Thiruvengadam, Raguchander; Ponnusamy, Balasubramanian; Ramasamy, Samiyappan

    2009-12-24

    Plant Growth Promoting Rhizobacteria (PGPR), Pseudomonas fluorescens strain KH-1 was found to exhibit plant growth promotional activity in rice under both in-vitro and in-vivo conditions. But the mechanism underlying such promotional activity of P. fluorescens is not yet understood clearly. In this study, efforts were made to elucidate the molecular responses of rice plants to P. fluorescens treatment through protein profiling. Two-dimensional polyacrylamide gel electrophoresis strategy was adopted to identify the PGPR responsive proteins and the differentially expressed proteins were analyzed by mass spectrometry. Priming of P. fluorescens, 23 different proteins found to be differentially expressed in rice leaf sheaths and MS analysis revealed the differential expression of some important proteins namely putative p23 co-chaperone, Thioredoxin h- rice, Ribulose-bisphosphate carboxylase large chain precursor, Nucleotide diPhosphate kinase, Proteosome sub unit protein and putative glutathione S-transferase protein. Functional analyses of the differential proteins were reported to be directly or indirectly involved in growth promotion in plants. Thus, this study confirms the primary role of PGPR strain KH-1 in rice plant growth promotion.

  15. Understanding the molecular basis of plant growth promotional effect of Pseudomonas fluorescens on rice through protein profiling

    Directory of Open Access Journals (Sweden)

    Thiruvengadam Raguchander

    2009-12-01

    Full Text Available Abstract Background Plant Growth Promoting Rhizobacteria (PGPR, Pseudomonas fluorescens strain KH-1 was found to exhibit plant growth promotional activity in rice under both in-vitro and in-vivo conditions. But the mechanism underlying such promotional activity of P. fluorescens is not yet understood clearly. In this study, efforts were made to elucidate the molecular responses of rice plants to P. fluorescens treatment through protein profiling. Two-dimensional polyacrylamide gel electrophoresis strategy was adopted to identify the PGPR responsive proteins and the differentially expressed proteins were analyzed by mass spectrometry. Results Priming of P. fluorescens, 23 different proteins found to be differentially expressed in rice leaf sheaths and MS analysis revealed the differential expression of some important proteins namely putative p23 co-chaperone, Thioredoxin h- rice, Ribulose-bisphosphate carboxylase large chain precursor, Nucleotide diPhosphate kinase, Proteosome sub unit protein and putative glutathione S-transferase protein. Conclusion Functional analyses of the differential proteins were reported to be directly or indirectly involved in growth promotion in plants. Thus, this study confirms the primary role of PGPR strain KH-1 in rice plant growth promotion.

  16. Fungicide-driven evolution and molecular basis of multidrug resistance in field populations of the grey mould fungus Botrytis cinerea.

    Directory of Open Access Journals (Sweden)

    Matthias Kretschmer

    2009-12-01

    Full Text Available The grey mould fungus Botrytis cinerea causes losses of commercially important fruits, vegetables and ornamentals worldwide. Fungicide treatments are effective for disease control, but bear the risk of resistance development. The major resistance mechanism in fungi is target protein modification resulting in reduced drug binding. Multiple drug resistance (MDR caused by increased efflux activity is common in human pathogenic microbes, but rarely described for plant pathogens. Annual monitoring for fungicide resistance in field isolates from fungicide-treated vineyards in France and Germany revealed a rapidly increasing appearance of B. cinerea field populations with three distinct MDR phenotypes. All MDR strains showed increased fungicide efflux activity and overexpression of efflux transporter genes. Similar to clinical MDR isolates of Candida yeasts that are due to transcription factor mutations, all MDR1 strains were shown to harbor activating mutations in a transcription factor (Mrr1 that controls the gene encoding ABC transporter AtrB. MDR2 strains had undergone a unique rearrangement in the promoter region of the major facilitator superfamily transporter gene mfsM2, induced by insertion of a retrotransposon-derived sequence. MDR2 strains carrying the same rearranged mfsM2 allele have probably migrated from French to German wine-growing regions. The roles of atrB, mrr1 and mfsM2 were proven by the phenotypes of knock-out and overexpression mutants. As confirmed by sexual crosses, combinations of mrr1 and mfsM2 mutations lead to MDR3 strains with higher broad-spectrum resistance. An MDR3 strain was shown in field experiments to be selected against sensitive strains by fungicide treatments. Our data document for the first time the rising prevalence, spread and molecular basis of MDR populations in a major plant pathogen in agricultural environments. These populations will increase the risk of grey mould rot and hamper the effectiveness of

  17. Expression of Tau Pathology-Related Proteins in Different Brain Regions: A Molecular Basis of Tau Pathogenesis.

    Science.gov (United States)

    Hu, Wen; Wu, Feng; Zhang, Yanchong; Gong, Cheng-Xin; Iqbal, Khalid; Liu, Fei

    2017-01-01

    Microtubule-associated protein tau is hyperphosphorylated and aggregated in affected neurons in Alzheimer disease (AD) brains. The tau pathology starts from the entorhinal cortex (EC), spreads to the hippocampus and frontal and temporal cortices, and finally to all isocortex areas, but the cerebellum is spared from tau lesions. The molecular basis of differential vulnerability of different brain regions to tau pathology is not understood. In the present study, we analyzed brain regional expressions of tau and tau pathology-related proteins. We found that tau was hyperphosphorylated at multiple sites in the frontal cortex (FC), but not in the cerebellum, from AD brain. The level of tau expression in the cerebellum was about 1/4 of that seen in the frontal and temporal cortices in human brain. In the rat brain, the expression level of tau with three microtubule-binding repeats (3R-tau) was comparable in the hippocampus, EC, FC, parietal-temporal cortex (PTC), occipital-temporal cortex (OTC), striatum, thalamus, olfactory bulb (OB) and cerebellum. However, the expression level of 4R-tau was the highest in the EC and the lowest in the cerebellum. Tau phosphatases, kinases, microtubule-related proteins and other tau pathology-related proteins were also expressed in a region-specific manner in the rat brain. These results suggest that higher levels of tau and tau kinases in the EC and low levels of these proteins in the cerebellum may accounts for the vulnerability and resistance of these representative brain regions to the development of tau pathology, respectively. The present study provides the regional expression profiles of tau and tau pathology-related proteins in the brain, which may help understand the brain regional vulnerability to tau pathology in neurodegenerative tauopathies.

  18. Growth of BaSi2 continuous films on Ge(111) by molecular beam epitaxy and fabrication of p-BaSi2/n-Ge heterojunction solar cells

    Science.gov (United States)

    Takabe, Ryota; Yachi, Suguru; Tsukahara, Daichi; Toko, Kaoru; Suemasu, Takashi

    2017-05-01

    We grew BaSi2 films on Ge(111) substrates by various growth methods based on molecular beam epitaxy (MBE). First, we attempted to form BaSi2 films directly on Ge(111) by MBE without templates. We next formed BaSi2 films using BaGe2 templates as commonly used for MBE growth of BaSi2 on Si substrates. Contrary to our prediction, the lateral growth of BaSi2 was not promoted by these two methods; BaSi2 formed not into a continuous film but into islands. Although streaky patterns of reflection high-energy electron diffraction were observed inside the growth chamber, no X-ray diffraction lines of BaSi2 were observed in samples taken out from the growth chamber. Such BaSi2 islands were easily to get oxidized. We finally attempted to form a continuous BaSi2 template layer on Ge(111) by solid phase epitaxy, that is, the deposition of amorphous Ba-Si layers onto MBE-grown BaSi2 epitaxial islands, followed by post annealing. We achieved the formation of an approximately 5-nm-thick BaSi2 continuous layer by this method. Using this BaSi2 layer as a template, we succeeded in forming a-axis-oriented 520-nm-thick BaSi2 epitaxial films on Ge substrates, although (111)-oriented Si grains were included in the grown layer. We next formed a B-doped p-BaSi2(20 nm)/n-Ge(111) heterojunction solar cell. A wide-spectrum response from 400 to 2000 nm was achieved. At an external bias voltage of 1 V, the external quantum efficiency reached as high as 60%, demonstrating the great potential of BaSi2/Ge combination. However, the efficiency of a solar cell under AM1.5 illumination was quite low (0.1%). The origin of such a low efficiency was examined.

  19. Molecular basis for the effects of zinc deficiency on spermatogenesis: An experimental study in the Sprague-dawley rat model

    Directory of Open Access Journals (Sweden)

    Alexander E Omu

    2015-01-01

    Full Text Available Introduction: The objective of this study is to investigate the molecular mechanisms underlying the effects of zinc deficiency on spermatogenesis in the Sprague-Dawley (SD rat. Materials and Methods: Three groups of eight adult male SD rats were maintained for 4 weeks on a normal diet as control, zinc deficient diet and zinc deficient diet with zinc supplementation of 28 mg zinc/kg body weight respectively. Using standard techniques, the following parameters were compared between the three groups of experimental animals at the end of 4 weeks: (a Serum zinc, magnesium (Mg, copper (Cu, selenium (Se and cadmium (Cd, (b serum sex hormones, malondialdehyde (MDA, superoxide dismutase (SOD and glutathione peroxidase (GPX, (c interleukin-4 (IL-4, tumor necrosis factor-alpha (TNF-α, Bcl-2, Bax and caspase-3 expression in the testes, (d assessment of apoptosis of testicular cells using electron microscopy and (e testicular volume and histology using the orchidometer and Johnsen score, respectively. Results: The zinc deficient group showed a reduction of testicular volume, serum concentrations of Zn, Cu, Se, Mg, SOD, GPX, IL-4, Bcl-2 and testosterone (P < 0.05, as well as increased levels of serum Cd, MDA and tissue TNF-α, Bax, caspase-3 and apoptosis of the germ cells (P < 0.05 compared with control and zinc supplementation groups. Conclusion: Zinc deficiency is associated with impaired spermatogenesis because of reduced testosterone production, increased oxidative stress and apoptosis. These findings suggest that zinc has a role in male reproduction.

  20. Studies on Molecular Mechanisms Underlying Spinocerebellar Ataxia Type 3

    DEFF Research Database (Denmark)

    Kristensen, Line Vildbrad

    . Even though a range of mechanisms contributing to polyQ diseases have been uncovered, there is still no treatment available. One of the more common polyQ diseases is SCA3, which is caused by a polyQ expansion in the ataxin-3 protein that normally functions as a deubiquitinating enzyme involved...... in protein quality control. In SCA3 patients polyQ expanded ataxin-3 forms intranuclear inclusions in various brain areas, but why the polyQ expansion of ataxin-3 leads to neuronal dysfunction is still not well understood. This thesis describes molecular biological investigations of ataxin-3 biology, aimed...... at furthering our understanding of SCA3 disease mechanisms. In manuscript I, we investigated if post-translational modifications of ataxin-3 were changed by the polyQ expansion. The ubiquitin chain topology and ubiquitination pattern of ataxin-3 were unaltered by the polyQ expansion. In contrast...

  1. Molecular Mechanism Underlying Lymphatic Metastasis in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Zhiwen Xiao

    2014-01-01

    Full Text Available As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer.

  2. Molecular basis of IgE-recognition of Lol p 5, a major allergen of rye-grass pollen.

    Science.gov (United States)

    Suphioglu, C; Blaher, B; Rolland, J M; McCluskey, J; Schäppi, G; Kenrick, J; Singh, M B; Knox, R B

    1998-04-01

    Grass pollen, especially of rye-grass (Lolium perenne). represents an important cause of type I allergy. Identification of IgE-binding (allergenic) epitopes of major grass pollen allergens is essential for understanding the molecular basis of interaction between allergens and human IgE antibodies and therefore facilitates the devising of safer and more effective diagnostic and immunotherapy reagents. The aim of this study was to identify the allergenic epitopes of Lol p 5, a major allergen of rye-grass pollen, immunodissect these epitopes further so that the amino acid residues critical for antibody binding can be determined and investigate the conservation and nature of these epitopes within the context of the natural grass pollen allergens. Peptides, 12-13 amino acid residues long and overlapping each other by 4 amino acid residues, based on the entire deduced amino acid sequence of the coding region of Lol p 5, were synthesised and assayed for IgE-binding. Two strong IgE-binding epitopes (Lol p 5 (49-60) and (265-276), referred to as peptides 7 and 34, respectively) were identified. These epitopes were further resolved by truncated peptides and amino acid replacement studies and the amino acid residues critical for IgE-binding determined (Lol p 5 (49-60) residue Lys57 and (265-276) residue Lys275). Sequences of these epitopes were conserved in related allergens and may form the conserved allergenic domains responsible for the cross-reactivity observed between pollen allergens of taxonomically related grasses. Furthermore, due to its strong IgE-reactivity, synthetic peptide Lol p 5 (265-276) was used to affinity-purify specific IgE antibodies which recognised proteins of other clinically important grass pollens. further indicating presence of allergenic cross-reactivity at the level of allergenic epitope. Moreover, Lol p 5 (265 276) demonstrated a strong capacity to inhibit IgE-binding to natural rye-grass pollen proteins highlighting the antibody accessibility

  3. Molecular investigations on grain filling rate under terminal heat ...

    African Journals Online (AJOL)

    Ezedom Theresa

    2013-07-10

    Jul 10, 2013 ... under terminal heat stress in bread wheat. (Triticum aestivum L.) Girish Chandra Pandey1, Jagadish ... ficantly in all the bread and durum wheat genotypes, because of significant interaction of each ..... wheat varieties and registered genetic stocks (Triticum L.). Technical. Bulletin No.13, Directorate of Wheat ...

  4. The thermodynamics of molecular cloud fragmentation : Star formation under non-Milky Way conditions

    NARCIS (Netherlands)

    Hocuk, S.; Spaans, M.

    Context. Properties of candidate stars, forming out of molecular clouds, depend on the ambient conditions of the parent cloud. We present a series of 2D and 3D simulations of fragmentation of molecular clouds in starburst regions, as well as of clouds under conditions in dwarf galaxies, leading to

  5. Molecular basis of colorectal cancer: Towards an individualized management? Bases moleculares del cáncer colorrectal: ¿Hacia un manejo individualizado?

    Directory of Open Access Journals (Sweden)

    J. Perea

    2011-01-01

    Full Text Available Colorectal cancer (CRC has become a highly relevant condition nowadays. In this respect, advances in the understanding of its molecular basis are key for an adequate management. From the time when the adenoma-carcinoma sequence was formulated as a carcinogenesis model to this day, when, among other things, three major carcinogenic pathways have been identified, the CRC concept has evolved from that of a single disease to the notion that each CRC is a differentiated condition in itself. The suppressor or chromosome instability pathway, the mutator or microsatellite instability pathway, and the methylator or CpG island methylation pathway allow various phenotypes to be identified within CRC. Similarly, the presence of different changes in certain genes confers several behaviors on CRC from both the prognostic and responsive standpoints to specific therapies. However, this apparent complexity does help develop the clinical management of this disease through the identification of novel, more specific therapy targets, and also markers for various behaviors within the condition, which will most likely lead us to an individualized management for these patients.La importancia que está adquiriendo el cáncer colorrectal (CCR hoy en día es importantísima. En este sentido, los avances en el conocimiento de sus bases moleculares son esenciales para su adecuado manejo. Desde la formulación del modelo de carcinogénesis de la secuencia adenoma-carcinoma hasta hoy, en que, entre otros aspectos, se han identificado tres grandes vías de carcinogénesis, el concepto de CCR ha llegado a transformarse desde el de una enfermedad única a la idea de que cada CCR es una entidad diferenciada respecto al resto de CCR. La vía supresora o de la inestabilidad cromosómica, la vía mutadora o de la inestabilidad de microsatélites, y la vía metiladora o del fenotipo metilador de islas CpG, permiten identificar diferentes fenotipos dentro del CCR. De la misma forma

  6. Exploring the molecular basis of insecticide resistance in the dengue vector Aedes aegypti: a case study in Martinique Island (French West Indies

    Directory of Open Access Journals (Sweden)

    Yébakima André

    2009-10-01

    Full Text Available Abstract Background The yellow fever mosquito Aedes aegypti is a major vector of dengue and hemorrhagic fevers, causing up to 100 million dengue infections every year. As there is still no medicine and efficient vaccine available, vector control largely based on insecticide treatments remains the only method to reduce dengue virus transmission. Unfortunately, vector control programs are facing operational challenges with mosquitoes becoming resistant to commonly used insecticides. Resistance of Ae. aegypti to chemical insecticides has been reported worldwide and the underlying molecular mechanisms, including the identification of enzymes involved in insecticide detoxification are not completely understood. Results The present paper investigates the molecular basis of insecticide resistance in a population of Ae. aegypti collected in Martinique (French West Indies. Bioassays with insecticides on adults and larvae revealed high levels of resistance to organophosphate and pyrethroid insecticides. Molecular screening for common insecticide target-site mutations showed a high frequency (71% of the sodium channel 'knock down resistance' (kdr mutation. Exposing mosquitoes to detoxification enzymes inhibitors prior to bioassays induced a significant increased susceptibility of mosquitoes to insecticides, revealing the presence of metabolic-based resistance mechanisms. This trend was biochemically confirmed by significant elevated activities of cytochrome P450 monooxygenases, glutathione S-transferases and carboxylesterases at both larval and adult stages. Utilization of the microarray Aedes Detox Chip containing probes for all members of detoxification and other insecticide resistance-related enzymes revealed the significant constitutive over-transcription of multiple detoxification genes at both larval and adult stages. The over-transcription of detoxification genes in the resistant strain was confirmed by using real-time quantitative RT

  7. Exploring the molecular basis of insecticide resistance in the dengue vector Aedes aegypti: a case study in Martinique Island (French West Indies).

    Science.gov (United States)

    Marcombe, Sébastien; Poupardin, Rodolphe; Darriet, Frederic; Reynaud, Stéphane; Bonnet, Julien; Strode, Clare; Brengues, Cecile; Yébakima, André; Ranson, Hilary; Corbel, Vincent; David, Jean-Philippe

    2009-10-26

    The yellow fever mosquito Aedes aegypti is a major vector of dengue and hemorrhagic fevers, causing up to 100 million dengue infections every year. As there is still no medicine and efficient vaccine available, vector control largely based on insecticide treatments remains the only method to reduce dengue virus transmission. Unfortunately, vector control programs are facing operational challenges with mosquitoes becoming resistant to commonly used insecticides. Resistance of Ae. aegypti to chemical insecticides has been reported worldwide and the underlying molecular mechanisms, including the identification of enzymes involved in insecticide detoxification are not completely understood. The present paper investigates the molecular basis of insecticide resistance in a population of Ae. aegypti collected in Martinique (French West Indies). Bioassays with insecticides on adults and larvae revealed high levels of resistance to organophosphate and pyrethroid insecticides. Molecular screening for common insecticide target-site mutations showed a high frequency (71%) of the sodium channel 'knock down resistance' (kdr) mutation. Exposing mosquitoes to detoxification enzymes inhibitors prior to bioassays induced a significant increased susceptibility of mosquitoes to insecticides, revealing the presence of metabolic-based resistance mechanisms. This trend was biochemically confirmed by significant elevated activities of cytochrome P450 monooxygenases, glutathione S-transferases and carboxylesterases at both larval and adult stages. Utilization of the microarray Aedes Detox Chip containing probes for all members of detoxification and other insecticide resistance-related enzymes revealed the significant constitutive over-transcription of multiple detoxification genes at both larval and adult stages. The over-transcription of detoxification genes in the resistant strain was confirmed by using real-time quantitative RT-PCR. These results suggest that the high level of

  8. Elucidating the molecular mechanisms underlying cellular response to biophysical cues using synthetic biology approaches

    NARCIS (Netherlands)

    Denning, Denise; Roos, Wouter H

    2016-01-01

    The use of synthetic surfaces and materials to influence and study cell behavior has vastly progressed our understanding of the underlying molecular mechanisms involved in cellular response to physicochemical and biophysical cues. Reconstituting cytoskeletal proteins and interfacing them with a

  9. Molecular Features Underlying Selectivity in Chicken Bitter Taste Receptors

    Directory of Open Access Journals (Sweden)

    Antonella Di Pizio

    2018-01-01

    Full Text Available Chickens sense the bitter taste of structurally different molecules with merely three bitter taste receptors (Gallus gallus taste 2 receptors, ggTas2rs, representing a minimal case of bitter perception. Some bitter compounds like quinine, diphenidol and chlorpheniramine, activate all three ggTas2rs, while others selectively activate one or two of the receptors. We focus on bitter compounds with different selectivity profiles toward the three receptors, to shed light on the molecular recognition complexity in bitter taste. Using homology modeling and induced-fit docking simulations, we investigated the binding modes of ggTas2r agonists. Interestingly, promiscuous compounds are predicted to establish polar interactions with position 6.51 and hydrophobic interactions with positions 3.32 and 5.42 in all ggTas2rs; whereas certain residues are responsible for receptor selectivity. Lys3.29 and Asn3.36 are suggested as ggTas2r1-specificity-conferring residues; Gln6.55 as ggTas2r2-specificity-conferring residue; Ser5.38 and Gln7.42 as ggTas2r7-specificity conferring residues. The selectivity profile of quinine analogs, quinidine, epiquinidine and ethylhydrocupreine, was then characterized by combining calcium-imaging experiments and in silico approaches. ggTas2r models were used to virtually screen BitterDB compounds. ~50% of compounds known to be bitter to human are likely to be bitter to chicken, with 25, 20, 37% predicted to be ggTas2r1, ggTas2r2, ggTas2r7 agonists, respectively. Predicted ggTas2rs agonists can be tested with in vitro and in vivo experiments, contributing to our understanding of bitter taste in chicken and, consequently, to the improvement of chicken feed.

  10. Molecular Basis for the Selective Inhibition of Respiratory Syncytial Virus RNA Polymerase by 2'-Fluoro-4'-Chloromethyl-Cytidine Triphosphate.

    Directory of Open Access Journals (Sweden)

    Jerome Deval

    2015-06-01

    Full Text Available Respiratory syncytial virus (RSV causes severe lower respiratory tract infections, yet no vaccines or effective therapeutics are available. ALS-8176 is a first-in-class nucleoside analog prodrug effective in RSV-infected adult volunteers, and currently under evaluation in hospitalized infants. Here, we report the mechanism of inhibition and selectivity of ALS-8176 and its parent ALS-8112. ALS-8176 inhibited RSV replication in non-human primates, while ALS-8112 inhibited all strains of RSV in vitro and was specific for paramyxoviruses and rhabdoviruses. The antiviral effect of ALS-8112 was mediated by the intracellular formation of its 5'-triphosphate metabolite (ALS-8112-TP inhibiting the viral RNA polymerase. ALS-8112 selected for resistance-associated mutations within the region of the L gene of RSV encoding the RNA polymerase. In biochemical assays, ALS-8112-TP was efficiently recognized by the recombinant RSV polymerase complex, causing chain termination of RNA synthesis. ALS-8112-TP did not inhibit polymerases from host or viruses unrelated to RSV such as hepatitis C virus (HCV, whereas structurally related molecules displayed dual RSV/HCV inhibition. The combination of molecular modeling and enzymatic analysis showed that both the 2'F and the 4'ClCH2 groups contributed to the selectivity of ALS-8112-TP. The lack of antiviral effect of ALS-8112-TP against HCV polymerase was caused by Asn291 that is well-conserved within positive-strand RNA viruses. This represents the first comparative study employing recombinant RSV and HCV polymerases to define the selectivity of clinically relevant nucleotide analogs. Understanding nucleotide selectivity towards distant viral RNA polymerases could not only be used to repurpose existing drugs against new viral infections, but also to design novel molecules.

  11. Melting curves of molecular hydrogen and molecular deuterium under high pressures between 20 and 373 K

    International Nuclear Information System (INIS)

    Diatschenko, V.; Chu, C.W.; Liebenberg, D.H.; Young, D.A.; Ross, M.; Mills, R.L.

    1985-01-01

    We determined the melting curve of molecular hydrogen and molecular deuterium at closely spaced intervals from 20 to 373 K by two different techniques using high-pressure diamond cells. The cells were loaded with liquid at low temperature or with compressed gas at room temperature. Empirical functions for the melting curves were evaluated from least-squares fits of the data. Values of the compressibility and Debye temperature were computed at melting, and the results are compared with those calculated from various theoretical models. The good agreement shows that the models are generally valid, although small systematic deviations may point the way toward refinements in modeling. Our study also demonstrates the need to determine a one-piece intermolecular potential valid over a wide pressure range by refitting all experimental data, including the shock data recently made available

  12. Molecular basis of structural makeup of hulless barley in relation to rumen degradation kinetics and intestinal availability in dairy cattle: A novel approach.

    Science.gov (United States)

    Damiran, D; Yu, P

    2011-10-01

    To date, no study has been done of molecular structures in relation to nutrient degradation kinetics and intestinal availability in dairy cattle. The objectives of this study were to (1) reveal molecular structures of hulless barley affected by structural alteration using molecular spectroscopy (diffuse reflectance infrared Fourier transform) as a novel approach, and (2) quantify structure features on a molecular basis in relation to digestive kinetics and nutritive value in the rumen and intestine in cattle. The modeled feeds in this study were 4 types of hulless barley (HB) cultivars modified in starch traits: (a) normal starch cultivar, (b) zero-amylose waxy, (c) waxy, and (d) high-amylose. The molecular structural features were determined using diffuse reflectance infrared Fourier transform spectroscopy in the mid-infrared region (ca. 4,000-800 cm(-1)) of the electromagnetic spectrum. The items assessed included infrared intensity attributed to protein amide I (ca. 1,715-1,575 cm(-1)), amide II (ca. 1,575-1,490 cm(-1)), α-helix (ca. 1,648-1,660 cm(-1)), β-sheet (ca. 1,625-1,640 cm(-1)), and their ratio, β-glucan (ca. 1,445-1,400 cm(-1)), total carbohydrates (CHO; ca. 1,188-820 cm(-1)) and their 3 major peaks, structural carbohydrates (ca. 1,277-1,190 cm(-1)), and ratios of amide I to II and amide I to CHO. The results show that (1) the zero-amylose waxy was the greatest in amide I and II peak areas, as well as in the ratio of protein amide I to CHO among HB; (2) α-helix-to-β-sheet ratio differed among HB: the high-amylose was the greatest, the zero-amylose waxy and waxy were the intermediate, and the normal starch was the lowest; (3) HB were similar in β-glucan and CHO molecular structural makeup; (4) altered starch HB cultivars were similar to each other, but were different from the normal starch cultivar in protein molecular makeup; and (5) the rate and extent of rumen degradation of starch and protein were highly related to the molecular structural

  13. Gaussian basis sets for use in correlated molecular calculations. XI. Pseudopotential-based and all-electron relativistic basis sets for alkali metal (K-Fr) and alkaline earth (Ca-Ra) elements

    Science.gov (United States)

    Hill, J. Grant; Peterson, Kirk A.

    2017-12-01

    New correlation consistent basis sets based on pseudopotential (PP) Hamiltonians have been developed from double- to quintuple-zeta quality for the late alkali (K-Fr) and alkaline earth (Ca-Ra) metals. These are accompanied by new all-electron basis sets of double- to quadruple-zeta quality that have been contracted for use with both Douglas-Kroll-Hess (DKH) and eXact 2-Component (X2C) scalar relativistic Hamiltonians. Sets for valence correlation (ms), cc-pVnZ-PP and cc-pVnZ-(DK,DK3/X2C), in addition to outer-core correlation [valence + (m-1)sp], cc-p(w)CVnZ-PP and cc-pwCVnZ-(DK,DK3/X2C), are reported. The -PP sets have been developed for use with small-core PPs [I. S. Lim et al., J. Chem. Phys. 122, 104103 (2005) and I. S. Lim et al., J. Chem. Phys. 124, 034107 (2006)], while the all-electron sets utilized second-order DKH Hamiltonians for 4s and 5s elements and third-order DKH for 6s and 7s. The accuracy of the basis sets is assessed through benchmark calculations at the coupled-cluster level of theory for both atomic and molecular properties. Not surprisingly, it is found that outer-core correlation is vital for accurate calculation of the thermodynamic and spectroscopic properties of diatomic molecules containing these elements.

  14. Gaussian basis sets for use in correlated molecular calculations. XI. Pseudopotential-based and all-electron relativistic basis sets for alkali metal (K-Fr) and alkaline earth (Ca-Ra) elements.

    Science.gov (United States)

    Hill, J Grant; Peterson, Kirk A

    2017-12-28

    New correlation consistent basis sets based on pseudopotential (PP) Hamiltonians have been developed from double- to quintuple-zeta quality for the late alkali (K-Fr) and alkaline earth (Ca-Ra) metals. These are accompanied by new all-electron basis sets of double- to quadruple-zeta quality that have been contracted for use with both Douglas-Kroll-Hess (DKH) and eXact 2-Component (X2C) scalar relativistic Hamiltonians. Sets for valence correlation (ms), cc-pVnZ-PP and cc-pVnZ-(DK,DK3/X2C), in addition to outer-core correlation [valence + (m-1)sp], cc-p(w)CVnZ-PP and cc-pwCVnZ-(DK,DK3/X2C), are reported. The -PP sets have been developed for use with small-core PPs [I. S. Lim et al., J. Chem. Phys. 122, 104103 (2005) and I. S. Lim et al., J. Chem. Phys. 124, 034107 (2006)], while the all-electron sets utilized second-order DKH Hamiltonians for 4s and 5s elements and third-order DKH for 6s and 7s. The accuracy of the basis sets is assessed through benchmark calculations at the coupled-cluster level of theory for both atomic and molecular properties. Not surprisingly, it is found that outer-core correlation is vital for accurate calculation of the thermodynamic and spectroscopic properties of diatomic molecules containing these elements.

  15. Reference Genes for qPCR Analysis in Resin-Tapped Adult Slash Pine As a Tool to Address the Molecular Basis of Commercial Resinosis

    Directory of Open Access Journals (Sweden)

    Júlio C. de Lima

    2016-06-01

    Full Text Available Pine oleoresin is a major source of terpenes, consisting of turpentine (mono- and sesquiterpenes and rosin (diterpenes fractions. Higher oleoresin yields are of economic interest, since oleoresin derivatives make up a valuable source of materials for chemical industries. Oleoresin can be extracted from living trees, often by the bark streak method, in which bark removal is done periodically, followed by application of stimulant paste containing sulfuric acid and other chemicals on the freshly wounded exposed surface. To better understand the molecular basis of chemically-stimulated and wound induced oleoresin production, we evaluated the stability of 11 putative reference genes for the purpose of normalization in studying Pinus elliottii gene expression during oleoresinosis. Samples for RNA extraction were collected from field-grown adult trees under tapping operations using stimulant pastes with different compositions and at various time points after paste application. Statistical methods established by geNorm, NormFinder, and BestKeeper softwares were consistent in pointing as adequate reference genes HISTO3 and UBI. To confirm expression stability of the candidate reference genes, expression profiles of putative P. elliottii orthologs of resin biosynthesis-related genes encoding Pinus contorta β-pinene synthase [PcTPS-(−β-pin1], P. contorta levopimaradiene/abietadiene synthase (PcLAS1, Pinus taeda α-pinene synthase [PtTPS-(+αpin], and P. taeda α-farnesene synthase (PtαFS were examined following stimulant paste application. Increased oleoresin yields observed in stimulated treatments using phytohormone-based pastes were consistent with higher expression of pinene synthases. Overall, the expression of all genes examined matched the expected profiles of oleoresin-related transcript changes reported for previously examined conifers.

  16. Molecular basis of processing-induced changes in protein structure in relation to intestinal digestion in yellow and green type pea (Pisum sativum L.): A molecular spectroscopic analysis.

    Science.gov (United States)

    Yu, Gloria Qingyu; Warkentin, Tom; Niu, Zhiyuan; Khan, Nazir A; Yu, Peiqiang

    2015-12-05

    The objectives of this study were (1) to quantify the protein inherent molecular structural features of green cotyledon (CDC Striker) and yellow cotyledon (CDC Meadow) pea (Pisum sativum L.) seeds using molecular spectroscopic technique (FT/IR-ATR); (2) measure the denaturation of protein molecular makeup in the two types of pea during dry roasting (120°C for 60 min), autoclaving (120°C for 60 min) or microwaving (for 5 min); and (3) correlate the heat-induced changes in protein molecular makeup to the corresponding changes in protein digestibility determined using modified three-step in vitro procedure. Compared with yellow-type, the green-type peas had higher (Pprotein content. Compared with yellow-type, the green-type peas had lower (Pprotein secondary structure makeup. All processing applications increased α-helix:β-sheet ratio, with the largest (Pprotein within the green (r=-0. 86) and yellow (r=0.81) pea-types. However, across the pea types the correlation was not significant. Principal component and hierarchical cluster analyses on the entire spectral data from the amide region (ca. 1727-1480 cm(-1)) were able to visualize and discriminate the structural difference between pea varieties and processing treatments. This study shows that the molecular spectroscopy can be used as a rapid tool to screen the protein value of raw and heat-treated peas. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients

    DEFF Research Database (Denmark)

    Andresen, B S; Bross, P; Udvari, S

    1997-01-01

    -causing mutations in 14 families in whom both mutations had not previously been reported. We then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showed that five...

  18. Kamptonema (Microcoleaceae, Cyanobacteria), a new genus derived from the polyphyletic Phormidium on the basis of combined molecular and cytomorphological markers

    Czech Academy of Sciences Publication Activity Database

    Strunecký, Otakar; Komárek, Jiří; Šmarda, J.

    2014-01-01

    Roč. 86, č. 2 (2014), 193-207 ISSN 0032-7786 R&D Projects: GA ČR GAP506/12/1818 Institutional support: RVO:67985939 Keywords : cyanobacteria * taxonomic revision * polyphasic approach Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.104, year: 2014

  19. Splitting of α-Helical Structure as Molecular Basis for Abolishing an Amyloid Formation by Multiple Glycosylation: A Molecular Dynamics Simulation Study

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Youngjin [Hoseo University, Asan (Korea, Republic of); Cho, Eunae; Jung, Seunho [Konkuk University, Seoul (Korea, Republic of)

    2016-07-15

    Molecular details played by glycosylation are complicated by the subtle nature of variations in the glycan structure, and this complexity is one of the research barriers to establish structure-function relationship on the protein modification. This is particularly true for understanding the exact structural consequence of the glycosylation of the biological proteins. The present MD simulation revealed molecular-level mechanism of the glycosylation effect on the peptide to understand the experimentally observed phenomenon for inhibiting amyloid formation in the model peptide. The galactose residue on the Ser17 undermined the helical integrity of main protein region by enhancing sugar–amino acid interaction and perturbing natural interactions between amino acid residues.

  20. Electron-vibrational transitions under molecular ions collisions with slow electrons

    International Nuclear Information System (INIS)

    Andreev, E.A.

    1993-01-01

    A concept of a multichannel quantum defect is considered and basic theoretic ratios of inelastic collisional processes with the participation of molecular positive ions and slow electrons playing an important role both in atmospheric and laboratory plasma, are presented. The problem of scattering channel number limitation with the provision of S-matrix unique character is considered. Different models of electron rotation-vibrational connection under collision of two-atom molecular ions with slow electrons are analysed. Taking N 2 + as an example, a high efficiency of transitions between different electron states of a molecular ion is shown. 73 refs., 9 figs., 1 tab

  1. Molecular basis of structural make-up of feeds in relation to nutrient absorption in ruminants, revealed with advanced molecular spectroscopy: A review on techniques and models

    Energy Technology Data Exchange (ETDEWEB)

    Rahman, Md. Mostafizar [Department of Animal and Poultry Science, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Yu, Peiqiang [Department of Animal and Poultry Science, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    2017-01-31

    Progress in ruminant feed research is no more feasible only based on wet chemical analysis, which is merely able to provide information on chemical composition of feeds regardless of their digestive features and nutritive value in ruminants. Studying internal structural make-up of functional groups/feed nutrients is often vital for understanding the digestive behaviors and nutritive values of feeds in ruminant because the intrinsic structure of feed nutrients is more related to its overall absorption. In this article, the detail information on the recent developments in molecular spectroscopic techniques to reveal microstructural information of feed nutrients and the use of nutrition models in regards to ruminant feed research was reviewed. The emphasis of this review was on (1) the technological progress in the use of molecular spectroscopic techniques in ruminant feed research; (2) revealing spectral analysis of functional groups of biomolecules/feed nutrients; (3) the use of advanced nutrition models for better prediction of nutrient availability in ruminant systems; and (4) the application of these molecular techniques and combination of nutrient models in cereals, co-products and pulse crop research. The information described in this article will promote better insight in the progress of research on molecular structural make-up of feed nutrients in ruminants.

  2. Photoabsorption in molecular nitrogen: A moment analysis of discrete-basis-set calculations in the static-exchange approximation

    International Nuclear Information System (INIS)

    Rescigno, T.N.; Bender, C.F.; McKoy, B.V.; Langhoff, P.W.

    1978-01-01

    Theoretical investigations of photoexcitation and ionization cross sections in molecular nitrogen are reported employing the recently devised Stieltjes--Tchebycheff moment-theory technique in the static-exchange approximation. The coupled-channel equations for photoabsorption are separated approximately by identifying the important physically distinct excitation processes associated with formation of the three lowest electronic states of the parent molecular ion. Approximate Rydberg series and pseudospectra of transition frequencies and oscillator strengths are constructed for the seven individual channel components identified using Hartree--Fock ionic core functions and normalizable Gaussian orbitals to describe the photoexcited and ejected electrons. Detailed comparisons of the theoretically determined discrete excitation series with available spectral data indicate general accord between the calculated and observed excitation frequencies and oscillator strengths, although there are some discrepancies and certain Rydberg series have apparently not yet been identified in the measured spectra. The total Stieltjes--Tchebycheff vertical photoionization cross section obtained from the discrete pseudospectra is in excellent agreement with recent electron--ion coincidence measurement of the cross section for parent--ion production from threshold to 50 eV excitation energy. Similarly, e calculated vertical partial cross sections for the production of the three lowest electronic states in the parent molecular ion are in excellent accord with the results of recent electron--electron coincidence and synchrotron--radiation branching ratio measurements. The origins of particularly intense resonancelike features in the discrete and continuum portions of the photoabsorption cross sections are discussed in terms of excitations into valencelike molecular orbitals

  3. Molecular Basis on Nitrogen Utilization in Rice(Recent Topics of the Agricultunal Biological Science in Tohoku University)

    OpenAIRE

    Toshihiko, HAYAKAWA; Soichi, KOJIMA; Mayumi, TABUCHI; Toru, KUDO; Tomoyuki, YAMAYA; Laboratory of Plant Cell Biochemistry, Department of Applied Plant Science, Division of Life Science, Graduate School of Agricultural Science, Tohoku University; Laboratory of Plant Cell Biochemistry, Department of Applied Plant Science, Division of Life Science, Graduate School of Agricultural Science, Tohoku University; Laboratory of Plant Cell Biochemistry, Department of Applied Plant Science, Division of Life Science, Graduate School of Agricultural Science, Tohoku University; Laboratory of Plant Cell Biochemistry, Department of Applied Plant Science, Division of Life Science, Graduate School of Agricultural Science, Tohoku University; Laboratory of Plant Cell Biochemistry, Department of Applied Plant Science, Division of Life Science, Graduate School of Agricultural Science, Tohoku University

    2008-01-01

    Rice (Oryza sativa L.) is the major provision for half of the world population and is the important model crop in terms of synteny. Nitrogen is a massive prerequisite element for rice during its life span. During evolutionary processes, rice has acquired strategic systems of nitrogen metabolism for the survival, i.e., the highly efficient ammonium assimilation in roots and nitrogen remobilization (nitrogen recycling). In our laboratory, research is underway to elucidate molecular mechanisms, ...

  4. New insights into heat induced structural changes of pectin methylesterase on fluorescence spectroscopy and molecular modeling basis

    Science.gov (United States)

    Nistor, Oana Viorela; Stănciuc, Nicoleta; Aprodu, Iuliana; Botez, Elisabeta

    2014-07-01

    Heat-induced structural changes of Aspergillus oryzae pectin methylesterase (PME) were studied by means of fluorescence spectroscopy and molecular modeling, whereas the functional enzyme stability was monitored by inactivation studies. The fluorescence spectroscopy experiments were performed at two pH value (4.5 and 7.0). At both pH values, the phase diagrams were linear, indicating the presence of two molecular species induced by thermal treatment. A red shift of 7 nm was observed at neutral pH by increasing temperature up to 60 °C, followed by a blue shift of 4 nm at 70 °C, suggesting significant conformational rearrangements. The quenching experiments using acrylamide and iodide demonstrate a more flexible conformation of enzyme with increasing temperature, especially at neutral pH. The experimental results were complemented with atomic level observations on PME model behavior after performing molecular dynamics simulations at different temperatures. The inactivation kinetics of PME in buffer solutions was fitted using a first-order kinetics model, resulting in activation energy of 241.4 ± 7.51 kJ mol-1.

  5. Scientific basis for the selection of absorbent underpads that remain securely attached to underlying bed or chair.

    Science.gov (United States)

    Edlich, Richard F; Winters, Kathryne L; Long, William B; Gubler, K Dean

    2006-01-01

    The occurrence of pressure ulcers in patients is very high in certain high-risk groups. These special high-risk groups include elderly patients, patients with spinal cord injuries, or any individual with an impaired ability to reposition. Prevention of pressure ulcers is by far the best treatment of this condition, warranting certain interventions and preventive measures. One major risk factor to be minimized is the exposure of skin to moisture. Underpads are often used to protect the skin of patients who are incontinent. These products effectively absorb moisture and present a quick-drying surface to the skin. The construction of an underpad should accomplish three goals. First, its backing should have a low coefficient of friction to prevent frictional skin injuries. Second, an inner absorbent core should rapidly contain moisture and disseminate it throughout the entire pad. Third, the core and coverstock should successfully work together to retain moisture and prevent wet-back or fluid return. The purpose of this study was to determine the performance of three commercially available underpads in reducing the development of pressure sores in patients at high risk. In this study we selected three underpads that could be securely attached to either the underlying bed or the chair. The three performance parameters examined were absorbent capacity, wetback prevention, and holding security of the underpads. Measurements of these performance parameters can be easily replicated in other laboratories. The results of these studies provide a scientific basis for selecting and purchasing an underpad to prevent pressure ulcers in patients. In this comprehensive evaluation, we assess an absorbent underpad with polyethylene flaps and two absorbent underpads with adhesive. The absorbent capacity results showed Tranquility SlimLine Peach Sheet to be the most absorbent. The wet-back results showed Tranquility SlimLine Peach Sheet to be the only underpad with no wet-back, with no

  6. Calculation of wave-functions with frozen orbitals in mixed quantum mechanics/molecular mechanics methods. II. Application of the local basis equation.

    Science.gov (United States)

    Ferenczy, György G

    2013-04-05

    The application of the local basis equation (Ferenczy and Adams, J. Chem. Phys. 2009, 130, 134108) in mixed quantum mechanics/molecular mechanics (QM/MM) and quantum mechanics/quantum mechanics (QM/QM) methods is investigated. This equation is suitable to derive local basis nonorthogonal orbitals that minimize the energy of the system and it exhibits good convergence properties in a self-consistent field solution. These features make the equation appropriate to be used in mixed QM/MM and QM/QM methods to optimize orbitals in the field of frozen localized orbitals connecting the subsystems. Calculations performed for several properties in divers systems show that the method is robust with various choices of the frozen orbitals and frontier atom properties. With appropriate basis set assignment, it gives results equivalent with those of a related approach [G. G. Ferenczy previous paper in this issue] using the Huzinaga equation. Thus, the local basis equation can be used in mixed QM/MM methods with small size quantum subsystems to calculate properties in good agreement with reference Hartree-Fock-Roothaan results. It is shown that bond charges are not necessary when the local basis equation is applied, although they are required for the self-consistent field solution of the Huzinaga equation based method. Conversely, the deformation of the wave-function near to the boundary is observed without bond charges and this has a significant effect on deprotonation energies but a less pronounced effect when the total charge of the system is conserved. The local basis equation can also be used to define a two layer quantum system with nonorthogonal localized orbitals surrounding the central delocalized quantum subsystem. Copyright © 2013 Wiley Periodicals, Inc.

  7. Defining the molecular basis of BubR1 kinetochore interactions and APC/C-CDC20 inhibition.

    Science.gov (United States)

    D'Arcy, Sheena; Davies, Owen R; Blundell, Tom L; Bolanos-Garcia, Victor M

    2010-05-07

    BubR1 is essential for the mitotic checkpoint that prevents aneuploidy in cellular progeny by triggering anaphase delay in response to kinetochores incorrectly/not attached to the mitotic spindle. Here, we define the molecular architecture of the functionally significant N-terminal region of human BubR1 and present the 1.8 A crystal structure of its tetratricopeptide repeat (TPR) domain. The structure reveals divergence from the classical TPR fold and is highly similar to the TPR domain of budding yeast Bub1. Shared distinctive features include a disordered loop insertion, a 3(10)-helix, a tight turn involving glycine positive Phi angles, and noncanonical packing of and between the TPR motifs. We also define the molecular determinants of the interaction between BubR1 and kinetochore protein Blinkin. We identify a shallow groove on the concave surface of the BubR1 TPR domain that forms multiple discrete and potentially cooperative interactions with Blinkin. Finally, we present evidence for a direct interaction between BubR1 and Bub1 mediated by regions C-terminal to their TPR domains. This interaction provides a mechanism for Bub1-dependent kinetochore recruitment of BubR1. We thus present novel molecular insights into the structure of BubR1 and its interactions at the kinetochore-microtubule interface. Our studies pave the way for future structure-directed engineering aimed at dissecting the roles of kinetochore-bound and other pools of BubR1 in vivo.

  8. Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability.

    Science.gov (United States)

    Gauthier-Vasserot, Alexandra; Thauvin-Robinet, Christel; Bruel, Ange-Line; Duffourd, Yannis; St-Onge, Judith; Jouan, Thibaud; Rivière, Jean-Baptiste; Heron, Delphine; Donadieu, Jean; Bellanné-Chantelot, Christine; Briandet, Claire; Huet, Frédéric; Kuentz, Paul; Lehalle, Daphné; Duplomb-Jego, Laurence; Gautier, Elodie; Maystadt, Isabelle; Pinson, Lucile; Amram, Daniel; El Chehadeh, Salima; Melki, Judith; Julia, Sophia; Faivre, Laurence; Thevenon, Julien

    2017-01-01

    Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. Overall, 30% of patients with congenital neutropenia (CN) remain without a molecular diagnosis after a multidisciplinary consultation and tedious diagnostic strategy. In the rare situations when neutropenia is identified and associated with intellectual disability (ID), there are few diagnostic hypotheses to test. This retrospective multicenter study reports on a clinically heterogeneous cohort of 10 unrelated patients with CN associated with ID and no molecular diagnosis prior to whole-exome sequencing (WES). WES provided a diagnostic yield of 40% (4/10). The results suggested that in many cases neutropenia and syndromic manifestations could not be assigned to the same molecular alteration. Three sub-groups of patients were highlighted: (i) severe, symptomatic chronic neutropenia, detected early in life, and related to a known mutation in the CN spectrum (ELANE); (ii) mild to moderate benign intermittent neutropenia, detected later, and associated with mutations in genes implicated in neurodevelopmental disorders (CHD2, HUWE1); and (iii) moderate to severe intermittent neutropenia as a probably undiagnosed feature of a newly reported syndrome (KAT6A). Unlike KAT6A, which seems to be associated with a syndromic form of CN, the other reported mutations may not explain the entire clinical picture. Although targeted gene sequencing can be discussed for the primary diagnosis of severe CN, we suggest that performing WES for the diagnosis of disorders associating CN with ID will not only provide the etiological diagnosis but will also pave the way towards personalized care and follow-up. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Molecular basis of the 14-3-3 protein-dependent activation of yeast neutral trehalase Nth1

    Czech Academy of Sciences Publication Activity Database

    Alblová, Miroslava; Šmídová, Aneta; Dočekal, V.; Veselý, J.; Herman, P.; Obšilová, Veronika; Obšil, Tomáš

    2017-01-01

    Roč. 114, č. 46 (2017), E9811-E9820 ISSN 0027-8424 R&D Projects: GA ČR(CZ) GA16-02739S; GA MŠk(CZ) ED1.1.00/02.0109; GA ČR(CZ) GA17-00726S Institutional support: RVO:67985823 Keywords : 14-3-3 protein * trehalase * crystal structure * enzyme * allostery Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biochemical research methods Impact factor: 9.661, year: 2016

  10. Structural and Biochemical Studies of a Fluoroacetyl-CoA-Specific Thioesterase Reveal a Molecular Basis for Fluorine Selectivity†,‡

    OpenAIRE

    Weeks, Amy M.; Coyle, Scott M.; Jinek, Martin; Doudna, Jennifer A.; Chang, Michelle C. Y.

    2010-01-01

    We have initiated a broad-based program aimed at understanding the molecular basis of fluorine specificity in enzymatic systems, and in this context, we report crystallographic and biochemical studies on a fluoroacetyl-coenzyme A (CoA) specific thioesterase (FlK) from Streptomyces cattleya. Our data establish that FlK is competent to protect its host from fluoroacetate toxicity in vivo and demonstrate a 106-fold discrimination between fluoroacetyl-CoA(kcat/KM=5×107M−1 s−1) and acetyl-CoA(kcat...

  11. Molecular Basis for DNA Double-Strand Break Annealing and Primer Extension by an NHEJ DNA Polymerase

    Directory of Open Access Journals (Sweden)

    Nigel C. Brissett

    2013-11-01

    Full Text Available Nonhomologous end-joining (NHEJ is one of the major DNA double-strand break (DSB repair pathways. The mechanisms by which breaks are competently brought together and extended during NHEJ is poorly understood. As polymerases extend DNA in a 5′-3′ direction by nucleotide addition to a primer, it is unclear how NHEJ polymerases fill in break termini containing 3′ overhangs that lack a primer strand. Here, we describe, at the molecular level, how prokaryotic NHEJ polymerases configure a primer-template substrate by annealing the 3′ overhanging strands from opposing breaks, forming a gapped intermediate that can be extended in trans. We identify structural elements that facilitate docking of the 3′ ends in the active sites of adjacent polymerases and reveal how the termini act as primers for extension of the annealed break, thus explaining how such DSBs are extended in trans. This study clarifies how polymerases couple break-synapsis to catalysis, providing a molecular mechanism to explain how primer extension is achieved on DNA breaks.

  12. Crystal Structures of Glycosyltransferase UGT78G1 Reveal the Molecular Basis for Glycosylation and Deglycosylation of (Iso)flavonoids

    Energy Technology Data Exchange (ETDEWEB)

    Modolo, Luzia V.; Li, Lenong; Pan, Haiyun; Blount, Jack W.; Dixon, Richard A.; Wang, Xiaoqiang; (SRNF)

    2010-09-21

    The glycosyltransferase UGT78G1 from Medicago truncatula catalyzes the glycosylation of various (iso)flavonoids such as the flavonols kaempferol and myricetin, the isoflavone formononetin, and the anthocyanidins pelargonidin and cyanidin. It also catalyzes a reverse reaction to remove the sugar moiety from glycosides. The structures of UGT78G1 bound with uridine diphosphate or with both uridine diphosphate and myricetin were determined at 2.1 {angstrom} resolution, revealing detailed interactions between the enzyme and substrates/products and suggesting a distinct binding mode for the acceptor/product. Comparative structural analysis and mutagenesis identify glutamate 192 as a key amino acid for the reverse reaction. This information provides a basis for enzyme engineering to manipulate substrate specificity and to design effective biocatalysts with glycosylation and/or deglycosylation activity.

  13. Contributions of a unique β-clamp to substrate recognition illuminates the molecular basis of exolysis in ferulic acid esterases.

    Science.gov (United States)

    Gruninger, Robert J; Cote, Chris; McAllister, Tim A; Abbott, D Wade

    2016-04-01

    Lignocellulosic biomass is a promising renewable resource; however, deconstruction of this material is still the rate-limiting step. Major obstacles in the biocatalytic turnover of lignocellulose are ester-linked decorations that prevent access to primary structural polysaccharides. Enzymes targeting these esters represent promising biotools for increasing bioconversion efficiency. Ruminant livestock are unique in their ability to degrade lignocellulose through the action of their gut microbiome. The anaerobic fungi (phylum Neocallimastigomycota) are key members of this ecosystem that express a large repertoire of carbohydrate-active enzymes (CAZymes) with little sequence identity with characterized CAZymes [Lombard, Golaconda, Drula, Coutinho and Henrissat (2014) Nucleic Acids Res. 42: , D490-D495]. We have identified a carbohydrate esterase family 1 (CE1) ferulic acid esterase (FAE) belonging to Anaeromyces mucronatus(AmCE1/Fae1a), and determined its X-ray structure in both the presence [1.55 Å (1 Å=0.1 nm)] and absence (1.60 Å) of ferulic acid. AmCE1 adopts an α/β-hydrolase fold that is structurally conserved with bacterial FAEs, and possesses a unique loop, termed the β-clamp, that encloses the ligand. Isothermal titration calorimetry reveals that substrate binding is driven by enthalpic contributions, which overcomes a large entropic penalty. A comparative analysis of AmCE1 with related enzymes has uncovered the apparent structural basis for differential FAE activities targeting cross-linking ferulic acid conjugates compared with terminal decorations. Based on comparisons to structurally characterized FAEs, we propose that the β-clamp may define the structural basis of exolytic activities in FAEs. This provides a structure-based tool for predicting exolysis and endolysis in CE1. These insights hold promise for rationally identifying enzymes tailored for bioconversion of biomass with variations in cell wall composition. © 2016 Authors; published by

  14. Molecular basis for vulnerability to mitochondrial and oxidative stress in a neuroendocrine CRI-G1 cell line.

    Directory of Open Access Journals (Sweden)

    Natasha Chandiramani

    2011-01-01

    Full Text Available Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases are linked to mitochondrial dysfunction, which leads to impaired cellular bioenergetics and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types.Starting with an insulinoma cell line as a model for a neuronal/endocrine cell type, we isolated a novel subclonal line (named CRI-G1-RS that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors than the parental CRI-G1 line (renamed CRI-G1-RR for clarity. Compared to parental RR cells, RS cells were also more vulnerable to direct oxidative stress, but equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition-induced apoptosis. Thus, differential vulnerability to mitochondrial toxins between these two cell types likely reflects differences in their ability to handle metabolically generated reactive oxygen species rather than differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1 inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2 decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3 increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; (4 increased expression of β cell-specific genes and transcription factors that specify/maintain β cell fate; and (5 reconstitution of glucose-stimulated insulin secretion.The molecular profile presented here will enable identification of individual genes or gene clusters that shape vulnerability to mitochondrial dysfunction and

  15. Accounting of 131l decomposition under retrospective assessment of its deposition on the basis of determination of 129l deposition

    Directory of Open Access Journals (Sweden)

    Gavrilin Yu.l.

    2013-12-01

    given article aimed a justification of approaches to account of radioactive decay of 131l in the course of determination of its ground deposition density on the basis of determination of the ground deposition density of 129l at the late stage after the accident.

  16. The yellow fever 17D vaccine virus: molecular basis of viral attenuation and its use as an expression vector

    Directory of Open Access Journals (Sweden)

    Galler R.

    1997-01-01

    Full Text Available The yellow fever (YF virus is the prototype flavivirus. The use of molecular techniques has unraveled the basic mechanisms of viral genome structure and expression. Recent trends in flavivirus research include the use of infectious clone technology with which it is possible to recover virus from cloned cDNA. Using this technique, mutations can be introduced at any point of the viral genome and their resulting effect on virus phenotype can be assessed. This approach has opened new possibilities to study several biological viral features with special emphasis on the issue of virulence/attenuation of the YF virus. The feasibility of using YF virus 17D vaccine strain, for which infectious cDNA is available, as a vector for the expression of heterologous antigens is reviewed

  17. A comparative study of the biologic and molecular basis of murine mammary carcinoma: a model for human breast cancer

    International Nuclear Information System (INIS)

    Schlom, J.; Kufe, D.; Hehlman, R.; Spiegelman, S.; Bentvelzen, P.; Michalides, R.; Hageman, P.

    1976-01-01

    Tritiated-DNA complementary to mouse mammary tumor virus (MMTV) RNA was synthesized in an endogeneous reaction with MMTV particles. This DNA was used as a probe via molecular hybridization to detect MMTV-specific RNA in 'spontaneous' mammary tumors of several strains of mice, including the 'nonproducer' BALB/c mammary tumors. MMTV-specific RNA was also found in certain normal tissues (spleen, kidney, and epididymis) of a high-mammary-cancer strain (GR). Aging or treatment with nonviral carcinogens also induced the appearance of MMTV-specific RNA in certain normal tissues of the low-mammary-cancer strains, C57BL and BALB/c. The relationship of the presence of MMTV-specific RNA to the etiology and pathogenesis of murine mammary neoplasia and its potential application to human breast cancer are discussed

  18. Improved Inhibition of Telomerase by Short Twisted Intercalating Nucleic Acids under Molecular Crowding Conditions

    DEFF Research Database (Denmark)

    Agarwal, Tani; Pradhan, Devranjan; Géci, Imrich

    2012-01-01

    Human telomeric DNA has the ability to fold into a 4-stranded G-quadruplex structure. Several G-quadruplex ligands are known to stabilize the structure and thereby inhibit telomerase activity. Such ligands have demonstrated efficient telomerase inhibition in dilute conditions, but under molecular...

  19. Foundational Concepts and Underlying Theories for Majors in "Biochemistry and Molecular Biology"

    Science.gov (United States)

    Tansey, John T.; Baird, Teaster, Jr.; Cox, Michael M.; Fox, Kristin M.; Knight, Jennifer; Sears, Duane; Bell, Ellis

    2013-01-01

    Over the past two years, through an NSF RCN UBE grant, the ASBMB has held regional workshops for faculty members and science educators from around the country that focused on identifying: 1) core principles of biochemistry and molecular biology, 2) essential concepts and underlying theories from physics, chemistry, and mathematics, and 3)…

  20. Molecular Mechanisms Underlying the Epileptogenesis and Seizure Progression in Tuberous Sclerosis Complex 1 Deficient Mouse Models

    Science.gov (United States)

    2016-10-01

    dysregulation in epileptogenesis in the developing brain? 2) What are the molecular mechanisms downstream of mTOR hyperactivation that trigger epileptogenesis...underlying epilepsy. Hopefully, a knowledge of these mechanisms will aid in a rational development of therapies. KEYWORDS Tuberous Sclerosis, Epilepsy

  1. Inhibition of Ca2+-activated Cl− channels by gallotannins as a possible molecular basis for health benefits of red wine and green tea

    Science.gov (United States)

    Namkung, Wan; Thiagarajah, Jay R.; Phuan, Puay-Wah; Verkman, A. S.

    2010-01-01

    TMEM16A was found recently to be a calcium-activated Cl− channel (CaCC). CaCCs perform important functions in cell physiology, including regulation of epithelial secretion, cardiac and neuronal excitability, and smooth muscle contraction. CaCC modulators are of potential utility for treatment of hypertension, diarrhea, and cystic fibrosis. Screening of drug and natural product collections identified tannic acid as an inhibitor of TMEM16A, with IC50 ∼ 6 μM and ∼100% inhibition at higher concentrations. Tannic acid inhibited CaCCs in multiple cell types but did not affect CFTR Cl− channels. Structure-activity analysis indicated the requirement of gallic or digallic acid substituents on a macromolecular scaffold (gallotannins), as are present in green tea and red wine. Other polyphenolic components of teas and wines, including epicatechin, catechin, and malvidin-3-glucoside, poorly inhibited CaCCs. Remarkably, a 1000-fold dilution of red wine and 100-fold dilution of green tea inhibited CaCCs by >50%. Tannic acid, red wine, and green tea inhibited arterial smooth muscle contraction and intestinal Cl− secretion. Gallotannins are thus potent CaCC inhibitors whose biological activity provides a potential molecular basis for the cardioprotective and antisecretory benefits of red wine and green tea.—Namkung, W., Thiagarajah, J. R., Phuan, P.-W., Verkman, A. S. Inhibition of Ca2+-activated Cl− channels by gallotannins as a possible molecular basis for health benefits of red wine and green tea. PMID:20581223

  2. Mixed-culture transcriptome analysis reveals the molecular basis of mixed-culture growth in Streptococcus thermophilus and Lactobacillus bulgaricus.

    Science.gov (United States)

    Sieuwerts, Sander; Molenaar, Douwe; van Hijum, Sacha A F T; Beerthuyzen, Marke; Stevens, Marc J A; Janssen, Patrick W M; Ingham, Colin J; de Bok, Frank A M; de Vos, Willem M; van Hylckama Vlieg, Johan E T

    2010-12-01

    Many food fermentations are performed using mixed cultures of lactic acid bacteria. Interactions between strains are of key importance for the performance of these fermentations. Yogurt fermentation by Streptococcus thermophilus and Lactobacillus bulgaricus (basonym, Lactobacillus delbrueckii subsp. bulgaricus) is one of the best-described mixed-culture fermentations. These species are believed to stimulate each other's growth by the exchange of metabolites such as folic acid and carbon dioxide. Recently, postgenomic studies revealed that an upregulation of biosynthesis pathways for nucleotides and sulfur-containing amino acids is part of the global physiological response to mixed-culture growth in S. thermophilus, but an in-depth molecular analysis of mixed-culture growth of both strains remains to be established. We report here the application of mixed-culture transcriptome profiling and a systematic analysis of the effect of interaction-related compounds on growth, which allowed us to unravel the molecular responses associated with batch mixed-culture growth in milk of S. thermophilus CNRZ1066 and L. bulgaricus ATCC BAA-365. The results indicate that interactions between these bacteria are primarily related to purine, amino acid, and long-chain fatty acid metabolism. The results support a model in which formic acid, folic acid, and fatty acids are provided by S. thermophilus. Proteolysis by L. bulgaricus supplies both strains with amino acids but is insufficient to meet the biosynthetic demands for sulfur and branched-chain amino acids, as becomes clear from the upregulation of genes associated with these amino acids in mixed culture. Moreover, genes involved in iron uptake in S. thermophilus are affected by mixed-culture growth, and genes coding for exopolysaccharide production were upregulated in both organisms in mixed culture compared to monocultures. The confirmation of previously identified responses in S. thermophilus using a different strain combination

  3. Molecular basis for the mutagenic and lethal effects of ultraviolet irradiation. Progress report, December 1, 1977--November 30, 1978

    International Nuclear Information System (INIS)

    Grossman, L.

    1978-07-01

    Our earlier work on the chemical basis of mutagenesis led to certain chemical generalities necessary to explain how certain mutagens such as UV light and hydroxylamine functioned in information transfer systems (replicative, transcriptive and translational). When such modifications were applied to biologically active DNA in a controlled manner biological expression was non-stoichiometric because much of the damage was removed from the DNA by repair systems. Our efforts were then directed to these systems which led to: the isolation, purification and characterization of endonucleases responsible for the first and controlling step in DNA repair referred to as incision in both M. luteus and E. coli; the isolation, purification and characterization of exonucleases responsible for the removal or excision of damaged nucleotides in M. luteus and human placental trophoblasts; the repair of UV damaged biologically active transforming and transfecting DNAs by purified endonucleases, exonucleases, DNA polymerase I and polynucleotide ligase from M. luteus and E. coli; the characterization of the dual gene control for incision phenomenon in M. luteus and E. coli; and isolation, purification and characterization of repair enzymes from human placenta

  4. Exploring the Molecular Basis for Selective Binding of Homoserine Dehydrogenase from Mycobacterium leprae TN toward Inhibitors: A Virtual Screening Study

    Directory of Open Access Journals (Sweden)

    Dongling Zhan

    2014-01-01

    Full Text Available Homoserine dehydrogenase (HSD from Mycobacterium leprae TN is an antifungal target for antifungal properties including efficacy against the human pathogen. The 3D structure of HSD has been firmly established by homology modeling methods. Using the template, homoserine dehydrogenase from Thiobacillus denitrificans (PDB Id 3MTJ, a sequence identity of 40% was found and molecular dynamics simulation was used to optimize a reliable structure. The substrate and co-factor-binding regions in HSD were identified. In order to determine the important residues of the substrate (l-aspartate semialdehyde (l-ASA binding, the ASA was docked to the protein; Thr163, Asp198, and Glu192 may be important because they form a hydrogen bond with HSD through AutoDock 4.2 software. neuraminidaseAfter use of a virtual screening technique of HSD, the four top-scoring docking hits all seemed to cation–π ion pair with the key recognition residue Lys107, and Lys207. These ligands therefore seemed to be new chemotypes for HSD. Our results may be helpful for further experimental investigations.

  5. Molecular basis for H3K36me3 recognition by the Tudor domain of PHF1

    Science.gov (United States)

    Musselman, Catherine A.; Avvakumov, Nikita; Watanabe, Reiko; Abraham, Christopher G.; Lalonde, Marie-Eve; Hong, Zehui; Allen, Christopher; Roy, Siddhartha; Nuñez, James K.; Nickoloff, Jac; Kulesza, Caroline A.; Yasui, Akira; Côté, Jacques; Kutateladze, Tatiana G.

    2013-01-01

    The PHD finger protein 1 (PHF1) is essential in epigenetic regulation and genome maintenance. Here, we demonstrate that the Tudor domain of human PHF1 binds to histone H3 trimethylated at Lys36 (H3K36me3). We report a 1.9 Å resolution crystal structure of the Tudor domain in complex with H3K36me3 and describe the molecular mechanism of H3K36me3 recognition using NMR analysis. Binding of PHF1 to H3K36me3 inhibits the ability of the Polycomb PRC2 complex to methylate H3K27 in vitro and in vivo. Laser micro-irradiation data reveal that PHF1 is transiently recruited to DNA double-strand breaks (DSBs), and PHF1 mutants impaired in the H3K36me3 interaction exhibit reduced retention at DSB sites. Together, our findings suggest that PHF1 can mediate deposition of the repressive H3K27me3 mark and acts as an early DNA damage response cofactor. PMID:23142980

  6. Wild-type catalase peroxidase vs G279D mutant type: Molecular basis of Isoniazid drug resistance in Mycobacterium tuberculosis.

    Science.gov (United States)

    Singh, Aishwarya; Singh, Aditi; Grover, Sonam; Pandey, Bharati; Kumari, Anchala; Grover, Abhinav

    2018-01-30

    Mycobacterium tuberculosis katG gene is responsible for production of an enzyme catalase peroxidase that peroxidises and activates the prodrug Isoniazid (INH), a first-line antitubercular agent. INH interacts with catalase peroxidase enzyme within its heme pocket and gets converted to an active form. Mutations occurring in katG gene are often linked to reduced conversion rates for INH. This study is focussed on one such mutation occurring at residue 279, where glycine often mutates to aspartic acid (G279D). In the present study, several structural analyses were performed to study the effect of this mutation on functionality of KatG protein. On comparison, mutant protein exhibited a lower docking score, smaller binding cavity and reduced affinity towards INH. Molecular dynamics analysis revealed the mutant to be more rigid and less compact than the native protein. Essential dynamics analysis determined correlated motions of residues within the protein structure. G279D mutant was found to have many residues that showed related motions and an undesirable effect on the functionality of protein. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Molecular Structural Basis for the Cold Adaptedness of the Psychrophilic β-Glucosidase BglU in Micrococcus antarcticus.

    Science.gov (United States)

    Miao, Li-Li; Hou, Yan-Jie; Fan, Hong-Xia; Qu, Jie; Qi, Chao; Liu, Ying; Li, De-Feng; Liu, Zhi-Pei

    2016-01-22

    Psychrophilic enzymes play crucial roles in cold adaptation of microbes and provide useful models for studies of protein evolution, folding, and dynamic properties. We examined the crystal structure (2.2-Å resolution) of the psychrophilic β-glucosidase BglU, a member of the glycosyl hydrolase 1 (GH1) enzyme family found in the cold-adapted bacterium Micrococcus antarcticus. Structural comparison and sequence alignment between BglU and its mesophilic and thermophilic counterpart enzymes (BglB and GlyTn, respectively) revealed two notable features distinct to BglU: (i) a unique long-loop L3 (35 versus 7 amino acids in others) involved in substrate binding and (ii) a unique amino acid, His299 (Tyr in others), involved in the stabilization of an ordered water molecule chain. Shortening of loop L3 to 25 amino acids reduced low-temperature catalytic activity, substrate-binding ability, the optimal temperature, and the melting temperature (Tm). Mutation of His299 to Tyr increased the optimal temperature, the Tm, and the catalytic activity. Conversely, mutation of Tyr301 to His in BglB caused a reduction in catalytic activity, thermostability, and the optimal temperature (45 to 35°C). Loop L3 shortening and H299Y substitution jointly restored enzyme activity to the level of BglU, but at moderate temperatures. Our findings indicate that loop L3 controls the level of catalytic activity at low temperatures, residue His299 is responsible for thermolability (particularly heat lability of the active center), and long-loop L3 and His299 are jointly responsible for the psychrophilic properties. The described structural basis for the cold adaptedness of BglU will be helpful for structure-based engineering of new cold-adapted enzymes and for the production of mutants useful in a variety of industrial processes at different temperatures. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  8. Non-Newtonian behavior and molecular structure of Cooee bitumen under shear flow

    DEFF Research Database (Denmark)

    Lemarchand, Claire; Bailey, Nicholas; Daivis, Peter

    2015-01-01

    The rheology and molecular structure of a model bitumen (Cooee bitumen) under shear are investigated in the non-Newtonian regime using non-equilibrium molecular dynamics simulations. The shear viscosity, normal stress differences, and pressure of the bitumen mixture are computed at different shear...... rates and different temperatures. The model bitumen is shown to be a shear-thinning fluid at all temperatures. In addition, the Cooee model is able to reproduce experimental results showing the formation of nanoaggregates composed of stacks of flat aromatic molecules in bitumen. These nanoaggregates...

  9. Molecular Basis of the Anti-Cancer Effects of Genistein Isoflavone in LNCaP Prostate Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Hartmann J

    2011-03-01

    Full Text Available Background: Prostate cancer is the most common form of non-skin cancer within the United States and the second leading cause of cancer deaths. Survival rates for the advanced disease remain relatively low, and conventional treatments may be accompanied by significant side effects. As a result, current research is aimed at alternative or adjuvant treatments that will target components of the signal transduction, cell-cycle and apoptosis pathways, to induce cell death with little or no toxic side effects to the patient. In this study, we investigated the effect of genistein isoflavone, a soy derivative, on expression levels of genes involved in these pathways. The mechanism of genistein-induced cell death was also investigated. The chemosensitivity of the LNCaP prostate cancer cells to genistein was investigated using ATP and MTS assays, and a caspase binding assay was used to determine apoptosis induction. Several molecular targets were determined using cDNA microarray and RT-PCR analysis.Results: The overall data revealed that genistein induces cell death in a time- and dose-dependent manner, and regulates expression levels of several genes involved in carcinogenesis and immunity. Several cell-cycle genes were down-regulated, including the mitotic kinesins, cyclins and cyclin-dependent kinases. Various members of the Bcl-2 family of apoptotic proteins were also affected. The DefB1 and the HLA membrane receptor genes involved in immunogenicity were also up-regulated.Conclusion: The results indicate that genistein inhibits growth of the hormone-dependent prostate cancer cells, LNCaP, via apoptosis induction through regulation of some of the genes involved in carcinogenesis of many tumors, and immunogenicity. This study augments the potential phytotherapeutic and immunotherapeutic significance of genistein isoflavone.

  10. Receptor model for the molecular basis of tissue selectivity of 1,4-dihydropyridine calcium channel drugs

    Science.gov (United States)

    Langs, David A.; Strong, Phyllis D.; Triggle, David J.

    1990-09-01

    Our analysis of the solid state conformations of nifedipine [dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate] and its 1,4-dihydropyridine (1,4-DHP) analogues produced a cartoon description of the important interactions between these drugs and their voltage-dependent calcium channel receptor. In the present study a molecular-level detailed model of the 1,4-DHP receptor binding site has been built from the published amino acid sequence of the 215-1 subunit of the voltage-dependent calcium channel isolated from rabbit skeletal muscle transverse tubule membranes. The voltage-sensing component of the channel described in this work differs from others reported for the homologous sodium channel in that it incorporates a water structure and a staggered, rather than eclipsed, hydrogen bonded S4 helix conformation. The major recognition surfaces of the receptor lie in helical grooves on the S4 or voltagesensing α-helix that is positioned in the center of the bundle of transmembrane helices that define each of the four calcium channel domains. Multiple binding clefts defined by Arg-X-X-Arg-P-X-X-S `reading frames' exist on the S4 strand. The tissue selectivity of nifedipine and its analogues may arise, in part, from conservative changes in the amino acid residues at the P and S positions of the reading frame that define the ester-binding regions of receptors from different tissues. The crystal structures of two tissue-selective nifedipine analogues, nimodipine [isopropyl (2-methoxyethyl) 1,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate] and nitrendipine [ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate] are reported. Nimodipine was observed to have an unusual ester side chain conformation that enhances the fit to the proposed ester-sensing region of the receptor.

  11. Physical Meaning of Virtual Kohn-Sham Orbitals and Orbital Energies: An Ideal Basis for the Description of Molecular Excitations.

    Science.gov (United States)

    van Meer, R; Gritsenko, O V; Baerends, E J

    2014-10-14

    In recent years, several benchmark studies on the performance of large sets of functionals in time-dependent density functional theory (TDDFT) calculations of excitation energies have been performed. The tested functionals do not approximate exact Kohn-Sham orbitals and orbital energies closely. We highlight the advantages of (close to) exact Kohn-Sham orbitals and orbital energies for a simple description, very often as just a single orbital-to-orbital transition, of molecular excitations. Benchmark calculations are performed for the statistical average of orbital potentials (SAOP) functional for the potential [J. Chem. Phys. 2000, 112, 1344; 2001, 114, 652], which approximates the true Kohn-Sham potential much better than LDA, GGA, mGGA, and hybrid potentials do. An accurate Kohn-Sham potential does not only perform satisfactorily for calculated vertical excitation energies of both valence and Rydberg transitions but also exhibits appealing properties of the KS orbitals including occupied orbital energies close to ionization energies, virtual-occupied orbital energy gaps very close to excitation energies, realistic shapes of virtual orbitals, leading to straightforward interpretation of most excitations as single orbital transitions. We stress that such advantages are completely lost in time-dependent Hartree-Fock and partly in hybrid approaches. Many excitations and excitation energies calculated with local density, generalized gradient, and hybrid functionals are spurious. There is, with an accurate KS, or even the LDA or GGA potentials, nothing problematic about the "band gap" in molecules: the HOMO-LUMO gap is close to the first excitation energy (the optical gap).

  12. Molecular medicine for the 21. century: A computational basis for design and critique of vaccines and therapeutics

    Energy Technology Data Exchange (ETDEWEB)

    Lapedes, A.; Myers, G.; Perelson, A.; Farber, R.; Tung, C.S. [Los Alamos National Lab., NM (United States). Theoretical Div.

    1997-08-01

    This is the final report of a three-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The kissing-loop RNA motif is thought to modulate different steps in the retroviral life cycle. Using an RNA folding protocol developed under this project, the authors are studying the folding of the potential kissing-loop motif in HIV. Using only limited information on base-springs, and the constraints based on the connectivities, they are modeling the structure and the flexibility of this particular structural motif and have developed three predicted structures with low conformational energy. Following on the earlier work which analyzed correlated mutations in the V3 loop of HIV, they have developed an evolutionary model which incorporates non-independent mutations at different sequence positions in model sequences. This model takes into account the effects of the phylogenetic tree on the analysis of mutations, and shows a higher correspondence of correlated positions with structurally adjacent positions in the model than previous analyses. Additional research under this project has dealt with analyzing the dynamics of HIV in vivo. Using some simple models and patient data, they were able to establish for the first time some quantitative estimates of HIV dynamics in vivo.

  13. The genetics of dementias. Part 1: Molecular basis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17

    Directory of Open Access Journals (Sweden)

    Anna Kowalska

    2009-06-01

    gene have been identified, mainly in families with autosomal dominant FTDP-17 but also in sporadic families with Pick’s disease and AD. The known DNA changes have been classified according to their molecular effects into at least two groups: mutations that change the biochemical properties of tau protein and mutations that alter the alternative splicing of mRNA and lead very often to the overproduction of the 4R tau isoform. The imbalance in the ratio of the synthesized 3R and 4R tau isoforms stimulates protein aggregation and initiates neurodegeneration, leading to the development of dementia.

  14. A geometrical correction for the inter- and intra-molecular basis set superposition error in Hartree-Fock and density functional theory calculations for large systems.

    Science.gov (United States)

    Kruse, Holger; Grimme, Stefan

    2012-04-21

    A semi-empirical counterpoise-type correction for basis set superposition error (BSSE) in molecular systems is presented. An atom pair-wise potential corrects for the inter- and intra-molecular BSSE in supermolecular Hartree-Fock (HF) or density functional theory (DFT) calculations. This geometrical counterpoise (gCP) denoted scheme depends only on the molecular geometry, i.e., no input from the electronic wave-function is required and hence is applicable to molecules with ten thousands of atoms. The four necessary parameters have been determined by a fit to standard Boys and Bernadi counterpoise corrections for Hobza's S66×8 set of non-covalently bound complexes (528 data points). The method's target are small basis sets (e.g., minimal, split-valence, 6-31G*), but reliable results are also obtained for larger triple-ζ sets. The intermolecular BSSE is calculated by gCP within a typical error of 10%-30% that proves sufficient in many practical applications. The approach is suggested as a quantitative correction in production work and can also be routinely applied to estimate the magnitude of the BSSE beforehand. The applicability for biomolecules as the primary target is tested for the crambin protein, where gCP removes intramolecular BSSE effectively and yields conformational energies comparable to def2-TZVP basis results. Good mutual agreement is also found with Jensen's ACP(4) scheme, estimating the intramolecular BSSE in the phenylalanine-glycine-phenylalanine tripeptide, for which also a relaxed rotational energy profile is presented. A variety of minimal and double-ζ basis sets combined with gCP and the dispersion corrections DFT-D3 and DFT-NL are successfully benchmarked on the S22 and S66 sets of non-covalent interactions. Outstanding performance with a mean absolute deviation (MAD) of 0.51 kcal/mol (0.38 kcal/mol after D3-refit) is obtained at the gCP-corrected HF-D3/(minimal basis) level for the S66 benchmark. The gCP-corrected B3LYP-D3/6-31G* model

  15. A geometrical correction for the inter- and intra-molecular basis set superposition error in Hartree-Fock and density functional theory calculations for large systems

    Science.gov (United States)

    Kruse, Holger; Grimme, Stefan

    2012-04-01

    A semi-empirical counterpoise-type correction for basis set superposition error (BSSE) in molecular systems is presented. An atom pair-wise potential corrects for the inter- and intra-molecular BSSE in supermolecular Hartree-Fock (HF) or density functional theory (DFT) calculations. This geometrical counterpoise (gCP) denoted scheme depends only on the molecular geometry, i.e., no input from the electronic wave-function is required and hence is applicable to molecules with ten thousands of atoms. The four necessary parameters have been determined by a fit to standard Boys and Bernadi counterpoise corrections for Hobza's S66×8 set of non-covalently bound complexes (528 data points). The method's target are small basis sets (e.g., minimal, split-valence, 6-31G*), but reliable results are also obtained for larger triple-ζ sets. The intermolecular BSSE is calculated by gCP within a typical error of 10%-30% that proves sufficient in many practical applications. The approach is suggested as a quantitative correction in production work and can also be routinely applied to estimate the magnitude of the BSSE beforehand. The applicability for biomolecules as the primary target is tested for the crambin protein, where gCP removes intramolecular BSSE effectively and yields conformational energies comparable to def2-TZVP basis results. Good mutual agreement is also found with Jensen's ACP(4) scheme, estimating the intramolecular BSSE in the phenylalanine-glycine-phenylalanine tripeptide, for which also a relaxed rotational energy profile is presented. A variety of minimal and double-ζ basis sets combined with gCP and the dispersion corrections DFT-D3 and DFT-NL are successfully benchmarked on the S22 and S66 sets of non-covalent interactions. Outstanding performance with a mean absolute deviation (MAD) of 0.51 kcal/mol (0.38 kcal/mol after D3-refit) is obtained at the gCP-corrected HF-D3/(minimal basis) level for the S66 benchmark. The gCP-corrected B3LYP-D3/6-31G* model

  16. RECEPTOR SUPERFAMILY OF TUMOR NECROSIS FACTOR Α, AND HSP90 HEAT SHOCK PROTEIN: A MOLECULAR BASIS FOR INTERACTIONS

    Directory of Open Access Journals (Sweden)

    N. V. Ryazantseva

    2011-01-01

    Full Text Available Abstract.  A  study  was  performed  aiming  to  investigate  interactions  between  TNFα  receptor  (TNF1 superfamily and heat shock protein Hsp90, using a Jurkat tumor cell line. The tumor cells cultured in presence of Hsp90 inhibitor (17-AAG showed increased numbers of cells, presenting surface TNFR1 and FasR, which facilitate  triggering  of  programmed  cell  death.  It  was  also  revealed  that  Hsp90  blockage  under  the  in  vitro conditions causes a decrease in FasL, while not affecting TNFα and sTNFR1 production by the tumor cells. (Med. Immunol., 2011, vol. 13, N 2-3, pp 247-252 

  17. Transcriptome analysis reveals the genetic basis underlying the biosynthesis of volatile oil, gingerols, and diarylheptanoids in ginger (Zingiber officinale Rosc.).

    Science.gov (United States)

    Jiang, Yusong; Liao, Qinhong; Zou, Yong; Liu, Yiqing; Lan, Jianbin

    2017-10-23

    Ginger (Zingiber officinale Rosc.) is a popular flavoring that widely used in Asian, and the volatile oil in ginger rhizomes adds a special fragrance and taste to foods. The bioactive compounds in ginger, such as gingerols, diarylheptanoids, and flavonoids, are of significant value to human health because of their anticancer, anti-oxidant, and anti-inflammatory properties. However, as a non-model plant, knowledge about the genome sequences of ginger is extremely limited, and this limits molecular studies on this plant. In this study, de novo transcriptome sequencing was performed to investigate the expression of genes associated with the biosynthesis of major bioactive compounds in matured ginger rhizome (MG), young ginger rhizome (YG), and fibrous roots of ginger (FR). A total of 361,876 unigenes were generated by de novo assembly. The expression of genes involved in the pathways responsible for the biosynthesis of major bioactive compounds differed between tissues (MG, YG, and FR). Two pathways that give rise to volatile oil, gingerols, and diarylheptanoids, the "terpenoid backbone biosynthesis" and "stilbenoid, diarylheptanoid and gingerol biosynthesis" pathways, were significantly enriched (adjusted P value < 0.05) for differentially expressed genes (DEGs) (FDR < 0.005) both between the FR and YG libraries, and the FR and MG libraries. Most of the unigenes mapped in these two pathways, including curcumin synthase, phenylpropanoylacetyl-CoA synthase, trans-cinnamate 4-monooxygenase, and 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase, were expressed to a significantly higher level (log 2 (fold-change) ≥ 1) in FR than in YG or MG. This study provides the first insight into the biosynthesis of bioactive compounds in ginger at a molecular level and provides valuable genome resources for future molecular studies on ginger. Moreover, our results establish that bioactive compounds in ginger may predominantly synthesized in the root and then transported to

  18. Fundamento molecular de la esteatosis hepática asociada a la obesidad Molecular basis of obesity-related hepatic steatosis

    Directory of Open Access Journals (Sweden)

    X. Buqué

    2008-09-01

    Full Text Available La enfermedad del hígado graso no alcohólico es una enfermedad inflamatoria hepática de carácter crónico de gran relevancia en la actualidad por su fuerte asociación con enfermedades de incidencia creciente como la obesidad y la diabetes mellitus tipo 2. En este trabajo se recoge buena parte del conocimiento existente sobre los mecanismos moleculares implicados en el establecimiento de la esteatosis hepática, el primer estadio de la enfermedad, y en su progreso a esteatohepatitis. Se ha prestado una atención especial al hígado graso asociado a la obesidad, clínica y experimental. En este caso, se valora la rata fa/fa, un modelo animal de obesidad con rasgos fenotípicos similares a los de la obesidad humana, incluyendo la resistencia a la insulina y la dislipemia. La esteatosis hepática se revela como una situación compleja, eminentemente metabólica, en la que se simultanean procesos metabólicos aparentemente contradictorios, así como estrés oxidativo, estrés de retículo endoplasmático, disfunción mitocondrial y descenso en la expresión de genes de supervivencia. En buena medida, en su base se sitúan señales extrahepáticas, como las producidas en una situación de resistencia periférica a la insulina asociada a un aumento de la masa adiposa y de ácidos grasos libres sistémicos, e internas, causantes de un desajuste de las funciones glucostática y lipidostática del hígado y de una mayor vulnerabilidad a otras agresiones.Non-alcoholic fatty liver disease is a chronic inflammation liver condition that is currently highly relevant because of its strong association with increasingly incident diseases such as obesity and type-2 diabetes mellitus. The primary purpose of this paper is to discuss the best part of current knowledge on the molecular mechanisms involved in hepatic steatosis development, the condition's initial stage, and on progression to steatohepatitis. Special attention has been paid to clinical and

  19. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting

    International Nuclear Information System (INIS)

    Reubi, Jean Claude; Waser, Beatrice

    2003-01-01

    the cases and lacked CCK 1 and NMB receptors. All gastrinomas had sst 2 and GLP-1 receptors; they expressed GRP receptors in three-quarters of the cases and CCK 1 or VPAC 1 in approximately half of the cases. Most bronchial carcinoids had VPAC 1 , while sst 1 , sst 2 and CCK 2 were found in two-thirds of the cases and BB 3 in one-third of the cases. These data provide evidence for the vast biological diversity of these neuroendocrine tumours. Moreover, the results represent a basis for starting and/or optimising the in vivo targeting of these tumours by selecting the suitable radiopeptides for tumour diagnosis and/or therapy. Finally, the data strongly encourage concomitant application of several radiopeptides to permit more efficient targeting of these tumours. (orig.)

  20. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting

    Energy Technology Data Exchange (ETDEWEB)

    Reubi, Jean Claude; Waser, Beatrice [Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, PO Box 62, 3010, Berne (Switzerland)

    2003-05-01

    particularly high density; they expressed sst{sub 2} in two-thirds and sst{sub 1} in approximately half of the cases and lacked CCK{sub 1} and NMB receptors. All gastrinomas had sst{sub 2} and GLP-1 receptors; they expressed GRP receptors in three-quarters of the cases and CCK{sub 1} or VPAC{sub 1} in approximately half of the cases. Most bronchial carcinoids had VPAC{sub 1}, while sst{sub 1}, sst{sub 2} and CCK{sub 2} were found in two-thirds of the cases and BB{sub 3} in one-third of the cases. These data provide evidence for the vast biological diversity of these neuroendocrine tumours. Moreover, the results represent a basis for starting and/or optimising the in vivo targeting of these tumours by selecting the suitable radiopeptides for tumour diagnosis and/or therapy. Finally, the data strongly encourage concomitant application of several radiopeptides to permit more efficient targeting of these tumours. (orig.)

  1. Exploring the molecular basis of dsRNA recognition by NS1 protein of influenza A virus using molecular dynamics simulation and free energy calculation.

    Science.gov (United States)

    Pan, Dabo; Sun, Huijun; Shen, Yulin; Liu, Huanxiang; Yao, Xiaojun

    2011-12-01

    The frequent outbreak of influenza pandemic and the limited available anti-influenza drugs highlight the urgent need for the development of new antiviral drugs. The dsRNA-binding surface of nonstructural protein 1 of influenza A virus (NS1A) is a promising target. The detailed understanding of NS1A-dsRNA interaction will be valuable for structure-based anti-influenza drug discovery. To characterize and explore the key interaction features between dsRNA and NS1A, molecular dynamics simulation combined with MM-GBSA calculations were performed. Based on the MM-GBSA calculations, we find that the intermolecular van der Waals interaction and the nonpolar solvation term provide the main driving force for the binding process. Meanwhile, 17 key residues from NS1A were identified to be responsible for the dsRNA binding. Compared with the wild type NS1A, all the studied mutants S42A, T49A, R38A, R35AR46A have obvious reduced binding free energies with dsRNA reflecting in the reduction of the polar and/or nonpolar interactions. In addition, the structural and energy analysis indicate the mutations have a small effect to the backbone structures but the loss of side chain interactions is responsible for the decrease of the binding affinity. The uncovering of NS1A-dsRNA recognition mechanism will provide some useful insights and new chances for the development of anti-influenza drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Expression profiling of a genetic animal model of depression reveals novel molecular pathways underlying depressive-like behaviours.

    Directory of Open Access Journals (Sweden)

    Ekaterini Blaveri

    2010-09-01

    Full Text Available The Flinders model is a validated genetic rat model of depression that exhibits a number of behavioural, neurochemical and pharmacological features consistent with those observed in human depression.In this study we have used genome-wide microarray expression profiling of the hippocampus and prefrontal/frontal cortex of Flinders Depression Sensitive (FSL and control Flinders Depression Resistant (FRL lines to understand molecular basis for the differences between the two lines. We profiled two independent cohorts of Flinders animals derived from the same colony six months apart, each cohort statistically powered to allow independent as well as combined analysis. Using this approach, we were able to validate using real-time-PCR a core set of gene expression differences that showed statistical significance in each of the temporally distinct cohorts, representing consistently maintained features of the model. Small but statistically significant increases were confirmed for cholinergic (chrm2, chrna7 and serotonergic receptors (Htr1a, Htr2a in FSL rats consistent with known neurochemical changes in the model. Much larger gene changes were validated in a number of novel genes as exemplified by TMEM176A, which showed 35-fold enrichment in the cortex and 30-fold enrichment in hippocampus of FRL animals relative to FSL.These data provide significant insights into the molecular differences underlying the Flinders model, and have potential relevance to broader depression research.

  3. Essential concepts and underlying theories from physics, chemistry, and mathematics for "biochemistry and molecular biology" majors.

    Science.gov (United States)

    Wright, Ann; Provost, Joseph; Roecklein-Canfield, Jennifer A; Bell, Ellis

    2013-01-01

    Over the past two years, through an NSF RCN UBE grant, the ASBMB has held regional workshops for faculty members from around the country. The workshops have focused on developing lists of Core Principles or Foundational Concepts in Biochemistry and Molecular Biology, a list of foundational skills, and foundational concepts from Physics, Chemistry, and Mathematics that all Biochemistry or Molecular Biology majors must understand to complete their major coursework. The allied fields working group created a survey to validate foundational concepts from Physics, Chemistry, and Mathematics identified from participant feedback at various workshops. One-hundred twenty participants responded to the survey and 68% of the respondents answered yes to the question: "We have identified the following as the core concepts and underlying theories from Physics, Chemistry, and Mathematics that Biochemistry majors or Molecular Biology majors need to understand after they complete their major courses: 1) mechanical concepts from Physics, 2) energy and thermodynamic concepts from Physics, 3) critical concepts of structure from chemistry, 4) critical concepts of reactions from Chemistry, and 5) essential Mathematics. In your opinion, is the above list complete?" Respondents also delineated subcategories they felt should be included in these broad categories. From the results of the survey and this analysis the allied fields working group constructed a consensus list of allied fields concepts, which will help inform Biochemistry and Molecular Biology educators when considering the ASBMB recommended curriculum for Biochemistry or Molecular Biology majors and in the development of appropriate assessment tools to gauge student understanding of how these concepts relate to biochemistry and molecular biology. © 2013 by The International Union of Biochemistry and Molecular Biology.

  4. Molecular mechanisms underlying the emergence of bacterial pathogens: an ecological perspective.

    Science.gov (United States)

    Bartoli, Claudia; Roux, Fabrice; Lamichhane, Jay Ram

    2016-02-01

    The rapid emergence of new bacterial diseases negatively affects both human health and agricultural productivity. Although the molecular mechanisms underlying these disease emergences are shared between human- and plant-pathogenic bacteria, not much effort has been made to date to understand disease emergences caused by plant-pathogenic bacteria. In particular, there is a paucity of information in the literature on the role of environmental habitats in which plant-pathogenic bacteria evolve and on the stress factors to which these microbes are unceasingly exposed. In this microreview, we focus on three molecular mechanisms underlying pathogenicity in bacteria, namely mutations, genomic rearrangements and the acquisition of new DNA sequences through horizontal gene transfer (HGT). We briefly discuss the role of these mechanisms in bacterial disease emergence and elucidate how the environment can influence the occurrence and regulation of these molecular mechanisms by directly impacting disease emergence. The understanding of such molecular evolutionary mechanisms and their environmental drivers will represent an important step towards predicting bacterial disease emergence and developing sustainable management strategies for crops. © 2015 BSPP AND JOHN WILEY & SONS LTD.

  5. Dangerous liaisons: Molecular basis for a syndemic relationship between Kaposi’s sarcoma and P. falciparum malaria

    Directory of Open Access Journals (Sweden)

    Katelyn L. Conant

    2013-03-01

    Full Text Available The most severe manifestations of malaria (caused by P. falciparum occur as a direct result of parasitemia following invasion of erythrocytes by post-liver blood-stage merozoites, and during subsequent cyto-adherence of infected erythrocytes to the vascular endothelium. However, the disproportionate epidemiologic clustering of severe malaria with aggressive forms of endemic diseases such as Kaposi’s sarcoma, a neoplasm that is etiologically linked to infection with Kaposi’s sarcoma-associated herpesvirus [KSHV], underscores the significance of previously unexplored co-pathogenetic interactions that have the potential to modify the overall disease burden in co-infected individuals. Based on recent studies of the mechanisms that P. falciparum and KSHV have evolved to interact with their mutual human host, several new perspectives are emerging that highlight a surprising convergence of biological themes potentially underlying their associated co-morbidities. Against this background, ongoing studies are rapidly constructing a fascinating new paradigm in which the major host receptors that control parasite invasion (Basigin/CD147 and cyto-adherence (CD36 are, surprisingly, also important targets for exploitation by KSHV. In this article, we consider the major pathobiological implications of the co-option of Basigin/CD147 and CD36 signaling pathways by both P. falciparum and KSHV, not only as essential host factors for parasite persistence but also as important mediators of the pro-angiogenic phenotype within the virus-infected endothelial microenvironment. Consequently, the triangulation of interactions between P. falciparum, KSHV, and their mutual human host articulates a syndemic relationship that points to a conceptual framework for prevalence of aggressive forms of Kaposi’s sarcoma in malaria endemic areas, with implications for the possibility of dual-use therapies against these debilitating infections in resource-limited parts of the

  6. National and sub-national under-five mortality profiles in Peru: a basis for informed policy decisions.

    Science.gov (United States)

    Huicho, Luis; Trelles, Miguel; Gonzales, Fernando

    2006-07-04

    Information on profiles for under-five causes of death is important to guide choice of child-survival interventions. Global level data have been published, but information at country level is scarce. We aimed at defining national and departmental trends and profiles of under-five mortality in Peru from 1996 through 2000. We used the Ministry of Health registered under-five mortality data. For correction of under-registration, a model life-table that fitted the age distribution of the population and of registered deaths was identified for each year. The mortality rates corresponding to these model life-tables were then assigned to each department in each particular year. Cumulative reduction in under-five mortality rate in the 1996-2000 period was estimated calculating the annual reduction slope for each department. Departmental level mortality profiles were constructed. Differences in mortality profiles and in mortality reduction between coastal, andean and jungle regions were also assessed. At country level, only 4 causes (pneumonia, diarrhoea, neonatal diseases and injuries) accounted for 68% of all deaths in 1996, and for 62% in 2000. There was 32.7% of under-five death reduction from 1996 to 2000. Diarrhoea and pneumonia deaths decreased by 84.5% and 41.8%, respectively, mainly in the andean region, whereas deaths due to neonatal causes and injuries decreased by 37.2% and 21.7%. For 1996-2000 period, the andean, coast and jungle regions accounted for 52.4%, 33.1% and 14.4% of deaths, respectively. These regions represent 41.0%, 46.4% and 12.6% of under-five population. Both diarrhoea and pneumonia constitute 30.6% of under-five deaths in the andean region. As a proportion, neonatal deaths remained stable in the country from 1996 to 2000, accounting for about 30% of under-five deaths, whereas injuries and "other" causes, including congenital anomalies, increased by about 5%. Under-five mortality declined substantially in all departments from 1996 to 2000, which

  7. National and sub-national under-five mortality profiles in Peru: a basis for informed policy decisions

    Directory of Open Access Journals (Sweden)

    Trelles Miguel

    2006-07-01

    Full Text Available Abstract Background Information on profiles for under-five causes of death is important to guide choice of child-survival interventions. Global level data have been published, but information at country level is scarce. We aimed at defining national and departmental trends and profiles of under-five mortality in Peru from 1996 through 2000. Methods We used the Ministry of Health registered under-five mortality data. For correction of under-registration, a model life-table that fitted the age distribution of the population and of registered deaths was identified for each year. The mortality rates corresponding to these model life-tables were then assigned to each department in each particular year. Cumulative reduction in under-five mortality rate in the 1996–2000 period was estimated calculating the annual reduction slope for each department. Departmental level mortality profiles were constructed. Differences in mortality profiles and in mortality reduction between coastal, andean and jungle regions were also assessed. Results At country level, only 4 causes (pneumonia, diarrhoea, neonatal diseases and injuries accounted for 68% of all deaths in 1996, and for 62% in 2000. There was 32.7% of under-five death reduction from 1996 to 2000. Diarrhoea and pneumonia deaths decreased by 84.5% and 41.8%, respectively, mainly in the andean region, whereas deaths due to neonatal causes and injuries decreased by 37.2% and 21.7%. For 1996–2000 period, the andean, coast and jungle regions accounted for 52.4%, 33.1% and 14.4% of deaths, respectively. These regions represent 41.0%, 46.4% and 12.6% of under-five population. Both diarrhoea and pneumonia constitute 30.6% of under-five deaths in the andean region. As a proportion, neonatal deaths remained stable in the country from 1996 to 2000, accounting for about 30% of under-five deaths, whereas injuries and "other" causes, including congenital anomalies, increased by about 5%. Conclusion Under

  8. National and sub-national under-five mortality profiles in Peru: a basis for informed policy decisions

    Science.gov (United States)

    Huicho, Luis; Trelles, Miguel; Gonzales, Fernando

    2006-01-01

    Background Information on profiles for under-five causes of death is important to guide choice of child-survival interventions. Global level data have been published, but information at country level is scarce. We aimed at defining national and departmental trends and profiles of under-five mortality in Peru from 1996 through 2000. Methods We used the Ministry of Health registered under-five mortality data. For correction of under-registration, a model life-table that fitted the age distribution of the population and of registered deaths was identified for each year. The mortality rates corresponding to these model life-tables were then assigned to each department in each particular year. Cumulative reduction in under-five mortality rate in the 1996–2000 period was estimated calculating the annual reduction slope for each department. Departmental level mortality profiles were constructed. Differences in mortality profiles and in mortality reduction between coastal, andean and jungle regions were also assessed. Results At country level, only 4 causes (pneumonia, diarrhoea, neonatal diseases and injuries) accounted for 68% of all deaths in 1996, and for 62% in 2000. There was 32.7% of under-five death reduction from 1996 to 2000. Diarrhoea and pneumonia deaths decreased by 84.5% and 41.8%, respectively, mainly in the andean region, whereas deaths due to neonatal causes and injuries decreased by 37.2% and 21.7%. For 1996–2000 period, the andean, coast and jungle regions accounted for 52.4%, 33.1% and 14.4% of deaths, respectively. These regions represent 41.0%, 46.4% and 12.6% of under-five population. Both diarrhoea and pneumonia constitute 30.6% of under-five deaths in the andean region. As a proportion, neonatal deaths remained stable in the country from 1996 to 2000, accounting for about 30% of under-five deaths, whereas injuries and "other" causes, including congenital anomalies, increased by about 5%. Conclusion Under-five mortality declined substantially in

  9. PWR-related integral safety experiments in the PKL 111 test facility SBLOCA under beyond-design-basis accident conditions

    Energy Technology Data Exchange (ETDEWEB)

    Weber, P.; Umminger, K.J.; Schoen, B. [Siemens AG Power Generation Group (KWU), Erlangen (France)

    1995-09-01

    The thermal hydraulic behavior of a PWR during beyond-design-basis accident scenarios is of vital interest for the verification and optimization of accident management procedures. Within the scope of the German reactor safety research program experiments were performed in the volumetrically scaled PKL 111 test facility by Siemens/KWU. This highly instrumented test rig simulates a KWU-design PWR (1300 MWe). In particular, the latest tests performed related to a SBLOCA with additional system failures, e.g. nitrogen entering the primary system. In the case of a SBLOCA, it is the goal of the operator to put the plant in a condition where the decay heat can be removed first using the low pressure emergency core cooling system and then the residual heat removal system. The experimental investigation presented assumed the following beyond-design-basis accident conditions: 0.5% break in a cold leg, 2 of 4 steam generators (SGs) isolated on the secondary side (feedwater- and steam line-valves closed), filled with steam on the primary side, cooldown of the primary system using the remaining two steam generators, high pressure injection system only in the two loops with intact steam generators, if possible no operator actions to reach the conditions for residual heat removal system activation. Furthermore, it was postulated that 2 of the 4 hot leg accumulators had a reduced initial water inventory (increased nitrogen inventory), allowing nitrogen to enter the primary system at a pressure of 15 bar and nearly preventing the heat transfer in the SGs ({open_quotes}passivating{close_quotes} U-tubes). Due to this the heat transfer regime in the intact steam generators changed remarkably. The primary system showed self-regulating system effects and heat transfer improved again (reflux-condenser mode in the U-tube inlet region).

  10. Recent progress in transition-metal-catalyzed reduction of molecular dinitrogen under ambient reaction conditions.

    Science.gov (United States)

    Nishibayashi, Yoshiaki

    2015-10-05

    This paper describes our recent progress in catalytic nitrogen fixation by using transition-metal-dinitrogen complexes as catalysts. Two reaction systems for the catalytic transformation of molecular dinitrogen into ammonia and its equivalent such as silylamine under ambient reaction conditions have been achieved by the molybdenum-, iron-, and cobalt-dinitrogen complexes as catalysts. Many new findings presented here may provide new access to the development of economical nitrogen fixation in place of the Haber-Bosch process.

  11. Molecular dynamics simulations of the melting curve of NiAl alloy under pressure

    OpenAIRE

    Wenjin Zhang; Yufeng Peng; Zhongli Liu

    2014-01-01

    The melting curve of B2-NiAl alloy under pressure has been investigated using molecular dynamics technique and the embedded atom method (EAM) potential. The melting temperatures were determined with two approaches, the one-phase and the two-phase methods. The first one simulates a homogeneous melting, while the second one involves a heterogeneous melting of materials. Both approaches reduce the superheating effectively and their results are close to each other at the applied pressures. By fit...

  12. Understanding the structural and energetic basis of PD-1 and monoclonal antibodies bound to PD-L1: A molecular modeling perspective.

    Science.gov (United States)

    Shi, Danfeng; Zhou, Shuangyan; Liu, Xuewei; Zhao, Chenxi; Liu, Huanxiang; Yao, Xiaojun

    2018-03-01

    The inhibitors blocking the interaction between programmed cell death protein 1(PD-1) and programmed death-ligand 1(PD-L1) can activate the immune response of T cell and eliminate cancer cells. The crystallographic studies have provided structural insights of the interactive interfaces between PD-L1 and its protein ligands. However, the hotspot residues on PD-L1 as well as structural and energetic basis for different protein ligands still need to be further investigated. Molecular modeling methods including molecular dynamics simulation, per-residue free energy decomposition, virtual alanine scanning mutagenesis and residue-residue contact analysis were used to qualitatively and quantitatively analyze the interactions between PD-L1 and different protein ligands. The results of virtual alanine scanning mutagenesis suggest that Y56, Q66, M115, D122, Y123, R125 are the hotspot residues on PD-L1. The residue-residue contact analysis further shows that PD-1 interacts with PD-L1 mainly by F and G strands while monoclonal antibodies like avelumab and BMS-936559 mainly interact with PD-L1 by CDR2 and CDR3 loops of the heavy chain. A structurally similar β-hairpin peptide with 13 or 14 residues was extracted from each protein ligand and these β-hairpin peptides were found tightly binding to the putative hotspot residues on PD-L1. This study recognizes the hotspot residues on PD-L1 and uncovers the common structural and energetic basis of different protein ligands binding to PD-L1. These results will be valuable for the design of small molecule or peptide inhibitors targeting on PD-L1. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Thermal hydraulic behavior of a PWR under beyond-design-basis accident conditions: Conclusions from an experimental program in a 4-loop test facility (PKL)

    International Nuclear Information System (INIS)

    Umminger, K.J.; Kastner, W.; Mandl, R.M.; Weber, P.

    1993-01-01

    Within the scope of German reactor safety research, extensive experiments covering the behavior of nuclear power plants under accident conditions have been carried out in the PKL test facility which simulates a 4-loop, 1,300 MWe KWU-designed PWR. While the investigations dealing with design-basis accidents and with the efficiency of the emergency core cooling systems have been largely completed, the main interest nowadays concentrates on the investigation of beyond-design-basis accidents to demonstrate the safety margins of nuclear power plants and to investigate the contribution of the built-in safety features for a further reduction of the residual risk. The thermal hydraulic behavior of a PWR under these extreme accident conditions was experimentally investigated within the PKL III B test program. This paper presents the fundamental findings with some of the most important results being discussed in detail. Future plans are also outlined

  14. Molecular Properties by Quantum Monte Carlo: An Investigation on the Role of the Wave Function Ansatz and the Basis Set in the Water Molecule

    Science.gov (United States)

    Zen, Andrea; Luo, Ye; Sorella, Sandro; Guidoni, Leonardo

    2014-01-01

    Quantum Monte Carlo methods are accurate and promising many body techniques for electronic structure calculations which, in the last years, are encountering a growing interest thanks to their favorable scaling with the system size and their efficient parallelization, particularly suited for the modern high performance computing facilities. The ansatz of the wave function and its variational flexibility are crucial points for both the accurate description of molecular properties and the capabilities of the method to tackle large systems. In this paper, we extensively analyze, using different variational ansatzes, several properties of the water molecule, namely, the total energy, the dipole and quadrupole momenta, the ionization and atomization energies, the equilibrium configuration, and the harmonic and fundamental frequencies of vibration. The investigation mainly focuses on variational Monte Carlo calculations, although several lattice regularized diffusion Monte Carlo calculations are also reported. Through a systematic study, we provide a useful guide to the choice of the wave function, the pseudopotential, and the basis set for QMC calculations. We also introduce a new method for the computation of forces with finite variance on open systems and a new strategy for the definition of the atomic orbitals involved in the Jastrow-Antisymmetrised Geminal power wave function, in order to drastically reduce the number of variational parameters. This scheme significantly improves the efficiency of QMC energy minimization in case of large basis sets. PMID:24526929

  15. Comparative Transcriptome Analysis of Latex Reveals Molecular Mechanisms Underlying Increased Rubber Yield in Hevea brasiliensis Self-Rooting Juvenile Clones.

    Science.gov (United States)

    Li, Hui-Liang; Guo, Dong; Zhu, Jia-Hong; Wang, Ying; Chen, Xiong-Ting; Peng, Shi-Qing

    2016-01-01

    Rubber tree (Hevea brasiliensis) self-rooting juvenile clones (JCs) are promising planting materials for rubber production. In a comparative trial between self-rooting JCs and donor clones (DCs), self-rooting JCs exhibited better performance in rubber yield. To study the molecular mechanism associated with higher rubber yield in self-rooting JCs, we sequenced and comparatively analyzed the latex of rubber tree self-rooting JCs and DCs at the transcriptome level. Total raw reads of 34,632,012 and 35,913,020 bp were obtained from the library of self-rooting JCs and DCs, respectively, by using Illumina HiSeq 2000 sequencing technology. De novo assemblies yielded 54689 unigenes from the library of self-rooting JCs and DCs. Among 54689 genes, 1716 genes were identified as differentially expressed between self-rooting JCs and DCs via comparative transcript profiling. Functional analysis showed that the genes related to the mass of categories were differentially enriched between the two clones. Several genes involved in carbohydrate metabolism, hormone metabolism and reactive oxygen species scavenging were up-regulated in self-rooting JCs, suggesting that the self-rooting JCs provide sufficient molecular basis for the increased rubber yielding, especially in the aspects of improved latex metabolisms and latex flow. Some genes encoding epigenetic modification enzymes were also differentially expressed between self-rooting JCs and DCs. Epigenetic modifications may lead to gene differential expression between self-rooting JCs and DCs. These data will provide new cues to understand the molecular mechanism underlying the improved rubber yield of H. brasiliensis self-rooting clones.

  16. The genetic basis underlying variation in production of the flavour compound diacetyl by Lactobacillus rhamnosus strains in milk.

    Science.gov (United States)

    Lo, Raquel; Ho, Van Thi Thuy; Bansal, Nidhi; Turner, Mark S

    2018-01-16

    Diacetyl and the closely related compound acetoin impart desirable buttery flavour and odour to many foods including cheese and are generated through the metabolism of citrate by lactic acid bacteria (LAB). To increase the levels of these compounds, adjunct cultures capable of producing them can be added to cheese fermentations. In this study, we compared the diacetyl and acetoin producing abilities of 13 Lactobacillus rhamnosus strains from cheese sources. Diacetyl and acetoin production was found to be a common feature of Lb. rhamnosus grown in milk, with 12 strains producing these compounds. Whole genome sequencing of four strains revealed that genes encoding the citrate metabolising pathway present in other LAB are conserved in Lb. rhamnosus. One strain was, however, totally defective in diacetyl and acetoin production. This was likely due to an inability to produce the diacetyl/acetoin precursor compound acetolactate resulting from a frameshift mutation in the acetolactate synthase (als) gene. Complementation of this defective strain with a complete als gene from a diacetyl producing strain restored production of diacetyl and acetoin to levels equivalent to naturally high producing strains. Introduction of the same als-containing plasmid into the probiotic Lb. rhamnosus strain GG also increased diacetyl and acetoin levels. In model cheesemaking experiments, the als-complemented strain produced very high levels of diacetyl and acetoin over 35days of ripening. These findings identify the genetic basis for natural variation in production of a key cheese flavour compound in Lb. rhamnosus strains. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent Cryptococcal Meningitis Infection

    Directory of Open Access Journals (Sweden)

    Johanna Rhodes

    2017-04-01

    Full Text Available Recurrence of meningitis due to Cryptococcus neoformans after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing (WGS to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis (CM. Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, while the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5, and RAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and nonsynonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in C. neoformans, and represent a novel pathway for rapid within-host adaptation and evolution of resistance to first-line antifungal drugs.

  18. Molecular and preclinical basis to inhibit PGE2 receptors EP2 and EP4 as a novel nonsteroidal therapy for endometriosis

    Science.gov (United States)

    Arosh, Joe A.; Lee, JeHoon; Balasubbramanian, Dakshnapriya; Stanley, Jone A.; Long, Charles R.; Meagher, Mary W.; Osteen, Kevin G.; Bruner-Tran, Kaylon L.; Burghardt, Robert C.; Starzinski-Powitz, Anna; Banu, Sakhila K.

    2015-01-01

    Endometriosis is a debilitating, estrogen-dependent, progesterone-resistant, inflammatory gynecological disease of reproductive age women. Two major clinical symptoms of endometriosis are chronic intolerable pelvic pain and subfertility or infertility, which profoundly affect the quality of life in women. Current hormonal therapies to induce a hypoestrogenic state are unsuccessful because of undesirable side effects, reproductive health concerns, and failure to prevent recurrence of disease. There is a fundamental need to identify nonestrogen or nonsteroidal targets for the treatment of endometriosis. Peritoneal fluid concentrations of prostaglandin E2 (PGE2) are higher in women with endometriosis, and this increased PGE2 plays important role in survival and growth of endometriosis lesions. The objective of the present study was to determine the effects of pharmacological inhibition of PGE2 receptors, EP2 and EP4, on molecular and cellular aspects of the pathogenesis of endometriosis and associated clinical symptoms. Using human fluorescent endometriotic cell lines and chimeric mouse model as preclinical testing platform, our results, to our knowledge for the first time, indicate that selective inhibition of EP2/EP4: (i) decreases growth and survival of endometriosis lesions; (ii) decreases angiogenesis and innervation of endometriosis lesions; (iii) suppresses proinflammatory state of dorsal root ganglia neurons to decrease pelvic pain; (iv) decreases proinflammatory, estrogen-dominant, and progesterone-resistant molecular environment of the endometrium and endometriosis lesions; and (v) restores endometrial functional receptivity through multiple mechanisms. Our novel findings provide a molecular and preclinical basis to formulate long-term nonestrogen or nonsteroidal therapy for endometriosis. PMID:26199416

  19. Genomic regions, cellular components and gene regulatory basis underlying pod length variations in cowpea (V. unguiculata L. Walp).

    Science.gov (United States)

    Xu, Pei; Wu, Xinyi; Muñoz-Amatriaín, María; Wang, Baogen; Wu, Xiaohua; Hu, Yaowen; Huynh, Bao-Lam; Close, Timothy J; Roberts, Philip A; Zhou, Wen; Lu, Zhongfu; Li, Guojing

    2017-05-01

    Cowpea (V. unguiculata L. Walp) is a climate resilient legume crop important for food security. Cultivated cowpea (V. unguiculata L) generally comprises the bushy, short-podded grain cowpea dominant in Africa and the climbing, long-podded vegetable cowpea popular in Asia. How selection has contributed to the diversification of the two types of cowpea remains largely unknown. In the current study, a novel genotyping assay for over 50 000 SNPs was employed to delineate genomic regions governing pod length. Major, minor and epistatic QTLs were identified through QTL mapping. Seventy-two SNPs associated with pod length were detected by genome-wide association studies (GWAS). Population stratification analysis revealed subdivision among a cowpea germplasm collection consisting of 299 accessions, which is consistent with pod length groups. Genomic scan for selective signals suggested that domestication of vegetable cowpea was accompanied by selection of multiple traits including pod length, while the further improvement process was featured by selection of pod length primarily. Pod growth kinetics assay demonstrated that more durable cell proliferation rather than cell elongation or enlargement was the main reason for longer pods. Transcriptomic analysis suggested the involvement of sugar, gibberellin and nutritional signalling in regulation of pod length. This study establishes the basis for map-based cloning of pod length genes in cowpea and for marker-assisted selection of this trait in breeding programmes. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  20. Detection of an inhibitory cortical gradient underlying peak shift in learning: a neural basis for a false memory.

    Science.gov (United States)

    Miasnikov, Alexandre A; Weinberger, Norman M

    2012-11-01

    Experience often does not produce veridical memory. Understanding false attribution of events constitutes an important problem in memory research. "Peak shift" is a well-characterized, controllable phenomenon in which human and animal subjects that receive reinforcement associated with one sensory stimulus later respond maximally to another stimulus in post-training stimulus generalization tests. Peak shift ordinarily develops in discrimination learning (reinforced CS+, unreinforced CS-) and has long been attributed to the interaction of an excitatory gradient centered on the CS+ and an inhibitory gradient centered on the CS-; the shift is away from the CS-. In contrast, we have obtained peak shifts during single tone frequency training, using stimulation of the cholinergic nucleus basalis (NB) to implant behavioral memory into the rat. As we also recorded cortical activity, we took the opportunity to investigate the possible existence of a neural frequency gradient that could account for behavioral peak shift. Behavioral frequency generalization gradients (FGGs, interruption of ongoing respiration) were determined twice before training while evoked potentials were recorded from the primary auditory cortex (A1), to obtain a baseline gradient of "habituatory" neural decrement. A post-training behavioral FGG obtained 24h after three daily sessions of a single tone paired with NB stimulation (200 trials/day) revealed a peak shift. The peak of the FGG was at a frequency lower than the CS while the cortical inhibitory gradient was at a frequency higher than the CS frequency. Further analysis indicated that the frequency location and magnitude of the gradient could account for the behavioral peak shift. These results provide a neural basis for a systematic case of memory misattribution and may provide an animal model for the study of the neural bases of a type of "false memory". Published by Elsevier Inc.

  1. Molecular characteristics of stress overshoot for polymer melts under start-up shear flow.

    Science.gov (United States)

    Jeong, Sohdam; Kim, Jun Mo; Baig, Chunggi

    2017-12-21

    Stress overshoot is one of the most important nonlinear rheological phenomena exhibited by polymeric liquids undergoing start-up shear at sufficient flow strengths. Despite considerable previous research, the fundamental molecular characteristics underlying stress overshoot remain unknown. Here, we analyze the intrinsic molecular mechanisms behind the overshoot phenomenon using atomistic nonequilibrium molecular dynamics simulations of entangled linear polyethylene melts under shear flow. Through a detailed analysis of the transient rotational chain dynamics, we identify an intermolecular collision angular regime in the vicinity of the chain orientation angle θ ≈ 20° with respect to the flow direction. The shear stress overshoot occurs via strong intermolecular collisions between chains in the collision regime at θ = 15°-25°, corresponding to a peak strain of 2-4, which is an experimentally well-known value. The normal stress overshoot appears at approximately θ = 10°, at a corresponding peak strain roughly equivalent to twice that for the shear stress. We provide plausible answers to several basic questions regarding the stress overshoot, which may further help understand other nonlinear phenomena of polymeric systems.

  2. Molecular basis of neural function

    International Nuclear Information System (INIS)

    Tucek, S.; Stipek, S.; Stastny, F.; Krivanek, J.

    1986-01-01

    The conference proceedings contain abstracts of plenary lectures, of young neurochemists' ESN honorary lectures, lectures at symposia and workshops and poster communications. Twenty abstracts were inputted in INIS. The subject of these were the use of autoradiography for the determination of receptors, cholecystokinin, nicotine, adrenaline, glutamate, aspartate, tranquilizers, for distribution and pharmacokinetics of obidoxime-chloride, for cell proliferation, mitosis of brain cells, DNA repair; radioimmunoassay of cholinesterase, tyrosinase; positron computed tomography of the brain; biological radiation effects on cholinesterase activity; tracer techniques for determination of adrenaline; and studies of the biological repair of nerves. (J.P.)

  3. Molecular basis of radiation syndrome

    International Nuclear Information System (INIS)

    Romantsev, E.F.; Blokhina, V.D.; Zhulanova, Z I.; Koshcheenko, N.N.; Nikol'skij, A.V.; Filippovich, I.V.

    1984-01-01

    The book is devoted to the analysis of the mechanism of action of ionizing radiation on the most important biochemical processes in the cells and tissues. The postirradiating disturbances of the metabolism of precursors of nucleic acids, biosynthesis of proteins, metabolism of prostaglandins and cyclic nucleotides were examined in detail. The biochemical mechanism of the interphase cell death was discussed. The analysis of the experimental facts about the effect of ionizing radiation with different dose rate upon the cell metabolism was made

  4. Molecular Basis of Essential Thrombocytosis

    Science.gov (United States)

    2008-06-01

    by a clinically visible journal [Ref. 11]. IX. INDIVIDUALS RECEIVING PAY Jean Wainer, BS Research Support Specialist © 2005 Schattauer GmbH...33 More recently, several techniques have been devised to directly compare cellular proteomes, including isotope -coded affinity tags (ICATs)34 and...derived tryptic peptides with oxygen -18, have been used to study the differential expression of platelet proteins.40 Limitations of proteomic techniques

  5. Molecular Basis of Circadian Photoreception

    Science.gov (United States)

    2006-06-30

    267, 16237-16243. Murakami, D.M., Miller, J.D., Fuller, C.A., 1989. The retinohypothalamic tract in the cat: retinal ganglion cell morphology and...Photochem Photobiol B 13, 5-17. Pickard, G.E., 1980. Morphological characteristics of retinal ganglion cells projecting to the suprachiasmatic nucleus: a...from archaea to humans. Annu Rev Cell Dev Biol 16, 365-392. Takahashi, J.S., DeCoursey, P.J., Bauman, L., Menaker, M., 1984. Spectral sensitivity

  6. Modified Motor Vehicles Travel Speed Models on the Basis of Curb Parking Setting under Mixed Traffic Flow

    Directory of Open Access Journals (Sweden)

    Zhenyu Mei

    2012-01-01

    Full Text Available The ongoing controversy about in what condition should we set the curb parking has few definitive answers because comprehensive research in this area has been lacking. Our goal is to present a set of heuristic urban street speed functions under mixed traffic flow by taking into account impacts of curb parking. Two impacts have been defined to classify and quantify the phenomena of motor vehicles' speed dynamics in terms of curb parking. The first impact is called Space impact, which is caused by the curb parking types. The other one is the Time impact, which results from the driver maneuvering in or out of parking space. In this paper, based on the empirical data collected from six typical urban streets in Nanjing, China, two models have been proposed to describe these phenomena for one-way traffic and two-way traffic, respectively. An intensive experiment has been conducted in order to calibrate and validate these proposed models, by taking into account the complexity of the model parameters. We also provide guidelines in terms of how to cluster and calculate those models' parameters. Results from these models demonstrated promising performance of modeling motor vehicles' speed for mixed traffic flow under the influence of curb parking.

  7. Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli.

    Science.gov (United States)

    Gat-Viks, Irit; Chevrier, Nicolas; Wilentzik, Roni; Eisenhaure, Thomas; Raychowdhury, Raktima; Steuerman, Yael; Shalek, Alex K; Hacohen, Nir; Amit, Ido; Regev, Aviv

    2013-04-01

    Individual genetic variation affects gene responsiveness to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness quantitative trait loci or reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant responds as an activator of the antiviral response; using RNA interference, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli.

  8. Neutral molecular cluster formation of sulfuric acid–dimethylamine observed in real time under atmospheric conditions

    CERN Document Server

    Kürten, Andreas; Simon, Mario; Sipilä, Mikko; Sarnela, Nina; Junninen, Heikki; Adamov, Alexey; Almeida, João; Amorim, Antonio; Bianchi, Federico; Breitenlechner, Martin; Dommen, Josef; Donahue, Neil M; Duplissy, Jonathan; Ehrhart, Sebastian; Flagan, Richard C; Franchin, Alessandro; Hakala, Jani; Hansel, Armin; Heinritzi, Martin; Hutterli, Manuel; Kangasluoma, Juha; Kirkby, Jasper; Laaksonen, Ari; Lehtipalo, Katrianne; Leiminger, Markus; Makhmutov, Vladimir; Mathot, Serge; Onnela, Antti; Petäjä, Tuukka; Praplan, Arnaud P; Riccobono, Francesco; Rissanen, Matti P; Rondo, Linda; Schobesberger, Siegfried; Seinfeld, John H; Steiner, Gerhard; Tomé, António; Tröstl, Jasmin; Winkler, Paul M; Williamson, Christina; Wimmer, Daniela; Ye, Penglin; Baltensperger, Urs; Carslaw, Kenneth S; Kulmala, Markku; Worsnop, Douglas R; Curtius, Joachim

    2014-01-01

    For atmospheric sulfuric acid (SA) concentrations the presence of dimethylamine (DMA) at mixing ratios of several parts per trillion by volume can explain observed boundary layer new particle formation rates. However, the concentration and molecular composition of the neutral (uncharged) clusters have not been reported so far due to the lack of suitable instrumentation. Here we report on experiments from the Cosmics Leaving Outdoor Droplets chamber at the European Organization for Nuclear Research revealing the formation of neutral particles containing up to 14 SA and 16 DMA molecules, corresponding to a mobility diameter of about 2 nm, under atmospherically relevant conditions. These measurements bridge the gap between the molecular and particle perspectives of nucleation, revealing the fundamental processes involved in particle formation and growth. The neutral clusters are found to form at or close to the kinetic limit where particle formation is limited only by the collision rate of SA molecules. Even tho...

  9. Molecular and Microbial Mechanisms Increasing Soil C Storage Under Future Rates of Anthropogenic N Deposition

    Energy Technology Data Exchange (ETDEWEB)

    Zak, Donald R. [Univ. of Michigan, Ann Arbor, MI (United States)

    2017-11-17

    A growing body of evidence reveals that anthropogenic N deposition can reduce the microbial decay of plant detritus and increase soil C storage across a wide range of terrestrial ecosystems. This aspect of global change has the potential to constrain the accumulation of anthropogenic CO2 in the Earth’s atmosphere, and hence slow the pace of climate warming. The molecular and microbial mechanisms underlying this biogeochemical response are not understood, and they are not a component of any coupled climate-biogeochemical model estimating ecosystem C storage, and hence, the future climate of an N-enriched Earth. Here, we report the use of genomic-enabled approaches to identify the molecular underpinnings of the microbial mechanisms leading to greater soil C storage in response to anthropogenic N deposition, thereby enabling us to better anticipate changes in soil C storage.

  10. The biological basis of radiotherapy

    International Nuclear Information System (INIS)

    Steel, G.G.; Adams, G.E.; Horwich, A.

    1989-01-01

    The focus of this book is the biological basis of radiotherapy. The papers presented include: Temporal stages of radiation action:free radical processes; The molecular basis of radiosensitivity; and Radiation damage to early-reacting normal tissue

  11. Nanomaterials under extreme environments: A study of structural and dynamic properties using reactive molecular dynamics simulations

    Science.gov (United States)

    Shekhar, Adarsh

    Nanotechnology is becoming increasingly important with the continuing advances in experimental techniques. As researchers around the world are trying to expand the current understanding of the behavior of materials at the atomistic scale, the limited resolution of equipment, both in terms of time and space, act as roadblocks to a comprehensive study. Numerical methods, in general and molecular dynamics, in particular act as able compliment to the experiments in our quest for understanding material behavior. In this research work, large scale molecular dynamics simulations to gain insight into the mechano-chemical behavior under extreme conditions of a variety of systems with many real world applications. The body of this work is divided into three parts, each covering a particular system: 1) Aggregates of aluminum nanoparticles are good solid fuel due to high flame propagation rates. Multi-million atom molecular dynamics simulations reveal the mechanism underlying higher reaction rate in a chain of aluminum nanoparticles as compared to an isolated nanoparticle. This is due to the penetration of hot atoms from reacting nanoparticles to an adjacent, unreacted nanoparticle, which brings in external heat and initiates exothermic oxidation reactions. 2) Cavitation bubbles readily occur in fluids subjected to rapid changes in pressure. We use billion-atom reactive molecular dynamics simulations on a 163,840-processor BlueGene/P supercomputer to investigate chemical and mechanical damages caused by shock-induced collapse of nanobubbles in water near amorphous silica. Collapse of an empty nanobubble generates high-speed nanojet, resulting in the formation of a pit on the surface. The pit contains a large number of silanol groups and its volume is found to be directly proportional to the volume of the nanobubble. The gas-filled bubbles undergo partial collapse and consequently the damage on the silica surface is mitigated. 3) The structure and dynamics of water confined in

  12. ESCA and electron diffraction studies of InP surface heated under As molecular beam exposure

    International Nuclear Information System (INIS)

    Sugiura, Hideo; Yamaguchi, Masafumi; Shibukawa, Atsushi

    1983-01-01

    Chemical composition of InP substrate surface heattreated under As molecular beam exposure in an ultrahigh vacuum chamber was studied with ESCA, and surface reconstruction of the substrate was examined by in-situ electron diffraction. The InP substrate heated under the exposure of As molecular beam has mirror surface up to 590 0 C while the surface of InP heated above 400 0 C in vacuum is roughened. The ESCA study shows that thin InAs layer (thickness 0 C under the exposure of As. The electron diffraction study indicates that the InP is cleaned at about 500 0 C in As pressures of 10 -7 - 10 -5 Torr. The InP surface is prevented from thermally decomposing by the coverage of the InAs layer, which may be formed through the following process: 2InPO 4 + As 4 → 2InAs + P 2 O 5 + As 2 O 3 . (author)

  13. Molecular hematology

    National Research Council Canada - National Science Library

    Provan, Drew; Gribben, John

    2010-01-01

    ... The molecular basis of hemophilia, 219 Paul LF Giangrande 4 The genetics of acute myeloid leukemias, 42 Carolyn J Owen & Jude Fitzgibbon 19 The molecular basis of von Willebrand disease, 233 Luciano Baronc...

  14. The role of stable α-synuclein oligomers in the molecular events underlying amyloid formation

    DEFF Research Database (Denmark)

    Lorenzen, Nikolai; Nielsen, Søren Bang; Buell, Alexander K.

    2014-01-01

    α-synuclein (αSN), whose aggregation is strongly implicated in the development of Parkinson’s disease (PD). The two types of oligomers are both formed under conditions where amyloid fibril formation is observed but differ in molecular weight by an order of magnitude. Both possess a degree of β......, either as precursors of fibrils or as species involved in the fibril elongation process or instead if they are associated with an aggregation process that is distinct from that generating mature fibrils. Here we describe and characterize in detail two well-defined oligomeric species formed by the protein...

  15. C sub 6 sub 0 fullerene and its molecular complexes under axial and shear deformation

    CERN Document Server

    Spitsina, N G; Bashkin, I V; Meletov, K P

    2002-01-01

    We have studied the pristine C sub 6 sub 0 and its molecular complexes with the organic donors bis(ethylenedithio) tetrathiafulvalene (BEDT-TTF or ET) and tetramethyltetraselenafulvalene (TMTSF) by means of ESR and Raman spectroscopy at high pressure. The important changes in the ESR signal of C sub 6 sub 0 were observed under axial pressure combined with shear deformation. It is shown that the treatment at a anisotropic pressure of 4 GPa results in a reduction in the symmetry of the C sub 6 sub 0 molecule and the formation of radicals. Treatment of the molecular complex of (ET) sub 2 centre dot C sub 6 sub 0 at a pressure of approx 4.5 GPa and a temperature of 150 deg. C leads to the formation of C sub 6 sub 0 dimers. The Raman spectra of the molecular complex C sub 6 sub 0 centre dot TMTSF centre dot 2(CS sub 2) were measured in situ at ambient temperature and pressures up to 9.5 GPa. The pressure behaviour of the Raman peaks reveals singularity at 5.0 +- 0.5 GPa related to the softening and splitting of so...

  16. Influence of the molecular modifications on the properties of EPDM elastomers under irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Davenas, J. E-mail: joel.davenas@univ-lyon1.fr; Stevenson, I.; Celette, N.; Vigier, G.; David, L

    2003-08-01

    The degradation of the mechanical behaviour of EPDM elastomers used as cable insulation materials has been investigated by mechanical spectroscopy and tensile tests for different formulations: unvulcanised EPDM, vulcanised and stabilised elastomer with an antioxidant. In all cases, {gamma}-irradiation of EPDM under oxygen leads to a reduction of the molecular mobility indicated by the shift of the glass transition relaxation temperature towards higher temperatures. Moreover, the molecular flow occurring above T{sub g} is suppressed after irradiation for the unvulcanised EPDM providing evidence of cross-linking. The competition between cross-linking and chain scissions is shown by the decrease of the storage modulus above the crystallites melting temperature ({approx}40 deg. C) at doses larger than 100 kGy. A strong increase of the Young modulus and reduction of the elongation at break of the non-vulcanised EPDM becoming more brittle are shown by stress/strain characterisations performed at 80 deg. C. At the opposite vulcanised EPDM exhibits higher elongation at break after crystallites melting. This evolution is interpreted by the competition between cross-linking and chain scissions, being hindered by the crystallites at room temperature. The intrinsic irradiation effects can be isolated after crystallite melting. The reduction of the molecular mobility can be explained by a chemi-crystallisation process assisted by chain scissions, leading to a more rigid phase upon irradiation.

  17. Influence of the molecular modifications on the properties of EPDM elastomers under irradiation

    International Nuclear Information System (INIS)

    Davenas, J.; Stevenson, I.; Celette, N.; Vigier, G.; David, L.

    2003-01-01

    The degradation of the mechanical behaviour of EPDM elastomers used as cable insulation materials has been investigated by mechanical spectroscopy and tensile tests for different formulations: unvulcanised EPDM, vulcanised and stabilised elastomer with an antioxidant. In all cases, γ-irradiation of EPDM under oxygen leads to a reduction of the molecular mobility indicated by the shift of the glass transition relaxation temperature towards higher temperatures. Moreover, the molecular flow occurring above T g is suppressed after irradiation for the unvulcanised EPDM providing evidence of cross-linking. The competition between cross-linking and chain scissions is shown by the decrease of the storage modulus above the crystallites melting temperature (∼40 deg. C) at doses larger than 100 kGy. A strong increase of the Young modulus and reduction of the elongation at break of the non-vulcanised EPDM becoming more brittle are shown by stress/strain characterisations performed at 80 deg. C. At the opposite vulcanised EPDM exhibits higher elongation at break after crystallites melting. This evolution is interpreted by the competition between cross-linking and chain scissions, being hindered by the crystallites at room temperature. The intrinsic irradiation effects can be isolated after crystallite melting. The reduction of the molecular mobility can be explained by a chemi-crystallisation process assisted by chain scissions, leading to a more rigid phase upon irradiation

  18. Changes in permittivity and density of molecular liquids under high pressure.

    Science.gov (United States)

    Kiselev, Vladimir D; Kornilov, Dmitry A; Konovalov, Alexander I

    2014-04-03

    We collected and analyzed the density and permittivity of 57 nonpolar and dipolar molecular liquids at different temperatures (143 sets) and pressures (555 sets). No equation was found that could accurately predict the change to polar liquid permittivity by the change of its density in the range of the pressures and temperatures tested. Consequently, the influence of high hydrostatic pressure and temperature on liquid permittivity may be a more complicated process compared to density changes. The pressure and temperature coefficients of permittivity can be drastically larger than the pressure and temperature coefficients of density, indicating that pressure and particularly temperature significantly affect the structure of molecular liquids. These changes have less influence on the density change but can strongly affect the permittivity change. The clear relationship between the tangent and secant moduli of the permittivity curvatures under pressure for various molecular liquids at different temperatures was obtained, from which one can calculate the Tait equation coefficients from the experimental values of the pressure influence on the permittivity at ambient pressure.

  19. Material Performance of Fully-Ceramic Micro-Encapsulated Fuel under Selected LWR Design Basis Scenarios: Final Report

    International Nuclear Information System (INIS)

    Boer, B.; Sen, R.S.; Pope, M.A.; Ougouag, A.M.

    2011-01-01

    The extension to LWRs of the use of Deep-Burn coated particle fuel envisaged for HTRs has been investigated. TRISO coated fuel particles are used in Fully-Ceramic Microencapsulated (FCM) fuel within a SiC matrix rather than the graphite of HTRs. TRISO particles are well characterized for uranium-fueled HTRs. However, operating conditions of LWRs are different from those of HTRs (temperature, neutron energy spectrum, fast fluence levels, power density). Furthermore, the time scales of transient core behavior during accidents are usually much shorter and thus more severe in LWRs. The PASTA code was updated for analysis of stresses in coated particle FCM fuel. The code extensions enable the automatic use of neutronic data (burnup, fast fluence as a function of irradiation time) obtained using the DRAGON neutronics code. An input option for automatic evaluation of temperature rise during anticipated transients was also added. A new thermal model for FCM was incorporated into the code; so-were updated correlations (for pyrocarbon coating layers) suitable to estimating dimensional changes at the high fluence levels attained in LWR DB fuel. Analyses of the FCM fuel using the updated PASTA code under nominal and accident conditions show: (1) Stress levels in SiC-coatings are low for low fission gas release (FGR) fractions of several percent, as based on data of fission gas diffusion in UO 2 kernels. However, the high burnup level of LWR-DB fuel implies that the FGR fraction is more likely to be in the range of 50-100%, similar to Inert Matrix Fuels (IMFs). For this range the predicted stresses and failure fractions of the SiC coating are high for the reference particle design (500 (micro)mm kernel diameter, 100 (micro)mm buffer, 35 (micro)mm IPyC, 35 (micro)mm SiC, 40 (micro)mm OPyC). A conservative case, assuming 100% FGR, 900K fuel temperature and 705 MWd/kg (77% FIMA) fuel burnup, results in a 8.0 x 10 -2 failure probability. For a 'best-estimate' FGR fraction of 50

  20. Molecular HIV screening.

    Science.gov (United States)

    Bourlet, Thomas; Memmi, Meriam; Saoudin, Henia; Pozzetto, Bruno

    2013-09-01

    Nuclear acid testing is more and more used for the diagnosis of infectious diseases. This paper focuses on the use of molecular tools for HIV screening. The term 'screening' will be used under the meaning of first-line HIV molecular techniques performed on a routine basis, which excludes HIV molecular tests designed to confirm or infirm a newly discovered HIV-seropositive patient or other molecular tests performed for the follow-up of HIV-infected patients. The following items are developed successively: i) presentation of the variety of molecular tools used for molecular HIV screening, ii) use of HIV molecular tools for the screening of blood products, iii) use of HIV molecular tools for the screening of organs and tissue from human origin, iv) use of HIV molecular tools in medically assisted procreation and v) use of HIV molecular tools in neonates from HIV-infected mothers.

  1. Comparative Phenotypical and Molecular Analyses of Arabidopsis Grown under Fluorescent and LED Light

    Directory of Open Access Journals (Sweden)

    Franka Seiler

    2017-06-01

    Full Text Available Comparative analyses of phenotypic and molecular traits of Arabidopsis thaliana grown under standardised conditions is still a challenge using climatic devices supplied with common light sources. These are in most cases fluorescent lights, which have several disadvantages such as heat production at higher light intensities, an invariable spectral output, and relatively rapid “ageing”. This results in non-desired variations of growth conditions and lowers the comparability of data acquired over extended time periods. In this study, we investigated the growth behaviour of Arabidopsis Col0 under different light conditions, applying fluorescent compared to LED lamps, and we conducted physiological as well as gene expression analyses. By changing the spectral composition and/or light intensity of LEDs we can clearly influence the growth behaviour of Arabidopsis and thereby study phenotypic attributes under very specific light conditions that are stable and reproducible, which is not necessarily given for fluorescent lamps. By using LED lights, we can also roughly mimic the sun light emission spectrum, enabling us to study plant growth in a more natural-like light set-up. We observed distinct growth behaviour under the different light regimes which was reflected by physiological properties of the plants. In conclusion, LEDs provide variable emission spectra for studying plant growth under defined, stable light conditions.

  2. A molecular perspective on the limits of life: Enzymes under pressure

    Directory of Open Access Journals (Sweden)

    Q. Huang

    2016-03-01

    Full Text Available From a purely operational standpoint, the existence of microbes that can grow under extreme conditions, or "extremophiles", leads to the question of how the molecules making up these microbes can maintain both their structure and function. While microbes that live under extremes of temperature have been heavily studied, those that live under extremes of pressure have been neglected, in part due to the difficulty of collecting samples and performing experiments under the ambient conditions of the microbe. However, thermodynamic arguments imply that the effects of pressure might lead to different organismal solutions than from the effects of temperature. Observationally, some of these solutions might be in the condensed matter properties of the intracellular milieu in addition to genetic modifications of the macromolecules or repair mechanisms for the macromolecules. Here, the effects of pressure on enzymes, which are proteins essential for the growth and reproduction of an organism, and some adaptations against these effects are reviewed and amplified by the results from molecular dynamics simulations. The aim is to provide biological background for soft matter studies of these systems under pressure.

  3. Molecular dynamics simulations of the structure evolutions of Cu-Zr metallic glasses under irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lang, Lin [College of Materials Science and Engineering, Hunan University, Changsha 410082 (China); Department of Applied Physics, School of Physics and Electronics, Hunan University, Changsha 410082 (China); Tian, Zean; Xiao, Shifang [Department of Applied Physics, School of Physics and Electronics, Hunan University, Changsha 410082 (China); Deng, Huiqiu, E-mail: hqdeng@hnu.edu.cn [Department of Applied Physics, School of Physics and Electronics, Hunan University, Changsha 410082 (China); Ao, Bingyun [Science and Technology on Surface Physics and Chemistry Laboratory, Mianyang 621907 (China); Chen, Piheng, E-mail: chenpiheng@caep.cn [Science and Technology on Surface Physics and Chemistry Laboratory, Mianyang 621907 (China); Hu, Wangyu [College of Materials Science and Engineering, Hunan University, Changsha 410082 (China)

    2017-02-15

    Highlights: • The structural evolution of Cu{sub 64.5}Zr{sub 35.5} MG under irradiation was studied. • The structure clusters were analyzed using the LSCA method. • Most of these radiation damages have been self-recovered quickly. - Abstract: Molecular dynamics simulations have been performed to investigate the structural evolution of Cu{sub 64.5}Zr{sub 35.5} metallic glasses under irradiation. The largest standard cluster analysis (LSCA) method was used to quantify the microstructure within the collision cascade regions. It is found that the majority of clusters within the collision cascade regions are full and defective icosahedrons. Not only the smaller structures (common neighbor subcluster) but also primary clusters greatly changed during the collision cascades; while most of these radiation damages self-recover quickly in the following quench states. These findings indicate the Cu-Zr metallic glasses have excellent irradiation-resistance properties.

  4. Molecular basis of interactions between mitochondrial proteins and hydroxyapatite in the presence of Triton X-100, as revealed by proteomic and recombinant techniques.

    Science.gov (United States)

    Yamamoto, Takenori; Tamaki, Haruna; Katsuda, Chie; Nakatani, Kiwami; Terauchi, Satsuki; Terada, Hiroshi; Shinohara, Yasuo

    2013-08-02

    Hydroxyapatite chromatography is a very important step in the purification of voltage-dependent anion channels (VDACs) and several members of solute carrier family 25 (Slc25) from isolated mitochondria. In the presence of Triton X-100, VDACs and Slc25 members present a peculiar property, i.e., a lack of interaction with hydroxyapatite, resulting in their presence in the flow-through fraction of hydroxyapatite chromatography. This property has allowed selective isolation of VDACs and Slc25 members from a mixture of total mitochondrial proteins. However, the reason why only these few proteins are selectively obtained in the presence of Triton X-100 from the flow-though fraction of hydroxyapatite chromatography has not yet been adequately understood. In this study, when we examined the protein species in the flow-through fractions by proteomic analysis, VDAC isoforms, Slc25 members, and some other membrane proteins were identified. All the mitochondrial proteins had in common high hydrophobicity over their entire protein sequences. When the proteins were fused to soluble proteins, the fused proteins showed affinity for hydroxyapatite even in the presence of Triton X-100. Based on these results, we discussed the molecular basis of the interactions between proteins and hydroxyapatite in the presence of Triton X-100. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Prevalence of Prostate Cancer Metastases after Intravenous Inoculation Provides Clues into the Molecular Basis of Dormancy in the Bone Marrow Microenvironment

    Directory of Open Access Journals (Sweden)

    Younghun Jung

    2012-05-01

    Full Text Available Bone is the preferred metastasis site of advanced prostate cancer (PCa. Using an in vivo murine model of human PCa cell metastasis to bone, we noted that the majority of animals that develop skeletal metastasis have either spinal lesions or lesions in the bones of the hindlimb. Much less frequently, lesions develop in the bones of the forelimb. We therefore speculated whether the environment of the forelimb bones is not permissive for the growth of PCa. Consequently, data on tumor prevalence were normalized to account for the number of PCa cells arriving after intravascular injection, marrow cellularity, and number of hematopoietic stem cell niches. None of these factors were able to account for the observed differences in tumor prevalence. An analysis of differential gene and protein levels identified that growth arrest specific-6 (GAS6 levels were significantly greater in the forelimb versus hindlimb bone marrow. When murine RM1 cells were implanted into subcutaneous spaces in immune competent animals, tumor growth in the GAS6-/- animals was greater than in GAS6+/+ wild-type animals. In an osseous environment, the human PC3 cell line grew significantly better in vertebral body transplants (vossicles derived from GAS6-/- animals than in vossicles derived from GAS6+/+ animals. Together, these data suggest that the differences in tumor prevalence after intravascular inoculation are a useful model to study the molecular basis of tumor dormancy. Importantly, these data suggest that therapeutic manipulation of GAS6 levels may prove useful as a therapy for metastatic disease.

  6. Sustained productivity in recombinant Chinese Hamster Ovary (CHO) cell lines: proteome analysis of the molecular basis for a process-related phenotype

    LENUS (Irish Health Repository)

    Meleady, Paula

    2011-07-24

    Abstract Background The ability of mammalian cell lines to sustain cell specific productivity (Qp) over the full duration of bioprocess culture is a highly desirable phenotype, but the molecular basis for sustainable productivity has not been previously investigated in detail. In order to identify proteins that may be associated with a sustained productivity phenotype, we have conducted a proteomic profiling analysis of two matched pairs of monoclonal antibody-producing Chinese hamster ovary (CHO) cell lines that differ in their ability to sustain productivity over a 10 day fed-batch culture. Results Proteomic profiling of inherent differences between the two sets of comparators using 2D-DIGE (Difference Gel Electrophoresis) and LC-MS\\/MS resulted in the identification of 89 distinct differentially expressed proteins. Overlap comparisons between the two sets of cell line pairs identified 12 proteins (AKRIB8, ANXA1, ANXA4, EIF3I, G6PD, HSPA8, HSP90B1, HSPD1, NUDC, PGAM1, RUVBL1 and CNN3) that were differentially expressed in the same direction. Conclusion These proteins may have an important role in sustaining high productivity of recombinant protein over the duration of a fed-batch bioprocess culture. It is possible that many of these proteins could be useful for future approaches to successfully manipulate or engineer CHO cells in order to sustain productivity of recombinant protein.

  7. Cloning of soluble alkaline phosphatase cDNA and molecular basis of the polymorphic nature in alkaline phosphatase isozymes of Bombyx mori midgut.

    Science.gov (United States)

    Itoh, M; Kanamori, Y; Takao, M; Eguchi, M

    1999-02-01

    A cDNA coding for soluble type alkaline phosphatase (sALP) of Bombyx mori was isolated. Deduced amino acid sequence showed high identities to various ALPs and partial similarities to ATPase of Manduca sexta. Using this cDNA sequence as a probe, the molecular basis of electrophoretic polymorphism in sALP and membrane-bound type ALP (mALP) was studied. As for mALP, the result suggested that post-translational modification was important for the proteins to express activity and to represent their extensive polymorphic nature, whereas the magnitude of activities was mainly regulated by transcription. On the other hand, sALP zymogram showed poor polymorphism, but one exception was the null mutant, in which the sALP gene was largely lost. Interestingly, the sALP gene was shown to be transcribed into two mRNAs of different sizes, 2.0 and 2.4 Kb. In addition to the null mutant of sALP, we found a null mutant for mALP. Both of these mutants seem phenotypically silent, suggesting that the functional differentiation between these isozymes is not perfect, so that they can still work mutually and complement each other as an indispensable enzyme for B. mori.

  8. A high-quality genome assembly of quinoa provides insights into the molecular basis of salt bladder-based salinity tolerance and the exceptional nutritional value

    Science.gov (United States)

    Zou, Changsong; Chen, Aojun; Xiao, Lihong; Muller, Heike M; Ache, Peter; Haberer, Georg; Zhang, Meiling; Jia, Wei; Deng, Ping; Huang, Ru; Lang, Daniel; Li, Feng; Zhan, Dongliang; Wu, Xiangyun; Zhang, Hui; Bohm, Jennifer; Liu, Renyi; Shabala, Sergey; Hedrich, Rainer; Zhu, Jian-Kang; Zhang, Heng

    2017-01-01

    Chenopodium quinoa is a halophytic pseudocereal crop that is being cultivated in an ever-growing number of countries. Because quinoa is highly resistant to multiple abiotic stresses and its seed has a better nutritional value than any other major cereals, it is regarded as a future crop to ensure global food security. We generated a high-quality genome draft using an inbred line of the quinoa cultivar Real. The quinoa genome experienced one recent genome duplication about 4.3 million years ago, likely reflecting the genome fusion of two Chenopodium parents, in addition to the γ paleohexaploidization reported for most eudicots. The genome is highly repetitive (64.5% repeat content) and contains 54 438 protein-coding genes and 192 microRNA genes, with more than 99.3% having orthologous genes from glycophylic species. Stress tolerance in quinoa is associated with the expansion of genes involved in ion and nutrient transport, ABA homeostasis and signaling, and enhanced basal-level ABA responses. Epidermal salt bladder cells exhibit similar characteristics as trichomes, with a significantly higher expression of genes related to energy import and ABA biosynthesis compared with the leaf lamina. The quinoa genome sequence provides insights into its exceptional nutritional value and the evolution of halophytes, enabling the identification of genes involved in salinity tolerance, and providing the basis for molecular breeding in quinoa. PMID:28994416

  9. Noise-Immune Cavity-Enhanced Optical Heterodyne Molecular Spectrometry Modelling Under Saturated Absorption

    Science.gov (United States)

    Dupré, Patrick

    2015-06-01

    The Noise-Immune Cavity-Enhanced Optical Heterodyne Molecular Spectrometry (NICE-OHMS) is a modern technique renowned for its ultimate sensitivity, because it combines long equivalent absorption length provided by a high finesse cavity, and a detection theoretically limited by the sole photon-shot-noise. One fallout of the high finesse is the possibility to accumulating strong intracavity electromagnetic fields (EMF). Under this condition, molecular transitions can be easy saturated giving rise to the usual Lamb dips (or hole burning). However, the unusual shape of the basically trichromatic EMF (due to the RF lateral sidebands) induces nonlinear couplings, i.e., new crossover transitions. An analytical methodology will be presented to calculate spectra provided by NICE-OHMS experiments. It is based on the solutions of the equations of motion of an open two-blocked-level system performed in the frequency-domain (optically thin medium). Knowing the transition dipole moment, the NICE-OHMS signals (``absorption-like'' and ``dispersion-like'') can be simulated by integration over the Doppler shifts and by paying attention to the molecular Zeeman sublevels and to the EMF polarization The approach has been validated by discussion experimental data obtained on two transitions of {C2H2} in the near-infrared under moderated saturation. One of the applications of the saturated absorption is to be able to simultaneously determine the transition intensity and the density number while only one these 2 quantities can only be assessed in nonlinear absorption. J. Opt. Soc. Am. B 32, 838 (2015) Optics Express 16, 14689 (2008)

  10. Molecular Characterization and Germination Analysis of Cotton (Gossypium hirsutum L. Genotypes under Water Deficit Irrigation

    Directory of Open Access Journals (Sweden)

    Eminur ELÇİ

    2016-09-01

    Full Text Available Cotton is an important crop in terms of economic and strategic impacts. Drought stress is one of the most important environmental stress factors which negatively affects growth and yield of plants in Turkey as occurred in many countries in the world. In this study, 11 different cotton cultivars selected based on their agronomical characters were tested under water deficit irrigation strategies. Thus, it was aimed to select and/or determine appropriate new varieties for breeding new national materials resistant to drought stress, and to characterize with the molecular microsatellite markers. According to the different irrigation levels (25%, 50%, 75% and 100% plants were observed under the stressed conditions at the irrigation levels of 50% and 25%. Among the tested varieties, Tamcot Sphinx, Tamcot 94, Tamcot CamdEs and BA525 varieties were found to be more water stress tolerant than others in terms of germination time and germinated plant. The UPGMA (Unweighted Pair-Group Method Using Arithmetic Averages analysis was carried out using 28 markers with average 0.306 polymorphism information content (PIC for molecular characterization studies. Based on the UPGMA results, the varieties were clustered into two groups. It is expected that the results obtained from this study might provide considerable data for improving new drought tolerant varieties.

  11. High-risk Long QT Syndrome Mutations in the Kv7.1 (KCNQ1) Pore Disrupt the Molecular Basis for Rapid K+ Permeation

    Science.gov (United States)

    Burgess, Don E.; Bartos, Daniel C.; Reloj, Allison R.; Campbell, Kenneth S.; Johnson, Jonathan N.; Tester, David J.; Ackerman, Michael J.; Fressart, Véronique; Denjoy, Isabelle; Guicheney, Pascale; Moss, Arthur J.; Ohno, Seiko; Horie, Minoru; Delisle, Brian P.

    2012-01-01

    Type 1 long QT syndrome (LQT1) syndrome is caused by loss-of-function mutations in the KCNQ1, which encodes the K+ channel (Kv7.1) that underlies the slowly activating delayed rectifier K+ current in the heart. Intragenic risk stratification suggests LQT1 mutations that disrupt conserved amino acid residues in the pore are an independent risk factor for LQT1-related cardiac events. The purpose of this study is to determine possible molecular mechanisms that underlie the loss-of-function for these high-risk mutations. Extensive genotype-phenotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confer a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated non-functional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamic simulations (MDS) of analogous mutations in KcsA (T85M-, T85A-, and G88R-KcsA) demonstrated that they disrupted the symmetrical distribution of the carbonyl oxygen atoms in the selectivity filter, which upset the balance between the strong attractive and K+-K+ repulsive forces required for rapid K+ permeation. We conclude high-risk LQT1 mutations in the pore likely disrupt the architectural and physical properties of the K+ channel selectivity filter. PMID:23092362

  12. High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation.

    Science.gov (United States)

    Burgess, Don E; Bartos, Daniel C; Reloj, Allison R; Campbell, Kenneth S; Johnson, Jonathan N; Tester, David J; Ackerman, Michael J; Fressart, Véronique; Denjoy, Isabelle; Guicheney, Pascale; Moss, Arthur J; Ohno, Seiko; Horie, Minoru; Delisle, Brian P

    2012-11-13

    Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1 gene, which encodes the K(+) channel (Kv7.1) that underlies the slowly activating delayed rectifier K(+) current in the heart. Intragenic risk stratification suggests LQT1 mutations that disrupt conserved amino acid residues in the pore are an independent risk factor for LQT1-related cardiac events. The purpose of this study is to determine possible molecular mechanisms that underlie the loss of function for these high-risk mutations. Extensive genotype-phenotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confers a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated nonfunctional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamics simulations of analogous mutations in KcsA (T85M-, T85A-, and G88R-KcsA) demonstrated that they disrupted the symmetrical distribution of the carbonyl oxygen atoms in the selectivity filter, which upset the balance between the strong attractive and K(+)-K(+) repulsive forces required for rapid K(+) permeation. We conclude high-risk LQT1 mutations in the pore likely disrupt the architectural and physical properties of the K(+) channel selectivity filter.

  13. Molecular mechanisms underlying the close association between soil Burkholderia and fungi

    Science.gov (United States)

    Stopnisek, Nejc; Zühlke, Daniela; Carlier, Aurélien; Barberán, Albert; Fierer, Noah; Becher, Dörte; Riedel, Katharina; Eberl, Leo; Weisskopf, Laure

    2016-01-01

    Bacterial species belonging to the genus Burkholderia have been repeatedly reported to be associated with fungi but the extent and specificity of these associations in soils remain undetermined. To assess whether associations between Burkholderia and fungi are widespread in soils, we performed a co-occurrence analysis in an intercontinental soil sample collection. This revealed that Burkholderia significantly co-occurred with a wide range of fungi. To analyse the molecular basis of the interaction, we selected two model fungi frequently co-occurring with Burkholderia, Alternaria alternata and Fusarium solani, and analysed the proteome changes caused by cultivation with either fungus in the widespread soil inhabitant B. glathei, whose genome we sequenced. Co-cultivation with both fungi led to very similar changes in the B. glathei proteome. Our results indicate that B. glathei significantly benefits from the interaction, which is exemplified by a lower abundance of several starvation factors that were highly expressed in pure culture. However, co-cultivation also gave rise to stress factors, as indicated by the increased expression of multidrug efflux pumps and proteins involved in oxidative stress response. Our data suggest that the ability of Burkholderia to establish a close association with fungi mainly lies in the capacities to utilize fungal-secreted metabolites and to overcome fungal defense mechanisms. This work indicates that beneficial interactions with fungi might contribute to the survival strategy of Burkholderia species in environments with sub-optimal conditions, including acidic soils. PMID:25989372

  14. Molecular mechanisms underlying the close association between soil Burkholderia and fungi.

    Science.gov (United States)

    Stopnisek, Nejc; Zühlke, Daniela; Carlier, Aurélien; Barberán, Albert; Fierer, Noah; Becher, Dörte; Riedel, Katharina; Eberl, Leo; Weisskopf, Laure

    2016-01-01

    Bacterial species belonging to the genus Burkholderia have been repeatedly reported to be associated with fungi but the extent and specificity of these associations in soils remain undetermined. To assess whether associations between Burkholderia and fungi are widespread in soils, we performed a co-occurrence analysis in an intercontinental soil sample collection. This revealed that Burkholderia significantly co-occurred with a wide range of fungi. To analyse the molecular basis of the interaction, we selected two model fungi frequently co-occurring with Burkholderia, Alternaria alternata and Fusarium solani, and analysed the proteome changes caused by cultivation with either fungus in the widespread soil inhabitant B. glathei, whose genome we sequenced. Co-cultivation with both fungi led to very similar changes in the B. glathei proteome. Our results indicate that B. glathei significantly benefits from the interaction, which is exemplified by a lower abundance of several starvation factors that were highly expressed in pure culture. However, co-cultivation also gave rise to stress factors, as indicated by the increased expression of multidrug efflux pumps and proteins involved in oxidative stress response. Our data suggest that the ability of Burkholderia to establish a close association with fungi mainly lies in the capacities to utilize fungal-secreted metabolites and to overcome fungal defense mechanisms. This work indicates that beneficial interactions with fungi might contribute to the survival strategy of Burkholderia species in environments with sub-optimal conditions, including acidic soils.

  15. Physiological and molecular alterations in plants exposed to high [CO2] under phosphorus stress.

    Science.gov (United States)

    Pandey, Renu; Zinta, Gaurav; AbdElgawad, Hamada; Ahmad, Altaf; Jain, Vanita; Janssens, Ivan A

    2015-01-01

    Atmospheric [CO2] has increased substantially in recent decades and will continue to do so, whereas the availability of phosphorus (P) is limited and unlikely to increase in the future. P is a non-renewable resource, and it is essential to every form of life. P is a key plant nutrient controlling the responsiveness of photosynthesis to [CO2]. Increases in [CO2] typically results in increased biomass through stimulation of net photosynthesis, and hence enhance the demand for P uptake. However, most soils contain low concentrations of available P. Therefore, low P is one of the major growth-limiting factors for plants in many agricultural and natural ecosystems. The adaptive responses of plants to [CO2] and P availability encompass alterations at morphological, physiological, biochemical and molecular levels. In general low P reduces growth, whereas high [CO2] enhances it particularly in C3 plants. Photosynthetic capacity is often enhanced under high [CO2] with sufficient P supply through modulation of enzyme activities involved in carbon fixation such as ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). However, high [CO2] with low P availability results in enhanced dry matter partitioning towards roots. Alterations in below-ground processes including root morphology, exudation and mycorrhizal association are influenced by [CO2] and P availability. Under high P availability, elevated [CO2] improves the uptake of P from soil. In contrast, under low P availability, high [CO2] mainly improves the efficiency with which plants produce biomass per unit P. At molecular level, the spatio-temporal regulation of genes involved in plant adaptation to low P and high [CO2] has been studied individually in various plant species. Genome-wide expression profiling of high [CO2] grown plants revealed hormonal regulation of biomass accumulation through complex transcriptional networks. Similarly, differential transcriptional regulatory networks are involved in P

  16. Molecular basis of calcium-sensitizing and desensitizing mutations of the human cardiac troponin C regulatory domain: a multi-scale simulation study.

    Directory of Open Access Journals (Sweden)

    Peter Michael Kekenes-Huskey

    Full Text Available Troponin C (TnC is implicated in the initiation of myocyte contraction via binding of cytosolic Ca²⁺ and subsequent recognition of the Troponin I switch peptide. Mutations of the cardiac TnC N-terminal regulatory domain have been shown to alter both calcium binding and myofilament force generation. We have performed molecular dynamics simulations of engineered TnC variants that increase or decrease Ca²⁺ sensitivity, in order to understand the structural basis of their impact on TnC function. We will use the distinction for mutants that are associated with increased Ca²⁺ affinity and for those mutants with reduced affinity. Our studies demonstrate that for GOF mutants V44Q and L48Q, the structure of the physiologically-active site II Ca²⁺ binding site in the Ca²⁺-free (apo state closely resembled the Ca²⁺-bound (holo state. In contrast, site II is very labile for LOF mutants E40A and V79Q in the apo form and bears little resemblance with the holo conformation. We hypothesize that these phenomena contribute to the increased association rate, k(on, for the GOF mutants relative to LOF. Furthermore, we observe significant positive and negative positional correlations between helices in the GOF holo mutants that are not found in the LOF mutants. We anticipate these correlations may contribute either directly to Ca²⁺ affinity or indirectly through TnI association. Our observations based on the structure and dynamics of mutant TnC provide rationale for binding trends observed in GOF and LOF mutants and will guide the development of inotropic drugs that target TnC.

  17. Equations of states for an ionic liquid under high pressure: A molecular dynamics simulation study

    International Nuclear Information System (INIS)

    Ribeiro, Mauro C.C.; Pádua, Agílio A.H.; Gomes, Margarida F.C.

    2014-01-01

    Highlights: • We compare different equation of states, EoS, for an ionic liquid under high pressure. • Molecular dynamics, MD, simulations have been used to evaluate the best EoS. • MD simulations show that a group contribution model can be extrapolated to P ∼ 1.0 GPa. • A perturbed hard-sphere EoS also fits the densities calculated by MD simulations. - Abstract: The high-pressure dependence of density given by empirical equation of states (EoS) for the ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate (or triflate), [C 4 C 1 im][TfO], is compared with results obtained by molecular dynamics (MD) simulations. Two EoS proposed for [C 4 C 1 im][TfO] in the pressure range of tens of MPa, which give very different densities when extrapolated to pressures beyond the original experiments, are compared with a group contribution model (GCM). The MD simulations provide support that one of the empirical EoS and the GCM is valid in the pressure range of hundreds of MPa. As an alternative to these EoS that are based on modified Tait equations, it is shown that a perturbed hard-sphere EoS based on the Carnahan–Starling–van der Waals equation also fits the densities calculated by MD simulations of [C 4 C 1 im][TfO] up to ∼1.0 GPa

  18. Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation of HIF-1/VEGF Signaling under Hypoxia

    Directory of Open Access Journals (Sweden)

    Meng-Chuan Chen

    2015-07-01

    Full Text Available Activation of hypoxia-induced hypoxia-inducible factors-1 (HIF-1 plays a critical role in promoting tumor angiogenesis, growth and metastasis. Low molecular weight fucoidan (LMWF is prepared from brown algae, and exhibits anticancer activity. However, whether LMWF attenuates hypoxia-induced angiogenesis in bladder cancer cells and the molecular mechanisms involved remain unclear. This is the first study to demonstrate that LMWF can inhibit hypoxia-stimulated H2O2 formation, HIF-1 accumulation and transcriptional activity vascular endothelial growth factor (VEGF secretion, and the migration and invasion in hypoxic human bladder cancer cells (T24 cells. LMWF also downregulated hypoxia-activated phosphorylation of PI3K/AKT/mTOR/p70S6K/4EBP-1 signaling in T24 cells. Blocking PI3K/AKT or mTOR activity strongly diminished hypoxia-induced HIF-1α expression and VEGF secretion in T24 cells, supporting the involvement of PI3K/AKT/mTOR in the induction of HIF-1α and VEGF. Additionally, LMWF significantly attenuated angiogenesis in vitro and in vivo evidenced by reduction of tube formation of hypoxic human umbilical vascular endothelial cells and blood capillary generation in the tumor. Similarly, administration of LMWF also inhibited the HIF-1α and VEGF expression in vivo, accompanied by a reduction of tumor growth. In summary, under hypoxia conditions, the antiangiogenic activity of LMWF in bladder cancer may be associated with suppressing HIF-1/VEGF-regulated signaling pathway.

  19. Thermal conductivity of graphene nanoribbons under shear deformation: A molecular dynamics simulation

    Science.gov (United States)

    Zhang, Chao; Hao, Xiao-Li; Wang, Cui-Xia; Wei, Ning; Rabczuk, Timon

    2017-01-01

    Tensile strain and compress strain can greatly affect the thermal conductivity of graphene nanoribbons (GNRs). However, the effect of GNRs under shear strain, which is also one of the main strain effect, has not been studied systematically yet. In this work, we employ reverse nonequilibrium molecular dynamics (RNEMD) to the systematical study of the thermal conductivity of GNRs (with model size of 4 nm × 15 nm) under the shear strain. Our studies show that the thermal conductivity of GNRs is not sensitive to the shear strain, and the thermal conductivity decreases only 12–16% before the pristine structure is broken. Furthermore, the phonon frequency and the change of the micro-structure of GNRs, such as band angel and bond length, are analyzed to explore the tendency of thermal conductivity. The results show that the main influence of shear strain is on the in-plane phonon density of states (PDOS), whose G band (higher frequency peaks) moved to the low frequency, thus the thermal conductivity is decreased. The unique thermal properties of GNRs under shear strains suggest their great potentials for graphene nanodevices and great potentials in the thermal managements and thermoelectric applications. PMID:28120921

  20. Mitochondrial C4375T mutation might be a molecular risk factor in a maternal Chinese hypertensive family under haplotype C.

    Science.gov (United States)

    Chen, Hong; Sun, Min; Fan, Zhen; Tong, Maoqing; Chen, Guodong; Li, Danhui; Ye, Jihui; Yang, Yumin; Zhu, Yongding; Zhu, Jianhua

    2017-12-04

    Here, we reported a Han Chinese essential hypertensive pedigree based on clinical hereditary and molecular data. To know the molecular basis on this family, mitochondrial genome of one proband from the family was identified through direct sequencing analysis. The age of onset year and affected degree of patients are different in this family. And matrilineal family members carrying C4375T mutation and belong to Eastern Asian halopgroup C. Phylogenetic analysis shows 4375C is highly conservative in 17 species. It is suggested that these mutations might participate in the development of hypertension in this family. And halopgroup C might play a modifying role on the phenotype in this Chinese hypertensive family.

  1. Disintegration of Ar2+ molecular ions under collisions with electrons in a plasma

    International Nuclear Information System (INIS)

    Ivanov, V.A.

    1992-01-01

    A spectroscopic experiment is carried out for investigation of disintegration of Ar 2 + ions by plasma electrons. For the first time in the wide electron temperature range from the room one up to T e ∼ 2 eV is measured the process rate constant. At temperatures lower 0.4 eV the obtained values agree well with published data on the value and temperature dependence of the coefficient of dissociative recombination of Ar 2 + with electrons. When temperature increasing in the range of T e =0.5-2 eV is found substantial rise of the rate of molecular ions disintegration, conditioned by starting dissociation mechanism under collicions with plasma electrons

  2. Structural phase transition and failure of nanographite sheets under high pressure: a molecular dynamics study

    International Nuclear Information System (INIS)

    Zhang Bin; Liang Yongcheng; Sun Huiyu

    2007-01-01

    Nanographite sheets under high compressive stresses at ambient temperature have been investigated through molecular dynamics simulations using the Tersoff-Brenner potential. Nanographite undergoes a soft to hard phase transition at a certain compressive stress, about 15 GPa. With increasing compressions, the bonding structures of nanographite are changed, interlayer sp 3 -bonds are formed, and nanographite transforms into a superhard carbon phase (SCP). Further compressions lead to the instabilities of the SCP. Although the detailed lattice structure of the SCP remains elusive, its compressive strength can approach 150 GPa, comparable to that of diamond. The maximum failure stresses of nanographite sheets are sensitive to the inter-and intra-layer interstices. Our results may explain paradoxical experimental results in the available literature

  3. Molecular dynamics simulation on the elastoplastic properties of copper nanowire under torsion

    Science.gov (United States)

    Yang, Yong; Li, Ying; Yang, Zailin; Zhang, Guowei; Wang, Xizhi; Liu, Jin

    2018-02-01

    Influences of different factors on the torsion properties of single crystal copper nanowire are studied by molecular dynamics method. The length, torsional rate, and temperature of the nanowire are discussed at the elastic-plastic critical point. According to the average potential energy curve and shear stress curve, the elastic-plastic critical angle is determined. Also, the dislocation at elastoplastic critical points is analyzed. The simulation results show that the single crystal copper nanowire can be strengthened by lengthening the model, decreasing the torsional rate, and lowering the temperature. Moreover, atoms move violently and dislocation is more likely to occur with a higher temperature. This work mainly describes the mechanical behavior of the model under different states.

  4. Surface functionalization of SPR chip for specific molecular interaction analysis under flow condition

    Directory of Open Access Journals (Sweden)

    Tao Ma

    2017-03-01

    Full Text Available Surface functionalization of sensor chip for probe immobilization is crucial for the biosensing applications of surface plasmon resonance (SPR sensors. In this paper, we report a method circulating the dopamine aqueous solution to coat polydopamine film on sensing surface for surface functionalization of SPR chip. The polydopamine film with available thickness can be easily prepared by controlling the circulation time and the biorecognition elements can be immobilized on the polydopamine film for specific molecular interaction analysis. These operations are all performed under flow condition in the fluidic system, and have the advantages of easy implementation, less time consuming, and low cost, because the reagents and devices used in the operations are routinely applied in most laboratories. In this study, the specific absorption between the protein A probe immobilized on the sensing surface and human immunoglobulin G in the buffer is monitored based on this surface functionalization strategy to demonstrated its feasibility for SPR biosensing applications.

  5. Molecular dynamics simulation of ZnO wurtzite phase under high and low pressures and temperatures

    Science.gov (United States)

    Chergui, Y.; Aouaroun, T.; Hadley, M. J.; Belkada, R.; Chemam, R.; Mekki, D. E.

    2017-11-01

    Isothermal and isobaric ensembles behaviours of ZnO wurtzite phase have been investigated, by parallel molecular dynamics method and using Buckingham potential, which contains long-range Coulomb, repulsive exponential, and attractive dispersion terms. To conduct our calculations, we have used dl_poly 4 software, under which the method is implemented. We have examined the influence of the temperature and pressure on molar volume in the ranges of 300-3000 K and 0-200 GPa. Isothermal-isobaric relationships, fluctuations, standard error, equilibrium time, molar volume and its variation versus time are predicted and analyzed. Our results are close to available experimental data and theoretical results.

  6. Molecular Mechanisms Underlying γ-Aminobutyric Acid (GABA) Accumulation in Giant Embryo Rice Seeds.

    Science.gov (United States)

    Zhao, Guo-Chao; Xie, Mi-Xue; Wang, Ying-Cun; Li, Jian-Yue

    2017-06-21

    To uncover the molecular mechanisms underlying GABA accumulation in giant embryo rice seeds, we analyzed the expression levels of GABA metabolism genes and contents of GABA and GABA metabolic intermediates in developing grains and germinated brown rice of giant embryo rice 'Shangshida No. 5' and normal embryo rice 'Chao2-10' respectively. In developing grains, the higher GABA contents in 'Shangshida No. 5' were accompanied with upregulation of gene transcripts and intermediate contents in the polyamine pathway and downregulation of GABA catabolic gene transcripts, as compared with those in 'Chao2-10'. In germinated brown rice, the higher GABA contents in 'Shangshida No. 5' were parallel with upregulation of OsGAD and polyamine pathway gene transcripts and Glu and polyamine pathway intermediate contents and downregulation of GABA catabolic gene transcripts. These results are the first to indicate that polyamine pathway and GABA catabolic genes play a crucial role in GABA accumulation in giant embryo rice seeds.

  7. First-principles studies of PETN molecular crystal vibrational frequencies under high pressure

    Science.gov (United States)

    Perger, Warren; Zhao, Jijun

    2005-07-01

    The vibrational frequencies of the PETN molecular crystal were calculated using the first-principles CRYSTAL03 program which employs an all-electron LCAO approach and calculates analytic first derivatives of the total energy with respect to atomic displacements. Numerical second derivatives were used to enable calculation of the vibrational frequencies at ambient pressure and under various states of compression. Three different density functionals, B3LYP, PW91, and X3LYP were used to examine the effect of the exchange-correlation functional on the vibrational frequencies. The pressure-induced shift of the vibrational frequencies will be presented and compared with experiment. The average deviation with experimental results is shown to be on the order of 2-3%, depending on the functional used.

  8. Thermal buckling behavior of defective CNTs under pre-load: A molecular dynamics study.

    Science.gov (United States)

    Mehralian, Fahimeh; Tadi Beni, Yaghoub; Kiani, Yaser

    2017-05-01

    Current study is concentrated on the extraordinary properties of defective carbon nanotubes (CNTs). The role of vacancy defects in thermal buckling response of precompressed CNTs is explored via molecular dynamics (MD) simulations. Defective CNTs are initially compressed at a certain ratio of their critical buckling strain and then undergo a uniform temperature rise. Comprehensive study is implemented on both armchair and zigzag CNTs with different vacancy defects including monovacancy, symmetric bivacancy and asymmetric bivacancy. The results reveal that defects have a pronounced impact on the buckling behavior of CNTs; interestingly, defective CNTs under compressive pre-load show higher resistance to thermal buckling than pristine ones. In the following, the buckling response of defective CNTs is shown to be dependent on the vacancy defects, location of defects and chirality. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Molecular Dynamics Simulation of Damage to Coiled Carbon Nanotubes under C Ion Irradiation

    International Nuclear Information System (INIS)

    Zhou Bin; Zhang Wei; Gong Wen-Bin; Wang Song; Ren Cui-Lan; Wang Cheng-Bin; Zhu Zhi-Yuan; Huai Ping

    2013-01-01

    The stability of coiled carbon nanotubes under C ion irradiation is investigated by molecular dynamics simulations. The defect statistics shows that small curvature coiled carbon nanotubes have better radiation tolerance than normal straight carbon nanotubes. To understand the effect of the curvature on defect production, the threshold displacement energies for the upper and lower walls, as well as those for the side parts, are calculated. The results show that the lower wall has better radiation tolerance than the upper wall. For the upper wall, a small increase in the curvature of nanotube axis gives rise to an increase in the radiation tolerance and then a decrease with the curvature becomes larger. However, for the lower wall, as the curvature of the nanotube axis increases, the radiation tolerance increases as the bonds compressed slightly in our simulation

  10. A hypothesis regarding the molecular mechanism underlying dietary soy-induced effects on seizure propensity.

    Directory of Open Access Journals (Sweden)

    Cara Jean Westmark

    2014-09-01

    Full Text Available Numerous neurological disorders including fragile X syndrome, Down syndrome, autism and Alzheimer’s disease are comorbid with epilepsy. We have observed elevated seizure propensity in mouse models of these disorders dependent on diet. Specifically, soy-based diets exacerbate audiogenic-induced seizures in juvenile mice. We have also found potential associations between the consumption of soy-based infant formula and seizure incidence, epilepsy comorbidity and autism diagnostic scores in autistic children by retrospective analyses of medical record data. In total, these data suggest that consumption of high levels of soy protein during postnatal development may affect neuronal excitability. Herein, we present our theory regarding the molecular mechanism underlying soy-induced effects on seizure propensity. We hypothesize that soy phytoestrogens interfere with metabotropic glutamate receptor signaling through an estrogen receptor-dependent mechanism, which results in elevated production of key synaptic proteins and decreased seizure threshold.

  11. Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

    Directory of Open Access Journals (Sweden)

    Zhen-Ye Zhang

    2017-09-01

    Full Text Available Large-conductance calcium-activated potassium channels (BK channels belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

  12. Establishment of Technical Collaboration basis between Korea and France for the development of severe accident assessment computer code under high burnup condition

    International Nuclear Information System (INIS)

    Kim, H. D.; Kim, D. H.; Park, S. Y.; Park, J. H.

    2005-10-01

    This project was performed by KAERI in the frame of construction of the international cooperative basis on the nuclear energy. This was supported from MOST under the title of 'Establishment of Technical Collaboration basis between Korea and France for the development of severe accident assessment computer code under high burn up condition'. The current operating NPP are converting the burned fuel to the wasted fuel after burn up of 40 GWD/MTU. But in Korea, burn up of more than 60 GWD/MTU will be expected because of the high fuel efficiency but also cost saving for storing the wasted fuel safely. The domestic research for the purpose of developing the fuel and the cladding that can be used under the high burn up condition up to 100 GWD/MTU is in progress now. But the current computer code adopts the model and the data that are valid only up to the 40 GWD/MTU at most. Therefore the current model could not take into account the phenomena that may cause differences in the fission product release behavior or in the core damage process due to the high burn up operation (more than 40 GWD/MTU). To evaluate the safety of the NPP with the high burn up fuel, the improvement of current severe accident code against the high burn up condition is an important research item. Also it should start without any delay. Therefore, in this study, an expert group was constructed to establish the research basis for the severe accident under high burn up conditions. From this expert group, the research items regarding the high burn up condition were selected and identified through discussion and technical seminars. Based on these selected items, the meeting between IRSN and KAERI to find out the cooperative research items on the severe accident under the high burn up condition was held in the IRSN headquater in Paris. After the meeting, KAERI and IRSN agreed to cooperate with each other on the selected items, and to co-host the international seminar, and to develop the model and to

  13. A proteomics approach to study the molecular basis of enhanced salt tolerance in barley (Hordeum vulgare L.) conferred by the root mutualistic fungus Piriformospora indica.

    Science.gov (United States)

    Alikhani, Mehdi; Khatabi, Behnam; Sepehri, Mozhgan; Nekouei, Mojtaba Khayam; Mardi, Mohsen; Salekdeh, Ghasem Hosseini

    2013-06-01

    Piriformospora indica is a root-interacting mutualistic fungus capable of enhancing plant growth, increasing plant resistance to a wide variety of pathogens, and improving plant stress tolerance under extreme environmental conditions. Understanding the molecular mechanisms by which P. indica can improve plant tolerance to stresses will pave the way to identifying the major mechanisms underlying plant adaptability to environmental stresses. We conducted greenhouse experiments at three different salt levels (0, 100 and 300 mM NaCl) on barley (Hordeum vulgare L.) cultivar "Pallas" inoculated with P. indica. Based on the analysis of variance, P. indica had a significant impact on the barley growth and shoot biomass under normal and salt stress conditions. P. indica modulated ion accumulation in colonized plants by increasing the foliar potassium (K(+))/sodium (Na(+)) ratio, as it is considered a reliable indicator of salt stress tolerance. P. indica induced calcium (Ca(2+)) accumulation and likely influenced the stress signal transduction. Subsequently, proteomic analysis of the barley leaf sheath using two-dimensional electrophoresis resulted in detection of 968 protein spots. Of these detected spots, the abundance of 72 protein spots changed significantly in response to salt treatment and P. indica-root colonization. Mass spectrometry analysis of responsive proteins led to the identification of 51 proteins. These proteins belonged to different functional categories including photosynthesis, cell antioxidant defense, protein translation and degradation, energy production, signal transduction and cell wall arrangement. Our results showed that P. indica induced a systemic response to salt stress by altering the physiological and proteome responses of the plant host.

  14. Investigation of the Material Basis Underlying the Correlation between Presbycusis and Kidney Deficiency in Traditional Chinese Medicine via GC/MS Metabolomics

    Directory of Open Access Journals (Sweden)

    Yang Dong

    2013-01-01

    Full Text Available Objective. To investigate the correlation between presbycusis and kidney deficiency as defined by traditional Chinese medicine (TCM and its material basis from the perspective of metabolism. Methods. Pure-tone audiometry was used to test auditory function. A kidney deficiency symptom scoring table was used to measure the kidney deficiency accumulated scores of the research subjects. Gas chromatography/mass spectrometry (GC/MS was used to measure the metabolites in the urine samples from 11 presbycusis patients and 9 elderly people with normal hearing. Results. Hearing loss in the elderly was positively correlated with kidney deficiency score in TCM. There were significant differences in urine metabolite profile between the presbycusis patients and the controls. A total of 23 differentially expressed metabolites were found. Kyoto Encyclopedia of Genes and Genomes (KEGG pathway analysis showed that these metabolites were related to glutathione metabolism, amino acid metabolism, glucose metabolism, the N-methyl-D-aspartic acid (NMDA receptor pathway, and the γ-aminobutyric acid (GABA receptor pathway. Conclusion. Glutathione metabolism, amino acid metabolism, glucose metabolism, NMDA receptors, and GABA receptors may be related to the pathogenesis of presbycusis and may be the material basis underlying the correlation between presbycusis and kidney deficiency in TCM.

  15. Investigation of the Material Basis Underlying the Correlation between Presbycusis and Kidney Deficiency in Traditional Chinese Medicine via GC/MS Metabolomics

    Science.gov (United States)

    Dong, Yang; Liu, Pu-Zhao; Song, Hai-Yan; Zhao, Yu-Ping; Li, Ming; Shi, Jian-Rong

    2013-01-01

    Objective. To investigate the correlation between presbycusis and kidney deficiency as defined by traditional Chinese medicine (TCM) and its material basis from the perspective of metabolism. Methods. Pure-tone audiometry was used to test auditory function. A kidney deficiency symptom scoring table was used to measure the kidney deficiency accumulated scores of the research subjects. Gas chromatography/mass spectrometry (GC/MS) was used to measure the metabolites in the urine samples from 11 presbycusis patients and 9 elderly people with normal hearing. Results. Hearing loss in the elderly was positively correlated with kidney deficiency score in TCM. There were significant differences in urine metabolite profile between the presbycusis patients and the controls. A total of 23 differentially expressed metabolites were found. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these metabolites were related to glutathione metabolism, amino acid metabolism, glucose metabolism, the N-methyl-D-aspartic acid (NMDA) receptor pathway, and the γ-aminobutyric acid (GABA) receptor pathway. Conclusion. Glutathione metabolism, amino acid metabolism, glucose metabolism, NMDA receptors, and GABA receptors may be related to the pathogenesis of presbycusis and may be the material basis underlying the correlation between presbycusis and kidney deficiency in TCM. PMID:24371466

  16. Molecular dynamics simulation of Cu/Au thin films under temperature gradient

    International Nuclear Information System (INIS)

    Li, Qibin; Peng, Xianghe; Peng, Tiefeng; Tang, Qizhong; Zhang, Xiaomin; Huang, Cheng

    2015-01-01

    Graphical abstract: Heat transportation in the thin films. - Highlights: • The coherent lattice interface is found at thin films after annealing. • The vacancies are observed clearly in the deposit thin films. • The defect and component will influence the energy transportation in the coatings. • The vacancies and lattice mismatch can enlarge the mobility of atoms. • The phonon transportation in thin films has no apparent rule. - Abstract: Three modulation period thin films, 1.8 nm Cu/3.6 nm Au, 2.7 nm Cu/2.7 nm Au and 3.6 nm Cu/1.8 nm Au, are obtained from deposition method and ideal modeling based on lattice constant, to examine their structures and thermophysical characteristics under temperature gradient. The coherent lattice interface is found both at deposit and ideal thin films after annealing. Also, the vacancies are observed clearly in the deposit thin films. The defect and component of thin films will influence the energy transportation in the coatings. The vacancies and lattice mismatch can enlarge the mobility of atoms and result in the failure of coating under the thermal stress. The power spectrum of atoms’ movement has no apparent rule for phonon transportation in thin films. The results are helpful to reveal the micro-mechanism and provide reasonable basis for the failure of metallic coatings.

  17. Molecular dynamics simulation of Cu/Au thin films under temperature gradient

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qibin, E-mail: qibinli@cqu.edu.cn [College of Aerospace Engineering, Chongqing University, Chongqing 400030 (China); State Key Laboratory of Coal Mine Disaster Dynamics and Control, Chongqing University, Chongqing 400030 (China); Chongqing Key Laboratory of Heterogeneous Material Mechanics, Chongqing University, Chongqing 400030 (China); Peng, Xianghe [College of Aerospace Engineering, Chongqing University, Chongqing 400030 (China); State Key Laboratory of Coal Mine Disaster Dynamics and Control, Chongqing University, Chongqing 400030 (China); Peng, Tiefeng, E-mail: pengtiefeng@cqu.edu.cn [State Key Laboratory of Coal Mine Disaster Dynamics and Control, Chongqing University, Chongqing 400030 (China); Tang, Qizhong [College of Aerospace Engineering, Chongqing University, Chongqing 400030 (China); Zhang, Xiaomin [College of Aerospace Engineering, Chongqing University, Chongqing 400030 (China); Chongqing Key Laboratory of Heterogeneous Material Mechanics, Chongqing University, Chongqing 400030 (China); Huang, Cheng [College of Aerospace Engineering, Chongqing University, Chongqing 400030 (China)

    2015-12-01

    Graphical abstract: Heat transportation in the thin films. - Highlights: • The coherent lattice interface is found at thin films after annealing. • The vacancies are observed clearly in the deposit thin films. • The defect and component will influence the energy transportation in the coatings. • The vacancies and lattice mismatch can enlarge the mobility of atoms. • The phonon transportation in thin films has no apparent rule. - Abstract: Three modulation period thin films, 1.8 nm Cu/3.6 nm Au, 2.7 nm Cu/2.7 nm Au and 3.6 nm Cu/1.8 nm Au, are obtained from deposition method and ideal modeling based on lattice constant, to examine their structures and thermophysical characteristics under temperature gradient. The coherent lattice interface is found both at deposit and ideal thin films after annealing. Also, the vacancies are observed clearly in the deposit thin films. The defect and component of thin films will influence the energy transportation in the coatings. The vacancies and lattice mismatch can enlarge the mobility of atoms and result in the failure of coating under the thermal stress. The power spectrum of atoms’ movement has no apparent rule for phonon transportation in thin films. The results are helpful to reveal the micro-mechanism and provide reasonable basis for the failure of metallic coatings.

  18. Molecular dynamics simulation of UO2 nanocrystals melting under isolated and periodic boundary conditions

    International Nuclear Information System (INIS)

    Boyarchenkov, A.S.; Potashnikov, S.I.; Nekrasov, K.A.; Kupryazhkin, A.Ya.

    2012-01-01

    Highlights: ► We perform MD simulation of UO 2 nanocrystals melting (in range of 768–49 152 ions). ► T(P) melting curves intersect zero near −20 GPa and saturate near 25 GPa. ► Reciprocal size dependences of nanocrystal melting point decrease nonlinearly. ► Linear and parabolic extrapolations to macroscopic values are considered. ► Melting point and density jump are reproduced, but heat of fusion is underestimated. - Abstract: Melting of uranium dioxide (UO 2 ) nanocrystals has been studied by molecular dynamics (MD) simulation. Ten recent and widely used sets of pair potentials were assessed in the rigid ion approximation. Both isolated (in vacuum) and periodic boundary conditions (PBC) were explored. Using barostat under PBC the pressure dependences of melting point were obtained. These curves intersected zero near −20 GPa, saturated near 25 GPa and increased nonlinearly in between. Using simulation of surface under isolated boundary conditions (IBC) recommended melting temperature and density jump were successfully reproduced. However, the heat of fusion is still underestimated. These melting characteristics were calculated for nanocrystals of cubic shape in the range of 768–49 152 particles (volume range of 10–1000 nm 3 ). The obtained reciprocal size dependences decreased nonlinearly. Linear and parabolic extrapolations to macroscopic values are considered. The parabolic one is found to be better suited for analysis of the data on temperature and heat of melting.

  19. Source-sink interaction: a century old concept under the light of modern molecular systems biology.

    Science.gov (United States)

    Chang, Tian-Gen; Zhu, Xin-Guang; Raines, Christine

    2017-07-20

    Many approaches to engineer source strength have been proposed to enhance crop yield potential. However, a well-co-ordinated source-sink relationship is required finally to realize the promised increase in crop yield potential in the farmer's field. Source-sink interaction has been intensively studied for decades, and a vast amount of knowledge about the interaction in different crops and under different environments has been accumulated. In this review, we first introduce the basic concepts of source, sink and their interactions, then summarize current understanding of how source and sink can be manipulated through both environmental control and genetic manipulations. We show that the source-sink interaction underlies the diverse responses of crops to the same perturbations and argue that development of a molecular systems model of source-sink interaction is required towards a rational manipulation of the source-sink relationship for increased yield. We finally discuss both bottom-up and top-down routes to develop such a model and emphasize that a community effort is needed for development of this model. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  20. Molecular dynamics simulations of ejecta production from sinusoidal tin surfaces under supported and unsupported shocks

    Science.gov (United States)

    Wu, Bao; Wu, FengChao; Zhu, YinBo; Wang, Pei; He, AnMin; Wu, HengAn

    2018-04-01

    Micro-ejecta, an instability growth process, occurs at metal/vacuum or metal/gas interface when compressed shock wave releases from the free surface that contains surface defects. We present molecular dynamics (MD) simulations to investigate the ejecta production from tin surface shocked by supported and unsupported waves with pressures ranging from 8.5 to 60.8 GPa. It is found that the loading waveforms have little effect on spike velocity while remarkably affect the bubble velocity. The bubble velocity of unsupported shock loading remains nonzero constant value at late time as observed in experiments. Besides, the time evolution of ejected mass in the simulations is compared with the recently developed ejecta source model, indicating the suppressed ejection of unmelted or partial melted materials. Moreover, different reference positions are chosen to characterize the amount of ejecta under different loading waveforms. Compared with supported shock case, the ejected mass of unsupported shock case saturates at lower pressure. Through the analysis on unloading path, we find that the temperature of tin sample increases quickly from tensile stress state to zero pressure state, resulting in the melting of bulk tin under decaying shock. Thus, the unsupported wave loading exhibits a lower threshold pressure causing the solid-liquid phase transition on shock release than the supported shock loading.

  1. Molecular dynamics simulations of ejecta production from sinusoidal tin surfaces under supported and unsupported shocks

    Directory of Open Access Journals (Sweden)

    Bao Wu

    2018-04-01

    Full Text Available Micro-ejecta, an instability growth process, occurs at metal/vacuum or metal/gas interface when compressed shock wave releases from the free surface that contains surface defects. We present molecular dynamics (MD simulations to investigate the ejecta production from tin surface shocked by supported and unsupported waves with pressures ranging from 8.5 to 60.8 GPa. It is found that the loading waveforms have little effect on spike velocity while remarkably affect the bubble velocity. The bubble velocity of unsupported shock loading remains nonzero constant value at late time as observed in experiments. Besides, the time evolution of ejected mass in the simulations is compared with the recently developed ejecta source model, indicating the suppressed ejection of unmelted or partial melted materials. Moreover, different reference positions are chosen to characterize the amount of ejecta under different loading waveforms. Compared with supported shock case, the ejected mass of unsupported shock case saturates at lower pressure. Through the analysis on unloading path, we find that the temperature of tin sample increases quickly from tensile stress state to zero pressure state, resulting in the melting of bulk tin under decaying shock. Thus, the unsupported wave loading exhibits a lower threshold pressure causing the solid-liquid phase transition on shock release than the supported shock loading.

  2. Molecular dynamics simulation of the local concentration and structure in multicomponent aerosol nanoparticles under atmospheric conditions.

    Science.gov (United States)

    Karadima, Katerina S; Mavrantzas, Vlasis G; Pandis, Spyros N

    2017-06-28

    Molecular dynamics (MD) simulations were employed to investigate the local structure and local concentration in atmospheric nanoparticles consisting of an organic compound (cis-pinonic acid or n-C 30 H 62 ), sulfate and ammonium ions, and water. Simulations in the isothermal-isobaric (NPT) statistical ensemble under atmospheric conditions with a prespecified number of molecules of the abovementioned compounds led to the formation of a nanoparticle. Calculations of the density profiles of all the chemical species in the nanoparticle, the corresponding radial pair distribution functions, and their mobility inside the nanoparticle revealed strong interactions developing between sulfate and ammonium ions. However, sulfate and ammonium ions prefer to populate the central part of the nanoparticle under the simulated conditions, whereas organic molecules like to reside at its outer surface. Sulfate and ammonium ions were practically immobile; in contrast, the organic molecules exhibited appreciable mobility at the outer surface of the nanoparticle. When the organic compound was a normal alkane (e.g. n-C 30 H 62 ), a well-organized (crystalline-like) phase was rapidly formed at the free surface of the nanoparticle and remained separate from the rest of the species.

  3. Bacterially-Associated Transcriptional Remodelling in a Distinct Genomic Subtype of Colorectal Cancer Provides a Plausible Molecular Basis for Disease Development.

    Directory of Open Access Journals (Sweden)

    Katie S Lennard

    Full Text Available The relevance of specific microbial colonisation to colorectal cancer (CRC disease pathogenesis is increasingly recognised, but our understanding of possible underlying molecular mechanisms that may link colonisation to disease in vivo remains limited. Here, we investigate the relationships between the most commonly studied CRC-associated bacteria (Enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, Fusobacterium spp., afaC+ E. coli, Enterococcus faecalis & Enteropathogenic E. coli and altered transcriptomic and methylation profiles of CRC patients, in order to gain insight into the potential contribution of these bacteria in the aetiopathogenesis of CRC. We show that colonisation by E. faecalis and high levels of Fusobacterium is associated with a specific transcriptomic subtype of CRC that is characterised by CpG island methylation, microsatellite instability and a significant increase in inflammatory and DNA damage pathways. Analysis of the significant, bacterially-associated changes in host gene expression, both at the level of individual genes as well as pathways, revealed a transcriptional remodeling that provides a plausible mechanistic link between specific bacterial colonisation and colorectal cancer disease development and progression in this subtype; these included upregulation of REG3A, REG1A and REG1P in the case of high-level colonization by Fusobacterium, and CXCL10 and BMI1 in the case of colonisation by E. faecalis. The enrichment of both E. faecalis and Fusobacterium in this CRC subtype suggests that polymicrobial colonisation of the colonic epithelium may well be an important aspect of colonic tumourigenesis.

  4. Assessment of molecular events during in vitro re-epithelialization under honey-alginate matrix ambience

    International Nuclear Information System (INIS)

    Barui, Ananya; Mandal, Naresh; Majumder, Subhadipa; Das, Raunak Kumar; Sengupta, Sanghamitra; Banerjee, Provas; Ray, Ajoy Kumar; RoyChaudhuri, Chirosree; Chatterjee, Jyotirmoy

    2013-01-01

    Re-epithelialization is one of the most important stages of cutaneous regeneration and its success requires supportive micro-ambience which may be provided with suitable bio-matrix. Biocompatibility and efficacy of such bio-matrix in re-epithelialization could be explored by multimodal analysis of structural and functional attributes of in vitro wound healing model including evaluation of prime molecular expressions of the epithelial cells during repair. Present study examines the influence of honey-alginate and alginate matrices on re-epithelialization in keratinocyte (HaCaT) population in a 2-D wound model. Cellular viability, proliferation and cell–cell adhesion status were assessed during wound closure using live/dead cell assay and by evaluating expressions of Ki67, p63 and E-cadherin along-with % change in cellular electrical impedance. Efficacy of honey-alginate matrix in comparison to only alginate one was demonstrated by a quicker reduction in wound gap, improved cellular viability, enhanced expressions of Ki67, p63 and its isoforms (TAp63, ΔNp63) as well as E-cadherin. Faster restoration of electrical attribute (% of impedance change) after wounding also indicated better impact of honey-alginate matrix in re-epithelialization. - Highlights: • Role of honey based matrix is evaluated in wound re-epithelialization. • Healing impact of matrix studied in 2D in vitro keratinocyte (HaCaT) wound model. • Faster impedance restoration indicated rapid healing rate of HaCaT under honey. • PCR observations showed faster initiation of cell proliferation under honey. • ICC study indicated better up-regulation of healing markers under honey matrix

  5. Assessment of molecular events during in vitro re-epithelialization under honey-alginate matrix ambience

    Energy Technology Data Exchange (ETDEWEB)

    Barui, Ananya [Centre for Healthcare Science and Technology, BESU, Shibpur, Howrah 711103, West Bengal (India); Mandal, Naresh [Dept. of Electronics and Telecommunication Engg., BESU, Shibpur, Howrah 711103, West Bengal (India); Majumder, Subhadipa [Department of Biochemistry, University of Calcutta Ballygunge, Circular Road, Kolkata 700 019, West Bengal (India); Das, Raunak Kumar [School of Medical Science and Technology, IIT, Kharagpur 721 302, West Bengal (India); Sengupta, Sanghamitra [Department of Biochemistry, University of Calcutta Ballygunge, Circular Road, Kolkata 700 019, West Bengal (India); Banerjee, Provas [School of Medical Science and Technology, IIT, Kharagpur 721 302, West Bengal (India); Ray, Ajoy Kumar; RoyChaudhuri, Chirosree [Dept. of Electronics and Telecommunication Engg., BESU, Shibpur, Howrah 711103, West Bengal (India); Chatterjee, Jyotirmoy, E-mail: jchatterjee@smst.iitkgp.ernet.in [School of Medical Science and Technology, IIT, Kharagpur 721 302, West Bengal (India)

    2013-08-01

    Re-epithelialization is one of the most important stages of cutaneous regeneration and its success requires supportive micro-ambience which may be provided with suitable bio-matrix. Biocompatibility and efficacy of such bio-matrix in re-epithelialization could be explored by multimodal analysis of structural and functional attributes of in vitro wound healing model including evaluation of prime molecular expressions of the epithelial cells during repair. Present study examines the influence of honey-alginate and alginate matrices on re-epithelialization in keratinocyte (HaCaT) population in a 2-D wound model. Cellular viability, proliferation and cell–cell adhesion status were assessed during wound closure using live/dead cell assay and by evaluating expressions of Ki67, p63 and E-cadherin along-with % change in cellular electrical impedance. Efficacy of honey-alginate matrix in comparison to only alginate one was demonstrated by a quicker reduction in wound gap, improved cellular viability, enhanced expressions of Ki67, p63 and its isoforms (TAp63, ΔNp63) as well as E-cadherin. Faster restoration of electrical attribute (% of impedance change) after wounding also indicated better impact of honey-alginate matrix in re-epithelialization. - Highlights: • Role of honey based matrix is evaluated in wound re-epithelialization. • Healing impact of matrix studied in 2D in vitro keratinocyte (HaCaT) wound model. • Faster impedance restoration indicated rapid healing rate of HaCaT under honey. • PCR observations showed faster initiation of cell proliferation under honey. • ICC study indicated better up-regulation of healing markers under honey matrix.

  6. Molecular Dynamics Simulation and Analysis of Interfacial Water at Selected Sulfide Mineral Surfaces under Anaerobic Conditions

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Jiaqi; Miller, Jan D.; Dang, Liem X.

    2014-04-10

    In this paper, we report on a molecular dynamics simulation (MDS) study of the behavior of interfacial water at selected sulfide mineral surfaces under anaerobic conditions. The study revealed the interfacial water structure and wetting characteristics of the pyrite (100) surface, galena (100) surface, chalcopyrite (012) surface, sphalerite (110) surface, and molybdenite surfaces (i.e., the face, armchair-edge, and zigzag-edge surfaces), including simulated contact angles, relative number density profiles, water dipole orientations, hydrogen-bonding, and residence times. For force fields of the metal and sulfur atoms in selected sulfide minerals used in the MDS, we used the universal force field (UFF) and another set of force fields optimized by quantum chemical calculations for interactions with interfacial water molecules at selected sulfide mineral surfaces. Simulation results for the structural and dynamic properties of interfacial water molecules indicate the natural hydrophobic character for the selected sulfide mineral surfaces under anaerobic conditions as well as the relatively weak hydrophobicity for the sphalerite (110) surface and two molybdenite edge surfaces. Part of the financial support for this study was provided by the U.S. Department of Energy (DOE) under Basic Science Grant No. DE-FG-03-93ER14315. The Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences (BES), of the DOE, funded work performed by Liem X. Dang. Battelle operates Pacific Northwest National Laboratory for DOE. The calculations were carried out using computer resources provided by BES. The authors are grateful to Professor Tsun-Mei Chang for valuable discussions.

  7. Molecular basis of the fructose-2,6-bisphosphatase reaction of PFKFB3: Transition state and the C-terminal function

    International Nuclear Information System (INIS)

    Cavalier, Michael C.; Kim, Song-Gun; Neau, David; Lee, Yong-Hwan

    2012-01-01

    The molecular basis of fructose-2,6-bisphosphatase (F-2,6-P 2 ase) of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) was investigated using the crystal structures of the human inducible form (PFKFB3) in a phospho-enzyme intermediate state (PFKFB3-P · F-6-P), in a transition state-analogous complex (PFKFB3 · AlF 4 ), and in a complex with pyrophosphate (PFKFB3 · PP i ) at resolutions of 2.45, 2.2, and 2.3 (angstrom), respectively. Trapping the PFKFB3-P · F-6-P intermediate was achieved by flash cooling the crystal during the reaction, and the PFKFB3 · AlF 4 and PFKFB3 · PP i complexes were obtained by soaking. The PFKFB3 · AlF 4 and PFKFB3 · PP i complexes resulted in removing F-6-P from the catalytic pocket. With these structures, the structures of the Michaelis complex and the transition state were extrapolated. For both the PFKFB3-P formation and break down, the phosphoryl donor and the acceptor are located within ∼5.1 (angstrom), and the pivotal point 2-P is on the same line, suggesting an 'in-line' transfer with a direct inversion of phosphate configuration. The geometry suggests that NE2 of His253 undergoes a nucleophilic attack to form a covalent N-P bond, breaking the 2O-P bond in the substrate. The resulting high reactivity of the leaving group, 2O of F-6-P, is neutralized by a proton donated by Glu322. Negative charges on the equatorial oxygen of the transient bipyramidal phosphorane formed during the transfer are stabilized by Arg252, His387, and Asn259. The C-terminal domain (residues 440-446) was rearranged in PFKFB3 · PP i , implying that this domain plays a critical role in binding of substrate to and release of product from the F-2,6-P 2 ase catalytic pocket. These findings provide a new insight into the understanding of the phosphoryl transfer reaction.

  8. Molecular basis for the interplay of apoptosis and proliferation mediated by Bcl-xL:Bim interactions in pancreatic cancer cells

    International Nuclear Information System (INIS)

    Abrol, Ravinder; Edderkaoui, Mouad; Goddard, William A.; Pandol, Stephen J.

    2012-01-01

    Highlights: ► Direct role of Bcl-2 protein interactions in cell proliferation is not clear. ► Designed Bcl-xL mutants show opposite effects on apoptosis and proliferation. ► Disrupting Bcl-xL:Bim interaction increased apoptosis in pancreatic cancer. ► Disrupting Bcl-xL:Bim interaction decreased proliferation in pancreatic cancer. ► Bcl-xL:Bim interaction can control both apoptosis and proliferation. -- Abstract: A major mechanism through which cancer cells avoid apoptosis is by promoting the association of anti-apoptotic members of the pro-survival Bcl-2 protein family (like Bcl-2 and Bcl-xL) with BH 3 domain-only proteins (like Bim and Bid). Apoptosis and cell proliferation have been shown to be linked for many cancers but the molecular basis for this link is far from understood. We have identified the Bcl-xL:Bim protein–protein interface as a direct regulator of proliferation and apoptosis in pancreatic cancer cells. We were able to predict and subsequently verify experimentally the effect of various Bcl-xL single-point mutants (at the position A142) on binding to Bim by structural analysis and computational modeling of the inter-residue interactions at the Bcl-xL:Bim protein–protein interface. The mutants A142N, A142Q, and A142Y decreased binding of Bim to Bcl-xL and A142S increased this binding. The Bcl-xL mutants, with decreased affinity for Bim, caused an increase in apoptosis and a corresponding decrease in cell proliferation. However, we could prevent these effects by introducing a small interfering RNA (siRNA) targeted at Bim. These results show a novel role played by the Bcl-xL:Bim interaction in regulating proliferation of pancreatic cancer cells at the expense of apoptosis. This study presents a physiologically relevant model of the Bcl-xL:Bim interface that can be used for rational therapeutic design for the inhibition of proliferation and cancer cell resistance to apoptosis.

  9. Molecular basis for the interplay of apoptosis and proliferation mediated by Bcl-xL:Bim interactions in pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Abrol, Ravinder, E-mail: abrol@wag.caltech.edu [Materials and Process Simulation Center, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (United States); Edderkaoui, Mouad [Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, CA 90073 (United States); Goddard, William A. [Materials and Process Simulation Center, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (United States); Pandol, Stephen J., E-mail: stephen.pandol@va.gov [Veterans Affairs Greater Los Angeles Healthcare System and UCLA, Los Angeles, CA 90073 (United States)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Direct role of Bcl-2 protein interactions in cell proliferation is not clear. Black-Right-Pointing-Pointer Designed Bcl-xL mutants show opposite effects on apoptosis and proliferation. Black-Right-Pointing-Pointer Disrupting Bcl-xL:Bim interaction increased apoptosis in pancreatic cancer. Black-Right-Pointing-Pointer Disrupting Bcl-xL:Bim interaction decreased proliferation in pancreatic cancer. Black-Right-Pointing-Pointer Bcl-xL:Bim interaction can control both apoptosis and proliferation. -- Abstract: A major mechanism through which cancer cells avoid apoptosis is by promoting the association of anti-apoptotic members of the pro-survival Bcl-2 protein family (like Bcl-2 and Bcl-xL) with BH{sub 3} domain-only proteins (like Bim and Bid). Apoptosis and cell proliferation have been shown to be linked for many cancers but the molecular basis for this link is far from understood. We have identified the Bcl-xL:Bim protein-protein interface as a direct regulator of proliferation and apoptosis in pancreatic cancer cells. We were able to predict and subsequently verify experimentally the effect of various Bcl-xL single-point mutants (at the position A142) on binding to Bim by structural analysis and computational modeling of the inter-residue interactions at the Bcl-xL:Bim protein-protein interface. The mutants A142N, A142Q, and A142Y decreased binding of Bim to Bcl-xL and A142S increased this binding. The Bcl-xL mutants, with decreased affinity for Bim, caused an increase in apoptosis and a corresponding decrease in cell proliferation. However, we could prevent these effects by introducing a small interfering RNA (siRNA) targeted at Bim. These results show a novel role played by the Bcl-xL:Bim interaction in regulating proliferation of pancreatic cancer cells at the expense of apoptosis. This study presents a physiologically relevant model of the Bcl-xL:Bim interface that can be used for rational therapeutic design for the

  10. Molecular mechanisms underlying memory consolidation of taste information in the cortex.

    Science.gov (United States)

    Gal-Ben-Ari, Shunit; Rosenblum, Kobi

    2011-01-01

    The senses of taste and odor are both chemical senses. However, whereas an organism can detect an odor at a relatively long distance from its source, taste serves as the ultimate proximate gatekeeper of food intake: it helps in avoiding poisons and consuming beneficial substances. The automatic reaction to a given taste has been developed during evolution and is well adapted to conditions that may occur with high probability during the lifetime of an organism. However, in addition to this automatic reaction, animals can learn and remember tastes, together with their positive or negative values, with high precision and in light of minimal experience. This ability of mammalians to learn and remember tastes has been studied extensively in rodents through application of reasonably simple and well defined behavioral paradigms. The learning process follows a temporal continuum similar to those of other memories: acquisition, consolidation, retrieval, relearning, and reconsolidation. Moreover, inhibiting protein synthesis in the gustatory cortex (GC) specifically affects the consolidation phase of taste memory, i.e., the transformation of short- to long-term memory, in keeping with the general biochemical definition of memory consolidation. This review aims to present a general background of taste learning, and to focus on recent findings regarding the molecular mechanisms underlying taste-memory consolidation in the GC. Specifically, the roles of neurotransmitters, neuromodulators, immediate early genes, and translation regulation are addressed.

  11. Molecular mechanisms underlying memory consolidation of taste information in the cortex

    Directory of Open Access Journals (Sweden)

    Shunit eGal-Ben-Ari

    2012-01-01

    Full Text Available The senses of taste and odor are both chemical senses. However, whereas an organism can detect an odor at a relatively long distance from its source, taste serves as the ultimate proximate gatekeeper of food intake: it helps in avoiding poisons and consuming beneficial substances. The automatic reaction to a given taste has been developed during evolution and is well adapted to conditions that may occur with high probability during the lifetime of an organism. However, in addition to this automatic reaction, animals can learn and remember tastes, together with their positive or negative values, with high precision and in light of minimal experience. This ability of mammalians to learn and remember tastes has been studied extensively in rodents through application of reasonably simple and well defined behavioral paradigms. The learning process follows a temporal continuum similar to those of other memories: acquisition, consolidation, retrieval, relearning, and reconsolidation. Moreover, inhibiting protein synthesis in the gustatory cortex specifically affects the consolidation phase of taste memory, i.e., the transformation of short- to long-term memory, in keeping with the general biochemical definition of memory consolidation. This review aims to present a general background of taste learning, and to focus on recent findings regarding the molecular mechanisms underlying taste memory consolidation in the gustatory cortex. Specifically, the role of neurotransmitters, meuromodulators, immediate early genes, and translation regulation are addressed.

  12. Molecular dynamics simulations of the melting curve of NiAl alloy under pressure

    International Nuclear Information System (INIS)

    Zhang, Wenjin; Peng, Yufeng; Liu, Zhongli

    2014-01-01

    The melting curve of B2-NiAl alloy under pressure has been investigated using molecular dynamics technique and the embedded atom method (EAM) potential. The melting temperatures were determined with two approaches, the one-phase and the two-phase methods. The first one simulates a homogeneous melting, while the second one involves a heterogeneous melting of materials. Both approaches reduce the superheating effectively and their results are close to each other at the applied pressures. By fitting the well-known Simon equation to our melting data, we yielded the melting curves for NiAl: 1783(1 + P/9.801) 0.298 (one-phase approach), 1850(1 + P/12.806) 0.357 (two-phase approach). The good agreement of the resulting equation of states and the zero-pressure melting point (calc., 1850 ± 25 K, exp., 1911 K) with experiment proved the correctness of these results. These melting data complemented the absence of experimental high-pressure melting of NiAl. To check the transferability of this EAM potential, we have also predicted the melting curves of pure nickel and pure aluminum. Results show the calculated melting point of Nickel agrees well with experiment at zero pressure, while the melting point of aluminum is slightly higher than experiment

  13. Transport in aluminized RDX under shock compression explored using molecular dynamics simulations

    International Nuclear Information System (INIS)

    Losada, M; Chaudhuri, S

    2014-01-01

    Shock response of energetic materials is controlled by a combination of mechanical response, thermal, transport, and chemical properties. How these properties interplay in condensed-phase energetic materials is of fundamental interest for improving predictive capabilities. Due to unknown nature of chemistry during the evolution and growth of high-temperature regions within the energetic material (so called hot spots), the connection between reactive and unreactive equations of state contain a high degree of empiricism. In particular, chemistry in materials with high degree of heterogeneity such as aluminized HE is of interest. In order to identify shock compression states and transport properties in high-pressure/temperature (HP-HT) conditions, we use molecular dynamics (MD) simulations in conjunction with the multi-scale shock technique (MSST). Mean square displacement calculations enabled us to track the diffusivity of stable gas products. Among decomposition products, H 2 O and CO 2 are found to be the dominant diffusing species under compression conditions. Heat transport and diffusion rates in decomposed RDX are compared and the comparison shows that around 2000 K, transport can be a major contribution during propagation of the reaction front.

  14. Time-Series Analyses of Transcriptomes and Proteomes Reveal Molecular Networks Underlying Oil Accumulation in Canola.

    Science.gov (United States)

    Wan, Huafang; Cui, Yixin; Ding, Yijuan; Mei, Jiaqin; Dong, Hongli; Zhang, Wenxin; Wu, Shiqi; Liang, Ying; Zhang, Chunyu; Li, Jiana; Xiong, Qing; Qian, Wei

    2016-01-01

    Understanding the regulation of lipid metabolism is vital for genetic engineering of canola ( Brassica napus L.) to increase oil yield or modify oil composition. We conducted time-series analyses of transcriptomes and proteomes to uncover the molecular networks associated with oil accumulation and dynamic changes in these networks in canola. The expression levels of genes and proteins were measured at 2, 4, 6, and 8 weeks after pollination (WAP). Our results show that the biosynthesis of fatty acids is a dominant cellular process from 2 to 6 WAP, while the degradation mainly happens after 6 WAP. We found that genes in almost every node of fatty acid synthesis pathway were significantly up-regulated during oil accumulation. Moreover, significant expression changes of two genes, acetyl-CoA carboxylase and acyl-ACP desaturase, were detected on both transcriptomic and proteomic levels. We confirmed the temporal expression patterns revealed by the transcriptomic analyses using quantitative real-time PCR experiments. The gene set association analysis show that the biosynthesis of fatty acids and unsaturated fatty acids are the most significant biological processes from 2-4 WAP and 4-6 WAP, respectively, which is consistent with the results of time-series analyses. These results not only provide insight into the mechanisms underlying lipid metabolism, but also reveal novel candidate genes that are worth further investigation for their values in the genetic engineering of canola.

  15. Molecular mechanisms underlying the role of microRNAs in the chemoresistance of pancreatic cancer.

    Science.gov (United States)

    Garajová, Ingrid; Le Large, Tessa Y; Frampton, Adam E; Rolfo, Christian; Voortman, Johannes; Giovannetti, Elisa

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is an extremely severe disease where the mortality and incidence rates are almost identical. This is mainly due to late diagnosis and limited response to current treatments. The tumor macroenvironment/microenvironment have been frequently reported as the major contributors to chemoresistance in PDAC, preventing the drugs from reaching their intended site of action (i.e., the malignant duct cells). However, the recent discovery of microRNAs (miRNAs) has provided new directions for research on mechanisms underlying response to chemotherapy. Due to their tissue-/disease-specific expression and high stability in tissues and biofluids, miRNAs represent new promising diagnostic and prognostic/predictive biomarkers and therapeutic targets. Furthermore, several studies have documented that selected miRNAs, such as miR-21 and miR-34a, may influence response to chemotherapy in several tumor types, including PDAC. In this review, we summarize the current knowledge on the role of miRNAs in PDAC and recent advances in understanding their role in chemoresistance through multiple molecular mechanisms.

  16. Molecular Mechanisms Underlying the Role of MicroRNAs in the Chemoresistance of Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Ingrid Garajová

    2014-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is an extremely severe disease where the mortality and incidence rates are almost identical. This is mainly due to late diagnosis and limited response to current treatments. The tumor macroenvironment/microenvironment have been frequently reported as the major contributors to chemoresistance in PDAC, preventing the drugs from reaching their intended site of action (i.e., the malignant duct cells. However, the recent discovery of microRNAs (miRNAs has provided new directions for research on mechanisms underlying response to chemotherapy. Due to their tissue-/disease-specific expression and high stability in tissues and biofluids, miRNAs represent new promising diagnostic and prognostic/predictive biomarkers and therapeutic targets. Furthermore, several studies have documented that selected miRNAs, such as miR-21 and miR-34a, may influence response to chemotherapy in several tumor types, including PDAC. In this review, we summarize the current knowledge on the role of miRNAs in PDAC and recent advances in understanding their role in chemoresistance through multiple molecular mechanisms.

  17. Reactive Molecular Dynamics Simulations to Understand Mechanical Response of Thaumasite under Temperature and Strain Rate Effects.

    Science.gov (United States)

    Hajilar, Shahin; Shafei, Behrouz; Cheng, Tao; Jaramillo-Botero, Andres

    2017-06-22

    Understanding the structural, thermal, and mechanical properties of thaumasite is of great interest to the cement industry, mainly because it is the phase responsible for the aging and deterioration of civil infrastructures made of cementitious materials attacked by external sources of sulfate. Despite the importance, effects of temperature and strain rate on the mechanical response of thaumasite had remained unexplored prior to the current study, in which the mechanical properties of thaumasite are fully characterized using the reactive molecular dynamics (RMD) method. With employing a first-principles based reactive force field, the RMD simulations enable the description of bond dissociation and formation under realistic conditions. From the stress-strain curves of thaumasite generated in the x, y, and z directions, the tensile strength, Young's modulus, and fracture strain are determined for the three orthogonal directions. During the course of each simulation, the chemical bonds undergoing tensile deformations are monitored to reveal the bonds responsible for the mechanical strength of thaumasite. The temperature increase is found to accelerate the bond breaking rate and consequently the degradation of mechanical properties of thaumasite, while the strain rate only leads to a slight enhancement of them for the ranges considered in this study.

  18. Molecular dynamics simulations of polyelectrolyte brushes under poor solvent conditions: origins of bundle formation.

    Science.gov (United States)

    He, Gui-Li; Merlitz, Holger; Sommer, Jens-Uwe

    2014-03-14

    Molecular dynamics simulations are applied to investigate salt-free planar polyelectrolyte brushes under poor solvent conditions. Starting above the Θ-point with a homogeneous brush and then gradually reducing the temperature, the polymers initially display a lateral structure formation, forming vertical bundles of chains. A further reduction of the temperature (or solvent quality) leads to a vertical collapse of the brush. By varying the size and selectivity of the counterions, we show that lateral structure formation persists and therefore demonstrate that the entropy of counterions being the dominant factor for the formation of the bundle phase. By applying an external compression force on the brush we calculate the minimal work done on the polymer phase only and prove that the entropy gain of counterions in the bundle state, as compared to the homogeneously collapsed state at the same temperature, is responsible for the lateral microphase segregation. As a consequence, the observed lateral structure formation has to be regarded universal for osmotic polymer brushes below the Θ-point.

  19. Atomistic simulations of highly conductive molecular transport junctions under realistic conditions

    KAUST Repository

    French, William R.; Iacovella, Christopher R.; Rungger, Ivan; Souza, Amaury Melo; Sanvito, Stefano; Cummings, Peter T.

    2013-01-01

    We report state-of-the-art atomistic simulations combined with high-fidelity conductance calculations to probe structure-conductance relationships in Au-benzenedithiolate (BDT)-Au junctions under elongation. Our results demonstrate that large increases in conductance are associated with the formation of monatomic chains (MACs) of Au atoms directly connected to BDT. An analysis of the electronic structure of the simulated junctions reveals that enhancement in the s-like states in Au MACs causes the increases in conductance. Other structures also result in increased conductance but are too short-lived to be detected in experiment, while MACs remain stable for long simulation times. Examinations of thermally evolved junctions with and without MACs show negligible overlap between conductance histograms, indicating that the increase in conductance is related to this unique structural change and not thermal fluctuation. These results, which provide an excellent explanation for a recently observed anomalous experimental result [Bruot et al., Nat. Nanotechnol., 2012, 7, 35-40], should aid in the development of mechanically responsive molecular electronic devices. © 2013 The Royal Society of Chemistry.

  20. Initial Chemical Events in CL-20 Under Extreme Conditions: An Ab Initio Molecular Dynamics Study

    National Research Council Canada - National Science Library

    Isaev, Olexandr; Kholod, Yana; Gorb, Leonid; Qasim, Mohammad; Fredrickson, Herb; Leszczynski, Jerzy

    2006-01-01

    .... In the present study molecular structure, electrostatic potential, vibrational spectrum and dynamics of thermal decomposition of CL-20 have been investigated by static and dynamic methods of ab...

  1. PCR ribotype prevalence and molecular basis of macrolide-lincosamide-streptogramin B (MLSB) and fluoroquinolone resistance in Irish clinical Clostridium difficile isolates.

    LENUS (Irish Health Repository)

    Solomon, Katie

    2011-09-01

    Antimicrobial use is recognized as a risk factor for Clostridium difficile infection (CDI) and outbreaks. We studied the relationship between PCR ribotype, antimicrobial susceptibility and the genetic basis of resistance in response to exposure to antimicrobial agents.

  2. Deciphering the molecular mechanisms underlying sea urchin reversible adhesion: A quantitative proteomics approach.

    Science.gov (United States)

    Lebesgue, Nicolas; da Costa, Gonçalo; Ribeiro, Raquel Mesquita; Ribeiro-Silva, Cristina; Martins, Gabriel G; Matranga, Valeria; Scholten, Arjen; Cordeiro, Carlos; Heck, Albert J R; Santos, Romana

    2016-04-14

    Marine bioadhesives have unmatched performances in wet environments, being an inspiration for biomedical applications. In sea urchins specialized adhesive organs, tube feet, mediate reversible adhesion, being composed by a disc, producing adhesive and de-adhesive secretions, and a motile stem. After tube foot detachment, the secreted adhesive remains bound to the substratum as a footprint. Sea urchin adhesive is composed by proteins and sugars, but so far only one protein, Nectin, was shown to be over-expressed as a transcript in tube feet discs, suggesting its involvement in sea urchin adhesion. Here we use high-resolution quantitative mass-spectrometry to perform the first study combining the analysis of the differential proteome of an adhesive organ, with the proteome of its secreted adhesive. This strategy allowed us to identify 163 highly over-expressed disc proteins, specifically involved in sea urchin reversible adhesion; to find that 70% of the secreted adhesive components fall within five protein groups, involved in exocytosis and microbial protection; and to provide evidences that Nectin is not only highly expressed in tube feet discs but is an actual component of the adhesive. These results give an unprecedented insight into the molecular mechanisms underlying sea urchin adhesion, and opening new doors to develop wet-reliable, reversible, and ecological biomimetic adhesives. Sea urchins attach strongly but in a reversible manner to substratum, being a valuable source of inspiration for industrial and biomedical applications. Yet, the molecular mechanisms governing reversible adhesion are still poorly studied delaying the engineering of biomimetic adhesives. We used the latest mass spectrometry techniques to analyze the differential proteome of an adhesive organ and the proteome of its secreted adhesive, allowing us to uncover the key players in sea urchin reversible adhesion. We demonstrate, that Nectin, a protein previously pointed out as potentially

  3. Molecular phenology in plants: in natura systems biology for the comprehensive understanding of seasonal responses under natural environments.

    Science.gov (United States)

    Kudoh, Hiroshi

    2016-04-01

    Phenology refers to the study of seasonal schedules of organisms. Molecular phenology is defined here as the study of the seasonal patterns of organisms captured by molecular biology techniques. The history of molecular phenology is reviewed briefly in relation to advances in the quantification technology of gene expression. High-resolution molecular phenology (HMP) data have enabled us to study phenology with an approach of in natura systems biology. I review recent analyses of FLOWERING LOCUS C (FLC), a temperature-responsive repressor of flowering, along the six steps in the typical flow of in natura systems biology. The extensive studies of the regulation of FLC have made this example a successful case in which a comprehensive understanding of gene functions has been progressing. The FLC-mediated long-term memory of past temperatures creates time lags with other seasonal signals, such as photoperiod and short-term temperature. Major signals that control flowering time have a phase lag between them under natural conditions, and hypothetical phase lag calendars are proposed as mechanisms of season detection in plants. Transcriptomic HMP brings a novel strategy to the study of molecular phenology, because it provides a comprehensive representation of plant functions. I discuss future perspectives of molecular phenology from the standpoints of molecular biology, evolutionary biology and ecology. © 2015 The Author. New Phytologist © 2015 New Phytologist Trust.

  4. The underlying physiological basis of the desert rodent Meriones shawi's survival to prolonged water deprivation: Central vasopressin regulation on peripheral kidney water channels AQPs-2.

    Science.gov (United States)

    Elgot, A; El Hiba, O; Belkouch, M; Gamrani, H

    2018-02-01

    Meriones shawi (M. shawi) is a particular semi-desert rodent known by its resistance to long periods of thirst. The aim of the present investigation is to clarify the underlying mechanisms allowing M. shawi to resist to hard conditions of dehydration. For this reason we used two different approaches: i) a morphometric study, which consists in measuring the effect of dehydration on body and kidneys weights as well as the report kidney weight/body weight, ii) By immunohistochemistry, we proceed to study the effect of dehydration on the immunoreactivity of central vasopressin (AVP) and the kidney aquaporin-2 (AQP-2) which is a channel protein that allows water to permeate across cell membranes. Our results showed both a body mass decrease accompanied by a remarkable kidneys hypertrophy. The immunohistochemical study showed a significant increase of AQP-2 immunoreactivity in the medullar part of Meriones kidneys allowing probably to Meriones a great ability to water retention. Consistently, we demonstrate that the increased AQP-2 expression occurred together with an increase in vasopressin (AVP) expression in both hypothalamic supraoptic (SON) and paraventricular nucleus (PVN), which are a major hub in the osmotic control circuitry. These various changes seen either in body weight and kidneys or at the cellular level might be the basis of peripheral control of body water homeostasis, providing to M. shawia strong resistance against chronic dehydration. Copyright © 2017 Elsevier GmbH. All rights reserved.

  5. STICK AND SLIP BEHAVIOR OF CONFINED OLIGOMER MELTS UNDER SHEAR - A MOLECULAR-DYNAMICS STUDY

    NARCIS (Netherlands)

    MANIAS, E; HADZIIOANNOU, G; BITSANIS, [No Value; TENBRINKE, G

    1993-01-01

    The flow behaviour of melts of short chains, confined in molecularly thin Couette flow geometries, is studied with molecular-dynamics simulations. The effect of wall attraction and confinement on the density and velocity profiles is analysed. In these highly inhomogeneous films, a strong correlation

  6. Non-sensitized selective photochemical reduction of CO2 to CO under visible light with an iron molecular catalyst.

    Science.gov (United States)

    Rao, Heng; Bonin, Julien; Robert, Marc

    2017-03-02

    A substituted tetraphenyl iron porphyrin, bearing positively charged trimethylammonio groups at the para position of each phenyl ring, demonstrates its ability as a homogeneous molecular catalyst to selectively reduce CO 2 to CO under visible light irradiation in organic media without the assistance of a sensitizer and no competitive hydrogen evolution for several days.

  7. Molecular plasmonics: The role of rovibrational molecular states in exciton-plasmon materials under strong-coupling conditions

    Science.gov (United States)

    Sukharev, Maxim; Charron, Eric

    2017-03-01

    We extend the model of exciton-plasmon materials to include a rovibrational structure of molecules using wave-packet propagations on electronic potential energy surfaces. Our model replaces conventional two-level emitters with more complex molecules, allowing us to examine the influence of alignment and vibrational dynamics on strong coupling with surface plasmon-polaritons. We apply the model to a hybrid system comprising a thin layer of molecules placed on top of a periodic array of slits. Rigorous simulations are performed for two types of molecular systems described by vibrational bound-bound and bound-continuum electronic transitions. Calculations reveal new features in transmission, reflection, and absorption spectra, including the observation of significantly higher values of the Rabi splitting and vibrational patterns clearly seen in the corresponding spectra. We also examine the influence of anisotropic initial conditions on optical properties of hybrid materials, demonstrating that the optical response of the system is significantly affected by an initial prealignment of the molecules. Our work demonstrates that prealigned molecules could serve as an efficient probe for the subdiffraction characterization of the near-field near metal interfaces.

  8. Molecular Processes Underlying the Structure and Assembly of Thin Films and Nanoparticles at Complex interfaces

    Energy Technology Data Exchange (ETDEWEB)

    Richmond, Geraldine [Univ. of Oregon, Eugene, OR (United States)

    2016-06-03

    Since 1995 we have pursued a number of different studies that are quite diverse in nature but with the common theme of using novel laser based methods to study important processes at buried interfaces. Studies of Corrosion, Passivation on n-GaAs(100)Methanol Photoelectrochemical Cell In these studies we have used picosecond photoluminescence and electrochemical studies to understand the GaAs/methanol interface. In our most extensive set of studies we conducted photo-illumination and XPS experiments to understand the chemistry occurring in the GaAs/methanol photoelectrochemical during photoexcitation. An important distinction between photocorrosion and photoetching of GaAs is elucidated by these studies. The dependence of GaAs photocorrosion on light intensity has been explored to better understand intrinsic differences between the lamplight studies and the picosecond photoluminescence studies. The effect of coating the GaAs with a sulfide layer prior to immersion in the cell has also been explored. This last result has led us to examine n-GaAs as a function of crystallographic orientation after exposure to aqueous Na2S containing solutions has been studied as a function of crystallographic orientation of the GaAs surface. The (100) and (110) surfaces are relatively similar, with significant amounts of As-S species present at the interface. The (111)B surface lacks this constituent, but shows significant amounts of metallic As. The XPS results have been correlated with the results of previous photocorrosion and passivation studies conducted in a photoelectrochemical cell. The studies indicate that the metallic As present at (111)B surface contributes strongly to the large surface recombination velocity found there, and to the inability of Na2S to passivate the (111)B surface. SAMS Under Water: Water Molecular Structure and Bonding at Hydrophobic Surfaces In these DOE sponsored studies we have been interested in learning the similarities and

  9. Phylogenetic and Molecular Evolutionary Analysis of Mitophagy Receptors under Hypoxic Conditions

    Directory of Open Access Journals (Sweden)

    Xiaomei Wu

    2017-07-01

    Full Text Available As animals evolved to use oxygen as the main strategy to produce ATP through the process of mitochondrial oxidative phosphorylation, the ability to adapt to fluctuating oxygen concentrations is a crucial component of evolutionary pressure. Three mitophagy receptors, FUNDC1, BNIP3 and NIX, induce the removal of dysfunctional mitochondria (mitophagy under prolonged hypoxic conditions in mammalian cells, to maintain oxygen homeostasis and prevent cell death. However, the evolutionary origins and structure-function relationships of these receptors remain poorly understood. Here, we found that FUN14 domain-containing proteins are present in archaeal, bacterial and eukaryotic genomes, while the family of BNIP3 domain-containing proteins evolved from early animals. We investigated conservation patterns of the critical amino acid residues of the human mitophagy receptors. These residues are involved in receptor regulation, mainly through phosphorylation, and in interaction with LC3 on the phagophore. Whereas FUNDC1 may be able to bind to LC3 under the control of post-translational regulations during the early evolution of vertebrates, BINP3 and NIX had already gained the ability for LC3 binding in early invertebrates. Moreover, FUNDC1 and BNIP3 each lack a layer of phosphorylation regulation in fishes that is conserved in land vertebrates. Molecular evolutionary analysis revealed that BNIP3 and NIX, as the targets of oxygen sensing HIF-1α, showed higher rates of substitution in fishes than in mammals. Conversely, FUNDC1 and its regulator MARCH5 showed higher rates of substitution in mammals. Thus, we postulate that the structural traces of mitophagy receptors in land vertebrates and fishes may reflect the process of vertebrate transition from water onto land, during which the changes in atmospheric oxygen concentrations acted as a selection force in vertebrate evolution. In conclusion, our study, combined with previous experimental results, shows that

  10. Nanopore wall-liquid interaction under scope of molecular dynamics study: Review

    Science.gov (United States)

    Tsukanov, A. A.; Psakhie, S. G.

    2017-12-01

    The present review is devoted to the analysis of recent molecular dynamics based on the numerical studies of molecular aspects of solid-fluid interaction in nanoscale channels. Nanopore wall-liquid interaction plays the crucial role in such processes as gas separation, water desalination, liquids decontamination, hydrocarbons and water transport in nano-fractured geological formations. Molecular dynamics simulation is one of the most suitable tools to study molecular level effects occurred in such multicomponent systems. The nanopores are classified by their geometry to four groups: nanopore in nanosheet, nanotube-like pore, slit-shaped nanopore and soft-matter nanopore. The review is focused on the functionalized nanopores in boron nitride nanosheets as novel selective membranes and on the slit-shaped nanopores formed by minerals.

  11. Molecular spectrum of laterally coupled quantum rings under intense terahertz radiation.

    Science.gov (United States)

    Baghramyan, Henrikh M; Barseghyan, Manuk G; Laroze, David

    2017-09-05

    We study the influence of intense THz laser radiation and electric field on molecular states of laterally coupled quantum rings. Laser radiation shows the capability to dissociate quantum ring molecule and add 2-fold degeneracy to the molecular states at the fixed value of the overlapping size between rings. It is shown that coupled to decoupled molecular states phase transition points form almost a straight line with a slope equal to two. In addition, the electric field direction dependent energy spectrum shows unexpected oscillations, demonstrating strong coupling between molecular states. Besides, intraband absorption is considered, showing both blue and redshifts in its spectrum. The obtained results can be useful for the controlling of degeneracy of the discrete energy spectrum of nanoscale structures and in the tunneling effects therein.

  12. D2+ Molecular complex in non-uniform height quantum ribbon under crossed electric and magnetic fields

    Science.gov (United States)

    Suaza, Y. A.; Laroze, D.; Fulla, M. R.; Marín, J. H.

    2018-05-01

    The D2+ molecular complex fundamental properties in a uniform and multi-hilled semiconductor quantum ribbon under orthogonal electric and magnetic fields are theoretically studied. The energy structure is calculated by using adiabatic approximation combined with diagonalization procedure. The D2+ energy structure is more strongly controlled by the geometrical structural hills than the Coulomb interaction. The formation of vibrational and rotational states is discussed. Aharanov-Bohm oscillation patterns linked to rotational states as well as the D2+ molecular complex stability are highly sensitive to the number of hills while electric field breaks the electron rotational symmetry and removes the energy degeneration between low-lying states.

  13. Physiological basis of genetic variation in leaf photosynthesis among rice (Oryza sativa L.) introgression lines under drought and well-watered conditions

    Science.gov (United States)

    Yin, Xinyou

    2012-01-01

    To understand the physiological basis of genetic variation and resulting quantitative trait loci (QTLs) for photosynthesis in a rice (Oryza sativa L.) introgression line population, 13 lines were studied under drought and well-watered conditions, at flowering and grain filling. Simultaneous gas exchange and chlorophyll fluorescence measurements were conducted at various levels of incident irradiance and ambient CO2 to estimate parameters of a model that dissects photosynthesis into stomatal conductance (g s), mesophyll conductance (g m), electron transport capacity (J max), and Rubisco carboxylation capacity (V cmax). Significant genetic variation in these parameters was found, although drought and leaf age accounted for larger proportions of the total variation. Genetic variation in light-saturated photosynthesis and transpiration efficiency (TE) were mainly associated with variation in g s and g m. One previously mapped major QTL of photosynthesis was associated with variation in g s and g m, but also in J max and V cmax at flowering. Thus, g s and g m, which were demonstrated in the literature to be responsible for environmental variation in photosynthesis, were found also to be associated with genetic variation in photosynthesis. Furthermore, relationships between these parameters and leaf nitrogen or dry matter per unit area, which were previously found across environmental treatments, were shown to be valid for variation across genotypes. Finally, the extent to which photosynthesis rate and TE can be improved was evaluated. Virtual ideotypes were estimated to have 17.0% higher photosynthesis and 25.1% higher TE compared with the best genotype investigated. This analysis using introgression lines highlights possibilities of improving both photosynthesis and TE within the same genetic background. PMID:22888131

  14. Molecular mechanisms underlying mancozeb-induced inhibition of TNF-alpha production

    International Nuclear Information System (INIS)

    Corsini, Emanuela; Viviani, Barbara; Birindelli, Sarah; Gilardi, Federica; Torri, Anna; Codeca, Ilaria; Lucchi, Laura; Bartesaghi, Stefano; Galli, Corrado L.; Marinovich, Marina; Colosio, Claudio

    2006-01-01

    Mancozeb, a polymeric complex of manganese ethylenebisdithiocarbamate with zinc salt, is widely used in agriculture as fungicide. Literature data indicate that ethylenebisdithiocarbamates (EBDTCs) may have immunomodulatory effects in humans. We have recently found in agricultural workers occupationally exposed to the fungicide mancozeb a statistically significant decrease in lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF) production in leukocytes. TNF is an essential proinflammatory cytokine whose production is normally stimulated during an infection. The purpose of this work was to establish an in vitro model reflecting in vivo data and to characterize the molecular mechanism of action of mancozeb. The human promyelocytic cell line THP-1 was used as in vitro model to study the effects of mancozeb and its main metabolite ethylenthiourea (ETU) on LPS-induced TNF release. Mancozeb, but not ETU, at non-cytotoxic concentrations (1-100 μg/ml), induced a dose- and time-dependent inhibition of LPS-induced TNF release, reflecting in vivo data. The modulatory effect observed was not limited to mancozeb but also other EBDTCs, namely zineb and ziram, showed similar inhibitory effects. Mancozeb must be added before or simultaneously to LPS in order to observe the effect, indicating that it acts on early events triggered by LPS. It is known that nuclear factor-κB (NF-κB) tightly regulates TNF transcription. We could demonstrate that mancozeb, modulating LPS-induced reactive oxygen species generation, prevented IκB degradation and NF-κB nuclear translocation, which in turn resulted in decreased TNF production. To further understand the mechanism of the effect of mancozeb on TNF transcription, THP-1 cells were transfected with NF-κB promoter-luciferase construct, and the effect of mancozeb on luciferase activity was measured. Cells transfected with promoter constructs containing κB site showed decreased LPS-induced luciferase activity relative to control

  15. Study of bond-energy variations in molecular systems under irradiation; Etude de la variation de l'energie de liaison dans les systemes moleculaires irradies

    Energy Technology Data Exchange (ETDEWEB)

    Naudet, G; Passe, S [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

    1968-07-01

    On the basis of experimental results selected from publications, the evolution of the bond energy of a molecular system under irradiation - leading to a more or less bound state - is studied. This variation of bond energy is then compared to the total bond energy of the initial system and to the energy absorbed in the system during the irradiation. This is done as a function of the nature of molecular system and the radiation spectrum and intensity. Our working method will first be explained, and the results obtained will then be given. (authors) [French] A l'aide de resultats experimentaux, selectionnes dans les publications, nous etudions l'evolution de l'energie de liaison d'un systeme moleculaire sous irradiation (evolution vers un etat plus ou moins lie), et nous comparons cette variation d'energie de liaison a l'energie totale de liaison du systeme initial et a l'energie absorbee dans le systeme au cours de l'irradiation. Ceci est fait en fonction de la nature du systeme moleculaire ainsi que du spectre et de l'intensite du rayonnement. Nous exposons d'abord notre methode de travail, puis les resultats obtenus. (auteurs)

  16. Thermophysical properties of liquid carbon dioxide under shock compressions: quantum molecular dynamic simulations.

    Science.gov (United States)

    Wang, Cong; Zhang, Ping

    2010-10-07

    Quantum molecular dynamics were used to calculate the equation of state, electrical, and optical properties of liquid carbon dioxide along the Hugoniot at shock pressures up to 74 GPa. The principal Hugoniot derived from the calculated equation of state is in good agreement with experimental results. Molecular dissociation and recombination are investigated through pair correlation functions and decomposition of carbon dioxide is found to be between 40 and 50 GPa along the Hugoniot, where nonmetal-metal transition is observed. In addition, the optical properties of shock compressed carbon dioxide are also theoretically predicted along the Hugoniot.

  17. A Shared Molecular and Genetic Basis for Food and Drug Addiction: Overcoming Hypodopaminergic Trait/State by Incorporating Dopamine Agonistic Therapy in Psychiatry.

    Science.gov (United States)

    Gold, Mark S; Badgaiyan, Rajendra D; Blum, Kenneth

    2015-09-01

    This article focuses on the shared molecular and neurogenetics of food and drug addiction tied to the understanding of reward deficiency syndrome. Reward deficiency syndrome describes a hypodopaminergic trait/state that provides a rationale for commonality in approaches for treating long-term reduced dopamine function across the reward brain regions. The identification of the role of DNA polymorphic associations with reward circuitry has resulted in new understanding of all addictive behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. 2012 Molecular Basis of Microbial One-Carbon Metabolism Gordon Research Conferences and Gordon Research Seminar, August 4-10,2012

    Energy Technology Data Exchange (ETDEWEB)

    Hanson, Thomas

    2012-08-10

    The 2012 Gordon Conference will present and discuss cutting-edge research in the field of microbial metabolism of C1 compounds. The conference will feature the roles and application of C1 metabolism in natural and synthetic systems at scales from molecules to ecosystems. The conference will stress molecular aspects of the unique metabolism exhibited by autotrophic bacteria, methanogens, methylotrophs, aerobic and anaerobic methanotrophs, and acetogens.

  19. Essential Concepts and Underlying Theories from Physics, Chemistry, and Mathematics for "Biochemistry and Molecular Biology" Majors

    Science.gov (United States)

    Wright, Ann; Provost, Joseph; Roecklein-Canfield, Jennifer A.; Bell, Ellis

    2013-01-01

    Over the past two years, through an NSF RCN UBE grant, the ASBMB has held regional workshops for faculty members from around the country. The workshops have focused on developing lists of Core Principles or Foundational Concepts in Biochemistry and Molecular Biology, a list of foundational skills, and foundational concepts from Physics, Chemistry,…

  20. On the effects of transforming the vibrational spectra of molecular systems under microwave radiation

    International Nuclear Information System (INIS)

    Serikov, A.A.

    1993-01-01

    This problem is analyzed within the quantum-classical theory of molecular spectra. It is shown that the above-mentioned spectrum transformation could be, in principle, realized in macromolecular systems with strong interaction, and attention is drawn to the resonance character of the effect. (author). 19 refs., 1 fig

  1. Molecular mechanisms underlying formation of long-term reward memories and extinction memories in the honeybee (Apis mellifera)

    Science.gov (United States)

    2014-01-01

    The honeybee (Apis mellifera) has long served as an invertebrate model organism for reward learning and memory research. Its capacity for learning and memory formation is rooted in the ecological need to efficiently collect nectar and pollen during summer to ensure survival of the hive during winter. Foraging bees learn to associate a flower's characteristic features with a reward in a way that resembles olfactory appetitive classical conditioning, a learning paradigm that is used to study mechanisms underlying learning and memory formation in the honeybee. Due to a plethora of studies on appetitive classical conditioning and phenomena related to it, the honeybee is one of the best characterized invertebrate model organisms from a learning psychological point of view. Moreover, classical conditioning and associated behavioral phenomena are surprisingly similar in honeybees and vertebrates, suggesting a convergence of underlying neuronal processes, including the molecular mechanisms that contribute to them. Here I review current thinking on the molecular mechanisms underlying long-term memory (LTM) formation in honeybees following classical conditioning and extinction, demonstrating that an in-depth analysis of the molecular mechanisms of classical conditioning in honeybees might add to our understanding of associative learning in honeybees and vertebrates. PMID:25225299

  2. Elucidating the Molecular Basis and Regulation of Chromium(VI) Reduction by Shewanella oneidensis MR-1 and Resistance to Metal Toxicity Using Integrated Biochemical, Genomic and Proteomic Approaches

    Energy Technology Data Exchange (ETDEWEB)

    Dorothea K. Thompson; Robert Hettich

    2007-02-06

    Shewanella oneidensis MR-1 is a model environmental organism that possesses diverse respiratory capacities, including the ability to reduce soluble Cr(VI) to sparingly soluble, less toxic Cr(III). Chromate is a serious anthropogenic pollutant found in subsurface sediment and groundwater environments due to its widespread use in defense and industrial applications. Effective bioremediation of chromate-contaminated sites requires knowledge of the molecular mechanisms and regulation of heavy metal resistance and biotransformation by dissimilatory metal-reducing bacteria. Towards this goal, our ERSP-funded work was focused on the identification and functional analysis of genes/proteins comprising the response pathways for chromate detoxification and/or reduction. Our work utilized temporal transcriptomic profiling and whole-cell proteomic analyses to characterize the dynamic molecular response of MR-1 to an acute chromate shock (up to 90 min) as well as to a 24-h, low-dose exposure. In addition, we have examined the transcriptome of MR-1 cells actively engaged in chromate reduction. These studies implicated the involvement of a functionally undefined DNA-binding response regulator (SO2426) and a putative azoreductase (SO3585) in the chromate stress response of MR-1.

  3. Genetic deficiency of the α subunit of the guanine nucleotide-binding protein G/sub s/ as the molecular basis for Albright hereditary osteodystrophy

    International Nuclear Information System (INIS)

    Levine, M.A.; Ahn, T.G.; Klupt, S.F.; Kaufman, K.D.; Smallwood, P.M.; Bourne, H.R.; Sullivan, K.A.; Van Dop, C.

    1988-01-01

    Patients who have pseudohypoparathyroidism type I associated with Albright hereditary osteodystrophy commonly have a genetic deficiency of the α subunit of the G protein that stimulated adenylyl cyclase αG/sub s/. To discover the molecular mechanism that causes αG/sub s/ deficiency in these patients, the authors examined eight kindreds with one or more members affected with Albright hereditary osteodystrophy or pseudohypoparathyroidism and αG/sub s/ deficiency. In these families, αG/sub s/, deficiency and the Albright hereditary osteodystrophy phenotype were transmitted together in a dominant inheritance pattern. Using a cDNA hybridization probe for αG/sub s/, restriction analysis with several analysis with several endonucleases showed no abnormalities of restriction fragments or gene dosage. RNA blot and dot blot analysis of total RNA from cultured fibroblasts obtained from the patients revealed ∼ 50% reduced mRNA levels for αG/sub s/ in affected members of six of the pedigrees but normal levels in affected members of the two other pedigrees, compared to mRNA levels in fibroblasts from unaffected individuals. By contrast, mRNA levels encoding the α subunit of the G protein that inhibits adenylyl cyclase were not altered. These findings suggest that several molecular mechanisms produce αG/sub s/ deficiency in patients with pseudohypoparathyroidism type Ia and that major gene rearrangements or deletions are not a common cause for αG/sub s/ deficiency in pseudohypoparathyroidism type I

  4. Cognitive neuroepigenetics: the next evolution in our understanding of the molecular mechanisms underlying learning and memory?

    Science.gov (United States)

    Marshall, Paul; Bredy, Timothy W.

    2016-07-01

    A complete understanding of the fundamental mechanisms of learning and memory continues to elude neuroscientists. Although many important discoveries have been made, the question of how memories are encoded and maintained at the molecular level remains. So far, this issue has been framed within the context of one of the most dominant concepts in molecular biology, the central dogma, and the result has been a protein-centric view of memory. Here, we discuss the evidence supporting a role for neuroepigenetic mechanisms, which constitute dynamic and reversible, state-dependent modifications at all levels of control over cellular function, and their role in learning and memory. This neuroepigenetic view suggests that DNA, RNA and protein each influence one another to produce a holistic cellular state that contributes to the formation and maintenance of memory, and predicts a parallel and distributed system for the consolidation, storage and retrieval of the engram.

  5. A study on EUV reticle surface molecular contamination under different storage conditions in a HVM foundry fab

    Science.gov (United States)

    Singh, SherJang; Yatzor, Brett; Taylor, Ron; Wood, Obert; Mangat, Pawitter

    2017-03-01

    The prospect of EUVL (Extreme Ultraviolet Lithography) insertion into HVM (High Volume Manufacturing) has never been this promising. As technology is prepared for "lab to fab" transition, it becomes important to comprehend challenges associated with integrating EUVL infrastructure within existing high volume chip fabrication processes in a foundry fab. The existing 193nm optical lithography process flow for reticle handling and storage in a fab atmosphere is well established and in-fab reticle contamination concerns are mitigated with the reticle pellicle. However EUVL reticle pellicle is still under development and if available, may only provide protection against particles but not molecular contamination. HVM fab atmosphere is known to be contaminated with trace amounts of AMC's (Atmospheric Molecular Contamination). If such contaminants are organic in nature and get absorbed on the reticle surface, EUV photon cause photo-dissociation resulting into carbon generation which is known to reduce multilayer reflectivity and also degrades exposure uniformity. Chemical diffusion and aggregation of other ions is also reported under the e-beam exposure of a EUV reticle which is known to cause haze issues in optical lithography. Therefore it becomes paramount to mitigate absorbed molecular contaminant concerns on EUVL reticle surface. In this paper, we have studied types of molecular contaminants that are absorbed on an EUVL reticle surface under HVM fab storage and handling conditions. Effect of storage conditions (gas purged vs atmospheric) in different storage pods (Dual pods, Reticle Clamshells) is evaluated. Absorption analysis is done both on ruthenium capping layer as well as TaBN absorber. Ru surface chemistry change as a result of storage is also studied. The efficacy of different reticle cleaning processes to remove absorbed contaminant is evaluated as well.

  6. Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

    OpenAIRE

    SOMASAGARA, RANGANATHA R.; DEEP, GAGAN; SHROTRIYA, SANGEETA; PATEL, MANISHA; AGARWAL, CHAPLA; AGARWAL, RAJESH

    2015-01-01

    Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcita...

  7. Molecular epidemiology is becoming complex under the dynamic HIV prevalence: The perspective from Harbin, China.

    Science.gov (United States)

    Shao, Bing; Song, Bo; Cao, Lijun; Du, Juan; Sun, Dongying; Lin, Yuanlong; Wang, Binyou; Wang, Fuxiang; Wang, Sunran

    2016-05-01

    Unlike most areas of China, HIV transmission via men who have sex with men (MSM) is increasing rapidly, and has become the main route of HIV transmission in Harbin city. The purpose of the current study was to elaborate the molecular epidemiologic characteristics of the new HIV epidemic. Eighty-one HIV-1 gag gene sequences (HXB2:806-1861) from local HIV infections were isolated; CRF01_AE predominated among HIV infections (71.6%), followed by subtype B (16.5%), CRF07_BC (6.2%), and unique recombinant strains (URFs; 6.2%). URFs were most often identified in the MSM population, which consisted of a recombination of CRF01_AE with subtype B or CRF07_BC. Six clusters were formed in this analysis; clusters I and II mainly circulated in southwest China. Clusters III and IV mainly circulated in southwest, southeast, and central China. Clusters V and VI mainly circulated in north and northeast China. Clusters III and IV may facilitate the transmission of the CRF01_AE strain from the southwest to the north and northeast regions of China. HIV subtypes are becoming diverse with the persistent epidemic in this geographic region. In brief, our results indicate that the molecular epidemiology of HIV is trending to be more complex. Thus, timely molecular epidemiologic supervision of HIV is necessary, especially for the MSM population. © 2015 Wiley Periodicals, Inc.

  8. Dynamical basis set

    International Nuclear Information System (INIS)

    Blanco, M.; Heller, E.J.

    1985-01-01

    A new Cartesian basis set is defined that is suitable for the representation of molecular vibration-rotation bound states. The Cartesian basis functions are superpositions of semiclassical states generated through the use of classical trajectories that conform to the intrinsic dynamics of the molecule. Although semiclassical input is employed, the method becomes ab initio through the standard matrix diagonalization variational method. Special attention is given to classical-quantum correspondences for angular momentum. In particular, it is shown that the use of semiclassical information preferentially leads to angular momentum eigenstates with magnetic quantum number Vertical BarMVertical Bar equal to the total angular momentum J. The present method offers a reliable technique for representing highly excited vibrational-rotational states where perturbation techniques are no longer applicable

  9. Enzymatic synthesis of RNAs capped with nucleotide analogues reveals the molecular basis for substrate selectivity of RNA capping enzyme: impacts on RNA metabolism.

    Directory of Open Access Journals (Sweden)

    Moheshwarnath Issur

    Full Text Available RNA cap binding proteins have evolved to specifically bind to the N7-methyl guanosine cap structure found at the 5' ends of eukaryotic mRNAs. The specificity of RNA capping enzymes towards GTP for the synthesis of this structure is therefore crucial for mRNA metabolism. The fact that ribavirin triphosphate was described as a substrate of a viral RNA capping enzyme, raised the possibility that RNAs capped with nucleotide analogues could be generated in cellulo. Owing to the fact that this prospect potentially has wide pharmacological implications, we decided to investigate whether the active site of the model Paramecium bursaria Chlorella virus-1 RNA capping enzyme was flexible enough to accommodate various purine analogues. Using this approach, we identified several key structural determinants at each step of the RNA capping reaction and generated RNAs harboring various different cap analogues. Moreover, we monitored the binding affinity of these novel capped RNAs to the eIF4E protein and evaluated their translational properties in cellulo. Overall, this study establishes a molecular rationale for the specific selection of GTP over other NTPs by RNA capping enzyme It also demonstrates that RNAs can be enzymatically capped with certain purine nucleotide analogs, and it also describes the impacts of modified RNA caps on specific steps involved in mRNA metabolism. For instance, our results indicate that the N7-methyl group of the classical N7-methyl guanosine cap is not always indispensable for binding to eIF4E and subsequently for translation when compensatory modifications are present on the capped residue. Overall, these findings have important implications for our understanding of the molecular determinants involved in both RNA capping and RNA metabolism.

  10. Distinguishing commercially grown Ganoderma lucidum from Ganoderma lingzhi from Europe and East Asia on the basis of morphology, molecular phylogeny, and triterpenic acid profiles.

    Science.gov (United States)

    Hennicke, Florian; Cheikh-Ali, Zakaria; Liebisch, Tim; Maciá-Vicente, Jose G; Bode, Helge B; Piepenbring, Meike

    2016-07-01

    In China and other countries of East Asia, so-called Ling-zhi or Reishi mushrooms are used in traditional medicine since several centuries. Although the common practice to apply the originally European name 'Ganoderma lucidum' to these fungi has been questioned by several taxonomists, this is still generally done in recent publications and with commercially cultivated strains. In the present study, two commercially sold strains of 'G. lucidum', M9720 and M9724 from the company Mycelia bvba (Belgium), are compared for their fruiting body (basidiocarp) morphology combined with molecular phylogenetic analyses, and for their secondary metabolite profile employing an ultra-performance liquid chromatography-electrospray ionization mass spectrometry (UPLC-ESIMS) in combination with a high resolution electrospray ionization mass spectrometry (HR-ESI-MS). According to basidiocarp morphology, the strain M9720 was identified as G. lucidum s.str. whereas M9724 was determined as Ganoderma lingzhi. In molecular phylogenetic analyses, the M9720 ITS and beta-tubulin sequences grouped with sequences of G. lucidum s.str. from Europe whereas those from M9724 clustered with sequences of G. lingzhi from East Asia. We show that an ethanol extract of ground basidiocarps from G. lucidum (M9720) contains much less triterpenic acids than found in the extract of G. lingzhi (M9724). The high amount of triterpenic acids accounts for the bitter taste of the basidiocarps of G. lingzhi (M9724) and of its ethanol extract. Apparently, triterpenic acids of G. lucidum s.str. are analyzed here for the first time. These results demonstrate the importance of taxonomy for commercial use of fungi. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Exploring the molecular mechanisms underlying the potentiation of exogenous growth hormone on alcohol-induced fatty liver diseases in mice

    Directory of Open Access Journals (Sweden)

    Tian Ya-ping

    2010-11-01

    Full Text Available Abstract Background Growth hormone (GH is an essential regulator of intrahepatic lipid metabolism by activating multiple complex hepatic signaling cascades. Here, we examined whether chronic exogenous GH administration (via gene therapy could ameliorate liver steatosis in animal models of alcoholic fatty liver disease (AFLD and explored the underlying molecular mechanisms. Methods Male C57BL/6J mice were fed either an alcohol or a control liquid diet with or without GH therapy for 6 weeks. Biochemical parameters, liver histology, oxidative stress markers, and serum high molecular weight (HMW adiponectin were measured. Quantitative real-time PCR and western blotting were also conducted to determine the underlying molecular mechanism. Results Serum HMW adiponectin levels were significantly higher in the GH1-treated control group than in the control group (3.98 ± 0.71 μg/mL vs. 3.07 ± 0.55 μg/mL; P P P P P Conclusions GH therapy had positive effects on AFLD and may offer a promising approach to prevent or treat AFLD. These beneficial effects of GH on AFLD were achieved through the activation of the hepatic adiponectin-SIRT1-AMPK and PPARα-AMPK signaling systems.

  12. Yield, Esterification Degree and Molecular Weight Evaluation of Pectins Isolated from Orange and Grapefruit Peels under Different Conditions

    Science.gov (United States)

    Sayah, Mohamed Yassine; Chabir, Rachida; Benyahia, Hamid; Rodi Kandri, Youssef; Ouazzani Chahdi, Fouad; Touzani, Hanan; Errachidi, Faouzi

    2016-01-01

    Orange (Citrus sinensis) and grapefruit (Citrus paradise) peels were used as a source of pectin, which was extracted under different conditions. The peels are used under two states: fresh and residual (after essential oil extraction). Organic acid (citric acid) and mineral acid (sulfuric acid) were used in the pectin extraction. The aim of this study is the evaluation the effect of extraction conditions on pectin yield, degree of esterification “DE” and on molecular weight “Mw”. Results showed that the pectin yield was higher using the residual peels. Moreover, both peels allow the obtainment of a high methoxyl pectin with DE >50%. The molecular weight was calculated using Mark-Houwink-Sakurada equation which describes its relationship with intrinsic viscosity. This later was determined using four equations; Huggins equation, kramer, Schulz-Blaschke and Martin equation. The molecular weight varied from 1.538 x1005 to 2.47x1005 g/mol for grapefruit pectin and from 1.639 x1005 to 2.471 x1005 g/mol for orange pectin. PMID:27644093

  13. Molecular mechanism of catalase activity change under sodium dodecyl sulfate-induced oxidative stress in the mouse primary hepatocytes.

    Science.gov (United States)

    Wang, Jing; Wang, Jiaxi; Xu, Chi; Liu, Rutao; Chen, Yadong

    2016-04-15

    Sodium dodecyl sulfate (SDS) contributes to adverse effects of organisms probably because of its ability to induce oxidative stress via changing the activity of antioxidant enzyme catalase (CAT). But the underlying molecular mechanisms still remain unclear. This study characterized the harmful effects of SDS-induced oxidative stress on the mouse primary hepatocytes as well as the structure and function of CAT molecule and investigated the underlying molecular mechanism. After 12h SDS (0.1μM to 0.2mM) exposure, no significant change was observed in CAT activity of the hepatocytes. After 0.5 and 0.8mM SDS exposure, the state of oxidative stress stimulated CAT production in the hepatocytes. The inhibition of CAT activity induced by directly interacting with SDS was unable to catch the synthesis of CAT and therefore resulted in the increased activity and elevated ROS level. Further molecular experiments showed that SDS prefers to bind to the interface with no direct effect on the active site and the structure of heme groups of CAT molecule. When the sites in the interface is saturated, SDS interacts with VAL 73, HIS 74, ASN 147 and PHE 152, the key residues of the enzyme activity, and leads to the decrease of CAT activity. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Understanding DNA Under Oxidative Stress and Sensitization: The Role of Molecular Modeling

    Directory of Open Access Journals (Sweden)

    Antonio eMonari

    2015-07-01

    Full Text Available DNA is constantly exposed to damaging threats coming from oxidative stress, i.e. from the presence of free radicals and reactive oxygen species. Sensitization from exogenous and endogenous compounds that strongly enhance the frequency of light-induced lesions also plays an important role. The experimental determination of DNA lesions, though a difficult subject, is somehow well established and allows to elucidate even extremely rare DNA lesions. In parallel, molecular modeling has become fundamental to clearly understand the fine mechanisms related to DNA defects induction. Indeed, it offers an unprecedented possibility to get access to an atomistic or even electronic resolution. Ab initio molecular dynamics may also describe the time-evolution of the molecular system and its reactivity. Yet the modeling of DNA (photo-reactions does necessitate elaborate multi-scale methodologies to tackle a damage induction reactivity that takes place in a complex environment. The double-stranded DNA environment is first characterized by a very high flexibility, that dynamical effects are to be taken into account, but also a strongly inhomogeneous electrostatic embedding. Additionally, one aims at capturing more subtle effects, such as the sequence selectivity which is of critical important for DNA damage. The structure and dynamics of the DNA/sensitizers complexes, as well as the photo-induced electron- and energy-transfer phenomena taking place upon sensitization, should be carefully modeled. Finally the factors inducing different repair ratios for different lesions should also be rationalized.In this review we will critically analyze the different computational strategies used to model DNA lesions. A clear picture of the complex interplay between reactivity and structural factors will be sketched. The use of proper multi-scale modeling leads to the in-depth comprehension of DNA lesions mechanism and also to the rational design of new chemo-therapeutic agents.

  15. Molecular and cell-based therapies for muscle degenerations: a road under construction.

    Science.gov (United States)

    Berardi, Emanuele; Annibali, Daniela; Cassano, Marco; Crippa, Stefania; Sampaolesi, Maurilio

    2014-01-01

    Despite the advances achieved in understanding the molecular biology of muscle cells in the past decades, there is still need for effective treatments of muscular degeneration caused by muscular dystrophies and for counteracting the muscle wasting caused by cachexia or sarcopenia. The corticosteroid medications currently in use for dystrophic patients merely help to control the inflammatory state and only slightly delay the progression of the disease. Unfortunately, walkers and wheel chairs are the only options for such patients to maintain independence and walking capabilities until the respiratory muscles become weak and the mechanical ventilation is needed. On the other hand, myostatin inhibition, IL-6 antagonism and synthetic ghrelin administration are examples of promising treatments in cachexia animal models. In both dystrophies and cachectic syndrome the muscular degeneration is extremely relevant and the translational therapeutic attempts to find a possible cure are well defined. In particular, molecular-based therapies are common options to be explored in order to exploit beneficial treatments for cachexia, while gene/cell therapies are mostly used in the attempt to induce a substantial improvement of the dystrophic muscular phenotype. This review focuses on the description of the use of molecular administrations and gene/stem cell therapy to treat muscular degenerations. It reviews previous trials using cell delivery protocols in mice and patients starting with the use of donor myoblasts, outlining the likely causes for their poor results and briefly focusing on satellite cell studies that raise new hope. Then it proceeds to describe recently identified stem/progenitor cells, including pluripotent stem cells and in relationship to their ability to home within a dystrophic muscle and to differentiate into skeletal muscle cells. Different known features of various stem cells are compared in this perspective, and the few available examples of their use in

  16. Molecular mechanisms underlying the regulation of brain-derived neurotrophic factor (BDNF) translation in dendrites

    OpenAIRE

    Pinheiro, Vera Lúcia Margarido

    2010-01-01

    Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra A especificidade espacial e temporal subjacente à diversidade de processos de plasticidade sináptica que ocorrem no sistema nervoso central está profundamente relacionada com a disponibilidade da proteína brain-derived neurotrophic factor (BDNF) em domínios sub-celulares distintos, especialmente na área pós-sinápti...

  17. Investigation of tribological properties of graphene oxide reinforced ultrahigh molecular weight polyethylene under artificial seawater lubricating condition

    Science.gov (United States)

    Pang, Wenchao; Ni, Zifeng; Wu, JiaLiang; Zhao, Yongwu

    2018-03-01

    A range of ultrahigh molecular weight polyethylene (UHMWPE)/graphene oxide (GO) nanocomposites were fabricated using liquid-phase ultrasonication mixing followed by hot-pressing. The wettability, water absorption and corrosion resistance of composites were studied to prove the composites were suitable for application in liquid environment. The tribological properties of composites under dry, deionized water and seawater lubricating condition were investigated. The results showed that the incorporation of GO decreased the wear rate of UHMWPE under different lubricating conditions and with the increase of GO addition, the wear rate of UHMWPE/GO composites decreased. UHMWPE/GO composites exhibited better tribological behaviors under seawater lubricating condition than other conditions, because good corrosion resistance and excellent wear resistance of UHMWPE/GO composites, and the lubricating effect of seawater is also indispensable.

  18. Crystal Structure of the Homo sapiens Kynureninase-3-Hydroxyhippuric Acid Inhibitor Complex: Insights into the Molecular Basis Of Kynureninase Substrate Specificity

    Energy Technology Data Exchange (ETDEWEB)

    Lima,Santiago; Kumar,Sunil; Gawandi,Vijay; Momany,Cory; Phillips,Robert S.; (Georgia)

    2009-02-23

    Homo sapiens kynureninase is a pyridoxal-5'-phosphate dependent enzyme that catalyzes the hydrolytic cleavage of 3-hydroxykynurenine to yield 3-hydroxyanthranilate and L-alanine as part of the tryptophan catabolic pathway leading to the de novo biosynthesis of NAD{sup +}. This pathway results in quinolinate, an excitotoxin that is an NMDA receptor agonist. High levels of quinolinate have been correlated with the etiology of neurodegenerative disorders such as AIDS-related dementia and Alzheimer's disease. We have synthesized a novel kynureninase inhibitor, 3-hydroxyhippurate, cocrystallized it with human kynureninase, and solved the atomic structure. On the basis of an analysis of the complex, we designed a series of His-102, Ser-332, and Asn-333 mutants. The H102W/N333T and H102W/S332G/N333T mutants showed complete reversal of substrate specificity between 3-hydroxykynurenine and L-kynurenine, thus defining the primary residues contributing to substrate specificity in kynureninases.

  19. Molecular analysis of aspermic Fasciola flukes from Korea on the basis of the nuclear ITS1 region and mitochondrial DNA markers and comparison with Japanese aspermic Fasciola flukes.

    Science.gov (United States)

    Ichikawa, Madoka; Itagaki, Tadashi

    2012-07-01

    It has been speculated that populations of aspermic Fasciola flukes in Korea and Japan have a close phylogenetic relationship. To evaluate this, we analyzed 33 Korean aspermic Fasciola flukes on the basis of nuclear ribosomal internal transcribed spacer 1 (ITS1) and mitochondrial NADH dehydrogenase subunit 1 (nad1) and cytochrome c oxidase 1 (cox1) sequences. Fh, Fg, and Fh/Fg types were detected in the ITS1 region and displayed the fragment patterns of F. hepatica, F. gigantica, and both species, respectively by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Additionally, three concatenated haplotypes of nad1 and cox1(nad1/cox1) were detected, and 2 of these, Kor1/Kor1 (Fsp1/Fsp1) haplotype and Kor2a/Kor2 (Fsp2/Fsp2) haplotype, were shared by Korean and Japanese aspermic flukes. The Fst value (0.019), calculated using the concatenated sequences, indicated that Korean and Japanese aspermic Fasciola populations were genetically undifferentiated. Interestingly, a combination of the Fh/Fg type and Kor1/Kor1 haplotype was found at the highest frequency in Korean aspermic flukes, whereas the Fg type and Fsp2/Fsp2 haplotype combination was found at a conspicuously high frequency in Japanese aspermic flukes. This indicates that a founder effect caused by the introduction of infected hosts may have played a key role in the introduction of aspermic Fasciola flukes from Korea into Japan.

  20. Molecular basis of substrate promiscuity for the SAM-dependent O-methyltransferase NcsB1, involved in the biosynthesis of the enediyne antitumor antibiotic neocarzinostatin.

    Science.gov (United States)

    Cooke, Heather A; Guenther, Elizabeth L; Luo, Yinggang; Shen, Ben; Bruner, Steven D

    2009-10-13

    The small molecule component of chromoprotein enediyne antitumor antibiotics is biosynthesized through a convergent route, incorporating amino acid, polyketide, and carbohydrate building blocks around a central enediyne hydrocarbon core. The naphthoic acid moiety of the enediyne neocarzinostatin plays key roles in the biological activity of the natural product by interacting with both the carrier protein and duplex DNA at the site of action. We have previously described the in vitro characterization of an S-adenosylmethionine-dependent O-methyltransferase (NcsB1) in the neocarzinostatin biosynthetic pathway [Luo, Y., Lin, S., Zhang, J., Cooke, H. A., Bruner, S. D., and Shen, B. (2008) J. Biol. Chem. 283, 14694-14702]. Here we provide a structural basis for NcsB1 activity, illustrating that the enzyme shares an overall architecture with a large family of S-adenosylmethionine-dependent proteins. In addition, NcsB1 represents the first enzyme to be structurally characterized in the biosynthetic pathway of neocarzinostatin. By cocrystallizing the enzyme with various combinations of the cofactor and substrate analogues, details of the active site structure have been established. Changes in subdomain orientation were observed via comparison of structures in the presence and absence of substrate, suggesting that reorientation of the enzyme is involved in binding of the substrate. In addition, residues important for substrate discrimination were predicted and probed through site-directed mutagenesis and in vitro biochemical characterization.

  1. Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer

    Directory of Open Access Journals (Sweden)

    Marzena Wojcik

    2018-01-01

    Full Text Available The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane, a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa, has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.

  2. Cellular Molecular Changes in Nerium oleander (L.) Cell Culture Under Gamma Radiation Stress

    International Nuclear Information System (INIS)

    Salama, I.M.; Abd EL-Megid, M.H.M.

    2017-01-01

    This study was done to analyze the relationship between the various effects of five different doses of gamma ray treatments (control, 0, 100, 200, 300 and 400 rad) on cell suspension culture of Nerium oleander belonging to the family Apocynaceae, Plant samples were collected from Egyptian flora. The five treatments of the plants were characterized by analyzing variability in frozen biomass cell suspension culture of N. oleander through SDS PAGE and peroxidase is ozymes. The electrophorogram showed a total of 36 bands of proteins with molecular weight ranging from 10 to 225 KDa. The protein diversity analysis was done based on the presence or the absence of bands trhus interpreting their relevance. The his togram analysis clearly showed a high degree of diversity a long these five treatments of the plant. The results of electrophoretic patterns of peroxidase is ozymes that was extracted from frozen biomass cell suspension cultures after receiving the different gamma doses revealed remarkable molecular changes in all treatments. These changes in peroxidase isozymes and protein bands indicate the effect of the different irradiation treatments on the gene expiration

  3. Radiation-induced enteropathy: Molecular basis of pentoxifylline–vitamin E anti-fibrotic effect involved TGF-β1 cascade inhibition

    International Nuclear Information System (INIS)

    Hamama, Saad; Gilbert-Sirieix, Marie; Vozenin, Marie-Catherine; Delanian, Sylvie

    2012-01-01

    Background: Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline–vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored. Methods: Ten patients suffering from radiation-induced enteropathy were treated with pentoxifylline–vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-β1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry. Results: Pentoxifylline–vitamin E combination induces regression of symptoms (SOMA) by −41% and −80% at 6 and 18 months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-β1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-β1/Smad targets (Col Iα1, FN1, PAI-1, CTGF), while it has no effect on the Rho/ROCK pathway. Conclusions: The anti-fibrotic effect of combined pentoxifylline–vitamin E is at least in part mediated by inhibition of the TGF-β1 cascade. It strengthens previous clinical data showing pentoxifylline–vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis.

  4. Adaptive response to mutagenesis and its molecular basis in a human T-cell leukemia line primed with a low dose of γ-rays

    International Nuclear Information System (INIS)

    Zhou, P.K.; Xiang, X.Q.; Sun, W.Z.; Liu, X.Y.; Zhang, Y.P.; Wei, K.

    1994-01-01

    The effect was studied of a low dose of γ-ray preexposure on the frequency and molecular spectrum of radiation-induced mutations at the hprt locus in a human T-cell leukemia line. When the cells were preexposed to 0.01 Gy of γ-rays, the yield of mutations induced by a subsequent 2-Gy challenge dose was reduced by 60%, compared with the 2 Gy of irradiation alone. The data of Southern blot analysis showed that 47% of the mutants induced by 2 Gy in the cells without low-dose preexposure were of the deletion or rearranged mutations type. In contrast, in the low-dose radioadapted cells the proportion of this type of 2-Gy-induced mutations decreased to 28%. This is close to the control level (22%) of spontaneous mutations. Our results confirm that a low dose of γ-ray preexposure leads to a decreased susceptibility to gene deletions and rearrangements after high-dose irradiation. (orig.)

  5. Insights into the molecular basis for substrate binding and specificity of the wild-type L-arginine/agmatine antiporter AdiC.

    Science.gov (United States)

    Ilgü, Hüseyin; Jeckelmann, Jean-Marc; Gapsys, Vytautas; Ucurum, Zöhre; de Groot, Bert L; Fotiadis, Dimitrios

    2016-09-13

    Pathogenic enterobacteria need to survive the extreme acidity of the stomach to successfully colonize the human gut. Enteric bacteria circumvent the gastric acid barrier by activating extreme acid-resistance responses, such as the arginine-dependent acid resistance system. In this response, l-arginine is decarboxylated to agmatine, thereby consuming one proton from the cytoplasm. In Escherichia coli, the l-arginine/agmatine antiporter AdiC facilitates the export of agmatine in exchange of l-arginine, thus providing substrates for further removal of protons from the cytoplasm and balancing the intracellular pH. We have solved the crystal structures of wild-type AdiC in the presence and absence of the substrate agmatine at 2.6-Å and 2.2-Å resolution, respectively. The high-resolution structures made possible the identification of crucial water molecules in the substrate-binding sites, unveiling their functional roles for agmatine release and structure stabilization, which was further corroborated by molecular dynamics simulations. Structural analysis combined with site-directed mutagenesis and the scintillation proximity radioligand binding assay improved our understanding of substrate binding and specificity of the wild-type l-arginine/agmatine antiporter AdiC. Finally, we present a potential mechanism for conformational changes of the AdiC transport cycle involved in the release of agmatine into the periplasmic space of E. coli.

  6. The Seminal fluid proteome of the polyandrous Red junglefowl offers insights into the molecular basis of fertility, reproductive ageing and domestication.

    Science.gov (United States)

    Borziak, Kirill; Álvarez-Fernández, Aitor; L Karr, Timothy; Pizzari, Tommaso; Dorus, Steve

    2016-11-02

    Seminal fluid proteins (SFPs) are emerging as fundamental contributors to sexual selection given their role in post-mating reproductive events, particularly in polyandrous species where the ejaculates of different males compete for fertilisation. SFP identification however remains taxonomically limited and little is known about avian SFPs, despite extensive work on sexual selection in birds. We characterize the SF proteome of the polyandrous Red junglefowl, Gallus gallus, the wild species that gave rise to the domestic chicken. We identify 1,141 SFPs, including proteins involved in immunity and antimicrobial defences, sperm maturation, and fertilisation, revealing a functionally complex SF proteome. This includes a predominant contribution of blood plasma proteins that is conserved with human SF. By comparing the proteome of young and old males with fast or slow sperm velocity in a balanced design, we identify proteins associated with ageing and sperm velocity, and show that old males that retain high sperm velocity have distinct proteome characteristics. SFP comparisons with domestic chickens revealed both qualitative and quantitative differences likely associated with domestication and artificial selection. Collectively, these results shed light onto the functional complexity of avian SF, and provide a platform for molecular studies of fertility, reproductive ageing, and domestication.

  7. Thermodynamic properties by equation of state and from Ab initio molecular dynamics of liquid potassium under pressure

    Science.gov (United States)

    Li, Huaming; Tian, Yanting; Sun, Yongli; Li, Mo; Nonequilibrium materials; physics Team; Computational materials science Team

    In this work, we apply a general equation of state of liquid and Ab initio molecular-dynamics method to study thermodynamic properties in liquid potassium under high pressure. Isothermal bulk modulus and molar volume of molten sodium are calculated within good precision as compared with the experimental data. The calculated internal energy data and the calculated values of isobaric heat capacity of molten potassium show the minimum along the isothermal lines as the previous result obtained in liquid sodium. The expressions for acoustical parameter and nonlinearity parameter are obtained based on thermodynamic relations from the equation of state. Both parameters for liquid potassium are calculated under high pressure along the isothermal lines by using the available thermodynamic data and numeric derivations. Furthermore, Ab initio molecular-dynamics simulations are used to calculate some thermodynamic properties of liquid potassium along the isothermal lines. Scientific Research Starting Foundation from Taiyuan university of Technology, Shanxi Provincial government (``100-talents program''), China Scholarship Council and National Natural Science Foundation of China (NSFC) under Grant No. 51602213.

  8. Unraveling the Root Proteome Changes and Its Relationship to Molecular Mechanism Underlying Salt Stress Response in Radish (Raphanus sativus L.

    Directory of Open Access Journals (Sweden)

    Xiaochuan Sun

    2017-07-01

    Full Text Available To understand the molecular mechanism underlying salt stress response in radish, iTRAQ-based proteomic analysis was conducted to investigate the differences in protein species abundance under different salt treatments. In total, 851, 706, and 685 differential abundance protein species (DAPS were identified between CK vs. Na100, CK vs. Na200, and Na100 vs. Na200, respectively. Functional annotation analysis revealed that salt stress elicited complex proteomic alterations in radish roots involved in carbohydrate and energy metabolism, protein metabolism, signal transduction, transcription regulation, stress and defense and transport. Additionally, the expression levels of nine genes encoding DAPS were further verified using RT-qPCR. The integrative analysis of transcriptomic and proteomic data in conjunction with miRNAs was further performed to strengthen the understanding of radish response to salinity. The genes responsible for signal transduction, ROS scavenging and transport activities as well as several key miRNAs including miR171, miR395, and miR398 played crucial roles in salt stress response in radish. Based on these findings, a schematic genetic regulatory network of salt stress response was proposed. This study provided valuable insights into the molecular mechanism underlying salt stress response in radish roots and would facilitate developing effective strategies toward genetically engineered salt-tolerant radish and other root vegetable crops.

  9. Investigating the molecular basis of local adaptation to thermal stress: population differences in gene expression across the transcriptome of the copepod Tigriopus californicus

    Directory of Open Access Journals (Sweden)

    Schoville Sean D

    2012-09-01

    Full Text Available Abstract Background Geographic variation in the thermal environment impacts a broad range of biochemical and physiological processes and can be a major selective force leading to local population adaptation. In the intertidal copepod Tigriopus californicus, populations along the coast of California show differences in thermal tolerance that are consistent with adaptation, i.e., southern populations withstand thermal stresses that are lethal to northern populations. To understand the genetic basis of these physiological differences, we use an RNA-seq approach to compare genome-wide patterns of gene expression in two populations known to differ in thermal tolerance. Results Observed differences in gene expression between the southern (San Diego and the northern (Santa Cruz populations included both the number of affected loci as well as the identity of these loci. However, the most pronounced differences concerned the amplitude of up-regulation of genes producing heat shock proteins (Hsps and genes involved in ubiquitination and proteolysis. Among the hsp genes, orthologous pairs show markedly different thermal responses as the amplitude of hsp response was greatly elevated in the San Diego population, most notably in members of the hsp70 gene family. There was no evidence of accelerated evolution at the sequence level for hsp genes. Among other sets of genes, cuticle genes were up-regulated in SD but down-regulated in SC, and mitochondrial genes were down-regulated in both populations. Conclusions Marked changes in gene expression were observed in response to acute sub-lethal thermal stress in the copepod T. californicus. Although some qualitative differences were observed between populations, the most pronounced differences involved the magnitude of induction of numerous hsp and ubiquitin genes. These differences in gene expression suggest that evolutionary divergence in the regulatory pathway(s involved in acute temperature stress may offer at

  10. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease.

    Science.gov (United States)

    Reiners, Jan; Nagel-Wolfrum, Kerstin; Jürgens, Karin; Märker, Tina; Wolfrum, Uwe

    2006-07-01

    Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. It is clinically and genetically heterogeneous and at least 12 chromosomal loci are assigned to three clinical USH types, namely USH1A-G, USH2A-C, USH3A (Davenport, S.L.H., Omenn, G.S., 1977. The heterogeneity of Usher syndrome. Vth Int. Conf. Birth Defects, Montreal; Petit, C., 2001. Usher syndrome: from genetics to pathogenesis. Annu. Rev. Genomics Hum. Genet. 2, 271-297). Mutations in USH type 1 genes cause the most severe form of USH. In USH1 patients, congenital deafness is combined with a pre-pubertal onset of retinitis pigmentosa (RP) and severe vestibular dysfunctions. Those with USH2 have moderate to severe congenital hearing loss, non-vestibular dysfunction and a later onset of RP. USH3 is characterized by variable RP and vestibular dysfunction combined with progressive hearing loss. The gene products of eight identified USH genes belong to different protein classes and families. There are five known USH1 molecules: the molecular motor myosin VIIa (USH1B); the two cell-cell adhesion cadherin proteins, cadherin 23 (USH1D) and protocadherin 15, (USH1F) and the scaffold proteins, harmonin (USH1C) and SANS (USH1G). In addition, two USH2 genes and one USH3A gene have been identified. The two USH2 genes code for the transmembrane protein USH2A, also termed USH2A ("usherin") and the G-protein-coupled 7-transmembrane receptor VLGR1b (USH2C), respectively, whereas the USH3A gene encodes clarin-1, a member of the clarin family which exhibits 4-transmembrane domains. Molecular analysis of USH1 protein function revealed that all five USH1 proteins are integrated into a protein network via binding to PDZ domains in the USH1C protein harmonin. Furthermore, this scaffold function of harmonin is supported by the USH1G protein SANS. Recently, we have shown that the USH2 proteins USH2A and VLGR1b as well as the candidate for USH2B, the sodium bicarbonate co-transporter NBC3, are also

  11. Molecular mechanisms underlying radio-induced fibro-genic differentiation and fibrosis targeted therapies

    International Nuclear Information System (INIS)

    Bourgier, C.

    2008-01-01

    Intestinal complications after radiotherapy are caused by transmural fibrosis (RIF) that impaired the quality of life of cancer patient survivors and considered permanent and irreversible until recently but recent molecular characterization of RIF offered new targeted opportunities for the development of anti-fibrotic therapies. In this thesis work, we identified activation of the Rho/ROCK pathway which is involved in the persistence of fibro-genic signals. In addition, among the new anti-fibrotic targeted therapies, we asked whether specific inhibition of Rho pathway, by Pravastatin could elicit anti-fibrotic action. Therefore, the therapeutic relevance of pravastatin as anti-fibrotic strategy was validated using two different models of intestinal and lung fibrosis. As statins are safe and well tolerated compounds, phase II clinical trial is envisioned within the next months to reverse established fibrosis after radiotherapy. (author)

  12. Molecular dynamics simulations of irradiation cascades in alpha-zirconium under macroscopic strain

    Energy Technology Data Exchange (ETDEWEB)

    Di, Sali [Department of Mechanical and Materials Engineering, Queen’s University, Kingston, ON, Canada K7L 3N6 (Canada); Yao, Zhongwen, E-mail: yaoz@me.queensu.ca [Department of Mechanical and Materials Engineering, Queen’s University, Kingston, ON, Canada K7L 3N6 (Canada); Daymond, Mark R. [Department of Mechanical and Materials Engineering, Queen’s University, Kingston, ON, Canada K7L 3N6 (Canada); Gao, Fei [Pacific Northwest National Laboratory, Richland, WA 99352 (United States)

    2013-05-15

    Numerous computer simulation studies have been performed on the radiation damage of zirconium. In contrast to most of the work in the literature which has focused on the effects of temperature and recoil energy on defect production and defect clustering, we have developed a computational model to consider the influence of elastic strain field on the formation of defects and their clusters, as strain is commonly present in a real reactor environment. In this work, irradiation induced displacement cascades in alpha-zirconium experiencing a macroscopic strain have been studied by molecular dynamics (MD) simulations using a many-body interatomic potential. The external strain mainly affects the size of defect clusters rather than the total number of defects. The sizes of interstitial and vacancy clusters respond differently to the external strain conditions.

  13. Mechanical properties of stanene under uniaxial and biaxial loading: A molecular dynamics study

    Energy Technology Data Exchange (ETDEWEB)

    Mojumder, Satyajit [Department of Mechanical Engineering, Bangladesh University of Engineering and Technology, Dhaka 1000 (Bangladesh); Amin, Abdullah Al [Department of Mechanical and Aerospace Engineering, Case western Reverse University, Cleveland, Ohio 44106 (United States); Islam, Md Mahbubul, E-mail: mmi122@psu.edu [Department of Mechanical and Nuclear Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802 (United States)

    2015-09-28

    Stanene, a graphene like two dimensional honeycomb structure of tin has attractive features in electronics application. In this study, we performed molecular dynamics simulations using modified embedded atom method potential to investigate mechanical properties of stanene. We studied the effect of temperature and strain rate on mechanical properties of α-stanene for both uniaxial and biaxial loading conditions. Our study suggests that with the increasing temperature, both the fracture strength and strain of the stanene decrease. Uniaxial loading in zigzag direction shows higher fracture strength and strain compared to the armchair direction, while no noticeable variation in the mechanical properties is observed for biaxial loading. We also found at a higher loading rate, material exhibits higher fracture strength and strain. These results will aid further investigation of stanene as a potential nano-electronics substitute.

  14. Magnetic fingerprint of individual Fe4 molecular magnets under compression by a scanning tunnelling microscope

    Science.gov (United States)

    Burgess, Jacob A. J.; Malavolti, Luigi; Lanzilotto, Valeria; Mannini, Matteo; Yan, Shichao; Ninova, Silviya; Totti, Federico; Rolf-Pissarczyk, Steffen; Cornia, Andrea; Sessoli, Roberta; Loth, Sebastian

    2015-09-01

    Single-molecule magnets (SMMs) present a promising avenue to develop spintronic technologies. Addressing individual molecules with electrical leads in SMM-based spintronic devices remains a ubiquitous challenge: interactions with metallic electrodes can drastically modify the SMM's properties by charge transfer or through changes in the molecular structure. Here, we probe electrical transport through individual Fe4 SMMs using a scanning tunnelling microscope at 0.5 K. Correlation of topographic and spectroscopic information permits identification of the spin excitation fingerprint of intact Fe4 molecules. Building from this, we find that the exchange coupling strength within the molecule's magnetic core is significantly enhanced. First-principles calculations support the conclusion that this is the result of confinement of the molecule in the two-contact junction formed by the microscope tip and the sample surface.

  15. Genetic and Molecular Mechanisms Underlying Symbiotic Specificity in Legume-Rhizobium Interactions.

    Science.gov (United States)

    Wang, Qi; Liu, Jinge; Zhu, Hongyan

    2018-01-01

    Legumes are able to form a symbiotic relationship with nitrogen-fixing soil bacteria called rhizobia. The result of this symbiosis is to form nodules on the plant root, within which the bacteria can convert atmospheric nitrogen into ammonia that can be used by the plant. Establishment of a successful symbiosis requires the two symbiotic partners to be compatible with each other throughout the process of symbiotic development. However, incompatibility frequently occurs, such that a bacterial strain is unable to nodulate a particular host plant or forms nodules that are incapable of fixing nitrogen. Genetic and molecular mechanisms that regulate symbiotic specificity are diverse, involving a wide range of host and bacterial genes/signals with various modes of action. In this review, we will provide an update on our current knowledge of how the recognition specificity has evolved in the context of symbiosis signaling and plant immunity.

  16. Molecular basis of perinatal hypophosphatasia with tissue-nonspecific alkaline phosphatase bearing a conservative replacement of valine by alanine at position 406. Structural importance of the crown domain.

    Science.gov (United States)

    Numa, Natsuko; Ishida, Yoko; Nasu, Makiko; Sohda, Miwa; Misumi, Yoshio; Noda, Tadashi; Oda, Kimimitsu

    2008-06-01

    Hypophosphatasia, a congenital metabolic disease related to the tissue-nonspecific alkaline phosphatase gene (TNSALP), is characterized by reduced serum alkaline phosphatase levels and defective mineralization of hard tissues. A replacement of valine with alanine at position 406, located in the crown domain of TNSALP, was reported in a perinatal form of hypophosphatasia. To understand the molecular defect of the TNSALP (V406A) molecule, we examined this missense mutant protein in transiently transfected COS-1 cells and in stable CHO-K1 Tet-On cells. Compared with the wild-type enzyme, the mutant protein showed a markedly reduced alkaline phosphatase activity. This was not the result of defective transport and resultant degradation of TNSALP (V406A) in the endoplasmic reticulum, as the majority of newly synthesized TNSALP (V406A) was conveyed to the Golgi apparatus and incorporated into a cold detergent insoluble fraction (raft) at a rate similar to that of the wild-type TNSALP. TNSALP (V406A) consisted of a dimer, as judged by sucrose gradient centrifugation, suggestive of its proper folding and correct assembly, although this mutant showed increased susceptibility to digestion by trypsin or proteinase K. When purified as a glycosylphosphatidylinositol-anchorless soluble form, the mutant protein exhibited a remarkably lower Kcat/Km value compared with that of the wild-type TNSALP. Interestingly, leucine and isoleucine, but not phenylalanine, were able to substitute for valine, pointing to the indispensable role of residues with a longer aliphatic side chain at position 406 of TNSALP. Taken together, this particular mutation highlights the structural importance of the crown domain with respect to the catalytic function of TNSALP.

  17. Roles of the β 146 histidyl residue in the molecular basis of the Bohr Effect of hemoglobin: A proton nuclear magnetic resonance study

    International Nuclear Information System (INIS)

    Busch, M.R.; Mace, J.E.; Ho, N.T.; Ho, Chien

    1991-01-01

    Assessment of the roles of the carboxyl-terminal β146 histidyl residues in the alkaline Bohr effect in human and normal adult hemoglobin by high-resolution proton nuclear magnetic resonance spectroscopy requires assignment of the resonances corresponding to these residues. By a careful spectroscopic study of human normal adult hemoglobin, enzymatically prepared des(His146β)-hemoglobin, and the mutant hemoglobins Cowtown (β146His → Leu) and York (β146His → Pro), the authors have resolved some of these conflicting results. By a close incremental variation of pH over a wide range in chloride-free 0.1 M N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid buffer, a single resonance has been found to be consistently missing in the proton nuclear magnetic resonance spectra of these hemoglobin variants. The results indicate that the contribution of the β146 histidyl residues is 0.52 H + /hemoglobin tetramer at pH 7.6, markedly less than 0.8 H + /hemoglobin tetramer estimated by study of the mutant hemoglobin Cowtown (β146His → Leu) by Shih and Perutz. They have found that at least two histidyl residues in the carbonmonoxy form of this mutant have pK values that are perturbed, and they suggest that these pK differences may in part account for this discrepancy. The results show that the pK values of β146 histidyl residues in the carbonmonoxy form of hemoglobin are substantially affected by the presence of chloride and other anions in the solvent, and thus, the contribution of this amino acid residue to the alkaline Bohr effect can be shown to vary widely in magnitude, depending on the solvent composition. These results demonstrate that the detailed molecular mechanisms of the alkaline Bohr effect are not unique but are affected both by the hemoglobin structure and by the interactions with the solvent components in which the hemoglobin molecule resides

  18. Multishell structure formation in Ni nanowire under uniaxial strain along <0 0 1> crystallographic direction: A molecular dynamics simulation

    Energy Technology Data Exchange (ETDEWEB)

    Wang Li, E-mail: wanglihxf@sdu.edu.c [School of Mechanical and Electrical Engineering, Shandong University at Weihai, 180 Wenhuaxi Road, Weihai 264209 (China); Peng Chuanxiao [Key Laboratory of Liquid Structure and Heredity of Materials, Ministry of Education, Shandong University, Jinan 250061 (China); Gong Jianhong [School of Mechanical and Electrical Engineering, Shandong University at Weihai, 180 Wenhuaxi Road, Weihai 264209 (China)

    2010-04-01

    Molecular dynamics simulations based upon embedded-atom-method potential are employed to explore the fracture behavior of Ni nanowire along <0 0 1> crystallographic direction at temperature of 300 K. We find the formation of (5,5) multishell structure (MS), which is transformed from (6,5) MS at the necking region of nanowire under the strain rate of 0.02%ps{sup -1}. A reorientation transformation from <0 0 1> to <1 1 0> is first detected before formation of (6,5) MS. The formed (5,5) MS is more stable and can be tensioned longer as lower strain rate is loaded.

  19. Reconstructing genealogies of serial samples under the assumption of a molecular clock using serial-sample UPGMA.

    Science.gov (United States)

    Drummond, A; Rodrigo, A G

    2000-12-01

    Reconstruction of evolutionary relationships from noncontemporaneous molecular samples provides a new challenge for phylogenetic reconstruction methods. With recent biotechnological advances there has been an increase in molecular sequencing throughput, and the potential to obtain serial samples of sequences from populations, including rapidly evolving pathogens, is fast being realized. A new method called the serial-sample unweighted pair grouping method with arithmetic means (sUPGMA) is presented that reconstructs a genealogy or phylogeny of sequences sampled serially in time using a matrix of pairwise distances. The resulting tree depicts the terminal lineages of each sample ending at a different level consistent with the sample's temporal order. Since sUPGMA is a variant of UPGMA, it will perform best when sequences have evolved at a constant rate (i.e., according to a molecular clock). On simulated data, this new method performs better than standard cluster analysis under a variety of longitudinal sampling strategies. Serial-sample UPGMA is particularly useful for analysis of longitudinal samples of viruses and bacteria, as well as ancient DNA samples, with the minimal requirement that samples of sequences be ordered in time.

  20. Morphological and molecular features of some freshwater prawn species under genus Macrobrachium Spence Bate, 1868 (Crustacea: Decapoda: Palaemonidae) from Myanmar.

    Science.gov (United States)

    Mar, Win; Kang, Peng-Fei; Mao, Bin; Wang, Yu-Feng

    2018-02-28

    Myanmar is abundant in lakes and rivers, yet only a few investigations on the fauna of shrimps and prawns have been conducted and no molecular characteristics of prawn species have been described. This study reveals the morphologically identification of five freshwater prawn species under the genus Macrobrachium, including M. cavernicola, M. australiense, M. johnsoni, M. josephi and Macrobrachium sp.WMY-2017. As there was no previous record and information concerning with M. australiense, M. johnsoni, M. josephi and Macrobrachium sp. WMY-2017, they were regarded as the first record from Myanmar. A fragment of Mitochondrial Cytochrome Oxidase I Gene (COI) was amplified successfully from three studied species: M. australiense, M. josephi, and Macrobrachium sp.WMY-2017. The interspecific divergences of studied species varied from 0.01 to 0.15. The phylogenetic tree based on COI fragment sequences showed that M. australiense was closely related to M. rosenbergii, while Macrobrachium sp. WMY-2017 was closest to M. josephi. The results of molecular phylogeny has clarified the relationship within the genus Macrobrachium and represents the first step toward understanding the pattern of speciation base on molecular approach in Myanmar.

  1. Computational Analysis of Molecular Interaction Networks Underlying Change of HIV-1 Resistance to Selected Reverse Transcriptase Inhibitors.

    Science.gov (United States)

    Kierczak, Marcin; Dramiński, Michał; Koronacki, Jacek; Komorowski, Jan

    2010-12-12

    Despite more than two decades of research, HIV resistance to drugs remains a serious obstacle in developing efficient AIDS treatments. Several computational methods have been developed to predict resistance level from the sequence of viral proteins such as reverse transcriptase (RT) or protease. These methods, while powerful and accurate, give very little insight into the molecular interactions that underly acquisition of drug resistance/hypersusceptibility. Here, we attempt at filling this gap by using our Monte Carlo feature selection and interdependency discovery method (MCFS-ID) to elucidate molecular interaction networks that characterize viral strains with altered drug resistance levels. We analyzed a number of HIV-1 RT sequences annotated with drug resistance level using the MCFS-ID method. This let us expound interdependency networks that characterize change of drug resistance to six selected RT inhibitors: Abacavir, Lamivudine, Stavudine, Zidovudine, Tenofovir and Nevirapine. The networks consider interdependencies at the level of physicochemical properties of mutating amino acids, eg,: polarity. We mapped each network on the 3D structure of RT in attempt to understand the molecular meaning of interacting pairs. The discovered interactions describe several known drug resistance mechanisms and, importantly, some previously unidentified ones. Our approach can be easily applied to a whole range of problems from the domain of protein engineering. A portable Java implementation of our MCFS-ID method is freely available for academic users and can be obtained at: http://www.ipipan.eu/staff/m.draminski/software.htm.

  2. Noncanonical structures and their thermodynamics of DNA and RNA under molecular crowding: beyond the Watson-Crick double helix.

    Science.gov (United States)

    Sugimoto, Naoki

    2014-01-01

    How does molecular crowding affect the stability of nucleic acid structures inside cells? Water is the major solvent component in living cells, and the properties of water in the highly crowded media inside cells differ from that in buffered solution. As it is difficult to measure the thermodynamic behavior of nucleic acids in cells directly and quantitatively, we recently developed a cell-mimicking system using cosolutes as crowding reagents. The influences of molecular crowding on the structures and thermodynamics of various nucleic acid sequences have been reported. In this chapter, we discuss how the structures and thermodynamic properties of nucleic acids differ under various conditions such as highly crowded environments, compartment environments, and in the presence of ionic liquids, and the major determinants of the crowding effects on nucleic acids are discussed. The effects of molecular crowding on the activities of ribozymes and riboswitches on noncanonical structures of DNA- and RNA-like quadruplexes that play important roles in transcription and translation are also described. © 2014 Elsevier Inc. All rights reserved.

  3. Transcription factors and molecular epigenetic marks underlying EpCAM overexpression in ovarian cancer

    NARCIS (Netherlands)

    van der Gun, B. T. F.; de Groote, M. L.; Kazemier, H. G.; Arendzen, A. J.; Terpstra, P.; Ruiters, M. H. J.; McLaughlin, P. M. J.; Rots, M. G.

    2011-01-01

    BACKGROUND: The epithelial cell adhesion molecule (EpCAM) is overexpressed on carcinomas, and its downregulation inhibits the oncogenic potential of multiple tumour types. Here, we investigated underlying mechanisms of epcam overexpression in ovarian carcinoma. METHODS: Expression of EpCAM and DNA

  4. Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs

    DEFF Research Database (Denmark)

    Francavilla, Chiara; Rigbolt, Kristoffer T.G.; Emdal, Kristina B

    2013-01-01

    The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferation...

  5. The neural basis of emotions varies over time: different regions go with onset- and offset-bound processes underlying emotion intensity.

    Science.gov (United States)

    Résibois, Maxime; Verduyn, Philippe; Delaveau, Pauline; Rotgé, Jean-Yves; Kuppens, Peter; Van Mechelen, Iven; Fossati, Philippe

    2017-08-01

    According to theories of emotion dynamics, emotions unfold across two phases in which different types of processes come to the fore: emotion onset and emotion offset. Differences in onset-bound processes are reflected by the degree of explosiveness or steepness of the response at onset, and differences in offset-bound processes by the degree of accumulation or intensification of the subsequent response. Whether onset- and offset-bound processes have distinctive neural correlates and, hence, whether the neural basis of emotions varies over time, still remains unknown. In the present fMRI study, we address this question using a recently developed paradigm that allows to disentangle explosiveness and accumulation. Thirty-one participants were exposed to neutral and negative social feedback, and asked to reflect on its contents. Emotional intensity while reading and thinking about the feedback was measured with an intensity profile tracking approach. Using non-negative matrix factorization, the resulting profile data were decomposed in explosiveness and accumulation components, which were subsequently entered as continuous regressors of the BOLD response. It was found that the neural basis of emotion intensity shifts as emotions unfold over time with emotion explosiveness and accumulation having distinctive neural correlates. © The Author (2017). Published by Oxford University Press.

  6. Nutritional Proteomics: Investigating molecular mechanisms underlying the health beneficial effect of functional foods

    Directory of Open Access Journals (Sweden)

    Yusuke Kawashima

    2013-07-01

    Full Text Available ABSTRACTObjective: We introduce a new technical and conceptual term “nutritional proteomics” by identifying and quantifying the proteins and their changes in a certain organ or tissue dependent on the food intake by utilizing a mass spectrometry-based proteomics technique.Purpose: Food intake is essentially important for every life on earth to sustain the physical as well as mental functions. The outcome of food intake will be manifested in the health state and its dysfunction. The molecular information about the protein expression change caused by diets will assist us to understand the significance of functional foods. We wish to develop nutritional proteomics to promote a new area in functional food studies for a better understanding of the role of functional foods in health and disease.Methods: We chose two classes of food ingredients to show the feasibility of nutritional proteomics, omega-3 polyunsaturated fatty acids and omega-6 polyunsaturated fatty acids both of which are involved in the inflammation/anti-inflammation axis. Each class of the polyunsaturated fatty acids was mixed in mouse chow respectively. The liver tissue of mice fed with omega-3 diet or omega-3 diet was analyzed by the state-of-the-art shotgun proteomics using nano-HPLC-ESI-MS/MS. The data were analyzed by the number of differentially expressed proteins that were guaranteed by 1% false discovery rate for protein identification and by the statistical significance of variance evaluated by p-value in two-tailed distribution analysis better than 0.05 (n=4. The differential pattern of protein expression was characterized with Gene Ontology designation.Results: The data analysis of the shotgun nutritional proteomics identified 2,810 proteins that are validated with 1% FDR. Among these 2,810 proteins, 125 were characterized with statistical significance of variance (p<0.05; n=4 between the omega-3 diet and the omega-6 diet by twotailed distribution analysis. The results

  7. A theoretical study of molecular structure, optical properties and bond activation of energetic compound FOX-7 under intense electric fields

    Science.gov (United States)

    Tao, Zhiqiang; Wang, Xin; Wei, Yuan; Lv, Li; Wu, Deyin; Yang, Mingli

    2017-02-01

    Molecular structure, vibrational and electronic absorption spectra, chemical reactivity of energetic compound FOX-7, one of the most widely used explosives, were studied computationally in presence of an electrostatic field of 0.01-0.05 a.u. The Csbnd N bond, which usually triggers the decomposition of FOX-7, is shortened/elongated under a parallel/antiparallel field. The Csbnd N bond activation energy varies with the external electric field, decreasing remarkably with the field strength in regardless of the field direction. This is attributed to two aspects: the bond weakening by the field parallel to the Csbnd N bond and the stabilization effect on the transition-state structure by the field antiparallel to the bond. The variations in the structure and property of FOX-7 under the electric fields were further analyzed with its distributional polarizability, which is dependent on the charge transfer characteristics through the Csbnd N bond.

  8. Mg doping of GaN grown by plasma-assisted molecular beam epitaxy under nitrogen-rich conditions

    International Nuclear Information System (INIS)

    Zhang Meng; Bhattacharya, Pallab; Guo Wei; Banerjee, Animesh

    2010-01-01

    Acceptor doping of GaN with Mg during plasma-assisted molecular beam epitaxy, under N-rich conditions and a relatively high growth temperature of 740 deg. C, was investigated. The p-doping level steadily increases with increasing Mg flux. The highest doping level achieved, determined from Hall measurements, is 2.1x10 18 cm -3 . The corresponding doping efficiency and hole mobility are ∼4.9% and 3.7 cm 2 /V s at room temperature. Cross-sectional transmission electron microscopy and photoluminescence measurements confirm good crystalline and optical quality of the Mg-doped layers. An InGaN/GaN quantum dot light emitting diode (λ peak =529 nm) with p-GaN contact layers grown under N-rich condition exhibits a low series resistance of 9.8 Ω.

  9. RNA sequencing of Populus x canadensis roots identifies key molecular mechanisms underlying physiological adaption to excess zinc.

    Directory of Open Access Journals (Sweden)

    Andrea Ariani

    Full Text Available Populus x canadensis clone I-214 exhibits a general indicator phenotype in response to excess Zn, and a higher metal uptake in roots than in shoots with a reduced translocation to aerial parts under hydroponic conditions. This physiological adaptation seems mainly regulated by roots, although the molecular mechanisms that underlie these processes are still poorly understood. Here, differential expression analysis using RNA-sequencing technology was used to identify the molecular mechanisms involved in the response to excess Zn in root. In order to maximize specificity of detection of differentially expressed (DE genes, we consider the intersection of genes identified by three distinct statistical approaches (61 up- and 19 down-regulated and validate them by RT-qPCR, yielding an agreement of 93% between the two experimental techniques. Gene Ontology (GO terms related to oxidation-reduction processes, transport and cellular iron ion homeostasis were enriched among DE genes, highlighting the importance of metal homeostasis in adaptation to excess Zn by P. x canadensis clone I-214. We identified the up-regulation of two Populus metal transporters (ZIP2 and NRAMP1 probably involved in metal uptake, and the down-regulation of a NAS4 gene involved in metal translocation. We identified also four Fe-homeostasis transcription factors (two bHLH38 genes, FIT and BTS that were differentially expressed, probably for reducing Zn-induced Fe-deficiency. In particular, we suggest that the down-regulation of FIT transcription factor could be a mechanism to cope with Zn-induced Fe-deficiency in Populus. These results provide insight into the molecular mechanisms involved in adaption to excess Zn in Populus spp., but could also constitute a starting point for the identification and characterization of molecular markers or biotechnological targets for possible improvement of phytoremediation performances of poplar trees.

  10. Sporulation environment influences spore properties in Bacillus: evidence and insights on underlying molecular and physiological mechanisms.

    Science.gov (United States)

    Bressuire-Isoard, Christelle; Broussolle, Véronique; Carlin, Frédéric

    2018-05-17

    Bacterial spores are resistant to physical and chemical insults, which make them a major concern for public health and for industry. Spores help bacteria to survive extreme environmental conditions that vegetative cells cannot tolerate. Spore resistance and dormancy are important properties for applications in medicine, veterinary health, food safety, crop protection, and other domains. The resistance of bacterial spores results from a protective multilayered structure and from the unique composition of the spore core. The mechanisms of sporulation and germination, the first stage after breaking of dormancy, and organization of spore structure have been extensively studied in Bacillus species. This review aims to illustrate how far the structure, composition and properties of spores are shaped by the environmental conditions in which spores form. We look at the physiological and molecular mechanisms underpinning how sporulation media and environment deeply affect spore yield, spore properties like resistance to wet heat and physical and chemical agents, germination, and further growth. For example, spore core water content decreases as sporulation temperature increases, and resistance to wet heat increases. Controlling the fate of Bacillus spores is pivotal to controlling bacterial risks and process efficiencies in, for example, the food industry, and better control hinges on better understanding how sporulation conditions influence spore properties.

  11. First principles molecular dynamics of metal/water interfaces under bias potential

    Science.gov (United States)

    Pedroza, Luana; Brandimarte, Pedro; Rocha, Alexandre; Fernandez-Serra, Marivi

    2014-03-01

    Understanding the interaction of the water-metal system at an atomic level is extremely important in electrocatalysts for fuel cells, photocatalysis among other systems. The question of the interface energetics involves a detailed study of the nature of the interactions between water-water and water-substrate. A first principles description of all components of the system is the most appropriate methodology in order to advance understanding of electrochemically processes. In this work we describe, using first principles molecular dynamics simulations, the dynamics of a combined surface(Au and Pd)/water system both in the presence and absence of an external bias potential applied to the electrodes, as one would come across in electrochemistry. This is accomplished using a combination of density functional theory (DFT) and non-equilibrium Green's functions methods (NEGF), thus accounting for the fact that one is dealing with an out-of-equilibrium open system, with and without van der Waals interactions. DOE Early Career Award No. DE-SC0003871.

  12. A general theory for the lifetimes of giant molecular clouds under the influence of galactic dynamics

    Science.gov (United States)

    Jeffreson, Sarah M. R.; Kruijssen, J. M. Diederik

    2018-05-01

    We propose a simple analytic theory for environmentally dependent molecular cloud lifetimes, based on the large-scale (galactic) dynamics of the interstellar medium. Within this theory, the cloud lifetime is set by the time-scales for gravitational collapse, galactic shear, spiral arm interactions, epicyclic perturbations, and cloud-cloud collisions. It is dependent on five observable quantities, accessible through measurements of the galactic rotation curve, the gas and stellar surface densities, and the gas and stellar velocity dispersions of the host galaxy. We determine how the relative importance of each dynamical mechanism varies throughout the space of observable galactic properties, and conclude that gravitational collapse and galactic shear play the greatest role in setting the cloud lifetime for the considered range of galaxy properties, while cloud-cloud collisions exert a much lesser influence. All five environmental mechanisms are nevertheless required to obtain a complete picture of cloud evolution. We apply our theory to the galaxies M31, M51, M83, and the Milky Way, and find a strong dependence of the cloud lifetime upon galactocentric radius in each case, with a typical cloud lifetime between 10 and 50 Myr. Our theory is ideally suited for systematic observational tests with the Atacama Large Millimetre/submillimetre array.

  13. Design principles and optimal performance for molecular motors under realistic constraints

    Science.gov (United States)

    Tu, Yuhai; Cao, Yuansheng

    2018-02-01

    The performance of a molecular motor, characterized by its power output and energy efficiency, is investigated in the motor design space spanned by the stepping rate function and the motor-track interaction potential. Analytic results and simulations show that a gating mechanism that restricts forward stepping in a narrow window in configuration space is needed for generating high power at physiologically relevant loads. By deriving general thermodynamics laws for nonequilibrium motors, we find that the maximum torque (force) at stall is less than its theoretical limit for any realistic motor-track interactions due to speed fluctuations. Our study reveals a tradeoff for the motor-track interaction: while a strong interaction generates a high power output for forward steps, it also leads to a higher probability of wasteful spontaneous back steps. Our analysis and simulations show that this tradeoff sets a fundamental limit to the maximum motor efficiency in the presence of spontaneous back steps, i.e., loose-coupling. Balancing this tradeoff leads to an optimal design of the motor-track interaction for achieving a maximum efficiency close to 1 for realistic motors that are not perfectly coupled with the energy source. Comparison with existing data and suggestions for future experiments are discussed.

  14. Molecular markers validation to drought resistance in wheat meal (Triticum aestivum L. under greenhouse conditions

    Directory of Open Access Journals (Sweden)

    Gabriel Julio

    2013-08-01

    Full Text Available With the aim to study the genetic resistance to drought and validate molecular markers co-localized with genes/QTLs for this factor, 16 varieties were evaluated as well as advanced lines of wheat meal (Triticum aestivum in two stages of crop development. Physiological parameters were considered: amount of chlorophyll (clo, wilting or severity degree (SEV and recovery (reco, morphological parameters: foliage dry matter (FDM and root dry matter (RDM, the integrated resistance mechanisms: water use efficiency (WUE, other parameters: number of grains (Ngrain and grain weight (Wgrain, biochemical parameters: Catalaza (CAT, Ascorbate Peroxidase (APX and Guaiacol Peroxidase (POX and three microsatellite markers (Xwmc603, Xwmc596, Xwmc9. Results showed significant differences for MSR and Ngrain. It was observed that Anzaldo, ERR2V.L-20, EARII2V.L-5, EARIZV.L-11, ERR2V.L-11 and EE2V.L-19 were the most resistant to drough water stress. There was a highly significant negative correlation between the MSR and Ngrain. All other variables showed low and non-significant correlations. In biochemical analyzes, the Anzaldo variety showed an increased enzymatic activity compared to controls in all cases (CAT-APX and POX, being the most resistant to water stress by drought. Finally, it was found that SSR markers (Xwmc596 and Xwmc9 are co-located with the gene / QTL of drought resistance and can be used for marker-assisted selection.

  15. Differential expression of EWI-2 in endometriosis, its functional role and underlying molecular mechanisms.

    Science.gov (United States)

    Zheng, Tingting; Yang, Jing

    2017-07-01

    We aimed to investigate EWI-2 expression in endometrium tissues collected from women with endometriosis at mRNA and protein levels, to evaluate its potential as a biomarker for endometriosis and to study its functional role via possible regulation of the PI3K/Akt signaling pathway. Endometrium tissues were collected from patients with endometriosis and healthy individuals. EWI-2 mRNA expression was evaluated using quantitative real-time PCR (qRT-PCR) while EWI-2 protein levels were determined by western blotting. For functional studies, EWI-2 shRNA was transfected in endometrial epithelial cells and the in vitro migration and invasion assays were performed using the Transwell chambers. EWI-2 was significantly downregulated in tissues obtained from patients with endometriosis compared with healthy individuals (P endometriosis diagnosis was 0.8942 (P = 0.003), 0.9643 (P = 0.0001), 0.9912 (P endometriosis in matched comparisons of data originated from the proliferative, early, middle, and late secretory phases. Over the menstrual cycle, the expression of EWI-2 was significantly decreased in the eutopic tissues compared to the ectopic tissues. Further cellular and molecular analyses showed that EWI-2 inhibited cell migration and invasion via the Akt signaling. Our findings suggested that downregulation of EWI-2 may contribute to endometriosis physiopathology and potentiate EWI-2 as a valuable diagnostic biomarker and therapeutic target for endometriosis. © 2017 Japan Society of Obstetrics and Gynecology.

  16. Molecular Technologies in Serbian Lowland Forestry under Climate Changes - Possibilities and Perspectives

    Directory of Open Access Journals (Sweden)

    Branislav Trudić

    2014-12-01

    Full Text Available Background and Purpose: Vojvodina province, the northern part of the Republic of Serbia, is predominantly lowland agricultural region with over 75% of arable land which in previous years, has been highly impacted by drought. The annual precipitation is lower than 700 mm and it is the limit for the growth and development of natural forest vegetation. Unfortunately, the atmospheric precipitation is still a major source of water for plant biodiversity. Taking these facts into account, it is highly recommended to primarily use the xerothermic tree species, which have a well-developed root system for “classical” afforestation. Some species from Salicaceae and Fagaceae like poplars, willows, oaks and beeches are surely the best option for afforestation in temperate zones strongly influenced by drought. Conclusions: In order to develop stress-based genomic information in Populus and the rest of woody plant species from Vojvodina, an integrated genetic research needs to be done. The aim of this particular paper is to analyse and summarize data regarding stress-based biotechnology perspectives in Vojvodina and to give recommendations for future forest tree breeding. Drought as a strong negative ecological factor must be carefully considered. In order to achieve sustainability, new forest management plans must consider wide approaches, from molecular to ecosystem level.

  17. Early molecular events involved in Pinus pinaster Ait. somatic embryo development under reduced water availability: transcriptomic and proteomic analyses.

    Science.gov (United States)

    Morel, Alexandre; Teyssier, Caroline; Trontin, Jean-François; Eliášová, Kateřina; Pešek, Bedřich; Beaufour, Martine; Morabito, Domenico; Boizot, Nathalie; Le Metté, Claire; Belal-Bessai, Leila; Reymond, Isabelle; Harvengt, Luc; Cadene, Martine; Corbineau, Françoise; Vágner, Martin; Label, Philippe; Lelu-Walter, Marie-Anne

    2014-09-01

    Maritime pine somatic embryos (SEs) require a reduction in water availability (high gellan gum concentration in the maturation medium) to reach the cotyledonary stage. This key switch, reported specifically for pine species, is not yet well understood. To facilitate the use of somatic embryogenesis for mass propagation of conifers, we need a better understanding of embryo development. Comparison of both transcriptome (Illumina RNA sequencing) and proteome [two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis with mass spectrometry (MS) identification] of immature SEs, cultured on either high (9G) or low (4G) gellan gum concentration, was performed, together with analysis of water content, fresh and dry mass, endogenous abscisic acid (ABA; gas chromatography-MS), soluble sugars (high-pressure liquid chromatography), starch and confocal laser microscope observations. This multiscale, integrated analysis was used to unravel early molecular and physiological events involved in SE development. Under unfavorable conditions (4G), the glycolytic pathway was enhanced, possibly in relation to cell proliferation that may be antagonistic to SE development. Under favorable conditions (9G), SEs adapted to culture constraint by activating specific protective pathways, and ABA-mediated molecular and physiological responses promoting embryo development. Our results suggest that on 9G, germin-like protein and ubiquitin-protein ligase could be used as predictive markers of SE development, whereas protein phosphatase 2C could be a biomarker for culture adaptive responses. This is the first characterization of early molecular mechanisms involved in the development of pine SEs following an increase in gellan gum concentration in the maturation medium, and it is also the first report on somatic embryogenesis in conifers combining transcriptomic and proteomic datasets. © 2014 Scandinavian Plant Physiology Society.

  18. Global transcriptomic profiling of aspen trees under elevated [CO2] to identify potential molecular mechanisms responsible for enhanced radial growth.

    Science.gov (United States)

    Wei, Hairong; Gou, Jiqing; Yordanov, Yordan; Zhang, Huaxin; Thakur, Ramesh; Jones, Wendy; Burton, Andrew

    2013-03-01

    Aspen (Populus tremuloides) trees growing under elevated [CO(2)] at a free-air CO(2) enrichment (FACE) site produced significantly more biomass than control trees. We investigated the molecular mechanisms underlying the observed increase in biomass by producing transcriptomic profiles of the vascular cambium zone (VCZ) and leaves, and then performed a comparative study to identify significantly changed genes and pathways after 12 years exposure to elevated [CO(2)]. In leaves, elevated [CO(2)] enhanced expression of genes related to Calvin cycle activity and linked pathways. In the VCZ, the pathways involved in cell growth, cell division, hormone metabolism, and secondary cell wall formation were altered while auxin conjugation, ABA synthesis, and cytokinin glucosylation and degradation were inhibited. Similarly, the genes involved in hemicellulose and pectin biosynthesis were enhanced, but some genes that catalyze important steps in lignin biosynthesis pathway were inhibited. Evidence from systemic analysis supported the functioning of multiple molecular mechanisms that underpin the enhanced radial growth in response to elevated [CO(2)].

  19. Different routes, same pathways: Molecular mechanisms under silver ion and nanoparticle exposures in the soil sentinel Eisenia fetida

    International Nuclear Information System (INIS)

    Novo, Marta; Lahive, Elma; Díez-Ortiz, María; Matzke, Marianne; Morgan, Andrew J.; Spurgeon, David J.; Svendsen, Claus; Kille, Peter

    2015-01-01

    Use of nanotechnology products is increasing; with silver (Ag) nanoparticles particularly widely used. A key uncertainty surrounding the risk assessment of AgNPs is whether their effects are driven through the same mechanism of action that underlies the toxic effects of Ag ions. We present the first full transcriptome study of the effects of Ag ions and NPs in an ecotoxicological model soil invertebrate, the earthworm Eisenia fetida. Gene expression analyses indicated similar mechanisms for both silver forms with toxicity being exerted through pathways related to ribosome function, sugar and protein metabolism, molecular stress, disruption of energy production and histones. The main difference seen between Ag ions and NPs was associated with potential toxicokinetic effects related to cellular internalisation and communication, with pathways related to endocytosis and cilia being significantly enriched. These results point to a common final toxicodynamic response, but initial internalisation driven by different exposure routes and toxicokinetic mechanisms. - Highlights: • Molecular effects underlying Ag ions and NPs exposure were studied in Eisenia fetida. • Full transcriptomic study of a genetically characterised lineage. • NPs and ions presented a similar toxicodynamic response. • Internalisation of the two Ag forms by different toxicokinetic mechanisms. - Transcriptomic analyses after exposure of earthworms to silver NPs or ions showed a final common toxicodynamic response, but internalisation by different toxicokinetic mechanisms

  20. Autophagy as a Molecular Target of Flavonoids Underlying their Protective Effects in Human Disease.

    Science.gov (United States)

    Prieto-Domínguez, Nestor; Garcia-Mediavilla, Maria V; Sanchez-Campos, Sonia; Mauriz, Jose L; Gonzalez-Gallego, Javier

    2018-01-01

    Autophagy is a cellular pathway with the ability to maintain cell homeostasis through the elimination of damaged or useless cellular components, and its deregulation may initiate or aggravate different human diseases. Flavonoids, a group of plant metabolites, are able to modulate different molecular and cellular processes including autophagy. To review the effects of flavonoids on autophagy pathway in both invasive and noninvasive human diseases, focusing on the global outcomes in their progression. Moreover, the efficacy of the combination of flavonoids with drugs or other natural nontoxic compounds was also reviewed. A literature search was performed to identify and analyze peer-reviewed publications containing in vitro and in vivo studies focused on autophagy deregulation in different proliferative and non-proliferative pathologies and the potential protective effects of flavonoids. Analyzed publications indicated that imbalance between cell death and survival induced by changes in autophagy play an important role in the pathophysiology of a number of human diseases. The use of different flavonoids as autophagy modulators, alone or in combination with other molecules, might be a worthy strategy in the treatment of cancer, neurodegenerative disorders, cardiovascular diseases, hepatic diseases, leishmaniasis, influenza, gastric ulcers produced by Helicobacter pylori infection, diabetes, asthma, age-related macular degeneration or osteoporosis. Flavonoids could potentially constitute important adjuvant agents of conventional therapies in the treatment of autophagy deregulation-related diseases. Moreover, combined therapy may help to diminish the doses of those conventional treatments, leading to reduced drug-derivative side effects and to improved patients' survival. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Effects of epigallocatechin gallate on lipid metabolism and its underlying molecular mechanism in broiler chickens.

    Science.gov (United States)

    Huang, J B; Zhang, Y; Zhou, Y B; Wan, X C; Zhang, J S

    2015-08-01

    The objective of this study was to investigate the effects of epigallocatechin gallate (EGCG) on fat metabolism and to establish the molecular mechanism of these effects in broilers. Seventy-two 28-day-old male Ross 308 broiler chickens were divided into three groups with different levels of EGCG supplementation for 4 weeks: normal control (NC) group, L-EGCG (a low-level supplement of EGCG, 40 mg/kg body weight daily) and H-EGCG (a high-level supplement of EGCG, 80 mg/kg body weight daily). After 4 weeks of oral administration, EGCG significantly reduced the level of abdominal fat deposition in broilers. The serum triglycerides and low-density lipoprotein cholesterol of chickens in H-EGCG group were also significantly decreased compared with the NC group, and the high-density lipoprotein cholesterol was notably increased at the same time. Moreover, the vital role of the liver and abdominal adipose tissue in lipid metabolism of poultry animals was examined through gene expression and enzyme activities related to fat anabolism and catabolism in these organs. Our data show that EGCG supplementation for 2 weeks significantly downregulated the expression of fatty acid synthesis and fat deposition-related genes, and upregulated the expression of genes involved in fatty a