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Sample records for orotic aciduria reveals

  1. Hereditary orotic aciduria with epilepsy and without megaloblastic anemia.

    PubMed

    Grohmann, Karina; Lauffer, Heinz; Lauenstein, Peter; Hoffmann, Georg F; Seidlitz, Günter

    2015-04-01

    Hereditary orotic aciduria is a rare metabolic disease that results from a defect of uridine-5-monophosphate synthase (UMPS). In affected patients, main clinical symptoms are a markedly increased urinary excretion of orotic acid combined with megaloblastic anemia. This report describes a new case of UMPS deficiency without megaloblastic anemia but with epilepsy. PMID:25757096

  2. Sensitive and Selective Determination of Orotic Acid in Biological Specimens Using a Novel Fluorogenic Reaction.

    PubMed

    Yin, Sheng; Dragusha, Shpend; Ejupi, Valon; Shibata, Takayuki; Kabashima, Tsutomu; Kai, Masaaki

    2015-07-01

    Orotic acid is an intermediate in the synthesis pathway of uridine-5'-monophosphate, and increases in body fluids of patients suffering from hereditary disorders such as orotic aciduria and hyperammonemia. In this study, we developed a spectrofluorometric method with or without high-performance liquid chromatography for the selective and sensitive quantification of orotic acid in human biological specimens, using 4-trifluoromethylbenzamidoxime (4-TFMBAO) as a fluorogenic reagent. This reagent provided intensive fluorescence for only orotic acid amongst 62 compounds including structurally related bio-substances such as nucleic acid bases, nucleosides, nucleotides, amino acids, vitamins, bilirubin, uric acid, urea, creatine, creatinine and sugars. Under optimized reaction conditions, orotic acid was reacted with 4-TFMBAO, K3[Fe(CN)6] and K2CO3 in an aqueous solution. The fluorescence produced from the orotic acid derivative was measured at an excitation of 340 nm and an emission of 460 nm. A concentration of 1.2 μM orotic acid per 1.0 mM creatinine in normal urine and 0.64 nmol orotic acid per 5.0 × 10(5) HeLa cells were determined by this method. The present method permitted the facile quantification of orotic acid in healthy human urine and cultured HeLa cells by spectrofluorometry and/or high-performance liquid chromatography. PMID:26026930

  3. Cytosinium orotate dihydrate.

    PubMed

    Portalone, Gustavo

    2013-01-01

    The title compound, C4H6N3O(+)·C5H3N2O4(-)·2H2O or Cyt(+)·Or(-)·2H2O, was synthesized by a reaction between cytosine (4-amino-2-hy-droxy-pyrimidine, Cyt) and orotic acid (2,4-dihy-droxy-6-carb-oxy-pyrimidine, Or) in aqueous solution. The two ions are joined by two N(+)-H⋯O(-) (±)-(CAHB) hydrogen bonds, forming a dimer with graph-set motif R2(2)(8). In the crystal, the ion pairs of the asymmetric unit are joined by four N-H⋯O inter-actions to adjacent dimers, forming hydrogen-bonded rings with R2(2)(8) graph-set motif in a two-dimensional network. The formation of the three-dimensional array is facilitated by water mol-ecules, which act as bridges between structural sub-units linked in R3(2)(8) and R3(2)(7) hydrogen-bonded rings. The orotate anion is essentially planar, as the dihedral angle between the planes defined by the carboxylate group and the uracil fragment is 4.0 (4)°. PMID:23476396

  4. Development of an assay to simultaneously measure orotic acid, amino acids, and acylcarnitines in dried blood spots

    PubMed Central

    Held, Patrice K.; Haynes, Christopher A.; De Jesús, Víctor R.; Baker, Mei W.

    2016-01-01

    Background Orotic aciduria in the presence of hyperammonemia is a key indicator for a defect in the urea cycle, specifically ornithine transcarbamylase (OTC) deficiency. Current newborn screening (NBS) protocols can detect several defects of the urea cycle, but screening for OTC deficiency remains a challenge due to the lack of a suitable assay. The purpose of this study was to develop a high-throughput assay to measure orotic acid in dried blood spot (DBS) specimens as an indicator for urea cycle dysfunction, which can be readily incorporated into routine NBS. Methods Orotic acid was extracted from DBS punches and analyzed using flow-injection analysis tandem mass spectrometry (FIA–MS/MS) with negative-mode ionization, requiring <2 min/sample run time. This method was then multiplexed into a conventional newborn screening assay for analysis of amino acids, acylcarnitines, and orotic acid. Results We describe 2 assays which can quantify orotic acid in DBS: a stand-alone method and a combined method for analysis of orotic acid, amino acids, and acylcarnitines. Both methods demonstrated orotic acid recovery of 75–85% at multiple levels of enrichment. Precision was also comparable to traditional FIA–MS/MS methods. Analysis of residual presumptively normal NBS specimens demonstrated a 5:1 signal to noise ratio and the average concentration of orotic acid was approximately 1.2 μmol/l. The concentration of amino acids and acylcarnitines as measured by the combined method showed no significant differences when compared to the conventional newborn screening assay. In addition, retrospective analysis of confirmed patients and presumptively normal newborn screening specimens suggests potential for the methods to identify patients with OTC deficiency, as well as other urea cycle defects. Conclusion The assays described here quantify orotic acid in DBS using a simple extraction and FIA–MS/MS analysis procedures that can be implemented into current NBS protocols. PMID

  5. Genetics Home Reference: 2-hydroxyglutaric aciduria

    MedlinePlus

    ... Climb National Information Centre for Metabolic Diseases (UK) Organic Acidemia Association: D-2 Hydroxyglutaric Aciduria Organic Acidemia Association: L-2 Hydroxyglutaric Aciduria Resource List ...

  6. Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70.

    PubMed

    Shchelochkov, Oleg A; Li, Fang-Yuan; Wang, Jing; Zhan, Hongli; Towbin, Jeffrey A; Jefferies, John Lynn; Wong, Lee-Jun; Scaglia, Fernando

    2010-01-01

    Mitochondrial disorders are a large and genetically heterogeneous group of disorders posing a significant diagnostic challenge. Only approximately 10-20% of patients have identifiable alterations in their mitochondrial DNA (mtDNA). The remaining ~80-90% of affected patients likely harbor mutations in nuclear genes, most of which are still poorly characterized, and therefore not amenable to efficient screening using currently available molecular methods. Here we present a patient, who has been followed since birth after presenting with neonatal hyperammonemia, lactic acidosis, Reye-like syndrome episodes, and ventricular tachyarrhythmia. Initial biochemical work-up revealed hyperalaninemia, normal plasma glutamine, mild orotic aciduria and significant amounts of urinary 3-methylglutaconic (3-MGC) and 3-methylglutaric (3-MGA) acids. Muscle biopsy demonstrated the presence of ragged-red fibers and non-specific structural abnormalities of mitochondria. The activities of respiratory chain enzymes (complexes I-IV) showed no deficiency. Mutational analysis of the entire mitochondrial genome did not reveal deleterious point mutations or large deletions. Long-term follow-up was significant for a later-onset hypertrophic cardiomyopathy, muscle weakness, and exercise intolerance. Although she had frequent episodes of Reye-like episodes in infancy and early childhood, mostly triggered by illnesses, these symptoms improved significantly with the onset of puberty. In the light of recent reports linking cases of type IV 3-methylglutaconic aciduria (3-MGCA) and hypertrophic cardiomyopathy to mutations in TMEM70, we proceeded with sequencing analysis of this gene. We identified one previously reported splice site mutation, c.317-2A>G and a novel mutation c.494G>A (p.G165D) in an evolutionarily conserved region predicted to be deleterious. This variant was not identified in 100 chromosomes of healthy control subjects and 200 chromosomes of patients with cardiomyopathies. Western

  7. Lithium orotate, carbonate and chloride: pharmacokinetics, polyuria in rats.

    PubMed Central

    Smith, D F

    1976-01-01

    1 The pharmacokinetics of the lithium ion administered as lithium orotate were studied in rats. Parallel studies were carried out with lithium carbonate and lithium chloride. 2 No differences in the uptake, distribution and excretion of the lithium ion were observed between lithium orotate, lithium carbonate and lithium chloride after single intraperitoneal, subcutaneous or intragastric injections (0.5-1.0 mEq lithium/kg) or after administration of the lithium salts for 20 days in the food. 3 The findings oppose the notion that the pharmacokinetics of the lithium ion given as lithium orotate differ from lithium chloride or lithium carbonate. 4 Polyuria and polydipsia developed more slowly in rats given lithium orotate than in those given lithium carbonate or lithium chloride, perhaps due to an effect of the orotate anion. PMID:1260219

  8. Production of orotic acid by a Klura3Δ mutant of Kluyveromyces lactis.

    PubMed

    Carvalho, Nuno; Coelho, Eduardo; Gales, Luís; Costa, Vítor; Teixeira, José António; Moradas-Ferreira, Pedro

    2016-06-01

    We demonstrated that a Klura3Δ, mutant of the yeast Kluyveromyces lactis is able to produce and secrete into the growth medium considerable amounts of orotic acid. Using yeast extract-peptone-glucose (YPD) based media we optimized production conditions in flask and bioreactor cultures. With cells grown in YPD 5% glucose medium, the best production in flask was obtained with a 1:12.5 ratio for flask: culture volume, 180 rpm, 28°C and 200 mM MOPS for pH stabilization at neutral values (initial culture pH at 8.0). The best production in a 2 L bioreactor was achieved at 500 rpm with 1 vvm aeration, 28°C and pH 7.0. Under these optimum conditions, similar rates of orotic acid production were obtained and maximum concentration achieved after 96 h was 6.7 g/L in flask and bioreactor cultures. These results revealed an excellent reproducibility between both systems and provided evidence for the biotechnological potential of Klura3Δ strain to produce orotic acid since the amounts obtained are comparable to the production in flask using a similar mutant of the industrially valuable Corynebacterium glutamicum. PMID:26707627

  9. The 3-methylglutaconic acidurias: what's new?

    PubMed

    Wortmann, Saskia B; Kluijtmans, Leo A; Engelke, Udo F H; Wevers, Ron A; Morava, Eva

    2012-01-01

    The heterogeneous group of 3-methylglutaconic aciduria (3-MGA-uria) syndromes includes several inborn errors of metabolism biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. Five distinct types have been recognized: 3-methylglutaconic aciduria type I is an inborn error of leucine catabolism; the additional four types all affect mitochondrial function through different pathomechanisms. We provide an overview of the expanding clinical spectrum of the 3-MGA-uria types and provide the newest insights into the underlying pathomechanisms. A diagnostic approach to the patient with 3-MGA-uria is presented, and we search for the connection between urinary 3-MGA excretion and mitochondrial dysfunction. PMID:20882351

  10. Accumulation of Pyrimidine Intermediate Orotate Decreases Virulence Factor Production in Pseudomonas aeruginosa.

    PubMed

    Niazy, Abdurahman; Hughes, Lee E

    2015-08-01

    The impact of orotate accumulation in the medically important bacterium Pseudomonas aeruginosa was studied by deleting pyrE, the gene encoding orotate phosphoribosyltransferase and responsible for converting orotate into orotate monophosphate within the de novo pyrimidine synthesis pathway. The pyrE mutant accumulated orotate and exhibited decreased production of hemolysin, casein protease, and elastase. Feeding orotate at a concentration of 51.25 μM to the wild type, PAO1, likewise decreased production of these factors except for hemolysin, which was not affected. A significant increase in the pigments pyocyanin and pyoverdin was also observed. Pyocyanin increase in the pyrE mutant was heightened when the mutant was supplemented with orotate. Although pyoverdin production in the wild-type PAO1 was unaffected by orotate supplementation, a decrease in the mutant's production was observed when supplemented with orotate. These results indicate a significant reduction in virulence factor production in the pyrE mutant and reduction in some virulence factors in the wild type when supplemented with orotate. PMID:25917504

  11. Behr's syndrome and 3-methylglutaconic aciduria.

    PubMed

    Sheffer, R N; Zlotogora, J; Elpeleg, O N; Raz, J; Ben-Ezra, D

    1992-10-15

    We examined three patients from two families of Jewish-Iraqi origin who had progressive reduction of visual acuity and childhood onset of bilateral optic nerve atrophy without additional retinal abnormalities. They had neurologic symptoms compatible with Behr's syndrome. Neurologic signs included increased tendon reflexes, a positive Babinski sign, progressive spastic paraplegia, dysarthria, head nodding, and horizontal nystagmus. Neurologic involvement varied between affected siblings. The patients excreted excessive amounts of 3-methylglutaconic acid and 3-methylglutaric acid in their urine. We compared the characteristic ophthalmic features and the spectrum of neurologic signs encountered in this recently delineated autosomal recessive clinical entity with those of previously described entities associated with 3-methylglutaconic aciduria. Patients with early-onset optic atrophy should be examined for neurologic signs and screened for organic aciduria. A detailed ophthalmic examination is important in patients with neurologic abnormalities compatible with Behr's syndrome. PMID:1384336

  12. Structure of Plasmodium falciparum orotate phosphoribosyltransferase with autologous inhibitory protein–protein interactions

    SciTech Connect

    Kumar, Shiva; Krishnamoorthy, Kalyanaraman; Mudeppa, Devaraja G.; Rathod, Pradipsinh K.

    2015-04-21

    P. falciparum orotate phosphoribosyltransferase, a potential target for antimalarial drugs and a conduit for prodrugs, crystallized as a structure with eight molecules per asymmetric unit that included some unique parasite-specific auto-inhibitory interactions between catalytic dimers. The most severe form of malaria is caused by the obligate parasite Plasmodium falciparum. Orotate phosphoribosyltransferase (OPRTase) is the fifth enzyme in the de novo pyrimidine-synthesis pathway in the parasite, which lacks salvage pathways. Among all of the malaria de novo pyrimidine-biosynthesis enzymes, the structure of P. falciparum OPRTase (PfOPRTase) was the only one unavailable until now. PfOPRTase that could be crystallized was obtained after some low-complexity sequences were removed. Four catalytic dimers were seen in the asymmetic unit (a total of eight polypeptides). In addition to revealing unique amino acids in the PfOPRTase active sites, asymmetric dimers in the larger structure pointed to novel parasite-specific protein–protein interactions that occlude the catalytic active sites. The latter could potentially modulate PfOPRTase activity in parasites and possibly provide new insights for blocking PfOPRTase functions.

  13. Structure of Plasmodium falciparum orotate phosphoribosyltransferase with autologous inhibitory protein–protein interactions

    PubMed Central

    Kumar, Shiva; Krishnamoorthy, Kalyanaraman; Mudeppa, Devaraja G.; Rathod, Pradipsinh K.

    2015-01-01

    The most severe form of malaria is caused by the obligate parasite Plasmodium falciparum. Orotate phosphoribosyltransferase (OPRTase) is the fifth enzyme in the de novo pyrimidine-synthesis pathway in the parasite, which lacks salvage pathways. Among all of the malaria de novo pyrimidine-biosynthesis enzymes, the structure of P. falciparum OPRTase (PfOPRTase) was the only one unavailable until now. PfOPRTase that could be crystallized was obtained after some low-complexity sequences were removed. Four catalytic dimers were seen in the asymmetic unit (a total of eight polypeptides). In addition to revealing unique amino acids in the PfOPRTase active sites, asymmetric dimers in the larger structure pointed to novel parasite-specific protein–protein interactions that occlude the catalytic active sites. The latter could potentially modulate PfOPRTase activity in parasites and possibly provide new insights for blocking PfOPRTase functions. PMID:25945715

  14. The mechanistic study of Leishmania major dihydro-orotate dehydrogenase based on steady- and pre-steady-state kinetic analysis.

    PubMed

    Reis, Renata A G; Ferreira, Patricia; Medina, Milagros; Nonato, M Cristina

    2016-03-01

    Leishmania major dihydro-orotate dehydrogenase (DHODHLm) has been considered as a potential therapeutic target against leishmaniasis. DHODHLm, a member of class 1A DHODH, oxidizes dihydro-orotate (DHO) to orotate (ORO) during pyrimidine biosynthesis using fumarate (FUM) as the oxidizing substrate. In the present study, the chemistry of reduction and reoxidation of the flavin mononucleotide (FMN) cofactor in DHODHLm was examined by steady- and pre-steady state kinetics under both aerobic and anaerobic environments. Our results provide for the first time the experimental evidence of co-operative behaviour in class 1A DHODH regulated by DHO binding and reveal that the initial reductive flavin half-reaction follows a mechanism with two steps. The first step is consistent with FMN reduction and shows a hyperbolic dependence on the DHO concentration with a limiting rate (kred) of 110±6 s(-1) and a K(DHO) d of 180±27 μM. Dissociation of the reduced flavin-ORO complex corresponds to the second step, with a limiting rate of 6 s(-1). In the oxidative half-reaction, the oxygen-sensitive reoxidation of the reduced FMN cofactor of DHODHLm by FUM exhibited a hyperbolic saturation profile dependent on FUM concentration allowing estimation of K(FUM) d and the limiting rate (kreox) of 258±53 μM and 35±2 s(-1), respectively. Comparison between steady- and pre-steady-state parameters together with studies of interaction for DHODHLm with both ORO and succinate (SUC), suggests that ORO release is the rate-limiting step in overall catalysis. Our results provide evidence of mechanistic differences between class 1A and class 2 individual half-reactions to be exploited for the development of selective inhibitors. PMID:26656485

  15. [Acute brainstem encephalitis and myelitis in a girl with isolated methylmalonic aciduria due to MUT gene defect].

    PubMed

    Liu, Yu-Peng; Ding, Yuan; Li, Xi-Yuan; Wang, Hai-Jun; Song, Jin-Qing; Ye, Jin-Tang; Wu, Tong-Fei; Yang, Yan-Ling

    2015-10-01

    Methylmalonyl CoA mutase deficiency due to MUT gene defect has been known as the main cause of isolated methylmalonic acidemia in Mainland China. This study reported a patient with isolated methylmalonic aciduria (MUT type) characterized as acute brainstem encephalitis and myelitis. The previously healthy girl presented with fever, lethargy and progressive weakness in her extremities at the age of 3 years and 2 months. Three day later, she had respiratory distress and consciousness. Cranial MRI revealed bilateral symmetrical lesion of pallidum, brain stem and spinal cord, indicating acute brainstem encephalitis and myelitis. Her blood propionylcarnitine (6.83 μmol/L vs normal range 1.0 to 5.0 μmol/L) and urinary methylmalonic acid (133.22 mmol/mol creatinine vs normal range 0.2 to 3.6 mmol/mol creatinine) increased significantly. Plasma total homocysteine was normal. On her MUT gene, a reported mutation (c.1630_1631GG>TA) and a novel mutation (c.1663C>T, p.A555T) were identified, which confirmed the diagnosis of methylmalonic aciduria (MUT type). After cobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine, progressive improvement has been observed. The clinical manifestation of patients with methylmalonic aciduria is complex. Metabolic study and gene analysis are keys for the diagnosis and treatment of the disorder. PMID:26483233

  16. 33 CFR 334.1420 - Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing range. 334.1420 Section 334.1420... AND RESTRICTED AREA REGULATIONS § 334.1420 Pacific Ocean off Orote Point, Apra Harbor, Island of...

  17. 33 CFR 334.1420 - Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing range. 334.1420 Section 334.1420... AND RESTRICTED AREA REGULATIONS § 334.1420 Pacific Ocean off Orote Point, Apra Harbor, Island of...

  18. 33 CFR 334.1420 - Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing range. 334.1420 Section 334.1420... AND RESTRICTED AREA REGULATIONS § 334.1420 Pacific Ocean off Orote Point, Apra Harbor, Island of...

  19. 33 CFR 334.1420 - Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing range. 334.1420 Section 334.1420... AND RESTRICTED AREA REGULATIONS § 334.1420 Pacific Ocean off Orote Point, Apra Harbor, Island of...

  20. 33 CFR 334.1420 - Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Pacific Ocean off Orote Point, Apra Harbor, Island of Guam, Marianas Islands; small arms firing range. 334.1420 Section 334.1420... AND RESTRICTED AREA REGULATIONS § 334.1420 Pacific Ocean off Orote Point, Apra Harbor, Island of...

  1. A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts.

    PubMed

    Burlina, A B; Dionisi-Vici, C; Bennett, M J; Gibson, K M; Servidei, S; Bertini, E; Hale, D E; Schmidt-Sommerfeld, E; Sabetta, G; Zacchello, F

    1994-01-01

    We describe four Italian male infants with a novel clinical phenotype characterized by orthostatic acrocyanosis, relapsing petechiae, chronic diarrhea, progressive pyramidal signs, mental retardation, and brain magnetic resonance imaging abnormalities. The first symptoms appeared after the termination of breast-feeding and introduction of formula feeding. Marked persistent 2-ethylmalonic aciduria was associated with abnormal excretion of C4-C5(n-butyryl-, isobutyryl-, isovaleryl-, and 2-methylbutyryl-)acylglycines and acylcarnitines and with intermittent lactic acidosis. Short- and branched-chain plasma acylcarnitine levels were also elevated. 2-Ethylmalonic aciduria is generally regarded as being indicative of a defect in fatty acid oxidation. Extensive studies of cultured fibroblasts failed to reveal such a defect. The observation of intermittent urinary excretion of 2-ethylhydracrylic acid pointed to involvement of the isoleucine R pathway in ethylmalonate biosynthesis. This hypothesis was tentatively corroborated by the biochemical responses to an oral isoleucine challenge in two patients. However, fibroblast studies showed normal oxidation rates of (14C)isoleucine (ul), indicating that this is not a defect of isoleucine oxidation expressed in skin fibroblasts. In one of two patients tested, cytochrome c oxidase activity was partially reduced (45%) in cultured fibroblasts. This unique clinical and biochemical phenotype identifies a new metabolic encephalopathy of yet undetermined cause. PMID:8283379

  2. Sensitization of the luminescence of europium and terbium ions by orotic acids in aqueous solutions

    SciTech Connect

    Davidenko, N.K.; Bukivskaya, G.A.

    1988-03-01

    The stability constants of the complexes of Eu/sup 3 +/ and Tb/sup 3 +/ with the dianions of orotic acid, 2-thioorotic acid, and 3-N-methylorotic acid have been determined at 20/sup 0/C and ..mu.. = 0.15 by a pH-potentiometric method. The influence of orotic acids on the luminescence properties of Eu/sup 3 +/ and Tb/sup 3 +/ has been studied. It has been shown as a result of a study of the excited states of orotic acid and its derivatives by a method based on the sensitized luminescence of the lanthanides that it is preferable to use the Tb/sup 3 +/ ion as an energy acceptor, since quenching of the luminescence by means of a charge-transfer process is observed in the complexes formed by the Eu/sup 3 +/ ion.

  3. A global outer-rise/outer-trench-slope (OR/OTS) earthquake study

    NASA Astrophysics Data System (ADS)

    Wartman, J. M.; Kita, S.; Kirby, S. H.; Choy, G. L.

    2009-12-01

    Using improved seismic, bathymetric, satellite gravity and other geophysical data, we investigated the seismicity patterns and focal mechanisms of earthquakes in oceanic lithosphere off the trenches of the world that are large enough to be well recorded at teleseismic distances. A number of prominent trends are apparent, some of which have been previously recognized based on more limited data [1], and some of which are largely new [2-5]: (1) The largest events and the highest seismicity rates tend to occur where Mesozoic incoming plates are subducting at high rates (e.g., those in the western Pacific and the Banda segment of Indonesia). The largest events are predominantly shallow normal faulting (SNF) earthquakes. Less common are reverse-faulting (RF) events that tend to be deeper and to be present along with SNF events where nearby seamounts, seamount chains and other volcanic features are subducting [Seno and Yamanaka, 1996]. Blooms of SNF OR/OTS events usually occur just after and seaward of great interplate thrust (IPT) earthquakes but are far less common after smaller IPT events. (2) Plates subducting at slow rates (<20 mm/a) often show sparse OR/OTS seismicity. It is unclear if such low activity is a long-term feature of these systems or is a consequence of the long return times of great IPT earthquakes (e.g., the sparse OR/OTS seismicity before the 26 December 2004 M9.2 Sumatra earthquake and many subsequent OR/OTS events). (3) OR/OTS shocks are generally sparse or absent where incoming plates are very young (<20 Ma) (e.g., Cascadia, southern Mexico, Nankai, and South Shetlands). (4) Subducting plates of intermediate age (20 to about 65 Ma) display a diversity of focal mechanisms and seismicity patterns. In the Philippines, NE Indonesia, and Melanesia, bands of reverse faulting events occur at or near the trench and SNF earthquakes are restricted to OR/OTS sites further from the trench. (5) Clustering of OR/OTS events of all types commonly occurs where

  4. Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect.

    PubMed

    Wortmann, Saskia B; Kluijtmans, Leo A J; Sequeira, Silvia; Wevers, Ron A; Morava, Eva

    2014-01-01

    Currently, six inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature are known. The "Primary 3-methylglutaconic aciduria," 3-methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted "Secondary 3-methylglutaconic acidurias" (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, "not otherwise specified (NOS) 3-MGA-uria"), the origin of 3-methylglutaconic aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-methylglutaconic aciduria. After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3-methylglutaconic aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-methylglutaconic aciduria and also provides a simple test to discriminate between primary and secondary 3-methylglutaconic aciduria in regular patient care. PMID:24757000

  5. Occurrences of methylmalonic aciduria and Hartnup disorder in the same family.

    PubMed

    Shih, V E; Coulombe, J T; Wadman, S K; Duran, M; Waelkens, J J

    1984-09-01

    Methylmalonic aciduria and Hartnup disorder are two rare autosomal recessively inherited metabolic disorders. We have described the coexistence of these disorders within the same pedigree in two unrelated families. This association was not found in 57 other families surveyed because of a proband known to have either methylmalonic aciduria or Hartnup disorder. PMID:6478642

  6. Glutaric aciduria type 1 as a cause of dystonic cerebral palsy

    PubMed Central

    Mohamed, Sarar; Hamad, Muddathir H.; Hassan, Hamdy H.; Salih, Mustafa A.

    2015-01-01

    Glutaric aciduria type 1 (GA1) is an inherited inborn error of metabolism caused by a deficiency of the enzyme glutaryl Co-A dehydrogenase (GCDH). Here, we report a 14-month-old Saudi boy with GA1 who presented with severe dystonia and was mis-diagnosed as cerebral palsy (CP). He presented to our institute with encephalopathy following an episode of gastroenteritis. His physical examination showed dystonia and spastic quadriplegia. His investigations revealed elevated both urinary 3-hydroxy glutaric acid, and serum glutarylcarnitine. The DNA analysis confirmed homozygosity for a mutation in the GCDH-coding gene (c.482G>A;p.R161Q). This case alerts pediatricians to consider GA1 as a differential diagnosis of children presenting with dystonic CP. PMID:26593172

  7. Positive-ion thermospray liquid chromatography-mass spectrometry: detection of organic acidurias.

    PubMed

    Buchanan, D N; Muenzer, J; Thoene, J G

    1990-12-14

    Positive-ion thermospray liquid chromatography-mass spectrometry (TSP-LC-MS) is used to detect organic acids via the direct injection of untreated urine from newborns and infants. Two methods are reported for the separation of organic acids. The separation of urinary organic acids is effected in either an acidic, pH 2.5 sulfuric acid, or a non-acidic, 0.05 M ammonium acetate, pH 6.8, mobile phase. Use of pH 2.5 sulfuric acid and an HPX-87H organic acid column produces better separation but has less sensitivity than the use of 0.05 M ammonium acetate, pH 6.8 and a C18 column. Positive ion TSP-LC-MS has been used to detect methylmalonic aciduria, 3-hydroxy-3-methylglutaric aciduria, propionic aciduria, isovaleric aciduria and argininosuccinic aciduria. PMID:1709942

  8. Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins

    PubMed Central

    Schwab, Marina A.; Sauer, Sven W.; Okun, Jürgen G.; Nijtmans, Leo G. J.; Rodenburg, Richard J. T.; van den Heuvel, Lambert P.; Dröse, Stefan; Brandt, Ulrich; Hoffmann, Georg F.; Ter Laak, Henk; Kölker, Stefan; Smeitink, Jan A. M.

    2006-01-01

    Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid cycle enzymes also revealed an inhibition by propionyl-CoA on respiratory chain complex III and α-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I–IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms. PMID:16686602

  9. Expression, purification and crystallization of Trypanosoma cruzi dihydroorotate dehydrogenase complexed with orotate

    SciTech Connect

    Inaoka, Daniel Ken; Takashima, Eizo; Osanai, Arihiro; Shimizu, Hironari; Nara, Takeshi; Aoki, Takashi; Harada, Shigeharu; Kita, Kiyoshi

    2005-10-01

    The Trypanosoma cruzi dihydroorotate dehydrogenase, a key enzyme in pyrimidine de novo biosynthesis and redox homeostasis, was crystallized in complex with its first reaction product, orotate. Dihydroorotate dehydrogenase (DHOD) catalyzes the oxidation of dihydroorotate to orotate, the fourth step and the only redox reaction in the de novo biosynthesis of pyrimidine. DHOD from Trypanosoma cruzi (TcDHOD) has been expressed as a recombinant protein in Escherichia coli and purified to homogeneity. Crystals of the TcDHOD–orotate complex were grown at 277 K by the sitting-drop vapour-diffusion technique using polyethylene glycol 3350 as a precipitant. The crystals diffract to better than 1.8 Å resolution using synchrotron radiation (λ = 0.900 Å). X-ray diffraction data were collected at 100 K and processed to 1.9 Å resolution with 98.2% completeness and an overall R{sub merge} of 7.8%. The TcDHOD crystals belong to the orthorhombic space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 67.87, b = 71.89, c = 123.27 Å. The presence of two molecules in the asymmetric unit (2 × 34 kDa) gives a crystal volume per protein weight (V{sub M}) of 2.2 Å{sup 3} Da{sup −1} and a solvent content of 44%.

  10. N-carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria.

    PubMed

    Filippi, Luca; Gozzini, Elena; Fiorini, Patrizio; Malvagia, Sabrina; la Marca, Giancarlo; Donati, Maria Alice

    2010-01-01

    In propionic aciduria and methylmalonic aciduria, hyperammonemia as a symptom of metabolic decompensation is one of the major clinical problems. Hyperammonemia is a true neonatal emergency with high mortality and neurological complications in most survivors. It requires a rapid and vigorous treatment in order to normalize the ammonia concentration as fast as possible. We report on two full-term neonates, one with propionic aciduria and the other with methylmalonic aciduria, whose plasma ammonia concentrations responded dramatically to oral N-carbamylglutamate. N-carbamylglutamate, added to the classic treatment, quickly normalized plasma ammonia levels in both patients and avoided the need of hemodialysis or peritoneal dialysis. A particularly sudden fall of ammonia was obtained in one patient through beginning N-carbamylglutamate treatment precociously. PMID:19887858

  11. Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in c7orf10.

    PubMed

    Sherman, Eric A; Strauss, Kevin A; Tortorelli, Silvia; Bennett, Michael J; Knerr, Ina; Morton, D Holmes; Puffenberger, Erik G

    2008-11-01

    While screening Old Order Amish children for glutaric aciduria type 1 (GA1) between 1989 and 1993, we found three healthy children who excreted abnormal quantities of glutaric acid but low 3-hydroxyglutaric acid, a pattern consistent with glutaric aciduria type 3 (GA3). None of these children had the GCDH c.1262C-->T mutation that causes GA1 among the Amish. Using single-nucleotide polymorphism (SNP) genotypes, we identified a shared homozygous 4.7 Mb region on chromosome 7. This region contained 25 genes including C7orf10, an open reading frame with a putative mitochondrial targeting sequence and coenzyme-A transferase domain. Direct sequencing of C7orf10 revealed that the three Amish individuals were homozygous for a nonsynonymous sequence variant (c.895C-->T, Arg299Trp). We then sequenced three non-Amish children with GA3 and discovered two nonsense mutations (c.322C-->T, Arg108Ter, and c.424C-->T, Arg142Ter) in addition to the Amish mutation. Two pathogenic alleles were identified in each of the six patients. There was no consistent clinical phenotype associated with GA3. In affected individuals, urine molar ratios of glutarate to its derivatives (3-hydroxyglutarate, glutarylcarnitine, and glutarylglycine) were elevated, suggesting impaired formation of glutaryl-CoA. These observations refine our understanding of the lysine-tryptophan degradation pathway and have important implications for the pathophysiology of GA1. PMID:18926513

  12. Genetic Mapping of Glutaric Aciduria, Type 3, to Chromosome 7 and Identification of Mutations in C7orf10

    PubMed Central

    Sherman, Eric A.; Strauss, Kevin A.; Tortorelli, Silvia; Bennett, Michael J.; Knerr, Ina; Morton, D. Holmes; Puffenberger, Erik G.

    2008-01-01

    While screening Old Order Amish children for glutaric aciduria type 1 (GA1) between 1989 and 1993, we found three healthy children who excreted abnormal quantities of glutaric acid but low 3-hydroxyglutaric acid, a pattern consistent with glutaric aciduria type 3 (GA3). None of these children had the GCDH c.1262C→T mutation that causes GA1 among the Amish. Using single-nucleotide polymorphism (SNP) genotypes, we identified a shared homozygous 4.7 Mb region on chromosome 7. This region contained 25 genes including C7orf10, an open reading frame with a putative mitochondrial targeting sequence and coenzyme-A transferase domain. Direct sequencing of C7orf10 revealed that the three Amish individuals were homozygous for a nonsynonymous sequence variant (c.895C→T, Arg299Trp). We then sequenced three non-Amish children with GA3 and discovered two nonsense mutations (c.322C→T, Arg108Ter, and c.424C→T, Arg142Ter) in addition to the Amish mutation. Two pathogenic alleles were identified in each of the six patients. There was no consistent clinical phenotype associated with GA3. In affected individuals, urine molar ratios of glutarate to its derivatives (3-hydroxyglutarate, glutarylcarnitine, and glutarylglycine) were elevated, suggesting impaired formation of glutaryl-CoA. These observations refine our understanding of the lysine-tryptophan degradation pathway and have important implications for the pathophysiology of GA1. PMID:18926513

  13. Orotate phosphoribosyl transferase MoPyr5 is involved in uridine 5'-phosphate synthesis and pathogenesis of Magnaporthe oryzae.

    PubMed

    Qi, Zhongqiang; Liu, Muxing; Dong, Yanhan; Yang, Jie; Zhang, Haifeng; Zheng, Xiaobo; Zhang, Zhengguang

    2016-04-01

    Orotate phosphoribosyl transferase (OPRTase) plays an important role in de novo and salvage pathways of nucleotide synthesis and is widely used as a screening marker in genetic transformation. However, the function of OPRTase in plant pathogens remains unclear. In this study, we characterized an ortholog of Saccharomyces cerevisiae Ura5, the OPRTase MoPyr5, from the rice blast fungus Magnaporthe oryzae. Targeted gene disruption revealed that MoPyr5 is required for mycelial growth, appressorial turgor pressure and penetration into plant tissues, invasive hyphal growth, and pathogenicity. Interestingly, the ∆Mopyr5 mutant is also involved in mycelial surface hydrophobicity. Exogenous uridine 5'-phosphate (UMP) restored vegetative growth and rescued the defect in pathogenicity on detached barley and rice leaf sheath. Collectively, our results show that MoPyr5 is an OPRTase for UMP biosynthesis in M. oryzae and indicate that UTP biosynthesis is closely linked with vegetative growth, cell wall integrity, and pathogenicity of fungus. Our results also suggest that UMP biosynthesis would be a good target for the development of novel fungicides against M. oryzae. PMID:26810198

  14. Glutaric aciduria type I: outcome in the Republic of Ireland.

    PubMed

    Naughten, E R; Mayne, P D; Monavari, A A; Goodman, S I; Sulaiman, G; Croke, D T

    2004-01-01

    Twenty-one patients have been diagnosed with glutaric aciduria type I over a 16-year period in the Republic of Ireland, 11 following clinical presentation and 10 following a high-risk screen. Nineteen have been managed with diet. Eight patients have died, of whom 7 were diagnosed clinically. Six had dystonic and one spastic cerebral palsy. Of the 11 patients who did not have cerebral palsy, 10 were diagnosed following a high-risk screen. Seven of the 11 have no abnormal neurological signs; 6 of the 7 have abnormal CT or MRI findings; and no case of striatal degeneration has occurred during the past 14 years in the high-risk screened group. PMID:15505400

  15. An interesting case of metabolic dystonia: L-2 hydroxyglutaric aciduria.

    PubMed

    Balaji, Padma; Viswanathan, V; Chellathurai, Amarnath; Panigrahi, Debasis

    2014-01-01

    L-2-hydroxyglutaric aciduria (L-2-HGA), a neurometabolic disorder caused by mutations in the L-2 hydroxyglutarate dehydrogenase (L-2-HGDH) gene, presents with psychomotor retardation, cerebellar ataxia, extrapyramidal symptoms, macrocephaly and seizures. Characteristic magnetic resonance imaging findings include subcortical cerebral white matter abnormalities with T2 hyperintensities of the dentate nucleus, globus pallidus, putamen and caudate nucleus. The diagnosis can be confirmed by elevated urinary L-2 hydroxyglutaric acid and mutational analysis of the L-2-HGDH gene. We report two siblings with dystonia diagnosed by classical neuroimaging findings with elevated urinary 2 hydroxyglutaric acid. Riboflavin therapy has shown promising results in a subset of cases, thus highlighting the importance of making the diagnosis in these patients. PMID:24753671

  16. An interesting case of metabolic dystonia: L-2 hydroxyglutaric aciduria

    PubMed Central

    Balaji, Padma; Viswanathan, V.; Chellathurai, Amarnath; Panigrahi, Debasis

    2014-01-01

    L-2-hydroxyglutaric aciduria (L-2-HGA), a neurometabolic disorder caused by mutations in the L-2 hydroxyglutarate dehydrogenase (L-2-HGDH) gene, presents with psychomotor retardation, cerebellar ataxia, extrapyramidal symptoms, macrocephaly and seizures. Characteristic magnetic resonance imaging findings include subcortical cerebral white matter abnormalities with T2 hyperintensities of the dentate nucleus, globus pallidus, putamen and caudate nucleus. The diagnosis can be confirmed by elevated urinary L-2 hydroxyglutaric acid and mutational analysis of the L-2-HGDH gene. We report two siblings with dystonia diagnosed by classical neuroimaging findings with elevated urinary 2 hydroxyglutaric acid. Riboflavin therapy has shown promising results in a subset of cases, thus highlighting the importance of making the diagnosis in these patients. PMID:24753671

  17. IDH2 mutations in patients with D-2-hydroxyglutaric aciduria.

    PubMed

    Kranendijk, Martijn; Struys, Eduard A; van Schaftingen, Emile; Gibson, K Michael; Kanhai, Warsha A; van der Knaap, Marjo S; Amiel, Jeanne; Buist, Neil R; Das, Anibh M; de Klerk, Johannis B; Feigenbaum, Annette S; Grange, Dorothy K; Hofstede, Floris C; Holme, Elisabeth; Kirk, Edwin P; Korman, Stanley H; Morava, Eva; Morris, Andrew; Smeitink, Jan; Sukhai, Rám N; Vallance, Hilary; Jakobs, Cornelis; Salomons, Gajja S

    2010-10-15

    Heterozygous somatic mutations in the genes encoding isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) were recently discovered in human neoplastic disorders. These mutations disable the enzymes' normal ability to convert isocitrate to 2-ketoglutarate (2-KG) and confer on the enzymes a new function: the ability to convert 2-KG to d-2-hydroxyglutarate (D-2-HG). We have detected heterozygous germline mutations in IDH2 that alter enzyme residue Arg(140) in 15 unrelated patients with d-2-hydroxyglutaric aciduria (D-2-HGA), a rare neurometabolic disorder characterized by supraphysiological levels of D-2-HG. These findings provide additional impetus for investigating the role of D-2-HG in the pathophysiology of metabolic disease and cancer. PMID:20847235

  18. [A case of late-onset cobalamin C disease (methylmalonic aciduria and homocystinuria, cobalamin C type)].

    PubMed

    Yamamoto, Mikie; Yasui, Kenichi; Watanabe, Yasuhiro; Kowa, Hisanori; Yamaguchi, Seiji; Nakashima, Kenji

    2015-01-01

    We report the case of an 18-year-old Japanese woman with cobalamin (cbl) C disease. She was born between non- consanguineous parents, and had easy fatigability from a childhood. At 14 years old, she developed renal failure, and had repeated psychosis during 2 years. At 16 old, she developed her gait disturbance and her symptoms fluctuated, but the cause of gait disturbance was unclear. At 18 years old, she was admitted with worsening of gait disturbance. Physical examination revealed spastic paraparesis and bilateral peroneal nerve paralyses. Homocystinuria and methylmalonic aciduria were detected, although serum vitamin B12 was within normal range. Gene mutation analysis revealed Gly147Asp (440G>A) and Trp157Ser (470G>C) in the MMACHC gene as a compound heterozygous mutation. We diagnosed her as having late-onset cbl C disease, and her gait disturbance and renal failure improved after intramuscular hydroxocobalamin administration. Although late-onset cbl C disease is rare in Japan, it an important to consider this congenital disease because symptoms are expected to improve by medical intervention. PMID:25672861

  19. Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.

    PubMed

    Tort, Frederic; García-Silva, María Teresa; Ferrer-Cortès, Xènia; Navarro-Sastre, Aleix; Garcia-Villoria, Judith; Coll, Maria Josep; Vidal, Enrique; Jiménez-Almazán, Jorge; Dopazo, Joaquín; Briones, Paz; Elpeleg, Orly; Ribes, Antonia

    2013-01-01

    3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient's fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available. PMID:23707711

  20. Chronic intermittent form of isovaleric aciduria in a 2-year-old boy

    PubMed Central

    Cho, Jin Min; Lee, Beom Hee; Kim, Gu-Hwan; Kim, Yoo-Mi; Choi, Jin-Ho

    2013-01-01

    Isovaleric aciduria (IVA) is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD). IVA presents either in the neonatal period as an acute episode of fulminant metabolic acidosis, which may lead to coma or death, or later as a "chronic intermittent form" that is associated with developmental delays, with or without recurrent acidotic episodes during periods of stress, such as infections. Here, we report the case of a 2-year old boy with IVA who presented with the chronic intermittent form. He was admitted to Asan Medical Center Children's Hospital with recurrent vomiting. Metabolic acidosis, hyperammonemia, elevated serum lactate and isovalerylcarnitine levels, and markedly increased urine isovalerylglycine concentration were noted. Sequence analysis of the IVD gene in the patient revealed the novel compound mutations-a missense mutation, c.986T>C (p.Met329Thr) and a frameshift mutation, c.1083del (p.Ile361fs*11). Following stabilization during the acute phase, the patient has remained in a stable condition on a low-leucine diet. PMID:24019846

  1. Correction of Methylmalonic Aciduria In Vivo Using a Codon-Optimized Lentiviral Vector

    PubMed Central

    Wong, Edward S.Y.; McIntyre, Chantelle; Peters, Heidi L.; Ranieri, Enzo; Anson, Donald S.

    2014-01-01

    Abstract Methylmalonic aciduria is a rare disorder of organic acid metabolism with limited therapeutic options, resulting in high morbidity and mortality. Positive results from combined liver/kidney transplantation suggest, however, that metabolic sink therapy may be efficacious. Gene therapy offers a more accessible approach for the treatment of methylmalonic aciduria than organ transplantation. Accordingly, we have evaluated a lentiviral vector–mediated gene transfer approach in an in vivo mouse model of methylmalonic aciduria. A mouse model of methylmalonic aciduria (Mut−/−MUTh2) was injected intravenously at 8 weeks of age with a lentiviral vector that expressed a codon-optimized human methylmalonyl coenzyme A mutase transgene, HIV-1SDmEF1αmurSigHutMCM. Untreated Mut−/−MUTh2 and normal mice were used as controls. HIV-1SDmEF1αmurSigHutMCM-treated mice achieved near-normal weight for age, and Western blot analysis demonstrated significant methylmalonyl coenzyme A enzyme expression in their livers. Normalization of liver methylmalonyl coenzyme A enzyme activity in the treated group was associated with a reduction in plasma and urine methylmalonic acid levels, and a reduction in the hepatic methylmalonic acid concentration. Administration of the HIV-1SDmEF1αmurSigHutMCM vector provided significant, although incomplete, biochemical correction of methylmalonic aciduria in a mouse model, suggesting that gene therapy is a potential treatment for this disorder. PMID:24568291

  2. Expression, purification and crystallization of Trypanosoma cruzi dihydroorotate dehydrogenase complexed with orotate.

    PubMed

    Inaoka, Daniel Ken; Takashima, Eizo; Osanai, Arihiro; Shimizu, Hironari; Nara, Takeshi; Aoki, Takashi; Harada, Shigeharu; Kita, Kiyoshi

    2005-10-01

    Dihydroorotate dehydrogenase (DHOD) catalyzes the oxidation of dihydroorotate to orotate, the fourth step and the only redox reaction in the de novo biosynthesis of pyrimidine. DHOD from Trypanosoma cruzi (TcDHOD) has been expressed as a recombinant protein in Escherichia coli and purified to homogeneity. Crystals of the TcDHOD-orotate complex were grown at 277 K by the sitting-drop vapour-diffusion technique using polyethylene glycol 3350 as a precipitant. The crystals diffract to better than 1.8 A resolution using synchrotron radiation (lambda = 0.900 A). X-ray diffraction data were collected at 100 K and processed to 1.9 A resolution with 98.2% completeness and an overall Rmerge of 7.8%. The TcDHOD crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 67.87, b = 71.89, c = 123.27 A. The presence of two molecules in the asymmetric unit (2 x 34 kDa) gives a crystal volume per protein weight (VM) of 2.2 A3 Da(-1) and a solvent content of 44%. PMID:16511183

  3. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.

    PubMed

    Wortmann, Saskia B; Duran, Marinus; Anikster, Yair; Barth, Peter G; Sperl, Wolfgang; Zschocke, Johannes; Morava, Eva; Wevers, Ron A

    2013-11-01

    Increased urinary 3-methylglutaconic acid excretion is a relatively common finding in metabolic disorders, especially in mitochondrial disorders. In most cases 3-methylglutaconic acid is only slightly elevated and accompanied by other (disease specific) metabolites. There is, however, a group of disorders with significantly and consistently increased 3-methylglutaconic acid excretion, where the 3-methylglutaconic aciduria is a hallmark of the phenotype and the key to diagnosis. Until now these disorders were labelled by roman numbers (I-V) in the order of discovery regardless of pathomechanism. Especially, the so called "unspecified" 3-methylglutaconic aciduria type IV has been ever growing, leading to biochemical and clinical diagnostic confusion. Therefore, we propose the following pathomechanism based classification and a simplified diagnostic flow chart for these "inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature". One should distinguish between "primary 3-methylglutaconic aciduria" formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the--currently known--three groups of "secondary 3-methylglutaconic aciduria". The latter should be further classified and named by their defective protein or the historical name as follows: i) defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) and ii) mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect). The remaining patients with significant and consistent 3-methylglutaconic aciduria in whom the above mentioned syndromes have been excluded, should be referred to as "not otherwise specified (NOS) 3-MGA-uria" until elucidation of the underlying pathomechanism enables proper (possibly extended) classification. PMID:23296368

  4. A case of L-2 hydroxyglutaric aciduria presenting as febrile seizure.

    PubMed

    Calik, M; Tuncer, F N; Sarikaya, S; Karakas, O; Cece, H; Iscan, A

    2014-01-01

    L-2 hydroxyglutaric aciduria (L2HGA) is a rare, infantile-onset, autosomal recessive organic aciduria affecting exclusively the central nervous system. A case is reported here of L2HGA presenting with macrocephaly and febrile seizure. Although there have been reports of epilepsy associated with L2HGA, to the best of our knowledge this is the second case in literature of febrile seizure in a patient with L2HGA. This report suggests that detailed neurological evaluation of macrocephalic children with febrile convulsion is important. Moreover, metabolic and genetic investigations may be necessary for these kinds of patients. PMID:25804013

  5. 5-fluoro-orotic acid induces chromosome alterations in genetically manipulated strains of Candida albicans.

    PubMed

    Wellington, Melanie; Kabir, M Anaul; Rustchenko, Elena

    2006-01-01

    We previously reported the occurrence of chromosome alterations in a Candida albicans prototrophic strain 3153A treated with 5-fluoro-orotic acid (5-FOA). In this study we investigated the mutagenic properties of 5-FOA with two derivatives of C. albicans strain CAF4-2 (ura3/ura3), each containing an ectopic copy of URA3 gene (ura3/ ura3 URA3) on a different chromosome. As expected, after the ura3/ura3 URA3 constructs were applied to 5-FOA containing solid medium, the "pop-outs" that lost URA3 appeared. However most of the "pop-outs" acquired various chromosome alterations. Thus constructs exposed to 5-FOA should be examined for chromosome alterations or the use of 5-FOA should be avoided. PMID:17040068

  6. Structural Properties, Order-Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms.

    PubMed

    Braun, Doris E; Nartowski, Karol P; Khimyak, Yaroslav Z; Morris, Kenneth R; Byrn, Stephen R; Griesser, Ulrich J

    2016-03-01

    Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order-disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration. PMID:26741914

  7. Structural Properties, Order–Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms

    PubMed Central

    2016-01-01

    Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order–disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration. PMID:26741914

  8. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea cycle disorder, and leads to deficiency of both urea...

  9. Dynamic Changes of Striatal and Extrastriatal Abnormalities in Glutaric Aciduria Type I

    ERIC Educational Resources Information Center

    Harting, Inga; Neumaier-Probst, Eva; Seitz, Angelika; Maier, Esther M.; Assmann, Birgit; Baric, Ivo; Troncoso, Monica; Muhlhausen, Chris; Zschocke, Johannes; Boy, Nikolas P. S.; Hoffmann, Georg F.; Garbade, Sven F.; Kolker, Stefan

    2009-01-01

    In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3-36 months). The frequency of striatal injury is significantly less in patients diagnosed as…

  10. The peripartum management of a patient with glutaric aciduria type 1.

    PubMed

    Ituk, Unyime S; Allen, Terrence K; Habib, Ashraf S

    2013-03-01

    The management of cesarean delivery for a parturient with placenta previa at 36 weeks' gestation and glutaric aciduria type 1 is presented. The management goal was to prevent encephalopathic crisis by ensuring adequate caloric intake with dextrose infusion and to provide carnitine supplementation and adequate anesthesia. PMID:23352788

  11. Vascular dysfunction as an additional pathomechanism in glutaric aciduria type I.

    PubMed

    Mühlhausen, C; Ergün, S; Strauss, K A; Koeller, D M; Crnic, L; Woontner, M; Goodman, S I; Ullrich, K; Braulke, T

    2004-01-01

    The metabolic hallmark of glutaric aciduria type I (GA I) is the deficiency of glutaryl-CoA dehydrogenase (GCDH) with subsequent accumulation of glutaric acid, 3-hydroxglutaric acid (3-OH-GA) and glutaconic acid. Current concepts regarding pathomechanisms of GA I focus on investigations of excitotoxic effects of 3-OH-GA. To identify pathogenetically relevant genes, microarray analyses were performed using brain material from GCDH-deficient (GCDH (-/-)) and control mice. These microarray data confirmed recent pathogenic models, but also revealed alterations in genes that had previously not been correlated to the disease, e.g. genes concerning vascular biology. Subsequent in vitro and in vivo experiments confirmed direct effects of 3-OH-GA on vascular permeability and endothelial integrity. Clinical observations underscore the involvement of vascular dysfunction. In MRI scans of GA I patients, subdural effusions as well as dilated transarachnoid vascular plexuses were detected independently of encephalopathic crises. In fact, some of these findings are already detectable shortly after birth. MRI scans of a GA I patient performed during an acute encephalopathic crisis detected a dilated intrastriatal vasculature with perivascular hyperintensity, indicating local extravasation. In conclusion, we hypothesize that 3-OH-GA affects prenatal development of vessels, thus leading to an increased vulnerability of endothelial structures and subsequent vascular dysfunction. These observations display an additional pathomechanism in GA I and might explain frontotemporal hypoplasia and chronic subdural effusions in this disease. Elucidation of the pathomechanisms of vascular dysfunction may give further insights into the pathogenesis of GA I. PMID:15505389

  12. Useful second-tier tests in expanded newborn screening of isovaleric acidemia and methylmalonic aciduria.

    PubMed

    Shigematsu, Yosuke; Hata, Ikue; Tajima, Go

    2010-10-01

    Common use of pivalate-generating antibiotics in newborns in Japan and low cutoff value of C5-acylcarnitine (C5) to detect mild forms of isovaleric acidemia (IVA) led to 1,065 positive results from IVA screening among 146,000 newborns tested by tandem mass spectrometry over the last 3 years. Using our method to determine isovalerylglycine (IVG) levels in dried blood spots (DBS) as a second-tier test with IVG cutoff value of 0.5 nmol/ml in DBS, one patient with severe IVA was identified, and no recall of the second DBS was needed. Retrospective analysis revealed that most patients with moderate to severe forms of IVA have decreased free-carnitine levels shortly after birth and higher levels of IVG than those of C5, which suggests that this method is useful in evaluating the severity of IVA. Another second-tier test, to measure methylmalonic acid (MMA) levels in DBS by gas chromatography/mass spectrometry (GC/MS), has been developed to overcome difficulties in screening methylmalonic aciduria (MMAU) and propionic acidemia. Methanol extract from DBS was dried and derivatized using N-methyl-N-(tert-butyldimethylsilyl)-trifluoroacetamide. GC/MS was performed using splitless injection, electron-impact ionization, and selected ion monitoring for data recording. MMAU patients had much higher DBS concentrations of MMA (24.2-321.9 nmol/ml) than control newborns (0.34 ± 0.11 nmol/ml). MMA measurement in DBS was thought to provide useful information about the severity of MMAU, as MMAU patients with high levels of MMA had decreased levels of free carnitine and mildly increased levels of propionylcarnitine. PMID:20440648

  13. Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria.

    PubMed

    Ruppert, T; Schumann, A; Gröne, H J; Okun, J G; Kölker, S; Morath, M A; Sauer, S W

    2015-12-15

    Methylmalonic acidurias (MMAurias) are a group of inherited disorders in the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol caused by complete or partial deficiency of methylmalonyl-CoA mutase (mut(0) and mut(-) subtype respectively) and by defects in the metabolism of its cofactor 5'-deoxyadenosylcobalamin (cblA, cblB or cblD variant 2 type). A long-term complication found in patients with mut(0) and cblB variant is chronic tubulointerstitial nephritis. The underlying pathomechanism has remained unknown. We established an in vitro model of tubular epithelial cells from patient urine (hTEC; 9 controls, 5 mut(0), 1 cblB). In all human tubular epithelial cell (hTEC) lines we found specific tubular markers (AQP1, UMOD, AQP2). Patient cells showed disturbance of energy metabolism in glycolysis, mitochondrial respiratory chain and Krebs cycle in concert with increased reactive oxygen species (ROS) formation. Electron micrographs indicated increased autophagosome production and endoplasmic reticulum stress, which was supported by positive acridine orange staining and elevated levels of LC3 II, P62 and pIRE1. Screening mTOR signaling revealed a release of inhibition of autophagy. Patient hTEC produced and secreted elevated amounts of the pro-inflammatory cytokine IL8, which was highly correlated with the acridine orange staining. Summarizing, hTEC of MMAuria patients are characterized by disturbed energy metabolism and ROS production that lead to increased autophagy and IL8 secretion. PMID:26420839

  14. Argininosuccinate Lyase Deficiency – Argininosuccinic Aciduria and Beyond

    PubMed Central

    Erez, Ayelet; Sreenath Nagamani, Sandesh C.; Lee, Brendan

    2011-01-01

    The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate Lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, i.e. the breakdown of argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of argininosuccinic acid in tissues, and excretion of argininosuccinic acid in urine leading to the condition argininosuccinic aciduria, ASA. ASA is an autosomal recessive disorder and is the second most common urea cycle disorder. In addition to the accumulation of argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine which is in common with all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell’s needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of argininosuccinic acid. This review article summarizes the clinical characterization

  15. Investigation of vital pathogenic target orotate phosphoribosyltransferases (OPRTase) from Thermus thermophilus HB8: Phylogenetic and molecular modeling approach.

    PubMed

    Surekha, Kanagarajan; Prabhu, Damodharan; Richard, Mariadasse; Nachiappan, Mutharasappan; Biswal, Jayashree; Jeyakanthan, Jeyaraman

    2016-06-01

    Biosynthesis pathways of pyrimidine and purine are shown to play an important role in regular cellular activities. The biosynthesis can occur either through de novo or salvage pathways based on the requirement of the cell. The pyrimidine biosynthesis pathway has been linked to several disorders and various autoimmune diseases. Orotate phosphoribosyl transferase (OPRTase) is an important enzyme which catalyzes the conversion of orotate to orotate monophosphate in the fifth step of pyrimidine biosynthesis. Phylogenetic analysis of 228 OPRTase sequences shows the distribution of proteins across different living forms of life. High structural similarities between Thermusthermophilus and other organisms kindled us to concentrate on OPRTase as an anti-pathogenic target. In this study, a homology model of OPRTase was constructed using 2P1Z as a template. About 100 ns molecular dynamics simulation was performed to investigate the conformational stability and dynamic patterns of the protein. The amino acid residues (Met1, Asp2, Glu43, Ala44, Glu47, Lys51, Ala157 and Leu158) lining in the binding site were predicted using SiteMap. Further, structure based virtual screening was performed on the predicted binding site using ChemBridge, Asinex, Binding, NCI, TosLab and Zinc databases. Compounds retrieved from the screening collections were manually clustered. The resultant protein-ligand complexes were subjected to molecular dynamics simulations, which further validates the binding modes of the hits. The study may provide better insight for designing potent anti-pathogenic agent. PMID:26861612

  16. Orotate phosphoribosyltransferase localizes to the Golgi complex and its expression levels affect the sensitivity to anti-cancer drug 5-fluorouracil.

    PubMed

    Hozumi, Yasukazu; Tanaka, Toshiaki; Nakano, Tomoyuki; Matsui, Hirooki; Nasu, Takashi; Koike, Shuji; Kakehata, Seiji; Ito, Tsukasa; Goto, Kaoru

    2015-01-01

    Orotate phosphoribosyltransferase (OPRT) is engaged in de novo pyrimidine synthesis. It catalyzes oronitine to uridine monophosphate (UMP), which is used for RNA synthesis. De novo pyrimidine synthesis has long been known to play an important role in providing DNA/RNA precursors for rapid proliferative activity of cancer cells. Furthermore, chemotherapeutic drug 5-fluorouracil (5-FU) is taken up into cancer cells and is converted to 5-fluoro-UMP (FUMP) by OPRT or to 5-fluoro-dUMP (FdUMP) through intermediary molecules by thymidine phosphorylase. These 5-FU metabolites are misincorporated into DNA/RNA, thereby producing dysfunction of these information processing. However, it remains unclear how the subcellular localization of OPRT and how its variable expression levels affect the response to 5-FU at the cellular level. In this study, immunocytochemical analysis reveals that OPRT localizes to the Golgi complex. Results also show that not only overexpression but also downregulation of OPRT render cells susceptible to 5-FU exposure, but it has no effect on DNA damaging agent doxorubicin. This study provides clues to elucidate the cellular response to 5-FU chemotherapy in relation to the OPRT expression level. PMID:26700594

  17. Impaired energy metabolism and abnormal muscle histology in mut- methylmalonic aciduria.

    PubMed

    Østergaard, E; Wibrand, F; Ørngreen, M C; Vissing, J; Horn, N

    2005-09-27

    The authors report a 27-year-old man with B12-responsive mut- methylmalonic aciduria associated with pure muscle symptoms. Two mutations were found in the methylmalonyl-CoA mutase gene. An exercise test showed a reduced maximal workload and reduced oxygen uptake, and a muscle biopsy showed subsarcolemmal accumulation of mitochondria and normal respiratory chain enzyme activities. These findings may be caused by inhibition of mitochondrial energy metabolism by methylmalonate or its metabolites. PMID:16186538

  18. [Peripheral nervous impairment in a patient with methylmalonic aciduria combined with hyperhomocysteinemia].

    PubMed

    Ji, Tao-yun; Zhang, Yue-hua; Li, Fei-tian; Qin, Jiong; Yang, Yan-ling

    2013-04-18

    Methylmalonic aciduria combined homocysteinemia can cause multisystemic damages, mainly involving central nervous system, while the peripheral nerves are rarely impaired. A 10-year-old boy complained of weakness of both lower extremities for 1 month. His past history showed mildly delay of intelligence as well as motor development. He had proteinuria when he was 3 years old and was diagnosed as epilepsy, which was controlled by sodium valproate when he was 8 years 6 months old. His physical examination showed attenuated bilateral knee jerk reflex, while the bilateral achilles tendon reflex was absent; the examination of sensation was normal and the bilateral Babinski sign was positive. The electromyography indicated injury of peripheral nerves. The elevated levels of urine methylmalonic aciduria and plasma homocysteinemia were consistent with the diagnosis of methylmalonic aciduria combined homocysteinemia. The pathogenic gene was confirmed as MMACHC, on which two pathogenic mutations (c.365A>T and c.609G>A) were detected. cblC defect was confirmed. He was treated by vitamin B12, calcium folinate, L-carnitine and betaine supplementation, and significant improvement was observed after 6 months. According to this case, we suggest that urinary organic acid analysis and plasma homocysteine should be performed in patients with unknown peripheral neuropathy, especially combined with multisystemic damages.Early diagnosis and treatment are important to improve the prognosis. PMID:23591356

  19. Molecular Genetic Characterization of 151 Mut-Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT.

    PubMed

    Forny, Patrick; Schnellmann, Anne-Sophie; Buerer, Celine; Lutz, Seraina; Fowler, Brian; Froese, D Sean; Baumgartner, Matthias R

    2016-08-01

    Isolated methylmalonic aciduria (MMA) is an autosomal-recessive disorder of propionate metabolism that is most commonly caused by mutations in the methylmalonyl-CoA mutase (MUT) gene (mut-type MMA). We investigated a cohort of 151 patients, classifying 114 patients as mut(0) and 32 as mut(-) (five not defined). As per the definition, mut(-) patients showed a higher propionate incorporation ratio in vitro, which was correlated to a considerably later age of onset compared with mut(0) patients. In all patients, we found a total of 110 different mutations, of which 41 were novel. While the missense alleles p.Asn219Tyr, p.Arg369His, and p.Arg694Trp recurred in >10 alleles, 47 mutations were identified only once, suggesting many patients carry private mutations. Deficient alleles in the mut(-) subclass were almost exclusively caused by missense mutations, found disproportionately in the C-terminal cofactor binding domain. On the contrary, only half of the mut(0) mutations were of the missense type. Western blot analysis revealed reduced MUT protein for all 34 cell lines (27 mut(0) , seven mut(-) ) tested, suggesting protein instability as a major mechanism of deficiency in mut-type MMA. This large-scale evaluation helps to characterize the landscape of MUT mutations and their relationship to dysfunction and disease. PMID:27167370

  20. Orotate phosphoribosyltransferase is overexpressed in malignant pleural mesothelioma: Dramatically responds one case in high OPRT expression

    PubMed Central

    Hamamoto, Yoichiro; Takeoka, Shinjiro; Mouri, Atsuto; Fukusumi, Munehisa; Wakuda, Kazushige; Ibe, Tatsuya; Honma, Chie; Arimoto, Yoshihito; Yamada, Kazuaki; Wagatsuma, Miyuki; Tashiro, Akito; Kamoshida, Shingo; Kamimura, Mitsuhiro

    2016-01-01

    ABSTRACT Objective: Malignant pleural mesothelioma (MPM) is a rare and aggressive, treatment-resistant cancer. Pemetrexed, an inhibitor of thymidylate synthase (TS), is used worldwide for MPM as a first-line chemotherapy regimen. However, there is little consensus for a second-line chemotherapy. S-1, a highly effective dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidine, mainly acts via a TS inhibitory mechanism similar to pemetrexed. Orotate phosphoribosyltransferase (OPRT) is a key enzyme related to the first step activation of 5-fluorouracil (5-FU) for inhibiting RNA synthesis. We investigated 5-FU related-metabolism proteins, especially focusing on OPRT expression, in MPM Methods and Patients: Fifteen MPM patients who were diagnosed between July 2004 and December 2013 were enrolled. We examined the protein levels of 5-FU metabolism-related enzymes (TS, DPD, OPRT, and thymidine phosphorylase [TP]) in 14 cases Results: High TS, DPD, OPRT, and TP expressions were seen in 28.6%, 71.4%, 85.7%, and 35.7% of patients, respectively. We found that OPRT expression was extremely high in MPM tissue. We experienced one remarkable case of highly effective S-1 combined therapy for pemetrexed refractory MPM. This case also showed high OPRT protein expression Conclusion: The present study suggests that OPRT expression is high in MPM tumors. Although pemetrexed is mainly used for MPM chemotherapy as a TS inhibitor, S-1 has potential as an anticancer drug not only as a TS inhibitor but also inhibiting RNA synthesis through the OPRT pathway. This is the first report investigating OPRT protein expressions in MPM. PMID:27274438

  1. Dietary sea cucumber cerebroside alleviates orotic acid-induced excess hepatic adipopexis in rats

    PubMed Central

    2012-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease in industrialized countries. The present study was undertaken to explore the preventive effect of dietary sea cucumber cerebroside (SCC) extracted from Acaudina molpadioides in fatty liver rats. Methods Male Wistar rats were randomly divided into four groups including normal control group, NAFLD model group, and two SCC-treated groups with SCC at 0.006% and 0.03% respectively. The fatty liver model was established by administration of 1% orotic acid (OA) to the rats. After 10d, serum and hepatic lipid levels were detected. And the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were also determined. Besides, to gain the potential mechanism, the changes of key enzymes and gene expressions related to the hepatic lipid metabolism were measured. Results Dietary SCC at the level of 0.006% and 0.03% ameliorated the hepatic lipid accumulation in fatty liver rats. SCC administration elevated the serum triglyceride (TG) level and the ALT, AST activities in OA-fed rats. The activities of hepatic lipogenic enzymes including fatty acid synthase (FAS), malic enzyme (ME) and glucose-6-phosphatedehydrogenase (G6PDH) were inhibited by SCC treatment. And the gene expressions of FAS, ME, G6PDH and sterol-regulatory element binding protein (SREBP-1c) were also reduced in rats fed SCC. However, dietary SCC didn't affect the activity and mRNA expression of carnitine palmitoyltransferase (CPT) in liver. Besides, suppression of microsomal triglyceride transfer protein (MTP) activity was observed in SCC-feeding rats. Conclusions These results suggested that dietary SCC could attenuate hepatic steatosis due to its inhibition of hepatic lipogenic gene expression and enzyme activity and the enhancement of TG secretion from liver. PMID:22569330

  2. Methylmalonic aciduria with homocystinuria: biochemical studies, treatment, and clinical course of a Cbl-C patient.

    PubMed

    Ribes, A; Briones, P; Vilaseca, M A; Lluch, M; Rodes, M; Maya, A; Campistol, J; Pascual, P; Suormala, T; Baumgartner, R

    1990-03-01

    A patient with infantile onset methylmalonic aciduria and homocystinuria (Cbl-C mutant) is described. Therapy with hydroxycobalamin, folate and vitamin B6 improved his condition. As hypomethioninaemia and homocystinaemia persisted, he was treated with intramuscular methylcobalamin, but without success. Treatment with betaine started at 25 months of age, normalized plasma methionine and elicited disappearance of homocystinaemia. Results of biochemical studies in cultured fibroblasts paralleled those described for other Cbl-C patients except that methylmalonyl-coenzyme A mutase activity in disrupted fibroblasts was in the normal range. PMID:2332011

  3. Insights into the mechanism of oxidation of dihydroorotate to orotate catalysed by human class 2 dihydroorotate dehydrogenase: a QM/MM free energy study.

    PubMed

    Alves, Cláudio Nahum; Silva, José Rogério A; Roitberg, Adrian E

    2015-07-21

    The dihydroorotate dehydrogenase (DHOD) enzyme catalyzes the unique redox reaction in the de novo pyrimidine biosynthesis pathway. In this reaction, the oxidation of dihydroorotate (DHO) to orotate (OA) and reduction of the flavin mononucleotide (FMN) cofactor is catalysed by DHOD. The class 2 DHOD, to which the human enzyme belongs, was experimentally shown to follow a stepwise mechanism but the data did not allow the determination of the order of bond-breaking in a stepwise oxidation of DHO. The goal of this study is to understand the reaction mechanism at the molecular level of class 2 DHOD, which may aid in the design of inhibitors that selectively impact the activity of only certain members of the enzyme family. In this paper, the catalytic mechanism of oxidation of DHO to OA in human DHOD was studied using a hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) approach and Molecular Dynamics (MD) simulations. The free energy barriers calculated reveal that the mechanism in human DHOD occurs via a stepwise reaction pathway. In the first step, a proton is abstracted from the C5 of DHO to the deprotonated Ser215 side chain. Whereas, in the second step, the transfer of the hydride or hydride equivalent from the C6 of DHO to the N5 of FMN, where free energy barrier calculated by the DFT/MM level is 10.84 kcal mol(-1). Finally, a residual decomposition analysis was carried out in order to elucidate the influence of the catalytic region residues during DHO oxidation. PMID:26087682

  4. Glutaric aciduria type 2 presenting with acute respiratory failure in an adult

    PubMed Central

    Ersoy, Ebru Ortac; Rama, Dorina; Ünal, Özlem; Sivri, Serap; Topeli, Arzu

    2015-01-01

    Glutaric aciduria (GTA) type II can be seen as late onset form with myopathic phenotype. We present a case of a 19-year old female with progressive muscle weakness was admitted in intensive care unit (ICU) with respiratory failure and acute renal failure. Patient was unconscious. Pupils were anisocoric and light reflex was absent. She had hepatomegaly. The laboratory results showed a glucose level of 70 mg/dl and the liver enzymes were high. The patient also had hyponatremia (117 mEq/L) and lactate level of 3.9 mmol/L. Tandem MS and organic acid analysis were compatible with GTA type II. Carnitine 1gr, riboflavin 100 mg and co-enzymeQ10 100 mg was arranged. After four months from beginning of treatment tandem MS results are improved. Respiratory failure, acute renal failure due to profound proximal myopathy can be due to glutaric aciduria type II that responded rapidly to appropriate therapy. PMID:26236614

  5. Glutaric aciduria type 2 presenting with acute respiratory failure in an adult.

    PubMed

    Ersoy, Ebru Ortac; Rama, Dorina; Ünal, Özlem; Sivri, Serap; Topeli, Arzu

    2015-01-01

    Glutaric aciduria (GTA) type II can be seen as late onset form with myopathic phenotype. We present a case of a 19-year old female with progressive muscle weakness was admitted in intensive care unit (ICU) with respiratory failure and acute renal failure. Patient was unconscious. Pupils were anisocoric and light reflex was absent. She had hepatomegaly. The laboratory results showed a glucose level of 70 mg/dl and the liver enzymes were high. The patient also had hyponatremia (117 mEq/L) and lactate level of 3.9 mmol/L. Tandem MS and organic acid analysis were compatible with GTA type II. Carnitine 1gr, riboflavin 100 mg and co-enzymeQ10 100 mg was arranged. After four months from beginning of treatment tandem MS results are improved. Respiratory failure, acute renal failure due to profound proximal myopathy can be due to glutaric aciduria type II that responded rapidly to appropriate therapy. PMID:26236614

  6. Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria.

    PubMed

    Dobson, C Melissa; Wai, Timothy; Leclerc, Daniel; Kadir, Hakan; Narang, Monica; Lerner-Ellis, Jordan P; Hudson, Thomas J; Rosenblatt, David S; Gravel, Roy A

    2002-12-15

    The methylmalonic acidurias are metabolic disorders resulting from deficient methylmalonyl-CoA mutase activity, a vitamin B(12)-dependent enzyme. We have cloned the gene for the cblB complementation group caused by deficient activity of a cob(I)alamin adenosyltransferase. This was accomplished by searching bacterial genomes for genes in close proximity to the methylmalonyl-CoA mutase gene that might encode a protein with the properties of an adenosyltransferase. A candidate was identified in the Archaeoglobus fulgidus genome and was used to probe the human genome database. It yielded a gene on chromosome 12q24 that encodes a predicted protein of 250 amino acids with 45% similarity to PduO in Salmonella enterica, a characterized cob(I)alamin adenosyltransferase. A northern blot revealed an RNA species of 1.1 kb predominating in liver and skeletal muscle. The gene was evaluated for deleterious mutations in cblB patient cell lines. Several mutations were identified including a 5 bp deletion (5del572gggcc576), two splice site mutations (IVS2-1G>T, IVS3-1G>A), andt several point mutations (A135T, R186W, R191W and E193K). Two additional amino acid substitutions (R19Q and M239K) were found in several patient cell lines but were found to be common polymorphisms (36% and 46%) in control alleles. The R186W mutation, which we suggest is disease-linked, is present in four of the six patient cell lines examined (homoallelic in two) and in 4 of 240 alleles in control samples. These data confirm that the identified gene, MMAB, corresponds to the cblB complementation group and has the appearance of a cob(I)alamin adenosyltransferase, as predicted from biochemical data. PMID:12471062

  7. Long-term fatty liver-induced insulin resistance in orotic acid-induced nonalcoholic fatty liver rats.

    PubMed

    Han, Xiuqing; Liu, Chunhua; Xue, Yong; Wang, Jingfeng; Xue, Changhu; Yanagita, Teruyoshi; Gao, Xiang; Wang, Yuming

    2016-04-01

    We investigated whether fatty liver preceded insulin resistance or vice versa using a long-term orotic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) model without the confounding effects of obesity and hyperlipidemia and explored the role of the liver in insulin resistance. Male Wistar rats were fed with or without OA supplementation for 30, 60, and 90 days. The NAFLD group showed increased liver lipid at 30, 60, and 90 days; glucose intolerance was noted at 60 and 90 days. Furthermore, partial liver proteins and gene expressions related to upstream signaling of insulin were decreased. However, the liver glycogen content was elevated, and gluconeogenesis genes expressions were obviously decreased at 90 days. The occurrence of fatty liver preceded insulin resistance in OA-induced NAFLD without the interference of obesity and hyperlipidemia, and hepatic insulin resistance may not play a conclusive role in insulin resistance in this model. PMID:26775542

  8. A Mouse Model of L-2-Hydroxyglutaric Aciduria, a Disorder of Metabolite Repair

    PubMed Central

    Rzem, Rim; Achouri, Younes; Marbaix, Etienne; Schakman, Olivier; Wiame, Elsa; Marie, Sandrine; Gailly, Philippe; Vincent, Marie-Françoise; Veiga-da-Cunha, Maria; Van Schaftingen, Emile

    2015-01-01

    The purpose of the present work was to progress in our understanding of the pathophysiology of L-2-hydroxyglutaric aciduria, due to a defect in L-2-hydroxyglutarate dehydrogenase, by creating and studying a mouse model of this disease. L-2-hydroxyglutarate dehydrogenase-deficient mice (l2hgdh-/-) accumulated L-2-hydroxyglutarate in tissues, most particularly in brain and testis, where the concentration reached ≈ 3.5 μmol/g. Male mice showed a 30% higher excretion of L-2-hydroxyglutarate compared to female mice, supporting that this dicarboxylic acid is partially made in males by lactate dehydrogenase C, a poorly specific form of this enzyme exclusively expressed in testes. Involvement of mitochondrial malate dehydrogenase in the formation of L-2-hydroxyglutarate was supported by the commensurate decrease in the formation of this dicarboxylic acid when down-regulating this enzyme in mouse l2hgdh-/- embryonic fibroblasts. The concentration of lysine and arginine was markedly increased in the brain of l2hgdh-/- adult mice. Saccharopine was depleted and glutamine was decreased by ≈ 40%. Lysine-α-ketoglutarate reductase, which converts lysine to saccharopine, was inhibited by L-2-hydroxyglutarate with a Ki of ≈ 0.8 mM. As low but significant activities of the bifunctional enzyme lysine-α-ketoglutarate reductase/saccharopine dehydrogenase were found in brain, these findings suggest that the classical lysine degradation pathway also operates in brain and is inhibited by the high concentrations of L-2-hydroxyglutarate found in l2hgdh-/- mice. Pathological analysis of the brain showed significant spongiosis. The vacuolar lesions mostly affected oligodendrocytes and myelin sheats, as in other dicarboxylic acidurias, suggesting that the pathophysiology of this model of leukodystrophy may involve irreversible pumping of a dicarboxylate in oligodendrocytes. Neurobehavioral testing indicated that the mice mostly suffered from a deficit in learning capacity. In

  9. 3-Hydroxy-3-methylglutaric aciduria with bilateral basal ganglia lesion: A case report

    PubMed Central

    HAO, XIAOSHENG; WANG, JIANGTAO; LIU, SONGYAN; CHEN, YINBO; ZHANG, YAN; HAO, YUNPENG

    2016-01-01

    3-Hydroxy-3-methylglutaric aciduria (3-HMG, OMIN 246450) is a rare autosomal recessive metabolic disorder caused by a deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase, a key enzyme in leucine metabolism and ketone body synthesis. Acute episodes of 3-HMG may be triggered by fasting or infection, and symptoms include vomiting, diarrhea, lethargy and hypotonia. If left untreated, prolonged hypoglycemia and metabolic acidosis may cause breathing problems, seizures, and coma. In addition, 3-HMG is associated with damage to the central nervous system, and there are several reports of white matter abnormality or cerebral atrophy. The presence of bilateral basal ganglia damage in 3-HMG has been rarely reported. Here, we present a case report of a 20-month old male with severe 3-HMG and prominent bilateral lesions in the basal ganglia. PMID:27284350

  10. The child with glutaric aciduria type I: anesthetic and perioperative management.

    PubMed

    Tsiotou, Adelais G; Malisiova, Anna; Bouzelos, Nikolaos; Velegrakis, Dimitrios

    2011-04-01

    Glutaric aciduria type I (GA-1) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase. It presents early in life, usually after an episode of fever, dehydration, infection or fasting, and results in metabolic decompensation and neurologic damage. We report the perioperative management of a 5-year-old boy admitted to the hospital for surgery because of neurogenic hip dislocation. Here we present the preoperative preparation, which focused on appropriate fluid administration and therapy intensification, as well as the safe anesthetic management with inhalation anesthesia and remifentanil, taking into consideration the mitochondrial basis of the disease. Furthermore, the role of postoperative care is emphasized in relation to stress response prophylaxis and the avoidance of complications related to the disorder. PMID:21221659

  11. White matter abnormalities in an adult patient with l-2-hydroxyglutaric aciduria.

    PubMed

    Yamamoto, Toshiyuki; Yoshioka, Seiichiro; Tsurusaki, Yoshinori; Shino, Shimada; Shimojima, Keiko; Shigematsu, Yosuke; Takeuchi, Yoshihiro; Matsumoto, Naomichi

    2016-01-01

    l-2-Hydroxyglutaric aciduria (l-2-HGA) is a rare inborn error of metabolism. Mainly, patients with this disorder exhibit neurological symptoms and characteristic neuroradiological findings, such as subcortical white matter abnormalities, which are believed to be caused by the toxicity of the accumulation of l-2-hydroxyglutaric acid. A genotype-first approach of the whole exome sequence was used to identify compound heterozygous mutations, c.584A>G (p.Y195C) and c.772T>C (p.C258R), in L2HGDH, the gene responsible for this disorder, in an adult patient with intellectual disability and intractable epilepsy. A retrospective assay confirmed the increased concentrations of 2-hydroxyglutaric acid in the urine. These results suggested that neuroradiological findings of subcortical white matter abnormalities are characteristic of l-2-HGA and that clinical exome sequencing has sufficient power to compensate for insufficient clinical evaluations. PMID:25982940

  12. Glutaric aciduria type II: biochemical investigation and treatment of a child diagnosed prenatally.

    PubMed

    Bennett, M J; Curnock, D A; Engel, P C; Shaw, L; Gray, R G; Hull, D; Patrick, A D; Pollitt, R J

    1984-01-01

    Two sibs with the acute neonatal form of glutaric aciduria type II (deficient in vivo activity of multiple acyl-CoA dehydrogenases) are described. In the second case diagnosis was made prenatally on the basis of reduced oxidation of palmitate by cultured amniotic fluid cells. With prompt intervention in the neonatal period and a carefully controlled diet later, this second progressed well up to 4 months of age but died suddenly of cardiac failure, probably attributable to accumulation of fat. Neither patient showed any congenital morphological abnormality. Cultured fibroblasts from the second case showed a marked defect in the oxidation of a range of substrates requiring acyl-CoA dehydrogenases for their catabolism, but residual activity for some substrates was quite high. Large quantities of sarcosine were excreted in urine, again suggesting that the mutation leaves some residual dehydrogenation activity. Butyryl-, octanoyl- and palmitoyl-CoA dehydrogenases were present in essentially normal quantities in postmortem liver. PMID:6207379

  13. Molecular and phenotypic characteristics of seven novel mutations causing branched-chain organic acidurias.

    PubMed

    Stojiljkovic, M; Klaassen, K; Djordjevic, M; Sarajlija, A; Brasil, S; Kecman, B; Grkovic, S; Kostic, J; Rodriguez-Pombo, P; Desviat, L R; Pavlovic, S; Perez, B

    2016-09-01

    Specific mitochondrial enzymatic deficiencies in the catabolism of branched-chain amino acids cause methylmalonic aciduria (MMA), propionic acidemia (PA) and maple syrup urine disease (MSUD). Disease-causing mutations were identified in nine unrelated branched-chain organic acidurias (BCOA) patients. We detected eight previously described mutations: p.Asn219Tyr, p.Arg369His p.Val553Glyfs*17 in MUT, p.Thr198Serfs*6 in MMAA, p.Ile144_Leu181del in PCCB, p.Gly288Valfs*11, p.Tyr438Asn in BCKDHA and p.Ala137Val in BCKDHB gene. Interestingly, we identified seven novel genetic variants: p.Leu549Pro, p.Glu564*, p.Leu641Pro in MUT, p.Tyr206Cys in PCCB, p.His194Arg, p.Val298Met in BCKDHA and p.Glu286_Met290del in BCKDHB gene. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants. Aberrant enzymes p.Leu549Pro MUT, p.Leu641Pro MUT and p.Tyr206Cys PCCB did not show residual activity in activity assays. In addition, activity of MUT enzymes was not rescued in the presence of vitamin B12 precursor in vitro which was in accordance with non-responsiveness or partial responsiveness of patients to vitamin B12 therapy. Our study brings the first molecular genetic data and detailed phenotypic characteristics for MMA, PA and MSUD patients for Serbia and the whole South-Eastern European region. Therefore, our study contributes to the better understanding of molecular landscape of BCOA in Europe and to general knowledge on genotype-phenotype correlation for these rare diseases. PMID:26830710

  14. Orotate phosphoribosyltransferase from baker's yeast: I. Kinetic analysis, chemical modification, and proton NMR spectroscopy of the enzyme substrate complex. II. Amino acid analysis and NMR spectroscopy of the protein

    SciTech Connect

    Strauss, R.S.

    1986-01-01

    Kinetic analysis of the effect of pH on the reversible reaction catalyzed by orotate phosphoribosyltransferase (OPRTase) from Baker's yeast revealed that different amino acid residues may enable the enzyme-catalyzed reactions to proceed in the forward and reverse directions, respectively. For the forward reaction, there appear to be at least two critical amino acid residues (pK's 4.6 and 7.1) which must be in a deprotonated state to reach a maximum activity near pH 8 which is maintained through pH 9.5. For the reverse reaction, maximum activity is reached near pH 7 (pK's at 5.4) and then the activity decreases at higher pH (pK's at 7.9 and possibly above 9). A theoretical proton NMR spectrum was generated for OPRTase, based on its amino acid composition. The spectrum thus produced has a similar number of major peaks to that of the actual spectrum taken at 300 MHz. Spectra collected at various pH values between 8 and 5, were consistent with the maintenance of the gross conformational structure of the enzyme over that pH range.

  15. Effects of candesartan cilexetil and amlodipine orotate on receptor for advanced glycation end products expression in the aortic wall of Otsuka Long-Evans Tokushima Fatty (OETFF) type 2 diabetic rats.

    PubMed

    Kang, Min-Kyu; Chung, Woo-Baek; Hong, Seul-Ki; Kim, Ok-Ran; Ihm, Sang-Hyun; Chang, Kiyuk; Seung, Ki-Bae

    2016-04-01

    The receptor for advanced glycation end products (RAGE) plays a key role in the development of vascular inflammation and acceleration of atherosclerosis in type 2 diabetes. We investigated the effect of candesartan cilexetil (CDRT) and amlodipine orotate (AMDP) on the expression of RAGE in the aortic walls of Otsuka Long-Evans Tokushima Fatty (OLETF) rats and AGE-treated endothelial cells. Twenty five-week-old OLETF rats were randomized to 8 week treatments consisting of CDRT (n = 8), AMDP (n = 8) or saline (control, n = 8). Immunohistochemical and dihydroethidine staining revealed reduced RAGE and reactive oxygen species (ROS) signals in rats treated with CDRT or AMDP compared with control rats. Both CDRT and AMDP suppressed the expression of p22phox and p47phox NADPH oxidase subunits. However, only CDRT significantly reduced expression of phosphorylated extracellular signal regulated kinase (pERK)1/2 in the aortic wall of OLETF rats. In addition, both drugs reduced RAGE expression and total and mitochondrial ROS production in the AGE-treated endothelial cells. Both ARBs and CCBs reduced RAGE expression in the aortic walls of OLETF rats, which was attributed to decreased ROS production through inhibition of NADPH oxidase. In addition, only CDRT reduced aortic expression of RAGE via suppression of the ERK1/2 pathway unlike AMDP. PMID:26960737

  16. Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction

    PubMed Central

    Fang, JingXian; Uchiumi, Takeshi; Yagi, Mikako; Matsumoto, Shinya; Amamoto, Rie; Takazaki, Shinya; Yamaza, Haruyoshi; Nonaka, Kazuaki; Kang, Dongchon

    2012-01-01

    Some mutations of the DHODH (dihydro-orotate dehydrogenase) gene lead to postaxial acrofacial dysostosis or Miller syndrome. Only DHODH is localized at mitochondria among enzymes of the de novo pyrimidine biosynthesis pathway. Since the pyrimidine biosynthesis pathway is coupled to the mitochondrial RC (respiratory chain) via DHODH, impairment of DHODH should affect the RC function. To investigate this, we used siRNA (small interfering RNA)-mediated knockdown and observed that DHODH knockdown induced cell growth retardation because of G2/M cell-cycle arrest, whereas pyrimidine deficiency usually causes G1/S arrest. Inconsistent with this, the cell retardation was not rescued by exogenous uridine, which should bypass the DHODH reaction for pyrimidine synthesis. DHODH depletion partially inhibited the RC complex III, decreased the mitochondrial membrane potential, and increased the generation of ROS (reactive oxygen species). We observed that DHODH physically interacts with respiratory complexes II and III by IP (immunoprecipitation) and BN (blue native)/SDS/PAGE analysis. Considering that pyrimidine deficiency alone does not induce craniofacial dysmorphism, the DHODH mutations may contribute to the Miller syndrome in part through somehow altered mitochondrial function. PMID:23216091

  17. Type III 3-Methylglutaconic Aciduria (Optic Atrophy Plus Syndrome, or Costeff Optic Atrophy Syndrome): Identification of the OPA3 Gene and Its Founder Mutation in Iraqi Jews

    PubMed Central

    Anikster, Yair; Kleta, Robert; Shaag, Avraham; Gahl, William A.; Elpeleg, Orly

    2001-01-01

    Type III 3-methylglutaconic aciduria (MGA) (MIM 258501) is a neuro-ophthalmologic syndrome that consists of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is increased. The disorder has been reported in ∼40 patients of Iraqi Jewish origin, allowing the mapping of the disease to chromosome 19q13.2-q13.3, by linkage analysis. To isolate the causative gene, OPA3, we sequenced four genes within the critical interval and identified, in the intronic sequence of a gene corresponding to cDNA clone FLJ22187, a point mutation that segregated with the type III MGA phenotype. The FLJ22187-cDNA clone, which we identified as the OPA3 gene, consists of two exons and encodes a peptide of 179 amino acid residues. Northern blot analysis revealed a primary transcript of ∼5.0 kb that was ubiquitously expressed, most prominently in skeletal muscle and kidney. Within the brain, the cerebral cortex, the medulla, the cerebellum, and the frontal lobe, compared to other parts of the brain, had slightly increased expression. The intronic G→C mutation abolished mRNA expression in fibroblasts from affected patients and was detected in 8 of 85 anonymous Israeli individuals of Iraqi Jewish origin. Milder mutations in OPA3 should be sought in patients with optic atrophy with later onset, even in the absence of additional neurological abnormalities. PMID:11668429

  18. Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model

    SciTech Connect

    Buck, Nicole E.; Pennell, Samuel D.; Wood, Leonie R.; Pitt, James J.; Allen, Katrina J.; Peters, Heidi L.

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer Fetal cells were transplanted into a methylmalonic acid mouse model. Black-Right-Pointing-Pointer Cell engraftment was detected in liver, spleen and bone marrow. Black-Right-Pointing-Pointer Biochemical disease correction was measured in blood samples. Black-Right-Pointing-Pointer A double dose of 5 million cells (1 week apart) proved more effective. Black-Right-Pointing-Pointer Higher levels of engraftment may be required for greater disease correction. -- Abstract: Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disorder using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 {+-} 156 (sham transplanted) to 338 {+-} 157 {mu}mol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 {+-} 4 (sham transplanted) to 5.3 {+-} 1.9 {mu}mol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may

  19. CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.

    PubMed

    Saunders, Carol; Smith, Laurie; Wibrand, Flemming; Ravn, Kirstine; Bross, Peter; Thiffault, Isabelle; Christensen, Mette; Atherton, Andrea; Farrow, Emily; Miller, Neil; Kingsmore, Stephen F; Ostergaard, Elsebet

    2015-02-01

    3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321*) and c.1249C>T (p.Arg417*). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation. PMID:25597511

  20. Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins

    PubMed Central

    Schmiesing, Jessica; Schlüter, Hartmut; Ullrich, Kurt; Braulke, Thomas; Mühlhausen, Chris

    2014-01-01

    Glutaric aciduria type 1 (GA1) is an inherited neurometabolic disorder caused by mutations in the GCDH gene encoding glutaryl-CoA dehydrogenase (GCDH), which forms homo- and heteromeric complexes in the mitochondrial matrix. GA1 patients are prone to the development of encephalopathic crises which lead to an irreversible disabling dystonic movement disorder. The clinical and biochemical manifestations of GA1 vary considerably and lack correlations to the genotype. Using an affinity chromatography approach we report here for the first time on the identification of mitochondrial proteins interacting directly with GCDH. Among others, dihydrolipoamide S-succinyltransferase (DLST) involved in the formation of glutaryl-CoA, and the β-subunit of the electron transfer flavoprotein (ETFB) serving as electron acceptor, were identified as GCDH binding partners. We have adapted the yellow fluorescent protein-based fragment complementation assay and visualized the oligomerization of GCDH as well as its direct interaction with DLST and ETFB in mitochondria of living cells. These data suggest that GCDH is a constituent of multimeric mitochondrial dehydrogenase complexes, and the characterization of their interrelated functions may provide new insights into the regulation of lysine oxidation and the pathophysiology of GA1. PMID:24498361

  1. A diet-induced mouse model for glutaric aciduria type I.

    PubMed

    Zinnanti, William J; Lazovic, Jelena; Wolpert, Ellen B; Antonetti, David A; Smith, Michael B; Connor, James R; Woontner, Michael; Goodman, Stephen I; Cheng, Keith C

    2006-04-01

    In the autosomal recessive human disease, glutaric aciduria type I (GA-1), glutaryl-CoA dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient (Gcdh-/-) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh-/- mice within 2-3 days and 7-8 days, respectively. High lysine alone resulted in vasogenic oedema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh-/- mice after 3-12 days. In contrast, most 8-week-old Gcdh-/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh-/- mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability. PMID:16446282

  2. Nitric-Oxide Supplementation for Treatment of Long-Term Complications in Argininosuccinic Aciduria

    PubMed Central

    Nagamani, Sandesh C.S.; Campeau, Philippe M.; Shchelochkov, Oleg A.; Premkumar, Muralidhar H.; Guse, Kilian; Brunetti-Pierri, Nicola; Chen, Yuqing; Sun, Qin; Tang, Yaoping; Palmer, Donna; Reddy, Anilkumar K.; Li, Li; Slesnick, Timothy C.; Feig, Daniel I.; Caudle, Susan; Harrison, David; Salviati, Leonardo; Marini, Juan C.; Bryan, Nathan S.; Erez, Ayelet; Lee, Brendan

    2012-01-01

    Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition. PMID:22541557

  3. CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

    PubMed Central

    Saunders, Carol; Smith, Laurie; Wibrand, Flemming; Ravn, Kirstine; Bross, Peter; Thiffault, Isabelle; Christensen, Mette; Atherton, Andrea; Farrow, Emily; Miller, Neil; Kingsmore, Stephen F.; Ostergaard, Elsebet

    2015-01-01

    3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321∗) and c.1249C>T (p.Arg417∗). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation. PMID:25597511

  4. CLPB Mutations Cause 3-Methylglutaconic Aciduria, Progressive Brain Atrophy, Intellectual Disability, Congenital Neutropenia, Cataracts, Movement Disorder

    PubMed Central

    Wortmann, Saskia B.; Ziętkiewicz, Szymon; Kousi, Maria; Szklarczyk, Radek; Haack, Tobias B.; Gersting, Søren W.; Muntau, Ania C.; Rakovic, Aleksandar; Renkema, G. Herma; Rodenburg, Richard J.; Strom, Tim M.; Meitinger, Thomas; Rubio-Gozalbo, M. Estela; Chrusciel, Elzbieta; Distelmaier, Felix; Golzio, Christelle; Jansen, Joop H.; van Karnebeek, Clara; Lillquist, Yolanda; Lücke, Thomas; Õunap, Katrin; Zordania, Riina; Yaplito-Lee, Joy; van Bokhoven, Hans; Spelbrink, Johannes N.; Vaz, Frédéric M.; Pras-Raves, Mia; Ploski, Rafal; Pronicka, Ewa; Klein, Christine; Willemsen, Michel A.A.P.; de Brouwer, Arjan P.M.; Prokisch, Holger; Katsanis, Nicholas; Wevers, Ron A.

    2015-01-01

    We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria. PMID:25597510

  5. Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide.

    PubMed Central

    Bruneau, J M; Yea, C M; Spinella-Jaegle, S; Fudali, C; Woodward, K; Robson, P A; Sautès, C; Westwood, R; Kuo, E A; Williamson, R A; Ruuth, E

    1998-01-01

    Leflunomide is currently in phase-III clinical trials for the treatment of rheumatoid arthritis. In this study, we have focused our efforts on the study of the mechanism of action of the active metabolite of leflunomide, A77 1726, in cells and tissue of human origin. The human high-affinity binding protein for radiolabelled A77 1726 was purified from solubilized U937 membranes by following the binding activity through the purification process and was characterized as the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH). The human and murine enzyme displayed identical pI and molecular mass values on SDS/PAGE (43 kDa), which contrasts notably with previous reports suggesting a molecular mass of 50 kDa for the human enzyme. DHO-DH activity was inhibited by A77 1726 and its analogue HR325 with similar potency in U937 and human spleen membrane preparations. HR325 was found to be anti-proliferative for phytohaemagglutinin-stimulated human peripheral blood mononuclear cells, at the same concentrations that caused accumulation of DHO and depletion of uridine. Supplementation of the cultures with exogenous uridine led to partial abrogation of the anti-proliferative effect. This is in line with our recent demonstration that the anti-proliferative effect in vitro of A77 1726 on lipopolysaccharide-stimulated mouse spleen cells was mediated by DHO-DH inhibition [Williamson, Yea, Robson, Curnock, Gadher, Hambleton, Woodward, Bruneau, Hambleton, Moss et al., (1995) J. Biol. Chem. 270, 22467-22472]. Thus, DHO-DH inhibition by A77 1726 and its analogues is responsible for the anti-proliferative effects in vitro of the compounds on human cells and is likely to be responsible for some of its effects in vivo. PMID:9820804

  6. Increased oxidative stress in patients with 3-hydroxy-3-methylglutaric aciduria.

    PubMed

    Dos Santos Mello, Mariana; Ribas, Graziela Schmitt; Wayhs, Carlos Alberto Yasin; Hammerschmidt, Tatiane; Guerreiro, Gilian Batista Balbueno; Favenzani, Jéssica Lamberty; Sitta, Ângela; de Moura Coelho, Daniella; Wajner, Moacir; Vargas, Carmen Regla

    2015-04-01

    3-hydroxy-3-methylglutaric aciduria (HMGA; OMIM 246450) is a rare autosomal recessive disorder, caused by the deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (4.1.3.4), which results in the accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Recent in vivo and in vitro animal studies have demonstrated that the accumulation of these metabolites can disturb the cellular redox homeostasis, which can contribute to the neurological manifestations presented by the patients. So, in the present work, we investigated oxidative stress parameters in plasma and urine samples from HMGA patients, obtained at the moment of diagnosis of this disorder and during therapy with low-protein diet and L-carnitine supplementation. It was verified that untreated HMGA patients presented higher levels of urinary di-tyrosine and plasma thiobarbituric acid-reactive substances (TBA-RS), which are markers of protein and lipid oxidative damage, respectively, as well as a reduction of the urinary antioxidant capacity. Treated HMGA patients also presented an increased protein oxidative damage, as demonstrated by their higher concentrations of plasma protein carbonyl groups and urinary di-tyrosine, as well as by the reduction of total sulfhydryl groups in plasma, in relation to controls. On the other hand, HMGA patients under therapy presented normal levels of TBA-RS and urinary antioxidant capacity, which can be related, at least in part, to the antioxidant and antiperoxidative effects exerted by L-carnitine. The results of this work are the first report showing that a redox imbalance occurs in patients with HMGA what reinforces the importance of the antioxidant therapy in this disorder. PMID:25557019

  7. Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts.

    PubMed Central

    Dubiel, B; Dabrowski, C; Wetts, R; Tanaka, K

    1983-01-01

    Using cultured skin fibroblasts, we studied the heterogeneity of inborn errors of leucine metabolism such as isovaleric acidemia (IVA), glutaric aciduria type II (GA II), and multiple carboxylase deficiency (MC). We first developed a simple macromolecular-labeling test to measure the ability of cells to oxidize [1-14C]isovaleric acid in situ in culture. Cells from two different lines were fused using polyethylene glycol, and the ability of the heterokaryons to oxidize [1-14C]isovaleric acid was tested by the macromolecular-labeling test. The MC line complemented with all 10 IVA lines tested; heterokaryons showed 99 +/- 68% more activity than the unfused mixture of component cells. GA II/IVA heterokaryons exhibited poor growth, but when the culture remained confluent, the GA II cells complemented with all six IVA lines tested, showing a 71 +/- 41% increase in activity. The relatively large standard deviations are due to a few experiments in which significant enhancement of macromolecular-labeling test activity was not observed upon fusion, but significant complementation was clearly observed in repeats of the same combinations. These results are consistent with our previous findings, which indicated that the decreased ability of GA II cells to oxidize isovaleryl-CoA involves a defective electron-transporting system rather than a defective isovaleryl-CoA dehydrogenase. IVA/IVA heterokaryons showed no complementation in any combination tested, indicating no detectable heterogeneity in isovaleric acidemia. This finding indicates that the same gene is mutated in all IVA lines. Previous results indicated that this gene codes for isovaleryl-CoA dehydrogenase. PMID:6630517

  8. Pharmacological chaperones as a potential therapeutic option in methylmalonic aciduria cblB type.

    PubMed

    Jorge-Finnigan, Ana; Brasil, Sandra; Underhaug, Jarl; Ruíz-Sala, Pedro; Merinero, Begoña; Banerjee, Ruma; Desviat, Lourdes R; Ugarte, Magdalena; Martinez, Aurora; Pérez, Belén

    2013-09-15

    Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene. This encodes the enzyme ATP:cob(I)alamin adenosyltransferase (ATR), which converts reduced cob(I)alamin to an active adenosylcobalamin cofactor. We recently reported the presence of destabilizing pathogenic mutations that retain some residual ATR activity. The aim of the present study was to seek pharmacological chaperones as a tailored therapy for stabilizing the ATR protein. High-throughput ligand screening of over 2000 compounds was performed; six were found to enhance the thermal stability of purified recombinant ATR. Further studies using a well-established bacterial system in which the recombinant ATR protein was expressed in the presence of these six compounds, showed them all to increase the stability of the wild-type ATR and the p.Ile96Thr mutant proteins. Compound V (N-{[(4-chlorophenyl)carbamothioyl]amino}-2-phenylacetamide) significantly increased this stability and did not act as an inhibitor of the purified protein. Importantly, compound V increased the activity of ATR in patient-derived fibroblasts harboring the destabilizing p.Ile96Thr mutation in a hemizygous state to within control range. When cobalamin was coadministrated with compound V, mutant ATR activity further improved. Oral administration of low doses of compound V to C57BL/6J mice for 12 days, led to increase in steady-state levels of ATR protein in liver and brain (disease-relevant organs). These results hold promise for the clinical use of pharmacological chaperones in MMA cblB type patients harboring chaperone-responsive mutations. PMID:23674520

  9. Pharmacological chaperones as a potential therapeutic option in methylmalonic aciduria cblB type

    PubMed Central

    Jorge-Finnigan, Ana; Brasil, Sandra; Underhaug, Jarl; Ruíz-Sala, Pedro; Merinero, Begoña; Banerjee, Ruma; Desviat, Lourdes R.; Ugarte, Magdalena; Martinez, Aurora; Pérez, Belén

    2013-01-01

    Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene. This encodes the enzyme ATP:cob(I)alamin adenosyltransferase (ATR), which converts reduced cob(I)alamin to an active adenosylcobalamin cofactor. We recently reported the presence of destabilizing pathogenic mutations that retain some residual ATR activity. The aim of the present study was to seek pharmacological chaperones as a tailored therapy for stabilizing the ATR protein. High-throughput ligand screening of over 2000 compounds was performed; six were found to enhance the thermal stability of purified recombinant ATR. Further studies using a well-established bacterial system in which the recombinant ATR protein was expressed in the presence of these six compounds, showed them all to increase the stability of the wild-type ATR and the p.Ile96Thr mutant proteins. Compound V (N-{[(4-chlorophenyl)carbamothioyl]amino}-2-phenylacetamide) significantly increased this stability and did not act as an inhibitor of the purified protein. Importantly, compound V increased the activity of ATR in patient-derived fibroblasts harboring the destabilizing p.Ile96Thr mutation in a hemizygous state to within control range. When cobalamin was coadministrated with compound V, mutant ATR activity further improved. Oral administration of low doses of compound V to C57BL/6J mice for 12 days, led to increase in steady-state levels of ATR protein in liver and brain (disease-relevant organs). These results hold promise for the clinical use of pharmacological chaperones in MMA cblB type patients harboring chaperone-responsive mutations. PMID:23674520

  10. Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.

    PubMed

    Kanabus, Marta; Shahni, Rojeen; Saldanha, José W; Murphy, Elaine; Plagnol, Vincent; Hoff, William Van't; Heales, Simon; Rahman, Shamima

    2015-03-01

    Whole exome sequencing was used to investigate the genetic cause of mitochondrial disease in two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria. Autosomal recessive inheritance in a gene encoding a mitochondrially targeted protein was assumed; the only variants which satisfied these criteria were c.1882C>T (p.Arg628Cys) and c.1915G>A (p.Glu639Lys) in the CLPB gene, encoding a heat shock protein/chaperonin responsible for disaggregating mitochondrial and cytosolic proteins. Functional studies, including quantitative PCR (qPCR) and Western blot, support pathogenicity of these mutations. Furthermore, molecular modelling suggests that the mutations disrupt interactions between subunits so that the CLPB hexamer cannot form or is unstable, thus impairing its role as a protein disaggregase. We conclude that accumulation of protein aggregates underlies the development of cataracts and nephrocalcinosis in CLPB deficiency, which is a novel genetic cause of 3-methylglutaconic aciduria. A common mitochondrial cause for 3-methylglutaconic aciduria appears to be disruption of the architecture of the mitochondrial membranes, as in Barth syndrome (tafazzin deficiency), Sengers syndrome (acylglycerol kinase deficiency) and MEGDEL syndrome (impaired remodelling of the mitochondrial membrane lipids because of SERAC1 mutations). We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3-methylglutaconic aciduria in CLPB deficiency. PMID:25595726

  11. Effect of betaine on the hepatic damage from orotic acid-induced fatty liver development in rats.

    PubMed

    Cha, Jae-Young; Kim, Hyeong-Soo; Moon, Hyung-In; Cho, Young-Su

    2011-12-13

    Betaine prevents hepatic damage caused by ethanol and carbone tetrachloride (CCl4) in rats. Present study was to investigate the effect of betaine on the hepatic microsomal triglyceride transfer protein (MTP) mRNA expression in orotic acid (OA)-induced fatty liver in rats. OA feeding was attributed to the significant increase in the hepatic levels of triglyceride and the serum levels of ALT and AST and resulted in typical histology of fatty liver contained numerous largely fat droplets. While concomitant supplementation of betaine to OA diet was slightly reduced the hepatic triglyceride concentrations and was significantly decreased ALT activity. Hepatic MTP mRNA expression by OA treatment increased by 14% despite triglyceride accumulation in the liver in OA treatment rats relative to rats fed a normal diet without OA supplemented, but MTP expression by simultaneous supplementation of OA and betaine was slightly decreased by 7.9% as compared to the OA-feeding rats. A significant elevation of TBARS contents in the liver homogenate, microsome, and mitochondrial fractions of the OA-feeding rats compared with the normal rats, however, these increases were significantly or slightly decreased by simultaneous addition of OA and betaine. The increases of hepatic OA and betaine levels in OA feeding rats was also found when compared to the normal rats, but these increases were significantly lowered in the concomitant supplementation OA and betaine. The content of Fe was significantly increased in the OA feeding rats, but this elevation showed significantly recovered as low as the normal level by concomitant with OA and betaine. Zinc content was also significantly decreased in the OA feeding rats compared with the normal rats, but this reduction was more significantly elevated by concomitant with OA and betaine. Hepatic glutathione content in the OA feeding rats was similar to that of the normal rats, but this content was slightly reduced without statistically significant

  12. Increased hepatic mitochondrial capacity in rats with hydroxy-cobalamin[c-lactam]-induced methylmalonic aciduria.

    PubMed Central

    Krahenbuhl, S; Ray, D B; Stabler, S P; Allen, R H; Brass, E P

    1990-01-01

    Treatment of rats with the vitamin B12 analogue hydroxy-cobalamin[c-lactam] (HCCL) impairs methylmalonyl-CoA mutase function and leads to methylmalonic aciduria due to intracellular accumulation of propionyl and methylmalonyl-CoA. Since accumulation of these acyl-CoAs disrupts normal cellular regulation, the present investigation characterized metabolism in hepatocytes and liver mitochondria from rats treated subcutaneously with HCCL or saline (control) by osmotic minipump. Consistent with decreased methylmalonyl-CoA mutase activity, 14CO2 production from 1-14C-propionate (1 mM) was decreased by 76% and 82% after 2-3 wk and 5-6 wk of HCCL treatment, respectively. In contrast, after 5-6 wk of HCCL treatment, 14CO2 production from 1-14C-pyruvate (10 mM) and 1-14C-palmitate (0.8 mM) were increased by 45% and 49%, respectively. In isolated liver mitochondria, state 3 oxidation rates were unchanged or decreased, and activities of the mitochondrial enzymes, citrate synthetase, succinate dehydrogenase, carnitine palmitoyltransferase, and glutamate dehydrogenase (expressed per milligram mitochondrial protein) were unaffected by HCCL treatment. In contrast, activities of the same enzymes were significantly increased in both liver homogenate (expressed per gram liver) and isolated hepatocytes (expressed per 10(6) cells) from HCCL-treated rats. The mitochondrial protein per gram liver, calculated on the basis of the recovery of the mitochondrial enzymes, increased by 39% in 5-6 wk HCCL-treated rats. Activities of lactate dehydrogenase, catalase, cyanide-insensitive palmitoyl-CoA oxidation, and arylsulfatase A in liver were not affected by HCCL treatment. Hepatic levels of mitochondrial mRNAs were elevated up to 10-fold in HCCL-treated animals as assessed by Northern blot analysis. Thus, HCCL treatment is associated with enhanced mitochondrial oxidative capacity and an increased mitochondrial protein content per gram liver. Increased mitochondrial oxidative capacity may be a

  13. Glutaric aciduria type II: observations in seven patients with neonatal- and late-onset disease.

    PubMed

    al-Essa, M A; Rashed, M S; Bakheet, S M; Patay, Z J; Ozand, P T

    2000-03-01

    The clinical, biochemical, and neuroradiologic findings and clinical follow-up of seven patients with glutaric aciduria type II are reported. Three phenotypes of the disease are encountered: neonatal-onset form with congenital anomalies (two patients) or without congenital anomalies (three patients) and late-onset form (two patients). The neonatal-onset form presents as an overwhelming illness, with severe hypoglycemia and metabolic acidosis leading to rapid death. Frequently it is associated with perinatal energy deprivation, a neonate with low birth weight and prematurity. The late-onset form presents with intermittent episodes of vomiting, hypoglycemia, and acidosis especially after meals rich in fat and/or proteins. All parents are consanguineous and have a first- or second-degree relationship. Initially, in the two phenotypes with neonatal onset and during crisis in the late-onset phenotype, routine laboratory evaluation showed severe metabolic acidosis, with an increased anion gap, hypoglycemia without ketonuria, and disturbed liver function tests. In the majority of patients with neonatal-onset forms, the kidneys, liver, and at times the spleen are enlarged with an increased echogenic pattern; however, no hepatic or renal cysts are detected. Cardiomegaly is observed in most patients. The diagnosis can be easily and rapidly reached through tandem mass spectrometry study of the blood and can further be confirmed by gas chromatography/mass spectrometry analysis of the urine organic acids. In this report, the magnetic resonance imaging/computed tomography brain studies showed brain atrophy, white matter disease, and in one patient, fluid-filled cavities in the periventricular area and putamina. Fluorine-18-labeled 2-fluoro-2-deoxyglucose positron emission tomographic (FDG PET) brain studies in two patients with late-onset disease showed slightly decreased activity in the cerebral cortex in one and in the caudate nuclei in the other. Brain FDG PET scan and

  14. Brain damage in methylmalonic aciduria: 2-methylcitrate induces cerebral ammonium accumulation and apoptosis in 3D organotypic brain cell cultures

    PubMed Central

    2013-01-01

    Background Methylmalonic aciduria is an inborn error of metabolism characterized by accumulation of methylmalonate (MMA), propionate and 2-methylcitrate (2-MCA) in body fluids. Early diagnosis and current treatment strategies aimed at limiting the production of these metabolites are only partially effective in preventing neurological damage. Methods To explore the metabolic consequences of methylmalonic aciduria on the brain, we used 3D organotypic brain cell cultures from rat embryos. We challenged the cultures at two different developmental stages with 1 mM MMA, propionate or 2-MCA applied 6 times every 12 h. In a dose–response experiment cultures were challenged with 0.01, 0.1, 0.33 and 1 mM 2-MCA. Immunohistochemical staining for different brain cell markers were used to assess cell viability, morphology and differentiation. Significant changes were validated by western blot analysis. Biochemical markers were analyzed in culture media. Apoptosis was studied by immunofluorescence staining and western blots for activated caspase-3. Results Among the three metabolites tested, 2-MCA consistently produced the most pronounced effects. Exposure to 2-MCA caused morphological changes in neuronal and glial cells already at 0.01 mM. At the biochemical level the most striking result was a significant ammonium increase in culture media with a concomitant glutamine decrease. Dose–response studies showed significant and parallel changes of ammonium and glutamine starting from 0.1 mM 2-MCA. An increased apoptosis rate was observed by activation of caspase-3 after exposure to at least 0.1 mM 2-MCA. Conclusion Surprisingly, 2-MCA, and not MMA, seems to be the most toxic metabolite in our in vitro model leading to delayed axonal growth, apoptosis of glial cells and to unexpected ammonium increase. Morphological changes were already observed at 2-MCA concentrations as low as 0.01 mM. Increased apoptosis and ammonium accumulation started at 0.1 mM thus suggesting that ammonium

  15. Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria

    PubMed Central

    Lam, Christina; Gallo, Linda K.; Dineen, Richard; Ciccone, Carla; Dorward, Heidi; Hoganson, George E.; Wolfe, Lynne; Gahl, William A.; Huizing, Marjan

    2014-01-01

    OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in the OPA3 gene located at 19q13.2-13.3. Here we describe two siblings with novel compound heterozygous variants in OPA3: c.1A>G (p.1M>V) in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6 months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5 years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient’s cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease. PMID:24749080

  16. Crystal Structure And Mutagenisis of the Metallochaperone MeaB: Insight Into the Causes of the Methylmalonic Aciduria

    SciTech Connect

    Hubbard, P.A.; Padovani, D.; Labunska, T.; Mahlstedt, S.A.; Banerjee, R.; Drennan, C.L.

    2009-06-01

    MeaB is an auxiliary protein that plays a crucial role in the protection and assembly of the B{sub 12}-dependent enzyme methylmalonyl-CoA mutase. Impairments in the human homologue of MeaB, MMAA, lead to methylmalonic aciduria, an inborn error of metabolism. To explore the role of this metallochaperone, its structure was solved in the nucleotide-free form, as well as in the presence of product, GDP. MeaB is a homodimer, with each subunit containing a central {alpha}/{beta}-core G domain that is typical of the GTPase family, as well as a-helical extensions at the N and C termini that are not found in other metalloenzyme chaperone GTPases. The C-terminal extension appears to be essential for nucleotide-independent dimerization, and the N-terminal region is implicated in protein-protein interaction with its partner protein, methylmalonyl-CoA mutase. The structure of MeaB confirms that it is a member of the G3E family of P-loop GTPases, which contains other putative metallochaperones HypB, CooC, and UreG. Interestingly, the so-called switch regions, responsible for signal transduction following GTP hydrolysis, are found at the dimer interface of MeaB instead of being positioned at the surface of the protein where its partner protein methylmalonyl-CoA mutase should bind. This observation suggests a large conformation change of MeaB must occur between the GDP- and GTP-bound forms of this protein. Because of their high sequence homology, the missense mutations in MMAA that result in methylmalonic aciduria have been mapped onto MeaB and, in conjunction with mutagenesis data, provide possible explanations for the pathology of this disease.

  17. C6-C10-dicarboxylic aciduria: biochemical considerations in relation to diagnosis of beta-oxidation defects.

    PubMed

    Gregersen, N; Kølvraa, S; Mortensen, P B; Rasmussen, K

    1982-01-01

    By means of gas chromatographic methods substantial amounts of the C6-C10-dicarboxylic acids, i.e. adipic, suberic and sebacic acids, have been found in the urine from children with unexplained attacks of lethargy and hypotonia, presumably related to episodes of fever and/or insufficient food intake. The course have once been fatal and is often characterized by severe hypoglycemia without ketonuria. Systematic gas chromatographic/mass spectrometric determinations of selected organic acid metabolites in the urine, together with enzymatic measurements in fibroblasts and clinical data from 4 patients of this category, have shown that the biochemical basis of this syndrome can be inborn errors of the beta-oxidation of fatty acids, localized to the medium-chain acyl-CoA dehydrogenation system. The biosynthesis of adipic, suberic and sebacic acids was studied using ketotic rats as the model, since ketosis in rats and humans is accompanied by excessive urinary excretion of adipic and suberic acids. A probable pathway for the production of the three dicarboxylic acids was found to be an initial omega-oxidation of the medium-chain C10-C14-monocarboxylic acids followed by beta-oxidation of the resulting medium-chain dicarboxylic acids. It is argued that the source of the omega-oxidizable monocarboxylic acids in ketosis most probably is the fat deposites, and it is speculated that the patients with beta-oxidation defects supplement this source with beta-oxidation intermediate medium-chain monocarboxylic acids, accumulated as a result of the defect. The ratio between the excreted amounts of adipic acid and sebacic acid in the urine from the patients with beta-oxidation defects is less than 50. This is in contrast to the ratio in urine from ketotic patients, where it is greater than 100. Adipic acid/sebacic acid ratio-measured by means of a gas chromatographic analysis-is therefore suggested as a tool in the diagnosis of dicarboxylic acidurias. Based on the clinical picture and

  18. Biomarker analysis in patients with advanced gastric cancer treated with S-1 plus cisplatin chemotherapy: orotate phosphoribosyltransferase expression is associated with treatment outcomes.

    PubMed

    Choi, In Sil; Lee, Hye Seung; Lee, Keun-Wook; Kim, Haeryoung; Kim, Ki Hwan; Kim, Yu Jung; Kim, Jee Hyun; Kim, Woo Ho; Lee, Jong Seok

    2011-12-01

    This study was performed to analyze the impact of protein expression related to fluoropyrimidine and cisplatin metabolism (thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, orotate phosphoribosyltransferase [OPRT], excision repair cross-complementation 1, Fanconi anemia complementation group D2, glutathione S-transferase P1, and X-ray repair cross-complementing group 1) on treatment outcomes in patients with metastatic or relapsed gastric cancer (MRGC) receiving S-1/cisplatin chemotherapy. Protein expression was measured by immunohistochemistry (IHC). Of the 43 patients who had received S-1 (80 mg/m2/day; days 1-14) and cisplatin (60 mg/m2; day 1) every 3 weeks and had available tissue blocks, IHC was successfully performed in 41 patients. Patients with high OPRT levels in tumor tissues (IHC score≥6) had superior progression-free survival (PFS) (23.3 vs. 14.1 weeks [median]) and overall survival (OS) (72.4 vs. 55.4 weeks [median]) to those with low OPRT levels (IHC score≤5; P-values<.05). Expression levels of other proteins were not predictive of treatment outcomes. In multivariate analysis, both a good performance status and a high OPRT level were independently associated with prolonged PFS and OS. The OPRT expression level may be a good predictive marker in S-1/cisplatin-treated patients with MRGC. PMID:20533001

  19. Oral and craniofacial findings in a patient with methylmalonic aciduria and homocystinuria: review and a case report.

    PubMed

    D'Alessandro, G; Tagariello, T; Piana, G

    2010-03-01

    Combined methylmalonic aciduria and homocystinuria (MMA-HC) is a rare metabolic disease characterized by an inborn defect in B12 vitamin metabolism. This case report concerns an 11-year-old patient with MMA-HC, which developed during the neonatal period. The patient shows some of the facial features that were already reported in the literature (high forehead, large floppy, low-set ears, flat philtrum and hypotonia of perioral and masticatory muscles) but no dolichocephalic skull nor long face. The patient also shows signs that had not been previously described: epicanthal folds, broad nasal bridge, long and flat philtrum, amimic expression and, particularly, a postural alteration (the head is rotated and bent towards the left shoulder, which is lower than the right one). Such alteration can be attributed to visual impairment and is responsible for breaking muscular and skeletal balance in the frontal plane, thus causing the horizontal planes of both maxillary bones to converge towards the right--as highlighted by the cephalometric analysis of the Teleradio-graph of the skull in Posteroanterior projection according to Ricketts. As for the patient's teeth, eruption times are normal, but there are anomalies of shape (chisel-like central incisors). As far as dental caries is concerned, the patient's DMFT is 4 (D=4, M=0, F=0). This clinical case highlights the need for dental prevention programs suggested by the pediatrician once the pathology is diagnosed. PMID:20357739

  20. Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: successful treatment with pantothenic acid.

    PubMed Central

    Ostman-Smith, I; Brown, G; Johnson, A; Land, J M

    1994-01-01

    A case of dilated cardiomyopathy in a young boy secondary to type II 3-methylglutaconic aciduria is described. A metabolic cause for his dilated cardiomyopathy was suspected because of the development on the electrocardiogram of an unusual "camel's hump" shape of the T waves, and of progressive thickening with increasing echogenicity of the left ventricular wall. He initially improved on digoxin treatment, but did not maintain the response with conventional dietary treatment for this condition. Supplementation with L-carnitine was associated with rapid deterioration in cardiac state, and may be contraindicated in this condition. At a point when the patient was moribund, large doses of pantothenic acid, a precursor of coenzyme A, produced a dramatic and sustained improvement in myocardial function and in growth, neutrophil cell count, hypocholesterolaemia, and hyperuricaemia, which suggests that limitation of availability of coenzyme A is a fundamental pathological process in this condition. The clinical improvement has been maintained for 13 months, and myocardial function is now nearly normal. Oral pantothenol, unlike pantothenic acid, is not efficacious. PMID:7833193

  1. Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria.

    PubMed

    Menao, Sebastián; López-Viñas, Eduardo; Mir, Cecilia; Puisac, Beatriz; Gratacós, Esther; Arnedo, María; Carrasco, Patricia; Moreno, Susana; Ramos, Mónica; Gil, María Concepción; Pié, Angeles; Ribes, Antonia; Pérez-Cerda, Celia; Ugarte, Magdalena; Clayton, Peter T; Korman, Stanley H; Serra, Dolors; Asins, Guillermina; Ramos, Feliciano J; Gómez-Puertas, Paulino; Hegardt, Fausto G; Casals, Nuria; Pié, Juan

    2009-03-01

    3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and L-leucine catabolism. The clinical acute symptoms include vomiting, convulsions, metabolic acidosis, hypoketotic hypoglycaemia and lethargy. To date, 33 mutations in 100 patients have been reported in the HMGCL gene. In this study 10 new mutations in 24 patients are described. They include: 5 missense mutations: c.109G>A, c.425C>T, c.521G>A, c.575T>C and c.598A>T, 2 nonsense mutations: c.242G>A and c.559G>T, one small deletion: c.853delC, and 2 mutations in intron regions: c.497+4A>G and c.750+1G>A. Two prevalent mutations were detected, 109G>T (E37X) in 38% of disease alleles analyzed and c.504_505delCT in 10% of them. Although patients are mainly of European origin (71%) and mostly Spanish (54%), the group is ethnically diverse and includes, for the first time, patients from Pakistan, Palestine and Ecuador. We also present a simple, efficient method to express the enzyme and we analyze the possible functional effects of missense mutations. The finding that all identified missense mutations cause a >95% decrease in the enzyme activity, indicates that the disease appears only in very severe genotypes." PMID:19177531

  2. N-Carbamylglutamate Is an Effective Treatment for Acute Neonatal Hyperammonaemia in a Patient with Methylmalonic Aciduria.

    PubMed

    Yap, Sufin; Leong, Huey Yin; Abdul Aziz, Fadzlina; Hassim, Haszlin; Sthaneshwar, Pavai; Teh, Ser Huy; Abdullah, Ili Syazwana; Ngu, Lock Hock; Mohamed, Zulqarnain

    2016-01-01

    N-carbamylglutamate (NCG) has been used in combination with ammonia scavengers (sodium benzoate, sodium phenylbutyrate) and dialysis to treat hyperammonaemia in methylmalonic aciduria (MMA). The sole use of NCG for acute neonatal hyperammonaemia secondary to MMA is demonstrated in a neonate presenting at day 9 with encephalopathy, severe metabolic acidosis, hyperammonaemia (1,089 μmol/l), ketonuria and urinary methylmalonic acids. Emergency treatment included discontinuing protein feeds, providing high calories, carnitine and hydroxocobalamin. NCG 200 mg given at 0 and 90 min decreased plasma ammonia dramatically from 1,089 to 567 µmol/l at 90 min and further to 236 µmol/l at 6 h. Normalisation of ammonia was achieved at 12 h with two further doses of NCG 100 mg. This allowed for early re-institution of feeds at 14 h, followed by metabolic stabilization and recovery. Due to the effectiveness of NCG in this case, the use of the more invasive conventional ammonia-lowering therapeutic options could be avoided. PMID:26907495

  3. Radioautographic visualization of differences in the pattern of (/sup 3/H)uridine and (/sup 3/H)orotic acid incorporation into the RNA of migrating columnar cells in the rat small intestine

    SciTech Connect

    Uddin, M.; Altmann, G.G.; Leblond, C.P.

    1984-05-01

    The epithelium of rat small intestine was radioautographed to examine whether RNA is synthesized by the salvage pathway as shown after (/sup 3/H)uridine injection or by the de novo pathway as shown after (/sup 3/H)orotic acid injection. The two modes of RNA synthesis were thus investigated during the migration of columnar cells from crypt base to villus top, and the rate of synthesis was assessed by counting silver grains over the nucleolus and nucleoplasm at six levels along the duodenal epithelium - that is, in the base, mid, and top regions of the crypts and in the base, mid, and top regions of the villi. Concomitant biochemical analyses established that, after injection of either (5-/sup 3/H)uridine or (5-/sup 3/H)orotic acid: (a) buffered glutaraldehyde fixative was as effective as perchloric acid or trichloroacetic acid in insolubilizing the nucleic acids of rat small intestine; (b) a major fraction of the nucleic acid label was in RNA, that is, 91% after (/sup 3/H)uridine and 72% after (/sup 3/H)orotic acid, with the rest in DNA; and (c) a substantial fraction of the RNA label was in poly A/sup +/ RNA (presumed to be messenger RNA). In radioautographs of duodenum prepared after (/sup 3/H)uridine injection, the count of silver grains was high over nucleolus and nucleoplasm in crypt base cells and gradually decreased at the upper levels up to the villus base. In the rest of the villus, the grain count over the nucleolus was negligible, while over the nucleoplasm it was low but significant.

  4. Dietary saponins of sea cucumber alleviate orotic acid-induced fatty liver in rats via PPARα and SREBP-1c signaling

    PubMed Central

    2010-01-01

    Background Nonalcoholic fatty liver disease is the most common chronic liver disease in the world, and is becoming increasingly prevalent. Saponins of sea cucumber (SSC) are proven to exhibit various biological activities. Therefore, the present study was undertaken to examine the effect of saponins extracted from sea cucumber (Pearsonothuria graeffei) on the preventive activity of fatty liver in rats. Methods Male Wistar rats were randomly divided into five groups, including normal control group, fatty liver model group, SSC-treated group with SSC at levels of 0.01%, 0.03% and 0.05%. Model rats were established by administration with 1% orotic acid (OA). After the experiment period, serum total cholesterol (TC), triglyceride (TG), and hepatic lipid concentrations were determined. To search for a possible mechanism, we examined the changes of key enzymes and transcriptional factors involved in hepatic lipids biosynthesis, fatty acid β-oxidation. Results Both 0.03% and 0.05% SSC treatment alleviated hepatic steatosis and reduced serum TG and TC concentration significantly in OA fed rats. Hepatic lipogenic enzymes, such as fatty acid synthase (FAS), malic enzyme (ME), and glucose-6-phosphate dehydrogenase (G6PDH) activities were inhibited by SSC treatment. SSC also decreased the gene expression of FAS, ME, G6PDH and sterol-regulatory element binding protein (SREBP-1c). Otherwise, the rats feeding with SSC showed increased carnitine palmitoyl transferase (CPT) activity in the liver. Hepatic peroxisome proliferator-activated receptor (PPARα), together with its target gene CPT and acyl-CoA oxidase (ACO) mRNA expression were also upregulated by SSC. Conclusions According to our study, the lipids-lowering effect of dietary SSC may be partly associated with the enhancement of β-oxidation via PPARα activation. In addition, the inhibited SREBP-1c- mediated lipogenesis caused by SSC may also contribute to alleviating fatty liver. PMID:20211032

  5. Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up.

    PubMed

    Haarmann, A; Mayr, M; Kölker, S; Baumgartner, E R; Schnierda, J; Hopfer, H; Devuyst, O; Baumgartner, M R

    2013-12-01

    Chronic renal failure is a well-known long-term complication of methylmalonic aciduria (MMA-uria), occurring even under apparently optimal metabolic management. The onset of renal dysfunction seems to be dependent on the type of defect and vitamin B12-responsiveness. We report on a patient with a vitamin B12-responsive cobalamin A type (cblA) MMA-uria caused by a homozygous stop mutation (p.R145X) in the cobalamin A gene (MMAA). She was diagnosed with chronic kidney disease (CKD) stage III at the age of 12 years. Following re-evaluation, the patient received vitamin B12 (hydroxocobalamin) treatment, resulting in a significant decrease in the concentration of methylmalonic acid (MMA) in urine and plasma. Until age 29 years glomerular filtration rate remained stable probably due to hydroxocobalamin treatment slowing down progression to end-stage renal failure. Kidney biopsies showed non-specific manifestations of chronic interstitial inflammation. The patient received a renal transplant at age 35 years. Under continuous treatment with hydroxocobalamin there is no evidence of kidney damage due to MMA-uria until the last follow-up 6 years after transplantation. This case report illustrates (i) a long-term follow-up of a patient with MMA-uria due to cblA deficiency, (ii) the involvement of the kidney as a target organ and (iii) the importance of early and adequate vitamin B12 substitution in responsive patients. Further investigation will be necessary to prove the protective effect of hydroxocobalamin in the kidney in vitamin B12-responsive patients. PMID:24095221

  6. Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I.

    PubMed

    Sauer, Sven W; Opp, Silvana; Komatsuzaki, Shoko; Blank, Anna-Eva; Mittelbronn, Michel; Burgard, Peter; Koeller, D M; Okun, Jürgen G; Kölker, Stefan

    2015-05-01

    Glutaric aciduria type I is an inherited defect in L-lysine, L-hydroxylysine and L-tryptophan degradation caused by deficiency of glutaryl-CoA dehydrogenase (GCDH). The majority of untreated patients presents with accumulation of neurotoxic metabolites - glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) - and striatal injury. Gcdh(-/-) mice display elevated levels of GA and 3-OH-GA but do not spontaneously develop striatal lesions. L-lysine-enriched diets (appr. 235 mg/d) were suggested to induce a neurological phenotype similar to affected patients. In our hands 93% of mice stressed according to the published protocol remained asymptomatic. To understand the underlying mechanism, we modified their genetic background (F1 C57BL6/Jx129/SvCrl) and increased the daily oral L-lysine supply (235-433 mg). We identified three modulating factors, (1) gender, (2) genetic background, and (3) amount of L-lysine. Male mice displayed higher vulnerability and inbreeding for more than two generations as well as elevating L-lysine supply increased the diet-induced mortality rate (up to 89%). Onset of first symptoms leads to strongly reduced intake of food and, thus, L-lysine suggesting a threshold for toxic metabolite production to induce neurological disease. GA and 3-OH-GA tissue concentrations did not correlate with dietary L-lysine supply but differed between symptomatic and asymptomatic mice. Cerebral activities of glyceraldehyde 3-phosphate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and aconitase were decreased. Symptomatic mice did not develop striatal lesions or intracerebral hemorrhages. We found severe spongiosis in the hippocampus of Gcdh(-/-) mice which was independent of dietary L-lysine supply. In conclusion, the L-lysine-induced pathology in Gcdh(-/-) mice depends on genetic and dietary parameters. PMID:25558815

  7. Multiple Acyl-CoA Dehydrogenation Deficiency (Glutaric Aciduria Type II) with a Novel Mutation of Electron Transfer Flavoprotein-Dehydrogenase in a Cat.

    PubMed

    Wakitani, Shoichi; Torisu, Shidow; Yoshino, Taiki; Hattanda, Kazuhisa; Yamato, Osamu; Tasaki, Ryuji; Fujita, Haruo; Nishino, Koichiro

    2014-01-01

    Multiple acyl-CoA dehydrogenation deficiency (MADD; also known as glutaric aciduria type II) is a human autosomal recessive disease classified as one of the mitochondrial fatty-acid oxidation disorders. MADD is caused by a defect in the electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) molecule, but as yet, inherited MADD has not been reported in animals. Here we present the first report of MADD in a cat. The affected animal presented with symptoms characteristic of MADD including hypoglycemia, hyperammonemia, vomiting, diagnostic organic aciduria, and accumulation of medium- and long-chain fatty acids in plasma. Treatment with riboflavin and L-carnitine ameliorated the symptoms. To detect the gene mutation responsible for MADD in this case, we determined the complete cDNA sequences of feline ETFα, ETFβ, and ETFDH. Finally, we identified the feline patient-specific mutation, c.692T>G (p.F231C) in ETFDH. The affected animal only carries mutant alleles of ETFDH. p.F231 in feline ETFDH is completely conserved in eukaryotes, and is located on the apical surface of ETFDH, receiving electrons from ETF. This study thus identified the mutation strongly suspected to have been the cause of MADD in this cat. PMID:24142280

  8. Next generation sequencing of patients with mut methylmalonic aciduria: Validation of somatic cell studies and identification of 16 novel mutations.

    PubMed

    Chu, Jordan; Pupavac, Mihaela; Watkins, David; Tian, Xia; Feng, Yanming; Chen, Stella; Fenter, Remington; Zhang, Victor W; Wang, Jing; Wong, Lee-Jun; Rosenblatt, David S

    2016-08-01

    Mutations in the MUT gene, which encodes the mitochondrial enzyme methylmalonyl-CoA mutase, are responsible for the mut form of methylmalonic aciduria (MMA). In this study, a next generation sequencing (NGS) based gene panel was used to analyze 53 patients that had been diagnosed with mut MMA by somatic cell complementation analysis. A total of 54 different mutations in MUT were identified in 48 patients; 16 novel mutations were identified, including 1 initiation site mutation (c.2T>C [p.M1?]), 1 missense mutation (c.566A>T [p.N189I]), 2 nonsense mutations (c.129G>A [p.W43*] and c.1975C>T [p.Q659*]), 2 mutations affecting splice sites (c.753+3A>G and c.754-2A>G), 8 small insertions, deletions, and duplications (c.29dupT [p.L10Ffs*39], c.55dupG [p.V19Gfs*30], c.631_633delGAG [p.E211del], c.795_796insT [p.M266Yfs*7], c.1061delCinsGGA [p.S354Wfs*20], c.1065_1068dupATGG [p.S357Mfs*5], c.1181dupT [p.L394Ffs*30], c.1240delG [p.E414Kfs*17]), a large insertion (c.146_147ins279), and a large deletion involving exon 13. Phenotypic rescue and cDNA analysis were used to confirm that the c.146_147ins279 and c.631_633delGAG mutations were associated with the decreased methylmalonyl-CoA mutase function observed in the patient fibroblasts. In five patients, the NGS panel did not confirm the diagnosis made by complementation analysis. One of these patients was found to carry 2 novel mutations (c.433G > A [p.E145K] and c.511A>C [p.N171H]) in the SUCLG1 gene. PMID:27233228

  9. Methylmalonic and propionic acidurias: management without or with a few supplements of specific amino acid mixture.

    PubMed

    Touati, G; Valayannopoulos, V; Mention, K; de Lonlay, P; Jouvet, P; Depondt, E; Assoun, M; Souberbielle, J C; Rabier, D; Ogier de Baulny, H; Saudubray, J-M

    2006-01-01

    In a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low-protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow-up and monitoring using measurements of urinary urea. Thirty-nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal-onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late-onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4-0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very

  10. Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation.

    PubMed

    Colak, Gozde; Pougovkina, Olga; Dai, Lunzhi; Tan, Minjia; Te Brinke, Heleen; Huang, He; Cheng, Zhongyi; Park, Jeongsoon; Wan, Xuelian; Liu, Xiaojing; Yue, Wyatt W; Wanders, Ronald J A; Locasale, Jason W; Lombard, David B; de Boer, Vincent C J; Zhao, Yingming

    2015-11-01

    The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins. We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD-/- fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency. Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria. Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases. PMID:26320211

  11. Nucleic acid labeling with ( sup 3 H)orotic acid and nucleotide profile in rats in protein deprivation, enteral and parenteral essential amino acid administration, and 5-fluorouracil treatment

    SciTech Connect

    Jakobsson, B.; el Hag, I.A.; Andersson, M.; Christensson, P.I.; Stenram, U. )

    1990-09-01

    Rats were fed a 0% casein diet for 1 week, with or without enteral or parenteral administration of essential amino acids, or a 25% casein diet, in one group supplemented with 5-fluorouracil treatment. Ninety minutes before sacrifice the rats were given a tracer of (3H)orotic acid. Incorporation into the acid soluble fraction, RNA, and DNA was determined in liver, small intestine, bone marrow, and kidney. Nucleotide profile was examined in liver and intestine. Protein deficiency caused inter alia a decrease in body weight; a decrease in RNA/DNA ratio and an increase in the specific RNA labeling in liver and kidney; an altered nucleotide profile in the liver; an increase in the nucleotide/DNA and RNA/DNA ratios and a decrease in the specific labeling of the acid soluble fraction, RNA, and DNA in the bone marrow. These changes were prevented to the same extent by giving essential amino acids, either orally or intravenously. The minor changes in intestinal nucleotide profile in protein deprivation were prevented to a slightly larger extent by amino acids orally than parenterally. 5-Fluorouracil treatment gave a decrease in the RNA/DNA ratio in the liver and kidney but an increase in the nucleotide/DNA and RNA/DNA ratios in the bone marrow. Nucleotide profiles were unaltered. The amount of DNA per gram of tissue decreased in bone marrow and increased in kidney. Parenteral administration per se resulted in almost no changes.

  12. Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC).

    PubMed

    Richard, Eva; Jorge-Finnigan, Ana; Garcia-Villoria, Judit; Merinero, Begoña; Desviat, Lourdes R; Gort, Laura; Briones, Paz; Leal, Fátima; Pérez-Cerdá, Celia; Ribes, Antonia; Ugarte, Magdalena; Pérez, Belén

    2009-11-01

    Methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC) is the most frequent genetic disorder of vitamin B(12) metabolism. The aim of this work was to identify the mutational spectrum in a cohort of cblC-affected patients and the analysis of the cellular oxidative stress and apoptosis processes, in the presence or absence of vitamin B(12). The mutational spectrum includes nine previously described mutations: c.3G>A (p.M1L), c.217C>T (p.R73X), c.271dupA (p.R91KfsX14), c.331C>T (p.R111X), c.394C>T (p.R132X), c.457C>T (p.R153X), c.481C>T (p.R161X), c.565C>A (p.R189S), and c.615C>G (p.Y205X), and two novel changes, c.90G>A (p.W30X) and c.81+2T>G (IVS1+2T>G). The most frequent change was the known c.271dupA mutation, which accounts for 85% of the mutant alleles characterized in this cohort of patients. Owing to its high frequency, a real-time PCR and subsequent high-resolution melting (HRM) analysis for this mutation has been established for diagnostic purposes. All cell lines studied presented a significant increase of intracellular reactive oxygen species (ROS) content, and also a high rate of apoptosis, suggesting that elevated ROS levels might induce apoptosis in cblC patients. In addition, ROS levels decreased in hydroxocobalamin-incubated cells, indicating that cobalamin might either directly or indirectly act as a scavenger of ROS. ROS production might be considered as a phenotypic modifier in cblC patients, and cobalamin supplementation or additional antioxidant drugs might suppress apoptosis and prevent cellular damage in these patients. PMID:19760748

  13. First reported case of lysinuric protein intolerance (LPI) in Lithuania, confirmed biochemically and by DNA analysis.

    PubMed

    Cimbalistiene, Loreta; Lehnert, Willy; Huoponen, Kirsi; Kucinskas, Vaidutis

    2007-01-01

    We report on an 18-year-old Lithuanian girl with hepatosplenomegaly noticed at birth, which progressed thereafter. The patient had to wait about 17 years for an accurate diagnosis and appropriate therapy. Lactase deficiency, congenital cataract of the right eye, and osteoporosis were observed. Episodes of drowsiness were caused by intake of high-protein food. Laboratory findings included slight hyperammonaemia, high plasma Citr, Ala, Gly, Glu, Ser levels, as well as citrullinuria, lysinuria, glutaminuria, alaninuria, argininuria, prolinuria, hydroxyprolinuria, ornithinuria, and orotic aciduria. Aversion to high-protein diet strongly suggested a disorder resulting in hyperammonaemia. Citrullinaemia was suspected. Subsequently the diagnosis of LPI was made on the basis of biochemical and clinical features. Molecular genetic testing revealed a mutation in the SLC7A7 gene, confirming the diagnosis. PMID:17666782

  14. Genetics Home Reference: argininosuccinic aciduria

    MedlinePlus

    ... belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occur ... by the body, to make a compound called urea that is excreted by the kidneys. In argininosuccinic ...

  15. Revealing Rembrandt

    PubMed Central

    Parker, Andrew J.

    2014-01-01

    The power and significance of artwork in shaping human cognition is self-evident. The starting point for our empirical investigations is the view that the task of neuroscience is to integrate itself with other forms of knowledge, rather than to seek to supplant them. In our recent work, we examined a particular aspect of the appreciation of artwork using present-day functional magnetic resonance imaging (fMRI). Our results emphasized the continuity between viewing artwork and other human cognitive activities. We also showed that appreciation of a particular aspect of artwork, namely authenticity, depends upon the co-ordinated activity between the brain regions involved in multiple decision making and those responsible for processing visual information. The findings about brain function probably have no specific consequences for understanding how people respond to the art of Rembrandt in comparison with their response to other artworks. However, the use of images of Rembrandt's portraits, his most intimate and personal works, clearly had a significant impact upon our viewers, even though they have been spatially confined to the interior of an MRI scanner at the time of viewing. Neuroscientific studies of humans viewing artwork have the capacity to reveal the diversity of human cognitive responses that may be induced by external advice or context as people view artwork in a variety of frameworks and settings. PMID:24795552

  16. Revealing Mercury

    NASA Astrophysics Data System (ADS)

    Prockter, L. M.; Solomon, S. C.; Head, J. W.; Watters, T. R.; Murchie, S. L.; Robinson, M. S.; Chapman, C. R.; McNutt, R. L.

    2009-04-01

    The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft, developed under NASA's Discovery Program, launched in August 2004. En route to insertion into orbit about Mercury in 2011, MESSENGER flies by Mercury three times. The first and second of these encounters were accomplished in January and October of 2008. These flybys viewed portions of Mercury's surface that were not observed by Mariner 10 during its reconnaissance of somewhat less than half of the planet in 1974-1975. All MESSENGER instruments operated during each flyby and returned a wealth of new data. Many of the new observations were focused on the planet's geology, including monochrome imaging at resolutions as high as 100 m/pixel, multispectral imaging in 11 filters at resolutions as high as 500 m/pixel, laser altimetry tracks extending over several thousands of kilometers, and high-resolution spectral measurements of several types of terrain. Here we present an overview of the first inferences on the global geology of Mercury from the MESSENGER observations. Whereas evidence for volcanism was equivocal from Mariner 10 data, the new MESSENGER images and altimetry provide compelling evidence that volcanism was widespread and protracted on Mercury. Color imaging reveals three common spectral units on the surface: a higher-reflectance, relatively red material occurring as a distinct class of smooth plains, typically with distinct embayment relationships interpreted to indicate volcanic emplacement; a lower-reflectance, relatively blue material typically excavated by impact craters and therefore inferred to be more common at depth; and a spectrally intermediate terrain that constitutes much of the uppermost crust. Three more minor spectral units are also seen: fresh crater ejecta, reddish material associated with rimless depressions interpreted to be volcanic centers, and high-reflectance deposits seen in some crater floors. Preliminary measurements of crater size

  17. How Are Preferences Revealed?

    PubMed Central

    Beshears, John; Choi, James J.; Laibson, David; Madrian, Brigitte C.

    2009-01-01

    Revealed preferences are tastes that rationalize an economic agent’s observed actions. Normative preferences represent the agent’s actual interests. It sometimes makes sense to assume that revealed preferences are identical to normative preferences. But there are many cases where this assumption is violated. We identify five factors that increase the likelihood of a disparity between revealed preferences and normative preferences: passive choice, complexity, limited personal experience, third-party marketing, and intertemporal choice. We then discuss six approaches that jointly contribute to the identification of normative preferences: structural estimation, active decisions, asymptotic choice, aggregated revealed preferences, reported preferences, and informed preferences. Each of these approaches uses consumer behavior to infer some property of normative preferences without equating revealed and normative preferences. We illustrate these issues with evidence from savings and investment outcomes. PMID:24761048

  18. N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy.

    PubMed

    Elpeleg, Orly; Shaag, Avraham; Ben-Shalom, Efrat; Schmid, Tal; Bachmann, Claude

    2002-12-01

    Carbamylphosphate synthase is the first enzymatic reaction of the urea cycle. Its activator, N-acetylglutamate, is synthesized from acetyl-CoA and glutamate in a reaction catalyzed by N-acetylglutamate synthase (NAGS). We have identified the putative human NAGS gene and report the first mutation in this gene in a family with carbamylglutamate responsive hyperammonemia and normal activity of the urea cycle enzymes. Mutation analysis has a higher diagnostic specificity than the enzymatic assay in NAGS deficiency. A therapeutic trial with carbamylglutamate is recommended whenever hyperammonemia without an organic aciduria, increased orotate excretion, or diagnostic amino acidemia/uria is detected. PMID:12447942

  19. US weapons secrets revealed

    SciTech Connect

    Norris, R.S.; Arkin, W.M.

    1993-03-01

    Extraordinary details have only recently been revealed about the struggle over the control of early U.S. nuclear weapons and their initial deployments abroad. The information comes from a newly declassified top secret report, part of a larger study, The History of the Strategic Arms Competition, 1945-1972, commissioned by Defense Secretary James R. Schlisinger in summer 1974.

  20. Revealing power in truth

    PubMed Central

    Lee, Kelley

    2015-01-01

    Jeremy Shiffman’s editorial appropriately calls on making all forms of power more apparent and accountable, notably productive power derived from expertise and claims to moral authority. This commentary argues that relationships based on productive power can be especially difficult to reveal in global health policy because of embedded notions about the nature of power and politics. Yet, it is essential to recognize that global health is shot through with power relationships, that they can take many forms, and that their explicit acknowledgement should be part of, rather than factored out of, any reform of global health governance. PMID:25844390

  1. The Universe Revealed

    NASA Astrophysics Data System (ADS)

    Spence, Pam

    1998-10-01

    The Universe is a bewildering place to the uninitiated. The concepts and theories that govern space seem complex and often contradictory. The Universe Revealed provides the keys to unlocking the wonders of the cosmos. Elegantly written and lavishly illustrated, it begins with the Sun and stretches through our solar system into deepest space. Lucid prose, written by many of the people who have shaped our current thinking on space, and spectacular photographs make the physics of the Universe accessible and provide a solid background for understanding the most recent astronomical discoveries. Covering the most intriguing features of the cosmos, the topics discussed range from the Earth and global warming to cosmic collisions and the size of the Universe. Major sections examine the Solar System, stars, galaxies, cosmology, and the observational techniques used by astronomers, both amateur and professional. The Universe Revealed represents the collaboration of internationally renowned experts in astronomy and cosmology, with contributions from authors including David Malin, F. Duccio Macchetto, Iain Nicholson, Neil Bone, Ian Ridpath, Seth Shostak, Mike Lancaster, Steve Miller, Ken Croswell, Geoff McNamara, and Steven Young. This extraordinary blend of astronomy, astrophysics, and cosmology, will appeal to amateur and armchair astronomers alike.

  2. Gusev's Rim Revealed

    NASA Technical Reports Server (NTRS)

    2004-01-01

    NASA's Mars Exploration Rover Spirit took this panoramic camera image on sol 91 (April 5, 2004). Spirit is looking to the southeast, and through the martian haze has captured the rim of Gusev Crater approximately 80 kilometers (49.7 miles) away on the horizon.

    The right side of this image reveals the portion of the crater edge that descends into the mouth of Ma'adim Vallis, a channel that opens into Gusev Crater. Spirit is currently traveling toward the informally named 'Columbia Hills,' which lie to the left of the region pictured here.

    This image is similar to a panoramic camera image taken on sol 68, but Gusev's ridge is more visible here because the atmospheric dust caused by winter dust storms has settled. Scientists expect to get even clearer images than this one in upcoming sols.

    This image has been modified to make the crater rim more visible.

  3. Titan Casts Revealing Shadow

    NASA Astrophysics Data System (ADS)

    2004-05-01

    A rare celestial event was captured by NASA's Chandra X-ray Observatory as Titan -- Saturn's largest moon and the only moon in the Solar System with a thick atmosphere -- crossed in front of the X-ray bright Crab Nebula. The X-ray shadow cast by Titan allowed astronomers to make the first X-ray measurement of the extent of its atmosphere. On January 5, 2003, Titan transited the Crab Nebula, the remnant of a supernova explosion that was observed to occur in the year 1054. Although Saturn and Titan pass within a few degrees of the Crab Nebula every 30 years, they rarely pass directly in front of it. "This may have been the first transit of the Crab Nebula by Titan since the birth of the Crab Nebula," said Koji Mori of Pennsylvania State University in University Park, and lead author on an Astrophysical Journal paper describing these results. "The next similar conjunction will take place in the year 2267, so this was truly a once in a lifetime event." Animation of Titan's Shadow on Crab Nebula Animation of Titan's Shadow on Crab Nebula Chandra's observation revealed that the diameter of the X-ray shadow cast by Titan was larger than the diameter of its solid surface. The difference in diameters gives a measurement of about 550 miles (880 kilometers) for the height of the X-ray absorbing region of Titan's atmosphere. The extent of the upper atmosphere is consistent with, or slightly (10-15%) larger, than that implied by Voyager I observations made at radio, infrared, and ultraviolet wavelengths in 1980. "Saturn was about 5% closer to the Sun in 2003, so increased solar heating of Titan may account for some of this atmospheric expansion," said Hiroshi Tsunemi of Osaka University in Japan, one of the coauthors on the paper. The X-ray brightness and extent of the Crab Nebula made it possible to study the tiny X-ray shadow cast by Titan during its transit. By using Chandra to precisely track Titan's position, astronomers were able to measure a shadow one arcsecond in

  4. Genetics Home Reference: combined malonic and methylmalonic aciduria

    MedlinePlus

    ... plays a role in the formation (synthesis) of fatty acids. Fatty acids are building blocks used to make fats (lipids). ... malonyl-CoA, which is the first step of fatty acid synthesis in cellular structures called mitochondria . Based on ...

  5. Revealing the Beast Within

    NASA Astrophysics Data System (ADS)

    2003-07-01

    Deeply Embedded Massive Stellar Clusters Discovered in Milky Way Powerhouse Summary Peering into a giant molecular cloud in the Milky Way galaxy - known as W49 - astronomers from the European Southern Observatory (ESO) have discovered a whole new population of very massive newborn stars . This research is being presented today at the International Astronomical Union's 25th General Assembly held in Sydney, Australia, by ESO-scientist João Alves. With the help of infrared images obtained during a period of excellent observing conditions with the ESO 3.5-m New Technology Telescope (NTT) at the La Silla Observatory (Chile), the astronomers looked deep into this molecular cloud and discovered four massive stellar clusters, with hot and energetic stars as massive as 120 solar masses. The exceedingly strong radiation from the stars in the largest of these clusters is "powering" a 20 light-year diameter region of mostly ionized hydrogen gas (a "giant HII region"). W49 is one of the most energetic regions of star formation in the Milky Way. With the present discovery, the true sources of the enormous energy have now been revealed for the first time, finally bringing to an end some decades of astronomical speculations and hypotheses. PR Photo 21a/03 : Colour Composite of W49A (NTT+SOFI). PR Photo 21b/03 : Radio and Near-Infrared Composite of W49A Giant molecular clouds Stars form predominantly inside Giant Molecular Clouds which populate our Galaxy, the Milky Way. One of the most prominent of these is W49 , which has a mass of a million solar masses. It is located some 37,000 light-years away and is the most luminous star-forming region known in our home galaxy: its luminosity is several million times the luminosity of our Sun. A smaller region within this cloud is denoted W49A - this is one of the strongest radio-emitting areas known in the Galaxy . Massive stars are excessive in all ways. Compared to their smaller and ligther brethren, they form at an Olympic speed and

  6. Electrocardiograph abnormalities revealed during laparoscopy

    PubMed Central

    Nijjer, Sukhjinder; Dubrey, Simon William

    2010-01-01

    This brief case presents a well patient in whom an electrocardiograph abnormality consistent with an accessory pathway was found during a routine procedure. We present the electrocardiographs, explain the underlying condition, and consider why the abnormality was revealed in this manner. PMID:22419949

  7. Ischemic Colitis Revealing Polyarteritis Nodosa

    PubMed Central

    Hamzaoui, Amira; Litaiem, Noureddine; Smiti Khanfir, M.; Ayadi, Sofiene; Nfoussi, Haifa; Houman, M. H.

    2013-01-01

    Ischemic colitis is one of the most common intestinal ischemic injuries. It results from impaired perfusion of blood to the bowel and is rarely caused by vasculitis. We report a case of ischemic colitis revealing polyarteritis nodosa (PAN) in a 55-year-old man. Histological examination of the resected colon led to the diagnosis of PAN. PMID:24382967

  8. Urticarial vasculitis reveals unsuspected thyroiditis.

    PubMed

    Ferreira, Olga; Mota, Alberto; Baudrier, Teresa; Azevedo, Filomena

    2012-01-01

    A 38-year-old woman presented with erythematous, violaceous plaques with a serpiginous and unusual appearance located on the left shoulder, left thigh, and right buttock, evolving for 5 days, which eventually became generalized. A skin biopsy revealed leukocytoclastic vasculitis and a diagnosis of urticarial vasculitis was made. The complete blood count, biochemistry, complement levels, and other immunological test results were unremarkable. However, antithyroid antibody titers were increased. Despite having normal thyroid function tests and an absence of specific symptoms, the patient underwent a thyroid ultrasound, which revealed features of thyroiditis, and was subsequently referred to an endocrinologist. Several diseases can be associated with urticarial vasculitis, namely infections and autoimmune connective-tissue disorders such as systemic lupus erythematosus and Sjögren syndrome. Thyroiditis is an uncommon association. PMID:23000939

  9. Identification of metabolites produced by Phanerochaete chrysosporium in the presence of amlodipine orotate using metabolomics.

    PubMed

    De Sotto, R B; Kim, K I; Kim, S; Song, K G; Park, Y

    2015-01-01

    Pharmaceuticals are very useful in treating human diseases but they are excreted to the environment sometimes in their original form or as byproducts of human metabolism. Pharmaceuticals and their metabolites have been proven by studies to be harmful to non-target ecological species and may be persistent in different water matrices. In this regard, there is an emergent need to eliminate these compounds to prevent their adverse effects on aquatic species. Biodegradation using white-rot fungi is a promising technology for the removal of recalcitrant compounds; however, products of fungal biodegradation can also be detrimental. In this novel study, we evaluated the ability of Phanerochaete chrysosporium to degrade amlodipine, an anti-hypertensive drug which was recently found in water systems. Analysis of amlodipine metabolites was done using quadrupole time-of-flight liquid chromatography mass spectrometry after the degradation set-up of 120 hours. Pharmaceutical degradation was seen using triple quadrupole liquid chromatography tandem mass spectrometry. Ninety-two significant metabolites (P-value ≤ 0.05) were significantly expressed after false discovery rate adjustment at a significance threshold of q = 0.05. Pyridine derivatives which were identified from samples became the basis of the proposed degradation pathway of amlodipine in this study. PMID:26398029

  10. Plan competitions reveal entrepreneurial talent

    SciTech Connect

    Madison, Alison L.

    2011-05-15

    Monthly economic diversity column for Tri-City Herald business section. Excerpt below: There’s something to be said for gaining valuable real-world experience in a structured, nurturing environment. Take for instance learning to scuba dive in the comfort of my resort pool rather than immediately hanging out with sharks while I figure out little things like oxygen tanks and avoiding underwater panic attacks. Likewise, graduate students are getting some excellent, supportive real-world training through university business plan competitions. These competitions are places where smart minds, new technologies, months of preparation and coaching, and some healthy pre-presentation jitters collide to reveal not only solid new business ideas, but also some promising entrepreneurial talent. In fact, professionals from around our region descend upon college campuses every spring to judge these events, which help to bridge the gap between academics and the real technology and business-driven economy.

  11. Revealing ontological commitments by magic.

    PubMed

    Griffiths, Thomas L

    2015-03-01

    Considering the appeal of different magical transformations exposes some systematic asymmetries. For example, it is more interesting to transform a vase into a rose than a rose into a vase. An experiment in which people judged how interesting they found different magic tricks showed that these asymmetries reflect the direction a transformation moves in an ontological hierarchy: transformations in the direction of animacy and intelligence are favored over the opposite. A second and third experiment demonstrated that judgments of the plausibility of machines that perform the same transformations do not show the same asymmetries, but judgments of the interestingness of such machines do. A formal argument relates this sense of interestingness to evidence for an alternative to our current physical theory, with magic tricks being a particularly pure source of such evidence. These results suggest that people's intuitions about magic tricks can reveal the ontological commitments that underlie human cognition. PMID:25490128

  12. CMB source apportionment during REVEAL

    SciTech Connect

    Lowenthal, D.H.; Gertler, A.W.; Wittorff, D.; Sakiyama, S.

    1997-01-01

    Source contributions to PM{sub 2.5} aerosol measured at Chilliwack and Pitt Meadows in the Lower Fraser Valley, B.C., Canada, during the REVEAL study, were estimated using chemical mass balance (CMB) receptor modeling. ON average, motor vehicles accounted for 34 and 43% of PM{sub 2.5} at Chilliwack and Pitt Meadows, respectively. Secondary sulfate and secondary nitrate were the next most significant PM{sub 2.5} components, accounting for 25 and 27%, respectively, at Chilliwack, and 27 and 12%, respectively, at Pitt Meadows. Geological material accounted for 3 and 5% of PM{sub 2.5} at Chilliwack and Pitt Meadows, respectively. A significant contribution of wood smoke was estimated for both sites: 8% at Chilliwack and 9% at Pitt Meadows.

  13. Archimedes: Accelerator Reveals Ancient Text

    SciTech Connect

    Bergmann, Uwe

    2004-02-24

    Archimedes (287-212 BC), who is famous for shouting 'Eureka' (I found it) is considered one of the most brilliant thinkers of all times. The 10th-century parchment document known as the 'Archimedes Palimpsest' is the unique source for two of the great Greek's treatises. Some of the writings, hidden under gold forgeries, have recently been revealed at the Stanford Synchrotron Radiation Laboratory at SLAC. An intense x-ray beam produced in a particle accelerator causes the iron in original ink, which has been partly erased and covered, to send out a fluorescence glow. A detector records the signal and a digital image showing the ancient writings is produced. Please join us in this fascinating journey of a 1,000-year-old parchment from its origin in the Mediterranean city of Constantinople to a particle accelerator in Menlo Park.

  14. Erosion and what it Reveals

    NASA Technical Reports Server (NTRS)

    2003-01-01

    [figure removed for brevity, see original site]

    Released 20 November 2003

    This image is located near the boundary between Syrtis Major and Isidis Planitia. The top of the image shows rough material that has eroded away from the lower portion of the image, revealing an underlying surface that has many small craters. It also reveals an ancient flow lobe that is barely discernable, crossing the southern part of the image (this flow lobe is much easier to see as a smooth region in the context image).

    Image information: VIS instrument. Latitude 16.4, Longitude 77.9 East (282.1 West). 19 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  15. Dunes reveal Titan's recent history

    NASA Astrophysics Data System (ADS)

    Savage, Christopher J.; Radebaugh, Jani

    2010-04-01

    Large fields of linear dunes are abundant on Titan, covering nearly 20% of the surface. They are among the youngest features and represent interactions between near-surface winds and sediment. This interaction may vary from area to area creating unique populations of eolian features identified by dune field parameters such as crest-to-crest spacing, dune width and orientation. These parameters respond to changes in near-surface conditions over periods of time ranging from minutes to many thousands of years depending on dune size and the duration of the changes. While pattern analysis of dune field parameters on Earth and, in this study, Titan reveals much about current climatic conditions, such as wind regimes and wetter vs. drier areas, many inferences about past conditions can also be made. Initial pattern analysis of linear dunes on Titan reveals a single population of linear dunes representing a large percentage of all observed dunes. This single population is the result of two leading possibilities: Either there has been only one long period of dune building, leading to very old cores that have been built upon over long periods of time, perhaps punctuated with few or many intervals of non-deposition; or the current conditions of dune building have persisted long enough to completely erase any evidence of previous conditions. We have not yet worked through all the input parameters to adjust Earth's time scales to Titan's, and thus it is not yet possible to give a precise age for Titan's dunes. However, if these large linear dunes are similar to Earth's large linear dunes, they may represent at least several thousand years of dune building.

  16. APEX reveals glowing stellar nurseries

    NASA Astrophysics Data System (ADS)

    2008-11-01

    Illustrating the power of submillimetre-wavelength astronomy, an APEX image reveals how an expanding bubble of ionised gas about ten light-years across is causing the surrounding material to collapse into dense clumps that are the birthplaces of new stars. Submillimetre light is the key to revealing some of the coldest material in the Universe, such as these cold, dense clouds. Glowing Stellar Nurseries ESO PR Photo 40/08 Glowing Stellar Nurseries The region, called RCW120, is about 4200 light years from Earth, towards the constellation of Scorpius. A hot, massive star in its centre is emitting huge amounts of ultraviolet radiation, which ionises the surrounding gas, stripping the electrons from hydrogen atoms and producing the characteristic red glow of so-called H-alpha emission. As this ionised region expands into space, the associated shock wave sweeps up a layer of the surrounding cold interstellar gas and cosmic dust. This layer becomes unstable and collapses under its own gravity into dense clumps, forming cold, dense clouds of hydrogen where new stars are born. However, as the clouds are still very cold, with temperatures of around -250˚ Celsius, their faint heat glow can only be seen at submillimetre wavelengths. Submillimetre light is therefore vital in studying the earliest stages of the birth and life of stars. The submillimetre-wavelength data were taken with the LABOCA camera on the 12-m Atacama Pathfinder Experiment (APEX) telescope, located on the 5000 m high plateau of Chajnantor in the Chilean Atacama desert. Thanks to LABOCA's high sensitivity, astronomers were able to detect clumps of cold gas four times fainter than previously possible. Since the brightness of the clumps is a measure of their mass, this also means that astronomers can now study the formation of less massive stars than they could before. The plateau of Chajnantor is also where ESO, together with international partners, is building a next generation submillimetre telescope, ALMA

  17. Hubble Images Reveal Jupiter's Auroras

    NASA Technical Reports Server (NTRS)

    1996-01-01

    These images, taken by the Hubble Space Telescope, reveal changes in Jupiter's auroral emissions and how small auroral spots just outside the emission rings are linked to the planet's volcanic moon, Io. The images represent the most sensitive and sharply-detailed views ever taken of Jovian auroras.

    The top panel pinpoints the effects of emissions from Io, which is about the size of Earth's moon. The black-and-white image on the left, taken in visible light, shows how Io and Jupiter are linked by an invisible electrical current of charged particles called a 'flux tube.' The particles - ejected from Io (the bright spot on Jupiter's right) by volcanic eruptions - flow along Jupiter's magnetic field lines, which thread through Io, to the planet's north and south magnetic poles. This image also shows the belts of clouds surrounding Jupiter as well as the Great Red Spot.

    The black-and-white image on the right, taken in ultraviolet light about 15 minutes later, shows Jupiter's auroral emissions at the north and south poles. Just outside these emissions are the auroral spots. Called 'footprints,' the spots are created when the particles in Io's 'flux tube' reach Jupiter's upper atmosphere and interact with hydrogen gas, making it fluoresce. In this image, Io is not observable because it is faint in the ultraviolet.

    The two ultraviolet images at the bottom of the picture show how the auroral emissions change in brightness and structure as Jupiter rotates. These false-color images also reveal how the magnetic field is offset from Jupiter's spin axis by 10 to 15 degrees. In the right image, the north auroral emission is rising over the left limb; the south auroral oval is beginning to set. The image on the left, obtained on a different date, shows a full view of the north aurora, with a strong emission inside the main auroral oval.

    The images were taken by the telescope's Wide Field and Planetary Camera 2 between May 1994 and September 1995.

    This image and

  18. Pharmacophore Modeling for Anti-Chagas Drug Design Using the Fragment Molecular Orbital Method

    PubMed Central

    Ohno, Kazuki; Orita, Masaya; Inoue, Masayuki; Shiba, Tomoo; Harada, Shigeharu; Honma, Teruki; Balogun, Emmanuel Oluwadare; da Rocha, Josmar Rodrigues; Montanari, Carlos Alberto; Kita, Kiyoshi; Sekijima, Masakazu

    2015-01-01

    Background Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that causes severe human health problems. To develop a new chemotherapeutic agent for the treatment of Chagas disease, we predicted a pharmacophore model for T. cruzi dihydroorotate dehydrogenase (TcDHODH) by fragment molecular orbital (FMO) calculation for orotate, oxonate, and 43 orotate derivatives. Methodology/Principal Findings Intermolecular interactions in the complexes of TcDHODH with orotate, oxonate, and 43 orotate derivatives were analyzed by FMO calculation at the MP2/6-31G level. The results indicated that the orotate moiety, which is the base fragment of these compounds, interacts with the Lys43, Asn67, and Asn194 residues of TcDHODH and the cofactor flavin mononucleotide (FMN), whereas functional groups introduced at the orotate 5-position strongly interact with the Lys214 residue. Conclusions/Significance FMO-based interaction energy analyses revealed a pharmacophore model for TcDHODH inhibitor. Hydrogen bond acceptor pharmacophores correspond to Lys43 and Lys214, hydrogen bond donor and acceptor pharmacophores correspond to Asn67 and Asn194, and the aromatic ring pharmacophore corresponds to FMN, which shows important characteristics of compounds that inhibit TcDHODH. In addition, the Lys214 residue is not conserved between TcDHODH and human DHODH. Our analysis suggests that these orotate derivatives should preferentially bind to TcDHODH, increasing their selectivity. Our results obtained by pharmacophore modeling provides insight into the structural requirements for the design of TcDHODH inhibitors and their development as new anti-Chagas drugs. PMID:25961853

  19. Plant transcriptomes reveal hidden guests.

    PubMed

    Zhu, Jiao; Wang, Guirong; Pelosi, Paolo

    2016-06-01

    With the wide adoption of transcriptome sequencing an ever increasing amount of information is becoming available, together with spurious data originating from contamination. We show that sometimes errors and inaccuracy can turn beneficial, revealing insect and arthropod pests when analysing plant transcriptomes. We have found a large number of soluble olfactory proteins, odorant-binding proteins (OBPs) and chemosensory proteins (CSPs), in plant databases, likely due to contamination by guest insects. In fact, both classes of proteins are only expressed in insects, with few CSPs also present in other arthropods. In addition, we found many sequences of the Niemann-Pick (Npc2) family, proteins dedicated to cholesterol transport in vertebrates and hypothesised to be involved in chemical communication in insects, but absent in plants. In several cases we were able to trace down members of the three classes of proteins to the insect or arthopod species responsible for contamination. Our work suggests that genes found in plants and recognised as contaminants can be turned into useful information to investigate plant-insect relationships or to identify new sequences from insects species not yet investigated. PMID:27130825

  20. Revealing ionic motion molecular solids

    NASA Astrophysics Data System (ADS)

    Thurzo, I.; Zahn, D. R. T.

    2006-01-01

    Thin films of mixed valence semiconductor copper-tetracyano-quinodimethane (Cu-TCNQ) and small molecule tris(8-hydroxyquinolinato)aluminum (Alq3) were investigated by current-voltage (I-V) and admittance (C-V,G-V) techniques in single-layer configuration with different combinations of electrodes. The predicted hysteresis of I-V curves and nearly constant loss (NCL) could be observed for both materials. When cycling devices between negative and positive biases, slowly decaying ionic transient currents interfere with steady-state currents and point to unidirectional motions of the ionic species with subsequent redox reaction at one of the electrodes. Plotting the frequency f dependence of the equivalent parallel capacitance at zero bias as log10 C(0) versus log10(f), the dielectric behavior of Cu-TCNQ and Alq3 complies with the effective-medium model for NCL in ionic conductors [J. R. Macdonald J. Appl. Phys. 94, 558 (2003)]. It also holds for a similar plot of the equivalent parallel zero-bias conductance G(0). The nature of the revealed mobile ions is discussed with emphasis on their sources.

  1. Reveal for Salmonella test system.

    PubMed

    Bird, C B; Miller, R L; Miller, B M

    1999-01-01

    The Reveal for Salmonella (RSS) test system is a presumptive qualitative test that detects the presence of Salmonella organisms in foods within 21 h total testing time, allowing the user to release negative products 24 h earlier than when using other rapid test kits. Foods are enriched with a proprietary resuscitation medium called Revive and then selectively enriched with either Selenite Cystine or Rappaport-Vassiliadis selective media. The enriched culture is used to inoculate the RSS detection device, which initiates a lateral flow through a reagent zone containing anti-Salmonella antibodies conjugated to colloidal gold particles that capture antigens present in the culture. The antigen-antibody complex migrates farther and is captured by an additional anti-Salmonella antibody, causing the colloidal gold to precipitate and form a visual line, indicating a positive result. A procedural control line also will form regardless of the presence of Salmonella organisms to indicate the test is working properly. Existing AOAC Official Methods for Salmonella organisms require a 48 h enrichment before testing. Hence, a food product has to be held before release, adding extra cost to the company and the consumer. The RSS test system was evaluated by quantitative spiking studies. Although AOAC encourages inclusion of naturally contaminated foods, almost all microbiological AOAC validation studies have been performed with artificially contaminated foods for absolute control over the study. The RSS test system is designed to test many food types for Salmonella organisms and has a limit of detection of 5-10 colony-forming units (cfu)/25 g with a false-negative rate of < 1% and a false-positive rate of < 5.0%. It showed an 81% overall agreement with the traditional procedure of the U.S. Department of Agriculture's Food Safety Inspection Service. PMID:10367381

  2. Focus groups reveal consumer ambivalence.

    PubMed

    1983-01-01

    According to qualitative research, Salvadoreans are ambivalent about the use of contraceptives. Since complete responsibility for management of the CSM project was accepted by the Association Demografica Salvadorena (ADS), the agency which operates the contraceptive social marketing project in El Salvador, in November 1980, the need for decisions in such areas as product price increases, introduction of new condom brands, promotion of the vaginal foaming tablet, and assessment of product sales performance had arisen. The ICSMP funded market research, completed during 1983, was intended to provide the data on which such decisions by ADS could be based. The qualitative research involved 8 focus groups, comprised of men and women, aged 18-45, contraceptive users and nonusers, from the middle and lower socioeconomic strata of the city of San Salvador and other suburban areas. In each group a moderator led discussion of family planning and probed respondents for specific attitudes, knowledge, and behavior regarding the use of contraceptives. To assess attitudes at a more emotional level, moderators asked respondents to "draw" their ideas on certain issues. A marked discrepancy was revealed between respondents' intellectual responses to the issues raised in group discussion, as opposed to their feelings expressed in the drawings. Intellectually, participants responded very positively to family planning practice, but when they were asked to draw their perceptions, ambivalent feelings emerged. Drawings of both the user and the nonuser convey primarily negative aspects for either choice. The user is tense and moody toward her children; the nonuser loses her attractiveness and "dies." Figures also show drawings of some of the attitudes of single and married male participants. 1 drawing shows an incomplete and a complete circle, symbolizing a sterilized man (incomplete) and a nonsterilized man (complete). Another picture depicts a chained man who has lost his freedom

  3. Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases.

    PubMed

    Yamada, Kazuhiro; Gherasim, Carmen; Banerjee, Ruma; Koutmos, Markos

    2015-12-01

    In mammals, B12 (or cobalamin) is an essential cofactor required by methionine synthase and methylmalonyl-CoA mutase. A complex intracellular pathway supports the assimilation of cobalamin into its active cofactor forms and delivery to its target enzymes. MMADHC (the methylmalonic aciduria and homocystinuria type D protein), commonly referred to as CblD, is a key chaperone involved in intracellular cobalamin trafficking, and mutations in CblD cause methylmalonic aciduria and/or homocystinuria. Herein, we report the first crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC (the methylmalonic aciduria and homocystinuria type C protein), or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway. CblD contains an α+β fold that is structurally reminiscent of the nitro-FMN reductase superfamily. Two of the closest structural relatives of CblD are CblC, a multifunctional enzyme important for cobalamin trafficking, and the activation domain of methionine synthase. CblD, CblC, and the activation domain of methionine synthase share several distinguishing features and, together with two recently described corrinoid-dependent reductive dehalogenases, constitute a new subclass within the nitro-FMN reductase superfamily. We demonstrate that CblD enhances oxidation of cob(II)alamin bound to CblC and that disease-causing mutations in CblD impair the kinetics of this reaction. The striking structural similarity of CblD to CblC, believed to be contiguous in the cobalamin trafficking pathway, suggests the co-option of molecular mimicry as a strategy for achieving its function. PMID:26364851

  4. A New Mouse Model of Mild Ornithine Transcarbamylase Deficiency (spf-j) Displays Cerebral Amino Acid Perturbations at Baseline and upon Systemic Immune Activation

    PubMed Central

    Tarasenko, Tatyana N.; Rosas, Odrick R.; Singh, Larry N.; Kristaponis, Kara; Vernon, Hilary; McGuire, Peter J.

    2015-01-01

    Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N). This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic:polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans. PMID:25647322

  5. Propionic acidemia and hyperlysinemia in a case with ornithine transcarbamylase (OTC) deficiency.

    PubMed

    Krieger, I; Bachmann, C; Gronemeyer, W H; Cejka, J

    1976-10-01

    A female infant with episodic hyperammonemia due to a disorder of the urea cycle and who had hyperlysinemia and an unusual elevation of short chain fatty acids, mainly propionate, is described. Both occurred apparently only during attacks of hyperammonemia. Propionic acidemia was ruled out by enzyme studies. OTC deficiency was diagnosed on the basis of: 1) decreased enzyme activity in leukocytes;2) hyperammonemia in response to protein intakes in excess of 2.0 g/kg/day; 3) orotic aciduria in the patient and her asymptomatic mother; 4) suggestive evidence of x-linked dominant inheritance; and 5) exclusion of citrullinemia, argininosuccinic aciduria, argininemia, and disorders of lysine metabolism that are associated with hyperammonemia. Homocitrullinuria, presence of epsilon-N-acetyl-l-lysine in urine, and absence of saccharopine indicate deficiency of the saccharopine pathway of lysine degradation. However, alpha-ketoglutarate reductase was normal in fibroblasts. Since these metabolites were observed only in conjunction with hyperammonemia but not after a lysine load, we suggest that there was competition between ammonia and lysine for alpha-ketoglutarate. The link between disorders of the urea cycle and short chain fatty acid metabolism remains unexplained.. PMID:977722

  6. REVEAL: Software Documentation and Platform Migration

    NASA Technical Reports Server (NTRS)

    Wilson, Michael A.; Veibell, Victoir T.; Freudinger, Lawrence C.

    2008-01-01

    The Research Environment for Vehicle Embedded Analysis on Linux (REVEAL) is reconfigurable data acquisition software designed for network-distributed test and measurement applications. In development since 2001, it has been successfully demonstrated in support of a number of actual missions within NASA s Suborbital Science Program. Improvements to software configuration control were needed to properly support both an ongoing transition to operational status and continued evolution of REVEAL capabilities. For this reason the project described in this report targets REVEAL software source documentation and deployment of the software on a small set of hardware platforms different from what is currently used in the baseline system implementation. This report specifically describes the actions taken over a ten week period by two undergraduate student interns and serves as a final report for that internship. The topics discussed include: the documentation of REVEAL source code; the migration of REVEAL to other platforms; and an end-to-end field test that successfully validates the efforts.

  7. Revealing advantage in a quantum network

    NASA Astrophysics Data System (ADS)

    Mukherjee, Kaushiki; Paul, Biswajit; Sarkar, Debasis

    2016-07-01

    The assumption of source independence was used to reveal nonlocal (apart from standard Bell-CHSH scenario) nature of correlations generated in entanglement swapping experiments. In this work, we have discussed the various utilities of this assumption to reveal nonlocality (via generation of nonbilocal correlations) and thereby exploiting quantumness under lesser requirements compared to some standard means of doing the same. We have also provided with a set of sufficient criteria, imposed on the states (produced by the sources) under which source independence can reveal nonbilocal nature of correlations in a quantum network.

  8. Hiding personal information reveals the worst

    PubMed Central

    John, Leslie K.; Barasz, Kate; Norton, Michael I.

    2016-01-01

    Seven experiments explore people’s decisions to share or withhold personal information, and the wisdom of such decisions. When people choose not to reveal information—to be “hiders”—they are judged negatively by others (experiment 1). These negative judgments emerge when hiding is volitional (experiments 2A and 2B) and are driven by decreases in trustworthiness engendered by decisions to hide (experiments 3A and 3B). Moreover, hiders do not intuit these negative consequences: given the choice to withhold or reveal unsavory information, people often choose to withhold, but observers rate those who reveal even questionable behavior more positively (experiments 4A and 4B). The negative impact of hiding holds whether opting not to disclose unflattering (drug use, poor grades, and sexually transmitted diseases) or flattering (blood donations) information, and across decisions ranging from whom to date to whom to hire. When faced with decisions about disclosure, decision-makers should be aware not just of the risk of revealing, but of what hiding reveals. PMID:26755591

  9. REVEAL: Software Documentation and Platform Migration

    NASA Technical Reports Server (NTRS)

    Wilson, Michael A.; Veibell, Victoir T.

    2011-01-01

    The Research Environment for Vehicle Embedded Analysis on Linux (REVEAL) is reconfigurable data acquisition software designed for network-distributed test and measurement applications. In development since 2001, it has been successfully demonstrated in support of a number of actual missions within NASA's Suborbital Science Program. Improvements to software configuration control were needed to properly support both an ongoing transition to operational status and continued evolution of REVEAL capabilities. For this reason the project described in this report targets REVEAL software source documentation and deployment of the software on a small set of hardware platforms different from what is currently used in the baseline system implementation. This presentation specifically describes the actions taken over a ten week period by two undergraduate student interns and serves as an overview of the content of the final report for that internship.

  10. Omics strategies for revealing Yersinia pestis virulence

    PubMed Central

    Yang, Ruifu; Du, Zongmin; Han, Yanping; Zhou, Lei; Song, Yajun; Zhou, Dongsheng; Cui, Yujun

    2012-01-01

    Omics has remarkably changed the way we investigate and understand life. Omics differs from traditional hypothesis-driven research because it is a discovery-driven approach. Mass datasets produced from omics-based studies require experts from different fields to reveal the salient features behind these data. In this review, we summarize omics-driven studies to reveal the virulence features of Yersinia pestis through genomics, trascriptomics, proteomics, interactomics, etc. These studies serve as foundations for further hypothesis-driven research and help us gain insight into Y. pestis pathogenesis. PMID:23248778

  11. Revealing a Child's Pathology: Physicians' Experiences

    ERIC Educational Resources Information Center

    Scelles, Regine; Aubert-Godard, Anne; Gargiulo, Marcela; Avant, Monique; Gortais, Jean

    2010-01-01

    In this study, 12 physicians and 12 care-givers were interviewed using semi-structured interviews. We explored physicians' experiences when they revealed a diagnosis. We also tried to understand which family members the physician was thinking of, with whom they identified themselves, and their first choice of the person to whom they prefer to…

  12. [Factor VII deficiency revealed by intracranial hemorrhage].

    PubMed

    Sfaihi Ben Mansour, L; Thabet, A; Aloulou, H; Turki, H; Chabchoub, I; Mhiri, F; Mnif, Z; Ben Ali, H; Kammoun, T; Hachicha, M

    2009-07-01

    Constitutional factor VII deficiency is a hereditary disease with recessive autosomic transmission. Its incidence is estimated to be 1/1,000,000 in the general population. We report a case of severe factor VII deficiency in infancy revealed by an intracranial hemorrhage in a 2-month-old infant. We describe the clinical, biological and therapeutic characteristics of this disease. PMID:19409767

  13. Eye Movements Reveal Dynamics of Task Control

    ERIC Educational Resources Information Center

    Mayr, Ulrich; Kuhns, David; Rieter, Miranda

    2013-01-01

    With the goal to determine the cognitive architecture that underlies flexible changes of control settings, we assessed within-trial and across-trial dynamics of attentional selection by tracking of eye movements in the context of a cued task-switching paradigm. Within-trial dynamics revealed a switch-induced, discrete delay in onset of…

  14. PULMONARY ARTERY ACCELERATED FLOW REVEALING HODGKIN'S LYMPHOMA.

    PubMed

    Ibrahim, Tony; Chehab, Ghassan; Saliba, Zakhia; Smayra, Tarek; Baz, Maria; Abdo, Lynn; Haddad, Fady; Abdel-Massih, Tony

    2016-01-01

    We present a case in which transthoracic echocardiography was the first diagnostic tool to suspect mediastinal Hodgkin's lymphoma by revealing a change in the hemodynamic of left pulmonary artery flow, and it was used as a follow-up method for monitoring treatment efficacy by demonstrating a normalization of pulmonary artery hemodynamics. PMID:27169170

  15. The cattle genome reveals its secrets

    PubMed Central

    Burt, David W

    2009-01-01

    The domesticated cow is the latest farm animal to have its genome sequenced and deciphered. The members of the Bovine Genome Consortium have published a series of papers on the assembly and what the sequence reveals so far about the biology of this ruminant and the consequences of its domestication. PMID:19439025

  16. [Skin metastases revealing a bronchial adenocarcinoma].

    PubMed

    Zemmez, Youssef; Zegmout, Adil; Hamama, Jalal; Bouhamidi, Ahmed; El Amraoui, Mohammed; El Azhari, Jaouad; Boui, Mohamed

    2016-01-01

    We report the case of bronchial carcinoma revealed by metastatic skin nodules on the scalp. This fairly common mode of discovery is often associated with poor prognosis. This study aims to underline the importance of directing the search for a primary lung cancer in cases of secondary skin involvement. PMID:27583066

  17. Septic sacroiliitis revealing an infectious endocarditis

    PubMed Central

    Mahfoudhi, Madiha; Hariz, Anis; Turki, Sami; Kheder, Adel

    2014-01-01

    We report the case of a 43-year-old man admitted for right hip ache and fever. Physical examination revealed a fever, an ache at the manipulation of the sacroiliac joint and a limitation of abduction and external rotation of the right hip. There was no murmur in cardiac auscultation. No anomaly was found at the conventional radiographs of the sacroiliac joint, while the pelvic MRI confirmed a right sacroiliitis. A sacroiliac puncture with a study of synovial fluid demonstrated the presence of Streptococcus viridans. The blood culture revealed the same germ. Transthoracic and transoesophageal echocardiography confirmed infectious endocarditis with vegetation in the mitral valve. He received penicillin G and gentamicin relayed by pristinamycin because of an allergy to penicillin G with a total duration of treatment of 40 days. His symptoms and the laboratory and radiological tests abnormalities resolved totally with no recurrence. PMID:25123569

  18. Orbital tumor revealing a systemic sarcoidosis.

    PubMed

    Hannanachi Sassi, Samia; Dhouib, Rim; Kanchal, Fatma; Doghri, Raoudha; Boujelbene, Nadia; Bouguila, Hedi; Mrad, Karima

    2015-01-01

    Ocular involvement is seen in approximately 25% of patients with sarcoidosis. Uveitis is the most common ocular manifestation, but sarcoidosis may involve any part of the eye. Orbital manifestations of sarcoidosis are uncommon with few series in the literature. A 65-year-old woman presented with redness of the right eye and painless, unilateral eyelid swelling. Orbital scanning revealed mass infiltrating the soft tissue of the inferior right orbital quadrant. Biopsy results showed nodular, noncaseating granulomas consistent with sarcoidosis. The complete systemic workup revealed systemic manifestations of sarcoidosis at the time of examination with hilar and mediastinal lymphadenopathies noted on CT scan. The orbital surgical treatment was followed by systemic prednisone therapy with good response. Although rare, orbital sarcoidosis must be considered in the evaluation of orbital tumors in elderly patients. A search for systemic findings should be undertaken and appropriate therapy should be instituted. PMID:25796029

  19. Mediastinal Mature Teratoma Revealed by Empyema.

    PubMed

    Raoufi, Mohammed; Herrak, Laila; Benali, Anas; Achaachi, Leila; El Ftouh, Mustapha; Bellarbi, Salma; Tilfine, Charaf; Taouarsa, Firdaous

    2016-01-01

    Teratomas are germ cell tumors, manifested with a great variety of clinical features; the most common extragonadal site is the anterior mediastinum. In this case, we report the patient with a large mature mediastinal teratoma with several components of ectodermal and endothermal epithelium. A 24-year-old female patient presented with history of persistent chest pain and progressively aggravating dyspnea for the previous 3 months. A chest X-ray showed a large opacity of the entire left hemithorax. Transcutaneous needle aspiration revealed a purulent fluid. The tube thoracostomy was introduced and the effusion was evacuated. Some weeks later, patient was seen in emergency for persistent cough and lateral chest pain. CT scan revealed a mass of the left hemithorax. The mass showed heterogeneous density, without compressing mediastinum great vessels and left hilar structures. Lipase value was elevated in needle aspiration. The patient underwent a total resection of the mediastinum mass via a left posterolateral thoracotomy. Microscopy revealed a mature teratoma with cystic structures. The patient subsequently made a full recovery. This case provide benign mediastinal teratoma with total atelectasis of left lung and elevated lipase value in needle transcutaneous aspiration; this event is explained by pancreatic component in the cystic tumor. Total removal of the tumor is adequate treatment for this type of teratoma and the prognosis is excellent. PMID:27144046

  20. Mediastinal Mature Teratoma Revealed by Empyema

    PubMed Central

    Raoufi, Mohammed; Herrak, Laila; Benali, Anas; Achaachi, Leila; El Ftouh, Mustapha; Bellarbi, Salma; Tilfine, Charaf; Taouarsa, Firdaous

    2016-01-01

    Teratomas are germ cell tumors, manifested with a great variety of clinical features; the most common extragonadal site is the anterior mediastinum. In this case, we report the patient with a large mature mediastinal teratoma with several components of ectodermal and endothermal epithelium. A 24-year-old female patient presented with history of persistent chest pain and progressively aggravating dyspnea for the previous 3 months. A chest X-ray showed a large opacity of the entire left hemithorax. Transcutaneous needle aspiration revealed a purulent fluid. The tube thoracostomy was introduced and the effusion was evacuated. Some weeks later, patient was seen in emergency for persistent cough and lateral chest pain. CT scan revealed a mass of the left hemithorax. The mass showed heterogeneous density, without compressing mediastinum great vessels and left hilar structures. Lipase value was elevated in needle aspiration. The patient underwent a total resection of the mediastinum mass via a left posterolateral thoracotomy. Microscopy revealed a mature teratoma with cystic structures. The patient subsequently made a full recovery. This case provide benign mediastinal teratoma with total atelectasis of left lung and elevated lipase value in needle transcutaneous aspiration; this event is explained by pancreatic component in the cystic tumor. Total removal of the tumor is adequate treatment for this type of teratoma and the prognosis is excellent. PMID:27144046

  1. Middle atmosphere composition revealed by satellite observations

    NASA Technical Reports Server (NTRS)

    Russell, J. M., III; Solomon, S.; Mccormick, M. P.; Miller, A. J.; Barnett, J. J.; Jones, R. L.; Rusch, D. W.

    1986-01-01

    A series of plots that describe the state of the stratosphere and to some degree, the mesosphere as revealed by satellite observations are shown. The pertinent instrument features, spatial and temporal coverage, and details of accuracy and precision for the experiments providing the data were described. The main features of zonal mean cross sections and polar stereographic projections were noted and intercomparisons were discussed where a parameter was measured by more than one experiment. The main purpose was to collect the available data in one place and provide enough inforamation on limitations or cautions about the data so that they could be used in model comparisons and science studies.

  2. Trench Reveals Two Faces of Soils

    NASA Technical Reports Server (NTRS)

    2004-01-01

    This approximate true-color image mosaic from the panoramic camera on the Mars Exploration Rover Opportunity shows a trench dug by the rover in the vicinity of the 'Anatolia' region. Two imprints from the rover's Mossbauer spectrometer instrument were left in the exposed soils. Detailed comparisons between soils exposed at the surface and those found at depth reveal that surface soils have higher levels of hematite while subsurface soils show fine particles derived from basalt. The trench is approximately 11 centimeters deep. This image was taken on sol 81 with the panoramic camera's 430-, 530- and 750-nanometer filters.

  3. Reveal quantum correlation in complementary bases

    PubMed Central

    Wu, Shengjun; Ma, Zhihao; Chen, Zhihua; Yu, Sixia

    2014-01-01

    An essential feature of genuine quantum correlation is the simultaneous existence of correlation in complementary bases. We reveal this feature of quantum correlation by defining measures based on invariance under a basis change. For a bipartite quantum state, the classical correlation is the maximal correlation present in a certain optimum basis, while the quantum correlation is characterized as a series of residual correlations in the mutually unbiased bases. Compared with other approaches to quantify quantum correlation, our approach gives information-theoretical measures that directly reflect the essential feature of quantum correlation. PMID:24503595

  4. Cerebral venous thrombosis revealing an ulcerative colitis

    PubMed Central

    Taous, Abdellah; Berri, Maha Aït; Lamsiah, Taoufik; Zainoun, Brahim; Ziadi, Tarik; Rouimi, Abdelhadi

    2016-01-01

    Cerebral venous thrombosis (CVT) has been reported as an uncommon and devastating complication of ulcerative colitis (UC), with an annual incidence varying between 0,5 to 6,7%. It is suspected to be a consequence of the hypercoagulable state occurring during disease relapse. We report a case of 22-year-old female patient presenting with CVT revealing an UC. Our case raises the awareness among health professionals about the inflammatory bowel diseases (IBD) as a rare etiology of CVT, and signifies the importance of considering antithrombotic prophylaxis in all hospitalised IBD patients, especially those with active disease. PMID:27279947

  5. Infections Revealing Complement Deficiency in Adults

    PubMed Central

    Audemard-Verger, A.; Descloux, E.; Ponard, D.; Deroux, A.; Fantin, B.; Fieschi, C.; John, M.; Bouldouyre, A.; Karkowsi, L.; Moulis, G.; Auvinet, H.; Valla, F.; Lechiche, C.; Davido, B.; Martinot, M.; Biron, C.; Lucht, F.; Asseray, N.; Froissart, A.; Buzelé, R.; Perlat, A.; Boutboul, D.; Fremeaux-Bacchi, V.; Isnard, S.; Bienvenu, B.

    2016-01-01

    Abstract Complement system is a part of innate immunity, its main function is to protect human from bacterial infection. As genetic disorders, complement deficiencies are often diagnosed in pediatric population. However, complement deficiencies can also be revealed in adults but have been poorly investigated. Herein, we describe a case series of infections revealing complement deficiency in adults to study clinical spectrum and management of complement deficiencies. A nationwide retrospective study was conducted in French university and general hospitals in departments of internal medicine, infectious diseases enrolling patients older than 15 years old who had presented at least one infection leading to a complement deficiency diagnosis. Forty-one patients included between 2002 and 2015 in 19 different departments were enrolled in this study. The male-to-female ratio was 1.3 and the mean age at diagnosis was 28 ± 14 (15–67) years. The main clinical feature was Neisseria meningitidis meningitis 75% (n = 31/41) often involving rare serotype: Y (n = 9) and W 135 (n = 7). The main complement deficiency observed was the common final pathway deficiency 83% (n = 34/41). Half of the cohort displayed severe sepsis or septic shock at diagnosis (n = 22/41) but no patient died. No patient had family history of complement deficiency. The mean follow-up was 1.15 ± 1.95 (0.1–10) years. Half of the patients had already suffered from at least one infection before diagnosis of complement deficiency: meningitis (n = 13), pneumonia (n = 4), fulminans purpura (n = 1), or recurrent otitis (n = 1). Near one-third (n = 10/39) had received prophylactic antibiotics (cotrimoxazole or penicillin) after diagnosis of complement deficiency. The vaccination coverage rate, at the end of the follow-up, for N meningitidis, Streptococcus pneumonia, and Haemophilius influenzae were, respectively, 90% (n = 33/37), 47% (n = 17/36), and 35

  6. What Eye Movements Reveal about Deaf Readers

    PubMed Central

    Bélanger, Nathalie N.; Rayner, Keith

    2014-01-01

    Levels of illiteracy in the deaf populations around the world have been extremely high for decades and much higher than the illiteracy levels found in the general population. Research has mostly focused on deaf readers’ difficulties rather than on their strengths, which can then inform reading education. Deaf readers are a unique population. They process language and the world surrounding them mostly via the visual channel and this greatly affects how they read or might learn to read. The study of eye movements in reading provides highly sophisticated information about how words and sentences are processed and our research with deaf readers reveals the importance of their uniqueness. PMID:26594098

  7. Apocalypto: revealing lost text with XMT

    NASA Astrophysics Data System (ADS)

    Mills, David; Davis, Graham R.; Lai, Yu-kun; Rosin, Paul

    2014-09-01

    "Can brute-force high-contrast tomography techniques and image processing techniques retrieve textual content from damaged heritage materials?" The Dental Institute at Queen Mary University of London (QMUL) is the leading centre for very high contrast X-Ray Microtomography imaging. The Apocalypto Project is our collaboration with the heritage community and experts in Computer Vision systems in the Computer Science Department at Cardiff University. This collaboration has developed techniques and a workflow that allows us to reveal textual content from moisture-damaged parchment rolls. This article will also present some initial results from burned and heat shrunken parchment rolls, an insect damaged Mamluk cap and a birch bark roll.

  8. The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome.

    PubMed

    Sofer, S; Schweiger, A; Blumkin, L; Yahalom, G; Anikster, Y; Lev, D; Ben-Zeev, B; Lerman-Sagie, T; Hassin-Baer, S

    2015-04-01

    Costeff syndrome is a rare genetic neuro-ophthalmological syndrome consisting of early-onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3-methylglutaconic acid and 3-methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean  = 85, z = -1) in the low-average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance. © 2015 Wiley Periodicals, Inc. PMID:25657044

  9. Metabolic biology of 3-methylglutaconic acid-uria: a new perspective

    PubMed Central

    Su, Betty; Ryan, Robert O.

    2014-01-01

    Summary Over the past twenty-five years a growing number of distinct syndromes / mutations associated with compromised mitochondrial function have been identified that share a common feature: urinary excretion of 3-methylglutaconic acid (3MGA). In the leucine degradation pathway, carboxylation of 3-methylcrotonyl CoA leads to formation of 3-methylglutaconyl CoA while 3-methylglutaconyl CoA hydratase converts this metabolite to 3-hydroxy-3-methylglutaryl CoA (HMG CoA). In “primary” 3MGA-uria, mutations in the hydratase are directly responsible for the accumulation of 3MGA. On the other hand, in all “secondary” 3MGA-urias, no defect in leucine catabolism exists and the metabolic origin of 3MGA is unknown. Herein, a path to 3MGA from mitochondrial acetyl CoA is proposed. The pathway is initiated when syndrome-associated mutations / DNA deletions result in decreased Krebs cycle flux. When this occurs, acetoacetyl CoA thiolase condenses two acetyl CoA into acetoacetyl CoA plus CoASH. Subsequently, HMG CoA synthase 2 converts acetoacetyl CoA and acetyl CoA to HMG CoA. Under syndrome-specific metabolic conditions, 3-methylglutaconyl CoA hydratase converts HMG CoA into 3-methylglutaconyl CoA in a reverse reaction of the leucine degradation pathway. This metabolite fails to proceed further up the leucine degradation pathway owing to the kinetic properties of 3-methylcrotonyl CoA carboxylase. Instead, hydrolysis of the CoA moiety of 3-methylglutaconyl CoA generates 3MGA, which appears in urine. If experimentally confirmed, this pathway provides an explanation for the occurrence of 3MGA in multiple disorders associated with compromised mitochondrial function. PMID:24407466

  10. Saturn's secrets revealed - A special report

    NASA Astrophysics Data System (ADS)

    Sutton, C.

    1980-11-01

    Scientific results of the encounter of Voyager 1 with Saturn are reported. Instruments on the Voyager spacecraft, which was launched on September 5, 1977 and flew within 124,200 km of the Saturn cloud tops on November 12, 1980, revealed the presence of several hundred rings within the six visible from earth, as well as eccentric rings, braiding and clumps within the narrow F ring, and spoke-like structures in the B ring. During its flight beneath the ring plane, Voyager 1 also discovered that the rings extend toward the visible surface of the cloud tops, and are composed of ice chunks or silicate with an icy coating about a meter in diameter. Observations of Titan revealed the satellite to have a dense atmosphere, composed primarily of molecular nitrogen, with as many as three layers of haze above the cloud tops. Three additional moons of Saturn were discovered apparently focusing ring particles, and the moon Janus, discovered from earth in 1966, was shown to be actually two moons. Close approaches to other Saturn satellites show Mimas, Tethys, Dione and Rhea to be heavily cratered, icy bodies, some with features indicating they had been struck by objects almost large enough to shatter them. Surface features on Saturn, which is covered by a deep layer of haze, and the details of the Saturn magnetosphere have also been observed.

  11. Exertional rhabdomyolysis and exercise intolerance revealing dystrophinopathies.

    PubMed

    Figarella-Branger, D; Baeta Machado, A M; Putzu, G A; Malzac, P; Voelckel, M A; Pellissier, J F

    1997-07-01

    Exercise intolerance associated with myalgias, muscle cramps or myoglobinuria may be associated with a dystrophinopathy. A search for abnormal dystrophin expression (using immunohistochemistry, immunoblot and DNA analysis) was carried out in a series of 15 patients. They were selected because they presented exercise intolerance, negative biochemical tests (lipid, glycogen and mitochondrial metabolism) and abnormal immunohistochemistry with at least one anti-dystrophin antibody (anti-Dys 1, rod domain; anti-Dys 2, C terminus; anti-Dys 3, N terminus). Lack of anti-Dys 1 immunoreactivity was seen in three patients and abnormal immunoreactivity with all three anti-dystrophin antibodies in two. Immunoblot confirmed the dystrophinopathy in these five patients only, and multiplex polymerase chain reaction DNA analysis revealed a deletion in the dystrophin gene in two of these patients, affecting the proximal part of the rod domain in one and the distal part of this domain in the other. The clinical, biological and histopathological features of the five patients reported here, together with the previous cases reported in the literature, are described and reveal that exercise intolerance associated with dystrophinopathy displays characteristic clinical, biological and immunohistochemical features and defines a new dystrophinopathy phenotype. The absence of staining in the rod domain provides a secure diagnosis of this syndrome. Dystrophinopathy is one etiology of idiopathic myoglobinuria, requiring genetic counseling. PMID:9224530

  12. Mammalian phylogeny reveals recent diversification rate shifts.

    PubMed

    Stadler, Tanja

    2011-04-12

    Phylogenetic trees of present-day species allow investigation of the rate of evolution that led to the present-day diversity. A recent analysis of the mammalian phylogeny challenged the view of explosive mammalian evolution after the Cretaceous-Tertiary (K/T) boundary (65 Mya). However, due to lack of appropriate methods, the diversification (speciation minus extinction) rates in the more recent past of mammalian evolution could not be determined. In this paper, I provide a method that reveals that the tempo of mammalian evolution did not change until ∼ 33 Mya. This constant period was followed by a peak of diversification rates between 33 and 30 Mya. Thereafter, diversification rates remained high and constant until 8.55 Mya. Diversification rates declined significantly at 8.55 and 3.35 Mya. Investigation of mammalian subgroups (marsupials, placentals, and the six largest placental subgroups) reveals that the diversification rate peak at 33-30 Mya is mainly driven by rodents, cetartiodactyla, and marsupials. The recent diversification rate decrease is significant for all analyzed subgroups but eulipotyphla, cetartiodactyla, and primates. My likelihood approach is not limited to mammalian evolution. It provides a robust framework to infer diversification rate changes and mass extinction events in phylogenies, reconstructed from, e.g., present-day species or virus data. In particular, the method is very robust toward noise and uncertainty in the phylogeny and can account for incomplete taxon sampling. PMID:21444816

  13. Interior Evolution of Ceres Revealed by Dawn

    NASA Astrophysics Data System (ADS)

    Raymond, Carol A.; Park, Ryan S.; Konopliv, Alex S.; Bland, Michael T.; Marchi, Simone; Castillo-Rogez, Julie C.; McCord, Thomas B.; Jaumann, Ralf; Russell, Christopher T.; Prettyman, Thomas H.

    2015-11-01

    Dawn's exploration of Ceres has revealed its geophysical characteristics, informing the processes that have shaped it. Dawn has determined the average diameter of Ceres to be 940 km, smaller than the previously estimated 975 km [1]. This implies a density of 2160 kg/m3, indicating that Ceres is less differentiated than predicted [2]. The low-degree gravity field is consistent with the body being in hydrostatic equilibrium and the magnitude of J2 implies some central condensation. Ceres' entire surface is cratered, implying the lack of a thick (10's of km) water ice layer at the surface. Variability in Ceres' crater morphology indicates that the near-surface layer has variable strength and rheology, likely due to heterogeneity in the near-surface mixture of rock, ice and salt. The lack of a number of expected large impact basins on Ceres can be interpreted to be the result of viscous relaxation, resurfacing or a combination of both. These data provide insights into Ceres' thermal evolution and mechanical properties, which appear to be unique to this warm, icy body.[1] Thomas, P. C., et al., Differentiation of the asteroid Ceres as revealed by its shape, Nature, 437, 224-226, 2005; [2] McCord et al., Ceres: Its Origin, Evolution and Structure and Dawn's Potential Contribution, Space Sci Rev DOI 10.1007/s11214-010-9729-9, 2011.

  14. Semantic priming revealed by mouse movement trajectories.

    PubMed

    Xiao, Kunchen; Yamauchi, Takashi

    2014-07-01

    Congruency effects are taken as evidence that semantic information can be processed automatically. However, these effects are often weak, and the straightforward association between primes and targets can exaggerate congruency effects. To address these problems, a mouse movement method is applied to scrutinize congruency effects. In one experiment, participants judged whether two numbers were the same ("3\\3") or different ("3\\5"), preceded by briefly presented pictures with either positive or negative connotations. Participants indicated their responses by clicking a "Same" or "Different" button on the computer screen, while their cursor trajectories were recorded for each trial. The trajectory data revealed greater deviation to unselected buttons in incongruent trials (e.g., "3\\5" preceded by a green traffic light picture). This effect was influenced by the type of responses but not by prime durations. We suggest that the mouse movement method can complement the reaction time to study masked semantic priming. PMID:24797040

  15. Neutron Imaging Reveals Internal Plant Hydraulic Dynamics

    SciTech Connect

    Warren, Jeffrey; Bilheux, Hassina Z; Kang, Misun; Voisin, Sophie; Cheng, Chu-Lin; Horita, Jusuke; Perfect, Edmund

    2013-01-01

    Many terrestrial ecosystem processes are constrained by water availability and transport within the soil. Knowledge of plant water fluxes is thus critical for assessing mechanistic processes linked to biogeochemical cycles, yet resolution of root structure and xylem water transport dynamics has been a particularly daunting task for the ecologist. Through neutron imaging, we demonstrate the ability to non-invasively monitor individual root functionality and water fluxes within Zea mays L. (maize) and Panicum virgatum L. (switchgrass) seedlings growing in a sandy medium. Root structure and growth were readily imaged by neutron radiography and neutron computed tomography. Seedlings were irrigated with water or deuterium oxide and imaged through time as a growth lamp was cycled on to alter leaf demand for water. Sub-millimeter scale resolution reveals timing and magnitudes of root water uptake, redistribution within the roots, and root-shoot hydraulic linkages, relationships not well characterized by other techniques.

  16. Open chromatin reveals the functional maize genome

    PubMed Central

    Rodgers-Melnick, Eli; Vera, Daniel L.; Bass, Hank W.

    2016-01-01

    Cellular processes mediated through nuclear DNA must contend with chromatin. Chromatin structural assays can efficiently integrate information across diverse regulatory elements, revealing the functional noncoding genome. In this study, we use a differential nuclease sensitivity assay based on micrococcal nuclease (MNase) digestion to discover open chromatin regions in the maize genome. We find that maize MNase-hypersensitive (MNase HS) regions localize around active genes and within recombination hotspots, focusing biased gene conversion at their flanks. Although MNase HS regions map to less than 1% of the genome, they consistently explain a remarkably large amount (∼40%) of heritable phenotypic variance in diverse complex traits. MNase HS regions are therefore on par with coding sequences as annotations that demarcate the functional parts of the maize genome. These results imply that less than 3% of the maize genome (coding and MNase HS regions) may give rise to the overwhelming majority of phenotypic variation, greatly narrowing the scope of the functional genome. PMID:27185945

  17. Social patterns revealed through random matrix theory

    NASA Astrophysics Data System (ADS)

    Sarkar, Camellia; Jalan, Sarika

    2014-11-01

    Despite the tremendous advancements in the field of network theory, very few studies have taken weights in the interactions into consideration that emerge naturally in all real-world systems. Using random matrix analysis of a weighted social network, we demonstrate the profound impact of weights in interactions on emerging structural properties. The analysis reveals that randomness existing in particular time frame affects the decisions of individuals rendering them more freedom of choice in situations of financial security. While the structural organization of networks remains the same throughout all datasets, random matrix theory provides insight into the interaction pattern of individuals of the society in situations of crisis. It has also been contemplated that individual accountability in terms of weighted interactions remains as a key to success unless segregation of tasks comes into play.

  18. Open chromatin reveals the functional maize genome.

    PubMed

    Rodgers-Melnick, Eli; Vera, Daniel L; Bass, Hank W; Buckler, Edward S

    2016-05-31

    Cellular processes mediated through nuclear DNA must contend with chromatin. Chromatin structural assays can efficiently integrate information across diverse regulatory elements, revealing the functional noncoding genome. In this study, we use a differential nuclease sensitivity assay based on micrococcal nuclease (MNase) digestion to discover open chromatin regions in the maize genome. We find that maize MNase-hypersensitive (MNase HS) regions localize around active genes and within recombination hotspots, focusing biased gene conversion at their flanks. Although MNase HS regions map to less than 1% of the genome, they consistently explain a remarkably large amount (∼40%) of heritable phenotypic variance in diverse complex traits. MNase HS regions are therefore on par with coding sequences as annotations that demarcate the functional parts of the maize genome. These results imply that less than 3% of the maize genome (coding and MNase HS regions) may give rise to the overwhelming majority of phenotypic variation, greatly narrowing the scope of the functional genome. PMID:27185945

  19. Revealing effective classifiers through network comparison

    NASA Astrophysics Data System (ADS)

    Gallos, Lazaros K.; Fefferman, Nina H.

    2014-11-01

    The ability to compare complex systems can provide new insight into the fundamental nature of the processes captured, in ways that are otherwise inaccessible to observation. Here, we introduce the n-tangle method to directly compare two networks for structural similarity, based on the distribution of edge density in network subgraphs. We demonstrate that this method can efficiently introduce comparative analysis into network science and opens the road for many new applications. For example, we show how the construction of a “phylogenetic tree” across animal taxa according to their social structure can reveal commonalities in the behavioral ecology of the populations, or how students create similar networks according to the University size. Our method can be expanded to study many additional properties, such as network classification, changes during time evolution, convergence of growth models, and detection of structural changes during damage.

  20. Metabolomics reveals metabolic biomarkers of Crohn's disease

    SciTech Connect

    Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.

    2009-06-01

    The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.

  1. Chain networking revealed by molecular dynamics simulation

    NASA Astrophysics Data System (ADS)

    Zheng, Yexin; Tsige, Mesfin; Wang, Shi-Qing

    Based on Kremer-Grest model for entangled polymer melts, we demonstrate how the response of a polymer glass depends critically on the chain length. After quenching two melts of very different chain lengths (350 beads per chain and 30 beads per chain) into deeply glassy states, we subject them to uniaxial extension. Our MD simulations show that the glass of long chains undergoes stable necking after yielding whereas the system of short chains is unable to neck and breaks up after strain localization. During ductile extension of the polymer glass made of long chain significant chain tension builds up in the load-bearing strands (LBSs). Further analysis is expected to reveal evidence of activation of the primary structure during post-yield extension. These results lend support to the recent molecular model 1 and are the simulations to demonstrate the role of chain networking. This work is supported, in part, by a NSF Grant (DMR-EAGER-1444859)

  2. Licking Microstructure Reveals Rapid Attenuation of Neophobia

    PubMed Central

    Monk, Kevin J.; Rubin, Benjamin D.

    2014-01-01

    Many animals hesitate when initially consuming a novel food and increase their consumption of that food between the first and second sessions of access—a process termed attenuation of neophobia (AN). AN has received attention as a model of learning and memory; it has been suggested that plasticity resulting from an association of the novel tastant with “safe outcome” results in a change in the neural response to the tastant during the second session, such that consumption increases. Most studies have reported that AN emerges only an hour or more after the end of the first exposure to the tastant, consistent with what is known of learning-related plasticity. But these studies have typically measured consumption, rather than real-time behavior, and thus the possibility exists that a more rapidly developing AN remains to be discovered. Here, we tested this possibility, examining both consumption and individual lick times in a novel variant of a brief-access task (BAT). When quantified in terms of consumption, data from the BAT accorded well with the results of a classic one-bottle task—both revealed neophobia/AN specific to higher concentrations (for instance, 28mM) of saccharin. An analysis of licking microstructure, however, additionally revealed a real-time correlate of neophobia—an explicit tendency, similarly specific for 28-mM saccharin, to cut short the initial bout of licks in a single trial (compared with water). This relative hesitancy (i.e., the shortness of the first lick bout to 28-mM saccharin compared with water) that constitutes neophobia not only disappeared between sessions but also gradually declined in magnitude across session 1. These data demonstrate that the BAT accurately measures AN, and that aspects of AN—and the processes underlying familiarization—begin within minutes of the very first taste. PMID:24363269

  3. Ceres Revealed in a Grain of Salt

    NASA Technical Reports Server (NTRS)

    Zolensky, M. E.; Bodnar, R. J.; Fries, M.; Chan, Q. H.-S.; Kebukawa, Y.; Mikouchi, T.; Hagiya, K.; Komatsu, M.; Ohsumi, K.; Steele, A.

    2016-01-01

    Introduction: Zag and Monahans (1998) are H chondrite regolith breccias containing 4.5 giga-year-old halite crystals which contain abundant inclusions of aqueous fluids, solids and organics. These all originated on a cryo-volcanically-active C class asteroid, probably 1 Ceres; the halite was transported to the regolith of the H chondrite parent asteroid, potentially 6 Hebe. Detailed analysis of these solids will thus potentially reveal the mineralogy of Ceres. Mineralogy of solids in the Monahans Halite Solid grains are present in the halites, which were entrained within the mother brines during eruption, including material from the interior and surface of the erupting body. The solids include abundant, widely variable organics that could not have been significantly heated (which would have resulted in the loss of fluids from the halite). Our analyses by Raman microprobe, SEM/EDX, synchrotron X-ray diffraction, UPLC-FD/QToF-MS, C-XANES and TEM reveal that these trapped grains include macromolecular carbon (MMC) similar in structure to CV3 chondrite matrix carbon, aliphatic carbon compounds, olivine (Fo99-59), high- and low-Ca pyroxene, feldspars, phyllosilicates, magnetite, sulfides, metal, lepidocrocite, carbonates, diamond, apatite and zeolites. Conclusions: The halite in Monahans and Zag derive from a water and carbon-rich object that was cryo-volcanically active in the early solar system, probably Ceres. The Dawn spacecraft found that Ceres includes C chondrite materials. Our samples include both protolith and aqueously-altered samples of the body, permitting understanding of alteration conditions. Whatever the halite parent body, it was rich in a wide variety of organics and warm, liquid water at the solar system's dawn.

  4. [Medium chain acyl-CoA dehydrogenase deficiency. Apropos of a case with demonstration of this enzyme deficiency].

    PubMed

    Collet, J P; Divry, P; Blanc, J F; Guibaud, P; David, M; Macabeo, V; Vibert, J; Hermier, M

    1984-12-01

    The medium chain acyl-CoA deshydrogenase defect: a new inherited metabolic disorder. This enzymatic defect blocks the catabolism of non esterified fatty acids during fasting. Thus, this disease is revealed by a coma due to hypoglycemia in a young child; the presence of dicarboxylic aciduria in such a situation is the main evidence for this diagnosis. Finally, the enzymatic studies performed on skin fibroblasts show a defect in medium chain acyl-CoA deshydrogenase. When a child is investigated away from a coma episode, the ketotic diet induces dicarboxylic aciduria but must be performed in an intensive care unit for its dangers. PMID:6535973

  5. Neutron Imaging Reveals Internal Plant Hydraulic Dynamics

    NASA Astrophysics Data System (ADS)

    Warren, J.; Bilheux, H.; Kang, M.; Voisin, S.; Cheng, C.; Horita, J.; Perfect, E.

    2011-12-01

    In situ quantification of soil-plant water fluxes have not been fully successful due to a lack of non-destructive techniques capable of revealing roots or water fluxes at relevant spatial scales. Neutron imaging is a unique non-invasive tool that can assess sub-millimeter scale material properties and transport in situ, and which has been successfully applied to characterize soil and plant water status. Here, we have applied neutron radiography and tomography to quantify water transport through individual maize roots in response to internal plant demand. Zea mays seedlings were grown for 10 days in Flint silica sand within 2.6 cm diameter Al chambers. Using a reactor-based neutron source at Oak Ridge National Laboratory (HFIR), water fluxes were tracked through the maize soil-root systems by collecting consecutive neutron radiographs over a 12 h period following irrigation with D2O. D has a much lower neutron attenuation than H, thus D2O displacement of existing H2O within the plant vascular system, or influx of D2O into previously dry tissue or soil is readily tracked by changes in image intensity through time. Plant water release and uptake was regulated by periodically cycling on a high-intensity grow light. From each maize replicate, selected regions of interest (ROI) were delineated around individual roots, root free soil, stem and leaf segments. Changes in ROI were tracked through time to reveal patterns of water flux. The hydration of root and stem tissue cycled in response to illumination; root water content often increased during darkness, then decreased with illumination as water was transported from the root into the stem. Relative root-shoot hydration through time illustrates the balance between demand, storage capacity and uptake, which varies depending on root characteristics and its localized soil environment. The dynamic transport of water between soil, individual roots, stems and leaves was readily visualized and quantified illustrating the value

  6. Revealing the Hot Side of Epsilon Aurigae

    NASA Astrophysics Data System (ADS)

    Hoard, Donald; Stencel, Robert; Howell, Steve

    2012-12-01

    We request a small investment of 24 minutes of Spitzer time, to obtain four IRAC observations of epsilon Aurigae. A naked eye object located near Capella, epsilon Aurigae is the eclipsing binary star with the longest known orbital period, showing a single long duration (~2 yr) eclipse every 27.1 yr. For much of the last 200 years, the nature of the eclipsing object defied explanation. We recently demonstrated that epsilon Aurigae consists of a high luminosity F0 post-AGB star in orbit with a B5 V star surrounded by a solar system sized (~8 AU diameter) disk of cool, dust-dominated material. The eclipse of epsilon Aurigae is a rare event; moreover, it is a unique astrophysical opportunity, since the backlighting of the disk by the high luminosity eclipsed star reveals details that cannot be detected in similar dusty disks around single stars. The current eclipse started in August 2009 and ended in July 2011; we are now in the post-eclipse phase, when the irradiation-heated side of the disk will begin rotating into view. The goals for these observations include: (1) extend our ongoing IRAC monitoring campaign covering the current eclipse to post-eclipse visits; (2) provide a consistent, well-calibrated space-based set of IR photometry for comparison with ongoing ground-based work; and (3) use the composite results to constrain the thermal profile of the disk. A key expectation of these particular observations is to reveal the irradiation-heated portion of the disk, which will be visible on its trailing side following eclipse. Observations of this side of the disk will be crucial to test and constrain new models of disk structure. As part of our overall monitoring campaign with Spitzer, Hubble, Herschel, and numerous ground-based facilities, these proposed observations will make an important contribution to the understanding of stellar evolution in binary stars, including mass transfer and evolution studies, along with new insights into astrophysical disks and post

  7. Niche engineering reveals complementary resource use.

    PubMed

    Gable, Jacob T; Crowder, David W; Northfield, Tobin D; Steffan, Shawn A; Snyder, William E

    2012-09-01

    Greater resource use by diverse communities might result from species occupying complementary niches. Demonstrating niche complementarity among species is challenging, however, due to the difficulty in relating differences between species in particular traits to their use of complementary resources. Here, we overcame this obstacle by exploiting plastic foraging behavior in a community of predatory insects common on Brassica oleracea plants in Washington, USA. These predators complemented one another by partitioning foraging space, with some species foraging primarily along leaf edges and others at leaf centers. We hypothesized that emergent biodiversity effects would occur when predators partitioned foraging space on leaves, but not when spatial complementarity was dampened. Indeed, on intact leaves, edge- and center-foraging predators combined to kill more prey than any single predator species could by itself. These emergent diversity effects, however, disappeared on plants damaged by the caterpillar Plutella xylostella. Caterpillar chew-holes brought edge habitats to the center of leaves, so that all predator species could attack aphids anywhere on plants. With spatial niche differences diminished, there were no benefits of predator diversity; the most voracious single predator species killed the most aphids. Thus, caterpillar herbivory determined whether multi-predator-species effects reflected complementarity or species' individual impacts. Our study provides direct evidence for a causative relationship between niche differentiation and increased resource consumption by diverse communities, as revealed by ecological engineers that homogenize the foraging environment. PMID:23094370

  8. VISTA Reveals the Secret of the Unicorn

    NASA Astrophysics Data System (ADS)

    2010-10-01

    A new infrared image from ESO's VISTA survey telescope reveals an extraordinary landscape of glowing tendrils of gas, dark clouds and young stars within the constellation of Monoceros (the Unicorn). This star-forming region, known as Monoceros R2, is embedded within a huge dark cloud. The region is almost completely obscured by interstellar dust when viewed in visible light, but is spectacular in the infrared. An active stellar nursery lies hidden inside a massive dark cloud rich in molecules and dust in the constellation of Monoceros. Although it appears close in the sky to the more familiar Orion Nebula it is actually almost twice as far from Earth, at a distance of about 2700 light-years. In visible light a grouping of massive hot stars creates a beautiful collection of reflection nebulae where the bluish starlight is scattered from parts of the dark, foggy outer layers of the molecular cloud. However, most of the new-born massive stars remain hidden as the thick interstellar dust strongly absorbs their ultraviolet and visible light. In this gorgeous infrared image taken from ESO's Paranal Observatory in northern Chile, the Visible and Infrared Survey Telescope for Astronomy (VISTA [1], eso0949) penetrates the dark curtain of cosmic dust and reveals in astonishing detail the folds, loops and filaments sculpted from the dusty interstellar matter by intense particle winds and the radiation emitted by hot young stars. "When I first saw this image I just said 'Wow!' I was amazed to see all the dust streamers so clearly around the Monoceros R2 cluster, as well as the jets from highly embedded young stellar objects. There is such a great wealth of exciting detail revealed in these VISTA images," says Jim Emerson, of Queen Mary, University of London and leader of the VISTA consortium. With its huge field of view, large mirror and sensitive camera, VISTA is ideal for obtaining deep, high quality infrared images of large areas of the sky, such as the Monoceros R2 region

  9. Overnight lexical consolidation revealed by speech segmentation.

    PubMed

    Dumay, Nicolas; Gareth Gaskell, M

    2012-04-01

    Two experiments explored the consolidation of spoken words, and assessed whether post-sleep novel competitor effects truly reflect engagement of these novel words in competition for lexical segmentation. Two types of competitor relationships were contrasted: the onset-aligned case (such as "frenzylk"), where the novel word is a close variant of the existing word: they start at the same time point and overlap on most of their segments; and the fully embedding case (such as "lirmucktoze"), where the existing word corresponds to a smaller embedded portion of its novel competitor and is thus less noticeable. Experiment 1 (pause detection) revealed a similar performance for both cases, with no competitor effect immediately after exposure, but significant inhibition after 24 h and seven days. Experiment 2 (word spotting) produced exactly the same pattern; however, as is the case with existing word carriers (cf. McQueen, Norris, & Cutler, 1994), the inhibition was much stronger for fully embedded than for onset-aligned targets (e.g., "lirmuckt" vs. "frenzyl"). Meanwhile, explicit measures of learning, i.e., free recall and recognition, improved over time. These results cannot be explained by either consolidation of episodic traces or acquisition of new phonological/dialectal variants. We argue instead that they reflect a general trait of vocabulary learning and consolidation. PMID:22261419

  10. Revealing Invisible Photonic Inscriptions: Images from Strain.

    PubMed

    Ding, Tao; Cao, Guoshuai; Schäfer, Christian G; Zhao, Qibin; Gallei, Markus; Smoukov, Stoyan K; Baumberg, Jeremy J

    2015-06-24

    Photonic structural materials have received intensive interest and have been strongly developed over the past few years for image displays, sensing, and anticounterfeit materials. Their "smartness" arises from their color responsivity to changes of environment, strain, or external fields. Here, we introduce a novel invisible photonic system that reveals encrypted images or characters by simply stretching, or immersing in solvents. This type of intriguing photonic material is composed of regularly arranged core-shell particles that are selectively cross-linked by UV irradiation, giving different strain response compared to un-cross-linked regions. The images reversibly appear and disappear when cycling the strain and releasing it. The unique advantages of this soft polymer opal system compared with other types of photonic gels are that it can be produced in roll to roll quantities, can be vigorously deformed to achieve strong color changes, and has no solvent evaporation issues because it is a photonic rubber system. We demonstrate potential applications together with a fabrication procedure which is straightforward and scalable, vital for user take-up. Our work deepens understanding of this rubbery photonic system based on core-shell nanospheres. PMID:26039279

  11. Chimaeric sounds reveal dichotomies in auditory perception

    NASA Astrophysics Data System (ADS)

    Smith, Zachary M.; Delgutte, Bertrand; Oxenham, Andrew J.

    2002-03-01

    By Fourier's theorem, signals can be decomposed into a sum of sinusoids of different frequencies. This is especially relevant for hearing, because the inner ear performs a form of mechanical Fourier transform by mapping frequencies along the length of the cochlear partition. An alternative signal decomposition, originated by Hilbert, is to factor a signal into the product of a slowly varying envelope and a rapidly varying fine time structure. Neurons in the auditory brainstem sensitive to these features have been found in mammalian physiological studies. To investigate the relative perceptual importance of envelope and fine structure, we synthesized stimuli that we call `auditory chimaeras', which have the envelope of one sound and the fine structure of another. Here we show that the envelope is most important for speech reception, and the fine structure is most important for pitch perception and sound localization. When the two features are in conflict, the sound of speech is heard at a location determined by the fine structure, but the words are identified according to the envelope. This finding reveals a possible acoustic basis for the hypothesized `what' and `where' pathways in the auditory cortex.

  12. Bone structure as revealed by microtomography

    NASA Astrophysics Data System (ADS)

    Hildebrand, Tor; Laib, Andres; Ulrich, Dieter; Kohlbrenner, Adrian; Ruegsegger, Peter

    1997-10-01

    The appearance of cancellous bone architecture is different for various skeletal sites and various disease states. In the iliac crest it is more plate-like, whereas in the spine rods dominate. During aging and disease plates are perforated and connecting rods are dissolved. There is a continuous shift from one structural type to the other. So traditional histomorphometric procedures, which are based on a fixed model type, will lead to questionable results. 3D microtomography allows to assess model independent structural parameters so that trabecular thickness, for example, can be determined directly. Not only mean thicknesses are available but also thickness histograms which are helpful to identify pathological states. Other features such as trabecular separation, degree of anisotropy and structural type index can be extracted from the 3D images and allow to characterize cancellous bone and its changes due to aging, disease and treatment. To fully exploit the significance of bone structure on bone strength large scale finite element (FE) analyses are performed. Hence microtomography, performed with a sufficiently fine isotropic spatial resolution, reveals information on the structural features of cancellous bone which were not available so far and which will, hopefully, lead to a better understanding of the pathogenesis of bone diseases and subsequently to improved treatment regimes.

  13. Biosignatures as revealed by spectropolarimetry of Earthshine.

    PubMed

    Sterzik, Michael F; Bagnulo, Stefano; Palle, Enric

    2012-03-01

    Low-resolution intensity spectra of Earth's atmosphere obtained from space reveal strong signatures of life ('biosignatures'), such as molecular oxygen and methane with abundances far from chemical equilibrium, as well as the presence of a 'red edge' (a sharp increase of albedo for wavelengths longer than 700 nm) caused by surface vegetation. Light passing through the atmosphere is strongly linearly polarized by scattering (from air molecules, aerosols and cloud particles) and by reflection (from oceans and land). Spectropolarimetric observations of local patches of Earth's sky light from the ground contain signatures of oxygen, ozone and water, and are used to characterize the properties of clouds and aerosols. When applied to exoplanets, ground-based spectropolarimetry can better constrain properties of atmospheres and surfaces than can standard intensity spectroscopy. Here we report disk-integrated linear polarization spectra of Earthshine, which is sunlight that has been first reflected by Earth and then reflected back to Earth by the Moon. The observations allow us to determine the fractional contribution of clouds and ocean surface, and are sensitive to visible areas of vegetation as small as 10 per cent. They represent a benchmark for the diagnostics of the atmospheric composition, mean cloud height and surfaces of exoplanets. PMID:22382980

  14. Revealing the values behind convenience food consumption.

    PubMed

    Botonaki, Anna; Mattas, Konstadinos

    2010-12-01

    The increasing importance of convenience in consumer food choices has attracted researchers' interest. In the effort to understand how convenience affects consumers' food preferences, values are believed to play an important role. The present study attempts to examine the way personal values suggested by Schwartz (1992) are associated with behaviour and attitudes regarding convenience food. A number of constructs describing food related attitudes and behaviours were developed and their relationship with personal values was analyzed following the methodology proposed by Brunsø, Scholderer, and Grunert (2004). Data were collected through a questionnaire survey from a random sample of consumers in Thessaloniki city, Greece. The results reveal that convenience food consumption and convenience orientation in the food domain are mainly connected with values that motivate people to seek new experiences, act independently and enhance their own personal interests, while are in conflict with values of conservation and self-transcendence. The opposite holds for other food related attitudes and behaviours like involvement with cooking and variety in diet. The findings seem to be of particular interest not only for marketers of food products, but also for food policy makers. PMID:20875475

  15. Dynamic Environmental Photosynthetic Imaging Reveals Emergent Phenotypes.

    PubMed

    Cruz, Jeffrey A; Savage, Linda J; Zegarac, Robert; Hall, Christopher C; Satoh-Cruz, Mio; Davis, Geoffry A; Kovac, William Kent; Chen, Jin; Kramer, David M

    2016-06-22

    Understanding and improving the productivity and robustness of plant photosynthesis requires high-throughput phenotyping under environmental conditions that are relevant to the field. Here we demonstrate the dynamic environmental photosynthesis imager (DEPI), an experimental platform for integrated, continuous, and high-throughput measurements of photosynthetic parameters during plant growth under reproducible yet dynamic environmental conditions. Using parallel imagers obviates the need to move plants or sensors, reducing artifacts and allowing simultaneous measurement on large numbers of plants. As a result, DEPI can reveal phenotypes that are not evident under standard laboratory conditions but emerge under progressively more dynamic illumination. We show examples in mutants of Arabidopsis of such "emergent phenotypes" that are highly transient and heterogeneous, appearing in different leaves under different conditions and depending in complex ways on both environmental conditions and plant developmental age. These emergent phenotypes appear to be caused by a range of phenomena, suggesting that such previously unseen processes are critical for plant responses to dynamic environments. PMID:27336966

  16. VISTA Reveals the Secret of the Unicorn

    NASA Astrophysics Data System (ADS)

    2010-10-01

    A new infrared image from ESO's VISTA survey telescope reveals an extraordinary landscape of glowing tendrils of gas, dark clouds and young stars within the constellation of Monoceros (the Unicorn). This star-forming region, known as Monoceros R2, is embedded within a huge dark cloud. The region is almost completely obscured by interstellar dust when viewed in visible light, but is spectacular in the infrared. An active stellar nursery lies hidden inside a massive dark cloud rich in molecules and dust in the constellation of Monoceros. Although it appears close in the sky to the more familiar Orion Nebula it is actually almost twice as far from Earth, at a distance of about 2700 light-years. In visible light a grouping of massive hot stars creates a beautiful collection of reflection nebulae where the bluish starlight is scattered from parts of the dark, foggy outer layers of the molecular cloud. However, most of the new-born massive stars remain hidden as the thick interstellar dust strongly absorbs their ultraviolet and visible light. In this gorgeous infrared image taken from ESO's Paranal Observatory in northern Chile, the Visible and Infrared Survey Telescope for Astronomy (VISTA [1], eso0949) penetrates the dark curtain of cosmic dust and reveals in astonishing detail the folds, loops and filaments sculpted from the dusty interstellar matter by intense particle winds and the radiation emitted by hot young stars. "When I first saw this image I just said 'Wow!' I was amazed to see all the dust streamers so clearly around the Monoceros R2 cluster, as well as the jets from highly embedded young stellar objects. There is such a great wealth of exciting detail revealed in these VISTA images," says Jim Emerson, of Queen Mary, University of London and leader of the VISTA consortium. With its huge field of view, large mirror and sensitive camera, VISTA is ideal for obtaining deep, high quality infrared images of large areas of the sky, such as the Monoceros R2 region

  17. Chandra Reveals Remains of Giant Eruption

    NASA Technical Reports Server (NTRS)

    2002-01-01

    This is a photo taken by NASA's Chandra X-ray Observatory that reveals the remains of an explosion in the form of two enormous arcs of multimillion-degree gas in the galaxy Centaurus A that appear to be part of a ring 25,000 light years in diameter. The size and location of the ring suggest that it could have been an explosion that occurred about 10 million years ago. A composite image made with radio (red and green), optical (yellow-orange), and X-ray data (blue) presents a sturning tableau of a turbulent galaxy. A broad band of dust and cold gas is bisected at an angle by opposing jets of high-energy particles blasting away from the supermassive black hole in the nucleus. Lying in a plane perpendicular to the jets are the two large arcs of x-ray emitting multi-million degree gas. This discovery can help astronomers better understand the cause and effect of violent outbursts from the vicinity of supermassive black holes of active galaxies. The Chandra program is managed by the Marshall Space Flight Center in Huntsville, Alabama.

  18. Sequence tagging reveals unexpected modifications in toxicoproteomics

    PubMed Central

    Dasari, Surendra; Chambers, Matthew C.; Codreanu, Simona G.; Liebler, Daniel C.; Collins, Ben C.; Pennington, Stephen R.; Gallagher, William M.; Tabb, David L.

    2010-01-01

    Toxicoproteomic samples are rich in posttranslational modifications (PTMs) of proteins. Identifying these modifications via standard database searching can incur significant performance penalties. Here we describe the latest developments in TagRecon, an algorithm that leverages inferred sequence tags to identify modified peptides in toxicoproteomic data sets. TagRecon identifies known modifications more effectively than the MyriMatch database search engine. TagRecon outperformed state of the art software in recognizing unanticipated modifications from LTQ, Orbitrap, and QTOF data sets. We developed user-friendly software for detecting persistent mass shifts from samples. We follow a three-step strategy for detecting unanticipated PTMs in samples. First, we identify the proteins present in the sample with a standard database search. Next, identified proteins are interrogated for unexpected PTMs with a sequence tag-based search. Finally, additional evidence is gathered for the detected mass shifts with a refinement search. Application of this technology on toxicoproteomic data sets revealed unintended cross-reactions between proteins and sample processing reagents. Twenty five proteins in rat liver showed signs of oxidative stress when exposed to potentially toxic drugs. These results demonstrate the value of mining toxicoproteomic data sets for modifications. PMID:21214251

  19. Revealing Invisible Photonic Inscriptions: Images from Strain

    PubMed Central

    2015-01-01

    Photonic structural materials have received intensive interest and have been strongly developed over the past few years for image displays, sensing, and anticounterfeit materials. Their “smartness” arises from their color responsivity to changes of environment, strain, or external fields. Here, we introduce a novel invisible photonic system that reveals encrypted images or characters by simply stretching, or immersing in solvents. This type of intriguing photonic material is composed of regularly arranged core–shell particles that are selectively cross-linked by UV irradiation, giving different strain response compared to un-cross-linked regions. The images reversibly appear and disappear when cycling the strain and releasing it. The unique advantages of this soft polymer opal system compared with other types of photonic gels are that it can be produced in roll to roll quantities, can be vigorously deformed to achieve strong color changes, and has no solvent evaporation issues because it is a photonic rubber system. We demonstrate potential applications together with a fabrication procedure which is straightforward and scalable, vital for user take-up. Our work deepens understanding of this rubbery photonic system based on core–shell nanospheres. PMID:26039279

  20. [The life of human hair follicle revealed].

    PubMed

    Bernard, Bruno A

    2006-02-01

    The human hair follicle is a unique appendage which results from epithelio-mesenchymal interactions initiated around the 3rd month of development. This appendage has a very complex structure, with a dermal compartment and an epithelial compartment. The dermal compartment comprises the connective tissue sheath and the dermal papilla, both of which are irrigated by microvessels. The epithelial compartment is made of highly replicating matrix cells giving rise to three concentrical domains, namely the outer root sheath, the inner root sheath and the hair shaft. The pigmentation unit, responsible for hair color, is made of fully active melanocytes located on top of the dermal papilla. Altogether a hair follicle contains more than 20 different cell types, engaged in different differentiation pathways and/or interacting with each other. This complex appendage has a unique behavior in mammals since, after a hair production phase, it involutes in place before entering a resting phase after which it renews itself under a cyclical but stochastic way, out of a double reservoir of pluripotent stem cells able to also regenerate epidermis. For yet unknown reasons, this well ordered process can be disturbed, provoking alopecia. The pigmentation unit also renews itself under a cyclical way, out of a melanocyte progenitor reservoir which progressively declines with time, provoking the hair whitening process. Finally, the shape of the hair shaft is programmed from the bulb. What makes this appendage unique and fascinating is its high degree of autonomy, its incredibly complex though stable structure, the number of different cell types interacting under an equilibrated way and its potential of regeneration. It represents a true paradigm of tissue homeostasis, exemplifying in a small living cylinder all the fundamental laws of cell-cell and tissue interactions. This life is revealed in this short synthesis. PMID:16457752

  1. World population profile reveals bleak data.

    PubMed

    1998-06-01

    This article presents selected demographic and HIV/AIDS indicators for 1998 and projections for 2010 for selected African countries. The statistics are provided by the US Bureau of the Census. The Census HIV/AIDS database is one of the best in the world. Findings reveal that Africa is the worst affected by AIDS. Eight countries are particularly affected: Zimbabwe, Namibia, Botswana, Swaziland, Zambia, Kenya, Malawi, and South Africa. In 1998, life expectancy declined by 25.7 years. Population growth is expected to decline from 2.5% to 1.1% due to the impact of AIDS mortality. HIV continues to spread in African countries and its spread and impact is not recorded in present data. With AIDS, life expectancy is likely to decline in Zimbabwe from 39.2 to 38.8 years during 1998-2010; without AIDS, it is expected to rise from 64.9 to 69.5 years during the same time period. Only in Zambia is there a slight increase in life expectancy with AIDS. The overwhelming poor life prospects for Africans are reflected in this article, which can provide statistics only for 21 of 53 African countries. The absence of data may mean low HIV prevalence, lack of data, or the beginning of the HIV epidemic. The UNDP provides a Human Poverty Index with indicators for deprivation in knowledge, deprivation in living standards, and longevity. African countries are likely to shift to the bottom of this index due to the impact of AIDS. PMID:12294386

  2. NASA's Hyperwall Revealing the Big Picture

    NASA Technical Reports Server (NTRS)

    Sellers, Piers

    2011-01-01

    NASA:s hyperwall is a sophisticated visualization tool used to display large datasets. The hyperwall, or video wall, is capable of displaying multiple high-definition data visualizations and/or images simultaneously across an arrangement of screens. Functioning as a key component at many NASA exhibits, the hyperwall is used to help explain phenomena, ideas, or examples of world change. The traveling version of the hyperwall is typically comprised of nine 42-50" flat-screen monitors arranged in a 3x3 array (as depicted below). However, it is not limited to monitor size or number; screen sizes can be as large as 52" and the arrangement of screens can include more than nine monitors. Generally, NASA satellite and model data are used to highlight particular themes in atmospheric, land, and ocean science. Many of the existing hyperwall stories reveal change across space and time, while others display large-scale still-images accompanied by descriptive, story-telling captions. Hyperwall content on a variety of Earth Science topics already exists and is made available to the public at: eospso.gsfc.nasa.gov/hyperwall. Keynote and PowerPoint presentations as well as Summary of Story files are available for download on each existing topic. New hyperwall content and accompanying files will continue being developed to promote scientific literacy across a diverse group of audience members. NASA invites the use of content accessible through this website but requests the user to acknowledge any and all data sources referenced in the content being used.

  3. Saturn Probe: Revealing Solar System Origins

    NASA Astrophysics Data System (ADS)

    Spilker, T. R.

    2015-12-01

    Comparative studies of the gas giant and ice giant planets are needed to reliably discriminate among competing theories of the origin and evolution of giant planets and the solar system, but we lack critical measurements. A Saturn atmospheric entry probe mission would fill a vital part of that gap, allowing comparative studies of Jupiter and Saturn, providing the basis for later comparisons with the ice giants Uranus and Neptune, and informing studies of extrasolar planetary systems now being characterized. The Galileo Probe mission provided the first in situ studies of Jupiter's atmosphere. Similar measurements at Saturn, Uranus and Neptune would provide an important comparative planetology context for the Galileo results. Cassini's "Proximal Orbits" in 2017 will reveal Saturn's internal structure to complement the Juno mission's similar measurements at Jupiter. A Saturn entry probe, complementing the Galileo Probe investigations at Jupiter, would complete a solid basis for improved understanding of both Jupiter and Saturn, an important stepping stone to understanding Uranus and Neptune and solar system formation and evolution. The 2012 Decadal Survey ("DS") added Saturn Probe science objectives to NASA's New Frontiers Program: highest-priority Tier 1 objectives any New Frontiers implementation must achieve, and Tier 2, high priority but lower than Tier 1. A DS mission concept study using extremely conservative assumptions concluded that a Saturn Probe project could fit within New Frontiers resource constraints, giving a PI confidence that they could pursue some Tier 2 objectives, customizing for the proper balance of science return, science team composition, procured or contributed instruments, etc. Contributed instruments could significantly enhance the payload and the science team for greater science return. They also provide international collaboration opportunities, with science benefits well demonstrated by missions such as Cassini-Huygens and Rosetta.

  4. Microradiometers Reveal Ocean Health, Climate Change

    NASA Technical Reports Server (NTRS)

    2013-01-01

    When NASA researcher Stanford Hooker is in the field, he pays close attention to color. For Hooker, being in the field means being at sea. On one such research trip to the frigid waters of the Arctic, with a Coast Guard icebreaker looming nearby and the snow-crusted ice shelf a few feet away, Hooker leaned over the edge of his small boat and lowered a tethered device into the bright turquoise water, a new product devised by a NASA partner and enabled by a promising technology for oceanographers and atmospheric scientists alike. Color is a function of light. Pure water is clear, but the variation in color observed during a visit to the beach or a flight along a coastline depends on the water s depth and the constituents in it, how far down the light penetrates and how it is absorbed and scattered by dissolved and suspended material. Hooker cares about ocean color because of what it can reveal about the health of the ocean, and in turn, the health of our planet. "The main thing we are interested in is the productivity of the water," Hooker says. The seawater contains phytoplankton, microscopic plants, which are the food base for the ocean s ecosystems. Changes in the water s properties, whether due to natural seasonal effects or human influence, can lead to problems for delicate ecosystems such as coral reefs. Ocean color can inform researchers about the quantities and distribution of phytoplankton and other materials, providing clues as to how the world ocean is changing. NASA s Coastal Zone Color Scanner, launched in 1978, was the first ocean color instrument flown on a spacecraft. Since then, the Agency s ocean color research capabilities have become increasingly sophisticated with the launch of the SeaWiFS instrument in 1997 and the twin MODIS instruments carried into orbit on NASA s Terra (1999) and Aqua (2002) satellites. The technology provides sweeping, global information on ocean color on a scale unattainable by any other means. One issue that arises from

  5. Passive seismology reveals biannual calving periodicity

    NASA Astrophysics Data System (ADS)

    Bartholomaus, T. C.; Larsen, C. F.; West, M. E.; Oneel, S.

    2013-12-01

    Iceberg calving is a large and variable component of the total mass loss from marine-terminating glaciers worldwide. However, the processes that control the size and variability of calving fluxes are poorly understood. Even more basic descriptions of iceberg calving, such as its seasonality, are uncertain. Here, we present nearly two years of automatically-estimated calving fluxes at Yahtse Glacier, a tidewater glacier whose terminus flows at ~7 km/yr towards the Gulf of Alaska. At the terminus, ice losses to calving and submarine melt total approximately 1.5 km^3/yr. In order to identify temporal variability in this mean rate, we develop a statistical model of calving size based on characteristics of calving-generated icequakes. These characteristics include 4 amplitude-based variables and 5 variables related to the shape of the icequake envelope. We build our model by combining automatically-detected icequakes (O'Neel et al., 2007) located at the terminus of Yahtse Glacier (Jones et al., 2013) with a training set of 1400 icequakes produced by visually-observed calving events (Bartholomaus et al., 2012). In each of the models tested (regression trees, multinomial logistic regression and multiple linear regession), icequake duration emerges as the single best predictor of iceberg size, consistent with past studies (Qamar, 1988; O'Neel et al., 2007). Additional predictors, such as the mean icequake amplitude and the kurtosis of the icequake envelope improve the predictive capability of the model and reduce the mean squared error to well-within the error of the in-person classification. Once validated, we apply our model to ~ 400,000 icequakes produced by calving events at Yahtse Glacier between June 2009 and September 2011. These results reveal fluctuations in calving rate at a range of timescales, including twice per year. We suggest that the roughly 50%, biannual variation in calving rate is the result of the trade-off between two competing processes at the

  6. Frantic activity revealed in dusty stellar factories

    NASA Astrophysics Data System (ADS)

    2009-01-01

    Thanks to the Very Large Telescope's acute and powerful near-infrared eye, astronomers have uncovered a host of new young, massive and dusty stellar nurseries in nearby galaxy NGC 253. The centre of this galaxy appears to harbour a twin of our own Milky Way's supermassive black hole. ESO PR Photo 02a/09 The Spiral Galaxy NGC 253 Astronomers from the Instituto de Astrofísica de Canarias (Spain) used NACO, a sharp-eyed adaptive optics instrument on ESO's Very Large Telescope (VLT), to study the fine detail in NGC 253, one of the brightest and dustiest spiral galaxies in the sky. Adaptive Optics (AO) corrects for the blurring effect introduced by the Earth's atmosphere. This turbulence causes the stars to twinkle in a way that delights poets, but frustrates astronomers, since it smears out the images. With AO in action the telescope can produce images that are as sharp as is theoretically possible, as if the telescope were in space. NACO revealed features in the galaxy that were only 11 light-years across. "Our observations provide us with so much spatially resolved detail that we can, for the first time, compare them with the finest radio maps for this galaxy -- maps that have existed for more than a decade," says Juan Antonio Fernández-Ontiveros, the lead author of the paper reporting the results [1]. Astronomers identified 37 distinct bright regions, a threefold increase on previous results, packed into a tiny region at the core of the galaxy, comprising just one percent of the galaxy's total size. The astronomers combined their NACO images with data from another VLT instrument, VISIR, as well as with images from the NASA/ESA Hubble Space Telescope and radio observations made by the Very Large Array and the Very Large Baseline Interferometer. Combining these observations, taken in different wavelength regimes, provided a clue to the nature of these regions. "We now think that these are probably very active nurseries that contain many stars bursting from their

  7. Shocking Detail of Superstar's Activity Revealed

    NASA Astrophysics Data System (ADS)

    1999-10-01

    NASA's Chandra X-ray Observatory has imaged Eta Carinae and revealed a hot inner core around this mysterious superstar. The new X-ray observation shows three distinct structures: an outer, horseshoe shaped ring about two light years in diameter, a hot inner core about 3 light months in diameter, and a hot central source less than a light month in diameter which may contain the superstar. All three structures are thought to represent shock waves produced by matter rushing away from the superstar at supersonic speeds. The temperature of the shock-heated gas ranges from 60 million degrees Celsius in the central regions to 3 million degrees Celsius on the outer structure. An earlier image of Eta Carinae by the Hubble Space Telescope revealed two spectacular bubbles of gas expanding in opposite directions away from a central bright region at speeds in excess of a million miles per hour. The inner region visible in the Chandra image has never been resolved before, and appears to be associated with a central disk of high velocity gas rushing out at much higher speeds perpendicular to the bipolar optical nebula. "It is not what I expected," said Dr. Fred Seward of the Harvard-Smithsonian Center for Astrophysics. "I expected to see a strong point source with a little diffuse emission cloud around it. Instead, we see just the opposite- a bright cloud of diffuse emission, and much less radiation from the center." "The Chandra image contains some puzzles for existing ideas of how a star can produce such hot and intense X-rays," agreed Prof. Kris Davidson of the University of Minnesota. "In the most popular theory, X-rays are made by colliding gas streams from two stars so close together that they'd look like a point source to us. But what happens to gas streams that escape to farther distances? The extended hot stuff in the middle of the new image gives demanding new conditions for any theory to meet." Eta Carinae is one of the most enigmatic and intriguing objects in our

  8. Chandra Data Reveal Rapidly Whirling Black Holes

    NASA Astrophysics Data System (ADS)

    2008-01-01

    A new study using results from NASA's Chandra X-ray Observatory provides one of the best pieces of evidence yet that many supermassive black holes are spinning extremely rapidly. The whirling of these giant black holes drives powerful jets that pump huge amounts of energy into their environment and affects galaxy growth. A team of scientists compared leading theories of jets produced by rotating supermassive black holes with Chandra data. A sampling of nine giant galaxies that exhibit large disturbances in their gaseous atmospheres showed that the central black holes in these galaxies must be spinning at near their maximum rates. People Who Read This Also Read... NASA’s Swift Satellite Catches First Supernova in The Act of Exploding Black Holes Have Simple Feeding Habits Jet Power and Black Hole Assortment Revealed in New Chandra Image Erratic Black Hole Regulates Itself "We think these monster black holes are spinning close to the limit set by Einstein's theory of relativity, which means that they can drag material around them at close to the speed of light," said Rodrigo Nemmen, a visiting graduate student at Penn State University, and lead author of a paper on the new results presented at American Astronomical Society in Austin, Texas. The research reinforces other, less direct methods previously used which have indicated that some stellar and supermassive black holes are spinning rapidly. According to Einstein's theory, a rapidly spinning black hole makes space itself rotate. This effect, coupled with gas spiraling toward the black hole, can produce a rotating, tightly wound vertical tower of magnetic field that flings a large fraction of the inflowing gas away from the vicinity of the black hole in an energetic, high-speed jet. Computer simulations by other authors have suggested that black holes may acquire their rapid spins when galaxies merge, and through the accretion of gas from their surroundings. "Extremely fast spin might be very common for large

  9. 21 CFR 1.21 - Failure to reveal material facts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Failure to reveal material facts. 1.21 Section 1... GENERAL ENFORCEMENT REGULATIONS General Labeling Requirements § 1.21 Failure to reveal material facts. (a... to reveal facts that are: (1) Material in light of other representations made or suggested...

  10. 21 CFR 1.21 - Failure to reveal material facts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Failure to reveal material facts. 1.21 Section 1... GENERAL ENFORCEMENT REGULATIONS General Labeling Requirements § 1.21 Failure to reveal material facts. (a) Labeling of a food, drug, device, or cosmetic shall be deemed to be misleading if it fails to reveal...

  11. 21 CFR 1.21 - Failure to reveal material facts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Failure to reveal material facts. 1.21 Section 1... GENERAL ENFORCEMENT REGULATIONS General Labeling Requirements § 1.21 Failure to reveal material facts. (a) Labeling of a food, drug, device, or cosmetic shall be deemed to be misleading if it fails to reveal...

  12. The lower atmosphere of Pluto revealed

    NASA Astrophysics Data System (ADS)

    2009-03-01

    ), attached to ESO's Very Large Telescope, have now revealed that the atmosphere as a whole, not just the upper atmosphere, has a mean temperature of minus 180 degrees Celsius, and so it is indeed "much hotter" than the surface. In contrast to the Earth's atmosphere [2], most, if not all, of Pluto's atmosphere is thus undergoing a temperature inversion: the temperature is higher, the higher in the atmosphere you look. The change is about 3 to 15 degrees per kilometre. On Earth, under normal circumstances, the temperature decreases through the atmosphere by about 6 degrees per kilometre. "It is fascinating to think that with CRIRES we are able to precisely measure traces of a gas in an atmosphere 100 000 times more tenuous than the Earth's, on an object five times smaller than our planet and located at the edge of the Solar System," says co-author Hans-Ulrich Käufl. "The combination of CRIRES and the VLT is almost like having an advanced atmospheric research satellite orbiting Pluto." The reason why Pluto's surface is so cold is linked to the existence of Pluto's atmosphere, and is due to the sublimation of the surface ice; much like sweat cools the body as it evaporates from the surface of the skin, this sublimation has a cooling effect on the surface of Pluto. In this respect, Pluto shares some properties with comets, whose coma and tails arise from sublimating ice as they approach the Sun. The CRIRES observations also indicate that methane is the second most common gas in Pluto's atmosphere, representing half a percent of the molecules. "We were able to show that these quantities of methane play a crucial role in the heating processes in the atmosphere and can explain the elevated atmospheric temperature," says Lellouch. Two different models can explain the properties of Pluto's atmosphere. In the first, the astronomers assume that Pluto's surface is covered with a thin layer of methane, which will inhibit the sublimation of the nitrogen frost. The second scenario invokes

  13. Dramatic Outburst Reveals Nearest Black Hole

    NASA Astrophysics Data System (ADS)

    2000-01-01

    Sgr. The radio observations revealed the presence of a jet escaping from the system at mind-boggling speeds. Only three other galactic X-ray stellar systems have been found to eject material at such speeds. They have been dubbed "microquasars" because, on a smaller scale, they resemble quasars, which lie at the hearts of distant galaxies and also spew out high-velocity jets of particles. In galaxy-core quasars, the black holes are millions of times more massive than the Sun; in the more nearby microquasars the black holes are roughly three to twenty times more massive than the Sun. The extremely high velocity of the jets suggests that their origin lies close to the event horizon of a black hole. Microquasar activity is thought to arise when the black hole in the binary system draws material away from its companion star. The material surrounding the black hole forms a rapidly spinning disk called an accretion disk. This disk is heated by friction to millions of degrees, causing it to emit X-rays. As spiralling gas moves into the gravity well of the black hole, it moves faster and faster. Magnetic fields in the disk are believed to expel the charged subatomic particles at speeds close to that of light. As the charged particles interact with the magnetic fields, they emit radio waves. If some of the material escapes by being magnetically expelled into space, the matter may continue moving at the tremendous speed it had attained near the black hole. After their ejection, the jets of particles expand and cool, fading from astronomers' view. V4641 Sgr excites astronomers because it is close and because it acted so differently from other microquasars. In other microquasars, outbursts have dimmed more slowly over weeks or months rather than hours. "There's something fundamentally different about this one; it's more extreme than any other example," Hjellming said. "And because this system happens to be so close to us, `it is very likely that there are more objects like V4641

  14. What Facial Appearance Reveals Over Time: When Perceived Expressions in Neutral Faces Reveal Stable Emotion Dispositions

    PubMed Central

    Adams, Reginald B.; Garrido, Carlos O.; Albohn, Daniel N.; Hess, Ursula; Kleck, Robert E.

    2016-01-01

    It might seem a reasonable assumption that when we are not actively using our faces to express ourselves (i.e., when we display nonexpressive, or neutral faces), those around us will not be able to read our emotions. Herein, using a variety of expression-related ratings, we examined whether age-related changes in the face can accurately reveal one’s innermost affective dispositions. In each study, we found that expressive ratings of neutral facial displays predicted self-reported positive/negative dispositional affect, but only for elderly women, and only for positive affect. These findings meaningfully replicate and extend earlier work examining age-related emotion cues in the face of elderly women (Malatesta et al., 1987a). We discuss these findings in light of evidence that women are expected to, and do, smile more than men, and that the quality of their smiles predicts their life satisfaction. Although ratings of old male faces did not significantly predict self-reported affective dispositions, the trend was similar to that found for old female faces. A plausible explanation for this gender difference is that in the process of attenuating emotional expressions over their lifetimes, old men reveal less evidence of their total emotional experiences in their faces than do old women. PMID:27445944

  15. What Facial Appearance Reveals Over Time: When Perceived Expressions in Neutral Faces Reveal Stable Emotion Dispositions.

    PubMed

    Adams, Reginald B; Garrido, Carlos O; Albohn, Daniel N; Hess, Ursula; Kleck, Robert E

    2016-01-01

    It might seem a reasonable assumption that when we are not actively using our faces to express ourselves (i.e., when we display nonexpressive, or neutral faces), those around us will not be able to read our emotions. Herein, using a variety of expression-related ratings, we examined whether age-related changes in the face can accurately reveal one's innermost affective dispositions. In each study, we found that expressive ratings of neutral facial displays predicted self-reported positive/negative dispositional affect, but only for elderly women, and only for positive affect. These findings meaningfully replicate and extend earlier work examining age-related emotion cues in the face of elderly women (Malatesta et al., 1987a). We discuss these findings in light of evidence that women are expected to, and do, smile more than men, and that the quality of their smiles predicts their life satisfaction. Although ratings of old male faces did not significantly predict self-reported affective dispositions, the trend was similar to that found for old female faces. A plausible explanation for this gender difference is that in the process of attenuating emotional expressions over their lifetimes, old men reveal less evidence of their total emotional experiences in their faces than do old women. PMID:27445944

  16. Stated and revealed inequality aversion in three subject pools

    PubMed Central

    Beranek, Benjamin; Cubitt, Robin; Gächter, Simon

    2016-01-01

    This paper reports data from three subject pools (n=717 subjects) using techniques based on those of Loewenstein, et al. (1989) and Blanco, et al. (2011) to obtain parameters, respectively, of stated and revealed inequality aversion. We provide a replication opportunity for those papers, with two innovations: (i) a design which allows stated and revealed preferences to be compared at the individual level; (ii) assessment of robustness of findings across subjects from a UK university, a Turkish university and Amazon Mechanical Turk. Our findings on stated aversion to inequality are qualitatively similar to those of Loewenstein, et al. in each of our subject pools, whereas there are notable differences between some of our findings on revealed preference and those of Blanco, et al. We find that revealed advantageous inequality aversion is often stronger than revealed dis-advantageous inequality aversion. In most subject pools, we find some (weak) correlation between corresponding parameters of stated and revealed inequality aversion. PMID:27069847

  17. 21 CFR 1.21 - Failure to reveal material facts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Failure to reveal material facts. 1.21 Section 1.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... to reveal facts that are: (1) Material in light of other representations made or suggested...

  18. 14. DETAIL VIEW, FLUTED PILASTER AND PANELLED REVEAL IN DOORWAY ...

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

    14. DETAIL VIEW, FLUTED PILASTER AND PANELLED REVEAL IN DOORWAY BETWEEN VESTIBULE AND STAIRHALL (NOTE WOOD GRAINING), WITH SCALE - Bowieville, 522 Church Road South, Leeland, Prince George's County, MD

  19. General view of the archaeological site showing excavation and revealing ...

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

    General view of the archaeological site showing excavation and revealing the steps leading down into the eighteenth-century burial vault - Harry Buck House, North of Main Street (14800 Governor Oden Bowie Drive), Upper Marlboro, Prince George's County, MD

  20. [An original revealing mode of sarcoidosis: Sweet's syndrome].

    PubMed

    Bricha, Myriem; Sqalli, Fatimazzahra; Hammi, Sanae; Bourkadi, Jamal Eddine

    2016-01-01

    Sweet's syndrome is a neutrophilic dermatosis which usually presents as an idiopathic disorder. The combination of Sweet's syndrome and sarcoidosis is rare. We report the clinical case of a Sweet's syndrome revealing sarcoidosis. PMID:27279949

  1. Everett Weinreb, Photographer, April 1989 FOUNDATION DETAIL REVEALED AS RESULT ...

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

    Everett Weinreb, Photographer, April 1989 FOUNDATION DETAIL REVEALED AS RESULT OF HOUSE DEMOLITION - Irvine Ranch Agricultural Headquarters, Boyd Tenant House, Southeast of Intersection of San Diego & Santa Ana Freeways, Irvine, Orange County, CA

  2. Direct sequencing of the human microbiome readily reveals community differences

    PubMed Central

    2010-01-01

    Culture-independent studies of human microbiota by direct genomic sequencing reveal quite distinct differences among communities, indicating that improved sequencing capacity can be most wisely utilized to study more samples, rather than more sequences per sample. PMID:20441597

  3. Revealing ecological networks using Bayesian network inference algorithms.

    PubMed

    Milns, Isobel; Beale, Colin M; Smith, V Anne

    2010-07-01

    Understanding functional relationships within ecological networks can help reveal keys to ecosystem stability or fragility. Revealing these relationships is complicated by the difficulties of isolating variables or performing experimental manipulations within a natural ecosystem, and thus inferences are often made by matching models to observational data. Such models, however, require assumptions-or detailed measurements-of parameters such as birth and death rate, encounter frequency, territorial exclusion, and predation success. Here, we evaluate the use of a Bayesian network inference algorithm, which can reveal ecological networks based upon species and habitat abundance alone. We test the algorithm's performance and applicability on observational data of avian communities and habitat in the Peak District National Park, United Kingdom. The resulting networks correctly reveal known relationships among habitat types and known interspecific relationships. In addition, the networks produced novel insights into ecosystem structure and identified key species with high connectivity. Thus, Bayesian networks show potential for becoming a valuable tool in ecosystem analysis. PMID:20715607

  4. Revealing the molecular signatures of host-pathogen interactions

    PubMed Central

    2011-01-01

    Advances in sequencing technology and genome-wide association studies are now revealing the complex interactions between hosts and pathogen through genomic variation signatures, which arise from evolutionary co-existence. PMID:22011345

  5. Genome-Wide Scan Reveals Mutation Associated with Melanoma

    MedlinePlus

    ... 1999 Spotlight on Research 2012 July 2012 (historical) Genome-Wide Scan Reveals Mutation Associated with Melanoma A ... out to see if a technology called whole genome sequencing would help them find other genetic risk ...

  6. Revealing of HII-regions in Galaxies with Panoramic Spectroscopy

    NASA Astrophysics Data System (ADS)

    Hakopian, S. A.; Balayan, S. K.

    2016-06-01

    Observations intended to investigation and revealing of nodes of processes of nuclear and starforming activity in galaxies were performed via panoramic spectroscopy. Data obtained on Mrk 1050 revealed evidence of starforming activity also outside the central engine of high surface brightness. Two small HII-regions, being likely a part of the chain, are located in the part of the spiral branch coming from the nucleus part.

  7. Hyperammonemia-induced encephalopathy: A rare devastating complication of bariatric surgery

    PubMed Central

    Kromas, Michelle L; Mousa, Omar Y; John, Savio

    2015-01-01

    The clinical manifestations of hyperammonemia are usually easily identifiable to the clinician when associated with liver disease and lead to prompt diagnosis and treatment. However, hyperammonemia-induced encephalopathy is rare in adults in the absence of overt liver disease, thus diagnosis is often delayed or missed leading to potentially life threatening complications. Without proper treatment, such patients can decompensate rapidly with poor outcomes including seizures, coma, and death. Early assessment of plasma ammonia levels in patients with normal hepatic function and characteristic symptoms of encephalopathy can lead to early intervention while investigating the underlying etiology. We describe a patient who presented with a 2-year progression of waxing and waning acute mental status changes after a Roux-en-Y gastric bypass surgery. He was found to have elevated ammonia level as well as orotic aciduria; results consistent with a urea cycle disorder. After consulting neurology as well as toxicology, he ultimately improved after dietary protein restriction, sodium benzoate and lactulose therapy. While rare, clinicians should have a high index of suspicion for late onset urea cycle disorders in symptomatic patients presenting with encephalopathy secondary to hyperammonemia. PMID:25954483

  8. Camelid genomes reveal evolution and adaptation to desert environments.

    PubMed

    Wu, Huiguang; Guang, Xuanmin; Al-Fageeh, Mohamed B; Cao, Junwei; Pan, Shengkai; Zhou, Huanmin; Zhang, Li; Abutarboush, Mohammed H; Xing, Yanping; Xie, Zhiyuan; Alshanqeeti, Ali S; Zhang, Yanru; Yao, Qiulin; Al-Shomrani, Badr M; Zhang, Dong; Li, Jiang; Manee, Manee M; Yang, Zili; Yang, Linfeng; Liu, Yiyi; Zhang, Jilin; Altammami, Musaad A; Wang, Shenyuan; Yu, Lili; Zhang, Wenbin; Liu, Sanyang; Ba, La; Liu, Chunxia; Yang, Xukui; Meng, Fanhua; Wang, Shaowei; Li, Lu; Li, Erli; Li, Xueqiong; Wu, Kaifeng; Zhang, Shu; Wang, Junyi; Yin, Ye; Yang, Huanming; Al-Swailem, Abdulaziz M; Wang, Jun

    2014-01-01

    Bactrian camel (Camelus bactrianus), dromedary (Camelus dromedarius) and alpaca (Vicugna pacos) are economically important livestock. Although the Bactrian camel and dromedary are large, typically arid-desert-adapted mammals, alpacas are adapted to plateaus. Here we present high-quality genome sequences of these three species. Our analysis reveals the demographic history of these species since the Tortonian Stage of the Miocene and uncovers a striking correlation between large fluctuations in population size and geological time boundaries. Comparative genomic analysis reveals complex features related to desert adaptations, including fat and water metabolism, stress responses to heat, aridity, intense ultraviolet radiation and choking dust. Transcriptomic analysis of Bactrian camels further reveals unique osmoregulation, osmoprotection and compensatory mechanisms for water reservation underpinned by high blood glucose levels. We hypothesize that these physiological mechanisms represent kidney evolutionary adaptations to the desert environment. This study advances our understanding of camelid evolution and the adaptation of camels to arid-desert environments. PMID:25333821

  9. [Ovarian torsion revealing an ovarian cavernous hemangioma in a child].

    PubMed

    M'pemba Loufoua-Lemay, A-B; Peko, J-F; Mbongo, J-A; Mokoko, J-C; Nzingoula, S

    2003-11-01

    The authors report one case of cavernous hemangioma of the left ovary, which was revealed by ovarian torsion. Such benign tumors of the blood vessels are rare in ovaries during childhood. This hemangioma was observed in a 13-year-old patient, who presented with abdominal and pelvic pain and vomiting. The pelvic mass was noted and sonography revealed a cystic tumor. An annexectomia was realized. Histology showed narcotized ovary cells, with an increased number of vascular channels composed of thin walled vessels, whose wall consisted of an endothelium. This aspect evoked a cavernous hemangioma of the ovary. PMID:14613693

  10. Perspective view. Fivestory reinforced concrete factory building reveals the structural ...

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

    Perspective view. Five-story reinforced concrete factory building reveals the structural frame on the exterior of the facade. Twelve bay facade facing onto Clay Avenue (north facade) has first floor openings bricked up. Mix of typical factory windows and glass block windows fill the majority of the openings on the rest of building - Russell Industrial Center, 1600 Clay Avenue, Detroit, MI

  11. Experimentally implementable criteria revealing substructures of genuine multipartite entanglement

    SciTech Connect

    Huber, Marcus; Schimpf, Hans; Gabriel, Andreas; Spengler, Christoph; Bruss, Dagmar; Hiesmayr, Beatrix C.

    2011-02-15

    We present a general framework that reveals substructures of genuine multipartite entanglement. Via simple inequalities it is possible to discriminate different sets of multipartite qubit states. These inequalities are beneficial regarding experimental examinations as only local measurements are required. Furthermore, the number of observables scales favorably with system size. In exemplary cases we demonstrate the noise resistance and discuss implementations.

  12. In Reporting Lobbying Expenses, Some Institutions Do Not Reveal All.

    ERIC Educational Resources Information Center

    Lederman, Douglas

    1998-01-01

    On a federal tax form, only 75 of 475 colleges and universities surveyed reported that they had spent money on lobbying, defined as direct contacts with legislators or executive-branch officials about specific bills. Guidelines concerning reporting are unclear and confusing, and some institutions reveal as little as possible. Data on 78…

  13. Adaptation to High Ethanol Reveals Complex Evolutionary Pathways.

    PubMed

    Voordeckers, Karin; Kominek, Jacek; Das, Anupam; Espinosa-Cantú, Adriana; De Maeyer, Dries; Arslan, Ahmed; Van Pee, Michiel; van der Zande, Elisa; Meert, Wim; Yang, Yudi; Zhu, Bo; Marchal, Kathleen; DeLuna, Alexander; Van Noort, Vera; Jelier, Rob; Verstrepen, Kevin J

    2015-11-01

    Tolerance to high levels of ethanol is an ecologically and industrially relevant phenotype of microbes, but the molecular mechanisms underlying this complex trait remain largely unknown. Here, we use long-term experimental evolution of isogenic yeast populations of different initial ploidy to study adaptation to increasing levels of ethanol. Whole-genome sequencing of more than 30 evolved populations and over 100 adapted clones isolated throughout this two-year evolution experiment revealed how a complex interplay of de novo single nucleotide mutations, copy number variation, ploidy changes, mutator phenotypes, and clonal interference led to a significant increase in ethanol tolerance. Although the specific mutations differ between different evolved lineages, application of a novel computational pipeline, PheNetic, revealed that many mutations target functional modules involved in stress response, cell cycle regulation, DNA repair and respiration. Measuring the fitness effects of selected mutations introduced in non-evolved ethanol-sensitive cells revealed several adaptive mutations that had previously not been implicated in ethanol tolerance, including mutations in PRT1, VPS70 and MEX67. Interestingly, variation in VPS70 was recently identified as a QTL for ethanol tolerance in an industrial bio-ethanol strain. Taken together, our results show how, in contrast to adaptation to some other stresses, adaptation to a continuous complex and severe stress involves interplay of different evolutionary mechanisms. In addition, our study reveals functional modules involved in ethanol resistance and identifies several mutations that could help to improve the ethanol tolerance of industrial yeasts. PMID:26545090

  14. The Basics of How to Reveal Epilepsy--Part Two

    ERIC Educational Resources Information Center

    Mittan, Robert J.

    2009-01-01

    In the April 2009 edition of "Exceptional Parent," Part One of this series explored why, for their own emotional well-being, it is so important for parents to tell others about their or their child's epilepsy. This month's installment will discuss the basics of how to reveal epilepsy to others, including some additional advantages one receives in…

  15. Carbohydrate active enzymes revealed in Coptotermes formosanus transcriptome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A normalized cDNA library of Coptotermes formosanus was constructed using mixed RNA isolated from workers, soldiers, nymphs and alates of both sexes. Sequencing of this library generated 131,637 EST and 25,939 unigenes were assembled. Carbohydrate active enzymes (CAZymes) revealed in this library we...

  16. [Ulcerated duodenitis revealing Henoch-Schönlein purpura].

    PubMed

    Marting, A; Defrance, P; Wain, E; Van Severen, M; Deflandre, J

    2015-01-01

    Inflammation and duodenal ulcers can meet many etiologies. We report the case of a young adult with an ulcerated duodenitis revealing Henoch-Schönlein purpura. The abdominal symptoms preceded the emergence of the classical cutaneous signs of the disease. PMID:26376566

  17. Adaptation to High Ethanol Reveals Complex Evolutionary Pathways

    PubMed Central

    Das, Anupam; Espinosa-Cantú, Adriana; De Maeyer, Dries; Arslan, Ahmed; Van Pee, Michiel; van der Zande, Elisa; Meert, Wim; Yang, Yudi; Zhu, Bo; Marchal, Kathleen; DeLuna, Alexander; Van Noort, Vera; Jelier, Rob; Verstrepen, Kevin J.

    2015-01-01

    Tolerance to high levels of ethanol is an ecologically and industrially relevant phenotype of microbes, but the molecular mechanisms underlying this complex trait remain largely unknown. Here, we use long-term experimental evolution of isogenic yeast populations of different initial ploidy to study adaptation to increasing levels of ethanol. Whole-genome sequencing of more than 30 evolved populations and over 100 adapted clones isolated throughout this two-year evolution experiment revealed how a complex interplay of de novo single nucleotide mutations, copy number variation, ploidy changes, mutator phenotypes, and clonal interference led to a significant increase in ethanol tolerance. Although the specific mutations differ between different evolved lineages, application of a novel computational pipeline, PheNetic, revealed that many mutations target functional modules involved in stress response, cell cycle regulation, DNA repair and respiration. Measuring the fitness effects of selected mutations introduced in non-evolved ethanol-sensitive cells revealed several adaptive mutations that had previously not been implicated in ethanol tolerance, including mutations in PRT1, VPS70 and MEX67. Interestingly, variation in VPS70 was recently identified as a QTL for ethanol tolerance in an industrial bio-ethanol strain. Taken together, our results show how, in contrast to adaptation to some other stresses, adaptation to a continuous complex and severe stress involves interplay of different evolutionary mechanisms. In addition, our study reveals functional modules involved in ethanol resistance and identifies several mutations that could help to improve the ethanol tolerance of industrial yeasts. PMID:26545090

  18. When Values and Behaviors Conflict: Immigrant BSW Students' Experiences Revealed

    ERIC Educational Resources Information Center

    Calderwood, Kimberly; Harper, Kim; Ball, Kellie; Liang, David

    2009-01-01

    This qualitative study reveals the discomfort seven immigrant bachelor of social work students reported experiencing when the behaviors expected of them as Canadian social workers conflicted with their fundamental family values. Behaviorally, participants had assimilated to Canadian and to social work cultures; however, the values they held from…

  19. Detail of south granite pier revealing riveted truss ends and ...

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

    Detail of south granite pier revealing riveted truss ends and iron footing plates on top of granite cap stones. View north - New York, New Haven & Hartford Railroad, Fort Point Channel Rolling Lift Bridge, Spanning Fort Point Channel, Boston, Suffolk County, MA

  20. Chemical milling solution reveals stress corrosion cracks in titanium alloy

    NASA Technical Reports Server (NTRS)

    Braski, D. N.

    1967-01-01

    Solution of hydrogen flouride, hydrogen peroxide, and water reveals hot salt stress corrosion cracks in various titanium alloys. After the surface is rinsed in water, dried, and swabbed with the solution, it can be observed by the naked eye or at low magnification.

  1. 24. Demolitin of Pier G reveals the center bays at ...

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

    24. Demolitin of Pier G reveals the center bays at the track well in transverse section. Note structural system of first, second, and third floors, as well as the monitor roof. - Lehigh Valley Railroad, Pier G, Jersey City, Hudson County, NJ

  2. Revealing Evidence of Spin in Galactic Black Holes

    NASA Astrophysics Data System (ADS)

    Miller, J. M.; Fabian, A. C.; Reynolds, C. S.; Nowak, M.; Wijnands, R.; Homan, J.; Belloni, T.; van der Klis, M.; Lewin, W. H. G.

    2002-12-01

    Our observations of Galactic black holes with Chandra and XMM-Newton have recently revealed broad, skewed Fe K-alpha emission lines similar to those seen in some AGN. If such lines are produced near the inner edge of the accretion disk, they can serve as an excellent spin diagnostic. Our analysis of the XMM-Newton spectrum of XTE J1650-500 reveals a strong, skewed Fe K-alpha emission line that requires near-maximal spin; with RXTE, we have discovered a 250 Hz QPO in this source which may also be produced near to the black hole. Although many Galactic black holes have been studied extensively, it is extremely rare that spectroscopic and timing studies both reveal features plausibly associated with the inner accretion disk. We will present the results of our XMM-Newton, Chandra, and RXTE observations of XTE J1650-500, as well as the results of our Chandra observations of Cygnus X-1 and preliminary results from our observations of GX 339-4 with XMM-Newton. We will discuss these results within the context of the relativistic Fe K lines reported by our group and others, and comment on the prospects for revealing evidence of spin in future observations. (JMM acknowledges support from the NSF through the Astronomy and Astrophysics Fellowship program.)

  3. Nilaja Sun's "No Child"...: Revealing Teaching and Learning through Theater

    ERIC Educational Resources Information Center

    Hetland, Lois

    2009-01-01

    This article presents an analysis of Nilaja Sun's one-woman play, "No Child" . . ., that applies the Studio Habits of Mind framework to reveal essential features of great teaching artistry and great teaching. The play conveys much about twenty-first century schools and the policies that control them; about respect, equity, justice, and the lack of…

  4. Natural Disasters that Reveal Cracks in Our Social Foundation

    ERIC Educational Resources Information Center

    Langer, Nieli

    2004-01-01

    The recent deaths of more than 13,000 French elderly in the European heat wave of 2003 revealed cracks in the social foundation of urban communities, here and abroad. The breakdown occurred in community services, neighborhood networks, and governmental agencies that were responsible for warning of impending dangers to at-risk elderly. This paper…

  5. Direct visualization reveals kinetics of meiotic chromosome synapsis

    SciTech Connect

    Rog, Ofer; Dernburg, Abby  F.

    2015-03-17

    The synaptonemal complex (SC) is a conserved protein complex that stabilizes interactions along homologous chromosomes (homologs) during meiosis. The SC regulates genetic exchanges between homologs, thereby enabling reductional division and the production of haploid gametes. Here, we directly observe SC assembly (synapsis) by optimizing methods for long-term fluorescence recording in C. elegans. We report that synapsis initiates independently on each chromosome pair at or near pairing centers—specialized regions required for homolog associations. Once initiated, the SC extends rapidly and mostly irreversibly to chromosome ends. Quantitation of SC initiation frequencies and extension rates reveals that initiation is a rate-limiting step in homolog interactions. Eliminating the dynein-driven chromosome movements that accompany synapsis severely retards SC extension, revealing a new role for these conserved motions. This work provides the first opportunity to directly observe and quantify key aspects of meiotic chromosome interactions and will enable future in vivo analysis of germline processes.

  6. Ascites and other incidental findings revealing undiagnosed systemic rheumatoid arthritis.

    PubMed

    Szeto, Matthew Chak Hin; Disney, Benjamin; Perkins, Philip; Wood, Gordon

    2015-01-01

    We describe a case of a 43-year-old man presenting to the gastroenterology outpatient department with exudative ascites. Mediastinal lymphadenopathy, pericardial effusion and pleural effusion were detected on further imaging. Further clinical examination revealed subcutaneous nodules on the left arm, which were confirmed to be rheumatoid nodules on histology. Inflammatory markers were elevated with positive serology for rheumatoid factor and anticyclic citrullinated protein antibody. Our investigations excluded tuberculosis, pancreatitis and malignancy in the patient. Following review by a rheumatologist, a diagnosis of systemic rheumatoid arthritis (RA) was made. Pleuritis and pericarditis are well recognised as extra-articular manifestation of RA. Ascites, however, is rarely recognised as a manifestation of RA. Our literature search revealed two other cases of ascites due to RA disease activity, and both patients had long-standing known RA. This case adds to the discussion on whether ascites and peritonitis should be classified as extra-articular manifestations of RA. PMID:26055583

  7. Stable Chromosome Condensation Revealed by Chromosome Conformation Capture.

    PubMed

    Eagen, Kyle P; Hartl, Tom A; Kornberg, Roger D

    2015-11-01

    Chemical cross-linking and DNA sequencing have revealed regions of intra-chromosomal interaction, referred to as topologically associating domains (TADs), interspersed with regions of little or no interaction, in interphase nuclei. We find that TADs and the regions between them correspond with the bands and interbands of polytene chromosomes of Drosophila. We further establish the conservation of TADs between polytene and diploid cells of Drosophila. From direct measurements on light micrographs of polytene chromosomes, we then deduce the states of chromatin folding in the diploid cell nucleus. Two states of folding, fully extended fibers containing regulatory regions and promoters, and fibers condensed up to 10-fold containing coding regions of active genes, constitute the euchromatin of the nuclear interior. Chromatin fibers condensed up to 30-fold, containing coding regions of inactive genes, represent the heterochromatin of the nuclear periphery. A convergence of molecular analysis with direct observation thus reveals the architecture of interphase chromosomes. PMID:26544940

  8. Benign Cystic Peritoneal Mesothelioma Revealed by Small Bowel Obstruction.

    PubMed

    Bray Madoué, Kaimba; Boniface, Moifo; Annick Laure, Edzimbi; Pierre, Herve

    2016-01-01

    Benign cystic peritoneal mesothelioma is a rare tumor which frequently occurs in women of reproductive age. Abdominal pain associated with pelvic or abdominal mass is the common clinical presentation. We report the case of a 22-year-old woman with a pathological proved benign cystic mesothelioma of the peritoneum revealed by a small bowel obstruction and a painful left-sided pelvic mass with signs of psoitis. Contrast enhanced abdominal CT-scan demonstrated a large pelvic cystic mass with mass effect on rectosigmoid and pelvic organs. The patient underwent surgical removal of the tumor. Pathological examination revealed the diagnosis of benign cystic mesothelioma of the peritoneum. The outcome was excellent with a 12-month recoil. PMID:27066288

  9. Albemarle–Pamlico Sounds revealed and stated preference data

    PubMed Central

    Whitehead, John C.

    2015-01-01

    In this article we describe the contingent valuation and behavior methods scenario developed in the 1995 Albemarle–Pamlico Sounds Survey. The survey elicits revealed and stated preference recreation behavior data which are used to estimate the value of water quality improvements [4,8]. The survey elicits willingness to pay data which are used to conduct a split-sample scope test [7]. The data are used to jointly estimate revealed and stated preference recreation and willingness to pay data [2,6]. The data has been, and can continue to be, used to investigate econometric specification [3], bid design and other nonmarket valuation issues. The data have been used as illustrations and examples in three books that develop nonmarket valuation methods [1,5,9]. Data are supplied with this article. PMID:26217724

  10. [Deep dorsal penile vein thrombosis revealing Behcet's disease].

    PubMed

    Beddouche, Ali; Ouaziz, Hicham; Zougaghi, Sinane; Alaoui, Abdelilah; Dergamoun, Hamza; El Sayegh, Hachem; Iken, Ali; Benslimane, Lounis; Nouini, Yassine

    2016-01-01

    Deep dorsal penile vein thrombosis (DDPVT)is a rare and little known urologic emergency. It requires an early etiological and symptomatic approach to preserve erectile function and prevent recurrences. This study reports a case of dorsal penile vein thrombosis revealed by spontaneous priapism that didn't resolve adequately and confirmed by penile Doppler ultrasound. After management of priapism and DDPVT, the etiological investigation revealed Behcet's disease whose diagnosis was based on the association of a major criteria, such as oral aphthous ulcers with 3 minor criteria such as: genital aphthous ulcers, ocular involvement, and a positive skin pathergy test within 24h. The patient underwent etiological treatment with good clinical evolution and preservation of erectile function. PMID:27583081

  11. Benign Cystic Peritoneal Mesothelioma Revealed by Small Bowel Obstruction

    PubMed Central

    Bray Madoué, Kaimba; Boniface, Moifo; Annick Laure, Edzimbi; Pierre, Herve

    2016-01-01

    Benign cystic peritoneal mesothelioma is a rare tumor which frequently occurs in women of reproductive age. Abdominal pain associated with pelvic or abdominal mass is the common clinical presentation. We report the case of a 22-year-old woman with a pathological proved benign cystic mesothelioma of the peritoneum revealed by a small bowel obstruction and a painful left-sided pelvic mass with signs of psoitis. Contrast enhanced abdominal CT-scan demonstrated a large pelvic cystic mass with mass effect on rectosigmoid and pelvic organs. The patient underwent surgical removal of the tumor. Pathological examination revealed the diagnosis of benign cystic mesothelioma of the peritoneum. The outcome was excellent with a 12-month recoil. PMID:27066288

  12. [Massive bilateral subconjunctival hemorrhage revealing acute lymphoblastic leukemia].

    PubMed

    Taamallah-Malek, I; Chebbi, A; Bouladi, M; Nacef, L; Bouguila, H; Ayed, S

    2013-03-01

    We report the case of 20-year-old patient who presented in emergency with bilateral massive, spontaneous subconjunctival hemorrhage. Clinical findings suggested a blood dyscrasia, which was confirmed by blood cell count. The patient was urgently referred to hematology where the diagnosis of acute lymphoblastic leukemia was made. This case highlights the importance of working up any unusual subconjunctival hemorrhage, as it may reveal, in certain cases, a severe life-threatening disease. PMID:23122838

  13. Molecular Markers Reveal Exclusively Clonal Reproduction in Trichophyton rubrum

    PubMed Central

    Gräser, Y.; Kühnisch, J.; Presber, W.

    1999-01-01

    Genotypic variability among 96 Trichophyton rubrum strains which displayed different colony morphologies and were collected from four continents was investigated. Twelve markers representing 57 loci were analyzed by PCR fingerprinting, amplified fragment length polymorphism, and random amplified monomorphic DNA markers. Interestingly, none of the methods used revealed any DNA polymorphism, indicating a strictly clonal mode of reproduction and a strong adaptation to human skin. PMID:10523582

  14. Transient light-induced intracellular oxidation revealed by redox biosensor

    SciTech Connect

    Kolossov, Vladimir L.; Beaudoin, Jessica N.; Hanafin, William P.; DiLiberto, Stephen J.; Kenis, Paul J.A.; Rex Gaskins, H.

    2013-10-04

    Highlights: •Time-resolved live cell imaging revealed light-induced oxidation. •Only the roGFP probe fused with glutaredoxin reveals photooxidation. •The transient oxidation is rapidly reduced by the cytosolic antioxidant system. •Intracellular photooxidation is media-dependent. •Oxidation is triggered exclusively by exposure to short wavelength excitation. -- Abstract: We have implemented a ratiometric, genetically encoded redox-sensitive green fluorescent protein fused to human glutaredoxin (Grx1-roGFP2) to monitor real time intracellular glutathione redox potentials of mammalian cells. This probe enabled detection of media-dependent oxidation of the cytosol triggered by short wavelength excitation. The transient nature of light-induced oxidation was revealed by time-lapse live cell imaging when time intervals of less than 30 s were implemented. In contrast, transient ROS generation was not observed with the parental roGFP2 probe without Grx1, which exhibits slower thiol-disulfide exchange. These data demonstrate that the enhanced sensitivity of the Grx1-roGFP2 fusion protein enables the detection of short-lived ROS in living cells. The superior sensitivity of Grx1-roGFP2, however, also enhances responsiveness to environmental cues introducing a greater likelihood of false positive results during image acquisition.

  15. Using metabarcoding to reveal and quantify plant-pollinator interactions.

    PubMed

    Pornon, André; Escaravage, Nathalie; Burrus, Monique; Holota, Hélène; Khimoun, Aurélie; Mariette, Jérome; Pellizzari, Charlène; Iribar, Amaia; Etienne, Roselyne; Taberlet, Pierre; Vidal, Marie; Winterton, Peter; Zinger, Lucie; Andalo, Christophe

    2016-01-01

    Given the ongoing decline of both pollinators and plants, it is crucial to implement effective methods to describe complex pollination networks across time and space in a comprehensive and high-throughput way. Here we tested if metabarcoding may circumvent the limits of conventional methodologies in detecting and quantifying plant-pollinator interactions. Metabarcoding experiments on pollen DNA mixtures described a positive relationship between the amounts of DNA from focal species and the number of trnL and ITS1 sequences yielded. The study of pollen loads of insects captured in plant communities revealed that as compared to the observation of visits, metabarcoding revealed 2.5 times more plant species involved in plant-pollinator interactions. We further observed a tight positive relationship between the pollen-carrying capacities of insect taxa and the number of trnL and ITS1 sequences. The number of visits received per plant species also positively correlated to the number of their ITS1 and trnL sequences in insect pollen loads. By revealing interactions hard to observe otherwise, metabarcoding significantly enlarges the spatiotemporal observation window of pollination interactions. By providing new qualitative and quantitative information, metabarcoding holds great promise for investigating diverse facets of interactions and will provide a new perception of pollination networks as a whole. PMID:27255732

  16. Using metabarcoding to reveal and quantify plant-pollinator interactions

    PubMed Central

    Pornon, André; Escaravage, Nathalie; Burrus, Monique; Holota, Hélène; Khimoun, Aurélie; Mariette, Jérome; Pellizzari, Charlène; Iribar, Amaia; Etienne, Roselyne; Taberlet, Pierre; Vidal, Marie; Winterton, Peter; Zinger, Lucie; Andalo, Christophe

    2016-01-01

    Given the ongoing decline of both pollinators and plants, it is crucial to implement effective methods to describe complex pollination networks across time and space in a comprehensive and high-throughput way. Here we tested if metabarcoding may circumvent the limits of conventional methodologies in detecting and quantifying plant-pollinator interactions. Metabarcoding experiments on pollen DNA mixtures described a positive relationship between the amounts of DNA from focal species and the number of trnL and ITS1 sequences yielded. The study of pollen loads of insects captured in plant communities revealed that as compared to the observation of visits, metabarcoding revealed 2.5 times more plant species involved in plant-pollinator interactions. We further observed a tight positive relationship between the pollen-carrying capacities of insect taxa and the number of trnL and ITS1 sequences. The number of visits received per plant species also positively correlated to the number of their ITS1 and trnL sequences in insect pollen loads. By revealing interactions hard to observe otherwise, metabarcoding significantly enlarges the spatiotemporal observation window of pollination interactions. By providing new qualitative and quantitative information, metabarcoding holds great promise for investigating diverse facets of interactions and will provide a new perception of pollination networks as a whole. PMID:27255732

  17. Transcriptome Reveals Cathepsin K in Periodontal Ligament Differentiation.

    PubMed

    Yamada, S; Ozaki, N; Tsushima, K; Yamaba, S; Fujihara, C; Awata, T; Sakashita, H; Kajikawa, T; Kitagaki, J; Yamashita, M; Yanagita, M; Murakami, S

    2016-08-01

    Periodontal ligaments (PDLs) play an important role in remodeling the alveolar bond and cementum. Characterization of the periodontal tissue transcriptome remains incomplete, and an improved understanding of PDL features could aid in developing new regenerative therapies. Here, we aimed to generate and analyze a large human PDL transcriptome. We obtained PDLs from orthodontic treatment patients, isolated the RNA, and used a vector-capping method to make a complementary DNA library from >20,000 clones. Our results revealed that 58% of the sequences were full length. Furthermore, our analysis showed that genes expressed at the highest frequencies included those for collagen type I, collagen type III, and proteases. We also found 5 genes whose expressions have not been previously reported in human PDL. To access which of the highly expressed genes might be important for PDL cell differentiation, we used real-time polymerase chain reaction to measure their expression in differentiating cells. Among the genes tested, the cysteine protease cathepsin K had the highest upregulation, so we measured its relative expression in several tissues, as well as in osteoclasts, which are known to express high levels of cathepsin K. Our results revealed that PDL cells express cathepsin K at similar levels as osteoclasts, which are both expressed at higher levels than those of the other tissues tested. We also measured cathepsin K protein expression and enzyme activity during cell differentiation and found that both increased during this process. Immunocytochemistry experiments revealed that cathepsin K localizes to the interior of lysosomes. Last, we examined the effect of inhibiting cathepsin K during cell differentiation and found that cathepsin K inhibition stimulated calcified nodule formation and increased the levels of collagen type I and osteocalcin gene expression. Based on these results, cathepsin K seems to regulate collagen fiber accumulation during human PDL cell

  18. Genes but Not Genomes Reveal Bacterial Domestication of Lactococcus Lactis

    PubMed Central

    Passerini, Delphine; Beltramo, Charlotte; Coddeville, Michele; Quentin, Yves; Ritzenthaler, Paul

    2010-01-01

    Background The population structure and diversity of Lactococcus lactis subsp. lactis, a major industrial bacterium involved in milk fermentation, was determined at both gene and genome level. Seventy-six lactococcal isolates of various origins were studied by different genotyping methods and thirty-six strains displaying unique macrorestriction fingerprints were analyzed by a new multilocus sequence typing (MLST) scheme. This gene-based analysis was compared to genomic characteristics determined by pulsed-field gel electrophoresis (PFGE). Methodology/Principal Findings The MLST analysis revealed that L. lactis subsp. lactis is essentially clonal with infrequent intra- and intergenic recombination; also, despite its taxonomical classification as a subspecies, it displays a genetic diversity as substantial as that within several other bacterial species. Genome-based analysis revealed a genome size variability of 20%, a value typical of bacteria inhabiting different ecological niches, and that suggests a large pan-genome for this subspecies. However, the genomic characteristics (macrorestriction pattern, genome or chromosome size, plasmid content) did not correlate to the MLST-based phylogeny, with strains from the same sequence type (ST) differing by up to 230 kb in genome size. Conclusion/Significance The gene-based phylogeny was not fully consistent with the traditional classification into dairy and non-dairy strains but supported a new classification based on ecological separation between “environmental” strains, the main contributors to the genetic diversity within the subspecies, and “domesticated” strains, subject to recent genetic bottlenecks. Comparison between gene- and genome-based analyses revealed little relationship between core and dispensable genome phylogenies, indicating that clonal diversification and phenotypic variability of the “domesticated” strains essentially arose through substantial genomic flux within the dispensable genome

  19. Interior Evolution of Ceres and Vesta Revealed by Dawn

    NASA Astrophysics Data System (ADS)

    Raymond, C. A.; Russell, C. T.; Bland, M. T.; Castillo, J. C.; De Sanctis, M. C.; Ermakov, A.; Jaumann, R.; Konopliv, A. S.; Marchi, S.; McCord, T. B.; McSween, H. Y., Jr.; Nathues, A.; Park, R. S.; Prettyman, T. H.; Toplis, M. J.; Zuber, M. T.

    2015-12-01

    Dawn's exploration of Vesta and Ceres has revealed their geophysical characteristics, informing the processes that shaped the bodies. Dawn has determined the average diameter of Ceres to be 940 km, smaller than the previously estimated 975 km [1]. This implies a density of 2160 kg/m3, indicating that Ceres is less differentiated than predicted [2]. Ceres' entire surface is cratered, implying the lack of a thick (10's of km) water ice layer at the surface. Variability in Ceres' crater morphology indicates that the near-surface layer has variable strength and rheology, likely due to heterogeneity in the near-surface mixture of rock, ice and salt. These observations may indicate that Ceres lost a significant amount of an original surface ice layer due to impact erosion. The lack of large impact basins on Ceres can be interpreted to be the result of viscous relaxation. These data provide insights into Ceres' thermal evolution and mechanical properties, which appear to be unique to this warm, icy body. In contrast to Ceres, Vesta formed very early and hot, resulting in a fully differentiated body. Dawn's exploration revealed geophysical and geochemical evidence for an iron-rich core and basaltic crust. However, unlike the pre-Dawn paradigm of Vesta's evolution, Dawn found that the crust and mantle of Vesta are less distinct than predicted by classical differentiation models. [1] Thomas, P. C., et al., Differentiation of the asteroid Ceres as revealed by its shape, Nature, 437, 224-226, 2005; [2] McCord et al., Ceres: Its Origin, Evolution and Structure and Dawn's Potential Contribution, Space Sci Rev
DOI 10.1007/s11214-010-9729-9, 2011.

  20. How the ``Blues'' reveals the intimacy of music and physics

    NASA Astrophysics Data System (ADS)

    Gibson, J. Murray

    2013-03-01

    Little do most people know when they hear blues piano - and you'll hear some live in this talk - that physics permeates the style, as it does all of music. Why should you care? By deconstructing blues piano the intimacy of physics, mathematics and music will be revealed in its glory.[1] The exercise says something about how the brains of the music composer and of the listener must be intimately linked to the physical principles of acoustics. And it provides a great vehicle to explain physical phenomena to non-scientists - everything from quantum mechanics to protein structure.

  1. Revealing and Characterizing Dark Excitons through Coherent Multidimensional Spectroscopy.

    PubMed

    Tollerud, Jonathan O; Cundiff, Steven T; Davis, Jeffrey A

    2016-08-26

    Dark excitons are of fundamental importance in a broad range of contexts but are difficult to study using conventional optical spectroscopy due to their weak interaction with light. We show how coherent multidimensional spectroscopy can reveal and characterize dark states. Using this approach, we identify parity-forbidden and spatially indirect excitons in InGaAs/GaAs quantum wells and determine details regarding lifetimes, homogeneous and inhomogeneous linewidths, broadening mechanisms, and coupling strengths. The observations of coherent coupling between these states and bright excitons hint at a role for a multistep process by which excitons in the barrier can relax into the quantum wells. PMID:27610881

  2. Tributaries of West Antarctic Ice Streams Revealed by RADARSAT Interferometry.

    PubMed

    Joughin; Gray; Bindschadler; Price; Morse; Hulbe; Mattar; Werner

    1999-10-01

    Interferometric RADARSAT data are used to map ice motion in the source areas of four West Antarctic ice streams. The data reveal that tributaries, coincident with subglacial valleys, provide a spatially extensive transition between slow inland flow and rapid ice stream flow and that adjacent ice streams draw from shared source regions. Two tributaries flow into the stagnant ice stream C, creating an extensive region that is thickening at an average rate of 0.49 meters per year. This is one of the largest rates of thickening ever reported in Antarctica. PMID:10514370

  3. Population dynamics of flaviviruses revealed by molecular phylogenies.

    PubMed Central

    Zanotto, P M; Gould, E A; Gao, G F; Harvey, P H; Holmes, E C

    1996-01-01

    The phylogeny of 123 complete envelope gene sequences was reconstructed in order to understand the evolution of tick- and mosquito-borne flaviviruses. An analysis of phylogenetic tree structure reveals a continual and asymmetric branching process in the tick-borne flaviviruses, compared with an explosive radiation in the last 200 years in viruses transmitted by mosquitoes. The distinction between these two viral groups probably reflects differences in modes of dispersal, propagation, and changes in the size of host populations. The most serious implication of this work is that growing human populations are being exposed to an expanding range of increasingly diverse viral strains. PMID:8570593

  4. Data mining of VDJ genes reveals interesting clues.

    PubMed

    Joshi, Rajani R; Gupta, Vinay K

    2006-01-01

    Hypervariability of the complementary determining regions in characteristic structure of Immunoglobulins and the distinct, cell-specific expressions of the genes coding for this important class of proteins pose intriguing problems in experimental and computational/informatics research requiring a special approach different from those for the other proteins. We present here an Average Linkage Hierarchical Clustering of the Homosapien VDJ genes and the Immunoglobulin polypeptides generated by them using special kind of data structures and correlation matrices in place of the microarray data. The results reveal interesting clues on the heterogeneity of exon - intron locations in these gene-families and its possible role in hypervariability of the Immunoglobulins. PMID:16842114

  5. Revealed distributional preferences: Individuals vs. teams☆☆☆

    PubMed Central

    Balafoutas, Loukas; Kerschbamer, Rudolf; Kocher, Martin; Sutter, Matthias

    2014-01-01

    We compare experimentally the revealed distributional preferences of individuals and teams in allocation tasks. We find that teams are significantly more benevolent than individuals in the domain of disadvantageous inequality while the benevolence in the domain of advantageous inequality is similar across decision makers. A consequence for the frequency of preference types is that while a substantial fraction of individuals is classified as inequality averse, this type disappears completely in teams. Spiteful types are markedly more frequent among individuals than among teams. On the other hand, by far more teams than individuals are classified as efficiency lovers. PMID:25843995

  6. [Neonatal adrenal hemorrhage revealed by jaundice: a case report].

    PubMed

    Oulmaati, A; Hays, S; Mory-Thomas, N; Bretones, P; Bensaid, M; Jordan, I; Bonfils, M; Godbert, I; Picaud, J-C

    2012-04-01

    The clinical presentation of adrenal hemorrhage varies, depending on the extent of hemorrhage as well as the amount of adrenal cortex involved by the hemorrhage. We report here a case of neonatal adrenal hemorrhage revealed by late onset of neonatal jaundice. This adrenal hemorrhage most probably resulted from shoulder dystocia. The aim of this work was to focus on the fact that jaundice can be caused by adrenal hemorrhage and to emphasize the crucial importance of abdominal ultrasound in cases of persistent jaundice. PMID:22424898

  7. Indentation Tests Reveal Geometry-Regulated Stiffening of Nanotube Junctions.

    PubMed

    Ozden, Sehmus; Yang, Yang; Tiwary, Chandra Sekhar; Bhowmick, Sanjit; Asif, Syed; Penev, Evgeni S; Yakobson, Boris I; Ajayan, Pulickel M

    2016-01-13

    Here we report a unique method to locally determine the mechanical response of individual covalent junctions between carbon nanotubes (CNTs), in various configurations such as "X", "Y", and "Λ"-like. The setup is based on in situ indentation using a picoindenter integrated within a scanning electron microscope. This allows for precise mapping between junction geometry and mechanical behavior and uncovers geometry-regulated junction stiffening. Molecular dynamics simulations reveal that the dominant contribution to the nanoindentation response is due to the CNT walls stretching at the junction. Targeted synthesis of desired junction geometries can therefore provide a "structural alphabet" for construction of macroscopic CNT networks with tunable mechanical response. PMID:26618517

  8. Nonclassical light revealed by the joint statistics of simultaneous measurements.

    PubMed

    Luis, Alfredo

    2016-04-15

    Nonclassicality cannot be a single-observable property, since the statistics of any quantum observable is compatible with classical physics. We develop a general procedure to reveal nonclassical behavior of light states from the joint statistics arising in the practical measurement of multiple observables. Beside embracing previous approaches, this protocol can disclose nonclassical features for standard examples of classical-like behavior, such as SU(2) and Glauber coherent states. When combined with other criteria, this would imply that every light state is nonclassical. PMID:27082346

  9. Anticipatory eye fixations reveal tool knowledge for tool interaction.

    PubMed

    Belardinelli, Anna; Barabas, Marissa; Himmelbach, Marc; Butz, Martin V

    2016-08-01

    Action-oriented eye-tracking studies have shown that eye fixations reveal much about current behavioral intentions. The eyes typically fixate those positions of a tool or an object where the fingers will be placed next, or those positions in a scene, where obstacles need to be avoided to successfully reach or transport a tool or object. Here, we asked to what extent eye fixations can also reveal active cognitive inference processes, which are expected to integrate bottom-up visual information with internal knowledge for planning suitable object interactions task-dependently. In accordance to the available literature, we expected that task-relevant knowledge will include sensorimotor, semantic, and mechanical aspects. To investigate if and in which way this internal knowledge influences eye fixation behavior while planning an object interaction, we presented pictures of familiar and unfamiliar tools and instructed participants to either pantomime 'lifting' or 'using' the respective tool. When confronted with unfamiliar tools, participants fixated the tool's effector part closer and longer in comparison with familiar tools. This difference was particularly prominent during 'using' trials when compared with 'lifting' trials. We suggest that this difference indicates that the brain actively extracts mechanical information about the unknown tool in order to infer its appropriate usage. Moreover, the successive fixations over a trial indicate that a dynamic, task-oriented, active cognitive process unfolds, which integrates available tool knowledge with visually gathered information to plan and determine the currently intended tool interaction. PMID:27068808

  10. Aberrant Activity in Degenerated Retinas Revealed by Electrical Imaging

    PubMed Central

    Zeck, Günther

    2016-01-01

    In this review, I present and discuss the current understanding of aberrant electrical activity found in the ganglion cell layer (GCL) of rod-degenerated (rd) mouse retinas. The reported electrophysiological properties revealed by electrical imaging using high-density microelectrode arrays can be subdivided between spiking activity originating from retinal ganglion cells (RGCs) and local field potentials (LFPs) reflecting strong trans-membrane currents within the GCL. RGCs in rd retinas show increased and rhythmic spiking compared to age-matched wild-type retinas. Fundamental spiking frequencies range from 5 to 15 Hz in various mouse models. The rhythmic RGC spiking is driven by a presynaptic network comprising AII amacrine and bipolar cells. In the healthy retina this rhythm-generating circuit is inhibited by photoreceptor input. A unique physiological feature of rd retinas is rhythmic LFP manifested as spatially-restricted low-frequency (5–15 Hz) voltage changes. Their spatiotemporal characterization revealed propagation and correlation with RGC spiking. LFPs rely on gap-junctional coupling and are shaped by glycinergic and by GABAergic transmission. The aberrant RGC spiking and LFPs provide a simple readout of the functionality of the remaining retinal circuitry which can be used in the development of improved vision restoration strategies. PMID:26903810

  11. Blue whale earplug reveals lifetime contaminant exposure and hormone profiles

    PubMed Central

    Trumble, Stephen J.; Robinson, Eleanor M.; Berman-Kowalewski, Michelle; Potter, Charles W.; Usenko, Sascha

    2013-01-01

    Lifetime contaminant and hormonal profiles have been reconstructed for an individual male blue whale (Balaenoptera musculus, Linnaeus 1758) using the earplug as a natural aging matrix that is also capable of archiving and preserving lipophilic compounds. These unprecedented lifetime profiles (i.e., birth to death) were reconstructed with a 6-mo resolution for a wide range of analytes including cortisol (stress hormone), testosterone (developmental hormone), organic contaminants (e.g., pesticides and flame retardants), and mercury. Cortisol lifetime profiles revealed a doubling of cortisol levels over baseline. Testosterone profiles suggest this male blue whale reached sexual maturity at approximately 10 y of age, which corresponds well with and improves on previous estimates. Early periods of the reconstructed contaminant profiles for pesticides (such as dichlorodiphenyltrichloroethanes and chlordanes), polychlorinated biphenyls, and polybrominated diphenyl ethers demonstrate significant maternal transfer occurred at 0–12 mo. The total lifetime organic contaminant burden measured between the earplug (sum of contaminants in laminae layers) and blubber samples from the same organism were similar. Total mercury profiles revealed reduced maternal transfer and two distinct pulse events compared with organic contaminants. The use of a whale earplug to reconstruct lifetime chemical profiles will allow for a more comprehensive examination of stress, development, and contaminant exposure, as well as improve the assessment of contaminant use/emission, environmental noise, ship traffic, and climate change on these important marine sentinels. PMID:24043814

  12. Ancient DNA sequence revealed by error-correcting codes.

    PubMed

    Brandão, Marcelo M; Spoladore, Larissa; Faria, Luzinete C B; Rocha, Andréa S L; Silva-Filho, Marcio C; Palazzo, Reginaldo

    2015-01-01

    A previously described DNA sequence generator algorithm (DNA-SGA) using error-correcting codes has been employed as a computational tool to address the evolutionary pathway of the genetic code. The code-generated sequence alignment demonstrated that a residue mutation revealed by the code can be found in the same position in sequences of distantly related taxa. Furthermore, the code-generated sequences do not promote amino acid changes in the deviant genomes through codon reassignment. A Bayesian evolutionary analysis of both code-generated and homologous sequences of the Arabidopsis thaliana malate dehydrogenase gene indicates an approximately 1 MYA divergence time from the MDH code-generated sequence node to its paralogous sequences. The DNA-SGA helps to determine the plesiomorphic state of DNA sequences because a single nucleotide alteration often occurs in distantly related taxa and can be found in the alternative codon patterns of noncanonical genetic codes. As a consequence, the algorithm may reveal an earlier stage of the evolution of the standard code. PMID:26159228

  13. Direct visualization reveals kinetics of meiotic chromosome synapsis

    DOE PAGESBeta

    Rog, Ofer; Dernburg, Abby  F.

    2015-03-17

    The synaptonemal complex (SC) is a conserved protein complex that stabilizes interactions along homologous chromosomes (homologs) during meiosis. The SC regulates genetic exchanges between homologs, thereby enabling reductional division and the production of haploid gametes. Here, we directly observe SC assembly (synapsis) by optimizing methods for long-term fluorescence recording in C. elegans. We report that synapsis initiates independently on each chromosome pair at or near pairing centers—specialized regions required for homolog associations. Once initiated, the SC extends rapidly and mostly irreversibly to chromosome ends. Quantitation of SC initiation frequencies and extension rates reveals that initiation is a rate-limiting step inmore » homolog interactions. Eliminating the dynein-driven chromosome movements that accompany synapsis severely retards SC extension, revealing a new role for these conserved motions. This work provides the first opportunity to directly observe and quantify key aspects of meiotic chromosome interactions and will enable future in vivo analysis of germline processes.« less

  14. Nanoscience of single polymer chains revealed by nanofishing.

    PubMed

    Nakajima, Ken; Nishi, Toshio

    2006-01-01

    The invention of atomic force microscopy (AFM) enabled us to study the statistical properties of single polymer chains by a method called "nanofishing," which stretches a single polymer chain adsorbed on a substrate with its one end by picking it at the other end. A force-extension curve obtained for a single polystyrene chain in a Theta solvent (cyclohexane) shows good agreement with a worm-like chain model and, therefore, gives microscopic information about entropic elasticity. Furthermore, the nanofishing technique can be used for dynamic viscoelastic measurement of single polymer chains. An AFM cantilever is mechanically oscillated at its resonant frequency during the stretching process. This technique enables the estimation of quantitative and simultaneous elongation-dependent changes of stiffness and viscosity of a single chain with the use of a phenomenological model. In this study, the effect of solvent on viscosity in low extension regions reveals that the viscosity is attributed to monomer-solvent friction. Thus, static and dynamic nanofishing techniques are shown to give powerful experimental proofs for several basic questions in polymer physics. The techniques are expected to reveal hidden properties of polymer chains or polymer solutions by any types of macroscopic measurements in the future. PMID:17099889

  15. Genome Sequencing Reveals a Phage in Helicobacter pylori

    PubMed Central

    Lehours, Philippe; Vale, Filipa F.; Bjursell, Magnus K.; Melefors, Ojar; Advani, Reza; Glavas, Steve; Guegueniat, Julia; Gontier, Etienne; Lacomme, Sabrina; Alves Matos, António; Menard, Armelle; Mégraud, Francis; Engstrand, Lars; Andersson, Anders F.

    2011-01-01

    ABSTRACT Helicobacter pylori chronically infects the gastric mucosa in more than half of the human population; in a subset of this population, its presence is associated with development of severe disease, such as gastric cancer. Genomic analysis of several strains has revealed an extensive H. pylori pan-genome, likely to grow as more genomes are sampled. Here we describe the draft genome sequence (63 contigs; 26× mean coverage) of H. pylori strain B45, isolated from a patient with gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The major finding was a 24.6-kb prophage integrated in the bacterial genome. The prophage shares most of its genes (22/27) with prophage region II of Helicobacter acinonychis strain Sheeba. After UV treatment of liquid cultures, circular DNA carrying the prophage integrase gene could be detected, and intracellular tailed phage-like particles were observed in H. pylori cells by transmission electron microscopy, indicating that phage production can be induced from the prophage. PCR amplification and sequencing of the integrase gene from 341 H. pylori strains from different geographic regions revealed a high prevalence of the prophage (21.4%). Phylogenetic reconstruction showed four distinct clusters in the integrase gene, three of which tended to be specific for geographic regions. Our study implies that phages may play important roles in the ecology and evolution of H. pylori. PMID:22086490

  16. Diffusion Tensor Imaging Reveals Evolution of Primate Brain Architectures

    PubMed Central

    Zhang, Degang; Guo, Lei; Zhu, Dajiang; Li, Kaiming; Li, Longchuan; Chen, Hanbo; Zhao, Qun; Hu, Xiaoping; Liu, Tianming

    2013-01-01

    Evolution of the brain has been an inherently interesting problem for centuries. Recent studies have indicated that neuroimaging is a powerful technique for studying brain evolution. In particular, a variety of reports have demonstrated that consistent white matter fiber connection patterns derived from diffusion tensor imaging (DTI) tractography reveal common brain architecture and are predictive of brain functions. In this paper, based on our recently discovered 358 Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOL) defined by consistent fiber connection patterns in DTI datasets of human brains, we derived 65 DICCCOLs that are common in macaque monkey, chimpanzee and human brains and 175 DICCCOLs that exhibit significant discrepancies amongst these three primate species. Qualitative and quantitative evaluations not only demonstrated the consistencies of anatomical locations and structural fiber connection patterns of these 65 common DICCCOLs across three primates, suggesting an evolutionarily-preserved common brain architecture, but also revealed regional patterns of evolutionarily-induced complexity and variability of those 175 discrepant DICCCOLs across the three species. PMID:23135357

  17. Computational Assembly of Polymorphic Amyloid Fibrils Reveals Stable Aggregates

    PubMed Central

    Smaoui, Mohamed Raef; Poitevin, Frédéric; Delarue, Marc; Koehl, Patrice; Orland, Henri; Waldispühl, Jérôme

    2013-01-01

    Amyloid proteins aggregate into polymorphic fibrils that damage tissues of the brain, nerves, and heart. Experimental and computational studies have examined the structural basis and the nucleation of short fibrils, but the ability to predict and precisely quantify the stability of larger aggregates has remained elusive. We established a complete classification of fibril shapes and developed a tool called CreateFibril to build such complex, polymorphic, modular structures automatically. We applied stability landscapes, a technique we developed to reveal reliable fibril structural parameters, to assess fibril stability. CreateFibril constructed HET-s, Aβ, and amylin fibrils up to 17 nm in length, and utilized a novel dipolar solvent model that captured the effect of dipole-dipole interactions between water and very large molecular systems to assess their aqueous stability. Our results validate experimental data for HET-s and Aβ, and suggest novel (to our knowledge) findings for amylin. In particular, we predicted the correct structural parameters (rotation angles, packing distances, hydrogen bond lengths, and helical pitches) for the one and three predominant HET-s protofilaments. We reveal and structurally characterize all known Aβ polymorphic fibrils, including structures recently classified as wrapped fibrils. Finally, we elucidate the predominant amylin fibrils and assert that native amylin is more stable than its amyloid form. CreateFibril and a database of all stable polymorphic fibril models we tested, along with their structural energy landscapes, are available at http://amyloid.cs.mcgill.ca. PMID:23442919

  18. Pneumoretroperitoneum and Pneumomediastinum Revealing a Left Colon Perforation

    PubMed Central

    Montori, Giulia; Di Giovanni, Giacomo; Mzoughi, Zeineb; Angot, Cedric; Al Samman, Sophie; Solaini, Leonardo; Cheynel, Nicolas

    2015-01-01

    Left colon perforation usually occurs in complicated diverticulitis or cancer. The most frequent signs are intraperitoneal abscess or peritonitis. In cases of retroperitoneal colonic perforation, diagnosis may be difficult. A 59-year-old woman presented with left thigh pain and with abdominal discomfort associated with mild dyspnea. Computed tomography scan showed air bubbles and purulent collection in the retroperitoneum, with subcutaneous emphysema extending from the left thigh to the neck. Computed tomography scan also revealed portal vein gas and thrombosis with multiple liver abscesses. An emergency laparotomy revealed a perforation of the proximal left colon. No masses were found. A left colectomy was performed. The retroperitoneum was drained and washed extensively. A negative pressure wound therapy was applied. A second-look laparotomy was performed 48 hours later. The retroperitoneum was drained and an end colostomy was performed. Intensive Care Unit postoperative stay was 9 days, and the patient was discharged on the 32nd postoperative day. Pneumoretroperitoneum and pneumomediastinum are rare signs of colonic retroperitoneal perforation. The diagnosis may be delayed, especially in the absence of peritoneal irritation. Clinical, laboratory, and especially radiologic parameters might be useful. Surgical treatment must be prompt to improve prognosis. PMID:26414818

  19. Previously Unrecognized Large Lunar Impact Basins Revealed by Topographic Data

    NASA Technical Reports Server (NTRS)

    Frey, Herbert V.

    2008-01-01

    The discovery of a large population of apparently buried impact craters on Mars, revealed as Quasi- Circular Depressions (QCDs) in Mars Orbiting Laser Altimeter (MOLA) data [1,2,3] and as Circular Thin Areas (CTAs) [4] in crustal thickness model data [5] leads to the obvious question: are there unrecognized impact features on the Moon and other bodies in the solar system? Early analysis of Clementine topography revealed several large impact basins not previously known [6,7], so the answer certainly is "Yes." How large a population of previously undetected impact basins, their size frequency distribution, and how much these added craters and basins will change ideas about the early cratering history and Late Heavy Bombardment on the Moon remains to be determined. Lunar Orbiter Laser Altimeter (LOLA) data [8] will be able to address these issues. As a prelude, we searched the state-of-the-art global topographic grid for the Moon, the Unified Lunar Control Net (ULCN) [9] for evidence of large impact features not previously recognized by photogeologic mapping, as summarized by Wilhelms [lo].

  20. Environmental and genetic perturbations reveal different networks of metabolic regulation

    PubMed Central

    Greenberg, Anthony J; Hackett, Sean R; Harshman, Lawrence G; Clark, Andrew G

    2011-01-01

    Progress in systems biology depends on accurate descriptions of biological networks. Connections in a regulatory network are identified as correlations of gene expression across a set of environmental or genetic perturbations. To use this information to predict system behavior, we must test how the nature of perturbations affects topologies of networks they reveal. To probe this question, we focused on metabolism of Drosophila melanogaster. Our source of perturbations is a set of crosses among 92 wild-derived lines from five populations, replicated in a manner permitting separate assessment of the effects of genetic variation and environmental fluctuation. We directly assayed activities of enzymes and levels of metabolites. Using a multivariate Bayesian model, we estimated covariance among metabolic parameters and built fine-grained probabilistic models of network topology. The environmental and genetic co-regulation networks are substantially the same among five populations. However, genetic and environmental perturbations reveal qualitative differences in metabolic regulation, suggesting that environmental shifts, such as diet modifications, produce different systemic effects than genetic changes, even if the primary targets are the same. PMID:22186737

  1. Circulating protein synthesis rates reveal skeletal muscle proteome dynamics.

    PubMed

    Shankaran, Mahalakshmi; King, Chelsea L; Angel, Thomas E; Holmes, William E; Li, Kelvin W; Colangelo, Marc; Price, John C; Turner, Scott M; Bell, Christopher; Hamilton, Karyn L; Miller, Benjamin F; Hellerstein, Marc K

    2016-01-01

    Here, we have described and validated a strategy for monitoring skeletal muscle protein synthesis rates in rodents and humans over days or weeks from blood samples. We based this approach on label incorporation into proteins that are synthesized specifically in skeletal muscle and escape into the circulation. Heavy water labeling combined with sensitive tandem mass spectrometric analysis allowed integrated synthesis rates of proteins in muscle tissue across the proteome to be measured over several weeks. Fractional synthesis rate (FSR) of plasma creatine kinase M-type (CK-M) and carbonic anhydrase 3 (CA-3) in the blood, more than 90% of which is derived from skeletal muscle, correlated closely with FSR of CK-M, CA-3, and other proteins of various ontologies in skeletal muscle tissue in both rodents and humans. Protein synthesis rates across the muscle proteome generally changed in a coordinate manner in response to a sprint interval exercise training regimen in humans and to denervation or clenbuterol treatment in rodents. FSR of plasma CK-M and CA-3 revealed changes and interindividual differences in muscle tissue proteome dynamics. In human subjects, sprint interval training primarily stimulated synthesis of structural and glycolytic proteins. Together, our results indicate that this approach provides a virtual biopsy, sensitively revealing individualized changes in proteome-wide synthesis rates in skeletal muscle without a muscle biopsy. Accordingly, this approach has potential applications for the diagnosis, management, and treatment of muscle disorders. PMID:26657858

  2. Circulating protein synthesis rates reveal skeletal muscle proteome dynamics

    PubMed Central

    Shankaran, Mahalakshmi; King, Chelsea L.; Angel, Thomas E.; Holmes, William E.; Li, Kelvin W.; Colangelo, Marc; Price, John C.; Turner, Scott M.; Bell, Christopher; Hamilton, Karyn L.; Miller, Benjamin F.; Hellerstein, Marc K.

    2015-01-01

    Here, we have described and validated a strategy for monitoring skeletal muscle protein synthesis rates in rodents and humans over days or weeks from blood samples. We based this approach on label incorporation into proteins that are synthesized specifically in skeletal muscle and escape into the circulation. Heavy water labeling combined with sensitive tandem mass spectrometric analysis allowed integrated synthesis rates of proteins in muscle tissue across the proteome to be measured over several weeks. Fractional synthesis rate (FSR) of plasma creatine kinase M-type (CK-M) and carbonic anhydrase 3 (CA-3) in the blood, more than 90% of which is derived from skeletal muscle, correlated closely with FSR of CK-M, CA-3, and other proteins of various ontologies in skeletal muscle tissue in both rodents and humans. Protein synthesis rates across the muscle proteome generally changed in a coordinate manner in response to a sprint interval exercise training regimen in humans and to denervation or clenbuterol treatment in rodents. FSR of plasma CK-M and CA-3 revealed changes and interindividual differences in muscle tissue proteome dynamics. In human subjects, sprint interval training primarily stimulated synthesis of structural and glycolytic proteins. Together, our results indicate that this approach provides a virtual biopsy, sensitively revealing individualized changes in proteome-wide synthesis rates in skeletal muscle without a muscle biopsy. Accordingly, this approach has potential applications for the diagnosis, management, and treatment of muscle disorders. PMID:26657858

  3. Revealing quantum correlation by negativity of the Wigner function

    NASA Astrophysics Data System (ADS)

    Taghiabadi, Razieh; Akhtarshenas, Seyed Javad; Sarbishaei, Mohsen

    2016-05-01

    We analyze two two-mode continuous variable separable states with the same marginal states. We adopt the definition of classicality in the form of well-defined positive Wigner function describing the state and find that although the states possess positive local Wigner functions, they exhibit negative Wigner functions for the global states. Using the negativity of Wigner function as an indicator of nonclassicality, we show that despite these states possess different negativities of the Wigner function, they do not reveal this difference as phase space nonclassicalities such as negativity of the Mandel Q parameter or quadrature squeezing. We then concentrate on quantum correlation of these states and show that quantum discord and local quantum uncertainty, as two well-defined measures of quantum correlation, manifest the difference between negativity of the Wigner functions. The non-Gaussianity of these states is also examined and show that the difference in behavior of their non-Gaussianity is the same as the difference between negativity of their Wigner functions. We also investigate the influence of correlation rank criterion and find that when the states can be produced locally from classical states, the Wigner functions cannot reveal their quantum correlations.

  4. Blue whale earplug reveals lifetime contaminant exposure and hormone profiles.

    PubMed

    Trumble, Stephen J; Robinson, Eleanor M; Berman-Kowalewski, Michelle; Potter, Charles W; Usenko, Sascha

    2013-10-15

    Lifetime contaminant and hormonal profiles have been reconstructed for an individual male blue whale (Balaenoptera musculus, Linnaeus 1758) using the earplug as a natural aging matrix that is also capable of archiving and preserving lipophilic compounds. These unprecedented lifetime profiles (i.e., birth to death) were reconstructed with a 6-mo resolution for a wide range of analytes including cortisol (stress hormone), testosterone (developmental hormone), organic contaminants (e.g., pesticides and flame retardants), and mercury. Cortisol lifetime profiles revealed a doubling of cortisol levels over baseline. Testosterone profiles suggest this male blue whale reached sexual maturity at approximately 10 y of age, which corresponds well with and improves on previous estimates. Early periods of the reconstructed contaminant profiles for pesticides (such as dichlorodiphenyltrichloroethanes and chlordanes), polychlorinated biphenyls, and polybrominated diphenyl ethers demonstrate significant maternal transfer occurred at 0-12 mo. The total lifetime organic contaminant burden measured between the earplug (sum of contaminants in laminae layers) and blubber samples from the same organism were similar. Total mercury profiles revealed reduced maternal transfer and two distinct pulse events compared with organic contaminants. The use of a whale earplug to reconstruct lifetime chemical profiles will allow for a more comprehensive examination of stress, development, and contaminant exposure, as well as improve the assessment of contaminant use/emission, environmental noise, ship traffic, and climate change on these important marine sentinels. PMID:24043814

  5. Functionalities of expressed messenger RNAs revealed from mutant phenotypes.

    PubMed

    Liao, Ben-Yang; Weng, Meng-Pin

    2016-07-01

    Total messenger RNAs mRNAs that are produced from a given gene under a certain set of conditions include both functional and nonfunctional transcripts. The high prevalence of nonfunctional mRNAs that have been detected in cells has raised questions regarding the functional implications of mRNA expression patterns and divergences. Phenotypes that result from the mutagenesis of protein-coding genes have provided the most straightforward descriptions of gene functions, and such data obtained from model organisms have facilitated investigations of the functionalities of expressed mRNAs. Mutant phenotype data from mouse tissues have revealed various attributes of functional mRNAs, including tissue-specificity, strength of expression, and evolutionary conservation. In addition, the role that mRNA expression evolution plays in driving morphological evolution has been revealed from studies designed to exploit morphological and physiological phenotypes of mouse mutants. Investigations into yeast essential genes (defined by an absence of colony growth after gene deletion) have further described gene regulatory strategies that reduce protein expression noise by mediating the rates of transcription and translation. In addition to the functional significance of expressed mRNAs as described in the abovementioned findings, the functionalities of other type of RNAs (i.e., noncoding RNAs) remain to be characterized with systematic mutations and phenotyping of the DNA regions that encode these RNA molecules. WIREs RNA 2016, 7:416-427. doi: 10.1002/wrna.1329 For further resources related to this article, please visit the WIREs website. PMID:26748449

  6. Ancient DNA sequence revealed by error-correcting codes

    PubMed Central

    Brandão, Marcelo M.; Spoladore, Larissa; Faria, Luzinete C. B.; Rocha, Andréa S. L.; Silva-Filho, Marcio C.; Palazzo, Reginaldo

    2015-01-01

    A previously described DNA sequence generator algorithm (DNA-SGA) using error-correcting codes has been employed as a computational tool to address the evolutionary pathway of the genetic code. The code-generated sequence alignment demonstrated that a residue mutation revealed by the code can be found in the same position in sequences of distantly related taxa. Furthermore, the code-generated sequences do not promote amino acid changes in the deviant genomes through codon reassignment. A Bayesian evolutionary analysis of both code-generated and homologous sequences of the Arabidopsis thaliana malate dehydrogenase gene indicates an approximately 1 MYA divergence time from the MDH code-generated sequence node to its paralogous sequences. The DNA-SGA helps to determine the plesiomorphic state of DNA sequences because a single nucleotide alteration often occurs in distantly related taxa and can be found in the alternative codon patterns of noncanonical genetic codes. As a consequence, the algorithm may reveal an earlier stage of the evolution of the standard code. PMID:26159228

  7. Memory activation reveals abnormal EEG in preclinical Huntington's disease.

    PubMed

    van der Hiele, Karin; Jurgens, Caroline K; Vein, Alla A; Reijntjes, Robert H A M; Witjes-Ané, Marie-Noëlle W; Roos, Raymund A C; van Dijk, Gert; Middelkoop, Huub A M

    2007-04-15

    The EEG is potentially useful as a marker of early Huntington's disease (HD). In dementia, the EEG during a memory activation challenge showed abnormalities where the resting EEG did not. We investigated whether memory activation also reveals EEG abnormalities in preclinical HD. Sixteen mutation carriers for HD and 13 nonmutation carriers underwent neurological, neuropsychological, MRI and EEG investigations. The EEG was registered during a rest condition, i.e. eyes closed, and a working memory task. In each condition we determined absolute power in the theta (4-8 Hz) and alpha (8-13 Hz) bands and subsequently calculated relative alpha power. The EEG during eyes closed did not differ between groups. The EEG during memory activation showed less relative alpha power in mutation carriers as compared to nonmutation carriers, even though memory performance was similar [F (1,27) = 10.87; P = 0.003]. Absolute powers also showed less alpha power [F (1,27) = 7.02; P = 0.013] but similar theta power. No correlations were found between absolute and relative alpha power on the one hand and neuropsychological scores, motor scores or number of CAG repeats on the other. In conclusion, memory activation reveals functional brain changes in Huntington's disease before clinical signs become overt. PMID:17266047

  8. Piriform Spider Silk Sequences Reveal Unique Repetitive Elements

    PubMed Central

    Perry, David J.; Bittencourt, Daniela; Siltberg-Liberles, Jessica; Rech, Elibio L.; Lewis, Randolph V.

    2010-01-01

    Orb-weaving spider silk fibers are assembled from very large, highly repetitive proteins. The repeated segments contain, in turn, short, simple repetitive amino acid motifs that account for the physical and mechanical properties of the assembled fiber. Of the six orb-weaver silk fibroins, the piriform silk that makes the attachment discs, which lashes the joints of the web and attaches dragline silk to surfaces has not been previously characterized. Piriform silk protein cDNAs were isolated from phage libraries of three species, A. trifasciata, N. clavipes, and N. cruentata. The deduced amino acid sequences from these genes revealed two new repetitive motifs: an alternating proline motif where every other amino acid is proline, and a glutamine-rich motif of 6 to 8 amino acids. Similar to other spider silk proteins, the repeated segments are large (>200 amino acids) and highly homogenized within a species. There is also substantial sequence similarity across the genes from the three species with particular conservation of the repetitive motifs. Northern blot analysis revealed that the messenger RNA is larger than 11kb and is expressed exclusively in the piriform glands of the spider. Phylogenetic analysis of the C-terminal regions of the new proteins with published spidroins robustly shows that the pirifom sequences form an ortholog group. PMID:20954740

  9. Membrane protein properties revealed through data-rich electrostatics calculations

    PubMed Central

    Guerriero, Christopher J.; Brodsky, Jeffrey L.; Grabe, Michael

    2015-01-01

    SUMMARY The electrostatic properties of membrane proteins often reveal many of their key biophysical characteristics, such as ion channel selectivity and the stability of charged membrane-spanning segments. The Poisson-Boltzmann (PB) equation is the gold standard for calculating protein electrostatics, and the software APBSmem enables the solution of the PB equation in the presence of a membrane. Here, we describe significant advances to APBSmem including: full automation of system setup, per-residue energy decomposition, incorporation of PDB2PQR, calculation of membrane induced pKa shifts, calculation of non-polar energies, and command-line scripting for large scale calculations. We highlight these new features with calculations carried out on a number of membrane proteins, including the recently solved structure of the ion channel TRPV1 and a large survey of 1,614 membrane proteins of known structure. This survey provides a comprehensive list of residues with large electrostatic penalties for being embedded in the membrane potentially revealing interesting functional information. PMID:26118532

  10. The Microbiome of Brazilian Mangrove Sediments as Revealed by Metagenomics

    PubMed Central

    Andreote, Fernando Dini; Jiménez, Diego Javier; Chaves, Diego; Dias, Armando Cavalcante Franco; Luvizotto, Danice Mazzer; Dini-Andreote, Francisco; Fasanella, Cristiane Cipola; Lopez, Maryeimy Varon; Baena, Sandra; Taketani, Rodrigo Gouvêa; de Melo, Itamar Soares

    2012-01-01

    Here we embark in a deep metagenomic survey that revealed the taxonomic and potential metabolic pathways aspects of mangrove sediment microbiology. The extraction of DNA from sediment samples and the direct application of pyrosequencing resulted in approximately 215 Mb of data from four distinct mangrove areas (BrMgv01 to 04) in Brazil. The taxonomic approaches applied revealed the dominance of Deltaproteobacteria and Gammaproteobacteria in the samples. Paired statistical analysis showed higher proportions of specific taxonomic groups in each dataset. The metabolic reconstruction indicated the possible occurrence of processes modulated by the prevailing conditions found in mangrove sediments. In terms of carbon cycling, the sequences indicated the prevalence of genes involved in the metabolism of methane, formaldehyde, and carbon dioxide. With respect to the nitrogen cycle, evidence for sequences associated with dissimilatory reduction of nitrate, nitrogen immobilization, and denitrification was detected. Sequences related to the production of adenylsulfate, sulfite, and H2S were relevant to the sulphur cycle. These data indicate that the microbial core involved in methane, nitrogen, and sulphur metabolism consists mainly of Burkholderiaceae, Planctomycetaceae, Rhodobacteraceae, and Desulfobacteraceae. Comparison of our data to datasets from soil and sea samples resulted in the allotment of the mangrove sediments between those samples. The results of this study add valuable data about the composition of microbial communities in mangroves and also shed light on possible transformations promoted by microbial organisms in mangrove sediments. PMID:22737213

  11. A complex North Atlantic permanent pycnocline revealed by Argo data

    NASA Astrophysics Data System (ADS)

    Feucher, Charlène; Maze, Guillaume; Mercier, Herlé

    2015-04-01

    In the North Atlantic subtropical gyre, the oceanic vertical structure of density is characterized by a region of rapid increase with depth. This layer is called the permanent pycnocline. The pycnocline is the transition layer between light, low-latitude, surface water masses which are ventilated every winter when penetrated locally by the mixed layer and dense, deeper water masses whose properties are set in the high latitudes. Assessing the structure and variability of the permanent pycnocline is of a major interest in the understanding of the climate system because the pycnocline embeds the warm water sphere and most of the wind-forced horizontal circulation. We characterized the large scale structure of the permanent pycnocline with in-situ data from the Argo array. We developed a new method to objectively characterize its properties (depth, thickness, temperature, salinity, density, potential vorticity). Results reveal a surprisingly complex structure with inhomogeneous properties. In the Gulf Stream recirculation region the pycnocline is deep, thick, the maximum of stratification is found in the middle on the layer and follow an isopycnal surface. But away from this textbook regional description, the pycnocline is characterized by vertical asymmetries and gradients in thermohaline properties. T/S distribution along the permanent pycnocline depth reveals a diversity of water masses. We will present the mean observed structure and properties of the permanent pycnocline and relate them to physical processes that constraint them.

  12. NeuCode Proteomics Reveals Bap1 Regulation of Metabolism.

    PubMed

    Baughman, Joshua M; Rose, Christopher M; Kolumam, Ganesh; Webster, Joshua D; Wilkerson, Emily M; Merrill, Anna E; Rhoads, Timothy W; Noubade, Rajkumar; Katavolos, Paula; Lesch, Justin; Stapleton, Donald S; Rabaglia, Mary E; Schueler, Kathy L; Asuncion, Raymond; Domeyer, Melanie; Zavala-Solorio, Jose; Reich, Michael; DeVoss, Jason; Keller, Mark P; Attie, Alan D; Hebert, Alexander S; Westphall, Michael S; Coon, Joshua J; Kirkpatrick, Donald S; Dey, Anwesha

    2016-07-12

    We introduce neutron-encoded (NeuCode) amino acid labeling of mice as a strategy for multiplexed proteomic analysis in vivo. Using NeuCode, we characterize an inducible knockout mouse model of Bap1, a tumor suppressor and deubiquitinase whose in vivo roles outside of cancer are not well established. NeuCode proteomics revealed altered metabolic pathways following Bap1 deletion, including profound elevation of cholesterol biosynthetic machinery coincident with reduced expression of gluconeogenic and lipid homeostasis proteins in liver. Bap1 loss increased pancreatitis biomarkers and reduced expression of mitochondrial proteins. These alterations accompany a metabolic remodeling with hypoglycemia, hypercholesterolemia, hepatic lipid loss, and acinar cell degeneration. Liver-specific Bap1 null mice present with fully penetrant perinatal lethality, severe hypoglycemia, and hepatic lipid deficiency. This work reveals Bap1 as a metabolic regulator in liver and pancreas, and it establishes NeuCode as a reliable proteomic method for deciphering in vivo biology. PMID:27373151

  13. Revealing short-period normal modes of the atmosphere

    NASA Astrophysics Data System (ADS)

    Shved, G. M.; Ermolenko, S. I.; Hoffmann, P.

    2015-09-01

    Barometer and seismometer measurements at Collm, Germany (51.3° N, 13.0° E) for all of 2002 are used to search for atmospheric normal modes (ANMs) in the frequency range 50-310 µHz. The measurements are spectrally analyzed using a 5-day window sliding along the 1-year series with a 1-day step. The subsequent analysis follows two procedures: (a) revealing features in the frequency distribution of the number of statistically significant spectral peaks in histograms built on the basis of these spectra and (b) calculating the multiplication spectra for the raw spectra. The two procedures yield the same result for the two instruments, i.e., reveal a periodicity in the clustering of atmospheric modes on the frequency axis with a period of ˜6 µHz. The fact that this period is close to 7 μHz, which is predicted by the crude theory of gravity—inertia ANMs [3] for their frequency distribution, suggests that ANMs are generated down to as small a period as ˜1 h.

  14. A systems biology approach reveals common metastatic pathways in osteosarcoma

    PubMed Central

    2012-01-01

    Background Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The survival rate of patients with metastatic disease remains very dismal. Nevertheless, metastasis is a complex process and a single-level analysis is not likely to identify its key biological determinants. In this study, we used a systems biology approach to identify common metastatic pathways that are jointly supported by both mRNA and protein expression data in two distinct human metastatic OS models. Results mRNA expression microarray and N-linked glycoproteomic analyses were performed on two commonly used isogenic pairs of human metastatic OS cell lines, namely HOS/143B and SaOS-2/LM7. Pathway analysis of the differentially regulated genes and glycoproteins separately revealed pathways associated to metastasis including cell cycle regulation, immune response, and epithelial-to-mesenchymal-transition. However, no common significant pathway was found at both genomic and proteomic levels between the two metastatic models, suggesting a very different biological nature of the cell lines. To address this issue, we used a topological significance analysis based on a “shortest-path” algorithm to identify topological nodes, which uncovered additional biological information with respect to the genomic and glycoproteomic profiles but remained hidden from the direct analyses. Pathway analysis of the significant topological nodes revealed a striking concordance between the models and identified significant common pathways, including “Cytoskeleton remodeling/TGF/WNT”, “Cytoskeleton remodeling/Cytoskeleton remodeling”, and “Cell adhesion/Chemokines and adhesion”. Of these, the “Cytoskeleton remodeling/TGF/WNT” was the top ranked common pathway from the topological analysis of the genomic and proteomic profiles in the two metastatic models. The up-regulation of proteins in the “Cytoskeleton remodeling/TGF/WNT” pathway in the SaOS-2/LM7 and HOS/143B models

  15. Endoperoxides Revealed as Origin of the Toxicity of Graphene Oxide.

    PubMed

    Pieper, Hanna; Chercheja, Serghei; Eigler, Siegfried; Halbig, Christian E; Filipovic, Milos R; Mokhir, Andriy

    2016-01-01

    Potential biomedicinal applications of graphene oxide (GO), for example, as a carrier of biomolecules or a reagent for photothermal therapy and biosensing, are limited by its cytotoxicity and mutagenicity. It is believed that these properties are at least partially caused by GO-induced oxidative stress in cells. However, it is not known which chemical fragments of GO are responsible for this unfavorable effect. We generated four GOs containing variable redox-active groups on the surface, including Mn(2+), C-centered radicals, and endoperoxides (EPs). A comparison of the abilities of these materials to generate reactive oxygen species in human cervical cancer cells revealed that EPs play a crucial role in GO-induced oxidative stress. These data could be applied to the rational design of biocompatible nontoxic GOs for biomedical applications. PMID:26549205

  16. Treated-skin temperature regularities revealed by IR thermography

    NASA Astrophysics Data System (ADS)

    Vainer, Boris G.

    2001-03-01

    Experimental results disclosing temperature change of human skin affected by various unnatural factors are presented in detail. Thermograms are obtained with the IR thermograph containing high performance InAs CID FPA-based photosensitive unit. Using logarithmic scale of time, evolution of skin temperature after moistening, spirit sponging, and olive oil lubrication is investigated. A comparative analysis of the resulting effects of treatments including alpha-hydroxy acid, cosmetic regenerating cream, spirit, and water, is made. Quantitative distinctions between skin regions characterized by ordinary, and depleted blood supply, including areas located directly above surface main vessels, are revealed. Strongly logarithmic time- dependence of a skin temperature is discovered when the skin is cooled down after its preliminary heating with a hot wax. Non-monotonic change of a local temperature during electrically active procedure is described. Low level light therapy equipment is also applied. A special role of the temperature of nose is discussed.

  17. Topological structure dynamics revealing collective evolution in active nematics

    PubMed Central

    Shi, Xia-qing; Ma, Yu-qiang

    2013-01-01

    Topological defects frequently emerge in active matter like bacterial colonies, cytoskeleton extracts on substrates, self-propelled granular or colloidal layers and so on, but their dynamical properties and the relations to large-scale organization and fluctuations in these active systems are seldom touched. Here we reveal, through a simple model for active nematics using self-driven hard elliptic rods, that the excitation, annihilation and transportation of topological defects differ markedly from those in non-active media. These dynamical processes exhibit strong irreversibility in active nematics in the absence of detailed balance. Moreover, topological defects are the key factors in organizing large-scale dynamic structures and collective flows, resulting in multi-spatial temporal effects. These findings allow us to control the self-organization of active matter through topological structures. PMID:24346733

  18. Structural characterization of human heparanase reveals insights into substrate recognition

    PubMed Central

    Wu, Liang; Viola, Cristina M.; Brzozowski, Andrzej M.; Davies, Gideon J.

    2016-01-01

    Heparan Sulfate (HS) is a glycosaminoglycan (GAG) which forms a key component of the extracellular matrix (ECM). Breakdown of HS is carried out by heparanase (HPSE), an endo-β-glucuronidase of the glycoside hydrolase (GH)79 family. Overexpression of HPSE is strongly linked to cancer metastases - reflecting breakdown of extracellular HS and release of stored growth factors. Here we present crystal structures of human HPSE at 1.6-1.9 Å resolution reveal how an endo-acting binding cleft is exposed by proteolytic activation of latent proHPSE. Oligosaccharide complexes map the substrate-binding and sulfate recognition motifs. These data shed light on the structure and interactions for a key enzyme involved in ECM maintenance, and provide a starting point for design of HPSE inhibitors as biochemical tools and anti-cancer therapeutics. PMID:26575439

  19. Locations of marine animals revealed by carbon isotopes.

    PubMed

    MacKenzie, Kirsteen M; Palmer, Martin R; Moore, Andy; Ibbotson, Anton T; Beaumont, William R C; Poulter, David J S; Trueman, Clive N

    2011-01-01

    Knowing the distribution of marine animals is central to understanding climatic and other environmental influences on population ecology. This information has proven difficult to gain through capture-based methods biased by capture location. Here we show that marine location can be inferred from animal tissues. As the carbon isotope composition of animal tissues varies with sea surface temperature, marine location can be identified by matching time series of carbon isotopes measured in tissues to sea surface temperature records. Applying this technique to populations of Atlantic salmon (Salmo salar L.) produces isotopically-derived maps of oceanic feeding grounds, consistent with the current understanding of salmon migrations, that additionally reveal geographic segregation in feeding grounds between individual philopatric populations and age-classes. Carbon isotope ratios can be used to identify the location of open ocean feeding grounds for any pelagic animals for which tissue archives and matching records of sea surface temperature are available. PMID:22355540

  20. Color preferences revealed by statistical color rendition metric

    NASA Astrophysics Data System (ADS)

    Liu, Anqing; Tuzikas, ArÅ«nas; Žukauskas, ArtÅ«ras; Vaicekauskas, Rimantas; Vitta, Pranciškus; Shur, Michael

    2013-09-01

    The color rendition engine based on the statistical metric allows us to uniquely quantify the characteristics of color quality of illumination and assess the color rendition preferences. We now report on using the color rendition engine for revealing individual and cultural differences in color quality preferences of 205 American and Chinese subjects. Our study demonstrated that the majority of individuals preferred the color blend with the same statistical figures of merit on the average but with a much larger spread of blends for Americans. For both groups, the color rendition preferences depended on the object being illuminated. This was demonstrated by illuminating a set of common colored objects and three different paintings. We conclude that the color quality of lighting can be optimized and enhanced using the feedback to change the spectral power distribution of the illuminating source depending on the object being illuminated and on the preferences of an individual observer and a cultural group.

  1. Proteomic profiling reveals insights into Triticeae stigma development and function.

    PubMed

    Nazemof, Nazila; Couroux, Philippe; Rampitsch, Christof; Xing, Tim; Robert, Laurian S

    2014-11-01

    To our knowledge, this study represents the first high-throughput characterization of a stigma proteome in the Triticeae. A total of 2184 triticale mature stigma proteins were identified using three different gel-based approaches combined with mass spectrometry. The great majority of these proteins are described in a Triticeae stigma for the first time. These results revealed many proteins likely to play important roles in stigma development and pollen-stigma interactions, as well as protection against biotic and abiotic stresses. Quantitative comparison of the triticale stigma transcriptome and proteome showed poor correlation, highlighting the importance of having both types of analysis. This work makes a significant contribution towards the elucidation of the Triticeae stigma proteome and provides novel insights into its role in stigma development and function. PMID:25170101

  2. Insights revealed by rodent models of sugar binge eating.

    PubMed

    Murray, Susan M; Tulloch, Alastair J; Chen, Eunice Y; Avena, Nicole M

    2015-12-01

    Binge eating is seen across the spectrum of eating disorder diagnoses as well as among individuals who do not meet diagnostic criteria. Analyses of the specific types of foods that are frequently binged upon reveal that sugar-rich items feature prominently in binge-type meals, making the effects of binge consumption of sugar an important focus of study. One avenue to do this involves the use of animal models. Foundational and recent studies of animal models of sugar bingeing, both outlined here, lend insight into the various neurotransmitters and neuropeptides that may participate in or be altered by this behavior. Further, several preclinical studies incorporating sugar bingeing paradigms have explored the utility of pharmacological agents that target such neural systems for reducing sugar bingeing in an effort to enhance clinical treatment. Indeed, the translational implications of findings generated using animal models of sugar bingeing are considered here, along with potential avenues for further study. PMID:26510689

  3. Pupillometry reveals reduced unconscious emotional reactivity in autism.

    PubMed

    Nuske, Heather J; Vivanti, Giacomo; Hudry, Kristelle; Dissanayake, Cheryl

    2014-09-01

    Recent theoretical conceptualisations have suggested that emotion processing impairments in autism stem from disruption to the sub-cortical, rapid emotion-processing system. We argue that a clear way to ascertain whether this system is affected in autism is by measuring unconscious emotional reactivity. Using backwards masking, we presented fearful expressions non-consciously (subliminally) as well as consciously (supraliminally), and measured pupillary responses as an index of emotional reactivity in 19 children with autism and 19 typically developing children, aged 2-5 years. The pupillary responses of the children with autism revealed reduced unconscious emotional reactivity, with no group differences on consciously presented emotion. Together, these results indicate a hyporesponsiveness to non-consciously presented emotion suggesting a fundamental difference in emotion processing in autism, which requires consciousness and more time. PMID:25017502

  4. Dramatic changes in electronic structure revealed by fractionally charged nuclei

    SciTech Connect

    Cohen, Aron J.; Mori-Sánchez, Paula

    2014-01-28

    Discontinuous changes in the electronic structure upon infinitesimal changes to the Hamiltonian are demonstrated. These are revealed in one and two electron molecular systems by full configuration interaction (FCI) calculations when the realm of the nuclear charge is extended to be fractional. FCI electron densities in these systems show dramatic changes in real space and illustrate the transfer, hopping, and removal of electrons. This is due to the particle nature of electrons seen in stretched systems and is a manifestation of an energy derivative discontinuity at constant number of electrons. Dramatic errors of density functional theory densities are seen in real space as this physics is missing from currently used approximations. The movements of electrons in these simple systems encapsulate those in real physical processes, from chemical reactions to electron transport and pose a great challenge for the development of new electronic structure methods.

  5. Physical Principles of Skeletal Minerals Revealed with Spectromicroscopy

    ScienceCinema

    Gilbert, Pupa [U of Wisconsin-Madison, Wisconsin, United States

    2010-01-08

    Skeletal elements of marine and terrestrial organisms have the most fascinating nano-to-macro-structures, attracting the attention of physicists, biologists, chemists, and materials scientists. Using X-PEEM spectromicroscopy we revealed some of the fundamental mechanisms leading to the formation of these biominerals. Specifically, we addressed the following questions and provided the answers: 1Q) How do teeth, bones, and echinoderm and mollusk shells acquire their unusual, curved and complex morphology, if they are composed of single crystals? 1A) Via amorphous precursor phases; 2Q) How does crystallinity propagate through the amorophous precursor phases in sea urchin spicules and teeth? 2A) By secondary nucleation, following random walk patterns; 3Q) How does iridescent mother-of-pearl become ordered? 3A) Gradually, through a kinetic mechanisms in which fastest growing single-crystals win the competition for space, thus end up being approximately co-oriented.

  6. Ternary structure reveals mechanism of a membrane diacylglycerol kinase

    SciTech Connect

    Li, Dianfan; Stansfeld, Phillip J.; Sansom, Mark S. P.; Keogh, Aaron; Vogeley, Lutz; Howe, Nicole; Lyons, Joseph A.; Aragao, David; Fromme, Petra; Fromme, Raimund; Basu, Shibom; Grotjohann, Ingo; Kupitz, Christopher; Rendek, Kimberley; Weierstall, Uwe; Zatsepin, Nadia A.; Cherezov, Vadim; Liu, Wei; Bandaru, Sateesh; English, Niall J.; Gati, Cornelius; Barty, Anton; Yefanov, Oleksandr; Chapman, Henry N.; Diederichs, Kay; Messerschmidt, Marc; Boutet, Sébastien; Williams, Garth J.; Marvin Seibert, M.; Caffrey, Martin

    2015-12-17

    Diacylglycerol kinase catalyses the ATP-dependent conversion of diacylglycerol to phosphatidic acid in the plasma membrane of Escherichia coli. The small size of this integral membrane trimer, which has 121 residues per subunit, means that available protein must be used economically to craft three catalytic and substrate-binding sites centred about the membrane/cytosol interface. How nature has accomplished this extraordinary feat is revealed here in a crystal structure of the kinase captured as a ternary complex with bound lipid substrate and an ATP analogue. Residues, identified as essential for activity by mutagenesis, decorate the active site and are rationalized by the ternary structure. The γ-phosphate of the ATP analogue is positioned for direct transfer to the primary hydroxyl of the lipid whose acyl chain is in the membrane. A catalytic mechanism for this unique enzyme is proposed. As a result, the active site architecture shows clear evidence of having arisen by convergent evolution.

  7. Divergence of multimodular polyketide synthases revealed by a didomain structure.

    PubMed

    Zheng, Jianting; Gay, Darren C; Demeler, Borries; White, Mark A; Keatinge-Clay, Adrian T

    2012-07-01

    The enoylreductase (ER) is the final common enzyme from modular polyketide synthases (PKSs) to be structurally characterized. The 3.0 Å-resolution structure of the didomain comprising the ketoreductase (KR) and ER from the second module of the spinosyn PKS reveals that ER shares an ∼600-Å(2) interface with KR distinct from that of the related mammalian fatty acid synthase (FAS). In contrast to the ER domains of the mammalian FAS, the ER domains of the second module of the spinosyn PKS do not make contact across the two-fold axis of the synthase. This monomeric organization may have been necessary in the evolution of multimodular PKSs to enable acyl carrier proteins to access each of their cognate enzymes. The isolated ER domain showed activity toward a substrate analog, enabling us to determine the contributions of its active site residues. PMID:22634636

  8. Divergence of multimodular polyketide synthases revealed by a didomain structure

    PubMed Central

    Zheng, Jianting; Gay, Darren C.; Demeler, Borries; White, Mark A.; Keatinge-Clay, Adrian T.

    2012-01-01

    The enoylreductase (ER) is the final common enzyme from modular polyketide synthases (PKSs) to be structurally characterized. The 3.0 Å resolution structure of the didomain comprised of the ketoreductase (KR) and ER from the second module of the spinosyn PKS reveals that ER shares an ~600 Å2 interface with KR distinct from that of the related mammalian fatty acid synthase (FAS). In contrast to the ER domains of the mammalian FAS, the ER domains of the second module of the spinosyn PKS do not make contact across the twofold axis of the synthase. This monomeric organization may have been necessary in the evolution of multimodular PKSs to enable acyl carrier proteins (ACPs) to access each of their cognate enzymes. The isolated ER domain showed activity towards a substrate analog, enabling the contributions of its active site residues to be determined. PMID:22634636

  9. Structure of plant photosystem I revealed by theoretical modeling.

    PubMed

    Jolley, Craig; Ben-Shem, Adam; Nelson, Nathan; Fromme, Petra

    2005-09-30

    Photosystem (PS) I is a large membrane protein complex vital for oxygenic photosynthesis, one of the most important biological processes on the planet. We present an "atomic" model of higher plant PSI, based on theoretical modeling using the recent 4.4 angstroms x-ray crystal structure of PSI from pea. Because of the lack of information on the amino acid side chains in the x-ray structural model and the high cofactor content in this system, novel modeling techniques were developed. Our model reveals some important structural features of plant PSI that were not visible in the crystal structure, and our model sheds light on the evolutionary relationship between plant and cyanobacterial PSI. PMID:15955818

  10. Synthetic protein interactions reveal a functional map of the cell

    PubMed Central

    Berry, Lisa K; Ólafsson, Guðjón; Ledesma-Fernández, Elena; Thorpe, Peter H

    2016-01-01

    To understand the function of eukaryotic cells, it is critical to understand the role of protein-protein interactions and protein localization. Currently, we do not know the importance of global protein localization nor do we understand to what extent the cell is permissive for new protein associations – a key requirement for the evolution of new protein functions. To answer this question, we fused every protein in the yeast Saccharomyces cerevisiae with a partner from each of the major cellular compartments and quantitatively assessed the effects upon growth. This analysis reveals that cells have a remarkable and unanticipated tolerance for forced protein associations, even if these associations lead to a proportion of the protein moving compartments within the cell. Furthermore, the interactions that do perturb growth provide a functional map of spatial protein regulation, identifying key regulatory complexes for the normal homeostasis of eukaryotic cells. DOI: http://dx.doi.org/10.7554/eLife.13053.001 PMID:27098839

  11. Anisotropic MRI contrast reveals enhanced ionic transport in plastic crystals.

    PubMed

    Romanenko, Konstantin; Jin, Liyu; Madsen, Louis A; Pringle, Jennifer M; O'Dell, Luke A; Forsyth, Maria

    2014-11-01

    Organic ionic plastic crystals (OIPCs) are attractive as solid-state electrolytes for electrochemical devices such as lithium-ion batteries and solar and fuel cells. OIPCs offer high ionic conductivity, nonflammability, and versatility of molecular design. Nevertheless, intrinsic ion transport behavior of OIPCs is not fully understood, and their measured properties depend heavily on thermal history. Solid-state magnetic resonance imaging experiments reveal a striking image contrast anisotropy sensitive to the orientation of grain boundaries in polycrystalline OIPCs. Probing triethyl(methyl)phosphonium bis(fluorosulfonyl)imide (P1222FSI) samples with different thermal history demonstrates vast variations in microcrystallite alignment. Upon slow cooling from the melt, microcrystallites exhibit a preferred orientation throughout the entire sample, leading to an order of magnitude increase in conductivity as probed using impedance spectroscopy. This investigation describes both a new conceptual window and a new characterization method for understanding polycrystalline domain structure and transport in plastic crystals and other solid-state conductors. PMID:25312993

  12. Mathematical Analysis of Biomolecular Network Reveals Connections Between Diseases

    NASA Astrophysics Data System (ADS)

    Wang, Guanyu

    2012-02-01

    Connections between cancer and metabolic diseases may consist in the complex network of interactions among a common set of biomolecules. By applying singularity and bifurcation analysis, the phenotypes constrained by the AKT signaling pathway are identified and mapped onto the parameter space, which include cancer and certain metabolic diseases. By considering physiologic properties (sensitivity, robustness and adaptivity) the AKT pathway must possess in order to efficiently sense growth factors and nutrients, the region of normal responses is located. The analysis illuminates the parameter space and reveals system-level mechanisms in regulating biological functions (cell growth, survival, proliferation and metabolism) and how their deregulation may lead to the development of diseases. The analytical expressions summarize the synergistic interactions among many molecules, which provides valuable insights into therapeutic interventions.

  13. Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes

    PubMed Central

    Chen, Rui; Mias, George I.; Li-Pook-Than, Jennifer; Jiang, Lihua; Lam, Hugo Y. K.; Chen, Rong; Miriami, Elana; Karczewski, Konrad J.; Hariharan, Manoj; Dewey, Frederick E.; Cheng, Yong; Clark, Michael J.; Im, Hogune; Habegger, Lukas; Balasubramanian, Suganthi; O'Huallachain, Maeve; Dudley, Joel T.; Hillenmeyer, Sara; Haraksingh, Rajini; Sharon, Donald; Euskirchen, Ghia; Lacroute, Phil; Bettinger, Keith; Boyle, Alan P.; Kasowski, Maya; Grubert, Fabian; Seki, Scott; Garcia, Marco; Whirl-Carrillo, Michelle; Gallardo, Mercedes; Blasco, Maria A.; Greenberg, Peter L.; Snyder, Phyllis; Klein, Teri E.; Altman, Russ B.; Butte, Atul; Ashley, Euan A.; Nadeau, Kari C.; Gerstein, Mark; Tang, Hua; Snyder, Michael

    2012-01-01

    SUMMARY Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here we present an integrative Personal Omics Profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14-month period. Our iPOP analysis revealed various medical risks, including Type II diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high coverage genomic and transcriptomic data, which provide the basis of our iPOP, discovered extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and disease states by connecting genomic information with additional dynamic omics activity. PMID:22424236

  14. Geophysical imaging reveals topographic stress control of bedrock weathering.

    PubMed

    St Clair, J; Moon, S; Holbrook, W S; Perron, J T; Riebe, C S; Martel, S J; Carr, B; Harman, C; Singha, K; Richter, D deB

    2015-10-30

    Bedrock fracture systems facilitate weathering, allowing fresh mineral surfaces to interact with corrosive waters and biota from Earth's surface, while simultaneously promoting drainage of chemically equilibrated fluids. We show that topographic perturbations to regional stress fields explain bedrock fracture distributions, as revealed by seismic velocity and electrical resistivity surveys from three landscapes. The base of the fracture-rich zone mirrors surface topography where the ratio of horizontal compressive tectonic stresses to near-surface gravitational stresses is relatively large, and it parallels the surface topography where the ratio is relatively small. Three-dimensional stress calculations predict these results, suggesting that tectonic stresses interact with topography to influence bedrock disaggregation, groundwater flow, chemical weathering, and the depth of the "critical zone" in which many biogeochemical processes occur. PMID:26516279

  15. Hybridization Reveals the Evolving Genomic Architecture of Speciation

    PubMed Central

    Kronforst, Marcus R.; Hansen, Matthew E.B.; Crawford, Nicholas G.; Gallant, Jason R.; Zhang, Wei; Kulathinal, Rob J.; Kapan, Durrell D.; Mullen, Sean P.

    2014-01-01

    SUMMARY The rate at which genomes diverge during speciation is unknown, as are the physical dynamics of the process. Here, we compare full genome sequences of 32 butterflies, representing five species from a hybridizing Heliconius butterfly community, to examine genome-wide patterns of introgression and infer how divergence evolves during the speciation process. Our analyses reveal that initial divergence is restricted to a small fraction of the genome, largely clustered around known wing-patterning genes. Over time, divergence evolves rapidly, due primarily to the origin of new divergent regions. Furthermore, divergent genomic regions display signatures of both selection and adaptive introgression, demonstrating the link between microevolutionary processes acting within species and the origin of species across macroevolutionary timescales. Our results provide a uniquely comprehensive portrait of the evolving species boundary due to the role that hybridization plays in reducing the background accumulation of divergence at neutral sites. PMID:24183670

  16. Oscillatory Enzyme Dynamics Revealed by Two-Dimensional Infrared Spectroscopy.

    PubMed

    Pagano, Philip; Guo, Qi; Kohen, Amnon; Cheatum, Christopher M

    2016-07-01

    Enzymes move on a variety of length and time scales. While much is known about large structural fluctuations that impact binding of the substrates and release of products, little is known about faster motions of enzymes and how these motions may influence enzyme-catalyzed reactions. This Letter reports frequency fluctuations of the azide anion bound to the active site of formate dehydrogenase measured via 2D IR spectroscopy. These measurements reveal an underdamped oscillatory component to the frequency-frequency correlation function when the azide is bound to the NAD(+) ternary complex. This oscillation disappears when the reduced cofactor is added, indicating that the oscillating contributions most likely come from the charged nicotinamide ring. These oscillatory motions may be relevant to donor-acceptor distance sampling of the catalyzed hydride transfer and therefore may give future insights into the dynamic behavior involved in enzyme catalysis. PMID:27305279

  17. Macrophage characteristics of stem cells revealed by transcriptome profiling

    SciTech Connect

    Charriere, Guillaume M.; Cousin, Beatrice; Arnaud, Emmanuelle; Saillan-Barreau, Corinne; Andre, Mireille; Massoudi, Ali; Dani, Christian; Penicaud, Luc; Casteilla, Louis . E-mail: casteil@toulouse.inserm.fr

    2006-10-15

    We previously showed that the phenotypes of adipocyte progenitors and macrophages were close. Using functional analyses and microarray technology, we first tested whether this intriguing relationship was specific to adipocyte progenitors or could be shared with other progenitors. Measurements of phagocytic activity and gene profiling analysis of different progenitor cells revealed that the latter hypothesis should be retained. These results encouraged us to pursue and to confirm our analysis with a gold-standard stem cell population, embryonic stem cells or ESC. The transcriptomic profiles of ESC and macrophages were clustered together, unlike differentiated ESC. In addition, undifferentiated ESC displayed higher phagocytic activity than other progenitors, and they could phagocytoze apoptotic bodies. These data suggest that progenitors and stem cells share some characteristics of macrophages. This opens new perspectives on understanding stem cell phenotype and functionalities such as a putative role of stem cells in tissue remodeling by discarding dead cells but also their immunomodulation or fusion properties.

  18. Inheritance Patterns in Citation Networks Reveal Scientific Memes

    NASA Astrophysics Data System (ADS)

    Kuhn, Tobias; Perc, Matjaž; Helbing, Dirk

    2014-10-01

    Memes are the cultural equivalent of genes that spread across human culture by means of imitation. What makes a meme and what distinguishes it from other forms of information, however, is still poorly understood. Our analysis of memes in the scientific literature reveals that they are governed by a surprisingly simple relationship between frequency of occurrence and the degree to which they propagate along the citation graph. We propose a simple formalization of this pattern and validate it with data from close to 50 million publication records from the Web of Science, PubMed Central, and the American Physical Society. Evaluations relying on human annotators, citation network randomizations, and comparisons with several alternative approaches confirm that our formula is accurate and effective, without a dependence on linguistic or ontological knowledge and without the application of arbitrary thresholds or filters.

  19. Central tolerance to self revealed by the autoimmune regulator.

    PubMed

    Chan, Alice Y; Anderson, Mark S

    2015-11-01

    The autoimmune regulator (Aire) was initially identified as the gene causing multiorgan system autoimmunity in humans, and deletion of this gene in mice also resulted in organ-specific autoimmunity. Aire regulates the expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), which play a critical role in the negative selection of autoreactive T cells and the generation of regulatory T cells. More recently, the role of Aire in the development of mTECs has helped elucidate its ability to present the spectrum of TSAs needed to prevent autoimmunity. Molecular characterization of the functional domains of Aire has revealed multiple binding partners that assist Aire's function in altering gene transcription and chromatin remodeling. These recent advances have further highlighted the importance of Aire in central tolerance. PMID:26579596

  20. [Hodgkin disease revealed by a nephrotic syndrome: A case report].

    PubMed

    Cheptou, M; Pichault, V; Campagni, R; Vodoff, M-V; Fischbach, M; Paillard, C

    2015-12-01

    Pediatric nephrotic syndrome (NS) is most often idiopathic or primary but in rare cases, it can be secondary to neoplasia. We report on a case of steroid-resistant NS revealing as a paraneoplastic syndrome of Hodgkin disease (HD) in a 12-year-old boy. The onset of the NS can be earlier, later, or simultaneous to the HD. Treatment of the lymphoma allows the disappearance of the NS. In the case we observed, the diagnosis of HD was delayed because HD presented with an isolated, hilar adenopathy in the absence of retroperitoneal or peripheral locations. In children aged 10 years or more presenting with NS, steroid-resistant or otherwise, a possible paraneoplastic origin such as Hodgkin lymphoma should always be taken into consideration and eventually eliminated. PMID:26598043

  1. Biosensor reveals multiple sources for mitochondrial NAD⁺.

    PubMed

    Cambronne, Xiaolu A; Stewart, Melissa L; Kim, DongHo; Jones-Brunette, Amber M; Morgan, Rory K; Farrens, David L; Cohen, Michael S; Goodman, Richard H

    2016-06-17

    Nicotinamide adenine dinucleotide (NAD(+)) is an essential substrate for sirtuins and poly(adenosine diphosphate-ribose) polymerases (PARPs), which are NAD(+)-consuming enzymes localized in the nucleus, cytosol, and mitochondria. Fluctuations in NAD(+) concentrations within these subcellular compartments are thought to regulate the activity of NAD(+)-consuming enzymes; however, the challenge in measuring compartmentalized NAD(+) in cells has precluded direct evidence for this type of regulation. We describe the development of a genetically encoded fluorescent biosensor for directly monitoring free NAD(+) concentrations in subcellular compartments. We found that the concentrations of free NAD(+) in the nucleus, cytoplasm, and mitochondria approximate the Michaelis constants for sirtuins and PARPs in their respective compartments. Systematic depletion of enzymes that catalyze the final step of NAD(+) biosynthesis revealed cell-specific mechanisms for maintaining mitochondrial NAD(+) concentrations. PMID:27313049

  2. Quasisoft X-ray Sources: their physical natures revealed

    NASA Astrophysics Data System (ADS)

    Di Stefano, Rosanne; Primini, Francis A.; Guo, Jincheng; Liu, Jifeng

    2016-04-01

    Quasisoft X-ray sources (QSSs) have been the Mona Lisa of X-ray sources. They have remained enigmatic, even though we have known of their existence and basic properties for more than a decade. QSSs have X-ray luminosities greater than 10^{36} erg/s, but emit few or no photons above 2 keV. They were discovered in external galaxies during searches for softer sources, supersoft X-ray sources (SSSs). Every external galaxy contains QSSs, but it has been challenging to find any in the Milky Way and the Magellanic Clouds. Recent work, however, reveals that a significant fraction of QSSs may be black holes. We review what is known about QSSs to date, because this obscure class of objects may at last to be ready for "prime time'', capable of identifying BHs in a wide range of Galactic environments.

  3. Comparative genomics reveals insights into avian genome evolution and adaptation

    PubMed Central

    Zhang, Guojie; Li, Cai; Li, Qiye; Li, Bo; Larkin, Denis M.; Lee, Chul; Storz, Jay F.; Antunes, Agostinho; Greenwold, Matthew J.; Meredith, Robert W.; Ödeen, Anders; Cui, Jie; Zhou, Qi; Xu, Luohao; Pan, Hailin; Wang, Zongji; Jin, Lijun; Zhang, Pei; Hu, Haofu; Yang, Wei; Hu, Jiang; Xiao, Jin; Yang, Zhikai; Liu, Yang; Xie, Qiaolin; Yu, Hao; Lian, Jinmin; Wen, Ping; Zhang, Fang; Li, Hui; Zeng, Yongli; Xiong, Zijun; Liu, Shiping; Zhou, Long; Huang, Zhiyong; An, Na; Wang, Jie; Zheng, Qiumei; Xiong, Yingqi; Wang, Guangbiao; Wang, Bo; Wang, Jingjing; Fan, Yu; da Fonseca, Rute R.; Alfaro-Núñez, Alonzo; Schubert, Mikkel; Orlando, Ludovic; Mourier, Tobias; Howard, Jason T.; Ganapathy, Ganeshkumar; Pfenning, Andreas; Whitney, Osceola; Rivas, Miriam V.; Hara, Erina; Smith, Julia; Farré, Marta; Narayan, Jitendra; Slavov, Gancho; Romanov, Michael N; Borges, Rui; Machado, João Paulo; Khan, Imran; Springer, Mark S.; Gatesy, John; Hoffmann, Federico G.; Opazo, Juan C.; Håstad, Olle; Sawyer, Roger H.; Kim, Heebal; Kim, Kyu-Won; Kim, Hyeon Jeong; Cho, Seoae; Li, Ning; Huang, Yinhua; Bruford, Michael W.; Zhan, Xiangjiang; Dixon, Andrew; Bertelsen, Mads F.; Derryberry, Elizabeth; Warren, Wesley; Wilson, Richard K; Li, Shengbin; Ray, David A.; Green, Richard E.; O’Brien, Stephen J.; Griffin, Darren; Johnson, Warren E.; Haussler, David; Ryder, Oliver A.; Willerslev, Eske; Graves, Gary R.; Alström, Per; Fjeldså, Jon; Mindell, David P.; Edwards, Scott V.; Braun, Edward L.; Rahbek, Carsten; Burt, David W.; Houde, Peter; Zhang, Yong; Yang, Huanming; Wang, Jian; Jarvis, Erich D.; Gilbert, M. Thomas P.; Wang, Jun

    2015-01-01

    Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits. PMID:25504712

  4. Structural characterization of human heparanase reveals insights into substrate recognition.

    PubMed

    Wu, Liang; Viola, Cristina M; Brzozowski, Andrzej M; Davies, Gideon J

    2015-12-01

    Heparan sulfate (HS) is a glycosaminoglycan that forms a key component of the extracellular matrix (ECM). Breakdown of HS is carried out by heparanase (HPSE), an endo-β-glucuronidase of the glycoside hydrolase 79 (GH79) family. Overexpression of HPSE results in breakdown of extracellular HS and release of stored growth factors and hence is strongly linked to cancer metastasis. Here we present crystal structures of human HPSE at 1.6-Å to 1.9-Å resolution that reveal how an endo-acting binding cleft is exposed by proteolytic activation of latent proHPSE. We used oligosaccharide complexes to map the substrate-binding and sulfate-recognition motifs. These data shed light on the structure and interactions of a key enzyme involved in ECM maintenance and provide a starting point for the design of HPSE inhibitors for use as biochemical tools and anticancer therapeutics. PMID:26575439

  5. Spring-Block Model Reveals Region-Like Structures

    PubMed Central

    Máté, Gabriell; Néda, Zoltán; Benedek, József

    2011-01-01

    A mechanical spring-block model is used for realizing an objective space partition of settlements from a geographic territory in region-like structures. The method is based on the relaxation-dynamics of the spring-block system and reveals in a hierarchical manner region-like entities at different spatial scales. It takes into account in an elegant manner both the spatiality of the elements and the connectivity relations among them. Spatiality is taken into account by using the geographic coordinates of the settlements, and by detecting the neighbors with the help of a Delaunay triangulation. Connectivity between neighboring settlements are quantified using a Pearson-like correlation for the relative variation of a relevant socio-economic parameter (population size, GDP, tax payed per inhabitant, etc.). The method is implemented in an interactive JAVA application and it is applied with success for an artificially generated society and for the case of USA, Hungary and Transylvania. PMID:21346819

  6. Silk protein aggregation kinetics revealed by Rheo-IR.

    PubMed

    Boulet-Audet, Maxime; Terry, Ann E; Vollrath, Fritz; Holland, Chris

    2014-02-01

    The remarkable mechanical properties of silk fibres stem from a multi-scale hierarchical structure created when an aqueous protein "melt" is converted to an insoluble solid via flow. To directly relate a silk protein's structure and function in response to flow, we present the first application of a Rheo-IR platform, which couples cone and plate rheology with attenuated total reflectance infrared spectroscopy. This technique provides a new window into silk processing by linking shear thinning to an increase in molecular alignment, with shear thickening affecting changes in the silk protein's secondary structure. Additionally, compared to other static characterization methods for silk, Rheo-IR proved particularly useful at revealing the intrinsic difference between natural (native) and reconstituted silk feedstocks. Hence Rheo-IR offers important novel insights into natural silk processing. This has intrinsic academic merit, but it might also be useful when designing reconstituted silk analogues alongside other polymeric systems, whether natural or synthetic. PMID:24200713

  7. MNase titration reveals differences between nucleosome occupancy and chromatin accessibility

    PubMed Central

    Mieczkowski, Jakub; Cook, April; Bowman, Sarah K.; Mueller, Britta; Alver, Burak H.; Kundu, Sharmistha; Deaton, Aimee M.; Urban, Jennifer A.; Larschan, Erica; Park, Peter J.; Kingston, Robert E.; Tolstorukov, Michael Y.

    2016-01-01

    Chromatin accessibility plays a fundamental role in gene regulation. Nucleosome placement, usually measured by quantifying protection of DNA from enzymatic digestion, can regulate accessibility. We introduce a metric that uses micrococcal nuclease (MNase) digestion in a novel manner to measure chromatin accessibility by combining information from several digests of increasing depths. This metric, MACC (MNase accessibility), quantifies the inherent heterogeneity of nucleosome accessibility in which some nucleosomes are seen preferentially at high MNase and some at low MNase. MACC interrogates each genomic locus, measuring both nucleosome location and accessibility in the same assay. MACC can be performed either with or without a histone immunoprecipitation step, and thereby compares histone and non-histone protection. We find that changes in accessibility at enhancers, promoters and other regulatory regions do not correlate with changes in nucleosome occupancy. Moreover, high nucleosome occupancy does not necessarily preclude high accessibility, which reveals novel principles of chromatin regulation. PMID:27151365

  8. Stochastic heart-rate model can reveal pathologic cardiac dynamics

    NASA Astrophysics Data System (ADS)

    Kuusela, Tom

    2004-03-01

    A simple one-dimensional Langevin-type stochastic difference equation can simulate the heart-rate fluctuations in a time scale from minutes to hours. The model consists of a deterministic nonlinear part and a stochastic part typical of Gaussian noise, and both parts can be directly determined from measured heart-rate data. Data from healthy subjects typically exhibit the deterministic part with two or more stable fixed points. Studies of 15 congestive heart-failure subjects reveal that the deterministic part of pathologic heart dynamics has no clear stable fixed points. Direct simulations of the stochastic model for normal and pathologic cases can produce statistical parameters similar to those of real subjects. Results directly indicate that pathologic situations simplify the heart-rate control system.

  9. Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.

    PubMed

    Drake, Justin M; Paull, Evan O; Graham, Nicholas A; Lee, John K; Smith, Bryan A; Titz, Bjoern; Stoyanova, Tanya; Faltermeier, Claire M; Uzunangelov, Vladislav; Carlin, Daniel E; Fleming, Daniel Teo; Wong, Christopher K; Newton, Yulia; Sudha, Sud; Vashisht, Ajay A; Huang, Jiaoti; Wohlschlegel, James A; Graeber, Thomas G; Witte, Owen N; Stuart, Joshua M

    2016-08-11

    We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here, we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that shed light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients. PMID:27499020

  10. Ternary structure reveals mechanism of a membrane diacylglycerol kinase

    PubMed Central

    Li, Dianfan; Stansfeld, Phillip J.; Sansom, Mark S. P.; Keogh, Aaron; Vogeley, Lutz; Howe, Nicole; Lyons, Joseph A.; Aragao, David; Fromme, Petra; Fromme, Raimund; Basu, Shibom; Grotjohann, Ingo; Kupitz, Christopher; Rendek, Kimberley; Weierstall, Uwe; Zatsepin, Nadia A.; Cherezov, Vadim; Liu, Wei; Bandaru, Sateesh; English, Niall J.; Gati, Cornelius; Barty, Anton; Yefanov, Oleksandr; Chapman, Henry N.; Diederichs, Kay; Messerschmidt, Marc; Boutet, Sébastien; Williams, Garth J.; Marvin Seibert, M.; Caffrey, Martin

    2015-01-01

    Diacylglycerol kinase catalyses the ATP-dependent conversion of diacylglycerol to phosphatidic acid in the plasma membrane of Escherichia coli. The small size of this integral membrane trimer, which has 121 residues per subunit, means that available protein must be used economically to craft three catalytic and substrate-binding sites centred about the membrane/cytosol interface. How nature has accomplished this extraordinary feat is revealed here in a crystal structure of the kinase captured as a ternary complex with bound lipid substrate and an ATP analogue. Residues, identified as essential for activity by mutagenesis, decorate the active site and are rationalized by the ternary structure. The γ-phosphate of the ATP analogue is positioned for direct transfer to the primary hydroxyl of the lipid whose acyl chain is in the membrane. A catalytic mechanism for this unique enzyme is proposed. The active site architecture shows clear evidence of having arisen by convergent evolution. PMID:26673816

  11. Microstructure of subretinal drusenoid deposits revealed by adaptive optics imaging.

    PubMed

    Meadway, Alexander; Wang, Xiaolin; Curcio, Christine A; Zhang, Yuhua

    2014-03-01

    Subretinal drusenoid deposits (SDD), a recently recognized lesion associated with progression of age-related macular degeneration, were imaged with adaptive optics scanning laser ophthalmoscopy (AO-SLO) and optical coherence tomography (AO-OCT). AO-SLO revealed a distinct en face structure of stage 3 SDD, showing a hyporeflective annulus surrounded reflective core packed with hyperreflective dots bearing a superficial similarity to the photoreceptors in the unaffected retina. However, AO-OCT suggested that the speckled appearance over the SDD rendered by AO-SLO was the lesion material itself, rather than photoreceptors. AO-OCT assists proper interpretation and understanding of the SDD structure and the lesions' impact on surrounding photoreceptors produced by AO-SLO and vice versa. PMID:24688808

  12. Surprise maximization reveals the community structure of complex networks

    NASA Astrophysics Data System (ADS)

    Aldecoa, Rodrigo; Marín, Ignacio

    2013-01-01

    How to determine the community structure of complex networks is an open question. It is critical to establish the best strategies for community detection in networks of unknown structure. Here, using standard synthetic benchmarks, we show that none of the algorithms hitherto developed for community structure characterization perform optimally. Significantly, evaluating the results according to their modularity, the most popular measure of the quality of a partition, systematically provides mistaken solutions. However, a novel quality function, called Surprise, can be used to elucidate which is the optimal division into communities. Consequently, we show that the best strategy to find the community structure of all the networks examined involves choosing among the solutions provided by multiple algorithms the one with the highest Surprise value. We conclude that Surprise maximization precisely reveals the community structure of complex networks.

  13. Surprise maximization reveals the community structure of complex networks.

    PubMed

    Aldecoa, Rodrigo; Marín, Ignacio

    2013-01-01

    How to determine the community structure of complex networks is an open question. It is critical to establish the best strategies for community detection in networks of unknown structure. Here, using standard synthetic benchmarks, we show that none of the algorithms hitherto developed for community structure characterization perform optimally. Significantly, evaluating the results according to their modularity, the most popular measure of the quality of a partition, systematically provides mistaken solutions. However, a novel quality function, called Surprise, can be used to elucidate which is the optimal division into communities. Consequently, we show that the best strategy to find the community structure of all the networks examined involves choosing among the solutions provided by multiple algorithms the one with the highest Surprise value. We conclude that Surprise maximization precisely reveals the community structure of complex networks. PMID:23320141

  14. Early MAVEN Deep Dip campaign reveals thermosphere and ionosphere variability.

    PubMed

    Bougher, S; Jakosky, B; Halekas, J; Grebowsky, J; Luhmann, J; Mahaffy, P; Connerney, J; Eparvier, F; Ergun, R; Larson, D; McFadden, J; Mitchell, D; Schneider, N; Zurek, R; Mazelle, C; Andersson, L; Andrews, D; Baird, D; Baker, D N; Bell, J M; Benna, M; Brain, D; Chaffin, M; Chamberlin, P; Chaufray, J-Y; Clarke, J; Collinson, G; Combi, M; Crary, F; Cravens, T; Crismani, M; Curry, S; Curtis, D; Deighan, J; Delory, G; Dewey, R; DiBraccio, G; Dong, C; Dong, Y; Dunn, P; Elrod, M; England, S; Eriksson, A; Espley, J; Evans, S; Fang, X; Fillingim, M; Fortier, K; Fowler, C M; Fox, J; Gröller, H; Guzewich, S; Hara, T; Harada, Y; Holsclaw, G; Jain, S K; Jolitz, R; Leblanc, F; Lee, C O; Lee, Y; Lefevre, F; Lillis, R; Livi, R; Lo, D; Ma, Y; Mayyasi, M; McClintock, W; McEnulty, T; Modolo, R; Montmessin, F; Morooka, M; Nagy, A; Olsen, K; Peterson, W; Rahmati, A; Ruhunusiri, S; Russell, C T; Sakai, S; Sauvaud, J-A; Seki, K; Steckiewicz, M; Stevens, M; Stewart, A I F; Stiepen, A; Stone, S; Tenishev, V; Thiemann, E; Tolson, R; Toublanc, D; Vogt, M; Weber, T; Withers, P; Woods, T; Yelle, R

    2015-11-01

    The Mars Atmosphere and Volatile Evolution (MAVEN) mission, during the second of its Deep Dip campaigns, made comprehensive measurements of martian thermosphere and ionosphere composition, structure, and variability at altitudes down to ~130 kilometers in the subsolar region. This altitude range contains the diffusively separated upper atmosphere just above the well-mixed atmosphere, the layer of peak extreme ultraviolet heating and primary reservoir for atmospheric escape. In situ measurements of the upper atmosphere reveal previously unmeasured populations of neutral and charged particles, the homopause altitude at approximately 130 kilometers, and an unexpected level of variability both on an orbit-to-orbit basis and within individual orbits. These observations help constrain volatile escape processes controlled by thermosphere and ionosphere structure and variability. PMID:26542579

  15. Ternary structure reveals mechanism of a membrane diacylglycerol kinase

    NASA Astrophysics Data System (ADS)

    Li, Dianfan; Stansfeld, Phillip J.; Sansom, Mark S. P.; Keogh, Aaron; Vogeley, Lutz; Howe, Nicole; Lyons, Joseph A.; Aragao, David; Fromme, Petra; Fromme, Raimund; Basu, Shibom; Grotjohann, Ingo; Kupitz, Christopher; Rendek, Kimberley; Weierstall, Uwe; Zatsepin, Nadia A.; Cherezov, Vadim; Liu, Wei; Bandaru, Sateesh; English, Niall J.; Gati, Cornelius; Barty, Anton; Yefanov, Oleksandr; Chapman, Henry N.; Diederichs, Kay; Messerschmidt, Marc; Boutet, Sébastien; Williams, Garth J.; Marvin Seibert, M.; Caffrey, Martin

    2015-12-01

    Diacylglycerol kinase catalyses the ATP-dependent conversion of diacylglycerol to phosphatidic acid in the plasma membrane of Escherichia coli. The small size of this integral membrane trimer, which has 121 residues per subunit, means that available protein must be used economically to craft three catalytic and substrate-binding sites centred about the membrane/cytosol interface. How nature has accomplished this extraordinary feat is revealed here in a crystal structure of the kinase captured as a ternary complex with bound lipid substrate and an ATP analogue. Residues, identified as essential for activity by mutagenesis, decorate the active site and are rationalized by the ternary structure. The γ-phosphate of the ATP analogue is positioned for direct transfer to the primary hydroxyl of the lipid whose acyl chain is in the membrane. A catalytic mechanism for this unique enzyme is proposed. The active site architecture shows clear evidence of having arisen by convergent evolution.

  16. Early MAVEN Deep Dip campaign reveals thermosphere and ionosphere variability

    NASA Astrophysics Data System (ADS)

    Bougher, S.; Jakosky, B.; Halekas, J.; Grebowsky, J.; Luhmann, J.; Mahaffy, P.; Connerney, J.; Eparvier, F.; Ergun, R.; Larson, D.; McFadden, J.; Mitchell, D.; Schneider, N.; Zurek, R.; Mazelle, C.; Andersson, L.; Andrews, D.; Baird, D.; Baker, D. N.; Bell, J. M.; Benna, M.; Brain, D.; Chaffin, M.; Chamberlin, P.; Chaufray, J.-Y.; Clarke, J.; Collinson, G.; Combi, M.; Crary, F.; Cravens, T.; Crismani, M.; Curry, S.; Curtis, D.; Deighan, J.; Delory, G.; Dewey, R.; DiBraccio, G.; Dong, C.; Dong, Y.; Dunn, P.; Elrod, M.; England, S.; Eriksson, A.; Espley, J.; Evans, S.; Fang, X.; Fillingim, M.; Fortier, K.; Fowler, C. M.; Fox, J.; Gröller, H.; Guzewich, S.; Hara, T.; Harada, Y.; Holsclaw, G.; Jain, S. K.; Jolitz, R.; Leblanc, F.; Lee, C. O.; Lee, Y.; Lefevre, F.; Lillis, R.; Livi, R.; Lo, D.; Ma, Y.; Mayyasi, M.; McClintock, W.; McEnulty, T.; Modolo, R.; Montmessin, F.; Morooka, M.; Nagy, A.; Olsen, K.; Peterson, W.; Rahmati, A.; Ruhunusiri, S.; Russell, C. T.; Sakai, S.; Sauvaud, J.-A.; Seki, K.; Steckiewicz, M.; Stevens, M.; Stewart, A. I. F.; Stiepen, A.; Stone, S.; Tenishev, V.; Thiemann, E.; Tolson, R.; Toublanc, D.; Vogt, M.; Weber, T.; Withers, P.; Woods, T.; Yelle, R.

    2015-11-01

    The Mars Atmosphere and Volatile Evolution (MAVEN) mission, during the second of its Deep Dip campaigns, made comprehensive measurements of martian thermosphere and ionosphere composition, structure, and variability at altitudes down to ~130 kilometers in the subsolar region. This altitude range contains the diffusively separated upper atmosphere just above the well-mixed atmosphere, the layer of peak extreme ultraviolet heating and primary reservoir for atmospheric escape. In situ measurements of the upper atmosphere reveal previously unmeasured populations of neutral and charged particles, the homopause altitude at approximately 130 kilometers, and an unexpected level of variability both on an orbit-to-orbit basis and within individual orbits. These observations help constrain volatile escape processes controlled by thermosphere and ionosphere structure and variability.

  17. Silicon-wafer-surface damage revealed by surface photovoltage measurements

    NASA Astrophysics Data System (ADS)

    Goodman, Alvin M.

    1982-11-01

    Anomalous results of surface photovoltage (SPV) measurements on Si wafers are shown to be associated with a damaged region beneath the illuminated surface of the wafer being measured. The anomaly is a concave-upward curvature of the I0(α-1) plot with an r2 value, derived from linear regression analysis, less than the normally observed minimum value (˜0.98). Removal of the damaged region by an appropriate etching procedure allows subsequent SPV measurements whose results are substantially free of the previously observed anomaly. The qualitative character of the anomaly can be reproduced by a simple theoretical model in which only one effect of the damage is considered; this effect is a diminished quantum efficiency for hole-electron pair generation by photon absorption in the damaged region. The results suggest the use of SPV measurements as a test procedure for revealing the presence of surface damage in Si wafers.

  18. Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium

    PubMed Central

    Ma, Li-Jun; van der Does, H. Charlotte; Borkovich, Katherine A.; Coleman, Jeffrey J.; Daboussi, Marie-Josée; Di Pietro, Antonio; Dufresne, Marie; Freitag, Michael; Grabherr, Manfred; Henrissat, Bernard; Houterman, Petra M.; Kang, Seogchan; Shim, Won-Bo; Woloshuk, Charles; Xie, Xiaohui; Xu, Jin-Rong; Antoniw, John; Baker, Scott E.; Bluhm, Burton H.; Breakspear, Andrew; Brown, Daren W.; Butchko, Robert A. E.; Chapman, Sinead; Coulson, Richard; Coutinho, Pedro M.; Danchin, Etienne G. J.; Diener, Andrew; Gale, Liane R.; Gardiner, Donald M.; Goff, Stephen; Hammond-Kosack, Kim E.; Hilburn, Karen; Hua-Van, Aurélie; Jonkers, Wilfried; Kazan, Kemal; Kodira, Chinnappa D.; Koehrsen, Michael; Kumar, Lokesh; Lee, Yong-Hwan; Li, Liande; Manners, John M.; Miranda-Saavedra, Diego; Mukherjee, Mala; Park, Gyungsoon; Park, Jongsun; Park, Sook-Young; Proctor, Robert H.; Regev, Aviv; Ruiz-Roldan, M. Carmen; Sain, Divya; Sakthikumar, Sharadha; Sykes, Sean; Schwartz, David C.; Turgeon, B. Gillian; Wapinski, Ilan; Yoder, Olen; Young, Sarah; Zeng, Qiandong; Zhou, Shiguo; Galagan, James; Cuomo, Christina A.; Kistler, H. Corby; Rep, Martijn

    2011-01-01

    Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusarium graminearum, Fusarium verticillioides and Fusarium oxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findings put the evolution of fungal pathogenicity into a new perspective. PMID:20237561

  19. Physical Principles of Skeletal Minerals Revealed with Spectromicroscopy

    SciTech Connect

    Gilbert, Pupa

    2009-08-05

    Skeletal elements of marine and terrestrial organisms have the most fascinating nano-to-macro-structures, attracting the attention of physicists, biologists, chemists, and materials scientists. Using X-PEEM spectromicroscopy we revealed some of the fundamental mechanisms leading to the formation of these biominerals. Specifically, we addressed the following questions and provided the answers: 1Q) How do teeth, bones, and echinoderm and mollusk shells acquire their unusual, curved and complex morphology, if they are composed of single crystals? 1A) Via amorphous precursor phases; 2Q) How does crystallinity propagate through the amorophous precursor phases in sea urchin spicules and teeth? 2A) By secondary nucleation, following random walk patterns; 3Q) How does iridescent mother-of-pearl become ordered? 3A) Gradually, through a kinetic mechanisms in which fastest growing single-crystals win the competition for space, thus end up being approximately co-oriented.

  20. Internal structure of sponge glass fiber revealed by ptychographic nanotomography.

    PubMed

    Birkbak, Mie E; Guizar-Sicairos, Manuel; Holler, Mirko; Birkedal, Henrik

    2016-04-01

    Sponge glass spicules have solicited great interest due to their mechanical and optical properties. Herein we use ptychographic nanotomography to obtain detailed insights into the internal structure of an anchor spicule from the Venus flower basket. The obtained dataset has 90nm resolution in 3D and provides quantitative determination of the electron density. The data reveal significant variations in electron density across the spicule. The central organic filament is found to be slightly but significantly displaced from the spicule central axis. Analysis of the electron density affords an estimate of a protein volume fraction in the organic filament of about 70%. In the highly mineralized part of the spicule, the electron density is seen to display circular symmetry and be neigh independent of position along the spicule long axis. Variations in the electron density beyond those included in current models of spicule mechanics are observed. PMID:26853498

  1. ID-Check: Online Concealed Information Test Reveals True Identity.

    PubMed

    Verschuere, Bruno; Kleinberg, Bennett

    2016-01-01

    The Internet has already changed people's lives considerably and is likely to drastically change forensic research. We developed a web-based test to reveal concealed autobiographical information. Initial studies identified a number of conditions that affect diagnostic efficiency. By combining these moderators, this study investigated the full potential of the online ID-check. Participants (n = 101) tried to hide their identity and claimed a false identity in a reaction time-based Concealed Information Test. Half of the participants were presented with personal details (e.g., first name, last name, birthday), whereas the others only saw irrelevant details. Results showed that participants' true identity could be detected with high accuracy (AUC = 0.98; overall accuracy: 86-94%). Online memory detection can reliably and validly detect whether someone is hiding their true identity. This suggests that online memory detection might become a valuable tool for forensic applications. PMID:26390033

  2. Karyotype revealed 47, xxy chromosome (Klinefelter syndrome): a case report.

    PubMed

    Jha, Chandra Bhushan; Dhungel, Shaligram; Rai, Dilip

    2007-09-01

    The Klinefelter syndrome is most common chromosomal cause of male infertility. However, the many cases of the syndrome remain undiagnosed due to variations in clinical presentation. A patient attended to surgical OPD with complaints of loss of secondary sexual characteristics and infertility. Physical examination revealed tall stature, thin built, small testes size, and absence of beard and pubic hairs. Karyotype and biochemical tests were performed to detect chromosomal abnormality as well hormonal level to confirm the diagnosis of androgen deficiency syndrome. Chromosomal complement confirmed the case of Klinefelter syndrome (47, XXY) causing androgen deficiency. Timely detection of Klinefelter syndrome is important to formulate further treatment modalities for the benefit of the patient. PMID:18092444

  3. Spanning tree separation reveals community structure in networks

    NASA Astrophysics Data System (ADS)

    Kim, Jongkwang; Wilhelm, Thomas

    2013-03-01

    We present a simple, intuitive, and effective approach for network clustering. It is based on basic concepts of linear algebra such as efficient calculation of spanning trees, and can be implemented in a few lines of code. We introduce the node separation measure spanning tree separation (STS) and the corresponding graph distance measure spanning tree vector similarity distance (STVSD). We demonstrate that the STS is a link salience measure able to identify the backbone of networks. The STVSD is used to reveal the hierarchical community structure of networks. We show that it, together with the clustering quality measure partition density, is on a par with the best graph or network clustering methods known, in terms of both quality and efficiency. In perspective, we note that our approach could also handle weighted and directed networks and could be used for identification of overlapping communities.

  4. Ultrafast cooling reveals microsecond-scale biomolecular dynamics.

    PubMed

    Polinkovsky, Mark E; Gambin, Yann; Banerjee, Priya R; Erickstad, Michael J; Groisman, Alex; Deniz, Ashok A

    2014-01-01

    The temperature-jump technique, in which the sample is rapidly heated by a powerful laser pulse, has been widely used to probe the fast dynamics of folding of proteins and nucleic acids. However, the existing temperature-jump setups tend to involve sophisticated and expensive instrumentation, while providing only modest temperature changes of ~10-15 °C, and the temperature changes are only rapid for heating, but not cooling. Here we present a setup comprising a thermally conductive sapphire substrate with light-absorptive nano-coating, a microfluidic device and a rapidly switched moderate-power infrared laser with the laser beam focused on the nano-coating, enabling heating and cooling of aqueous solutions by ~50 °C on a 1-μs time scale. The setup is used to probe folding and unfolding dynamics of DNA hairpins after direct and inverse temperature jumps, revealing low-pass filter behaviour during periodic temperature variations. PMID:25517430

  5. Integrative Acoustic Mapping Reveals Hudson RIver Sediment Processes an Habitats

    NASA Astrophysics Data System (ADS)

    Nitsche, F. O.; Bell, R.; Carbotte, S. M.; Ryan, W. B. F.; Slagle, A.; Chillrud, S.; Kenna, T.; Flood, R.; Ferrini, V.; Cerrato, R.; McHugh, C.; Strayer, D.

    2005-06-01

    Rivers and estuaries around the world are the focus of human settlements and activities. Needs for clean water, ecosystem preservation, commercial navigation, industrial development, and recreational access compete for the use of estuaries, and management of these resources requires a detailed understanding of estuarine morphology and sediment dynamics. This article presents an overview of the first estuary-wide study of a heavily used estuary, the Hudson River, based on high-resolution acoustic mapping of the river bottom. The integration of three high-resolution acoustic methods with extensive sampling reveals an unexpected complexity of bottom features and allows detailed classification of the benthic environment in terms of riverbed morphology, sediment type, and sedimentary processes.

  6. Graph analysis of cortical networks reveals complex anatomical communication substrate

    NASA Astrophysics Data System (ADS)

    Zamora-López, Gorka; Zhou, Changsong; Kurths, Jürgen

    2009-03-01

    Sensory information entering the nervous system follows independent paths of processing such that specific features are individually detected. However, sensory perception, awareness, and cognition emerge from the combination of information. Here we have analyzed the corticocortical network of the cat, looking for the anatomical substrate which permits the simultaneous segregation and integration of information in the brain. We find that cortical communications are mainly governed by three topological factors of the underlying network: (i) a large density of connections, (ii) segregation of cortical areas into clusters, and (iii) the presence of highly connected hubs aiding the multisensory processing and integration. Statistical analysis of the shortest paths reveals that, while information is highly accessible to all cortical areas, the complexity of cortical information processing may arise from the rich and intricate alternative paths in which areas can influence each other.

  7. Early allelic selection in maize as revealed by ancient DNA.

    PubMed

    Jaenicke-Després, Viviane; Buckler, Ed S; Smith, Bruce D; Gilbert, M Thomas P; Cooper, Alan; Doebley, John; Pääbo, Svante

    2003-11-14

    Maize was domesticated from teosinte, a wild grass, by approximately 6300 years ago in Mexico. After initial domestication, early farmers continued to select for advantageous morphological and biochemical traits in this important crop. However, the timing and sequence of character selection are, thus far, known only for morphological features discernible in corn cobs. We have analyzed three genes involved in the control of plant architecture, storage protein synthesis, and starch production from archaeological maize samples from Mexico and the southwestern United States. The results reveal that the alleles typical of contemporary maize were present in Mexican maize by 4400 years ago. However, as recently as 2000 years ago, allelic selection at one of the genes may not yet have been complete. PMID:14615538

  8. Comparative genomics reveals insights into avian genome evolution and adaptation.

    PubMed

    Zhang, Guojie; Li, Cai; Li, Qiye; Li, Bo; Larkin, Denis M; Lee, Chul; Storz, Jay F; Antunes, Agostinho; Greenwold, Matthew J; Meredith, Robert W; Ödeen, Anders; Cui, Jie; Zhou, Qi; Xu, Luohao; Pan, Hailin; Wang, Zongji; Jin, Lijun; Zhang, Pei; Hu, Haofu; Yang, Wei; Hu, Jiang; Xiao, Jin; Yang, Zhikai; Liu, Yang; Xie, Qiaolin; Yu, Hao; Lian, Jinmin; Wen, Ping; Zhang, Fang; Li, Hui; Zeng, Yongli; Xiong, Zijun; Liu, Shiping; Zhou, Long; Huang, Zhiyong; An, Na; Wang, Jie; Zheng, Qiumei; Xiong, Yingqi; Wang, Guangbiao; Wang, Bo; Wang, Jingjing; Fan, Yu; da Fonseca, Rute R; Alfaro-Núñez, Alonzo; Schubert, Mikkel; Orlando, Ludovic; Mourier, Tobias; Howard, Jason T; Ganapathy, Ganeshkumar; Pfenning, Andreas; Whitney, Osceola; Rivas, Miriam V; Hara, Erina; Smith, Julia; Farré, Marta; Narayan, Jitendra; Slavov, Gancho; Romanov, Michael N; Borges, Rui; Machado, João Paulo; Khan, Imran; Springer, Mark S; Gatesy, John; Hoffmann, Federico G; Opazo, Juan C; Håstad, Olle; Sawyer, Roger H; Kim, Heebal; Kim, Kyu-Won; Kim, Hyeon Jeong; Cho, Seoae; Li, Ning; Huang, Yinhua; Bruford, Michael W; Zhan, Xiangjiang; Dixon, Andrew; Bertelsen, Mads F; Derryberry, Elizabeth; Warren, Wesley; Wilson, Richard K; Li, Shengbin; Ray, David A; Green, Richard E; O'Brien, Stephen J; Griffin, Darren; Johnson, Warren E; Haussler, David; Ryder, Oliver A; Willerslev, Eske; Graves, Gary R; Alström, Per; Fjeldså, Jon; Mindell, David P; Edwards, Scott V; Braun, Edward L; Rahbek, Carsten; Burt, David W; Houde, Peter; Zhang, Yong; Yang, Huanming; Wang, Jian; Jarvis, Erich D; Gilbert, M Thomas P; Wang, Jun

    2014-12-12

    Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits. PMID:25504712

  9. Spring-block model reveals region-like structures.

    PubMed

    Máté, Gabriell; Néda, Zoltán; Benedek, József

    2011-01-01

    A mechanical spring-block model is used for realizing an objective space partition of settlements from a geographic territory in region-like structures. The method is based on the relaxation-dynamics of the spring-block system and reveals in a hierarchical manner region-like entities at different spatial scales. It takes into account in an elegant manner both the spatiality of the elements and the connectivity relations among them. Spatiality is taken into account by using the geographic coordinates of the settlements, and by detecting the neighbors with the help of a Delaunay triangulation. Connectivity between neighboring settlements are quantified using a Pearson-like correlation for the relative variation of a relevant socio-economic parameter (population size, GDP, tax payed per inhabitant, etc.). The method is implemented in an interactive JAVA application and it is applied with success for an artificially generated society and for the case of USA, Hungary and Transylvania. PMID:21346819

  10. Revealing the superior perceptibility of words in Arabic.

    PubMed

    Jordan, Timothy R; Paterson, Kevin B; Almabruk, Abubaker A A

    2010-01-01

    When alphabetic stimuli are presented very briefly, people perceive real words better than nonwords. It is generally accepted that this word superiority effect reflects the efficiency of visual word perception. However, much of what is known about this effect comes from research conducted in languages using the Latin alphabet (eg English, French, Italian), and little is known about whether alphabetic languages with visual properties fundamentally different from Latinate languages also produce word superiority effects. We report an experiment in which stimuli (words, illegal nonwords, and pseudowords) were presented in Arabic, which is a cursive script, read from right to left. The findings revealed advantages for words over pseudowords and illegal nonwords, and for pseudowords over illegal nonwords, indicating that the superiority effects reported for Latinate languages are also observed in Arabic. Implications of these findings for understanding the processes involved in word recognition are discussed. PMID:20465177

  11. Multicentric Castleman's Disease in a Child Revealed by Chronic Diarrhea

    PubMed Central

    Benmiloud, Sarra; Chaouki, Sana; Atmani, Samir; Hida, Moustapha

    2015-01-01

    Multicentric Castleman's disease is a rare benign and unexplained lymphoproliferative disorder that is extremely uncommon in children. It presents with fever, systemic symptoms, generalized lymphadenopathy, and laboratory markers of inflammation. Its treatment is not standardized and its prognosis is poor. We report a novel case of multicentric Castleman's disease in a 13-year-old girl who had presented with chronic diarrhea as the only initial presenting symptom. The diagnosis of celiac or inflammatory bowel diseases was suspected, but two and a half years later, the diagnosis of multicentric Castleman's disease was brought following the appearance of abdominal mass whose biopsy revealed Castleman's disease in the plasma cell form. The outcome was favorable after treatment by corticosteroid, chemotherapy, and surgery. The occurrence of diarrhea as the initial symptom of multicentric Castleman's disease without lymph node involvement is very rare. This case report underlines the diagnostic difficulties and the long interval between onset and diagnosis when diarrhea occurs first. PMID:25737793

  12. MNase titration reveals differences between nucleosome occupancy and chromatin accessibility.

    PubMed

    Mieczkowski, Jakub; Cook, April; Bowman, Sarah K; Mueller, Britta; Alver, Burak H; Kundu, Sharmistha; Deaton, Aimee M; Urban, Jennifer A; Larschan, Erica; Park, Peter J; Kingston, Robert E; Tolstorukov, Michael Y

    2016-01-01

    Chromatin accessibility plays a fundamental role in gene regulation. Nucleosome placement, usually measured by quantifying protection of DNA from enzymatic digestion, can regulate accessibility. We introduce a metric that uses micrococcal nuclease (MNase) digestion in a novel manner to measure chromatin accessibility by combining information from several digests of increasing depths. This metric, MACC (MNase accessibility), quantifies the inherent heterogeneity of nucleosome accessibility in which some nucleosomes are seen preferentially at high MNase and some at low MNase. MACC interrogates each genomic locus, measuring both nucleosome location and accessibility in the same assay. MACC can be performed either with or without a histone immunoprecipitation step, and thereby compares histone and non-histone protection. We find that changes in accessibility at enhancers, promoters and other regulatory regions do not correlate with changes in nucleosome occupancy. Moreover, high nucleosome occupancy does not necessarily preclude high accessibility, which reveals novel principles of chromatin regulation. PMID:27151365

  13. Deciphering CAPTCHAs: what a Turing test reveals about human cognition.

    PubMed

    Hannagan, Thomas; Ktori, Maria; Chanceaux, Myriam; Grainger, Jonathan

    2012-01-01

    Turning Turing's logic on its head, we used widespread letter-based Turing Tests found on the internet (CAPTCHAs) to shed light on human cognition. We examined the basis of the human ability to solve CAPTCHAs, where machines fail. We asked whether this is due to our use of slow-acting inferential processes that would not be available to machines, or whether fast-acting automatic orthographic processing in humans has superior robustness to shape variations. A masked priming lexical decision experiment revealed efficient processing of CAPTCHA words in conditions that rule out the use of slow inferential processing. This shows that the human superiority in solving CAPTCHAs builds on a high degree of invariance to location and continuous transforms, which is achieved during the very early stages of visual word recognition in skilled readers. PMID:22396750

  14. A tylosin ketoreductase reveals how chirality is determined in polyketides.

    PubMed

    Keatinge-Clay, Adrian T

    2007-08-01

    Because it controls the majority of polyketide stereocenters, the ketoreductase (KR) is a central target in engineering polyketide synthases (PKSs). To elucidate the mechanisms of stereocontrol, the structure of KR from the first module of the tylosin PKS was determined. A comparison with a recently solved erythromycin KR that operates on the same substrate explains why their products have opposite alpha-substituent chiralities. The structure reveals how polyketides are guided into the active site by key residues in different KR types. There are four types of reductase-competent KRs, each capable of fixing a unique combination of alpha-substituent and beta-hydroxyl group chiralities, as well as two types of reductase-incompetent KRs that control alpha-substituent chirality alone. A protocol to assign how a module will enforce substituent chirality based on its sequence is presented. PMID:17719489

  15. Mediated amperometry reveals different modes of yeast responses to sugars.

    PubMed

    Garjonyte, Rasa; Melvydas, Vytautas; Malinauskas, Albertas

    2016-02-01

    Menadione-mediated amperometry at carbon paste electrodes modified with various yeasts (Saccharomyces cerevisiae, Candida pulcherrima, Pichia guilliermondii and Debaryomyces hansenii) was employed to monitor redox activity inside the yeast cells induced by glucose, fructose, sucrose, maltose or galactose. Continuous measurements revealed distinct modes (transient or gradually increasing) of the current development during the first 2 to 3 min after subjection to glucose, fructose and sucrose at electrodes containing S. cerevisiae and non-Saccharomyces strains. Different modes (increasing or decreasing) of the current development after yeast subjection to galactose at electrodes with S. cerevisiae or D. hansenii and at electrodes with C. pulcherrima and P. guilliermondii suggested different mechanisms of galactose assimilation. PMID:26523505

  16. The genome of Tetranychus urticae reveals herbivorous pest adaptations

    PubMed Central

    Grbić, Miodrag; Van Leeuwen, Thomas; Clark, Richard M.; Rombauts, Stephane; Rouzé, Pierre; Grbić, Vojislava; Osborne, Edward J.; Dermauw, Wannes; Ngoc, Phuong Cao Thi; Ortego, Félix; Hernández-Crespo, Pedro; Diaz, Isabel; Martinez, Manuel; Navajas, Maria; Sucena, Élio; Magalhães, Sara; Nagy, Lisa; Pace, Ryan M.; Djuranović, Sergej; Smagghe, Guy; Iga, Masatoshi; Christiaens, Olivier; Veenstra, Jan A.; Ewer, John; Villalobos, Rodrigo Mancilla; Hutter, Jeffrey L.; Hudson, Stephen D.; Velez, Marisela; Yi, Soojin V.; Zeng, Jia; Pires-daSilva, Andre; Roch, Fernando; Cazaux, Marc; Navarro, Marie; Zhurov, Vladimir; Acevedo, Gustavo; Bjelica, Anica; Fawcett, Jeffrey A.; Bonnet, Eric; Martens, Cindy; Baele, Guy; Wissler, Lothar; Sanchez-Rodriguez, Aminael; Tirry, Luc; Blais, Catherine; Demeestere, Kristof; Henz, Stefan R.; Gregory, T. Ryan; Mathieu, Johannes; Verdon, Lou; Farinelli, Laurent; Schmutz, Jeremy; Lindquist, Erika; Feyereisen, René; Van de Peer, Yves

    2016-01-01

    The spider mite Tetranychus urticae is a cosmopolitan agricultural pest with an extensive host plant range and an extreme record of pesticide resistance. Here we present the completely sequenced and annotated spider mite genome, representing the first complete chelicerate genome. At 90 megabases T. urticae has the smallest sequenced arthropod genome. Compared with other arthropods, the spider mite genome shows unique changes in the hormonal environment and organization of the Hox complex, and also reveals evolutionary innovation of silk production. We find strong signatures of polyphagy and detoxification in gene families associated with feeding on different hosts and in new gene families acquired by lateral gene transfer. Deep transcriptome analysis of mites feeding on different plants shows how this pest responds to a changing host environment. The T. urticae genome thus offers new insights into arthropod evolution and plant–herbivore interactions, and provides unique opportunities for developing novel plant protection strategies. PMID:22113690

  17. Proteomic profiling reveals insights into Triticeae stigma development and function

    PubMed Central

    Nazemof, Nazila; Couroux, Philippe; Rampitsch, Christof; Xing, Tim; Robert, Laurian S.

    2014-01-01

    To our knowledge, this study represents the first high-throughput characterization of a stigma proteome in the Triticeae. A total of 2184 triticale mature stigma proteins were identified using three different gel-based approaches combined with mass spectrometry. The great majority of these proteins are described in a Triticeae stigma for the first time. These results revealed many proteins likely to play important roles in stigma development and pollen–stigma interactions, as well as protection against biotic and abiotic stresses. Quantitative comparison of the triticale stigma transcriptome and proteome showed poor correlation, highlighting the importance of having both types of analysis. This work makes a significant contribution towards the elucidation of the Triticeae stigma proteome and provides novel insights into its role in stigma development and function. PMID:25170101

  18. T-cadherin structures reveal a novel adhesive binding mechanism

    SciTech Connect

    Ciatto, Carlo; Bahna, Fabiana; Zampieri, Niccolò; VanSteenhouse, Harper C.; Katsamba, Phini S; Ahlsen, Goran; Harrison, Oliver J.; Brasch, Julia; Jin, Xiangshu; Posy, Shoshana; Vendome, Jeremie; Ranscht, Barbara; Jessell, Thomas M.; Honig, Barry; Shapiro, Lawrence

    2010-03-30

    Vertebrate genomes encode 19 classical cadherins and about 100 nonclassical cadherins. Adhesion by classical cadherins depends on binding interactions in their N-terminal EC1 domains, which swap N-terminal {beta}-strands between partner molecules from apposing cells. However, strand-swapping sequence signatures are absent from nonclassical cadherins, raising the question of how these proteins function in adhesion. Here, we show that T-cadherin, a glycosylphosphatidylinositol (GPI)-anchored cadherin, forms dimers through an alternative nonswapped interface near the EC1-EC2 calcium-binding sites. Mutations within this interface ablate the adhesive capacity of T-cadherin. These nonadhesive T-cadherin mutants also lose the ability to regulate neurite outgrowth from T-cadherin-expressing neurons. Our findings reveal the likely molecular architecture of the T-cadherin homophilic interface and its requirement for axon outgrowth regulation. The adhesive binding mode used by T-cadherin may also be used by other nonclassical cadherins

  19. Ethiopian population dermatoglyphic study reveals linguistic stratification of diversity.

    PubMed

    Yohannes, Seile; Bekele, Endashaw

    2015-01-01

    The manifestation of ethnic, blood type, & gender-wise population variations regarding Dermatoglyphic manifestations are of interest to assess intra-group diversity and differentiation. The present study reports on the analysis of qualitaive and quantitative finger Dermatoglyphic traits of 382 individuals cross-sectionally sampled from an administrative region of Ethiopia, consisting of five ethnic cohorts from the Afro-Asiatic & Nilo-Saharan affiliations. These Dermatoglyphic parameters were then applied in the assessment of diversity & differentiation, including Heterozygosity, Fixation, Panmixia, Wahlund's variance, Nei's measure of genetic diversity, and thumb & finger pattern genotypes, which were inturn used in homology inferences as summarized by a Neighbour-Joining tree constructed from Nei's standard genetic distance. Results revealed significant correlation between Dermatoglyphics & population parameters that were further found to be in concordance with the historical accounts of the ethnic groups. Such inductions as the ancient north-eastern presence and subsequent admixure events of the Oromos (PII= 15.01), the high diversity of the Amharas (H= 0.1978, F= 0.6453, and P= 0.4144), and the Nilo-Saharan origin of the Berta group (PII= 10.66) are evidences to this. The study has further tested the possibility of applying Dermatoglyphics in population genetic & anthropologic research, highlighting on the prospect of developing a method to trace back population origins & ancient movement patterns. Additionally, linguistic clustering was deemed significant for the Ethiopian population, coinciding with recent genome wide studies that have ascertained that linguistic clustering as to being more crucial than the geographical patterning in the Ethiopian context. Finally, Dermatoglyphic markers have been proven to be endowed with a strong potential as non-invasive preliminary tools applicable prior to genetic studies to analyze ethnically sub-divided populations and

  20. Subfield profitability analysis reveals an economic case for cropland diversification

    NASA Astrophysics Data System (ADS)

    Brandes, E.; McNunn, G. S.; Schulte, L. A.; Bonner, I. J.; Muth, D. J.; Babcock, B. A.; Sharma, B.; Heaton, E. A.

    2016-01-01

    Public agencies and private enterprises increasingly desire to achieve ecosystem service outcomes in agricultural systems, but are limited by perceived conflicts between economic and ecosystem service goals and a lack of tools enabling effective operational management. Here we use Iowa—an agriculturally homogeneous state representative of the Maize Belt—to demonstrate an economic rationale for cropland diversification at the subfield scale. We used a novel computational framework that integrates disparate but publicly available data to map ˜3.3 million unique potential management polygons (9.3 Mha) and reveal subfield opportunities to increase overall field profitability. We analyzed subfield profitability for maize/soybean fields during 2010-2013—four of the most profitable years in recent history—and projected results for 2015. While cropland operating at a loss of US 250 ha-1 or more was negligible between 2010 and 2013 at 18 000-190 000 ha (<2% of row-crop land), the extent of highly unprofitable land increased to 2.5 Mha, or 27% of row-crop land, in the 2015 projection. Aggregation of these areas to the township level revealed ‘hotspots’ for potential management change in Western, Central, and Northeast Iowa. In these least profitable areas, incorporating conservation management that breaks even (e.g., planting low-input perennials), into low-yielding portions of fields could increase overall cropland profitability by 80%. This approach is applicable to the broader region and differs substantially from the status quo of ‘top-down’ land management for conservation by harnessing private interest to align profitability with the production of ecosystem services.

  1. Architecture of cognitive flexibility revealed by lesion mapping

    PubMed Central

    Barbey, Aron K.; Colom, Roberto; Grafman, Jordan

    2013-01-01

    Neuroscience has made remarkable progress in understanding the architecture of human intelligence, identifying a distributed network of brain structures that support goal-directed, intelligent behavior. However, the neural foundations of cognitive flexibility and adaptive aspects of intellectual function remain to be well characterized. Here, we report a human lesion study (n = 149) that investigates the neural bases of key competencies of cognitive flexibility (i.e., mental flexibility and the fluent generation of new ideas) and systematically examine their contributions to a broad spectrum of cognitive and social processes, including psychometric intelligence (Wechsler Adult Intelligence Scale), emotional intelligence (Mayer, Salovey, Caruso Emotional Intelligence Test), and personality (Neuroticism–Extraversion–Openness Personality Inventory). Latent variable modeling was applied to obtain error-free indices of each factor, followed by voxel-based lesion-symptom mapping to elucidate their neural substrates. Regression analyses revealed that latent scores for psychometric intelligence reliably predict latent scores for cognitive flexibility (adjusted R2 = 0.94). Lesion mapping results further indicated that these convergent processes depend on a shared network of frontal, temporal, and parietal regions, including white matter association tracts, which bind these areas into an integrated system. A targeted analysis of the unique variance explained by cognitive flexibility further revealed selective damage within the right superior temporal gyrus, a region known to support insight and the recognition of novel semantic relations. The observed findings motivate an integrative framework for understanding the neural foundations of adaptive behavior, suggesting that core elements of cognitive flexibility emerge from a distributed network of brain regions that support specific competencies for human intelligence. PMID:23721727

  2. Running over rough terrain reveals limb control for intrinsic stability

    PubMed Central

    Daley, Monica A.; Biewener, Andrew A.

    2006-01-01

    Legged animals routinely negotiate rough, unpredictable terrain with agility and stability that outmatches any human-built machine. Yet, we know surprisingly little about how animals accomplish this. Current knowledge is largely limited to studies of steady movement. These studies have revealed fundamental mechanisms used by terrestrial animals for steady locomotion. However, it is unclear whether these models provide an appropriate framework for the neuromuscular and mechanical strategies used to achieve dynamic stability over rough terrain. Perturbation experiments shed light on this issue, revealing the interplay between mechanics and neuromuscular control. We measured limb mechanics of helmeted guinea fowl (Numida meleagris) running over an unexpected drop in terrain, comparing their response to predictions of the mass–spring running model. Adjustment of limb contact angle explains 80% of the variation in stance-phase limb loading following the perturbation. Surprisingly, although limb stiffness varies dramatically, it does not influence the response. This result agrees with a mass–spring model, although it differs from previous findings on humans running over surfaces of varying compliance. However, guinea fowl sometimes deviate from mass–spring dynamics through posture-dependent work performance of the limb, leading to substantial energy absorption following the perturbation. This posture-dependent actuation allows the animal to absorb energy and maintain desired velocity on a sudden substrate drop. Thus, posture-dependent work performance of the limb provides inherent velocity control over rough terrain. These findings highlight how simple mechanical models extend to unsteady conditions, providing fundamental insights into neuromuscular control of movement and the design of dynamically stable legged robots and prosthetic devices. PMID:17032779

  3. Architecture of cognitive flexibility revealed by lesion mapping.

    PubMed

    Barbey, Aron K; Colom, Roberto; Grafman, Jordan

    2013-11-15

    Neuroscience has made remarkable progress in understanding the architecture of human intelligence, identifying a distributed network of brain structures that support goal-directed, intelligent behavior. However, the neural foundations of cognitive flexibility and adaptive aspects of intellectual function remain to be well characterized. Here, we report a human lesion study (n=149) that investigates the neural bases of key competencies of cognitive flexibility (i.e., mental flexibility and the fluent generation of new ideas) and systematically examine their contributions to a broad spectrum of cognitive and social processes, including psychometric intelligence (Wechsler Adult Intelligence Scale), emotional intelligence (Mayer, Salovey, Caruso Emotional Intelligence Test), and personality (Neuroticism-Extraversion-Openness Personality Inventory). Latent variable modeling was applied to obtain error-free indices of each factor, followed by voxel-based lesion-symptom mapping to elucidate their neural substrates. Regression analyses revealed that latent scores for psychometric intelligence reliably predict latent scores for cognitive flexibility (adjusted R(2)=0.94). Lesion mapping results further indicated that these convergent processes depend on a shared network of frontal, temporal, and parietal regions, including white matter association tracts, which bind these areas into an integrated system. A targeted analysis of the unique variance explained by cognitive flexibility further revealed selective damage within the right superior temporal gyrus, a region known to support insight and the recognition of novel semantic relations. The observed findings motivate an integrative framework for understanding the neural foundations of adaptive behavior, suggesting that core elements of cognitive flexibility emerge from a distributed network of brain regions that support specific competencies for human intelligence. PMID:23721727

  4. Sand Dunes And Large Rocks Revealed By Camera 1

    NASA Technical Reports Server (NTRS)

    1976-01-01

    Sand dunes and large rocks are revealed in this panorama picture of Mars, the first photograph taken by Viking l's Camera 1 on July 23. The horizon is approximately 3 kilometers (2 miles) away. The left and right thirds of this picture are the same areas that were photographed on July 20 (Sol O) by Camera 2 and provide stereo coverage. The middle third reveals a part of the Martian surface not seen on the July 20 panorama. The late afternoon sun is high in the sky over the left side of the picture. The support struts of the S-band high-gain antenna extend to the top of the picture. The American flags are located on the two RTG (Radioisotope Thermoelectric Generator) wind screens. In the middle third of the picture, the rocky surface is covered by thick deposits of wind-blown material, forming numerous dunes. At the center of the picture on the horizon are two low hills which may be part of the rim of a distant crater. Two very large rocks are visible in the middleground; the nearer one is 3 meters (10 feet) in diameter and is 8 meters (25 feet) from the spacecraft. A cloud layer is visible halfway between the horizon and the top of the picture. The meteorology boom is located right of center. Behind it, the 'White Mesa' is visible, which could be seen on the far left side of the Sol O Camera 2 panorama. In the near ground are numerous rocks about 10 cm (4 inches) across, with horseshoe-shaped scour marks on their upwind side and wind tails in their lee. The fine-grained material in front of them contains small pits formed by impact of material kicked out by the Lander spacecraft's rocket engines.

  5. Next Generation Sequencing Reveals the Hidden Diversity of Zooplankton Assemblages

    PubMed Central

    Harmer, Rachel A.; Somerfield, Paul J.; Atkinson, Angus

    2013-01-01

    Background Zooplankton play an important role in our oceans, in biogeochemical cycling and providing a food source for commercially important fish larvae. However, difficulties in correctly identifying zooplankton hinder our understanding of their roles in marine ecosystem functioning, and can prevent detection of long term changes in their community structure. The advent of massively parallel next generation sequencing technology allows DNA sequence data to be recovered directly from whole community samples. Here we assess the ability of such sequencing to quantify richness and diversity of a mixed zooplankton assemblage from a productive time series site in the Western English Channel. Methodology/Principle Findings Plankton net hauls (200 µm) were taken at the Western Channel Observatory station L4 in September 2010 and January 2011. These samples were analysed by microscopy and metagenetic analysis of the 18S nuclear small subunit ribosomal RNA gene using the 454 pyrosequencing platform. Following quality control a total of 419,041 sequences were obtained for all samples. The sequences clustered into 205 operational taxonomic units using a 97% similarity cut-off. Allocation of taxonomy by comparison with the National Centre for Biotechnology Information database identified 135 OTUs to species level, 11 to genus level and 1 to order, <2.5% of sequences were classified as unknowns. By comparison a skilled microscopic analyst was able to routinely enumerate only 58 taxonomic groups. Conclusions Metagenetics reveals a previously hidden taxonomic richness, especially for Copepoda and hard-to-identify meroplankton such as Bivalvia, Gastropoda and Polychaeta. It also reveals rare species and parasites. We conclude that Next Generation Sequencing of 18S amplicons is a powerful tool for elucidating the true diversity and species richness of zooplankton communities. While this approach allows for broad diversity assessments of plankton it may become increasingly

  6. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

    PubMed Central

    Math, M.; Tarpey, Patrick; Varela, Ignacio; Phillimore, Benjamin; Begum, Sharmin; McDonald, Neil Q.; Butler, Adam; Jones, David; Raine, Keiran; Latimer, Calli; Santos, Claudio R.; Nohadani, Mahrokh; Eklund, Aron C.; Spencer-Dene, Bradley; Clark, Graham; Pickering, Lisa; Stamp, Gordon; Gore, Martin; Szallasi, Zoltan; Downward, Julian; Futreal, P. Andrew

    2016-01-01

    Background Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. Methods To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Results Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Conclusions Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through

  7. Four not six: Revealing culturally common facial expressions of emotion.

    PubMed

    Jack, Rachael E; Sun, Wei; Delis, Ioannis; Garrod, Oliver G B; Schyns, Philippe G

    2016-06-01

    As a highly social species, humans generate complex facial expressions to communicate a diverse range of emotions. Since Darwin's work, identifying among these complex patterns which are common across cultures and which are culture-specific has remained a central question in psychology, anthropology, philosophy, and more recently machine vision and social robotics. Classic approaches to addressing this question typically tested the cross-cultural recognition of theoretically motivated facial expressions representing 6 emotions, and reported universality. Yet, variable recognition accuracy across cultures suggests a narrower cross-cultural communication supported by sets of simpler expressive patterns embedded in more complex facial expressions. We explore this hypothesis by modeling the facial expressions of over 60 emotions across 2 cultures, and segregating out the latent expressive patterns. Using a multidisciplinary approach, we first map the conceptual organization of a broad spectrum of emotion words by building semantic networks in 2 cultures. For each emotion word in each culture, we then model and validate its corresponding dynamic facial expression, producing over 60 culturally valid facial expression models. We then apply to the pooled models a multivariate data reduction technique, revealing 4 latent and culturally common facial expression patterns that each communicates specific combinations of valence, arousal, and dominance. We then reveal the face movements that accentuate each latent expressive pattern to create complex facial expressions. Our data questions the widely held view that 6 facial expression patterns are universal, instead suggesting 4 latent expressive patterns with direct implications for emotion communication, social psychology, cognitive neuroscience, and social robotics. (PsycINFO Database Record PMID:27077757

  8. Microsporidian genome analysis reveals evolutionary strategies for obligate intracellular growth

    PubMed Central

    Cuomo, Christina A.; Desjardins, Christopher A.; Bakowski, Malina A.; Goldberg, Jonathan; Ma, Amy T.; Becnel, James J.; Didier, Elizabeth S.; Fan, Lin; Heiman, David I.; Levin, Joshua Z.; Young, Sarah; Zeng, Qiandong; Troemel, Emily R.

    2012-01-01

    Microsporidia comprise a large phylum of obligate intracellular eukaryotes that are fungal-related parasites responsible for widespread disease, and here we address questions about microsporidia biology and evolution. We sequenced three microsporidian genomes from two species, Nematocida parisii and Nematocida sp1, which are natural pathogens of Caenorhabditis nematodes and provide model systems for studying microsporidian pathogenesis. We performed deep sequencing of transcripts from a time course of N. parisii infection. Examination of pathogen gene expression revealed compact transcripts and a dramatic takeover of host cells by Nematocida. We also performed phylogenomic analyses of Nematocida and other microsporidian genomes to refine microsporidian phylogeny and identify evolutionary events of gene loss, acquisition, and modification. In particular, we found that all microsporidia lost the tumor-suppressor gene retinoblastoma, which we speculate could accelerate the parasite cell cycle and increase the mutation rate. We also found that microsporidia acquired transporters that could import nucleosides to fuel rapid growth. In addition, microsporidian hexokinases gained secretion signal sequences, and in a functional assay these were sufficient to export proteins out of the cell; thus hexokinase may be targeted into the host cell to reprogram it toward biosynthesis. Similar molecular changes appear during formation of cancer cells and may be evolutionary strategies adopted independently by microsporidia to proliferate rapidly within host cells. Finally, analysis of genome polymorphisms revealed evidence for a sexual cycle that may provide genetic diversity to alleviate problems caused by clonal growth. Together these events may explain the emergence and success of these diverse intracellular parasites. PMID:22813931

  9. Comparison on extreme pathways reveals nature of different biological processes

    PubMed Central

    2014-01-01

    Background Constraint-based reconstruction and analysis (COBRA) is used for modeling genome-scale metabolic networks (MNs). In a COBRA model, extreme pathways (ExPas) are the edges of its conical solution space, which is formed by all viable steady-state flux distributions. ExPa analysis has been successfully applied to MNs to reveal their phenotypic capabilities and properties. Recently, the COBRA framework has been extended to transcriptional regulatory networks (TRNs) and transcriptional and translational networks (TTNs), so efforts are needed to determine whether ExPa analysis is also effective on these two types of networks. Results In this paper, the ExPas resulting from the COBRA models of E.coli's MN, TRN and TTN were horizontally compared from 5 aspects: (1) Total number and the ratio of their amount to reaction amount; (2) Length distribution; (3) Reaction participation; (4) Correlated reaction sets (CoSets); (5) interconnectivity degree. Significant discrepancies in above properties were observed during the comparison, which reveals the biological natures of different biological processes. Besides, by demonstrating the application of ExPa analysis on E.coli, we provide a practical guidance of an improved approach to compute ExPas on COBRA models of TRNs. Conclusions ExPas of E.coli's MN, TRN and TTN have different properties, which are strongly connected with various biological natures of biochemical networks, such as topological structure, specificity and redundancy. Our study shows that ExPas are biologically meaningful on the newborn models and suggests the effectiveness of ExPa analysis on them. PMID:24565046

  10. [Munchhausen syndrome by proxy revealed by falsely toxic methotrexate levels].

    PubMed

    Charfi, Rim; Trabelsi, Sameh; Salouage, Issam; Gaïes, Emna; Jebabli, Nadia; Lakhal, Mohamed; Klouz, Anis

    2012-01-01

    Methotrexate is an antifolate drug used intravenously at high-dose in acute lymphocytic leukemia (ALL). Therapeutic drug monitoring is required to identify patients at risk of developing toxicity and to control folinic acid rescue. We report a case of Münchausen syndrome by proxy revealed by high and persistent falsely toxic methotrexate plasmatic levels. A 12 year-old child was treated with chemotherapy including methotrexate every 70 days for an ALL. The last methotrexate plasmatic level was 0.15 μmol/L at the 72th hour of the infusion. Then, he was treated by oral rout low-dose methotrexate. Ten days after methotrexate infusion, the patient consulted for asthenia, vomiting and presented a mucositis. Methotrexate plasmatic level was 2323 μmol/L. Renal function was normal. All drugs' intake was stopped. Folinic acid rescue was instituted. Even though there was no clinical sign of toxicity, therapeutic drug monitoring showed persistent high methotrexate plasmatic levels. Investigations eliminated measurement errors and pharmacokinetic problems. A deliberate methotrexate addition in each child blood sample brought by the mother was highly suspected. We confirmed this hypothesis by measuring methotrexate plasmatic levels in three samples: one brought by the mother, the second brought by the child's doctor and the last collected in our laboratory. Methotrexate plasmatic levels were respectively over 10,000 μmol/L (first sample) and lower than 0.02 μmol/L (the two others). The diagnosis of Munchausen's syndrome by proxy revealed by falsely toxic methotrexate plasmatic levels was made and the mother was addressed to the psychiatric department. PMID:22484536

  11. Antibody protection reveals extended epitopes on the human TSH receptor.

    PubMed

    Latif, Rauf; Teixeira, Avelino; Michalek, Krzysztof; Ali, M Rejwan; Schlesinger, Max; Baliram, Ramkumarie; Morshed, Syed A; Davies, Terry F

    2012-01-01

    Stimulating, and some blocking, antibodies to the TSH receptor (TSHR) have conformation-dependent epitopes reported to involve primarily the leucine rich repeat region of the ectodomain (LRD). However, successful crystallization of TSHR residues 22-260 has omitted important extracellular non-LRD residues including the hinge region which connects the TSHR ectodomain to the transmembrane domain and which is involved in ligand induced signal transduction. The aim of the present study, therefore, was to determine if TSHR antibodies (TSHR-Abs) have non-LRD binding sites outside the LRD. To obtain this information we employed the method of epitope protection in which we first protected TSHR residues 1-412 with intact TSHR antibodies and then enzymatically digested the unprotected residues. Those peptides remaining were subsequently delineated by mass spectrometry. Fourteen out of 23 of the reported stimulating monoclonal TSHR-Ab crystal contact residues were protected by this technique which may reflect the higher binding energies of certain residues detected in this approach. Comparing the protected epitopes of two stimulating TSHR-Abs we found both similarities and differences but both antibodies also contacted the hinge region and the amino terminus of the TSHR following the signal peptide and encompassing cysteine box 1 which has previously been shown to be important for TSH binding and activation. A monoclonal blocking TSHR antibody revealed a similar pattern of binding regions but the residues that it contacted on the LRD were again distinct. These data demonstrated that conformationally dependent TSHR-Abs had epitopes not confined to the LRDs but also incorporated epitopes not revealed in the available crystal structure. Furthermore, the data also indicated that in addition to overlapping contact regions within the LRD, there are unique epitope patterns for each of the antibodies which may contribute to their functional heterogeneity. PMID:22957097

  12. Microsporidian genome analysis reveals evolutionary strategies for obligate intracellular growth.

    PubMed

    Cuomo, Christina A; Desjardins, Christopher A; Bakowski, Malina A; Goldberg, Jonathan; Ma, Amy T; Becnel, James J; Didier, Elizabeth S; Fan, Lin; Heiman, David I; Levin, Joshua Z; Young, Sarah; Zeng, Qiandong; Troemel, Emily R

    2012-12-01

    Microsporidia comprise a large phylum of obligate intracellular eukaryotes that are fungal-related parasites responsible for widespread disease, and here we address questions about microsporidia biology and evolution. We sequenced three microsporidian genomes from two species, Nematocida parisii and Nematocida sp1, which are natural pathogens of Caenorhabditis nematodes and provide model systems for studying microsporidian pathogenesis. We performed deep sequencing of transcripts from a time course of N. parisii infection. Examination of pathogen gene expression revealed compact transcripts and a dramatic takeover of host cells by Nematocida. We also performed phylogenomic analyses of Nematocida and other microsporidian genomes to refine microsporidian phylogeny and identify evolutionary events of gene loss, acquisition, and modification. In particular, we found that all microsporidia lost the tumor-suppressor gene retinoblastoma, which we speculate could accelerate the parasite cell cycle and increase the mutation rate. We also found that microsporidia acquired transporters that could import nucleosides to fuel rapid growth. In addition, microsporidian hexokinases gained secretion signal sequences, and in a functional assay these were sufficient to export proteins out of the cell; thus hexokinase may be targeted into the host cell to reprogram it toward biosynthesis. Similar molecular changes appear during formation of cancer cells and may be evolutionary strategies adopted independently by microsporidia to proliferate rapidly within host cells. Finally, analysis of genome polymorphisms revealed evidence for a sexual cycle that may provide genetic diversity to alleviate problems caused by clonal growth. Together these events may explain the emergence and success of these diverse intracellular parasites. PMID:22813931

  13. Micro-spectroscopic mapping: revealing internal structures of zircon crystals

    NASA Astrophysics Data System (ADS)

    Nasdala, L.; Reiners, P. W.; Hanchar, J. M.

    2003-04-01

    Natural zircon crystals typically deviate from perfect crystallinity and ideal chemical composition. If non-ideality features are not homogeneously distributed within a crystal but show a heterogeneity pattern, this is referred to as its "internal structure". Internal structures of zircon are mostly first caused by the heterogeneous incorporation of trace elements during crystal growth. Over time, these primary patterns may become more complex after being overprinted by radioactive self-irradiation and heterogeneous alteration or recrystallization. Internal structures may provide valuable information about the origin and post-growth history of zircon crystals. Further, they need to be recognized for sound microprobe dating, for instance to avoid biased results when straddling zones of different age. Revealing internal structures has thus become an important tool in zircon research. It is mostly done by means of backscattered electrons or cathodoluminescence imaging. These two techniques are advantageous over optical microscopy in the cross-polarized mode as the volume resolution is better and simple polished mounts instead of doubly-sided sections are needed. A disadvantage, however, is that the impact of electron beam during analysis causes local structural changes. Quantitative studies of the real structure of zircon samples, such as determination of the degree of the radiation damage, is therefore tainted with potential uncertainty when being done after electron probe analysis. As an alternative, we present images of internal zircon structures generated through visible laser excitation and mapping of the Raman and photoluminescence light. Due to the time-consuming mapping procedure, such images will perhaps not be routinely used. For detailed studies, however, they may provide most valuable information. Photoluminescence maps provide, for instance, information on both the distribution of rare earth elements (band integrals) and the short-range order (band

  14. HUBBLE REVEALS THE HEART OF THE WHIRLPOOL GALAXY

    NASA Technical Reports Server (NTRS)

    2002-01-01

    New images from NASA's Hubble Space Telescope are helping researchers view in unprecedented detail the spiral arms and dust clouds of a nearby galaxy, which are the birth sites of massive and luminous stars. The Whirlpool galaxy, M51, has been one of the most photogenic galaxies in amateur and professional astronomy. Easily photographed and viewed by smaller telescopes, this celestial beauty is studied extensively in a range of wavelengths by large ground- and space-based observatories. This Hubble composite image shows visible starlight as well as light from the emission of glowing hydrogen, which is associated with the most luminous young stars in the spiral arms. M51, also known as NGC 5194, is having a close encounter with a nearby companion galaxy, NGC 5195, just off the upper edge of this image. The companion's gravitational pull is triggering star formation in the main galaxy, as seen in brilliant detail by numerous, luminous clusters of young and energetic stars. The bright clusters are highlighted in red by their associated emission from glowing hydrogen gas. This Wide Field Planetary Camera 2 image enables a research group, led by Nick Scoville (Caltech), to clearly define the structure of both the cold dust clouds and the hot hydrogen and link individual clusters to their parent dust clouds. Team members include M. Polletta (U. Geneva); S. Ewald and S. Stolovy (Caltech); R. Thompson and M. Rieke (U. of Arizona). Intricate structure is also seen for the first time in the dust clouds. Along the spiral arms, dust 'spurs' are seen branching out almost perpendicular to the main spiral arms. The regularity and large number of these features suggests to astronomers that previous models of 'two-arm' spiral galaxies may need to be revisited. The new images also reveal a dust disk in the nucleus, which may provide fuel for a nuclear black hole. The team is also studying this galaxy at near-infrared wavelengths with the NICMOS instrument onboard Hubble. At these

  15. Episodic Sexual Transmission of HIV Revealed by Molecular Phylodynamics

    PubMed Central

    Rambaut, Andrew; Pozniak, Anton; Leigh Brown, Andrew J.

    2008-01-01

    Background The structure of sexual contact networks plays a key role in the epidemiology of sexually transmitted infections, and their reconstruction from interview data has provided valuable insights into the spread of infection. For HIV, the long period of infectivity has made the interpretation of contact networks more difficult, and major discrepancies have been observed between the contact network and the transmission network revealed by viral phylogenetics. The high rate of HIV evolution in principle allows for detailed reconstruction of links between virus from different individuals, but often sampling has been too sparse to describe the structure of the transmission network. The aim of this study was to analyze a high-density sample of an HIV-infected population using recently developed techniques in phylogenetics to infer the short-term dynamics of the epidemic among men who have sex with men (MSM). Methods and Findings Sequences of the protease and reverse transcriptase coding regions from 2,126 patients, predominantly MSM, from London were compared: 402 of these showed a close match to at least one other subtype B sequence. Nine large clusters were identified on the basis of genetic distance; all were confirmed by Bayesian Monte Carlo Markov chain (MCMC) phylogenetic analysis. Overall, 25% of individuals with a close match with one sequence are linked to 10 or more others. Dated phylogenies of the clusters using a relaxed clock indicated that 65% of the transmissions within clusters took place between 1995 and 2000, and 25% occurred within 6 mo after infection. The likelihood that not all members of the clusters have been identified renders the latter observation conservative. Conclusions Reconstruction of the HIV transmission network using a dated phylogeny approach has revealed the HIV epidemic among MSM in London to have been episodic, with evidence of multiple clusters of transmissions dating to the late 1990s, a period when HIV prevalence is known

  16. Cold exposure reveals two populations of microtubules in pulmonary endothelia.

    PubMed

    Ochoa, Cristhiaan D; Stevens, Troy; Balczon, Ron

    2011-01-01

    Microtubules are composed of α-tubulin and β-tubulin dimers. Microtubules yield tubulin dimers when exposed to cold, which reassemble spontaneously to form microtubule fibers at 37°C. However, mammalian neurons, glial cells, and fibroblasts have cold-stable microtubules. While studying the microtubule toxicity mechanisms of the exotoxin Y from Pseudomonas aeruginosa in pulmonary microvascular endothelial cells, we observed that some endothelial microtubules were very difficult to disassemble in the cold. As a consequence, we designed studies to test the hypothesis that microvascular endothelium has a population of cold-stable microtubules. Pulmonary microvascular endothelial cells and HeLa cells (control) were grown under regular cell culture conditions, followed by exposure to an ice-cold water bath and a microtubule extraction protocol. Polymerized microtubules were detected by immunofluorescence confocal microscopy and Western blot analyses. After cold exposure, immunofluorescence revealed that the majority of HeLa cell microtubules disassembled, whereas a smaller population of endothelial cell microtubules disassembled. Immunoblot analyses showed that microvascular endothelial cells express the microtubule cold-stabilizing protein N-STOP (neuronal stable tubule-only polypeptides), and that N-STOP binds to endothelial microtubules after cold exposure, but not if microtubules are disassembled with nocodazole before cold exposure. Hence, pulmonary endothelia have a population of cold-stable microtubules. PMID:20971804

  17. Revealing biological information using data structuring and automated learning.

    PubMed

    Mohorianu, Irina; Moulton, Vincent

    2010-11-01

    The intermediary steps between a biological hypothesis, concretized in the input data, and meaningful results, validated using biological experiments, commonly employ bioinformatics tools. Starting with storage of the data and ending with a statistical analysis of the significance of the results, every step in a bioinformatics analysis has been intensively studied and the resulting methods and models patented. This review summarizes the bioinformatics patents that have been developed mainly for the study of genes, and points out the universal applicability of bioinformatics methods to other related studies such as RNA interference. More specifically, we overview the steps undertaken in the majority of bioinformatics analyses, highlighting, for each, various approaches that have been developed to reveal details from different perspectives. First we consider data warehousing, the first task that has to be performed efficiently, optimizing the structure of the database, in order to facilitate both the subsequent steps and the retrieval of information. Next, we review data mining, which occupies the central part of most bioinformatics analyses, presenting patents concerning differential expression, unsupervised and supervised learning. Last, we discuss how networks of interactions of genes or other players in the cell may be created, which help draw biological conclusions and have been described in several patents. PMID:21288193

  18. Cytoplasmic Dynamics Reveals Two Modes of Nucleoid-Dependent Mobility

    PubMed Central

    Stylianidou, Stella; Kuwada, Nathan J.; Wiggins, Paul A.

    2014-01-01

    It has been proposed that forces resulting from the physical exclusion of macromolecules from the bacterial nucleoid play a central role in organizing the bacterial cell, yet this proposal has not been quantitatively tested. To investigate this hypothesis, we mapped the generic motion of large protein complexes in the bacterial cytoplasm through quantitative analysis of thousands of complete cell-cycle trajectories of fluorescently tagged ectopic MS2-mRNA complexes. We find the motion of these complexes in the cytoplasm is strongly dependent on their spatial position along the long axis of the cell, and that their dynamics are consistent with a quantitative model that requires only nucleoid exclusion and membrane confinement. This analysis also reveals that the nucleoid increases the mobility of MS2-mRNA complexes, resulting in a fourfold increase in diffusion coefficients between regions of the lowest and highest nucleoid density. These data provide strong quantitative support for two modes of nucleoid action: the widely accepted mechanism of nucleoid exclusion in organizing the cell and a newly proposed mode, in which the nucleoid facilitates rapid motion throughout the cytoplasm. PMID:25468347

  19. Recombination patterns reveal information about centromere location on linkage maps.

    PubMed

    Limborg, Morten T; McKinney, Garrett J; Seeb, Lisa W; Seeb, James E

    2016-05-01

    Linkage mapping is often used to identify genes associated with phenotypic traits and for aiding genome assemblies. Still, many emerging maps do not locate centromeres - an essential component of the genomic landscape. Here, we demonstrate that for genomes with strong chiasma interference, approximate centromere placement is possible by phasing the same data used to generate linkage maps. Assuming one obligate crossover per chromosome arm, information about centromere location can be revealed by tracking the accumulated recombination frequency along linkage groups, similar to half-tetrad analyses. We validate the method on a linkage map for sockeye salmon (Oncorhynchus nerka) with known centromeric regions. Further tests suggest that the method will work well in other salmonids and other eukaryotes. However, the method performed weakly when applied to a male linkage map (rainbow trout; O. mykiss) characterized by low and unevenly distributed recombination - a general feature of male meiosis in many species. Further, a high frequency of double crossovers along chromosome arms in barley reduced resolution for locating centromeric regions on most linkage groups. Despite these limitations, our method should work well for high-density maps in species with strong recombination interference and will enrich many existing and future mapping resources. PMID:26561199

  20. Initiation process of a thrust fault revealed by analog experiments

    NASA Astrophysics Data System (ADS)

    Yamada, Yasuhiro; Dotare, Tatsuya; Adam, Juergen; Hori, Takane; Sakaguchi, Hide

    2016-04-01

    We conducted 2D (cross-sectional) analog experiments with dry sand using a high resolution digital image correlation (DIC) technique to reveal initiation process of a thrust fault in detail, and identified a number of "weak shear bands" and minor uplift prior to the thrust initiation. The observations suggest that the process can be divided into three stages. Stage 1: characterized by a series of abrupt and short-lived weak shear bands at the location where the thrust will be generated later. Before initiation of the fault, the area to be the hanging wall starts to uplift. Stage 2: defined by the generation of the new thrust and its active displacement. The location of the new thrust seems to be constrained by its associated back-thrust, produced at the foot of the surface slope (by the previous thrust). The activity of the previous thrust turns to zero once the new thrust is generated, but the timing of these two events is not the same. Stage 3: characterized by a constant displacement along the (new) thrust. Similar minor shear bands can be seen in the toe area of the Nankai accretionary prism, SW Japan and we can correlate the along-strike variations in seismic profiles to the model results that show the characteristic features in each thrust development stage.

  1. Cassava root membrane proteome reveals activities during storage root maturation.

    PubMed

    Naconsie, Maliwan; Lertpanyasampatha, Manassawe; Viboonjun, Unchera; Netrphan, Supatcharee; Kuwano, Masayoshi; Ogasawara, Naotake; Narangajavana, Jarunya

    2016-01-01

    Cassava (Manihot esculenta Crantz) is one of the most important crops of Thailand. Its storage roots are used as food, feed, starch production, and be the important source for biofuel and biodegradable plastic production. Despite the importance of cassava storage roots, little is known about the mechanisms involved in their formation. This present study has focused on comparison of the expression profiles of cassava root proteome at various developmental stages using two-dimensional gel electrophoresis and LC-MS/MS. Based on an anatomical study using Toluidine Blue, the secondary growth was confirmed to be essential during the development of cassava storage root. To investigate biochemical processes occurring during storage root maturation, soluble and membrane proteins were isolated from storage roots harvested from 3-, 6-, 9-, and 12-month-old cassava plants. The proteins with differential expression pattern were analysed and identified to be associated with 8 functional groups: protein folding and degradation, energy, metabolism, secondary metabolism, stress response, transport facilitation, cytoskeleton, and unclassified function. The expression profiling of membrane proteins revealed the proteins involved in protein folding and degradation, energy, and cell structure were highly expressed during early stages of development. Integration of these data along with the information available in genome and transcriptome databases is critical to expand knowledge obtained solely from the field of proteomics. Possible role of identified proteins were discussed in relation with the activities during storage root maturation in cassava. PMID:26547558

  2. Quantification of the stapedial reflex reveals delayed responses in autism.

    PubMed

    Lukose, Richard; Brown, Kevin; Barber, Carol M; Kulesza, Randy Joseph

    2013-10-01

    Autism is a developmental disorder characterized, in part, by sensory abnormalities. It is well established that most if not all patients with autism have problems with auditory processing, ranging from deafness to hyperacusis, and physiological testing of auditory function (i.e. auditory brain stem responses) implicates brain stem dysfunction in autism. Additionally, previous research from this lab has revealed significantly fewer auditory brain stem neurons in autistic subjects as young as 2 years of age. These observations have led us to hypothesize that objective, noninvasive measures of auditory function can be used as an early screening tool to identify neonates with an elevated risk of carrying a diagnosis of autism. Here, we provide a detailed quantitative investigation of the acoustic stapedial reflex (ASR), a three- or four-neuron brain stem circuit, in young autistic subjects and normal developing controls. Indeed, we find significantly lower thresholds, responses occurring at significantly longer latency and right-left asymmetry in autistic subjects. The results from this investigation support deficits in auditory function as a cardinal feature of autism and suggest that individuals with autism can be identified by their ASR responses. PMID:23825093

  3. Revealing Bell's nonlocality for unstable systems in high energy physics

    NASA Astrophysics Data System (ADS)

    Hiesmayr, Beatrix C.; Di Domenico, Antonio; Curceanu, Catalina; Gabriel, Andreas; Huber, Marcus; Larsson, Jan-Åke; Moskal, Pawel

    2012-01-01

    Entanglement and its consequences—in particular the violation of Bell inequalities, which defies our concepts of realism and locality—have been proven to play key roles in Nature by many experiments for various quantum systems. Entanglement can also be found in systems not consisting of ordinary matter and light, i.e. in massive meson-antimeson systems. Bell inequalities have been discussed for these systems, but up to date no direct experimental test to conclusively exclude local realism was found. This mainly stems from the fact that one only has access to a restricted class of observables and that these systems are also decaying. In this Letter we put forward a Bell inequality for unstable systems which can be tested at accelerator facilities with current technology. Herewith, the long awaited proof that such systems at different energy scales can reveal the sophisticated " dynamical" nonlocal feature of Nature in a direct experiment gets feasible. Moreover, the role of entanglement and mathcal{CP} violation, an asymmetry between matter and antimatter, is explored, a special feature offered only by these meson-antimeson systems.

  4. Geometric morphometric analysis reveals sexual dimorphism in the distal femur.

    PubMed

    Cavaignac, Etienne; Savall, Frederic; Faruch, Marie; Reina, Nicolas; Chiron, Philippe; Telmon, Norbert

    2016-02-01

    An individual's sex can be determined by the shape of their distal femur. The goal of this study was to show that differences in distal femur shape related to sexual dimorphism could be identified, visualized, and quantified using 3D geometric morphometric analysis. Geometric morphometric analysis was carried out on CT scans of the distal femur of 256 subjects living in the south of France. Ten landmarks were defined on 3D reconstructions of the distal femur. Both traditional metric and geometric morphometric analyses were carried out on these bone reconstructions; these analyses identified trends in bone shape in sex-based subgroups. Sex-related differences in shape were statistically significant. The subject's sex was correctly assigned in 77.3% of cases using geometric morphometric analysis. This study has shown that geometric morphometric analysis of the distal femur is feasible and has revealed sexual dimorphism differences in this bone segment. This reliable, accurate method could be used for virtual autopsy and be used to perform diachronic and interethnic comparisons. Moreover, this study provides updated morphometric data for a modern population in the south of France. PMID:26743712

  5. Seismic Tremor Reveals Subglacial Discharge at Tidewater Glaciers

    NASA Astrophysics Data System (ADS)

    Bartholomaus, T. C.; Larsen, C. F.; O'Neel, S.; West, M. E.; Amundson, J. M.; Walter, J. I.; Catania, G. A.; Stearns, L. A.; Walker, R. T.; Sutherland, D.; Shroyer, E.; Nash, J. D.

    2014-12-01

    Subglacial discharge from the termini of tidewater glaciers drives submarine terminus melting, influences fjord circulation, erodes and redeposits subglacial sediment, and is a central component of proglacial marine ecosystems. The timing and variability of subglacial discharge can also exert a strong influence on the upstream flow of tidewater glaciers through hydrology-mediated changes in basal motion. However, a lack of observations of subglacial discharge at the ice-ocean interface hinders progress in understanding these processes and contributes to some of the largest uncertainties in sea level rise projections. Here we demonstrate that passive seismic observations collected adjacent to glaciers can meet this observational need. At tidewater and lake-terminating glaciers in Alaska and Greenland, we observe hourly to seasonal variations in low-amplitude, background seismic noise, termed glacio-hydraulic tremor. Variations in tremor amplitude correlate with discharge during the drainage of a glacially-dammed lake and reveal increases in discharge efficiency over the course of the melt season. Recordings of glacio-hydraulic tremor across a range of settings suggest widespread utility for our method. Reliable prediction of future sea level rise requires observations of subglacial discharge that elicit physical insight and can validate models. Our findings provide a platform for new understanding of ice-ocean interactions and related oceanographic, geologic, and ecological disciplines.

  6. Identification of disulfide bond isomerase substrates reveals bacterial virulence factors

    PubMed Central

    Ren, Guoping; Champion, Matthew M.; Huntley, Jason F.

    2014-01-01

    Summary Bacterial pathogens are exposed to toxic molecules inside the host and require efficient systems to form and maintain correct disulfide bonds for protein stability and function. The intracellular pathogen Francisella tularensis encodes a disulfide bond formation protein ortholog, DsbA, which previously was reported to be required for infection of macrophages and mice. However, the molecular mechanisms by which F. tularensis DsbA contributes to virulence are unknown. Here, we demonstrate that F. tularensis DsbA is a bifunctional protein that oxidizes and, more importantly, isomerizes complex disulfide connectivity in substrates. A single amino acid in the conserved cis-proline loop of the DsbA thioredoxin domain was shown to modulate both isomerase activity and F. tularensis virulence. Trapping experiments in F. tularensis identified over 50 F. tularensis DsbA substrates, including outer membrane proteins, virulence factors, and many hypothetical proteins. Six of these hypothetical proteins were randomly selected and deleted, revealing two novel proteins, FTL_1548 and FTL_1709, which are required for F. tularensis virulence. We propose that the extreme virulence of F. tularensis is partially due to the bifunctional nature of DsbA, that many of the newly-identified substrates are required for virulence, and that the development of future DsbA inhibitors could have broad anti-bacterial implications. PMID:25257164

  7. Historical Reconstruction Reveals Recovery in Hawaiian Coral Reefs

    PubMed Central

    Kittinger, John N.; Pandolfi, John M.; Blodgett, Jonathan H.; Hunt, Terry L.; Jiang, Hong; Maly, Kepā; McClenachan, Loren E.; Schultz, Jennifer K.; Wilcox, Bruce A.

    2011-01-01

    Coral reef ecosystems are declining worldwide, yet regional differences in the trajectories, timing and extent of degradation highlight the need for in-depth regional case studies to understand the factors that contribute to either ecosystem sustainability or decline. We reconstructed social-ecological interactions in Hawaiian coral reef environments over 700 years using detailed datasets on ecological conditions, proximate anthropogenic stressor regimes and social change. Here we report previously undetected recovery periods in Hawaiian coral reefs, including a historical recovery in the MHI (∼AD 1400–1820) and an ongoing recovery in the NWHI (∼AD 1950–2009+). These recovery periods appear to be attributed to a complex set of changes in underlying social systems, which served to release reefs from direct anthropogenic stressor regimes. Recovery at the ecosystem level is associated with reductions in stressors over long time periods (decades+) and large spatial scales (>103 km2). Our results challenge conventional assumptions and reported findings that human impacts to ecosystems are cumulative and lead only to long-term trajectories of environmental decline. In contrast, recovery periods reveal that human societies have interacted sustainably with coral reef environments over long time periods, and that degraded ecosystems may still retain the adaptive capacity and resilience to recover from human impacts. PMID:21991311

  8. Geometric Mechanics Reveals Optimal Complex Terrestrial Undulation Patterns

    NASA Astrophysics Data System (ADS)

    Gong, Chaohui; Astley, Henry; Schiebel, Perrin; Dai, Jin; Travers, Matthew; Goldman, Daniel; Choset, Howie; CMU Team; GT Team

    Geometric mechanics offers useful tools for intuitively analyzing biological and robotic locomotion. However, utility of these tools were previously restricted to systems that have only two internal degrees of freedom and in uniform media. We show kinematics of complex locomotors that make intermittent contacts with substrates can be approximated as a linear combination of two shape bases, and can be represented using two variables. Therefore, the tools of geometric mechanics can be used to analyze motions of locomotors with many degrees of freedom. To demonstrate the proposed technique, we present studies on two different types of snake gaits which utilize combinations of waves in the horizontal and vertical planes: sidewinding (in the sidewinder rattlesnake C. cerastes) and lateral undulation (in the desert specialist snake C. occipitalis). C. cerastes moves by generating posteriorly traveling body waves in the horizontal and vertical directions, with a relative phase offset equal to +/-π/2 while C. occipitalismaintains a π/2 offset of a frequency doubled vertical wave. Geometric analysis reveals these coordination patterns enable optimal movement in the two different styles of undulatory terrestrial locomotion. More broadly, these examples demonstrate the utility of geometric mechanics in analyzing realistic biological and robotic locomotion.

  9. Phenotypic Expression in Wheat Revealed Using FT-IR Microspectroscopy

    SciTech Connect

    Brewer, L.; Wetzel, D

    2009-01-01

    Wheat selected for cultivation through the centuries has a glume that is 'soft' instead of 'tough' as naturally occurring. In production, this is desirable because it enables mechanical threshing with efficient separation of kernel from the head of each stalk without damaging the kernel. FT-IR microspectroscopy provides chemically based, objective assessment of genetic expression by measuring the extent of genetic expression. In the Microbeam Molecular Spectroscopy Laboratory, Manhattan, KS, an imaging FT-IR microspectrometer with a detector array focused on the image plane was used to obtain spectral data from dissected glume specimens of nine tough and eleven soft wheat cultivars in a rectangular mapping pattern. With cellulose as the substrate, the extent of lignification is measurable from the ratio of the lignin (1508 cm{sup -1}) baseline adjusted band area to the representative cellulosic (1370 cm{sup -1}) band area. A distinction between soft and tough glumes is obtained in numerical terms. Using a band ratio minimizes variation due to thickness differences. While analyzing mapped sections of glume, care is taken to avoid tabulation of spectral data from vascular bundles. Inclusion of these data would to avoid tabulation of spectral data from vascular bundles. Inclusion of these data would bias the analysis toward the composition of highly lignified vascular bundles. Spatially resolved focal plane array FT-IR microspectroscopy reveals the extent of glume lignification that is coincident with the toughness trait. This enables breeders to rank the degree of lignin expression and discriminate between soft and tough breeding results.

  10. Planarian Phototactic Assay Reveals Differential Behavioral Responses Based on Wavelength

    PubMed Central

    Paskin, Taylor R.; Jellies, John; Bacher, Jessica; Beane, Wendy S.

    2014-01-01

    Planarians are free-living aquatic flatworms that possess a well-documented photophobic response to light. With a true central nervous system and simple cerebral eyes (ocelli), planarians are an emerging model for regenerative eye research. However, comparatively little is known about the physiology of their photoreception or how their behavior is affected by various wavelengths. Most phototactic studies have examined planarian behavior using white light. Here, we describe a novel planarian behavioral assay to test responses to small ranges of visible wavelengths (red, blue, green), as well as ultraviolet (UV) and infrared (IR) which have not previously been examined. Our data show that planarians display behavioral responses across a range of wavelengths. These responses occur in a hierarchy, with the shortest wavelengths (UV) causing the most intense photophobic responses while longer wavelengths produce no effect (red) or an apparent attraction (IR). In addition, our data reveals that planarian photophobia is comprised of both a general photophobic response (that drives planarians to escape the light source regardless of wavelength) and wavelength-specific responses that encompass specific behavioral reactions to individual wavelengths. Our results serve to improve the understanding of planarian phototaxis and suggest that behavioral studies performed with white light mask a complex behavioral interaction with the environment. PMID:25493551

  11. Super-resolution Microscopy Reveals Compartmentalization of Peroxisomal Membrane Proteins.

    PubMed

    Galiani, Silvia; Waithe, Dominic; Reglinski, Katharina; Cruz-Zaragoza, Luis Daniel; Garcia, Esther; Clausen, Mathias P; Schliebs, Wolfgang; Erdmann, Ralf; Eggeling, Christian

    2016-08-12

    Membrane-associated events during peroxisomal protein import processes play an essential role in peroxisome functionality. Many details of these processes are not known due to missing spatial resolution of technologies capable of investigating peroxisomes directly in the cell. Here, we present the use of super-resolution optical stimulated emission depletion microscopy to investigate with sub-60-nm resolution the heterogeneous spatial organization of the peroxisomal proteins PEX5, PEX14, and PEX11 around actively importing peroxisomes, showing distinct differences between these peroxins. Moreover, imported protein sterol carrier protein 2 (SCP2) occupies only a subregion of larger peroxisomes, highlighting the heterogeneous distribution of proteins even within the peroxisome. Finally, our data reveal subpopulations of peroxisomes showing only weak colocalization between PEX14 and PEX5 or PEX11 but at the same time a clear compartmentalized organization. This compartmentalization, which was less evident in cases of strong colocalization, indicates dynamic protein reorganization linked to changes occurring in the peroxisomes. Through the use of multicolor stimulated emission depletion microscopy, we have been able to characterize peroxisomes and their constituents to a yet unseen level of detail while maintaining a highly statistical approach, paving the way for equally complex biological studies in the future. PMID:27311714

  12. Revealing the structure of the world airline network

    PubMed Central

    Verma, T.; Araújo, N. A. M.; Herrmann, H. J.

    2014-01-01

    Resilience of most critical infrastructures against failure of elements that appear insignificant is usually taken for granted. The World Airline Network (WAN) is an infrastructure that reduces the geographical gap between societies, both small and large, and brings forth economic gains. With the extensive use of a publicly maintained data set that contains information about airports and alternative connections between these airports, we empirically reveal that the WAN is a redundant and resilient network for long distance air travel, but otherwise breaks down completely due to removal of short and apparently insignificant connections. These short range connections with moderate number of passengers and alternate flights are the connections that keep remote parts of the world accessible. It is surprising, insofar as there exists a highly resilient and strongly connected core consisting of a small fraction of airports (around 2.3%) together with an extremely fragile star-like periphery. Yet, in spite of their relevance, more than 90% of the world airports are still interconnected upon removal of this core. With standard and unconventional removal measures we compare both empirical and topological perceptions for the fragmentation of the world. We identify how the WAN is organized into different classes of clusters based on the physical proximity of airports and analyze the consequence of this fragmentation. PMID:25005934

  13. Revealing catastrophic failure of leaf networks under stress.

    PubMed

    Brodribb, Timothy J; Bienaimé, Diane; Marmottant, Philippe

    2016-04-26

    The intricate patterns of veins that adorn the leaves of land plants are among the most important networks in biology. Water flows in these leaf irrigation networks under tension and is vulnerable to embolism-forming cavitations, which cut off water supply, ultimately causing leaf death. Understanding the ways in which plants structure their vein supply network to protect against embolism-induced failure has enormous ecological and evolutionary implications, but until now there has been no way of observing dynamic failure in natural leaf networks. Here we use a new optical method that allows the initiation and spread of embolism bubbles in the leaf network to be visualized. Examining embolism-induced failure of architecturally diverse leaf networks, we found that conservative rules described the progression of hydraulic failure within veins. The most fundamental rule was that within an individual venation network, susceptibility to embolism always increased proportionally with the size of veins, and initial nucleation always occurred in the largest vein. Beyond this general framework, considerable diversity in the pattern of network failure was found between species, related to differences in vein network topology. The highest-risk network was found in a fern species, where single events caused massive disruption to leaf water supply, whereas safer networks in angiosperm leaves contained veins with composite properties, allowing a staged failure of water supply. These results reveal how the size structure of leaf venation is a critical determinant of the spread of embolism damage to leaves during drought. PMID:27071104

  14. The Mass Donor of Scorpius X-1 Revealed

    NASA Astrophysics Data System (ADS)

    Steeghs, D.; Casares, J.

    2002-03-01

    We present the first detection of the mass donor star in the prototype X-ray binary Scorpius X-1. Phase-resolved spectroscopy revealed narrow emission line components from the irradiated secondary star. Radial velocity fits to the Bowen blend emission are used to establish an absolute orbital ephemeris and derive an accurate value for the systemic velocity, γ=-113.8+/-0.6 km s-1. Emission from the irradiated front side of the secondary leads to solid limits to the radial velocity of the mass donor of 87<~K2<~148 km s-1. In conjunction with an upper limit to the velocity of the primary K1<=53 km s-1, we derive a firm limit on the mass ratio of Sco X-1 of q<~0.61. A likely set of system parameters satisfying the various constraints as well as the recent inclination estimate by Fomalont, Geldzahler, & Bradshaw (2001) is K1=40 km s-1, K2=133 km s-1, q=0.30 corresponding to component masses of M1=1.4Msolar and M2=0.42Msolar for an orbital inclination of 38°.

  15. Pyrosequencing Reveals Fungal Communities in the Rhizosphere of Xinjiang Jujube

    PubMed Central

    Wang, Xiao-Hui; Li, Jian-Gui; Qin, Wei; Xiao, Cheng-Ze; Zhao, Xu; Jiang, Hong-Xia; Sui, Jun-Kang; Sa, Rong-Bo; Wang, Wei-Yan; Liu, Xun-Li

    2015-01-01

    Fungi are important soil components as both decomposers and plant symbionts and play a major role in ecological and biogeochemical processes. However, little is known about the richness and structure of fungal communities. DNA sequencing technologies allow for the direct estimation of microbial community diversity, avoiding culture-based biases. We therefore used 454 pyrosequencing to investigate the fungal communities in the rhizosphere of Xinjiang jujube. We obtained no less than 40,488 internal transcribed spacer (ITS) rDNA reads, the number of each sample was 6943, 6647, 6584, 6550, 6860, and 6904, and we used bioinformatics and multivariate statistics to analyze the results. The index of diversity showed greater richness in the rhizosphere fungal community of a 3-year-old jujube than in that of an 8-year-old jujube. Most operational taxonomic units belonged to Ascomycota, and taxonomic analyses identified Hypocreales as the dominant fungal order. Our results demonstrated that the fungal orders are present in different proportions in different sampling areas. Redundancy analysis (RDA) revealed a significant correlation between soil properties and the abundance of fungal phyla. Our results indicated lower fungal diversity in the rhizosphere of Xinjiang jujube than that reported in other studies, and we hope our findings provide a reference for future research. PMID:25685820

  16. Small molecules reveal an alternative mechanism of Bax activation

    PubMed Central

    Brahmbhatt, Hetal; Uehling, David; Al-awar, Rima; Leber, Brian; Andrews, David

    2016-01-01

    The pro-apoptotic protein Bax commits a cell to death by permeabilizing the mitochondrial outer membrane (MOM). To obtain small-molecule probes for elucidating the molecular mechanism(s) of Bax activation, we screened for compounds that induced Bax-mediated liposome permeabilization. We identified five structurally different small molecules that promoted both Bax targeting to and oligomerization at membranes. All five compounds initiated Bax oligomerization in the absence of membranes by a mechanism unlike Bax activation by Bcl-2 homology 3 domain (BH3) proteins. Some of the compounds induced Bax/Bak-dependent apoptosis in cells. Activation of Bax by the most active compound was poorly inhibited by the anti-apoptotic protein Bcl-XL and requires a cysteine residue at position 126 of Bax that is not required for activation by BH3 proteins. Our results reveal a novel pathway for Bax activation independent of pro-apoptotic BH3 proteins that may have important implications for the regulation of Bax activity in cells. PMID:26916338

  17. Comparative Genomic Indexing Reveals the Phylogenomics of Escherichia coli Pathogens

    PubMed Central

    Anjum, Muna F.; Lucchini, Sacha; Thompson, Arthur; Hinton, Jay C. D.; Woodward, Martin J.

    2003-01-01

    The Escherichia coli O26 serogroup includes important food-borne pathogens associated with human and animal diarrheal disease. Current typing methods have revealed great genetic heterogeneity within the O26 group; the data are often inconsistent and focus only on verotoxin (VT)-positive O26 isolates. To improve current understanding of diversity within this serogroup, the genomic relatedness of VT-positive and -negative O26 strains was assessed by comparative genomic indexing. Our results clearly demonstrate that irrespective of virulence characteristics and pathotype designation, the O26 strains show greater genomic similarity to each other than to any other strain included in this study. Our data suggest that enteropathogenic and VT-expressing E. coli O26 strains represent the same clonal lineage and that VT-expressing E. coli O26 strains have gained additional virulence characteristics. Using this approach, we established the core genes which are central to the E. coli species and identified regions of variation from the E. coli K-12 chromosomal backbone. PMID:12874348

  18. Single-cell chromatin accessibility reveals principles of regulatory variation.

    PubMed

    Buenrostro, Jason D; Wu, Beijing; Litzenburger, Ulrike M; Ruff, Dave; Gonzales, Michael L; Snyder, Michael P; Chang, Howard Y; Greenleaf, William J

    2015-07-23

    Cell-to-cell variation is a universal feature of life that affects a wide range of biological phenomena, from developmental plasticity to tumour heterogeneity. Although recent advances have improved our ability to document cellular phenotypic variation, the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of mammalian DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells by assay for transposase-accessible chromatin using sequencing (ATAC-seq) integrated into a programmable microfluidics platform. Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provide insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type-specific accessibility variance across eight cell types. Targeted perturbations of cell cycle or transcription factor signalling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome compartments de novo, linking single-cell accessibility variation to three-dimensional genome organization. Single-cell analysis of DNA accessibility provides new insight into cellular variation of the 'regulome'. PMID:26083756

  19. Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

    SciTech Connect

    Huo, Lu; Davis, Ian; Liu, Fange; Andi, Babak; Esaki, Shingo; Iwaki, Hiroaki; Hasegawa, Yoshie; Orville, Allen M.; Liu, Aimin

    2015-01-07

    Aldehydes are ubiquitous intermediates in metabolic pathways and their innate reactivity can often make them quite unstable. There are several aldehydic intermediates in the metabolic pathway for tryptophan degradation that can decay into neuroactive compounds that have been associated with numerous neurological diseases. An enzyme of this pathway, 2-aminomuconate-6-semialdehyde dehydrogenase, is responsible for ‘disarming’ the final aldehydic intermediate. Here we show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms: resting state, one binary and two ternary complexes, and a covalent, thioacyl intermediate. We also report the crystal structures of a tetrahedral, thiohemiacetal intermediate, a thioacyl intermediate and an NAD+-bound complex from an active site mutant. These covalent intermediates are characterized by single-crystal and solution-state electronic absorption spectroscopy. The crystal structures reveal that the substrate undergoes an E/Z isomerization at the enzyme active site before an sp3-to-sp2 transition during enzyme-mediated oxidation.

  20. Mitochondrial Genome Sequences Effectively Reveal the Phylogeny of Hylobates Gibbons

    PubMed Central

    Chan, Yi-Chiao; Roos, Christian; Inoue-Murayama, Miho; Inoue, Eiji; Shih, Chih-Chin; Pei, Kurtis Jai-Chyi; Vigilant, Linda

    2010-01-01

    Background Uniquely among hominoids, gibbons exist as multiple geographically contiguous taxa exhibiting distinctive behavioral, morphological, and karyotypic characteristics. However, our understanding of the evolutionary relationships of the various gibbons, especially among Hylobates species, is still limited because previous studies used limited taxon sampling or short mitochondrial DNA (mtDNA) sequences. Here we use mtDNA genome sequences to reconstruct gibbon phylogenetic relationships and reveal the pattern and timing of divergence events in gibbon evolutionary history. Methodology/Principal Findings We sequenced the mitochondrial genomes of 51 individuals representing 11 species belonging to three genera (Hylobates, Nomascus and Symphalangus) using the high-throughput 454 sequencing system with the parallel tagged sequencing approach. Three phylogenetic analyses (maximum likelihood, Bayesian analysis and neighbor-joining) depicted the gibbon phylogenetic relationships congruently and with strong support values. Most notably, we recover a well-supported phylogeny of the Hylobates gibbons. The estimation of divergence times using Bayesian analysis with relaxed clock model suggests a much more rapid speciation process in Hylobates than in Nomascus. Conclusions/Significance Use of more than 15 kb sequences of the mitochondrial genome provided more informative and robust data than previous studies of short mitochondrial segments (e.g., control region or cytochrome b) as shown by the reliable reconstruction of divergence patterns among Hylobates gibbons. Moreover, molecular dating of the mitogenomic divergence times implied that biogeographic change during the last five million years may be a factor promoting the speciation of Sundaland animals, including Hylobates species. PMID:21203450

  1. Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

    DOE PAGESBeta

    Huo, Lu; Davis, Ian; Liu, Fange; Andi, Babak; Esaki, Shingo; Iwaki, Hiroaki; Hasegawa, Yoshie; Orville, Allen M.; Liu, Aimin

    2015-01-07

    Aldehydes are ubiquitous intermediates in metabolic pathways and their innate reactivity can often make them quite unstable. There are several aldehydic intermediates in the metabolic pathway for tryptophan degradation that can decay into neuroactive compounds that have been associated with numerous neurological diseases. An enzyme of this pathway, 2-aminomuconate-6-semialdehyde dehydrogenase, is responsible for ‘disarming’ the final aldehydic intermediate. Here we show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms: resting state, one binary and two ternary complexes, and a covalent, thioacyl intermediate. We also report the crystal structures of a tetrahedral, thiohemiacetal intermediate, a thioacylmore » intermediate and an NAD+-bound complex from an active site mutant. These covalent intermediates are characterized by single-crystal and solution-state electronic absorption spectroscopy. The crystal structures reveal that the substrate undergoes an E/Z isomerization at the enzyme active site before an sp3-to-sp2 transition during enzyme-mediated oxidation.« less

  2. [Meningococcal Septicemia Revealing Multiple Myeloma: A Case Report].

    PubMed

    Arakawa, Risturo; Mori, Nobuaki; Kagawa, Narito; Higuchi, Akiko; Tanaka, Masashi; Aoki, Yasuko; Seki, Shiko; Suzuki, Ryo

    2016-05-01

    Meningococcal infection is among the most devastating diseases. It is rarely seen in Japan. However, several environmental and host factors have been associated with increased risks of Neisseria meningitidis infection. We present a case of invasive N. meningitidis infection that revealed the presence of multiple myeloma. A 55-year-old Japanese man was admitted with fever and altered consciousness. He was sent to the intensive care unit for septic shock and disseminated intravascular coagulation. In addition to standard septic shock and multiple organ failure treatment, polymyxin-B immobilized column direct hemoperfusion was performed. His blood culture was positive for N. meningitidis. The patient gradually improved and was discharged on day 35. We evaluated the risk factors for the development of meningococcal infection. A laboratory examination showed that the patient was negative for human immunodeficiency virus antibody and had a normal total complement function. However, his serum immunoglobulin G level was high, and serum and urine protein electrophoresis detected a monoclonal gammopathy. A bone marrow examination led to the diagnosis of multiple myeloma. Because N. meningitidis bacteria spreads between individuals in close contact through the exchange of oral secretions, droplet precautions and antimicrobial chemoprophylaxis (ciprofloxacin, 500 mg) were implemented to prevent the spread of the meningococcal infection. Sporadic meningococcal infection warrants an evaluation for immunodeficiency and the prevention of secondary infection. PMID:27529971

  3. Revealing Amphiphilic Nanodornains of Anti-Biofouling Polymer Coatings

    SciTech Connect

    Amadei, CA; Yang, R; Chiesa, M; Gleason, KK; Santos, S

    2014-04-09

    Undesired bacterial adhesion and biofilm formation on wetted surfaces leads to significant economic and environmental costs in various industries. Amphiphilic coatings with molecular hydrophilic and hydrophobic patches can mitigate such biofouling effectively in an environmentally friendly manner. The coatings are synthesized by copolymerizing (Hydroxyethyl)methacrylate and perfluorodecylacrylate via initiated chemical vapor deposition (iCVD). In previous studies, the size of the patches was estimated to be similar to 1.4-1.75 nm by fitting protein adsorption data to a theoretical model. However, no direct observations of the molecular heterogeneity exist and therefore the origin of the fouling resistance of amphiphilic coatings remains unclear. Here, the amphiphilic nature is investigated by amplitude modulation atomic force microscopy (AM-AFM). High-resolution images obtained by penetrating and oscillating the AFM tip under the naturally present water layer with sub-nanometer amplitudes reveal, for the first time, the existence of amphiphilic nanodomains (1-2 nm(2)). Compositional heterogeneity at the nanoscale is further corroborated by a statistical analysis on the data obtained with dynamic AM-AFM force spectroscopy. Variations in the long range attractive forces, responsible for water affinity, are also identified. These nanoscopic results on the polymers wettability are also confirmed by contact angle measurements (i.e., static and dynamic). The unprecedented ability to visualize the amphiphilic nanodomains as well as sub-nanometer crystalline structures provides strong evidence for the existence of previously postulated nanostructures, and sheds light on the underlying antifouling mechanism of amphiphilic chemistry.

  4. Scurvy revealed by difficulty walking: three cases in young children.

    PubMed

    Kitcharoensakkul, Maleewan; Schulz, Christa G; Kassel, Rachel; Khanna, Geetika; Liang, Shannon; Ngwube, Alexander; Baszis, Kevin W; Hunstad, David A; White, Andrew J

    2014-06-01

    Scurvy is rare in developed countries but is known to cause lower-extremity pain and refusal to ambulate in children. Since the discovery of the link between scurvy and dietary deficiency of ascorbic acid, there has been a substantial decrease in its prevalence and recognition. Here we describe 3 cases of scurvy in young children presenting with difficulty walking. Only 1 of 3 patients had gingival lesions at the initial presentation. Two cases underwent an extensive evaluation for hematologic and rheumatologic diseases before the diagnosis of scurvy was made. Dietary histories eventually revealed that all 3 patients had sharply limited intake of fruits and vegetables secondary to oral aversion, and 1 patient had autism. Radiographic changes of long bones were observed in all patients. Interestingly, all patients had concomitant vitamin D deficiency. After replacement with vitamin C, all patients recovered and started to walk again with improved leg pain. These clinical manifestations and radiologic findings highlight the importance for rheumatologists to have a higher index of suspicion for scurvy in nonambulatory children. PMID:24847751

  5. Distributed neural system for emotional intelligence revealed by lesion mapping

    PubMed Central

    Colom, Roberto; Grafman, Jordan

    2014-01-01

    Cognitive neuroscience has made considerable progress in understanding the neural architecture of human intelligence, identifying a broadly distributed network of frontal and parietal regions that support goal-directed, intelligent behavior. However, the contributions of this network to social and emotional aspects of intellectual function remain to be well characterized. Here we investigated the neural basis of emotional intelligence in 152 patients with focal brain injuries using voxel-based lesion-symptom mapping. Latent variable modeling was applied to obtain measures of emotional intelligence, general intelligence and personality from the Mayer, Salovey, Caruso Emotional Intelligence Test (MSCEIT), the Wechsler Adult Intelligence Scale and the Neuroticism-Extroversion-Openness Inventory, respectively. Regression analyses revealed that latent scores for measures of general intelligence and personality reliably predicted latent scores for emotional intelligence. Lesion mapping results further indicated that these convergent processes depend on a shared network of frontal, temporal and parietal brain regions. The results support an integrative framework for understanding the architecture of executive, social and emotional processes and make specific recommendations for the interpretation and application of the MSCEIT to the study of emotional intelligence in health and disease. PMID:23171618

  6. Microscopic study reveals the singular origins of growth

    NASA Astrophysics Data System (ADS)

    Yaari, G.; Nowak, A.; Rakocy, K.; Solomon, S.

    2008-04-01

    Anderson [Science 177, 293 (1972)] proposed the concept of complexity in order to describe the emergence and growth of macroscopic collective patterns out of the simple interactions of many microscopic agents. In the physical sciences this paradigm was implemented systematically and confirmed repeatedly by successful confrontation with reality. In the social sciences however, the possibilities to stage experiments to validate it are limited. During the 90's a series of dramatic political and economic events have provided the opportunity to do so. We exploit the resulting empirical evidence to validate a simple agent based alternative to the classical logistic dynamics. The post-liberalization empirical data from Poland confirm the theoretical prediction that the dynamics is dominated by singular rare events which insure the resilience and adaptability of the system. We have shown that growth is led by few singular “growth centers" (Fig. 1), that initially developed at a tremendous rate (Fig. 3), followed by a diffusion process to the rest of the country and leading to a positive growth rate uniform across the counties. In addition to the interdisciplinary unifying potential of our generic formal approach, the present work reveals the strong causal ties between the “softer" social conditions and their “hard" economic consequences.

  7. Genetic investigation within Lactococcus garvieae revealed two genomic lineages.

    PubMed

    Ferrario, Chiara; Ricci, Giovanni; Borgo, Francesca; Rollando, Alessandro; Fortina, Maria Grazia

    2012-07-01

    The diversity of a collection of 49 Lactococcus garvieae strains, including isolates of dairy, fish, meat, vegetable and cereal origin, was explored using a molecular polyphasic approach comprising PCR-ribotyping, REP and RAPD-PCR analyses and a multilocus restriction typing (MLRT) carried out on six partial genes (atpA, tuf, dltA, als, gapC, and galP). This approach allowed high-resolution cluster analysis in which two major groups were distinguishable: one group included dairy isolates, the other group meat isolates. Unexpectedly, of the 12 strains coming from fish, four grouped with dairy isolates, whereas the others with meat isolates. Likewise, strains isolated from vegetables allocated between the two main groups. These findings revealed high variability within the species at both gene and genome levels. The observed genetic heterogeneity among L. garvieae strains was not entirely coherent with the ecological niche of origin of the strains, but rather supports the idea of an early separation of L. garvieae population into two independent genomic lineages. PMID:22568590

  8. Nicotinamide Riboside Kinase Structures Reveal New Pathways to NAD+

    PubMed Central

    Bogan, Katrina L; Belenky, Peter; Wojcik, Marzena; Seidle, Heather F; Nedyalkova, Lyudmila; Yang, Tianle; Sauve, Anthony A; Park, Hee-Won; Brenner, Charles

    2007-01-01

    The eukaryotic nicotinamide riboside kinase (Nrk) pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+) by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize the distinctive carboxamide group of nicotinamide riboside. Indeed, nicotinic acid riboside is a specific substrate of human Nrk enzymes and is utilized in yeast in a novel biosynthetic pathway that depends on Nrk and NAD+ synthetase. Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+. PMID:17914902

  9. Network deconstruction reveals network structure in responsive microgels.

    PubMed

    Smith, Michael H; Herman, Emily S; Lyon, L Andrew

    2011-04-14

    Detailed characterization of hydrogel particle erosion revealed critical physicochemical differences between spheres, where network decomposition was informative of network structure. Real-time, in situ monitoring of the triggered erosion of colloidal hydrogels (microgels) was performed via multiangle light scattering. The solution-average molar mass and root-mean-square radii of eroding particles were measured as a function of time for microgels prepared from N-isopropylacrylamide (NIPAm) or N-isopropylmethacrylamide (NIPMAm), copolymerized with a chemically labile cross-linker (1,2-dihydroxylethylene)bisacrylamide (DHEA). Precipitation polymerization was employed to yield particles of comparable dimensions but with distinct topological features. Heterogeneous cross-linker incorporation resulted in a heterogeneous network structure for pNIPAm microgels. During the erosion reaction, mass loss proceeded from the exterior toward the interior of the polymer. In contrast, pNIPMAm microgels had a more homogeneous network structure, which resulted in a more uniform mass loss throughout the particle during erosion. Although both particle types degraded into low molar mass products, pNIPAm microgels were incapable of complete dissolution due to the presence of nondegradable cross-links arising from chain transfer and branching during particle synthesis. The observations described herein provide insight into key design parameters associated with the synthesis of degradable hydrogel particles, which may be of use in various biotechnological applications. PMID:21425815

  10. Can strong correlations be experimentally revealed for Ҡ -mesons?

    NASA Astrophysics Data System (ADS)

    Hiesmayr, Beatrix C.

    2014-11-01

    In 1964 the physicists John St. Bell working at CERN took the 1935-idea of Einstein-Podolsky-Rosen seriously and found that all theories based on local realism have to satisfy a certain inequality, nowadays dubbed Bell's inequality. Experiments with ordinary matter systems or light show violations of Bell's inequality favouring the quantum theory though a loophole free experiment has not yet been performed. This contribution presents an experimentally feasible Bell inequality for systems at higher energy scales, i.e. entangled neutral Ҡ -meson pairs that are typically produced in Φ -mesons decays or proton-antiproton annihilation processes. Strong requirements have to be overcome in order to achieve a conclusive tests, such a proposal was recently published. Surprisingly, this new Bell inequality reveals new features for weakly decaying particles, in particular, a strong sensitivity to the combined charge-conjugation-parity (CP) symmetry. Here-with, a puzzling relation between a symmetry breaking for mesons and Bell's inequality—which is a necessary and sufficient condition for the security of quantum cryptography protocols— is established. This becomes the more important since CP symmetry is related to the cosmological question why the antimatter disappeared after the Big Bang.

  11. Maximal Neighbor Similarity Reveals Real Communities in Networks

    NASA Astrophysics Data System (ADS)

    Žalik, Krista Rizman

    2015-12-01

    An important problem in the analysis of network data is the detection of groups of densely interconnected nodes also called modules or communities. Community structure reveals functions and organizations of networks. Currently used algorithms for community detection in large-scale real-world networks are computationally expensive or require a priori information such as the number or sizes of communities or are not able to give the same resulting partition in multiple runs. In this paper we investigate a simple and fast algorithm that uses the network structure alone and requires neither optimization of pre-defined objective function nor information about number of communities. We propose a bottom up community detection algorithm in which starting from communities consisting of adjacent pairs of nodes and their maximal similar neighbors we find real communities. We show that the overall advantage of the proposed algorithm compared to the other community detection algorithms is its simple nature, low computational cost and its very high accuracy in detection communities of different sizes also in networks with blurred modularity structure consisting of poorly separated communities. All communities identified by the proposed method for facebook network and E-Coli transcriptional regulatory network have strong structural and functional coherence.

  12. From C to Parton Sea: How Supercomputing Reveals Nucleon Structure

    NASA Astrophysics Data System (ADS)

    Lin, Huey-Wen

    2016-03-01

    Studying the structure of nucleons is not only important to understanding the strong interactions of quarks and gluons, but also to improving the precision of new-physics searches. Since a broad class of experiments, including the LHC and dark-matter detection, require interactions with nucleons, the mission to probe femtoscale physics is also essential for disentangling Standard-Model contributions from potential new physics. These SM backgrounds require parton distribution functions (PDFs) as inputs. However, after decades of experiments and theoretical efforts, there still remain many unknowns, especially in the sea flavor structure and transversely polarized structure. In a discrete spacetime, we can make a direct numerical calculation of the implications of QCD using sufficiently large supercomputing resources. A nonperturbative approach from first principles, lattice QCD, provides hope to expand our understanding of nucleon structure, especially in regions that are difficult to observe in experiments. In this work, we present a first direct calculation of the Bjorken-x dependence of the PDFs using Large-Momentum Effective Theory (LaMET) and comment on the surprising result revealed for the nucleon sea-flavor asymmetry. The work of HWL is supported in part by the M. Hildred Blewett Fellowship of the American Physical Society, www.aps.org.

  13. Colored microspheres reveal interarterial microvascular anastomoses in canine myocardium.

    PubMed

    Cicutti, N; Rakusan, K; Downey, H F

    1992-01-01

    While the presence of microvascular intercommunication within an individual myocardial arterial bed is well documented, there is a paucity of data to support the existence of anastomoses emanating from independent arterial beds. Simultaneous in-vivo infusion of two different colored microsphere suspensions into the left anterior descending (LAD) and left circumflex (LCx) coronary arteries identified a specific interface region of canine myocardium that was perfused by both arterial branches. Subsequent microscopic/morphometric analysis of 40 microns serial sections in eight hearts revealed clustering of microspheres in their respective perfusion territories (red microspheres in the LAD region away from the interface, blue microspheres in the LCx field away from the interface), along with a mutually perfused borderzone. In each tissue section, two regions within this zone were identified and their maximum widths measured. One region was defined as the Interface Transition Zone (ITZ) (mean width = 5251 +/- 770 microns; mean +/- SD). This region was formed by an intermingling of microvessels supplied by the parent arteries of the adjacent perfusion territories; it separated tissue containing only one or the other colored microspheres. The second region was defined as the Boundary Watershed Zone (BWZ) (mean zone width = 3151 +/- 611 microns; mean +/- SD). This region was formed by capillaries containing sphere aggregates of both colors; it was located exclusively within the ITZ. In addition, the ITZ and BWZ were significantly wider in subepicardial than in subendocardial regions (p less than 0.001). PMID:1417709

  14. The eyes of Tullimonstrum reveal a vertebrate affinity.

    PubMed

    Clements, Thomas; Dolocan, Andrei; Martin, Peter; Purnell, Mark A; Vinther, Jakob; Gabbott, Sarah E

    2016-04-28

    Tullimonstrum gregarium is an iconic soft-bodied fossil from the Carboniferous Mazon Creek Lagerstätte (Illinois, USA). Despite a large number of specimens and distinct anatomy, various analyses over the past five decades have failed to determine the phylogenetic affinities of the 'Tully monster', and although it has been allied to such disparate phyla as the Mollusca, Annelida or Chordata, it remains enigmatic. The nature and phylogenetic affinities of Tullimonstrum have defied confident systematic placement because none of its preserved anatomy provides unequivocal evidence of homology, without which comparative analysis fails. Here we show that the eyes of Tullimonstrum possess ultrastructural details indicating homology with vertebrate eyes. Anatomical analysis using scanning electron microscopy reveals that the eyes of Tullimonstrum preserve a retina defined by a thick sheet comprising distinct layers of spheroidal and cylindrical melanosomes. Time-of-flight secondary ion mass spectrometry and multivariate statistics provide further evidence that these microbodies are melanosomes. A range of animals have melanin in their eyes, but the possession of melanosomes of two distinct morphologies arranged in layers, forming retinal pigment epithelium, is a synapomorphy of vertebrates. Our analysis indicates that in addition to evidence of colour patterning, ecology and thermoregulation, fossil melanosomes can also carry a phylogenetic signal. Identification in Tullimonstrum of spheroidal and cylindrical melanosomes forming the remains of retinal pigment epithelium indicates that it is a vertebrate; considering its body parts in this new light suggests it was an anatomically unusual member of total group Vertebrata. PMID:27074512

  15. Eukaryote Culturomics of the Gut Reveals New Species

    PubMed Central

    Gouba, Nina; Raoult, Didier; Drancourt, Michel

    2014-01-01

    The repertoire of microeukaryotes in the human gut has been poorly explored, mainly in individuals living in northern hemisphere countries. We further explored this repertoire using PCR-sequencing and culture in seven individuals living in four tropical countries. A total of 41 microeukaryotes including 38 different fungal species and three protists were detected. Four fungal species, Davidiella tassiana, Davidiella sp., Corticiaceae sp., and Penicillium sp., were uniquely detected by culture; 27 fungal species were uniquely detected using PCR-sequencing and Candida albicans, Candida glabrata, Trichosporon asahii, Clavispora lusitaniae, Debaryomyces hansenii, Malassezia restricta, and Malassezia sp. were detected using both molecular and culture methods. Fourteen microeukaryotes were shared by the seven individuals, whereas 27 species were found in only one individual, including 11 species in Amazonia, nine species in Polynesia, five species in India, and two species in Senegal. These data support a worldwide distribution of Malassezia sp., Trichosporon sp., and Candida sp. in the gut mycobiome. Here, 13 fungal species and two protists, Stentor roeseli and Vorticella campanula, were observed for first time in the human gut. This study revealed a previously unsuspected diversity in the repertoire of human gut microeukaryotes, suggesting spots for further exploring this repertoire. PMID:25210972

  16. Beyond Contagion: Reality Mining Reveals Complex Patterns of Social Influence.

    PubMed

    Alshamsi, Aamena; Pianesi, Fabio; Lepri, Bruno; Pentland, Alex; Rahwan, Iyad

    2015-01-01

    Contagion, a concept from epidemiology, has long been used to characterize social influence on people's behavior and affective (emotional) states. While it has revealed many useful insights, it is not clear whether the contagion metaphor is sufficient to fully characterize the complex dynamics of psychological states in a social context. Using wearable sensors that capture daily face-to-face interaction, combined with three daily experience sampling surveys, we collected the most comprehensive data set of personality and emotion dynamics of an entire community of work. From this high-resolution data about actual (rather than self-reported) face-to-face interaction, a complex picture emerges where contagion (that can be seen as adaptation of behavioral responses to the behavior of other people) cannot fully capture the dynamics of transitory states. We found that social influence has two opposing effects on states: adaptation effects that go beyond mere contagion, and complementarity effects whereby individuals' behaviors tend to complement the behaviors of others. Surprisingly, these effects can exhibit completely different directions depending on the stable personality or emotional dispositions (stable traits) of target individuals. Our findings provide a foundation for richer models of social dynamics, and have implications on organizational engineering and workplace well-being. PMID:26313449

  17. Lipidome analysis reveals antifungal polyphenol curcumin affects membrane lipid homeostasis.

    PubMed

    Sharma, Monika; Dhamgaye, Sanjiveeni; Singh, Ashutosh; Prasad, Rajendra

    2012-01-01

    This study shows that antifungal curcumin (CUR), significantly depletes ergosterol levels in Candida albicans. CUR while displaying synergy with fluconazole (FLC) lowers ergosterol. However, CUR alone at its synergistic concentration (lower than MIC50), could not affect ergosterol contents. For deeper insight of CUR effects on lipids, we performed high throughput mass spectroscopy (MS) based lipid profiling of C. albicans cells. The lipidome analysis revealed that there were no major changes in phosphoglycerides (PGLs) composition following CUR treatment of Candida, however, significant differences in molecular species of PGLs were detected. Among major SPLs, CUR treatment resulted in the reduction of ceramide and accumulation of IPCs levels. The lipidome of CUR treated cells confirmed a dramatic drop in the ergosterol levels with a simultaneous accumulation of its biosynthetic precursors. This was further supported by the fact that the mutants defective in ergosterol biosynthesis (ERG2 and ERG11) and those lacking the transcription factor regulating ergosterol biosynthesis, UPC2, were highly susceptible to CUR. Our study first time shows that CUR, for its antifungal activity, targets and down regulates delta 5, 6 desaturase (ERG3) resulting in depletion of ergosterol. This results in parallel accumulation of ergosterol biosynthetic precursors, generation of reactive oxygen species (ROS) and cell death. PMID:22201946

  18. Global Isotope Metabolomics Reveals Adaptive Strategies for Nitrogen Assimilation.

    PubMed

    Kurczy, Michael E; Forsberg, Erica M; Thorgersen, Michael P; Poole, Farris L; Benton, H Paul; Ivanisevic, Julijana; Tran, Minerva L; Wall, Judy D; Elias, Dwayne A; Adams, Michael W W; Siuzdak, Gary

    2016-06-17

    Nitrogen cycling is a microbial metabolic process essential for global ecological/agricultural balance. To investigate the link between the well-established ammonium and the alternative nitrate assimilation metabolic pathways, global isotope metabolomics was employed to examine three nitrate reducing bacteria using (15)NO3 as a nitrogen source. In contrast to a control (Pseudomonas stutzeri RCH2), the results show that two of the isolates from Oak Ridge, Tennessee (Pseudomonas N2A2 and N2E2) utilize nitrate and ammonia for assimilation concurrently with differential labeling observed across multiple classes of metabolites including amino acids and nucleotides. The data reveal that the N2A2 and N2E2 strains conserve nitrogen-containing metabolites, indicating that the nitrate assimilation pathway is a conservation mechanism for the assimilation of nitrogen. Co-utilization of nitrate and ammonia is likely an adaption to manage higher levels of nitrite since the denitrification pathways utilized by the N2A2 and N2E2 strains from the Oak Ridge site are predisposed to the accumulation of the toxic nitrite. The use of global isotope metabolomics allowed for this adaptive strategy to be investigated, which would otherwise not have been possible to decipher. PMID:27045776

  19. Acoustic telemetry reveals cryptic residency of whale sharks

    PubMed Central

    Cagua, E. Fernando; Cochran, Jesse E. M.; Rohner, Christoph A.; Prebble, Clare E. M.; Sinclair-Taylor, Tane H.; Pierce, Simon J.; Berumen, Michael L.

    2015-01-01

    Although whale sharks (Rhincodon typus) have been documented to move thousands of kilometres, they are most frequently observed at a few predictable seasonal aggregation sites. The absence of sharks at the surface during visual surveys has led to the assumption that sharks disperse to places unknown during the long ‘off-seasons’ at most of these locations. Here we compare 2 years of R. typus visual sighting records from Mafia Island in Tanzania to concurrent acoustic telemetry of tagged individuals. Sightings revealed a clear seasonal pattern with a peak between October and February and no sharks observed at other times. By contrast, acoustic telemetry demonstrated year-round residency of R. typus. The sharks use a different habitat in the off-season, swimming deeper and further away from shore, presumably in response to prey distributions. This behavioural change reduces the sharks' visibility, giving the false impression that they have left the area. We demonstrate, for the first time to our knowledge, year-round residency of unprovisioned, individual R. typus at an aggregation site, and highlight the importance of using multiple techniques to study the movement ecology of marine megafauna. PMID:25832816

  20. Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

    SciTech Connect

    Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius; Han, Gye Won; Liu, Wei; Zatsepin, Nadia A.; James, Daniel; Wang, Dingjie; Nelson, Garrett; Weierstall, Uwe; Sawaya, Michael R.; Xu, Qingping; Messerschmidt, Marc; Williams, Garth J.; Boutet, Sébastien; Yefanov, Oleksandr M.; White, Thomas A.; Wang, Chong; Ishchenko, Andrii; Tirupula, Kalyan C.; Desnoyer, Russell; Coe, Jesse; Conrad, Chelsie E.; Fromme, Petra; Stevens, Raymond C.; Katritch, Vsevolod; Karnik, Sadashiva S.; Cherezov, Vadim

    2015-05-07

    We report that angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9 Å resolution. The AT1R-ZD7155 complex structure revealed key structural features ofAT1R and critical interactions for ZD7155 binding. Finally, docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.

  1. Early Neolithic Water Wells Reveal the World's Oldest Wood Architecture

    PubMed Central

    Tegel, Willy; Elburg, Rengert; Hakelberg, Dietrich; Stäuble, Harald; Büntgen, Ulf

    2012-01-01

    The European Neolithization ∼6000−4000 BC represents a pivotal change in human history when farming spread and the mobile style of life of the hunter-foragers was superseded by the agrarian culture. Permanent settlement structures and agricultural production systems required fundamental innovations in technology, subsistence, and resource utilization. Motivation, course, and timing of this transformation, however, remain debatable. Here we present annually resolved and absolutely dated dendroarchaeological information from four wooden water wells of the early Neolithic period that were excavated in Eastern Germany. A total of 151 oak timbers preserved in a waterlogged environment were dated between 5469 and 5098 BC and reveal unexpectedly refined carpentry skills. The recently discovered water wells enable for the first time a detailed insight into the earliest wood architecture and display the technological capabilities of humans ∼7000 years ago. The timbered well constructions made of old oak trees feature an unopened tree-ring archive from which annually resolved and absolutely dated environmental data can be culled. Our results question the principle of continuous evolutionary development in prehistoric technology, and contradict the common belief that metal was necessary for complex timber constructions. Early Neolithic craftsmanship now suggests that the first farmers were also the first carpenters. PMID:23284685

  2. An acoustic microscopy technique reveals hidden morphological defenses in Daphnia.

    PubMed

    Laforsch, Christian; Ngwa, Wilfred; Grill, Wolfgang; Tollrian, Ralph

    2004-11-01

    Inducible defenses are common strategies for coping with the selective force of predation in heterogeneous environments. In recent years the conspicuous and often dramatic morphological plasticity of several waterflea species of the genus Daphnia have been found to be inducible defenses activated by chemical cues released by predators. However, the exact defensive mechanisms remained mysterious. Because even some minute morphological alterations proved to be protective against predatory invertebrates, it has been suggested that the visible morphological changes are only the tip of the iceberg of the entire protective mechanisms. Here we applied a method of ultrasonic microscopy with vector contrast at 1.2 GHz to probe hidden morphological defenses. We found that induction with predator kairomones increases the stability of the carapace in two Daphnia species up to 350%. This morphological plasticity provides a major advantage for the induced morphs during predation because predatory invertebrates need to crush or puncture the carapace of their prey to consume them. Our ultrastructural analyses revealed that the internal architecture of the carapace ensures maximal rigidity with minimal material investment. Our results uncover hidden morphological plasticity and suggest a reconsideration of former classification systems in defended and undefended genotypes in Daphnia and possibly in other prey organisms as well. PMID:15520396

  3. Graphene grain boundary resistivity revealed by scanning tunneling potentiometry

    NASA Astrophysics Data System (ADS)

    Durand, Corentin; Clark, Kendal W.; Zhang, Xiaoguang; Vlassiouk, Ivan V.; Li, An-Ping; Oak Ridge National Lab Team

    2014-03-01

    All large-scale graphene films contain extended topological defects dividing graphene into domains or grains. Here, we study grain boundary (GB) resistivity in CVD graphene on Cu subsequently transferred to a SiO2 substrate. By using a scanning tunneling potentiometry (STP) setup with a cryogenic four-probe STM, the spatial variation of the local electrochemical potential is resolved across individual GBs on a graphene surface in the presence of a current. The 2D distributions of electric field and conductivity were then numerically extracted by solving conduction equations. The derived conductivity of individual grains was compared to that measured with microscopic four-probe STM method to provide a model-independent determination of conductivity map for specific type of defect in graphene. The resistance of a GB is found to change with the width of the disordered transition region between adjacent grains. A quantitative modeling of boundary resistance reveals the increased electron Fermi wave vector within the boundary region, possibly due to boundary induced charge density variation.

  4. In vivo behavior of NTBI revealed by automated quantification system.

    PubMed

    Ito, Satoshi; Ikuta, Katsuya; Kato, Daisuke; Lynda, Addo; Shibusa, Kotoe; Niizeki, Noriyasu; Toki, Yasumichi; Hatayama, Mayumi; Yamamoto, Masayo; Shindo, Motohiro; Iizuka, Naomi; Kohgo, Yutaka; Fujiya, Mikihiro

    2016-08-01

    Non-Tf-bound iron (NTBI), which appears in serum in iron overload, is thought to contribute to organ damage; the monitoring of serum NTBI levels may therefore be clinically useful in iron-overloaded patients. However, NTBI quantification methods remain complex, limiting their use in clinical practice. To overcome the technical difficulties often encountered, we recently developed a novel automated NTBI quantification system capable of measuring large numbers of samples. In the present study, we investigated the in vivo behavior of NTBI in human and animal serum using this newly established automated system. Average NTBI in healthy volunteers was 0.44 ± 0.076 μM (median 0.45 μM, range 0.28-0.66 μM), with no significant difference between sexes. Additionally, serum NTBI rapidly increased after iron loading, followed by a sudden disappearance. NTBI levels also decreased in inflammation. The results indicate that NTBI is a unique marker of iron metabolism, unlike other markers of iron metabolism, such as serum ferritin. Our new automated NTBI quantification method may help to reveal the clinical significance of NTBI and contribute to our understanding of iron overload. PMID:27086349

  5. Covert Waking Brain Activity Reveals Instantaneous Sleep Depth

    PubMed Central

    McKinney, Scott M.; Dang-Vu, Thien Thanh; Buxton, Orfeu M.; Solet, Jo M.; Ellenbogen, Jeffrey M.

    2011-01-01

    The neural correlates of the wake-sleep continuum remain incompletely understood, limiting the development of adaptive drug delivery systems for promoting sleep maintenance. The most useful measure for resolving early positions along this continuum is the alpha oscillation, an 8–13 Hz electroencephalographic rhythm prominent over posterior scalp locations. The brain activation signature of wakefulness, alpha expression discloses immediate levels of alertness and dissipates in concert with fading awareness as sleep begins. This brain activity pattern, however, is largely ignored once sleep begins. Here we show that the intensity of spectral power in the alpha band actually continues to disclose instantaneous responsiveness to noise—a measure of sleep depth—throughout a night of sleep. By systematically challenging sleep with realistic and varied acoustic disruption, we found that sleepers exhibited markedly greater sensitivity to sounds during moments of elevated alpha expression. This result demonstrates that alpha power is not a binary marker of the transition between sleep and wakefulness, but carries rich information about immediate sleep stability. Further, it shows that an empirical and ecologically relevant form of sleep depth is revealed in real-time by EEG spectral content in the alpha band, a measure that affords prediction on the order of minutes. This signal, which transcends the boundaries of classical sleep stages, could potentially be used for real-time feedback to novel, adaptive drug delivery systems for inducing sleep. PMID:21408616

  6. First cranial remains of a gondwanatherian mammal reveal remarkable mosaicism.

    PubMed

    Krause, David W; Hoffmann, Simone; Wible, John R; Kirk, E Christopher; Schultz, Julia A; von Koenigswald, Wighart; Groenke, Joseph R; Rossie, James B; O'Connor, Patrick M; Seiffert, Erik R; Dumont, Elizabeth R; Holloway, Waymon L; Rogers, Raymond R; Rahantarisoa, Lydia J; Kemp, Addison D; Andriamialison, Haingoson

    2014-11-27

    Previously known only from isolated teeth and lower jaw fragments recovered from the Cretaceous and Palaeogene of the Southern Hemisphere, the Gondwanatheria constitute the most poorly known of all major mammaliaform radiations. Here we report the discovery of the first skull material of a gondwanatherian, a complete and well-preserved cranium from Upper Cretaceous strata in Madagascar that we assign to a new genus and species. Phylogenetic analysis strongly supports its placement within Gondwanatheria, which are recognized as monophyletic and closely related to multituberculates, an evolutionarily successful clade of Mesozoic mammals known almost exclusively from the Northern Hemisphere. The new taxon is the largest known mammaliaform from the Mesozoic of Gondwana. Its craniofacial anatomy reveals that it was herbivorous, large-eyed and agile, with well-developed high-frequency hearing and a keen sense of smell. The cranium exhibits a mosaic of primitive and derived features, the disparity of which is extreme and probably reflective of a long evolutionary history in geographic isolation. PMID:25383528

  7. Transcriptome meta-analysis reveals dysregulated pathways in nasopharyngeal carcinoma.

    PubMed

    Tulalamba, Warut; Larbcharoensub, Noppadol; Sirachainan, Ekaphop; Tantiwetrueangdet, Aunchalee; Janvilisri, Tavan

    2015-08-01

    Nasopharyngeal carcinoma (NPC) is a malignant cancer arising from the epithelial surface of the nasopharynx that mostly appears in advanced stages of the disease, leading to a poor prognosis. To date, a number of mRNA profiling investigations on NPC have been reported in order to identify suitable biomarkers for early detection. However, the results may be specific to each study with distinct sample types. In this study, an integrative meta-analysis of NPC transcriptome data was performed to determine dysregulated pathways, potentially leading to identification of molecular markers. Ten independent NPC gene expression profiling microarray datasets, including 135 samples from NPC cell lines, primary cell lines, and tissues were assimilated into a meta-analysis and cross-validation to identify a cohort of genes that were significantly dysregulated in NPC. Bioinformatics analyses of these genes revealed the significant pathways and individual players involving in cellular metabolism, cell cycle regulation, DNA repair, as well as ErbB pathway. Altogether, we propose that dysregulation of these molecular pathways in NPC might play a role in the NPC pathogenesis, providing clues, which could eventually translate into diagnostic and therapeutic approaches. PMID:25724187

  8. Prolonged stimulus exposure reveals prolonged neurobehavioral response patterns.

    PubMed

    Johnson, Brett A; Woo, Cynthia C; Zeng, Yu; Xu, Zhe; Hingco, Edna E; Ong, Joan; Leon, Michael

    2010-05-15

    Although it has been shown repeatedly that minimum response times in sensory systems can be quite short, organisms more often continue to respond to sensory stimuli over considerably longer periods of time. The continuing response to sensory stimulation may be a more realistic assessment of natural sensory responses, so we determined for how long a stimulus would evoke a response in naïve, freely moving animals. Specifically, we determined for how long such rats responded to odorants during continuous passive exposures by monitoring their sniffing with whole-body plethysmography. We found that naïve rats continue to sniff odorants vigorously for up to 3 minutes, much longer than what has been reported for highly trained, highly motivated rats. Patterns of 2-deoxyglucose (2-DG) uptake in the glomerular layer of the rat olfactory bulb also were seen after only 1-5 minutes of odorant exposure, overlapping with the period of increased respiration to odorants. Moreover, these 2-DG uptake patterns closely resembled the patterns that emerge from prolonged odorant exposures, suggesting that activity mapping over prolonged periods can identify areas of activity that are present when rats are still attending and responding to odorant stimuli. Given these findings, it seems important to consider the possibility that prolonged exposure to other sensory stimuli will reveal more realistic neural response patterns. PMID:20232477

  9. Statistical universals reveal the structures and functions of human music

    PubMed Central

    Savage, Patrick E.; Brown, Steven; Sakai, Emi; Currie, Thomas E.

    2015-01-01

    Music has been called “the universal language of mankind.” Although contemporary theories of music evolution often invoke various musical universals, the existence of such universals has been disputed for decades and has never been empirically demonstrated. Here we combine a music-classification scheme with statistical analyses, including phylogenetic comparative methods, to examine a well-sampled global set of 304 music recordings. Our analyses reveal no absolute universals but strong support for many statistical universals that are consistent across all nine geographic regions sampled. These universals include 18 musical features that are common individually as well as a network of 10 features that are commonly associated with one another. They span not only features related to pitch and rhythm that are often cited as putative universals but also rarely cited domains including performance style and social context. These cross-cultural structural regularities of human music may relate to roles in facilitating group coordination and cohesion, as exemplified by the universal tendency to sing, play percussion instruments, and dance to simple, repetitive music in groups. Our findings highlight the need for scientists studying music evolution to expand the range of musical cultures and musical features under consideration. The statistical universals we identified represent important candidates for future investigation. PMID:26124105

  10. Circular RNA profile in gliomas revealed by identification tool UROBORUS

    PubMed Central

    Song, Xiaofeng; Zhang, Naibo; Han, Ping; Moon, Byoung-San; Lai, Rose K.; Wang, Kai; Lu, Wange

    2016-01-01

    Recent evidence suggests that many endogenous circular RNAs (circRNAs) may play roles in biological processes. However, the expression patterns and functions of circRNAs in human diseases are not well understood. Computationally identifying circRNAs from total RNA-seq data is a primary step in studying their expression pattern and biological roles. In this work, we have developed a computational pipeline named UROBORUS to detect circRNAs in total RNA-seq data. By applying UROBORUS to RNA-seq data from 46 gliomas and normal brain samples, we detected thousands of circRNAs supported by at least two read counts, followed by successful experimental validation on 24 circRNAs from the randomly selected 27 circRNAs. UROBORUS is an efficient tool that can detect circRNAs with low expression levels in total RNA-seq without RNase R treatment. The circRNAs expression profiling revealed more than 476 circular RNAs differentially expressed in control brain tissues and gliomas. Together with parental gene expression, we found that circRNA and its parental gene have diversified expression patterns in gliomas and control brain tissues. This study establishes an efficient and sensitive approach for predicting circRNAs using total RNA-seq data. The UROBORUS pipeline can be accessed freely for non-commercial purposes at http://uroborus.openbioinformatics.org/. PMID:26873924

  11. Transcriptome Profiling Reveals TGF-β Signaling Involvement in Epileptogenesis

    PubMed Central

    Cacheaux, Luisa P; Ivens, Sebastian; David, Yaron; Lakhter, Alexander J; Bar-Klein, Guy; Shapira, Michael; Heinemann, Uwe; Friedman, Alon; Kaufer, Daniela

    2010-01-01

    Brain injury may result in the development of epilepsy, one of the most common neurological disorders. We previously demonstrated that albumin is critical in the generation of epilepsy following blood-brain barrier (BBB) compromise. Here we identify TGF-β pathway activation as the underlying mechanism. We demonstrate that direct activation of the TGF-β pathway by TGF-β1 results in epileptiform activity similar to that following exposure to albumin. Co-immunoprecipitation revealed binding of albumin to TGF-β receptor II and Smad2 phosphorylation confirmed downstream activation of this pathway. Transcriptome profiling demonstrated similar expression patterns following BBB breakdown, albumin and TGF-β1 exposure, including modulation of genes associated with the TGF-β pathway, early astrocytic activation, inflammation, and reduced inhibitory transmission. Importantly, TGF-β pathway blockers suppressed most albumin-induced transcriptional changes and prevented the generation of epileptiform activity. Our present data identifies the TGF-β pathway as a novel putative epileptogenic signaling cascade and therapeutic target for the prevention of injury-induced epilepsy. PMID:19605630

  12. Enzyme kinetics: the whole picture reveals hidden meanings.

    PubMed

    Pinto, Maria F; Estevinho, Berta N; Crespo, Rosa; Rocha, Fernando A; Damas, Ana M; Martins, Pedro M

    2015-06-01

    The methodology adopted by Michaelis and Menten in 1913 is still routinely used to characterize the catalytic power and selectivity of enzymes. These kinetic measurements must be performed soon after the purified enzyme is mixed with a large excess of substrate. Other time scales and solution compositions are no less physiologically relevant, but fall outside the range of applicability of the classical formalism. Here we show that the complete picture of an enzyme's mode of function is critically obscured by the limited scope of conventional kinetic analysis, even in the simplest case of a single active site without inhibition. This picture is now unveiled in a mathematically closed form that remains valid over the reaction time for all combinations of enzyme/substrate concentrations and rate constants. Algebraic simplicity is maintained in the new formalism when stationary reaction phases are considered. By achieving this century-old objective, the otherwise hidden role of the reversible binding step is revealed and atypical kinetic profiles are explained. Most singular kinetic behaviors are identified in a critical region of conditions that coincide with typical cell conditions. Because it is not covered by the Michaelis-Menten model, the critical region has been missed until now by low- and high-throughput screenings of new drugs. New possibilities are therefore raised for novel and once-promising inhibitors to therapeutically target enzymes. PMID:25808291

  13. Revealing the Intricate Effect of Collaboration on Innovation

    PubMed Central

    Inoue, Hiroyasu; Liu, Yang-Yu

    2015-01-01

    We studied the Japan and U.S. patent records of several decades to demonstrate the effect of collaboration on innovation. We found that statistically inventor teams slightly outperform solo inventors while company teams perform equally well as solo companies. By tracking the performance record of individual teams, we found that inventor teams’ performance generally degrades with more repeat collaborations. Though company teams’ performance displays strongly bursty behavior, long-term collaboration does not significantly help innovation. To systematically study the effect of repeat collaboration, we defined the repeat collaboration number of a team as the average number of collaborations over all the teammate pairs. We found that mild repeat collaboration improves the performance of Japanese inventor teams and U.S. company teams. Yet, excessive repeat collaboration does not significantly help innovation at both the inventor and company levels in both countries. To control for unobserved heterogeneity, we performed a detailed regression analysis and the results were consistent with our simple observations. The presented results revealed the intricate effect of collaboration on innovation, which may also be observed in other creative projects. PMID:25799138

  14. Nicotinamide riboside kinase structures reveal new pathways to NAD+.

    PubMed

    Tempel, Wolfram; Rabeh, Wael M; Bogan, Katrina L; Belenky, Peter; Wojcik, Marzena; Seidle, Heather F; Nedyalkova, Lyudmila; Yang, Tianle; Sauve, Anthony A; Park, Hee-Won; Brenner, Charles

    2007-10-01

    The eukaryotic nicotinamide riboside kinase (Nrk) pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+) by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize the distinctive carboxamide group of nicotinamide riboside. Indeed, nicotinic acid riboside is a specific substrate of human Nrk enzymes and is utilized in yeast in a novel biosynthetic pathway that depends on Nrk and NAD+ synthetase. Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+. PMID:17914902

  15. Seabird movement reveals the ecological footprint of fishing vessels.

    PubMed

    Bodey, Thomas W; Jessopp, Mark J; Votier, Stephen C; Gerritsen, Hans D; Cleasby, Ian R; Hamer, Keith C; Patrick, Samantha C; Wakefield, Ewan D; Bearhop, Stuart

    2014-06-01

    Exploitation of the seas is currently unsustainable, with increasing demand for marine resources placing intense pressure on the Earth's largest ecosystem [1]. The scale of anthropogenic effects varies from local to entire ocean basins [1-3]. For example, discards of commercial capture fisheries can have both positive and negative impacts on scavengers at the population and community-level [2-6], although this is driven by individual foraging behaviour [3,7]. Currently, we have little understanding of the scale at which individual animals initiate such behaviours. We use the known interaction between fisheries and a wide-ranging seabird, the Northern gannet Morus bassanus[3], to investigate how fishing vessels affect individual birds' behaviours in near real-time. We document the footprint of fishing vessels' (≥15 m length) influence on foraging decisions (≤11 km), and a potential underlying behavioural mechanism, by revealing how birds respond differently to vessels depending on gear type and activity. Such influences have important implications for fisheries, including the proposed discard ban [8]), and wider marine management. PMID:24892908

  16. Strategy revealing phenotypic differences among synthetic oscillator designs.

    PubMed

    Lomnitz, Jason G; Savageau, Michael A

    2014-09-19

    Considerable progress has been made in identifying and characterizing the component parts of genetic oscillators, which play central roles in all organisms. Nonlinear interaction among components is sufficiently complex that mathematical models are required to elucidate their elusive integrated behavior. Although natural and synthetic oscillators exhibit common architectures, there are numerous differences that are poorly understood. Utilizing synthetic biology to uncover basic principles of simpler circuits is a way to advance understanding of natural circadian clocks and rhythms. Following this strategy, we address the following questions: What are the implications of different architectures and molecular modes of transcriptional control for the phenotypic repertoire of genetic oscillators? Are there designs that are more realizable or robust? We compare synthetic oscillators involving one of three architectures and various combinations of the two modes of transcriptional control using a methodology that provides three innovations: a rigorous definition of phenotype, a procedure for deconstructing complex systems into qualitatively distinct phenotypes, and a graphical representation for illuminating the relationship between genotype, environment, and the qualitatively distinct phenotypes of a system. These methods provide a global perspective on the behavioral repertoire, facilitate comparisons of alternatives, and assist the rational design of synthetic gene circuitry. In particular, the results of their application here reveal distinctive phenotypes for several designs that have been studied experimentally as well as a best design among the alternatives that has yet to be constructed and tested. PMID:25019938

  17. Individual olfactory perception reveals meaningful nonolfactory genetic information

    PubMed Central

    Secundo, Lavi; Snitz, Kobi; Weissler, Kineret; Pinchover, Liron; Shoenfeld, Yehuda; Loewenthal, Ron; Agmon-Levin, Nancy; Frumin, Idan; Bar-Zvi, Dana; Shushan, Sagit; Sobel, Noam

    2015-01-01

    Each person expresses a potentially unique subset of ∼400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the “olfactory fingerprint.” Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals using 28 odors and 54 descriptors. We found that each person had a unique olfactory fingerprint (P < 10−10), which was odor specific but descriptor independent. We could identify individuals from this pool using randomly selected sets of 7 odors and 11 descriptors alone. Extrapolating from this data, we determined that using 34 odors and 35 descriptors we could individually identify each of the 7 billion people on earth. Olfactory perception, however, fluctuates over time, calling into question our proposed perceptual readout of presumably stable genetic makeup. To test whether fingerprints remain informative despite this temporal fluctuation, building on the linkage between olfactory receptors and HLA, we hypothesized that olfactory perception may relate to HLA. We obtained olfactory fingerprints and HLA typing for 130 individuals, and found that olfactory fingerprint matching using only four odorants was significantly related to HLA matching (P < 10−4), such that olfactory fingerprints can save 32% of HLA tests in a population screen (P < 10−6). In conclusion, a precise measure of olfactory perception reveals meaningful nonolfactory genetic information. PMID:26100865

  18. Osmolyte perturbation reveals conformational equilibria in spin-labeled proteins

    PubMed Central

    López, Carlos J; Fleissner, Mark R; Guo, Zhefeng; Kusnetzow, Ana K; Hubbell, Wayne L

    2009-01-01

    Recent evidence suggests that proteins at equilibrium can exist in a manifold of conformational substates, and that these substates play important roles in protein function. Therefore, there is great interest in identifying regions in proteins that are in conformational exchange. Electron paramagnetic resonance spectra of spin-labeled proteins containing the nitroxide side chain (R1) often consist of two (or more) components that may arise from slow exchange between conformational substates (lifetimes > 100 ns). However, crystal structures of proteins containing R1 have shown that multicomponent spectra can also arise from equilibria between rotamers of the side chain itself. In this report, it is shown that these scenarios can be distinguished by the response of the system to solvent perturbation with stabilizing osmolytes such as sucrose. Thus, site-directed spin labeling (SDSL) emerges as a new tool to explore slow conformational exchange in proteins of arbitrary size, including membrane proteins in a native-like environment. Moreover, equilibrium between substates with even modest differences in conformation is revealed, and the simplicity of the method makes it suitable for facile screening of multiple proteins. Together with previously developed strategies for monitoring picosecond to millisecond backbone dynamics, the results presented here expand the timescale over which SDSL can be used to explore protein flexibility. PMID:19585559

  19. Diagnostic phylogenetics reveals a new Porcine circovirus 2 cluster.

    PubMed

    Davies, Brendan; Wang, Xiong; Dvorak, Cheryl M T; Marthaler, Douglas; Murtaugh, Michael P

    2016-06-01

    Porcine circovirus 2 (PCV2) was prevalent in swine in the United States before PCV2-associated disease (PCVAD) appeared in 2006. Limited nucleotide sequencing of open reading frame 2 (ORF2) encoding capsid, the only structural protein, revealed the presence of two genotypes, PCV2a and PCV2b. Later, PCV2c and mutant PCV2b, or PCV2d, were also described. However, extensive PCV2 ORF2 sequence databases in veterinary diagnostic laboratories have not been analyzed systematically to determine the genetic diversity of field isolates. Here, we interrogated >1100 PCV2 ORF2 nucleotide sequences to assess population diversity and genetic variation. We detected a novel PCV2 genotype that is substantially different, primarily in ORF2, from all known PCV2. Notably, ORF2 contains a unique carboxyl terminal amino acid insertion resulting in a 238 amino acid ORF2. All other PCV2 ORF2 proteins are 233 or 234 aa in length. Phylogenetic analysis indicates that it is more ancient than other PCV2 genotypes. The findings demonstrate the value of analyzing routine diagnostic laboratory sequence databases in population genetic analyses of animal pathogens. PMID:26948261

  20. Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action

    PubMed Central

    Huo, Lu; Davis, Ian; Liu, Fange; Andi, Babak; Esaki, Shingo; Iwaki, Hiroaki; Hasegawa, Yoshie; Orville, Allen M.; Liu, Aimin

    2015-01-01

    Aldehydes are ubiquitous intermediates in metabolic pathways and their innate reactivity can often make them quite unstable. There are several aldehydic intermediates in the metabolic pathway for tryptophan degradation that can decay into neuroactive compounds that have been associated with numerous neurological diseases. An enzyme of this pathway, 2-aminomuconate-6-semialdehyde dehydrogenase, is responsible for ‘disarming’ the final aldehydic intermediate. Here we show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms: resting state, one binary and two ternary complexes, and a covalent, thioacyl intermediate. We also report the crystal structures of a tetrahedral, thiohemiacetal intermediate, a thioacyl intermediate and an NAD+-bound complex from an active site mutant. These covalent intermediates are characterized by single-crystal and solution-state electronic absorption spectroscopy. The crystal structures reveal that the substrate undergoes an E/Z isomerization at the enzyme active site before an sp3-to-sp2 transition during enzyme-mediated oxidation. PMID:25565451

  1. Deep sequencing reveals 50 novel genes for recessive cognitive disorders.

    PubMed

    Najmabadi, Hossein; Hu, Hao; Garshasbi, Masoud; Zemojtel, Tomasz; Abedini, Seyedeh Sedigheh; Chen, Wei; Hosseini, Masoumeh; Behjati, Farkhondeh; Haas, Stefan; Jamali, Payman; Zecha, Agnes; Mohseni, Marzieh; Püttmann, Lucia; Vahid, Leyla Nouri; Jensen, Corinna; Moheb, Lia Abbasi; Bienek, Melanie; Larti, Farzaneh; Mueller, Ines; Weissmann, Robert; Darvish, Hossein; Wrogemann, Klaus; Hadavi, Valeh; Lipkowitz, Bettina; Esmaeeli-Nieh, Sahar; Wieczorek, Dagmar; Kariminejad, Roxana; Firouzabadi, Saghar Ghasemi; Cohen, Monika; Fattahi, Zohreh; Rost, Imma; Mojahedi, Faezeh; Hertzberg, Christoph; Dehghan, Atefeh; Rajab, Anna; Banavandi, Mohammad Javad Soltani; Hoffer, Julia; Falah, Masoumeh; Musante, Luciana; Kalscheuer, Vera; Ullmann, Reinhard; Kuss, Andreas Walter; Tzschach, Andreas; Kahrizi, Kimia; Ropers, H Hilger

    2011-10-01

    Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function. PMID:21937992

  2. Multiple etiologies for Alzheimer disease are revealed by segregation analysis

    SciTech Connect

    Rao, V.S.; Connor-Lacke, L.; Cupplies, L.A.; Growdon, J.H.; Farrer, L.A.; Duijn, C.M. van

    1994-11-01

    We have evaluated several transmission models for Alzheimer disease (AD), using the logistic regressive approach in 401 nuclear families of consecutively ascertained and rigorously diagnosed probands. Models postulating no major gene effect, random environmental transmission, recessive inheritance, and sporadic occurrence were rejected under varied assumptions regarding the associations among sex, age, and major gene susceptibility. Transmission of the disorder was not fully explained by a single Mendelian model for all families. Stratification of families as early- and late-onset by using the median of family mean onset ages showed that, regardless of the model studied, two groups of families fit better than a single group. AD in early-onset families is transmitted as an autosomal dominant trait with full penetrance in both sexes and has a gene frequency of 1.5%. Dominant inheritance also gave the best fit of the data in late-onset families, but this hypothesis was rejected, suggesting the presence of heterogeneity within this subset. Our study also revealed that genetically nonsusceptible males and females develop AD, indicating the presence of phenocopies within early-onset and late-onset groups. Moreover, our results suggest that the higher risk to females is not solely due to their increased longevity. 50 refs., 5 tabs.

  3. Next generation sequencing in synovial sarcoma reveals novel gene mutations.

    PubMed

    Vlenterie, Myrella; Hillebrandt-Roeffen, Melissa H S; Flucke, Uta E; Groenen, Patricia J T A; Tops, Bastiaan B J; Kamping, Eveline J; Pfundt, Rolph; de Bruijn, Diederik R H; Geurts van Kessel, Ad H M; van Krieken, Han J H J M; van der Graaf, Winette T A; Versleijen-Jonkers, Yvonne M H

    2015-10-27

    Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults. PMID:26415226

  4. Ternary structure reveals mechanism of a membrane diacylglycerol kinase

    DOE PAGESBeta

    Li, Dianfan; Stansfeld, Phillip J.; Sansom, Mark S. P.; Keogh, Aaron; Vogeley, Lutz; Howe, Nicole; Lyons, Joseph A.; Aragao, David; Fromme, Petra; Fromme, Raimund; et al

    2015-12-17

    Diacylglycerol kinase catalyses the ATP-dependent conversion of diacylglycerol to phosphatidic acid in the plasma membrane of Escherichia coli. The small size of this integral membrane trimer, which has 121 residues per subunit, means that available protein must be used economically to craft three catalytic and substrate-binding sites centred about the membrane/cytosol interface. How nature has accomplished this extraordinary feat is revealed here in a crystal structure of the kinase captured as a ternary complex with bound lipid substrate and an ATP analogue. Residues, identified as essential for activity by mutagenesis, decorate the active site and are rationalized by the ternarymore » structure. The γ-phosphate of the ATP analogue is positioned for direct transfer to the primary hydroxyl of the lipid whose acyl chain is in the membrane. A catalytic mechanism for this unique enzyme is proposed. As a result, the active site architecture shows clear evidence of having arisen by convergent evolution.« less

  5. Proteomics Analysis Reveals Previously Uncharacterized Virulence Factors in Vibrio proteolyticus

    PubMed Central

    Ray, Ann; Kinch, Lisa N.; de Souza Santos, Marcela; Grishin, Nick V.

    2016-01-01

    ABSTRACT Members of the genus Vibrio include many pathogens of humans and marine animals that share genetic information via horizontal gene transfer. Hence, the Vibrio pan-genome carries the potential to establish new pathogenic strains by sharing virulence determinants, many of which have yet to be characterized. Here, we investigated the virulence properties of Vibrio proteolyticus, a Gram-negative marine bacterium previously identified as part of the Vibrio consortium isolated from diseased corals. We found that V. proteolyticus causes actin cytoskeleton rearrangements followed by cell lysis in HeLa cells in a contact-independent manner. In search of the responsible virulence factor involved, we determined the V. proteolyticus secretome. This proteomics approach revealed various putative virulence factors, including active type VI secretion systems and effectors with virulence toxin domains; however, these type VI secretion systems were not responsible for the observed cytotoxic effects. Further examination of the V. proteolyticus secretome led us to hypothesize and subsequently demonstrate that a secreted hemolysin, belonging to a previously uncharacterized clan of the leukocidin superfamily, was the toxin responsible for the V. proteolyticus-mediated cytotoxicity in both HeLa cells and macrophages. Clearly, there remains an armory of yet-to-be-discovered virulence factors in the Vibrio pan-genome that will undoubtedly provide a wealth of knowledge on how a pathogen can manipulate host cells. PMID:27460800

  6. Super-resolution Microscopy Reveals Compartmentalization of Peroxisomal Membrane Proteins*

    PubMed Central

    Galiani, Silvia; Waithe, Dominic; Reglinski, Katharina; Cruz-Zaragoza, Luis Daniel; Garcia, Esther; Clausen, Mathias P.; Schliebs, Wolfgang; Erdmann, Ralf; Eggeling, Christian

    2016-01-01

    Membrane-associated events during peroxisomal protein import processes play an essential role in peroxisome functionality. Many details of these processes are not known due to missing spatial resolution of technologies capable of investigating peroxisomes directly in the cell. Here, we present the use of super-resolution optical stimulated emission depletion microscopy to investigate with sub-60-nm resolution the heterogeneous spatial organization of the peroxisomal proteins PEX5, PEX14, and PEX11 around actively importing peroxisomes, showing distinct differences between these peroxins. Moreover, imported protein sterol carrier protein 2 (SCP2) occupies only a subregion of larger peroxisomes, highlighting the heterogeneous distribution of proteins even within the peroxisome. Finally, our data reveal subpopulations of peroxisomes showing only weak colocalization between PEX14 and PEX5 or PEX11 but at the same time a clear compartmentalized organization. This compartmentalization, which was less evident in cases of strong colocalization, indicates dynamic protein reorganization linked to changes occurring in the peroxisomes. Through the use of multicolor stimulated emission depletion microscopy, we have been able to characterize peroxisomes and their constituents to a yet unseen level of detail while maintaining a highly statistical approach, paving the way for equally complex biological studies in the future. PMID:27311714

  7. Immunoprofiling of Rice Root Cortex Reveals Two Cortical Subdomains

    PubMed Central

    Henry, Sophia; Divol, Fanchon; Bettembourg, Mathilde; Bureau, Charlotte; Guiderdoni, Emmanuel; Périn, Christophe; Diévart, Anne

    2016-01-01

    The formation and differentiation of aerenchyma, i.e., air-containing cavities that are critical for flooding tolerance, take place exclusively in the cortex. The understanding of development and differentiation of the cortex is thus an important issue; however, studies on this tissue are limited, partly because of the lack of available molecular tools. We screened a commercially available library of cell wall antibodies to identify markers of cortical tissue in rice roots. Out of the 174 antibodies screened, eight were cortex-specific. Our analysis revealed that two types of cortical tissues are present in rice root seedlings. We named these cell layers “inner” and “outer” based on their location relative to the stele. We then used the antibodies to clarify cell identity in lateral roots. Without these markers, previous studies could not distinguish between the cortex and sclerenchyma in small lateral roots. By immunostaining lateral root sections, we showed that the internal ground tissue in small lateral roots has outer cortical identity. PMID:26779208

  8. Phosphoproteomic analysis reveals regulatory mechanisms at the kidney filtration barrier.

    PubMed

    Rinschen, Markus M; Wu, Xiongwu; König, Tim; Pisitkun, Trairak; Hagmann, Henning; Pahmeyer, Caroline; Lamkemeyer, Tobias; Kohli, Priyanka; Schnell, Nicole; Schermer, Bernhard; Dryer, Stuart; Brooks, Bernard R; Beltrao, Pedro; Krueger, Marcus; Brinkkoetter, Paul T; Benzing, Thomas

    2014-07-01

    Diseases of the kidney filtration barrier are a leading cause of ESRD. Most disorders affect the podocytes, polarized cells with a limited capacity for self-renewal that require tightly controlled signaling to maintain their integrity, viability, and function. Here, we provide an atlas of in vivo phosphorylated, glomerulus-expressed proteins, including podocyte-specific gene products, identified in an unbiased tandem mass spectrometry-based approach. We discovered 2449 phosphorylated proteins corresponding to 4079 identified high-confidence phosphorylated residues and performed a systematic bioinformatics analysis of this dataset. We discovered 146 phosphorylation sites on proteins abundantly expressed in podocytes. The prohibitin homology domain of the slit diaphragm protein podocin contained one such site, threonine 234 (T234), located within a phosphorylation motif that is mutated in human genetic forms of proteinuria. The T234 site resides at the interface of podocin dimers. Free energy calculation through molecular dynamic simulations revealed a role for T234 in regulating podocin dimerization. We show that phosphorylation critically regulates formation of high molecular weight complexes and that this may represent a general principle for the assembly of proteins containing prohibitin homology domains. PMID:24511133

  9. Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

    DOE PAGESBeta

    Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius; Han, Gye Won; Liu, Wei; Zatsepin, Nadia A.; James, Daniel; Wang, Dingjie; Nelson, Garrett; Weierstall, Uwe; et al

    2015-05-07

    We report that angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9 Å resolution. Themore » AT1R-ZD7155 complex structure revealed key structural features ofAT1R and critical interactions for ZD7155 binding. Finally, docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.« less

  10. Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs

    SciTech Connect

    Curtis, Bruce A.; Tanifuji, Goro; Burki, Fabien; Gruber, Ansgar; Irimia, Manuuel; Maruyama, Shinichiro; Arias, Maria C.; Ball, Steven G.; Gile, Gillian H.; Hirakawa, Yoshihisa; Hopkins, Julia F.; Kuo, Alan; Rensing, Stefan A.; Schmutz, Jeremy; Symeonidi, Aikaterini; Elias, Marek; Eveleigh, Robert J. M.; Herman, Emily K.; Klute, Mary J.; Nakayama, Takuro; Obornik, Miroslav; Reyes-Prieto, Adrian; Armbrust, E. Virginia; Aves, Stephen J.; Beiko, Robert G.; Coutinho, Pedro; Dacks, Joel B.; Durnford, Dion G.; Fast, Naomi M.; Green, Beverley R.; Grisdale, Cameron J.; Hempel, Franziska; Henrissat, Bernard; Hoppner, Marc P.; Ishida, Ken-Ichiro; Kim, Eunsoo; Koreny, Ludek; Kroth, Peter G.; Liu, Yuan; Malik, Shehre-Banoo; Maier, Uwe G.; McRose, Darcy; Mock, Thomas; Neilson, Jonathan A. D.; Onodera, Naoko T.; Poole, Anthony M.; Pritham, Ellen J.; Richards, Thomas A.; Rocap, Gabrielle; Roy, Scott W.; Sarai, Chihiro; Schaack, Sarah; Shirato, Shu; Slamovits, Claudio H.; Spencer, Davie F.; Suzuki, Shigekatsu; Worden, Alexandra Z.; Zauner, Stefan; Barry, Kerrie; Bell, Callum; Bharti, Arvind K.; Crow, John A.; Grimwood, Jane; Kramer, Robin; Lindquist, Erika; Lucas, Susan; Salamov, Asaf; McFadden, Geoffrey I.; Lane, Christopher E.; Keeling, Patrick J.; Gray, Michael W.; Grigoriev, Igor V.; Archibald, John M.

    2012-08-10

    Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have 21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host- and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.

  11. Maximal Neighbor Similarity Reveals Real Communities in Networks

    PubMed Central

    Žalik, Krista Rizman

    2015-01-01

    An important problem in the analysis of network data is the detection of groups of densely interconnected nodes also called modules or communities. Community structure reveals functions and organizations of networks. Currently used algorithms for community detection in large-scale real-world networks are computationally expensive or require a priori information such as the number or sizes of communities or are not able to give the same resulting partition in multiple runs. In this paper we investigate a simple and fast algorithm that uses the network structure alone and requires neither optimization of pre-defined objective function nor information about number of communities. We propose a bottom up community detection algorithm in which starting from communities consisting of adjacent pairs of nodes and their maximal similar neighbors we find real communities. We show that the overall advantage of the proposed algorithm compared to the other community detection algorithms is its simple nature, low computational cost and its very high accuracy in detection communities of different sizes also in networks with blurred modularity structure consisting of poorly separated communities. All communities identified by the proposed method for facebook network and E-Coli transcriptional regulatory network have strong structural and functional coherence. PMID:26680448

  12. Effective Connectivity Reveals Strategy Differences in an Expert Calculator

    PubMed Central

    Minati, Ludovico; Sigala, Natasha

    2013-01-01

    Mathematical reasoning is a core component of cognition and the study of experts defines the upper limits of human cognitive abilities, which is why we are fascinated by peak performers, such as chess masters and mental calculators. Here, we investigated the neural bases of calendrical skills, i.e. the ability to rapidly identify the weekday of a particular date, in a gifted mental calculator who does not fall in the autistic spectrum, using functional MRI. Graph-based mapping of effective connectivity, but not univariate analysis, revealed distinct anatomical location of “cortical hubs” supporting the processing of well-practiced close dates and less-practiced remote dates: the former engaged predominantly occipital and medial temporal areas, whereas the latter were associated mainly with prefrontal, orbitofrontal and anterior cingulate connectivity. These results point to the effect of extensive practice on the development of expertise and long term working memory, and demonstrate the role of frontal networks in supporting performance on less practiced calculations, which incur additional processing demands. Through the example of calendrical skills, our results demonstrate that the ability to perform complex calculations is initially supported by extensive attentional and strategic resources, which, as expertise develops, are gradually replaced by access to long term working memory for familiar material. PMID:24086291

  13. Circular RNA profile in gliomas revealed by identification tool UROBORUS.

    PubMed

    Song, Xiaofeng; Zhang, Naibo; Han, Ping; Moon, Byoung-San; Lai, Rose K; Wang, Kai; Lu, Wange

    2016-05-19

    Recent evidence suggests that many endogenous circular RNAs (circRNAs) may play roles in biological processes. However, the expression patterns and functions of circRNAs in human diseases are not well understood. Computationally identifying circRNAs from total RNA-seq data is a primary step in studying their expression pattern and biological roles. In this work, we have developed a computational pipeline named UROBORUS to detect circRNAs in total RNA-seq data. By applying UROBORUS to RNA-seq data from 46 gliomas and normal brain samples, we detected thousands of circRNAs supported by at least two read counts, followed by successful experimental validation on 24 circRNAs from the randomly selected 27 circRNAs. UROBORUS is an efficient tool that can detect circRNAs with low expression levels in total RNA-seq without RNase R treatment. The circRNAs expression profiling revealed more than 476 circular RNAs differentially expressed in control brain tissues and gliomas. Together with parental gene expression, we found that circRNA and its parental gene have diversified expression patterns in gliomas and control brain tissues. This study establishes an efficient and sensitive approach for predicting circRNAs using total RNA-seq data. The UROBORUS pipeline can be accessed freely for non-commercial purposes at http://uroborus.openbioinformatics.org/. PMID:26873924

  14. Multifunctional proteins revealed by overlapping clustering in protein interaction network

    PubMed Central

    Chapple, Charles E.; Guénoche, Alain; Brun, Christine

    2012-01-01

    Motivation: Multifunctional proteins perform several functions. They are expected to interact specifically with distinct sets of partners, simultaneously or not, depending on the function performed. Current graph clustering methods usually allow a protein to belong to only one cluster, therefore impeding a realistic assignment of multifunctional proteins to clusters. Results: Here, we present Overlapping Cluster Generator (OCG), a novel clustering method which decomposes a network into overlapping clusters and which is, therefore, capable of correct assignment of multifunctional proteins. The principle of OCG is to cover the graph with initial overlapping classes that are iteratively fused into a hierarchy according to an extension of Newman's modularity function. By applying OCG to a human protein–protein interaction network, we show that multifunctional proteins are revealed at the intersection of clusters and demonstrate that the method outperforms other existing methods on simulated graphs and PPI networks. Availability: This software can be downloaded from http://tagc.univ-mrs.fr/welcome/spip.php?rubrique197 Contact: brun@tagc.univ-mrs.fr Supplementary information: Supplementary data are available at Bioinformatics online. PMID:22080466

  15. Revealing the structure of the world airline network

    NASA Astrophysics Data System (ADS)

    Verma, T.; Araújo, N. A. M.; Herrmann, H. J.

    2014-07-01

    Resilience of most critical infrastructures against failure of elements that appear insignificant is usually taken for granted. The World Airline Network (WAN) is an infrastructure that reduces the geographical gap between societies, both small and large, and brings forth economic gains. With the extensive use of a publicly maintained data set that contains information about airports and alternative connections between these airports, we empirically reveal that the WAN is a redundant and resilient network for long distance air travel, but otherwise breaks down completely due to removal of short and apparently insignificant connections. These short range connections with moderate number of passengers and alternate flights are the connections that keep remote parts of the world accessible. It is surprising, insofar as there exists a highly resilient and strongly connected core consisting of a small fraction of airports (around 2.3%) together with an extremely fragile star-like periphery. Yet, in spite of their relevance, more than 90% of the world airports are still interconnected upon removal of this core. With standard and unconventional removal measures we compare both empirical and topological perceptions for the fragmentation of the world. We identify how the WAN is organized into different classes of clusters based on the physical proximity of airports and analyze the consequence of this fragmentation.

  16. Transcriptome profiling reveals mosaic genomic origins of modern cultivated barley

    PubMed Central

    Dai, Fei; Chen, Zhong-Hua; Wang, Xiaolei; Li, Zefeng; Jin, Gulei; Wu, Dezhi; Cai, Shengguan; Wang, Ning; Wu, Feibo; Nevo, Eviatar; Zhang, Guoping

    2014-01-01

    The domestication of cultivated barley has been used as a model system for studying the origins and early spread of agrarian culture. Our previous results indicated that the Tibetan Plateau and its vicinity is one of the centers of domestication of cultivated barley. Here we reveal multiple origins of domesticated barley using transcriptome profiling of cultivated and wild-barley genotypes. Approximately 48-Gb of clean transcript sequences in 12 Hordeum spontaneum and 9 Hordeum vulgare accessions were generated. We reported 12,530 de novo assembled transcripts in all of the 21 samples. Population structure analysis showed that Tibetan hulless barley (qingke) might have existed in the early stage of domestication. Based on the large number of unique genomic regions showing the similarity between cultivated and wild-barley groups, we propose that the genomic origin of modern cultivated barley is derived from wild-barley genotypes in the Fertile Crescent (mainly in chromosomes 1H, 2H, and 3H) and Tibet (mainly in chromosomes 4H, 5H, 6H, and 7H). This study indicates that the domestication of barley may have occurred over time in geographically distinct regions. PMID:25197090

  17. Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

    PubMed Central

    Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius; Han, Gye Won; Liu, Wei; Zatsepin, Nadia A.; James, Daniel; Wang, Dingjie; Nelson, Garrett; Weierstall, Uwe; Sawaya, Michael R.; Xu, Qingping; Messerschmidt, Marc; Williams, Garth J.; Boutet, Sébastien; Yefanov, Oleksandr M.; White, Thomas A.; Wang, Chong; Ishchenko, Andrii; Tirupula, Kalyan C.; Desnoyer, Russell; Coe, Jesse; Conrad, Chelsie E.; Fromme, Petra; Stevens, Raymond C.; Katritch, Vsevolod; Karnik, Sadashiva S.; Cherezov, Vadim

    2015-01-01

    SUMMARY Angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9 Å resolution. The AT1R-ZD7155 complex structure revealed key structural features of AT1R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design. PMID:25913193

  18. Proteomics Analysis Reveals Novel RASSF2 Interaction Partners.

    PubMed

    Barnoud, Thibaut; Wilkey, Daniel W; Merchant, Michael L; Clark, Jennifer A; Donninger, Howard

    2016-01-01

    RASSF2 is a tumor suppressor that shares homology with other Ras-association domain (RASSF) family members. It is a powerful pro-apoptotic K-Ras effector that is frequently inactivated in many human tumors. The exact mechanism by which RASSF2 functions is not clearly defined, but it likely acts as a scaffolding protein, modulating the activity of other pro-apoptotic effectors, thereby regulating and integrating tumor suppressor pathways. However, only a limited number of RASSF2 interacting partners have been identified to date. We used a proteomics based approach to identify additional RASSF2 interactions, and thereby gain a better insight into the mechanism of action of RASSF2. We identified several proteins, including C1QBP, Vimentin, Protein phosphatase 1G and Ribonuclease inhibitor that function in diverse biological processes, including protein post-translational modifications, epithelial-mesenchymal transition, cell migration and redox homeostasis, which have not previously been reported to interact with RASSF2. We independently validated two of these novel interactions, C1QBP and Vimentin and found that the interaction with C1QBP was enhanced by K-Ras whereas, interestingly, the Vimentin interaction was reduced by K-Ras. Additionally, RASSF2/K-Ras regulated the acetylation of Vimentin. Our data thus reveal novel mechanisms by which RASSF2 may exert its functions, several of which may be Ras-regulated. PMID:26999212

  19. Individual Differences Reveal Correlates of Hidden Hearing Deficits

    PubMed Central

    Masud, Salwa; Mehraei, Golbarg; Verhulst, Sarah; Shinn-Cunningham, Barbara G.

    2015-01-01

    Clinical audiometry has long focused on determining the detection thresholds for pure tones, which depend on intact cochlear mechanics and hair cell function. Yet many listeners with normal hearing thresholds complain of communication difficulties, and the causes for such problems are not well understood. Here, we explore whether normal-hearing listeners exhibit such suprathreshold deficits, affecting the fidelity with which subcortical areas encode the temporal structure of clearly audible sound. Using an array of measures, we evaluated a cohort of young adults with thresholds in the normal range to assess both cochlear mechanical function and temporal coding of suprathreshold sounds. Listeners differed widely in both electrophysiological and behavioral measures of temporal coding fidelity. These measures correlated significantly with each other. Conversely, these differences were unrelated to the modest variation in otoacoustic emissions, cochlear tuning, or the residual differences in hearing threshold present in our cohort. Electroencephalography revealed that listeners with poor subcortical encoding had poor cortical sensitivity to changes in interaural time differences, which are critical for localizing sound sources and analyzing complex scenes. These listeners also performed poorly when asked to direct selective attention to one of two competing speech streams, a task that mimics the challenges of many everyday listening environments. Together with previous animal and computational models, our results suggest that hidden hearing deficits, likely originating at the level of the cochlear nerve, are part of “normal hearing.” PMID:25653371

  20. Phylogenies reveal predictive power of traditional medicine in bioprospecting

    PubMed Central

    Saslis-Lagoudakis, C. Haris; Savolainen, Vincent; Williamson, Elizabeth M.; Forest, Félix; Wagstaff, Steven J.; Baral, Sushim R.; Watson, Mark F.; Pendry, Colin A.; Hawkins, Julie A.

    2012-01-01

    There is controversy about whether traditional medicine can guide drug discovery, and investment in bioprospecting informed by ethnobotanical data has fluctuated. One view is that traditionally used medicinal plants are not necessarily efficacious and there are no robust methods for distinguishing those which are most likely to be bioactive when selecting species for further testing. Here, we reconstruct a genus-level molecular phylogenetic tree representing the 20,000 species found in the floras of three disparate biodiversity hotspots: Nepal, New Zealand, and the Cape of South Africa. Borrowing phylogenetic methods from community ecology, we reveal significant clustering of the 1,500 traditionally used species, and provide a direct measure of the relatedness of the three medicinal floras. We demonstrate shared phylogenetic patterns across the floras: related plants from these regions are used to treat medical conditions in the same therapeutic areas. This finding strongly indicates independent discovery of plant efficacy, an interpretation corroborated by the presence of a significantly greater proportion of known bioactive species in these plant groups than in random samples. We conclude that phylogenetic cross-cultural comparisons can focus screening efforts on a subset of traditionally used plants that are richer in bioactive compounds, and could revitalize the use of traditional knowledge in bioprospecting. PMID:22984175

  1. Transcriptome profiling reveals mosaic genomic origins of modern cultivated barley.

    PubMed

    Dai, Fei; Chen, Zhong-Hua; Wang, Xiaolei; Li, Zefeng; Jin, Gulei; Wu, Dezhi; Cai, Shengguan; Wang, Ning; Wu, Feibo; Nevo, Eviatar; Zhang, Guoping

    2014-09-16

    The domestication of cultivated barley has been used as a model system for studying the origins and early spread of agrarian culture. Our previous results indicated that the Tibetan Plateau and its vicinity is one of the centers of domestication of cultivated barley. Here we reveal multiple origins of domesticated barley using transcriptome profiling of cultivated and wild-barley genotypes. Approximately 48-Gb of clean transcript sequences in 12 Hordeum spontaneum and 9 Hordeum vulgare accessions were generated. We reported 12,530 de novo assembled transcripts in all of the 21 samples. Population structure analysis showed that Tibetan hulless barley (qingke) might have existed in the early stage of domestication. Based on the large number of unique genomic regions showing the similarity between cultivated and wild-barley groups, we propose that the genomic origin of modern cultivated barley is derived from wild-barley genotypes in the Fertile Crescent (mainly in chromosomes 1H, 2H, and 3H) and Tibet (mainly in chromosomes 4H, 5H, 6H, and 7H). This study indicates that the domestication of barley may have occurred over time in geographically distinct regions. PMID:25197090

  2. Parallel Selection Revealed by Population Sequencing in Chicken.

    PubMed

    Qanbari, Saber; Seidel, Michael; Strom, Tim-Mathias; Mayer, Klaus F X; Preisinger, Ruedi; Simianer, Henner

    2015-12-01

    Human-driven selection during domestication and subsequent breed formation has likely left detectable signatures within the genome of modern chicken. The elucidation of these signatures of selection is of interest from the perspective of evolutionary biology, and for identifying genes relevant to domestication and improvement that ultimately may help to further genetically improve this economically important animal. We used whole genome sequence data from 50 hens of commercial white (WL) and brown (BL) egg-laying chicken along with pool sequences of three meat-type chicken to perform a systematic screening of past selection in modern chicken. Evidence of positive selection was investigated in two steps. First, we explored evidence of parallel fixation in regions with overlapping elevated allele frequencies in replicated populations of layers and broilers, suggestive of selection during domestication or preimprovement ages. We confirmed parallel fixation in BCDO2 and TSHR genes and found four candidates including AGTR2, a gene heavily involved in "Ascites" in commercial birds. Next, we explored differentiated loci between layers and broilers suggestive of selection during improvement in chicken. This analysis revealed evidence of parallel differentiation in genes relevant to appearance and production traits exemplified with the candidate gene OPG, implicated in Osteoporosis, a disorder related to overconsumption of calcium in egg-laying hens. Our results illustrate the potential for population genetic techniques to identify genomic regions relevant to the phenotypes of importance to breeders. PMID:26568375

  3. Substrate Channel in Nitrogenase Revealed by a Molecular Dynamics Approach

    SciTech Connect

    Smith, Dayle; Danyal, Karamatullah; Raugei, Simone; Seefeldt, Lance C.

    2014-03-22

    Mo-dependent nitrogenase catalyzes the biological reduction of N2 to 2NH3 at the FeMo-cofactor buried deep inside the MoFe protein. Access of substrates, such as N2, to the active site is likely restricted by the surrounding protein, requiring substrate channels that lead from the surface to the active site. Earlier studies on crystallographic structures of the MoFe protein have suggested three putative substrate channels. Here, we have utilized sub-microsecond atomistic molecular dynamics simulations to allow the nitrogenase MoFe protein to explore its conformational space in an aqueous solution at physiological ionic strength, revealing a putative substrate channel not previously reported. The viability of the proposed channel was tested by examining the free energy of passage of N2 from the surface through the channel to FeMo-cofactor, with discovery of a very low energy barrier. These studies point to a viable substrate channel in nitrogenase that appears during thermal motions of the protein in an aqueous environment that approaches a face of FeMo-cofactor earlier implicated in substrate binding.

  4. Historical reconstruction reveals recovery in Hawaiian coral reefs.

    PubMed

    Kittinger, John N; Pandolfi, John M; Blodgett, Jonathan H; Hunt, Terry L; Jiang, Hong; Maly, Kepā; McClenachan, Loren E; Schultz, Jennifer K; Wilcox, Bruce A

    2011-01-01

    Coral reef ecosystems are declining worldwide, yet regional differences in the trajectories, timing and extent of degradation highlight the need for in-depth regional case studies to understand the factors that contribute to either ecosystem sustainability or decline. We reconstructed social-ecological interactions in Hawaiian coral reef environments over 700 years using detailed datasets on ecological conditions, proximate anthropogenic stressor regimes and social change. Here we report previously undetected recovery periods in Hawaiian coral reefs, including a historical recovery in the MHI (~AD 1400-1820) and an ongoing recovery in the NWHI (~AD 1950-2009+). These recovery periods appear to be attributed to a complex set of changes in underlying social systems, which served to release reefs from direct anthropogenic stressor regimes. Recovery at the ecosystem level is associated with reductions in stressors over long time periods (decades+) and large spatial scales (>10(3) km(2)). Our results challenge conventional assumptions and reported findings that human impacts to ecosystems are cumulative and lead only to long-term trajectories of environmental decline. In contrast, recovery periods reveal that human societies have interacted sustainably with coral reef environments over long time periods, and that degraded ecosystems may still retain the adaptive capacity and resilience to recover from human impacts. PMID:21991311

  5. Archaeopteryx feathers and bone chemistry fully revealed via synchrotron imaging

    PubMed Central

    Bergmann, U.; Morton, R. W.; Manning, P. L.; Sellers, W. I.; Farrar, S.; Huntley, K. G.; Wogelius, R. A.; Larson, P.

    2010-01-01

    Evolution of flight in maniraptoran dinosaurs is marked by the acquisition of distinct avian characters, such as feathers, as seen in Archaeopteryx from the Solnhofen limestone. These rare fossils were pivotal in confirming the dinosauria-avian lineage. One of the key derived avian characters is the possession of feathers, details of which were remarkably preserved in the Lagerstätte environment. These structures were previously simply assumed to be impressions; however, a detailed chemical analysis has, until now, never been completed on any Archaeopteryx specimen. Here we present chemical imaging via synchrotron rapid scanning X-ray fluorescence (SRS-XRF) of the Thermopolis Archaeopteryx, which shows that portions of the feathers are not impressions but are in fact remnant body fossil structures, maintaining elemental compositions that are completely different from the embedding geological matrix. Our results indicate phosphorous and sulfur retention in soft tissue as well as trace metal (Zn and Cu) retention in bone. Other previously unknown chemical details of Archaeopteryx are also revealed in this study including: bone chemistry, taphonomy (fossilization process), and curation artifacts. SRS-XRF represents a major advancement in the study of the life chemistry and fossilization processes of Archaeopteryx and other extinct organisms because it is now practical to image the chemistry of large specimens rapidly at concentration levels of parts per million. This technique has wider application to the archaeological, forensic, and biological sciences, enabling the mapping of “unseen” compounds critical to understanding biological structures, modes of preservation, and environmental context. PMID:20457935

  6. Genetically engineered immunoglobulins reveal structural features controlling segmental flexibility.

    PubMed Central

    Schneider, W P; Wensel, T G; Stryer, L; Oi, V T

    1988-01-01

    We have carried out nanosecond fluorescence polarization studies of genetically engineered immunoglobulins to determine the structural features controlling their segmental flexibility. The proteins studied were hybrids of a relatively rigid isotype (mouse IgG1) and a relatively flexible one (mouse IgG2a). They have identical light chains and heavy chain variable regions and have the same combining sites for epsilon-dansyl-L-lysine, a fluorescent hapten. The fluorescence of the bound dansyl chromophore was excited at 348 nm with subnanosecond laser pulses, and the emission in the nanosecond time range was measured with a single-photon-counting apparatus. The emission anisotropy kinetics of the hybrid antibodies revealed that segmental flexibility is controlled by the heavy chain constant region 1 (CH1) as well as by the hinge. In contrast, the CH2 and CH3 domains did not influence segmental flexibility. The hinge and CH1 domains must be properly matched to allow facile movement of the Fab units. Studies of hybrids of IgG1 and IgG2a within CH1 showed that the loop formed by residues 131-139 is important in controlling segmental flexibility. X-ray crystallographic studies by others of human IgG1 have shown that this loop makes several van der Waals contacts with the hinge. Images PMID:3128789

  7. Interactome Analysis Reveals Ezrin Can Adopt Multiple Conformational States*

    PubMed Central

    Viswanatha, Raghuvir; Wayt, Jessica; Ohouo, Patrice Y.; Smolka, Marcus B.; Bretscher, Anthony

    2013-01-01

    Ezrin, a member of the ezrin-radixin-moesin family (ERM), is an essential regulator of the structure of microvilli on the apical aspect of epithelial cells. Ezrin provides a linkage between membrane-associated proteins and F-actin, oscillating between active/open and inactive/closed states, and is regulated in part by phosphorylation of a C-terminal threonine. In the open state, ezrin can bind a number of ligands, but in the closed state the ligand-binding sites are inaccessible. In vitro analysis has proposed that there may be a third hyperactivated form of ezrin. To gain a better understanding of ezrin, we conducted an unbiased proteomic analysis of ezrin-binding proteins in an epithelial cell line, Jeg-3. We refined our list of interactors by comparing the interactomes using quantitative mass spectrometry between wild-type ezrin, closed ezrin, open ezrin, and hyperactivated ezrin. The analysis reveals several novel interactors confirmed by their localization to microvilli, as well as a significant class of proteins that bind closed ezrin. Taken together, the data indicate that ezrin can exist in three different conformational states, and different ligands “perceive” ezrin conformational states differently. PMID:24151071

  8. Pyrosequencing reveals regional differences in fruit-associated fungal communities.

    PubMed

    Taylor, Michael W; Tsai, Peter; Anfang, Nicole; Ross, Howard A; Goddard, Matthew R

    2014-09-01

    We know relatively little of the distribution of microbial communities generally. Significant work has examined a range of bacterial communities, but the distribution of microbial eukaryotes is less well characterized. Humans have an ancient association with grape vines (Vitis vinifera) and have been making wine since the dawn of civilization, and fungi drive this natural process. While the molecular biology of certain fungi naturally associated with vines and wines is well characterized, complementary investigations into the ecology of fungi associated with fruiting plants is largely lacking. DNA sequencing technologies allow the direct estimation of microbial diversity from a given sample, avoiding culture-based biases. Here, we use deep community pyrosequencing approaches, targeted at the 26S rRNA gene, to examine the richness and composition of fungal communities associated with grapevines and test for geographical community structure among four major regions in New Zealand (NZ). We find over 200 taxa using this approach, which is 10-fold more than previously recovered using culture-based methods. Our analyses allow us to reject the null hypothesis of homogeneity in fungal species richness and community composition across NZ and reveal significant differences between major areas. PMID:24650123

  9. Small molecules reveal an alternative mechanism of Bax activation.

    PubMed

    Brahmbhatt, Hetal; Uehling, David; Al-Awar, Rima; Leber, Brian; Andrews, David

    2016-04-15

    The pro-apoptotic protein Bax commits a cell to death by permeabilizing the mitochondrial outer membrane (MOM). To obtain small-molecule probes for elucidating the molecular mechanism(s) of Bax activation, we screened for compounds that induced Bax-mediated liposome permeabilization. We identified five structurally different small molecules that promoted both Bax targeting to and oligomerization at membranes. All five compounds initiated Bax oligomerization in the absence of membranes by a mechanism unlike Bax activation by Bcl-2 homology 3 domain (BH3) proteins. Some of the compounds induced Bax/Bak-dependent apoptosis in cells. Activation of Bax by the most active compound was poorly inhibited by the anti-apoptotic protein Bcl-XL and requires a cysteine residue at position 126 of Bax that is not required for activation by BH3 proteins. Our results reveal a novel pathway for Bax activation independent of pro-apoptotic BH3 proteins that may have important implications for the regulation of Bax activity in cells. PMID:26916338

  10. Sequential analysis of the numerical Stroop effect reveals response suppression.

    PubMed

    Cohen Kadosh, Roi; Gevers, Wim; Notebaert, Wim

    2011-09-01

    Automatic processing of irrelevant stimulus dimensions has been demonstrated in a variety of tasks. Previous studies have shown that conflict between relevant and irrelevant dimensions can be reduced when a feature of the irrelevant dimension is repeated. The specific level at which the automatic process is suppressed (e.g., perceptual repetition, response repetition), however, is less understood. In the current experiment we used the numerical Stroop paradigm, in which the processing of irrelevant numerical values of 2 digits interferes with the processing of their physical size, to pinpoint the precise level of the suppression. Using a sequential analysis, we dissociated perceptual repetition from response repetition of the relevant and irrelevant dimension. Our analyses of reaction times, error rates, and diffusion modeling revealed that the congruity effect is significantly reduced or even absent when the response sequence of the irrelevant dimension, rather than the numerical value or the physical size, is repeated. These results suggest that automatic activation of the irrelevant dimension is suppressed at the response level. The current results shed light on the level of interaction between numerical magnitude and physical size as well as the effect of variability of responses and stimuli on automatic processing. PMID:21500951

  11. First cranial remains of a gondwanatherian mammal reveal remarkable mosaicism

    NASA Astrophysics Data System (ADS)

    Krause, David W.; Hoffmann, Simone; Wible, John R.; Kirk, E. Christopher; Schultz, Julia A.; von Koenigswald, Wighart; Groenke, Joseph R.; Rossie, James B.; O'Connor, Patrick M.; Seiffert, Erik R.; Dumont, Elizabeth R.; Holloway, Waymon L.; Rogers, Raymond R.; Rahantarisoa, Lydia J.; Kemp, Addison D.; Andriamialison, Haingoson

    2014-11-01

    Previously known only from isolated teeth and lower jaw fragments recovered from the Cretaceous and Palaeogene of the Southern Hemisphere, the Gondwanatheria constitute the most poorly known of all major mammaliaform radiations. Here we report the discovery of the first skull material of a gondwanatherian, a complete and well-preserved cranium from Upper Cretaceous strata in Madagascar that we assign to a new genus and species. Phylogenetic analysis strongly supports its placement within Gondwanatheria, which are recognized as monophyletic and closely related to multituberculates, an evolutionarily successful clade of Mesozoic mammals known almost exclusively from the Northern Hemisphere. The new taxon is the largest known mammaliaform from the Mesozoic of Gondwana. Its craniofacial anatomy reveals that it was herbivorous, large-eyed and agile, with well-developed high-frequency hearing and a keen sense of smell. The cranium exhibits a mosaic of primitive and derived features, the disparity of which is extreme and probably reflective of a long evolutionary history in geographic isolation.

  12. Spatial Congruity Effects Reveal Metaphorical Thinking, not Polarity Correspondence

    PubMed Central

    Dolscheid, Sarah; Casasanto, Daniel

    2015-01-01

    Spatial congruity effects have often been interpreted as evidence for metaphorical thinking, but an alternative account based on polarity correspondence (a.k.a. markedness) has challenged this view. Here we compared metaphor- and polarity-correspondence-based explanations for spatial congruity effects, using musical pitch as a testbed. In one experiment, English speakers classified high- and low-frequency pitches as “high” and “low,” or as “front” and “back,” to determine whether space-pitch congruity effects could be elicited by any marked spatial continuum. Although both pairs of terms describe bipolar spatial continuums, we found congruity effects only for high/low judgments, indicating that markedness is not sufficient to produce space-pitch congruity effects. A second experiment confirmed that there were no space-pitch congruity effects for another pair of terms that have clear markedness (big/small), but which do not denote spatial height. By contrast, this experiment showed congruity effects for words that cued an appropriate vertical spatial schema (tall/short), even though these words are not used conventionally in English to describe pitches, ruling out explanations for the observed pattern of results based on verbal polysemy. Together, results suggest that space-pitch congruity effects reveal metaphorical uses of spatial schemas, not polarity correspondence effects. PMID:26635713

  13. Next generation sequencing in synovial sarcoma reveals novel gene mutations

    PubMed Central

    Vlenterie, Myrella; Hillebrandt-Roeffen, Melissa H.S.; Flucke, Uta E.; Groenen, Patricia J.T.A.; Tops, Bastiaan B.J.; Kamping, Eveline J.; Pfundt, Rolph; de Bruijn, Diederik R.H.; van Kessel, Ad H.M. Geurts; van Krieken, Han J.H.J.M.; van der Graaf, Winette T.A.; Versleijen-Jonkers, Yvonne M.H.

    2015-01-01

    Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults. PMID:26415226

  14. Integrative modelling reveals mechanisms linking productivity and plant species richness

    NASA Astrophysics Data System (ADS)

    Grace, James B.; Anderson, T. Michael; Seabloom, Eric W.; Borer, Elizabeth T.; Adler, Peter B.; Harpole, W. Stanley; Hautier, Yann; Hillebrand, Helmut; Lind, Eric M.; Pärtel, Meelis; Bakker, Jonathan D.; Buckley, Yvonne M.; Crawley, Michael J.; Damschen, Ellen I.; Davies, Kendi F.; Fay, Philip A.; Firn, Jennifer; Gruner, Daniel S.; Hector, Andy; Knops, Johannes M. H.; MacDougall, Andrew S.; Melbourne, Brett A.; Morgan, John W.; Orrock, John L.; Prober, Suzanne M.; Smith, Melinda D.

    2016-01-01

    How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems.

  15. Global Population Genetic Structure of Caenorhabditis remanei Reveals Incipient Speciation

    PubMed Central

    Dey, Alivia; Jeon, Yong; Wang, Guo-Xiu; Cutter, Asher D.

    2012-01-01

    Mating system transitions dramatically alter the evolutionary trajectories of genomes that can be revealed by contrasts of species with disparate modes of reproduction. For such transitions in Caenorhabditis nematodes, some major causes of genome variation in selfing species have been discerned. And yet, we have only limited understanding of species-wide population genetic processes for their outcrossing relatives, which represent the reproductive state of the progenitors of selfing species. Multilocus–multipopulation sequence polymorphism data provide a powerful means to uncover the historical demography and evolutionary processes that shape genomes. Here we survey nucleotide polymorphism across the X chromosome for three populations of the outcrossing nematode Caenorhabditis remanei and demonstrate its divergence from a fourth population describing a closely related new species from China, C. sp. 23. We find high genetic variation globally and within each local population sample. Despite geographic barriers and moderate genetic differentiation between Europe and North America, considerable gene flow connects C. remanei populations. We discovered C. sp. 23 while investigating C. remanei, observing strong genetic differentiation characteristic of reproductive isolation that was confirmed by substantial F2 hybrid breakdown in interspecific crosses. That C. sp. 23 represents a distinct biological species provides a cautionary example of how standard practice can fail for mating tests of species identity in this group. This species pair permits full application of divergence population genetic methods to obligately outcrossing species of Caenorhabditis and also presents a new focus for interrogation of the genetics and evolution of speciation with the Caenorhabditis model system. PMID:22649079

  16. Excited states of ribosome translocation revealed through integrative molecular modeling

    PubMed Central

    Whitford, Paul C.; Ahmed, Aqeel; Yu, Yanan; Hennelly, Scott P.; Tama, Florence; Spahn, Christian M. T.; Onuchic, José N.; Sanbonmatsu, Karissa Y.

    2011-01-01

    The dynamic nature of biomolecules leads to significant challenges when characterizing the structural properties associated with function. While X-ray crystallography and imaging techniques (such as cryo-electron microscopy) can reveal the structural details of stable molecular complexes, strategies must be developed to characterize configurations that exhibit only marginal stability (such as intermediates) or configurations that do not correspond to minima on the energy landscape (such as transition-state ensembles). Here, we present a methodology (MDfit) that utilizes molecular dynamics simulations to generate configurations of excited states that are consistent with available biophysical and biochemical measurements. To demonstrate the approach, we present a sequence of configurations that are suggested to be associated with transfer RNA (tRNA) movement through the ribosome (translocation). The models were constructed by combining information from X-ray crystallography, cryo-electron microscopy, and biochemical data. These models provide a structural framework for translocation that may be further investigated experimentally and theoretically to determine the precise energetic character of each configuration and the transition dynamics between them. PMID:22080606

  17. Excited states of ribosome translocation revealed through integrative molecular modeling.

    PubMed

    Whitford, Paul C; Ahmed, Aqeel; Yu, Yanan; Hennelly, Scott P; Tama, Florence; Spahn, Christian M T; Onuchic, José N; Sanbonmatsu, Karissa Y

    2011-11-22

    The dynamic nature of biomolecules leads to significant challenges when characterizing the structural properties associated with function. While X-ray crystallography and imaging techniques (such as cryo-electron microscopy) can reveal the structural details of stable molecular complexes, strategies must be developed to characterize configurations that exhibit only marginal stability (such as intermediates) or configurations that do not correspond to minima on the energy landscape (such as transition-state ensembles). Here, we present a methodology (MDfit) that utilizes molecular dynamics simulations to generate configurations of excited states that are consistent with available biophysical and biochemical measurements. To demonstrate the approach, we present a sequence of configurations that are suggested to be associated with transfer RNA (tRNA) movement through the ribosome (translocation). The models were constructed by combining information from X-ray crystallography, cryo-electron microscopy, and biochemical data. These models provide a structural framework for translocation that may be further investigated experimentally and theoretically to determine the precise energetic character of each configuration and the transition dynamics between them. PMID:22080606

  18. Revealing the wood and the trees: reporting qualitative research.

    PubMed

    Blignault, Ilse; Ritchie, Jan

    2009-08-01

    Qualitative research methodologies, which are oriented to better understanding of the context, meaning and experiences of people's lives, have much to contribute to health promotion. For researchers trained in quantitative methods, writing up qualitative research for a peer-reviewed journal can be a challenge, especially keeping within the prescribed word limits. How well you explain and disseminate your research will influence how others evaluate its quality; this has implications not only for what you write and the terminology you use but for how you structure your article. This paper provides a general guide to presenting qualitative research for publication in a way that has meaning for authors and readers, is acceptable to editors and reviewers, and meets criteria for high standards of qualitative research reporting across the board. We discuss the writing of all sections of an article, placing particular emphasis on how you might best present your findings, illustrating our points with examples drawn from previous issues of this Journal. Overall, we emphasise that reporting qualitative research involves sharing both the process and the findings, that is, revealing both the wood and the trees. PMID:19642963

  19. Key herbivores reveal limited functional redundancy on inshore coral reefs

    NASA Astrophysics Data System (ADS)

    Johansson, C. L.; van de Leemput, I. A.; Depczynski, M.; Hoey, A. S.; Bellwood, D. R.

    2013-12-01

    Marine ecosystems are facing increasing exposure to a range of stressors and declines in critical ecological functions. The likelihood of further loss of functions and resilience is dependent, in part, on the extent of functional redundancy (i.e. the capacity of one species to functionally compensate for the loss of another species) within critical functional groups. We used multiple metrics; species richness, generic richness, abundance and reserve capacity (i.e. the relative number of individuals available to fulfil the function if the numerically dominant species is lost), as indicators to assess the potential functional redundancy of four functional groups of herbivorous fishes (browsers, excavators, grazers and scrapers) in two of the worlds' most intact coral reef ecosystems: the Great Barrier Reef (GBR) and Ningaloo Reef in Western Australia. We found marked variations in potential redundancy among habitats within each reef system and functional groups. Despite negligible fishing of herbivorous fishes, coastal habitats in both reef systems had lower functional redundancy compared to offshore locations for all herbivorous fishes collectively and the four functional groups independently. This pattern was consistent in all four indicators of redundancy. The potential vulnerability of these coastal habitats is highlighted by recent shifts from coral to macroalgal dominance on several coastal reefs of the GBR. Our approach provides a simple yet revealing evaluation of potential functional redundancy. Moreover, it highlights the spatial variation in potential vulnerability and resilience of reef systems.

  20. Integrating Phosphoproteome and Transcriptome Reveals New Determinants of Macrophage Multinucleation*

    PubMed Central

    Rotival, Maxime; Ko, Jeong-Hun; Srivastava, Prashant K.; Kerloc'h, Audrey; Montoya, Alex; Mauro, Claudio; Faull, Peter; Cutillas, Pedro R.; Petretto, Enrico; Behmoaras, Jacques

    2015-01-01

    Macrophage multinucleation (MM) is essential for various biological processes such as osteoclast-mediated bone resorption and multinucleated giant cell-associated inflammatory reactions. Here we study the molecular pathways underlying multinucleation in the rat through an integrative approach combining MS-based quantitative phosphoproteomics (LC-MS/MS) and transcriptome (high-throughput RNA-sequencing) to identify new regulators of MM. We show that a strong metabolic shift toward HIF1-mediated glycolysis occurs at transcriptomic level during MM, together with modifications in phosphorylation of over 50 proteins including several ARF GTPase activators and polyphosphate inositol phosphatases. We use shortest-path analysis to link differential phosphorylation with the transcriptomic reprogramming of macrophages and identify LRRFIP1, SMARCA4, and DNMT1 as novel regulators of MM. We experimentally validate these predictions by showing that knock-down of these latter reduce macrophage multinucleation. These results provide a new framework for the combined analysis of transcriptional and post-translational changes during macrophage multinucleation, prioritizing essential genes, and revealing the sequential events leading to the multinucleation of macrophages. PMID:25532521

  1. Genomic analysis of primordial dwarfism reveals novel disease genes.

    PubMed

    Shaheen, Ranad; Faqeih, Eissa; Ansari, Shinu; Abdel-Salam, Ghada; Al-Hassnan, Zuhair N; Al-Shidi, Tarfa; Alomar, Rana; Sogaty, Sameera; Alkuraya, Fowzan S

    2014-02-01

    Primordial dwarfism (PD) is a disease in which severely impaired fetal growth persists throughout postnatal development and results in stunted adult size. The condition is highly heterogeneous clinically, but the use of certain phenotypic aspects such as head circumference and facial appearance has proven helpful in defining clinical subgroups. In this study, we present the results of clinical and genomic characterization of 16 new patients in whom a broad definition of PD was used (e.g., 3M syndrome was included). We report a novel PD syndrome with distinct facies in two unrelated patients, each with a different homozygous truncating mutation in CRIPT. Our analysis also reveals, in addition to mutations in known PD disease genes, the first instance of biallelic truncating BRCA2 mutation causing PD with normal bone marrow analysis. In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause. An additional novel PD disease candidate gene XRCC4 was identified by autozygome/exome analysis, and the knockout mouse phenotype is highly compatible with PD. Thus, we add a number of novel genes to the growing list of PD-linked genes, including one which we show to be linked to a novel PD syndrome with a distinct facial appearance. PD is extremely heterogeneous genetically and clinically, and genomic tools are often required to reach a molecular diagnosis. PMID:24389050

  2. Parallel Selection Revealed by Population Sequencing in Chicken

    PubMed Central

    Qanbari, Saber; Seidel, Michael; Strom, Tim-Mathias; Mayer, Klaus F.X.; Preisinger, Ruedi; Simianer, Henner

    2015-01-01

    Human-driven selection during domestication and subsequent breed formation has likely left detectable signatures within the genome of modern chicken. The elucidation of these signatures of selection is of interest from the perspective of evolutionary biology, and for identifying genes relevant to domestication and improvement that ultimately may help to further genetically improve this economically important animal. We used whole genome sequence data from 50 hens of commercial white (WL) and brown (BL) egg-laying chicken along with pool sequences of three meat-type chicken to perform a systematic screening of past selection in modern chicken. Evidence of positive selection was investigated in two steps. First, we explored evidence of parallel fixation in regions with overlapping elevated allele frequencies in replicated populations of layers and broilers, suggestive of selection during domestication or preimprovement ages. We confirmed parallel fixation in BCDO2 and TSHR genes and found four candidates including AGTR2, a gene heavily involved in “Ascites” in commercial birds. Next, we explored differentiated loci between layers and broilers suggestive of selection during improvement in chicken. This analysis revealed evidence of parallel differentiation in genes relevant to appearance and production traits exemplified with the candidate gene OPG, implicated in Osteoporosis, a disorder related to overconsumption of calcium in egg-laying hens. Our results illustrate the potential for population genetic techniques to identify genomic regions relevant to the phenotypes of importance to breeders. PMID:26568375

  3. Revealing hidden regularities with a general approach to fission

    NASA Astrophysics Data System (ADS)

    Schmidt, Karl-Heinz; Jurado, Beatriz

    2015-12-01

    Selected aspects of a general approach to nuclear fission are described with the focus on the possible benefit of meeting the increasing need of nuclear data for the existing and future emerging nuclear applications. The most prominent features of this approach are the evolution of quantum-mechanical wave functions in systems with complex shape, memory effects in the dynamics of stochastic processes, the influence of the Second Law of thermodynamics on the evolution of open systems in terms of statistical mechanics, and the topological properties of a continuous function in multi-dimensional space. It is demonstrated that this approach allows reproducing the measured fission barriers and the observed properties of the fission fragments and prompt neutrons. Our approach is based on sound physical concepts, as demonstrated by the fact that practically all the parameters have a physical meaning, and reveals a high degree of regularity in the fission observables. Therefore, we expect a good predictive power within the region extending from Po isotopes to Sg isotopes where the model parameters have been adjusted. Our approach can be extended to other regions provided that there is enough empirical information available that allows determining appropriate values of the model parameters. Possibilities for combining this general approach with microscopic models are suggested. These are supposed to enhance the predictive power of the general approach and to help improving or adjusting the microscopic models. This could be a way to overcome the present difficulties for producing evaluations with the required accuracy.

  4. Designed protein reveals structural determinants of extreme kinetic stability

    PubMed Central

    Broom, Aron; Ma, S. Martha; Xia, Ke; Rafalia, Hitesh; Trainor, Kyle; Colón, Wilfredo; Gosavi, Shachi; Meiering, Elizabeth M.

    2015-01-01

    The design of stable, functional proteins is difficult. Improved design requires a deeper knowledge of the molecular basis for design outcomes and properties. We previously used a bioinformatics and energy function method to design a symmetric superfold protein composed of repeating structural elements with multivalent carbohydrate-binding function, called ThreeFoil. This and similar methods have produced a notably high yield of stable proteins. Using a battery of experimental and computational analyses we show that despite its small size and lack of disulfide bonds, ThreeFoil has remarkably high kinetic stability and its folding is specifically chaperoned by carbohydrate binding. It is also extremely stable against thermal and chemical denaturation and proteolytic degradation. We demonstrate that the kinetic stability can be predicted and modeled using absolute contact order (ACO) and long-range order (LRO), as well as coarse-grained simulations; the stability arises from a topology that includes many long-range contacts which create a large and highly cooperative energy barrier for unfolding and folding. Extensive data from proteomic screens and other experiments reveal that a high ACO/LRO is a general feature of proteins with strong resistances to denaturation and degradation. These results provide tractable approaches for predicting resistance and designing proteins with sufficient topological complexity and long-range interactions to accommodate destabilizing functional features as well as withstand chemical and proteolytic challenge. PMID:26554002

  5. Dense sampling reveals behavioral oscillations in rapid visual categorization.

    PubMed

    Drewes, Jan; Zhu, Weina; Wutz, Andreas; Melcher, David

    2015-01-01

    Perceptual systems must create discrete objects and events out of a continuous flow of sensory information. Previous studies have demonstrated oscillatory effects in the behavioral outcome of low-level visual tasks, suggesting a cyclic nature of visual processing as the solution. To investigate whether these effects extend to more complex tasks, a stream of "neutral" photographic images (not containing targets) was rapidly presented (20 ms/image). Embedded were one or two presentations of a randomly selected target image (vehicles and animals). Subjects reported the perceived target category. On dual-presentation trials, the ISI varied systematically from 0 to 600 ms. At randomized timing before first target presentation, the screen was flashed with the intent of creating a phase reset in the visual system. Sorting trials by temporal distance between flash and first target presentation revealed strong oscillations in behavioral performance, peaking at 5 Hz. On dual-target trials, longer ISIs led to reduced performance, implying a temporal integration window for object category discrimination. The "animal" trials exhibited a significant oscillatory component around 5 Hz. Our results indicate that oscillatory effects are not mere fringe effects relevant only with simple stimuli, but are resultant from the core mechanisms of visual processing and may well extend into real-life scenarios. PMID:26542183

  6. Ecoinformatics Reveals Effects of Crop Rotational Histories on Cotton Yield

    PubMed Central

    Meisner, Matthew H.; Rosenheim, Jay A.

    2014-01-01

    Crop rotation has been practiced for centuries in an effort to improve agricultural yield. However, the directions, magnitudes, and mechanisms of the yield effects of various crop rotations remain poorly understood in many systems. In order to better understand how crop rotation influences cotton yield, we used hierarchical Bayesian models to analyze a large ecoinformatics database consisting of records of commercial cotton crops grown in California's San Joaquin Valley. We identified several crops that, when grown in a field the year before a cotton crop, were associated with increased or decreased cotton yield. Furthermore, there was a negative association between the effect of the prior year's crop on June densities of the pest Lygus hesperus and the effect of the prior year's crop on cotton yield. This suggested that some crops may enhance L. hesperus densities in the surrounding agricultural landscape, because residual L. hesperus populations from the previous year cannot continuously inhabit a focal field and attack a subsequent cotton crop. In addition, we found that cotton yield declined approximately 2.4% for each additional year in which cotton was grown consecutively in a field prior to the focal cotton crop. Because L. hesperus is quite mobile, the effects of crop rotation on L. hesperus would likely not be revealed by small plot experimentation. These results provide an example of how ecoinformatics datasets, which capture the true spatial scale of commercial agriculture, can be used to enhance agricultural productivity. PMID:24465657

  7. Artemin Crystal Structure Reveals Insights into Heparan Sulfate Binding

    SciTech Connect

    Silvian,L.; Jin, P.; Carmillo, P.; Boriack-Sjodin, P.; Pelletier, C.; Rushe, M.; Gong, B.; Sah, D.; Pepinsky, B.; Rossomando, A.

    2006-01-01

    Artemin (ART) promotes the growth of developing peripheral neurons by signaling through a multicomponent receptor complex comprised of a transmembrane tyrosine kinase receptor (cRET) and a specific glycosylphosphatidylinositol-linked co-receptor (GFR{alpha}3). Glial cell line-derived neurotrophic factor (GDNF) signals through a similar ternary complex but requires heparan sulfate proteoglycans (HSPGs) for full activity. HSPG has not been demonstrated as a requirement for ART signaling. We crystallized ART in the presence of sulfate and solved its structure by isomorphous replacement. The structure reveals ordered sulfate anions bound to arginine residues in the pre-helix and amino-terminal regions that were organized in a triad arrangement characteristic of heparan sulfate. Three residues in the pre-helix were singly or triply substituted with glutamic acid, and the resulting proteins were shown to have reduced heparin-binding affinity that is partly reflected in their ability to activate cRET. This study suggests that ART binds HSPGs and identifies residues that may be involved in HSPG binding.

  8. Metabolomics reveals insect metabolic responses associated with fungal infection.

    PubMed

    Xu, Yong-Jiang; Luo, Feifei; Gao, Qiang; Shang, Yanfang; Wang, Chengshu

    2015-06-01

    The interactions between insects and pathogenic fungi are complex. We employed metabolomic techniques to profile insect metabolic dynamics upon infection by the pathogenic fungus Beauveria bassiana. Silkworm larvae were infected with fungal spores and microscopic observations demonstrated that the exhaustion of insect hemocytes was coupled with fungal propagation in the insect body cavity. Metabolomic analyses revealed that fungal infection could significantly alter insect energy and nutrient metabolisms as well as the immune defense responses, including the upregulation of carbohydrates, amino acids, fatty acids, and lipids, but the downregulation of eicosanoids and amines. The insect antifeedant effect of the fungal infection was evident with the reduced level of maclurin (a component of mulberry leaves) in infected insects but elevated accumulations in control insects. Insecticidal and cytotoxic mycotoxins like oosporein and beauveriolides were also detected in insects at the later stages of infection. Taken together, the metabolomics data suggest that insect immune responses are energy-cost reactions and the strategies of nutrient deprivation, inhibition of host immune responses, and toxin production would be jointly employed by the fungus to kill insects. The data obtained in this study will facilitate future functional studies of genes and pathways associated with insect-fungus interactions. PMID:25895944

  9. Response trajectories reveal conflict phase in image-word mismatch.

    PubMed

    van Vugt, Floris T; Cavanagh, Patrick

    2012-02-01

    In the present study, response trajectories were used in a picture–word conflict task to determine the timing of intermediate processing stages that are relatively inaccessible to response time measures. A marker was placed above or below the word ABOVE or BELOW so that its location was congruent or in conflict with the word's meaning. To report either word location(above or below the marker) or word meaning, participants moved a mouse upward toward the appropriate top left or right answer corner on the display screen.Their response trajectories showed a number of distinctive features: First, at about 200 ms after stimulus onset(the "decision moment"), the trajectory abruptly began to arc toward the appropriate answer corner; second,when the word's meaning and position were in conflict,the trajectory showed an interruption that continued until the conflict was resolved. By varying the SOA of the word and marker onsets, we found that the word meaning and word position became available at approximately 325 ms and 251 ms, respectively, after their onsets, and that the delay to resolve conflicts was about 138 ms. The timing of these response trajectory events was more stable than any extracted from the final response times, demonstrating the power of response trajectories to reveal processing stages that are only poorly resolved, if at all, by response time measures [added]. PMID:22219088

  10. Metabolic phenotyping reveals a lipid mediator response to ionizing radiation.

    PubMed

    Laiakis, Evagelia C; Strassburg, Katrin; Bogumil, Ralf; Lai, Steven; Vreeken, Rob J; Hankemeier, Thomas; Langridge, James; Plumb, Robert S; Fornace, Albert J; Astarita, Giuseppe

    2014-09-01

    Exposure to ionizing radiation has dramatically increased in modern society, raising serious health concerns. The molecular response to ionizing radiation, however, is still not completely understood. Here, we screened mouse serum for metabolic alterations following an acute exposure to γ radiation using a multiplatform mass-spectrometry-based strategy. A global, molecular profiling revealed that mouse serum undergoes a series of significant molecular alterations following radiation exposure. We identified and quantified bioactive metabolites belonging to key biochemical pathways and low-abundance, oxygenated, polyunsaturated fatty acids (PUFAs) in the two groups of animals. Exposure to γ radiation induced a significant increase in the serum levels of ether phosphatidylcholines (PCs) while decreasing the levels of diacyl PCs carrying PUFAs. In exposed mice, levels of pro-inflammatory, oxygenated metabolites of arachidonic acid increased, whereas levels of anti-inflammatory metabolites of omega-3 PUFAs decreased. Our results indicate a specific serum lipidomic biosignature that could be utilized as an indicator of radiation exposure and as novel target for therapeutic intervention. Monitoring such a molecular response to radiation exposure might have implications not only for radiation pathology but also for countermeasures and personalized medicine. PMID:25126707

  11. Revealing accretion onto black holes through X-ray reflection

    NASA Astrophysics Data System (ADS)

    Plant, D.; Fender, R.; Ponti, G.; Munoz-Darias, T.; Coriat, M.

    2014-07-01

    Understanding the dynamics behind black hole state transitions and the changes they reflect in outbursts has become long-standing problem. The X-ray reflection spectrum describes the interaction between the hard X-ray source (the power-law continuum) and the cool accretion disc it illuminates, and thus permits an indirect view of how the two evolve. We present a systematic analysis of the reflection spectrum throughout three outbursts (500+ RXTE observations) of the black hole binary GX 339-4, representing the largest study applying a self-consistent treatment of reflection to date. Particular attention is payed to the coincident evolution of the power-law and reflection, which can be used to determine the accretion geometry. The hard state is found to be distinctly reflection weak, however the ratio of reflection to power-law gradually increases as the source luminosity rises. In contrast the reflection is found dominate the power-law throughout most of the soft state, with increasing supremacy as the source decays. Using results from archival and AO-12 observations of GX 339-4 with XMM-Newton we reveal the dynamics driving this evolution and the nature of accretion onto black holes in outburst.

  12. Protein-RNA networks revealed through covalent RNA marks

    PubMed Central

    Lapointe, Christopher P.; Wilinski, Daniel; Saunders, Harriet A. J.; Wickens, Marvin

    2015-01-01

    Protein-RNA networks are ubiquitous and central in biological control. We present an approach, termed “RNA Tagging,” that identifies protein-RNA interactions in vivo by analyzing purified cellular RNA, without protein purification or crosslinking. An RNA-binding protein of interest is fused to an enzyme that adds uridines to the end of RNA. RNA targets bound by the chimeric protein in vivo are covalently marked with uridines and subsequently identified from extracted RNA using high-throughput sequencing. We used this approach to identify hundreds of RNAs bound by a Saccharomyces cerevisiae PUF protein, Puf3p. The method revealed that while RNA-binding proteins productively bind specific RNAs to control their function, they also “sample” RNAs without exerting a regulatory effect. We exploited the method to uncover hundreds of new and likely regulated targets for a protein without canonical RNA-binding domains, Bfr1p. The RNA Tagging approach is well-suited to detect and analyze protein-RNA networks in vivo. PMID:26524240

  13. Knock-out models reveal new aquaporin functions.

    PubMed

    Verkman, Alan S

    2009-01-01

    Knockout mice have been informative in the discovery of unexpected biological functions of aquaporins. Knockout mice have confirmed the predicted roles of aquaporins in transepithelial fluid transport, as in the urinary concentrating mechanism and glandular fluid secretion. A less obvious, though predictable role of aquaporins is in tissue swelling under stress, as in the brain in stroke, tumor and infection. Phenotype analysis of aquaporin knockout mice has revealed several unexpected cellular roles of aquaporins whose mechanisms are being elucidated. Aquaporins facilitate cell migration, as seen in aquaporin-dependent tumor angiogenesis and tumor metastasis, by a mechanism that may involve facilitated water transport in lamellipodia of migrating cells. The ' aquaglyceroporins', aquaporins that transport both glycerol and water, regulate glycerol content in epidermis, fat and other tissues, and lead to a multiplicity of interesting consequences of gene disruption including dry skin, resistance to skin carcinogenesis, impaired cell proliferation and altered fat metabolism. An even more surprising role of a mammalian aquaporin is in neural signal transduction in the central nervous system. The many roles of aquaporins might be exploited for clinical benefit by modulation of aquaporin expression/function - as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer. PMID:19096787

  14. Experimental evolution reveals hidden diversity in evolutionary pathways

    PubMed Central

    Lind, Peter A; Farr, Andrew D; Rainey, Paul B

    2015-01-01

    Replicate populations of natural and experimental organisms often show evidence of parallel genetic evolution, but the causes are unclear. The wrinkly spreader morph of Pseudomonas fluorescens arises repeatedly during experimental evolution. The mutational causes reside exclusively within three pathways. By eliminating these, 13 new mutational pathways were discovered with the newly arising WS types having fitnesses similar to those arising from the commonly passaged routes. Our findings show that parallel genetic evolution is strongly biased by constraints and we reveal the genetic bases. From such knowledge, and in instances where new phenotypes arise via gene activation, we suggest a set of principles: evolution proceeds firstly via pathways subject to negative regulation, then via promoter mutations and gene fusions, and finally via activation by intragenic gain-of-function mutations. These principles inform evolutionary forecasting and have relevance to interpreting the diverse array of mutations associated with clinically identical instances of disease in humans. DOI: http://dx.doi.org/10.7554/eLife.07074.001 PMID:25806684

  15. Acoustic telemetry reveals cryptic residency of whale sharks.

    PubMed

    Cagua, E Fernando; Cochran, Jesse E M; Rohner, Christoph A; Prebble, Clare E M; Sinclair-Taylor, Tane H; Pierce, Simon J; Berumen, Michael L

    2015-04-01

    Although whale sharks (Rhincodon typus) have been documented to move thousands of kilometres, they are most frequently observed at a few predictable seasonal aggregation sites. The absence of sharks at the surface during visual surveys has led to the assumption that sharks disperse to places unknown during the long 'off-seasons' at most of these locations. Here we compare 2 years of R. typus visual sighting records from Mafia Island in Tanzania to concurrent acoustic telemetry of tagged individuals. Sightings revealed a clear seasonal pattern with a peak between October and February and no sharks observed at other times. By contrast, acoustic telemetry demonstrated year-round residency of R. typus. The sharks use a different habitat in the off-season, swimming deeper and further away from shore, presumably in response to prey distributions. This behavioural change reduces the sharks' visibility, giving the false impression that they have left the area. We demonstrate, for the first time to our knowledge, year-round residency of unprovisioned, individual R. typus at an aggregation site, and highlight the importance of using multiple techniques to study the movement ecology of marine megafauna. PMID:25832816

  16. TEMPRANILLO Reveals the Mesophyll as Crucial for Epidermal Trichome Formation.

    PubMed

    Matías-Hernández, Luis; Aguilar-Jaramillo, Andrea E; Osnato, Michela; Weinstain, Roy; Shani, Eilon; Suárez-López, Paula; Pelaz, Soraya

    2016-03-01

    Plant trichomes are defensive specialized epidermal cells. In all accepted models, the epidermis is the layer involved in trichome formation, a process controlled by gibberellins (GAs) in Arabidopsis rosette leaves. Indeed, GA activates a genetic cascade in the epidermis for trichome initiation. Here we report that TEMPRANILLO (TEM) genes negatively control trichome initiation not only from the epidermis but also from the leaf layer underneath the epidermis, the mesophyll. Plants over-expressing or reducing TEM specifically in the mesophyll, display lower or higher trichome numbers, respectively. We surprisingly found that fluorescently labeled GA3 accumulates exclusively in the mesophyll of leaves, but not in the epidermis, and that TEM reduces its accumulation and the expression of several newly identified GA transporters. This strongly suggests that TEM plays an essential role, not only in GA biosynthesis, but also in regulating GA distribution in the mesophyll, which in turn directs epidermal trichome formation. Moreover, we show that TEM also acts as a link between GA and cytokinin signaling in the epidermis by negatively regulating downstream genes of both trichome formation pathways. Overall, these results call for a re-evaluation of the present theories of trichome formation as they reveal mesophyll essential during epidermal trichome initiation. PMID:26802039

  17. Spectrins in axonal cytoskeletons: Dynamics revealed by extensions and fluctuations

    NASA Astrophysics Data System (ADS)

    Lai, Lipeng; Cao, Jianshu

    2014-07-01

    The macroscopic properties, the properties of individual components, and how those components interact with each other are three important aspects of a composited structure. An understanding of the interplay between them is essential in the study of complex systems. Using axonal cytoskeleton as an example system, here we perform a theoretical study of slender structures that can be coarse-grained as a simple smooth three-dimensional curve. We first present a generic model for such systems based on the fundamental theorem of curves. We use this generic model to demonstrate the applicability of the well-known worm-like chain (WLC) model to the network level and investigate the situation when the system is stretched by strong forces (weakly bending limit). We specifically studied recent experimental observations that revealed the hitherto unknown periodic cytoskeleton structure of axons and measured the longitudinal fluctuations. Instead of focusing on single molecules, we apply analytical results from the WLC model to both single molecule and network levels and focus on the relations between extensions and fluctuations. We show how this approach introduces constraints to possible local dynamics of the spectrin tetramers in the axonal cytoskeleton and finally suggests simple but self-consistent dynamics of spectrins in which the spectrins in one spatial period of axons fluctuate in-sync.

  18. Polymyalgia Rheumatica Revealing a Lymphoma: A Two-Case Report.

    PubMed

    Verhoeven, Frank; Guillot, Xavier; Chouk, Mickaël; Prati, Clément; Wendling, Daniel

    2016-01-01

    Introduction. Polymyalgia rheumatica (PMR) is one of the most common inflammatory rheumatism types in elderly population. The link between cancer and PMR is a matter of debate. Methods. We report two cases of PMR leading to the diagnosis of lymphoma and the growing interest of PET-TDM in this indication. Results. A 84-year-old man known for idiopathic neutropenia presented an inflammatory arthromyalgia of the limb girdle since one month. Blood exams highlighted the presence of a monoclonal B cell clone. Bone marrow concluded to a B cell lymphoma of the marginal zone. He was successfully treated with 0.3 mg/kg/d of prednisone, and response was sustained after 6 months. A 73-year-old man known for prostatic neoplasia in remission for 5 years presented arthromyalgia of the limb girdle since one month. PET-CT revealed bursitis of the hips and the shoulders, no prostatic cancer recurrence, and a metabolically active iliac lymphadenopathy whose pathologic exam concluded to a low grade follicular lymphoma. He was successfully treated with 0.3 mg/kg/d of prednisone. Conclusion. These observations may imply that lymphoma is sometimes already present when PMR is diagnosed and PET-CT is a useful tool in the initial assessment of PMR to avoid missing neoplasia. PMID:27597921

  19. Integrative modelling reveals mechanisms linking productivity and plant species richness.

    PubMed

    Grace, James B; Anderson, T Michael; Seabloom, Eric W; Borer, Elizabeth T; Adler, Peter B; Harpole, W Stanley; Hautier, Yann; Hillebrand, Helmut; Lind, Eric M; Pärtel, Meelis; Bakker, Jonathan D; Buckley, Yvonne M; Crawley, Michael J; Damschen, Ellen I; Davies, Kendi F; Fay, Philip A; Firn, Jennifer; Gruner, Daniel S; Hector, Andy; Knops, Johannes M H; MacDougall, Andrew S; Melbourne, Brett A; Morgan, John W; Orrock, John L; Prober, Suzanne M; Smith, Melinda D

    2016-01-21

    How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems. PMID:26760203

  20. Revealing the intricate effect of collaboration on innovation.

    PubMed

    Inoue, Hiroyasu; Liu, Yang-Yu

    2015-01-01

    We studied the Japan and U.S. patent records of several decades to demonstrate the effect of collaboration on innovation. We found that statistically inventor teams slightly outperform solo inventors while company teams perform equally well as solo companies. By tracking the performance record of individual teams, we found that inventor teams' performance generally degrades with more repeat collaborations. Though company teams' performance displays strongly bursty behavior, long-term collaboration does not significantly help innovation. To systematically study the effect of repeat collaboration, we defined the repeat collaboration number of a team as the average number of collaborations over all the teammate pairs. We found that mild repeat collaboration improves the performance of Japanese inventor teams and U.S. company teams. Yet, excessive repeat collaboration does not significantly help innovation at both the inventor and company levels in both countries. To control for unobserved heterogeneity, we performed a detailed regression analysis and the results were consistent with our simple observations. The presented results revealed the intricate effect of collaboration on innovation, which may also be observed in other creative projects. PMID:25799138