Sample records for twelve laci mutations

  1. Mutational spectra of the lacI transgene isolated from Big Blue{reg_sign} mice exposed to three carcinogenic aromatic amines

    Energy Technology Data Exchange (ETDEWEB)

    Staedtler, F.; Locher, F.; Sreenan, G. [Sandoz Pharma AG, Basel (Switzerland)] [and others


    In order to evaluate the in vivo genotoxic potential of three putative genotoxic mouse liver carcinogens, high doses of 4-chloro-o-phenylenediamine, 2-nitro-p-phenylenediamine and 2, 4-diaminotoluene were tested short term in the Big Blue{reg_sign} transgenic mouse mutation assay. Small statistically significant increases in the lacI mutant frequencies in the liver by factors 1.7 to 2.0 were found. A representative number of 347 lacI mutants isolated from liver tissue of male and female animals were analyses by DNA sequencing. The mutational spectra were examined with the Adams-Skopek algorithm. The spontaneous mutational spectra from untreated male and female animals were similar and consistent with spectral Big Blue{reg_sign} control data stored in the lacI database. Most of the background mutations were located in the 5{prime} portion of the coding region of the lacI gene. Single base substitutions were most prominent. G:C to A:T transitions and G:C to T:A transversions occurred predominatly and were preferentially located at CpG sites. Despite the increases observed in the mutant frequencies of the treated animals, the corresponding mutational spectra did not differ from the controls. However, it is possible that certain classes of point mutations were substantially increased but not detected due to the limited number of sequenced mutants. In two animals treated with 2, 4- diaminotoluene unusually high mutant frequencies and the multiple occurrence of certain mutations in the liver was observed. From one of these animals six lacI mutants isolated from colon tissue were all different. Since 2, 4-diaminotoluene was shown to induce liver cell proliferation these results may reflect clonal expansion of single mutated liver cells.

  2. Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients. (United States)

    Huang, Yu; Yang, Lu; Wang, Jianchun; Yang, Fan; Xiao, Ying; Xia, Rongjun; Yuan, Xianhou; Yan, Mingshan


    Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized mainly by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. This disease is caused by mutations of the ataxia telangiectasia mutated (Atm) gene. More than 500 Atm mutations that are responsible for A-T have been identified so far. However, there have been very few A-T cases reported in China, and only two Chinese A-T patients have undergone Atm gene analysis. In order to systemically investigate A-T in China and map their Atm mutation spectrum, we recruited eight Chinese A-T patients from six unrelated families nationwide. Using direct sequencing of genomic DNA and the multiplex ligation-dependent probe amplification, we identified twelve pathogenic Atm mutations, including one missense, four nonsense, five frameshift, one splicing, and one large genomic deletion. All the Atm mutations we identified were novel, and no homozygous mutation and founder-effect mutation were found. These results suggest that Atm mutations in Chinese populations are diverse and distinct largely from those in other ethnic areas.

  3. Cartography: LACIE's spatial processor (United States)

    Rader, M. L.; Vela, R. R. (Principal Investigator)


    The spatial processing needs of LACIE include the location of agricultural test sites, and the registration of ground truth to LANDSAT imagery. The technological aspects of LACIE cartographic support, the need for cartography in satellite crop surveys, and proposed improvements which would enhance support of future programs are discussed.

  4. LACIE sampling design (United States)

    Feiveson, A. H.; Chhikara, R. S.; Hallum, C. R. (Principal Investigator)


    The sampling design in LACIE consisted of two major components, one for wheat acreage estimation and one for wheat yield prediction. The acreage design was basically a classical survey for which the sampling unit was a 5- by 6-nautical mile segment; however, there were complications caused by measurement errors and loss of data. Yield was predicted by sampling meteorological data from weather stations within a region and then using those data as input to previously fitted regression equations. Wheat production was not estimated directly, but was computed by multiplying yield and acreage estimates. The allocation of samples to countries is discussed as well as the allocation and selection of segments in strata/substrata.

  5. Stereoselective metabolism of the environmental mammary carcinogen 6-nitrochrysene to trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene by aroclor 1254-treated rat liver microsomes and their comparative mutation profiles in a laci mammary epithelial cell line. (United States)

    Sun, Yuan-Wan; Guttenplan, Joseph B; Khmelnitsky, Michael; Krzeminski, Jacek; Boyiri, Telih; Amin, Shantu; El-Bayoumy, Karam


    The environmental pollutant 6-nitrochrysene (6-NC) is a powerful mammary carcinogen and mutagen in rats. Our previous studies have shown that 6-NC is metabolized to trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene (1,2-DHD-6-NC) in rats and in several in vitro systems, including human breast tissue, and the latter is the proximate carcinogenic form in the rat mammary gland. Because optically active enantiomers of numerous polynuclear aromatic hydrocarbon (PAH) metabolites including chrysene have different biological activities, we hypothesized that the stereochemical course of 6-NC metabolism might play a significant role in the carcinogenic/mutagenic activities of the parent 6-NC. The goal of this study is to evaluate the effect of stereochemistry on the mutagenicity of 1,2-DHD-6-NC using the cII gene of lacI mammary epithelial cells in vitro. Resolution of (+/-)-1,2-DHD-6-NC was obtained by either nonchiral or chiral stationary phase HPLC methods. We determined that the ratio of (-)-[R,R]- and (+)-[S,S]-1,2-DHD-6-NC formed in the metabolism of 6-NC by rat liver microsomes is 88:12. The mutation fractions and mutation spectra of [R,R] and [S,S]-enantiomers were examined. Our results showed that the [R,R]-isomer is a significantly (p GC, AT > TA, and GC > TA substitutions, and these are similar to those obtained from 6-NC in vivo in the mammary glands of rats treated with 6-NC. The mutation spectra of the [S,S]-isomer were similar to the [R,R]-isomer, but a higher percentage of AT > GC substitutions in the [R,R]-isomer was noted. On the basis of the results of the present study, we hypothesize that [R,R]-1,2-DHD-6-NC is the proximate carcinogen of 6-NC in the rat mammary gland in vivo and will test this hypothesis in a future study.

  6. Lightweight autonomous chemical identification system (LACIS) (United States)

    Lozos, George; Lin, Hai; Burch, Timothy


    Smiths Detection and Intelligent Optical Systems have developed prototypes for the Lightweight Autonomous Chemical Identification System (LACIS) for the US Department of Homeland Security. LACIS is to be a handheld detection system for Chemical Warfare Agents (CWAs) and Toxic Industrial Chemicals (TICs). LACIS is designed to have a low limit of detection and rapid response time for use by emergency responders and could allow determination of areas having dangerous concentration levels and if protective garments will be required. Procedures for protection of responders from hazardous materials incidents require the use of protective equipment until such time as the hazard can be assessed. Such accurate analysis can accelerate operations and increase effectiveness. LACIS is to be an improved point detector employing novel CBRNE detection modalities that includes a militaryproven ruggedized ion mobility spectrometer (IMS) with an array of electro-resistive sensors to extend the range of chemical threats detected in a single device. It uses a novel sensor data fusion and threat classification architecture to interpret the independent sensor responses and provide robust detection at low levels in complex backgrounds with minimal false alarms. The performance of LACIS prototypes have been characterized in independent third party laboratory tests at the Battelle Memorial Institute (BMI, Columbus, OH) and indoor and outdoor field tests at the Nevada National Security Site (NNSS). LACIS prototypes will be entering operational assessment by key government emergency response groups to determine its capabilities versus requirements.

  7. The LACIE data bases: Design considerations (United States)

    Westberry, L. E. (Principal Investigator)


    The implementation of direct access storage devices for LACIE is discussed with emphasis on the storage and retrieval of image data. Topics covered include the definition of the problem, the solution methodology (design decisions), the initial operational structure, and the modifications which were incorporated. Some conclusions and projections of future problems to be solved are also presented.

  8. MEFV Gene Profile in Northwest of Iran, Twelve Common MEFV Gene Mutations Analysis in 216 Patients with Familial Mediterranean Fever

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    Farhad Salehzadeh


    Full Text Available Familial Mediterranean Fever (FMF is a hereditary autoinflammatory disease with autosomal recessive inheritance pattern often seen around the Mediterranean Sea. It is characterized by recurrent episodes of fever and polyserositis and rash. Recently, MEFV gene analysis determines the definitive diagnosis of FMF. In this study, we analyzed 12 MEFV gene mutations in more than 200 FMF patients, previously diagnosed by Tel-Hashomer clinical criteria, in northwest of Iran, located in the proximity of the Mediterranean Sea. In the northwest of Iran (Ardabil, 216 patients with FMF diagnosis, based on Tel-Hashomer criteria, referred to the genetic laboratory to be tested for the following mutations; P369S, F479L, M680I(G/C, M680I(G/A, I692del, M694V, M694I, K695R, V726A, A744S, R761H, E148Q. All patients were screened for MEFV gene mutations by a reverse hybridization assay (FMF Strip Assay, Vienna lab, Vienna, Austria according to manufacturer’s instructions. Among these FMF patients, no mutation was detected in 51 (23/62% patients, but 165 (76/38% patients had one or two mutations, 33 patients (15/28% homozygous, 86 patients (39/81% compound heterozygous and 46 patients (21/29% were heterozygous. The most common mutations were M694V (23/61%, V726A (11/11% and E148Q (9/95% respectively. MEFV gene mutations showed similarities and dissimilarities in different ethnic groups, while it is common among Arabs and Armenians genotype. Since common 12 MEFV gene analysis could not detect up to 50% of our patients, who had FMF on the basis of clinical Tel-Hashomer criteria, clinical criteria is still the best way in the diagnosis of FMF in this area.

  9. Immersion freezing of biological particles at LACIS (United States)

    Clauss, T.; Hartmann, S.; Temkiv, T. S.; Augustin, S.; Gosewinkel Karlson, U.; Sahyoun, M. M.; Niedermeier, D.; Wex, H.; Voigtländer, J.; Raddatz, M.; Stratmann, F.


    Biological particles, especially bacteria being ubiquitous in the atmosphere, belong to the most efficient ice nuclei (IN) (Möhler, 2008) and hence might have a large impact on weather and climate. In this study, the immersion freezing behavior of different size segregated biological particles is investigated at the laminar flow tube LACIS (Leipzig Aerosol Cloud Interaction Simulator, Hartmann et al., 2011). For these experiments, SNOMAX and outer membrane vesicles (OMV) are used as IN. SNOMAX industrially produced from Pseudomonas-syringae bacteria, which are very ice nucleation active, can be seen as a proxy for ice nucleating bacteria in general. On the surface of these bacteria, ice nucleating proteins that initiate the freezing are situated (Maki et al., 1974). Additionally, it has been found that some ice nucleating bacteria strains have the ability to produce OMV, i.e., strangulated parts of the bacterial cell consisting of the same membrane material (Phelps et al., 1986). These OMV might contain the same ice nucleating proteins on their surface and thus might be able to nucleate ice as well. The OMV used in our experiments were extracted from bacteria cultivated from rain samples collected in Denmark from 30 m height. In our experiments, the biological particles are suspended in air via atomization, size selected by means of a Differential Mobility Particle Sizer, and then fed into LACIS. In LACIS, well defined droplets are produced by activating the biological particles to cloud droplets, so that each droplet contains only one biological particle. By decreasing the temperature in LACIS, these droplets are frozen. To determine the ice fraction, i.e., the fraction of frozen droplets to all particles, the liquid and frozen droplets are distinguished by means of a newly self-built optical device, which is positioned under LACIS, using the depolarization of light scattered by a single particle. The ice fractions are measured as a function of temperature and

  10. LACIE area sampling frame and sample selection (United States)

    Liszcz, C. J. (Principal Investigator)


    Transparent acetate overlays containing agricultural boundaries within each of the LACIE countries were prepared and registered to operational navigation charts (ONC's). Full frame LANDSAT color-infrared images of the same scale as the ONC's (1:1 million) were used to identify agricultural boundaries based on discernible agricultural field patterns. Preliminary steps taken in the preparation of the base map overlay, and the construction of an overlay of the base map physical features are described as well as the construction of the agricultural and nonagricultural delineation overlay.

  11. Lacie Skwarim移动硬盘

    Institute of Scientific and Technical Information of China (English)


    21世纪的商务办公是什么Style?是奢侈!是品牌!忘掉性能参数和指标吧,能表现你的品位才是最重要的!由世界知名设计师Karim Rashid亲自操刀设计的Lacie Skwarim移动硬盘在技术上已太普通不过,但大师的手笔下靛蓝色与靓粉色的塑料颗粒外壳设计不仅为其内娇小的1.8英寸硬盘提供了全方位的保护,

  12. Mutagenicity of ultraviolet A radiation in the lacI transgene in Big Blue mouse embryonic fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang-in [Division of Biology, Beckman Research Institute of the City of Hope National Medical Center, 1450 East Duarte Road, Duarte, CA 91010 (United States); Pfeifer, Gerd P. [Division of Biology, Beckman Research Institute of the City of Hope National Medical Center, 1450 East Duarte Road, Duarte, CA 91010 (United States); Besaratinia, Ahmad [Division of Biology, Beckman Research Institute of the City of Hope National Medical Center, 1450 East Duarte Road, Duarte, CA 91010 (United States)]. E-mail:


    Sunlight ultraviolet A (UVA) irradiation has been implicated in the etiology of human skin cancer. A genotoxic mode of action for UVA radiation has been suggested that involves photosensitization reactions giving rise to promutagenic DNA lesions. We investigated the mutagenicity of UVA in the lacI transgene in Big Blue mouse embryonic fibroblasts. UVA irradiation of these cells at a physiologically relevant dose of 18 J/cm{sup 2} caused a 2.8-fold increase in the lacI mutant frequency relative to control, i.e., 12.12 {+-} 1.84 versus 4.39 {+-} 1.99 x 10{sup -5} (mean {+-} S.D.). DNA sequencing analysis showed that of 100 UVA-induced mutant plaques and 54 spontaneously arisen control plaques, 97 and 51, respectively, contained a minimum of one mutation along the lacI transgene. The vast majority of both induced- and spontaneous mutations were single base substitutions, although less frequently, there were also single and multiple base deletions and insertions, and tandem base substitutions. Detailed mutation spectrometry analysis revealed that G:C {sup {yields}} T:A transversions, the signature mutations of oxidative DNA damage, were significantly induced by UVA irradiation (P < 0.003). The absolute frequency of this type of mutations was 7.4-fold increased consequent to UVA irradiation as compared to control (3.38 versus 0.454 x 10{sup -5}; P < 0.00001). These findings are in complete agreement with those previously observed in the cII transgene of the same model system, and reaffirm the notion that intracellular photosensitization reactions causing promutagenic oxidative DNA damage are involved in UVA genotoxicity.

  13. Helix dynamics in LacY: helices II/IV (United States)

    Liu, Zhenyu; Madej, M. Gregor; Kaback, H. Ronald


    Biochemical and biophysical studies based upon crystal structures of both a mutant and wild-type lactose permease from Escherichia coli (LacY) in an inward-facing conformation have led to a model for the symport mechanism in which both sugar- and H+-binding sites are alternatively accessible to either side of the membrane. Previous findings indicate that the face of helix II with Asp68 is important for the conformational changes that occur during turnover. As shown here, replacement of Asp68 at the cytoplasmic end of helix II, particularly with Glu, abolishes active transport, but the mutants retain the ability to bind galactopyranoside. In the x-ray structure, Asp68 and Lys131 (helix IV) lie within ∼4.2 Å of each other. Although a double mutant with Cys replacements at both position 68 and 131 cross-links efficiently, single replacements for Lys131 exhibit very significant transport activity. Site-directed alkylation studies show that sugar binding by the Asp68 mutants causes closure of the cytoplasmic cavity, like wild-type LacY; but strikingly, the probability of opening the periplasmic pathway upon sugar binding is markedly reduced. Taken together with previous mutagenesis and cross-linking studies, the findings lead to a model in which replacement of Asp68 blocks a conformational transition involving helices II and IV that is important for opening the periplasmic cavity. Evidence is also presented suggesting that movements of helices II and IV are coupled functionally with movements in the pseudo-symmetrically paired helices VIII and X. PMID:20043916

  14. A new optical ice particle counter at LACIS (United States)

    Bieligk, Henner; Voelker, Georg Sebastian; Clauss, Tina; Grundmann, Marius; Stratmann, Frank


    Clouds play an important role within the climate system, especially for the radiative energy budget of the earth. The radiative properties of a cloud depend strongly on the fractions of ice crystals and water droplets, their size distributions, and the ice crystal shapes within the particular cloud. One option to gain this kind of information is using optical particle counters. A new optical particle counter is developed for laboratory work and is based on the concept of the Thermostabilized Optical Particle Spectrometer for the Detection of Ice Particles (TOPS-Ice, Clauss et al., 2013). TOPS-Ice uses linearly polarized green laser light and the depolarization of the scattered light at a scattering angle of 42.5° to discriminate between liquid water droplets and ice crystals in the lower μm range. However, the measurements are usually limited to ice fractions in the order of 1%. To improve the determination of the ice fraction, several modifications of the original setup are implemented including an additional detection system at another scattering angle. The new scattering angle is optimized for least interference between the droplet and ice signals. This is achieved by finding the angle with the maximum difference in scattered intensity of water droplets compared to ice crystals with the same volume equivalent diameter. The suitable scattering angle of 100° for linearly polarized light was chosen based on calculations using T-Matrix method, Lorenz-Mie theory, Müller matrices and distribution theory. The new optical setup is designed to run in combination with a laminar flow tube, the so-called Leipzig Aerosol Cloud Interaction Simulator (LACIS, Stratmann et al., 2004; Hartmann et al., 2011). Using LACIS and its precisely controlled thermodynamic conditions, we are able to form small water droplets and ice crystals which will then be detected, classified and sized by our new optical device. This setup is planned to be tested in ice measurements including

  15. The Periplasmic Cavity of LacY Mutant Cys154→Gly : How Open Is Open?

    NARCIS (Netherlands)

    Jiang, Xiaoxu; Driessen, Arnold J.M.; Feringa, Ben L.; Kaback, H. Ronald


    The lactose permease from Escherichia coli (LacY) is a galactoside/H+ symporter that catalyzes the coupled stoichiometric transport of a sugar and an H+ across the cytoplasmic membrane. X-ray crystal structures of WT LacY and the conformationally restricted mutant Cys154→Gly exhibit an inward-facing

  16. An assessment of LACIE and related methodologies for conducting crop inventories (United States)

    Tokerud, R. E.; Quirein, J. A.


    The Large Area Crop Inventory Experiment (LACIE) is a joint undertaking of the U.S. Department of Agriculture, the National Oceanic and Atmospheric Administration of the U.S. Department of Commerce, and the National Aeronautics and Space Administration. It is designed to verify an economically important application of remote sensing from earth orbital satellites. The first two phases of the experiment have been completed. A description of the experiment and a short discussion on the results and conclusions of the first two phases are presented. The LACIE design is compared with other designs for conducting crop inventories. An integrated design methodology (based upon accumulated LACIE experience) is discussed for conducting crop acreage surveys in developing countries.

  17. LACIS-T - A humid wind tunnel for investigating the Interactions between Cloud Microphysics and Turbulence (United States)

    Voigtländer, Jens; Niedermeier, Dennis; Siebert, Holger; Shaw, Raymond; Schumacher, Jörg; Stratmann, Frank


    To improve the fundamental and quantitative understanding of the interactions between cloud microphysical and turbulent processes, the Leibniz Institute for Tropospheric Research (TROPOS) has built up a new humid wind tunnel (LACIS-T). LACIS-T allows for the investigation of cloud microphysical processes, such as cloud droplet activation and freezing, under-well defined thermodynamic and turbulent flow conditions. It therewith allows for the straight forward continuation, extension, and completion of the cloud microphysics related investigations carried out at the Leipzig Aerosol Cloud Interaction Simulator (LACIS) under laminar flow conditions. Characterization of the wind tunnel with respect to flow, thermodynamics, and droplet microphysics is carried out with probes mounted inside (pitot tube and hot-wire anemometer for mean velocity and fluctuations, Pt100 sensor for mean temperature, cold-wire sensor for temperature fluctuations is in progress, as well as a dew-point mirror for mean water vapor concentration, a Lyman-alpha sensor for water vapor fluctuations is in progress) the measurement section, and from outside with optical detection methods (a laser light sheet is available for cloud droplet visualization, a digital holography system for detection of cloud droplet size distributions will be installed for tests in February 2017), respectively. Computational fluid dynamics (CFD) simulations have been carried out for defining suitable experimental conditions and assisting the interpretation of the experimental data. In this work, LACIS-T, its fundamental operating principle, and first preliminary results from ongoing characterization efforts will be presented.

  18. Function, Structure, and Evolution of the Major Facilitator Superfamily: The LacY Manifesto

    Directory of Open Access Journals (Sweden)

    M. Gregor Madej


    Full Text Available The major facilitator superfamily (MFS is a diverse group of secondary transporters with members found in all kingdoms of life. A paradigm for MFS is the lactose permease (LacY of Escherichia coli, which couples the stoichiometric translocation of a galactopyranoside and an H+ across the cytoplasmic membrane. LacY has been the test bed for the development of many methods applied for the analysis of transport proteins. X-ray structures of an inward-facing conformation and the most recent structure of an almost occluded conformation confirm many conclusions from previous studies. Although structure models are critical, they are insufficient to explain the catalysis of transport. The clues to understanding transport are based on the principles of enzyme kinetics. Secondary transport is a dynamic process—static snapshots of X-ray crystallography describe it only partially. However, without structural information, the underlying chemistry is virtually impossible to conclude. A large body of biochemical/biophysical data derived from systematic studies of site-directed mutants in LacY suggests residues critically involved in the catalysis, and a working model for the symport mechanism that involves alternating access of the binding site is presented. The general concepts derived from the bacterial LacY are examined for their relevance to other MFS transporters.

  19. The Twelve Hotel, Barna : Video


    Irish Food Channel


    Fergus O'Halloran, Managing Director of The Twelve Hotel in Barna in County Galway, talks about his philosophy in running this unique boutique hotel. Reproduced with kind permission from John & Sally McKenna. 3.35 mins

  20. Disseny d'una instal·lació solar eficient a temperatures al voltant dels 100ºC


    Penalva Cobas, Pablo


    El projecte es basa en l’estudi i el disseny d’una instal·lació solar tèrmica per tal de obtenir, amb un rendiment acceptable, fluid caloportador a temperatures més altes de 100 °C, per a la posterior obtenció de vapor d’aigua en domicilis. Durant el projecte es dissenyarà una instal·lació per tal que, a temperatures altes, el seu rendiment no disminueixi de la manera que ho fan actualment els captadors plans. Per això es buscarà altres tipus de captadors que utilitzen altres tecnologies i...

  1. Local gene regulation details a recognition code within the LacI transcriptional factor family.

    Directory of Open Access Journals (Sweden)

    Francisco M Camas

    Full Text Available The specific binding of regulatory proteins to DNA sequences exhibits no clear patterns of association between amino acids (AAs and nucleotides (NTs. This complexity of protein-DNA interactions raises the question of whether a simple set of wide-coverage recognition rules can ever be identified. Here, we analyzed this issue using the extensive LacI family of transcriptional factors (TFs. We searched for recognition patterns by introducing a new approach to phylogenetic footprinting, based on the pervasive presence of local regulation in prokaryotic transcriptional networks. We identified a set of specificity correlations--determined by two AAs of the TFs and two NTs in the binding sites--that is conserved throughout a dominant subgroup within the family regardless of the evolutionary distance, and that act as a relatively consistent recognition code. The proposed rules are confirmed with data of previous experimental studies and by events of convergent evolution in the phylogenetic tree. The presence of a code emphasizes the stable structural context of the LacI family, while defining a precise blueprint to reprogram TF specificity with many practical applications.

  2. Maurits Ebben, Margriet Lacy-Bruijn, and Rolof van Hövell tot Westerflier (eds., Alba: General and Servant to the Crown

    Directory of Open Access Journals (Sweden)

    José Eloy Hortal Muñoz


    Full Text Available Maurits Ebben, Margriet Lacy-Bruijn, and Rolof van Hövell tot Westerflier (eds., Alba:  General and Servant to the Crown (Rotterdam: Karwansaray publishers, 2013, 464 pp., isbn 978 94 90258 08 5.

  3. Examination of laboratory-generated coated soot particles: An overview of the LACIS Experiment in November (LExNo) campaign (United States)

    Stratmann, F.; Bilde, M.; Dusek, U.; Frank, G. P.; Hennig, T.; Henning, S.; Kiendler-Scharr, A.; Kiselev, A.; Kristensson, A.; Lieberwirth, I.; Mentel, T. F.; PöSchl, U.; Rose, D.; Schneider, J.; Snider, J. R.; Tillmann, R.; Walter, S.; Wex, H.


    In the suite of laboratory measurements described here and in companion articles we deal with the hygroscopic growth and activation behavior of coated soot particles synthesized to mimic those of an atmospheric aerosol originating from biomass combustion. The investigations were performed during the measurement campaign LACIS Experiment in November (LExNo) which took place at the Leipzig Aerosol Cloud Interaction Simulator (LACIS). The specific goals of this campaign were (1) to perform a critical supersaturation measurement intercomparison using data sets from three different cloud condensation nucleus (CCN) instruments (two static thermal gradient type, one stream-wise thermal gradient type) and LACIS, (2) to examine particle hygroscopic growth (hydrated particle size as function of relative humidity) for particle characteristics such as aerosol mass spectrometer (AMS) measured soluble mass and particle morphology, and (3) to relate critical supersaturations derived from both measurements of soluble mass and high-humidity tandem differential mobility analyzer (HH-TDMA) determined growth factors to critical supersaturations measured by means of the CCN instruments. This paper provides information on the particle synthesis techniques used during LExNo, an overview concerning the particle characterization measurements performed, and, by proving relations between measured composition, hygroscopic growth, and activation data, lay the foundations for the detailed investigations described in the companion studies. In the context of the present paper, excellent agreement of the critical supersaturations measured with three different CCN instruments and LACIS was observed. Furthermore, clear relations between coating masses determined with AMS and both hygroscopic growth factors at 98% RH and measured critical supersaturations could be seen. Also, a strong correlation between measured hygroscopic growth (growth factors at 98%) and measured critical supersaturation for all

  4. Transanal rectopexy - twelve case studies

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    Rubens Henrique Oleques Fernandes


    Full Text Available OBJECTIVES: This study analyzed the results of transanal rectopexy and showed the benefits of this surgical technique. METHOD: Twelve patients were submitted to rectopexy between 1997 and 2011. The surgical technique used was transanal rectopexy, where the mesorectum was fixed to the sacrum with nonabsorbable suture. Three patients had been submitted to previous surgery, two by the Delorme technique and one by the Thiersch technique. RESULTS: Postoperative hospital stay ranged from 1 to 4 days. One patient (8.3% had intraoperative hematoma, which was treated with local compression and antibiotics. One patient (8.3% had residual mucosal prolapse, which was resected. Prolapse recurrence was seen in one case (8.3%. Improved incontinence occurred in 75% of patients and one patient reported obstructed evacuation in the first month after surgery. No death occurred. CONCLUSION: Transanal rectopexy is a simple, low cost technique, which has shown good efficacy in rectal prolapse control.OBJETIVO: O presente estudo analisou os resultados da retopexia pela via transanal e expôs os benefícios desta técnica cirúrgica. MÉTODO: Doze pacientes com prolapso foram operados no período de 1997 a 2011. A técnica cirúrgica usada foi a retopexia transanal, onde o mesorreto foi fixado ao sacro com fio inabsorvível. Três pacientes tinham cirurgia prévia, dois pela técnica de Delorme e um pela técnica de Thiersch. RESULTADOS: A permanência hospitalar pós-operatória variou de 1- 4 dias. Uma paciente (8,3% apresentou hematoma transoperatório que foi tratado com compressão local e antibioticoterapia. Um paciente apresentou prolapso mucoso residual (8,3%, que foi ressecado. Houve recidiva da procidência em um caso (8,3%. A melhora da incontinência ocorreu em 75% dos pacientes e uma paciente apresentou bloqueio evacuatório no primeiro mês após a cirurgia. Não houve mortalidade entre os pacientes operados. CONCLUSÃO: A retopexia transanal é uma t

  5. Structural evidence for induced fit and a mechanism for sugar/H+ symport in LacY

    DEFF Research Database (Denmark)

    Mirza, Osman Asghar; Guan, Lan; Verner, Gill


    Cation-coupled active transport is an essential cellular process found ubiquitously in all living organisms. Here, we present two novel ligand-free X-ray structures of the lactose permease (LacY) of Escherichia coli determined at acidic and neutral pH, and propose a model for the mechanism...... of coupling between lactose and H+ translocation. No sugar-binding site is observed in the absence of ligand, and deprotonation of the key residue Glu269 is associated with ligand binding. Thus, substrate induces formation of the sugar-binding site, as well as the initial step in H+ transduction....

  6. Protection by dietary compounds against mutation in a transgenic rodent. (United States)

    de Boer, J G


    One of the most relevant biomarkers of genotoxicity and, potentially, carcinogenesis is the occurrence of mutations. Data indicate that carcinogens are highly specific with regard to their target tissue in inducing both tumors and mutations. This specificity may reflect the dependence on tissue-specific metabolic activation, the organ-specific environment or both. Ideally, therefore, mutation should be determined in a real animal rather than in a cell culture system. The lacI transgenic rodent model provides such a system. We have used this model to investigate tissue, species and sex specificity of mutation induced by selected dietary carcinogens and to examine how some compounds may alter the induction of mutation. We have studied mutation using several chemicals, including the dietary heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the environmentally important aromatic hydrocarbon benzo[a]pyrene and the food contaminant aflatoxin B1. We have shown that the mutagenic potency of these chemicals can be modulated by other dietary compounds, including green tea and conjugated linoleic acid, and the dioxin 2,3,7,8-tetrachlorodibenzo[b,e][1,4]dioxin (TCDD). These results demonstrate that the lacI transgenic rodent is a useful model for the study of chemoprevention in vivo.


    Effects of the Antimutagens Vanillin and Cinnamaldehyde on Spontaneous Mutation in E. coli lacI Strains and on Global Gene Epression in Salmonella TAlO4 and Human HepG2 Cells In previous work we have shown that vanillin (VAN) and cinnamaldehyde (CIN) are dietary antimutag...


    Effects of the Antimutagens Vanillin and Cinnamaldehyde on Spontaneous Mutation in E. coli lacI Strains and on Global Gene Epression in Salmonella TAlO4 and Human HepG2 Cells In previous work we have shown that vanillin (VAN) and cinnamaldehyde (CIN) are dietary antimutag...

  9. Mythematics Solving the Twelve Labors of Hercules

    CERN Document Server

    Huber, Michael


    How might Hercules, the most famous of the Greek heroes, have used mathematics to complete his astonishing Twelve Labors? From conquering the Nemean Lion and cleaning out the Augean Stables, to capturing the Erymanthean Boar and entering the Underworld to defeat the three-headed dog Cerberus, Hercules and his legend are the inspiration for this book of fun and original math puzzles. While Hercules relied on superhuman strength to accomplish the Twelve Labors, Mythematics shows how math could have helped during his quest. How does Hercules defeat the Lernean Hydra and stop its heads from multip

  10. An Overview of Ecological Footprinting and Other Tools and Their Application to the Development of Sustainability Process: Audit and Methodology at Holme Lacy College, UK (United States)

    Dawe, Gerald F. M.; Vetter, Arnie; Martin, Stephen


    A sustainability audit of Holme Lacy College is described. The approach adopted a "triple bottom line" assessment, comprising a number of key steps: a scoping review utilising a revised Royal Institution of Chartered Surveyors project appraisal tool; an environmental impact assessment based on ecological footprinting and a social and economic…

  11. Comparative analysis of twelve Dothideomycete plant pathogens

    Energy Technology Data Exchange (ETDEWEB)

    Ohm, Robin; Aerts, Andrea; Salamov, Asaf; Goodwin, Stephen B.; Grigoriev, Igor


    The Dothideomycetes are one of the largest and most diverse groups of fungi. Many are plant pathogens and pose a serious threat to agricultural crops grown for biofuel, food or feed. Most Dothideomycetes have only a single host and related Dothideomycete species can have very diverse host plants. Twelve Dothideomycete genomes have currently been sequenced by the Joint Genome Institute and other sequencing centers. They can be accessed via Mycocosm which has tools for comparative analysis

  12. Twelve tips for peer observation of teaching. (United States)

    Siddiqui, Zarrin Seema; Jonas-Dwyer, Diana; Carr, Sandra E


    This paper outlines twelve tips for undertaking peer observation of teaching in medical education, using the peer review model and the experiences of the authors. An accurate understanding of teaching effectiveness is required by individuals, medical schools, and universities to evaluate the learning environment and to substantiate academic and institutional performance. Peer Observation of Teaching is one tool that provides rich, qualitative evidence for teachers, quite different from closed-ended student evaluations. When Peer Observation of Teaching is incorporated into university practice and culture, and is conducted in a mutually respectful and supportive way, it has the potential to facilitate reflective change and growth for teachers.

  13. Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. (United States)

    De Lonlay, P; Benelli, C; Fouque, F; Ganguly, A; Aral, B; Dionisi-Vici, C; Touati, G; Heinrichs, C; Rabier, D; Kamoun, P; Robert, J J; Stanley, C; Saudubray, J M


    Hyperinsulinism and hyperammonemia syndrome has been reported as a cause of moderately severe hyperinsulinism with diffuse involvement of the pancreas. The disorder is caused by gain of function mutations in the GLUD1 gene, resulting in a decreased inhibitory effect of guanosine triphosphate on the glutamate dehydrogenase (GDH) enzyme. Twelve unrelated patients (six males, six females) with hyperinsulinism and hyperammonemia syndrome have been investigated. The phenotypes were clinically heterogeneous, with neonatal and infancy-onset hypoglycemia and variable responsiveness to medical (diazoxide) and dietary (leucine-restricted diet) treatment. Hyperammonemia (90-200 micromol/L, normal carbamylglutamate administration. The patients had mean basal GDH activity (18.3 +/- 0.9 nmol/min/mg protein) not different from controls (17.9 +/- 1.8 nmol/min/mg protein) in cultured lymphoblasts. The sensitivity of GDH activity to inhibition by guanosine triphosphate was reduced in all patient lymphoblast cultures (IC(50), or concentrations required for 50% inhibition of GDH activity, ranging from 140 to 580 nM, compared with control IC(50) value of 83 +/- 1.0 nmol/L). The allosteric effect of ADP was within the normal range. The activating effect of leucine on GDH activity varied among the patients, with a significant decrease of sensitivity that was correlated with the negative clinical response to a leucine-restricted diet in plasma glucose levels in four patients. Molecular studies were performed in 11 patients. Heterozygous mutations were localized in the antenna region (four patients in exon 11, two patients in exon 12) as well as in the guanosine triphosphate binding site (two patients in exon 6, two patients in exon 7) of the GLUD1 gene. No mutation has been found in one patient after sequencing the exons 5-13 of the gene.

  14. Combining ability of twelve maize populations

    Directory of Open Access Journals (Sweden)

    Vacaro Elton


    Full Text Available Genetic progress depends on germplasm quality and breeding methods. Twelve maize populations and their crosses were evaluated to estimate combining ability and potential to be included as source populations in breeding programs. Plant height, point of insertion of the first ear, number of ears per plant, number of grains per ear, root and stalk lodging and grain yield were studied in two locations in Brazil, during the 1997/98 season. Genotype sum of squares was divided into general (GCA and specific (SCA combining ability. Results indicated the existence of genetic divergence for all traits analyzed, where additive effects were predominant. The high heterosis levels observed, mainly in Xanxerê, suggested the environmental influence on the manifestation of this genetic phenomenon. Populations revealed potential to be used in breeding programs; however, those more intensively submitted to selection could provide larger genetic progress, showing the importance of population improvement for the increment of the heterosis in maize.

  15. Mutations induced by ultraviolet light

    Energy Technology Data Exchange (ETDEWEB)

    Pfeifer, Gerd P. [Department of Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010 (United States)]. E-mail:; You, Young-Hyun [Department of Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010 (United States); Besaratinia, Ahmad [Department of Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010 (United States)


    The different ultraviolet (UV) wavelength components, UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5'-TCG and 5'-CCG, and these are localized at several mutational hotspots. Since 5'-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6-9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24-32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340-400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms

  16. Cambiar el arte para cambiar el mundo (Una perspectiva feminista Diálogo abierto con Suzanne Lacy

    Directory of Open Access Journals (Sweden)

    Elena García-Oliveros


    Full Text Available Este artículo ahonda en la perspectiva activista y transformadora de las artistas feministas que surgieron en la década de los años 70, indagando en su particular visión acerca de la capacidad del arte para crear nuevos modelos sociales integradores. A partir del caso de la artista norteamericana Suzanne Lacy, con quien las autoras han mantenido diversos encuentros de carácter público en el Centro de Arte Contemporáneo Matadero de Madrid, se pormenorizan las estrategias que el feminismo ha trabado en torno al arte público y se busca una redefinición de los ejes principales que sustentan el medio artístico actual: la autoría, la obra y su difusión y el valor final de la pieza. La investigación continúa con los estudios de caso de la artista ciberfeminista Shu Lea Cheang, la artista de origen paraguayo Faith Wilding y el colectivo madrileño Toxic Lesbian.

  17. Estado de la investigación en Habilidades Sociales en el Laboratorio de Comportamiento Interpersonal (LACI Cordoba – Argentina

    Directory of Open Access Journals (Sweden)

    Valeria Morán


    Full Text Available Partiendo de la tendencia de crecimiento en la producción de literatura en el área de Habilidades Sociales, se plantea como objetivo realizar una revisión sobre la temática, a los fines de describir los trabajos realizados por el Grupo de investigación LACI (Laboratorio de Comportamiento Interpersonal situado en Córdoba, Argentina. Dicho laboratorio constituye un núcleo  del Grupo de Relações Interpessoais e Habilidades Sociais (RIHS de la Universidade Federal de São Carlos, Brasil, dirigido por los Doctores Zilda Del Prette y Almir Del Prette. Se concluye que la producción científica sobre Habilidades Sociales se realiza específicamente en torno a estudiantes y profesionales de la salud, así como también se concentra en el desarrollo de instrumentos fiables y válidos para la evaluación de las Habilidades Sociales. Se discuten los resultados identificando tendencias futuras de investigación.

  18. Twelve tips for getting your manuscript published. (United States)

    Cook, David A


    The author shares twelve practical tips on how to navigate the process of getting a manuscript published. These tips, which apply to all fields of academic writing, advise that during the initial preparation phase authors should: (1) plan early to get it out the door; (2) address authorship and writing group expectations up front; (3) maintain control of the writing; (4) ensure complete reporting; (5) use electronic reference management software; (6) polish carefully before they submit; (7) select the right journal; and (8) follow journal instructions precisely. Rejection after the first submission is likely, and when this occurs authors should (9) get it back out the door quickly, but first (10) take seriously all reviewer and editor suggestions. Finally, when the invitation comes to revise and resubmit, authors should (11) respond carefully to every reviewer suggestion, even if they disagree, and (12) get input from others as they revise. The author also shares detailed suggestions on the creation of effective tables and figures, and on how to respond to reviewer critiques.

  19. Antifouling activity of twelve demosponges from Brazil

    Directory of Open Access Journals (Sweden)

    SM. Ribeiro

    Full Text Available Benthic marine organisms are constantly exposed to fouling, which is harmful to most host species. Thus, the production of secondary metabolites containing antifouling properties is an important ecological advantage for sessile organisms and may also provide leading compounds for the development of antifouling paints. High antifouling potential of sponges has been demonstrated in the Indian and Pacific oceans and in the Caribbean and Mediterranean seas. Brazilian sponges remain understudied concerning antifouling activities. Only two scientific articles reported this activity in sponges of Brazil. The objective of this study was to test crude extracts of twelve species of sponges from Brazil against the attachment of the mussel Perna perna through laboratorial assays, and highlight promising species for future studies. The species Petromica citrina, Amphimedon viridis, Desmapsamma anchorata, Chondrosia sp., Polymastia janeirensis, Tedania ignis, Aplysina fulva, Mycale angulosa, Hymeniacidon heliophila, Dysidea etheria, Tethya rubra, and Tethya maza were frozen and freeze-dried before extraction with acetone or dichloromethane. The crude extract of four species significantly inhibited the attachment of byssus: Tethya rubra (p = 0.0009, Tethya maza (p = 0.0039, Petromica citrina (p = 0.0277, and Hymeniacidon heliophila (p = 0.00003. These species, specially, should be the target of future studies to detail the substances involved in the ability antifouling well as to define its amplitude of action.

  20. Twelve Elastic Constants of Betula platyphylla Suk.

    Institute of Scientific and Technical Information of China (English)

    Wang Liyu; Lu Zhenyou


    Wood elastic constants are needed to describe the elastic behaviors of wood and be taken as an important design parameter for wood-based composite materials and structural materials. This paper clarified the relationships between compliance coefficients and engineering elastic constants combined with orthotropic properties of wood, and twelve elastic constants of Betula platyphylla Suk. were measured by electrical strain gauges. Spreading the adhesive quantity cannot be excessive or too little when the strain flakes were glued. If excessive, the glue layer was too thick which would influence the strain flakes' performance, and if too little, glues plastered were not firm, which could not accurately transmit the strain. Wood as an orthotropic material, its modulus of elasticity and poisson's ratios are related by two formulas:μij /Ei =μji /Ej and μij 0.95) between the reciprocal of elastic modulus MOE-1 and the square of the ratio of depth to length (h/l)2, which indicate that shear modulus values measured were reliable by three point bending experiment.

  1. Hepatic Angiosarcoma: a Review of Twelve Cases

    Institute of Scientific and Technical Information of China (English)

    Qiang Li; Xishan Hao


    OBJECTIVE Hepatic angiosarcoma (HAS), a lethal disease, is the most common sarcoma arising in the liver. Little information about the epidemiology, etiology, diagnosis and management of HAS has been reported. Increased familiarity with this disease will facilitate correct diagnosis and help to improve management of this condition in the future.The objective of this study was to describe cases of hepatic angiosarcoma and to discuss the etiologic, diagnostic, therapeutic features and prognosis of this tumor. This report not only serves to give more evidence of the relationship between hepatic angiosarcoma and carcinogenic exposure, but also demonstrates the key points in different methods of diagnosis and the optimal treatment of hepatic angiosarcoma.METHODS Twelve cases of hepatic angiosareoma were analyzed retrospectively, representing the different character in clinical presentations and laboratory computed tomographical scans; pathological data and treatment are described. Clinical and biologic follow-up was carried out for two years after surgical treatment.RESULTS There were nine men and three women varying in ages from 57 to 71 years with an average of 64.3 years. Ten patientshad a history of exposure to vinyl chloride or thorotrast. Mild or moderate abdominal pain and bloating, abdominal mass and fever were the common clinical presentations. Tumors were visualized by ultrasonography and CT scans in all patients. Biochemical profiles yielded variable results and proved to be of little value in detection or diagnosis. Surgical resection was feasible for each patient who was treated as follows: two wedge resections, six segementectomies and four bisegmentectomies. Five patients received Neoadjuvant chemotherapy postoperatively. The survival rate of those cases was poor. The maximum survival time was fourteen months. The mean survival time for this chemotherapeutic group was 11 months. The difference between the survival time of those treated with an operation

  2. The twelve dimensional super (2+2)-brane

    CERN Document Server

    Hewson, S F


    We discuss supersymmetry in twelve dimensions and present a covariant supersymmetric action for a brane with worldsheet signature (2,2), called a super (2+2)-brane, propagating in the osp(64,12) superspace. This superspace is explicitly constructed, and is trivial in the sense that the spinorial part is a trivial bundle over spacetime, unlike the twisted superspace of usual Poincare supersymmetry. For consistency, it is necessary to take a projection of the superspace. This is the same as the projection required for worldvolume supersymmetry. Upon compactification of this superspace, a torsion is naturally introduced and we produce the membrane and type IIB string actions in 11 and 10 dimensional Minkowski spacetimes. In addition, the compactification of the twelve dimensional supersymmetry algebra produces the correct algebras for these theories, including central charges. These considerations thus give the type IIB string and M-theory a single twelve dimensional origin.

  3. Alcoholics anonymous and other twelve-step programs in recovery. (United States)

    Detar, D Todd


    Recovery is a new way of life for many patients; a life without substances to alter their moods but with a major change improving the physical, psychological, and emotional stability with improved overall health outcomes. The Twelve Steps of the Alcoholics Anonymous (AA) are the foundation of the AA, describing both the necessary actions and the spiritual basis for the recovery program of the AA. The Twelve Steps of the AA provide a structure for which a patient with alcoholism may turn for an answer to their problem of alcohol use, abuse, or dependence. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. The strong coupling regime of twelve flavors QCD

    NARCIS (Netherlands)

    Silva, Tiago Nunes da; Pallante, Elisabetta


    We summarize the results recently reported in Ref.[1] [A. Deuzeman, M.P. Lombardo, T. Nunes da Silva and E. Pallante,"The bulk transition of QCD with twelve flavors and the role of improvement"] for the SU(3) gauge theory with Nf=12 fundamental flavors, and we add some numerical evidence and theoret

  5. EFFORTS Technical annex for the twelve month progress report

    DEFF Research Database (Denmark)

    Andreasen, Jan Lasson; Eriksen, Morten; Thomas christensen, Thomas Vennick;

    The present report is documentation for the work carried out at DTU during the second year of project activity. The report describes the work completed by DTU in general as well as on the active sub-tasks within materials properties, friction modelling and physical modelling, over the last twelve...

  6. Human Evolution in Science Textbooks from Twelve Different Countries (United States)

    Quessada, Marie-Pierre; Clement, Pierre; Oerke, Britta; Valente, Adriana


    What kinds of images of human beings illustrate human evolution in school textbooks? A comparison between the textbooks of eighteen different countries (twelve European countries and six non-European countries) was attempted. In six countries (Algeria, Malta, Morocco, Mozambique, Portugal, and Tunisia), we did not find any chapter on the topic of…

  7. Bibliography of Spanish Materials for Students, Grades Seven through Twelve. (United States)

    California State Dept. of Education, Sacramento.

    This annotated bibliography of Spanish materials for students in grades seven through twelve is divided into the following categories: (1) Art, Drama, Music, and Poetry; (2) Books in Series; (3) Culture; (4) Dictionaries and Encyclopedias; (5) Literature; (6) Mathematics; (7) Physical Education, Health, and Recreation; (8) Reading and Language…

  8. A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Garza, Rene [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Hudson, Robert A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); McMahan, C. Alex [Department of Pathology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Walter, Christi A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); South Texas Veterans Healthcare System, San Antonio, TX 78229 (United States); Vogel, Kristine S. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States)]. E-mail:


    Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF = 4.70) when compared to normal peripheral nerve and brain (MF = 2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

  9. The dioxin TCDD protects against aflatoxin-induced mutation in female rats, but not in male rats. (United States)

    Thornton, A S; Oda, Y; Stuart, G R; Holcroft, J; de Boer, J G


    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant and a potent carcinogen in laboratory rodents. When combined with other environmental toxins, it has been shown to increase the (geno)toxicity of some compounds. In this study, the effect of TCDD on the mutagenicity of aflatoxin-B1 (AFB1) was examined in the rat liver using a lacI transgenic rodent mutation assay. AFB1 induces GC-->TA transversions. Since TCDD is known to have a differential effect in male and female rodents, both sexes were studied. The data showed that a 6-week pre-exposure to TCDD had no significant effect on the frequency of aflatoxin-induced mutation in the liver of male rats. However, the TCDD treatment completely prevented the aflatoxin-induced transversion mutations in female animals.

  10. Twelve Theses on Reactive Rules for the Web


    Bry, François; Eckert, Michael


    Reactivity, the ability to detect and react to events, is an essential functionality in many information systems. In particular, Web systems such as online marketplaces, adaptive (e.g., recommender) sys- tems, and Web services, react to events such as Web page updates or data posted to a server. This article investigates issues of relevance in designing high-level programming languages dedicated to reactivity on the Web. It presents twelve theses on features desira...

  11. The twelve theses: a call to a new reformation

    Directory of Open Access Journals (Sweden)

    John Shelby Spong


    Full Text Available With every discovery emerging from the world of science over the last 500 years concerning the origins of the universe and of life itself, the traditional explanations offered by the Christian Church appeared to be more and more dated and irrelevant.  Christian leaders, unable to embrace the knowledge revolution seemed to believe  that the only way to save Christianity was not to disturb the old patterns either by listening to, much less by entertaining the new knowledge. I tried to articulate this challenge in a book entitled: Why Christianity Must Change or Die, published in 1998.  In that book I examined in detail the issues that I was convinced Christianity must address. Shortly after that book was published I reduced its content to twelve theses, which I attached in Luther-like fashion to the great doors on the Chapel of Mansfield College at Oxford University in the United Kingdom. I then mailed copies of those Twelve Theses to every acknowledged Christian leader of the world. It was an attempt to call them into a debate on the real issues that I was certain the Christian Church now faced.  I framed my twelve theses in the boldest, most provocative language possible, designed primarily to elicit response and debate. I welcome responses from Christians everywhere.  I claim no expertise or certainty in developing answers, but I am quite confident that I do understand the problems we are facing as Christians who are seeking to relate to the 21st century.

  12. Twelve positions in a β-lactamase that can expand its substrate spectrum with a single amino acid substitution.

    Directory of Open Access Journals (Sweden)

    Hyojeong Yi

    Full Text Available The continuous evolution of β-lactamases resulting in bacterial resistance to β-lactam antibiotics is a major concern in public health, and yet the underlying molecular basis or the pattern of such evolution is largely unknown. We investigated the mechanics of the substrate fspectrum expansion of the class A β-lactamase using PenA of Burkholderia thailandensis as a model. By analyzing 516 mutated enzymes that acquired the ceftazidime-hydrolyzing activity, we found twelve positions with single amino acid substitutions (altogether twenty-nine different substitutions, co-localized at the active-site pocket area. The ceftazidime MIC (minimum inhibitory concentration levels and the relative frequency in the occurrence of substitutions did not correlate well with each other, and the latter appeared be largely influenced by the intrinsic mutational biases present in bacteria. Simulation studies suggested that all substitutions caused a congruent effect, expanding the space in a conserved structure called the omega loop, which in turn increased flexibility at the active site. A second phase of selection, in which the mutants were placed under increased antibiotic pressure, did not result in a second mutation in the coding region, but a mutation that increased gene expression arose in the promoter. This result suggests that the twelve amino acid positions and their specific substitutions in PenA may represent a comprehensive repertoire of the enzyme's adaptability to a new substrate. These mapped substitutions represent a comprehensive set of general mechanical paths to substrate spectrum expansion in class A β-lactamases that all share a functional evolutionary mechanism using common conserved residues.

  13. Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.

    Directory of Open Access Journals (Sweden)

    Zheng Wang

    Full Text Available Axial spondylometaphyseal dysplasia (axial SMD is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2 as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

  14. Twelve tips for teaching medical students with dyslexia. (United States)

    Shaw, Sebastian Charles Keith; Anderson, John Leeds


    Dyslexia is a common learning difficulty. As a result of SS' own experiences as a medical student with dyslexia, we have been researching and teaching on this topic for the past two years. Here, we present twelve tips for teaching medical students with dyslexia. These are gathered from our personal experiences and research, discussions with other educators, and wider literature on the topic. This article aims to shed some light on dyslexia, and also to make practical suggestions. Teaching students with dyslexia should not be a daunting experience. Small changes to existing methods, at minor effort, can make a difference - for example, adding pastel colors to slide backgrounds or avoiding Serif fonts. These tips can help educators gain more insight into dyslexia and incorporate small, beneficial adaptations into their teaching.

  15. Antibacterial activities of extracts from twelve Centaurea species from Turkey

    Directory of Open Access Journals (Sweden)

    Tekeli Yener


    Full Text Available Members of the genus Centaurea (Asteraceae have been used in traditional plant-based medicine. The methanol extracts of twelve Centaurea species, of which five are endemic to Turkey flora, were screened for antibacterial activity against four bacteria (Escherichia coli, Bacillus cereus, Salmonella enteritidis, Staphylococcus aureus. The antibacterial activity was evaluated by the microdilution method and the minimum inhibition concentrations (MIC of the extracts were determined. C. cariensis subsp. microlepis exhibited an antimicrobial effect on all tested microorganisms. The extracts from eight Centaurea species (C. balsamita, C. calolepis, C. cariensis subsp. maculiceps, C. cariensis subsp. microlepis, C. kotschyi var. kotschyi, C. solstitialis subsp. solstitialis, C. urvillei subsp. urvillei and C. virgata possessed antibacterial activity against several of the tested microorganisms.

  16. Twelve tips on how to compile a medical educator's portfolio. (United States)

    Dalton, Claudia Lucy; Wilson, Anthony; Agius, Steven


    Medical education is an expanding area of specialist interest for medical professionals. Whilst most doctors will be familiar with the compilation of clinical portfolios for scrutiny of their clinical practice and provision of public accountability, teaching portfolios used specifically to gather and demonstrate medical education activity remain uncommon in many non-academic settings. For aspiring and early career medical educators in particular, their value should not be underestimated. Such a medical educator's portfolio (MEP) is a unique compendium of evidence that is invaluable for appraisal, revalidation, and promotion. It can stimulate and provide direction for professional development, and is a rich source for personal reflection and learning. We recommend that all new and aspiring medical educators prepare an MEP, and suggest twelve tips on how to skillfully compile one.

  17. Spectroscopy of twelve Type Ia supernovae at intermediate redshift

    CERN Document Server

    Balland, C; Pain, R; Walton, N A; Amanullah, R; Astier, Pierre; Ellis, Richard S; Fabbro, S; Goobar, A; Hardin, D; Hook, I M; Irwin, M J; McMahon, R M; Mendez, J M; Ruiz-Lapuente, P; Sainton, G; Schahmaneche, K; Stanishev, V


    We present spectra of twelve Type Ia supernovae obtained in 1999 at the William Herschel Telescope and the Nordic Optical Telescope during a search for Type Ia supernovae (SN Ia) at intermediate redshift. The spectra range from z=0.178 to z=0.493, including five high signal-to-noise ratio SN Ia spectra in the still largely unexplored range 0.15 < z < 0.3. Most of the spectra were obtained before or around restframe B-band maximum light. None of them shows the peculiar spectral features found in low-redshift over- or under-luminous SN Ia. Expansion velocities of characteristic spectral absorption features such as SiII at 6355 angs., SII at 5640 angs. and CaII at 3945 angs. are found consistent with their low-z SN Ia counterparts.

  18. Oral papillary squamous cell carcinoma in twelve dogs. (United States)

    Nemec, A; Murphy, B G; Jordan, R C; Kass, P H; Verstraete, F J M


    Papillary squamous cell carcinoma (PSCC) is a distinct histological subtype of oral squamous cell carcinoma (SCC), described in both dogs and man. In dogs, PSCC has long been considered a malignant oral tumour of very young animals, but it has recently been reported to occur in adult dogs as well. The aim of this study was to describe the major clinicopathological characteristics of canine oral PSCC (COPSCC). Twelve dogs diagnosed with COPSCC were included in this retrospective study (1990-2012). The majority (75%) of the dogs were >6 years of age (median age 9 years). All tumours were derived from the gingiva of dentate jaws, with 66.7% affecting the rostral aspects of the jaws. The gross appearance of the lesions varied, with one having an intraosseous component only. The majority (91.7%) of the tumours were advanced lesions (T2 and T3), but no local or distant metastases were noted. Microscopically, two patterns were seen: (1) invasion of bone forming a cup-shaped indentation in the bone or a deeply cavitating cyst within the bone (cavitating pattern), (2) histologically malignant growth, but lack of apparent bone invasion (non-cavitating pattern). The microscopical appearance corresponded to imaging findings in a majority of cases, with cavitating forms presenting with a cyst-like pattern of bone loss or an expansile mass on imaging and non-cavitating forms showing an infiltrative pattern of bone destruction on imaging. These features suggest two distinct biological behaviours of COPSCC.

  19. Sensitivity and growth of twelve Elatior begonia cultivars to ozone

    Energy Technology Data Exchange (ETDEWEB)

    Reinert, R.A.; Nelson, P.V.


    Twelve cultivars of Elatior begonia (Begonia X hiemalis Fotsch.) were exposed to O/sub 3/ at 25 and 50 pphM. The 'Schwabenland' group, 'Whisper 'O' Pink', and 'Improved Krefeld Orange' were the most sensitive, whereas 'Ballerina', 'Mikkell Limelight', and 'Turo' were the least sensitive. 'Rennaisance', 'Heirloom' 'Nixe', and 'Fantasy' were intermediate in sensitivity. The dry weight of foliage (stems plus leaves) of 9 cultivars exposed to O/sub 3/ was significantly less than that of control plants. Ozone at 25 and 50 pphM inhibited flower growth (including peduncles) and development in 4 and 8 of the 12 cultivars, respectively. Differences in flower weight ranged from 43 to 105% of the control at 25 pphM and from 25 to 98% of the control at 50 pphM, depending on cultivar. 1 table.

  20. Twelve tips for designing and running longitudinal integrated clerkships. (United States)

    Ellaway, Rachel; Graves, Lisa; Berry, Sue; Myhre, Doug; Cummings, Beth-Ann; Konkin, Jill


    Longitudinal integrated clerkships (LICs) involve learners spending an extended time in a clinical setting (or a variety of interlinked clinical settings) where their clinical learning opportunities are interwoven through continuities of patient contact and care, continuities of assessment and supervision, and continuities of clinical and cultural learning. Our twelve tips are grounded in the lived experiences of designing, implementing, maintaining, and evaluating LICs, and in the extant literature on LICs. We consider: general issues (anticipated benefits and challenges associated with starting and running an LIC); logistical issues (how long each longitudinal experience should last, where it will take place, the number of learners who can be accommodated); and integration issues (how the LIC interfaces with the rest of the program, and the need for evaluation that aligns with the dynamics of the LIC model). Although this paper is primarily aimed at those who are considering setting up an LIC in their own institutions or who are already running an LIC we also offer our recommendations as a reflection on the broader dynamics of medical education and on the priorities and issues we all face in designing and running educational programs.

  1. Commercializing Government-sponsored Innovations: Twelve Successful Buildings Case Studies (United States)

    Brown, M. A.; Berry, L. G.; Goel, R. K.


    This report examines the commercialization and use of R and D results funded by DOE's Office of Buildings and Community Systems (OBCS), an office that is dedicated to improving the energy efficiency of the nation's buildings. Three goals guided the research described in this report: to improve understanding of the factors that hinder or facilitate the transfer of OBCS R and D results, to determine which technology transfer strategies are most effective and under what circumstances each is appropriate, and to document the market penetration and energy savings achieved by successfully-commercialized innovations that have received OBCS support. Twelve successfully-commercialized innovations are discussed here. The methodology employed involved a review of the literature, interviews with innovation program managers and industry personnel, and data collection from secondary sources. Six generic technology transfer strategies are also described. Of these, contracting R and D to industrial partners is found to be the most commonly used strategy in our case studies. The market penetration achieved to date by the innovations studied ranges from less than 1% to 100%. For the three innovations with the highest predicted levels of energy savings (i.e., the flame retention head oil burner, low-E windows, and solid-state ballasts), combined cumulative savings by the year 2000 are likely to approach 2 quads. To date the energy savings for these three innovations have been about 0.2 quads. Our case studies illustrate the important role federal agencies can play in commercializing new technologies.

  2. The strong coupling regime of twelve flavors QCD

    CERN Document Server

    da Silva, Tiago Nunes


    We summarize the results recently reported in Ref.[1] [A. Deuzeman, M.P. Lombardo, T. Nunes da Silva and E. Pallante,"The bulk transition of QCD with twelve flavors and the role of improvement"] for the SU(3) gauge theory with Nf=12 fundamental flavors, and we add some numerical evidence and theoretical discussion. In particular, we study the nature of the bulk transition that separates a chirally broken phase at strong coupling from a chirally restored phase at weak coupling. When a non-improved action is used, a rapid crossover is observed at small bare quark masses. Our results confirm a first order nature for this transition, in agreement with previous results we obtained using an improved action. As shown in Ref.[1], when improvement of the action is used, the transition is preceded by a second rapid crossover at weaker coupling and an exotic phase emerges, where chiral symmetry is not yet broken. This can be explained [1] by the non hermiticity of the improved lattice Transfer matrix, arising from the c...

  3. The Synthesis and Antitumor Activity of Twelve Galloyl Glucosides

    Directory of Open Access Journals (Sweden)

    Chang-Wei Li


    Full Text Available Twelve galloyl glucosides 1–12, showing diverse substitution patterns with two or three galloyl groups, were synthesized using commercially available, low-cost D-glucose and gallic acid as starting materials. Among them, three compounds, methyl 3,6-di-O-galloyl-α-D-glucopyranoside (9, ethyl 2,3-di-O-galloyl-α-D-glucopyranoside (11 and ethyl 2,3-di-O-galloyl-β-D-glucopyranoside (12, are new compounds and other six, 1,6-di-O-galloyl-β-D-glucopyranose (1, 1,4,6-tri-O-galloyl-β-D-glucopyranose (2, 1,2-di-O-galloyl-β-D-glucopyranose (3, 1,3-di-O-galloyl-β-D-glucopyranose (4, 1,2,3-tri-O-galloyl-α-D-glucopyranose (6 and methyl 3,4,6-tri-O-galloyl-α-D-glucopyranoside (10, were synthesized for the first time in the present study. In in vitro MTT assay, 1–12 inhibited human cancer K562, HL-60 and HeLa cells with inhibition rates ranging from 64.2% to 92.9% at 100 μg/mL, and their IC50 values were determined to be varied in 17.2–124.7 μM on the tested three human cancer cell lines. In addition, compounds 1–12 inhibited murine sarcoma S180 cells with inhibition rates ranging from 38.7% to 52.8% at 100 μg/mL in the in vitro MTT assay, and in vivo antitumor activity of 1 and 2 was also detected in murine sarcoma S180 tumor-bearing Kunming mice using taxol as positive control.

  4. [Twelve years of working of Brazzaville cancer registry]. (United States)

    Nsondé Malanda, Judith; Nkoua Mbon, Jean Bernard; Bambara, Augustin Tozoula; Ibara, Gérard; Minga, Benoît; Nkoua Epala, Brice; Gombé Mbalawa, Charles


    The Brazzaville cancer registry was created in 1996 with the support of the International Agency Research against Cancer (IARC) which is located in Lyon, France. The Brazzaville cancer registry is a registry which is based on population which records new cancer cases occurring in Brazzaville by using Canreg 4.0 Software. Its aim is to supply useful information to fight against cancer to physicians and to decision makers. We conducted this study whose target was to determine the incidence of cancer in Brazzaville during twelve years, from January 1st, 1998 to December 31, 2009. During that period 6,048 new cancer cases were recorded: 3,377 women (55.8%), 2,384 men (39.4%), and 287 children (4.8%) from 0 to 14 years old with an annual average of 504 cases. Middle age to the patient's diagnosis was 49.5 years in female sex and 505.5 years old for male sex. The incidence rate of cancers in Brazzaville was 39.8 or 100.000 inhabitants per year and by sex we observed 49 to female sex and 35.2 for male sex. The first cancers localizations observed to women were in order of frequency: breast, cervix uterine, liver ovaries, hematopoietic system, to men : liver, prostate, hematopoietic system, colon and stomach; to children : retina, kidney, hematopoietic system, liver and bones. These rates are the basis to know the burden of cancer among all pathologies of Brazzaville and the achievement of a national cancer control program.

  5. Commercializing government-sponsored innovations: Twelve successful buildings case studies

    Energy Technology Data Exchange (ETDEWEB)

    Brown, M.A.; Berry, L.G.; Goel, R.K.


    This report examines the commercialization and use of R and D results funded by DOE's Office of Buildings and Community Systems (OBCS), an office that is dedicated to improving the energy efficiency of the nation's buildings. Three goals guided the research described in this report: to improve understanding of the factors that hinder or facilitate the transfer of OBCS R and D results, to determine which technology transfer strategies are most effective and under what circumstances each is appropriate, and to document the market penetration and energy savings achieved by successfully-commercialized innovations that have received OBCS support. Twelve successfully-commercialized innovations are discussed here. The methodology employed involved a review of the literature, interviews with innovation program managers and industry personnel, and data collection from secondary sources. Six generic technology transfer strategies are also described. Of these, contracting R and D to industrial partners is found to be the most commonly used strategy in our case studies. The market penetration achieved to date by the innovations studied ranges from less than 1% to 100%. For the three innovations with the highest predicted levels of energy savings (i.e., the flame retention head oil burner, low-E windows, and solid-state ballasts), combined cumulative savings by the year 2000 are likely to approach 2 quads. To date the energy savings for these three innovations have been about 0.2 quads. Our case studies illustrate the important role federal agencies can play in commercializing new technologies. 27 refs., 21 figs., 4 tabs.

  6. An Experiment in Humanistic Management within Community College District Twelve, Centralia/Olympia, Washington. (United States)

    Miller, Dale A.; Hurley, John A.

    Community College District Twelve, a multi-college district serving a two-county area in southwestern Washington, has attempted to incorporate at administrative levels many of the humanistic, process-oriented principles of management discussed by Maslow and Maccoby. A concept of the ideal leadership style for District Twelve guides the selection…

  7. Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene

    Directory of Open Access Journals (Sweden)

    Lehrke Stephanie


    Full Text Available Abstract Background Mutations in MYBPC3 encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM and may also lead to dilated cardiomyopathy (DCM. MYBPC3 mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different MYBPC3 mutations. Methods 87 patients with HCM and 71 patients with DCM were screened for MYBPC3 mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded. Results In 16 HCM (18.4% and two DCM (2.8% index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2% had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1% suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families. Conclusion MYBPC3 mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with MYBPC3 mutations require thorough clinical risk assessment.

  8. The impact of alcoholics anonymous on other substance abuse-related twelve-step programs. (United States)

    Laudet, Alexandre B


    This chapter explores the influence of the AA model on self-help fellowships addressing problems of drug dependence. Fellowships that have adapted the twelve-step recovery model to other substances of abuse are reviewed; next similarities and differences between AA and drug-recovery twelve-step organizations are examined; finally, we present empirical findings on patterns of attendance and perceptions of AA and Narcotics Anonymous (NA) among polydrug-dependent populations, many of whom are cross-addicted to alcohol. Future directions in twelve-step research are noted in closing.


    Institute of Scientific and Technical Information of China (English)



    In many years' clinical practice, I used blood-letting method of “Twelve Well-points” to treat emergencies as coma, syncope, acute infantile convulsion, wind-stroke syndrome, hysteria, epilepsy, etc. and have achieved immediate results.

  10. High-resolution melting facilitates mutation screening of PYGM in patients with McArdle disease

    DEFF Research Database (Denmark)

    Duno, M.; Quinlivan, R.; Vissing, J.


    variations. Thirteen of these are pathogenic, and three were classified as polymorphisms. Nine variations had not previously been described. One of the novel mutations, c.2430C > T, was initially predicted to result in a silent G810G change, but cDNA analysis demonstrated that the mutation led to abnormal m......Mutations in PYGM, encoding the muscle-specific glycogen phosphorylase (myophosphorylase), are responsible for McArdle disease. Among Caucasians, a large proportion of patients are homozygous for the R50X mutation, but other mutations can affect all the 20 exons of PYGM, making mutation detection...... laborious. We have developed a high-resolution melting (HRM) assay for mutation detection in PYGM. Twelve McArdle patients were investigated, in whom pre-screening had ruled out homozygosity or compound heterozygosity for the two common G205S and R50X mutations. In total, we identified 16 different...

  11. CF Mutation Panel (United States)

    ... Testing; Cystic Fibrosis Transmembrane Conductance Regulator Mutation Analysis; CFTR Mutation Analysis Formal name: Cystic Fibrosis Gene Mutation ... an elevated immunoreactive trypsinogen (IRT) or positive sweat chloride test , to confirm the diagnosis of cystic fibrosis. ...

  12. Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy. (United States)

    Nemethova, Martina; Radvanszky, Jan; Kadasi, Ludevit; Ascher, David B; Pires, Douglas E V; Blundell, Tom L; Porfirio, Berardino; Mannoni, Alessandro; Santucci, Annalisa; Milucci, Lia; Sestini, Silvia; Biolcati, Gianfranco; Sorge, Fiammetta; Aurizi, Caterina; Aquaron, Robert; Alsbou, Mohammed; Lourenço, Charles Marques; Ramadevi, Kanakasabapathi; Ranganath, Lakshminarayan R; Gallagher, James A; van Kan, Christa; Hall, Anthony K; Olsson, Birgitta; Sireau, Nicolas; Ayoob, Hana; Timmis, Oliver G; Sang, Kim-Hanh Le Quan; Genovese, Federica; Imrich, Richard; Rovensky, Jozef; Srinivasaraghavan, Rangan; Bharadwaj, Shruthi K; Spiegel, Ronen; Zatkova, Andrea


    Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.

  13. Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on ‘black bone disease' in Italy (United States)

    Nemethova, Martina; Radvanszky, Jan; Kadasi, Ludevit; Ascher, David B; Pires, Douglas E V; Blundell, Tom L; Porfirio, Berardino; Mannoni, Alessandro; Santucci, Annalisa; Milucci, Lia; Sestini, Silvia; Biolcati, Gianfranco; Sorge, Fiammetta; Aurizi, Caterina; Aquaron, Robert; Alsbou, Mohammed; Marques Lourenço, Charles; Ramadevi, Kanakasabapathi; Ranganath, Lakshminarayan R; Gallagher, James A; van Kan, Christa; Hall, Anthony K; Olsson, Birgitta; Sireau, Nicolas; Ayoob, Hana; Timmis, Oliver G; Le Quan Sang, Kim-Hanh; Genovese, Federica; Imrich, Richard; Rovensky, Jozef; Srinivasaraghavan, Rangan; Bharadwaj, Shruthi K; Spiegel, Ronen; Zatkova, Andrea


    Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650–85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy. PMID:25804398

  14. Chapter Twelve

    African Journals Online (AJOL)


    dissemination in Nigeria· Some local jingles from Radio Nigeria Purity F.M. .... Indigenous Language in Advertisement: Problems and Prospects – Thecla ... the rural newspapers from performing their role of rural development· The ..... Sharma Raman, M· and, S (2004), Technical Communication Principle and Practice· India:.

  15. Mutations Induced by Benzo[a]pyrene and Dibenzo[a,l]pyrene in lacI Transgenic B6C3F1 Mouse Lung Result from Stable DNA Adducts (United States)

    Dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P) are carcinogenic polycyclic aromatic hydrocarbons (PAH) that are each capable of forming a variety of covalent adducts with DNA. Some of the DNA adducts formed by these PAHs have been demonstrated to spontaneously depurina...

  16. Isolation and characterization of twelve microsatellite loci for the Japanese Devilray (Mobula japanica)

    NARCIS (Netherlands)

    Poortvliet, Marloes; Galvan-Magana, Felipe; Bernardi, Giacomo; Croll, Donald A.; Olsen, Jeanine L.


    Twelve polymorphic microsatellites loci were characterized for Mobula japanica (Japanese Devilray) using an enrichment protocol. All but two loci were in Hardy-Weinberg equilibrium with no evidence of linkage disequilibrium or null-alleles for a sample of 40 individuals from two populations. The num

  17. 17 CFR 210.3-06 - Financial statements covering a period of nine to twelve months. (United States)


    ... ACT OF 1933, SECURITIES EXCHANGE ACT OF 1934, PUBLIC UTILITY HOLDING COMPANY ACT OF 1935, INVESTMENT COMPANY ACT OF 1940, INVESTMENT ADVISERS ACT OF 1940, AND ENERGY POLICY AND CONSERVATION ACT OF 1975... to twelve months. Except with respect to registered investment companies, the filing of...

  18. Twelve new species of Triplocania Roesler (Psocodea: 'Psocoptera': Ptiloneuridae), from South America. (United States)

    Silva Neto, Alberto Moreira Da; Aldrete, Alfonso N García; Rafael, José Albertino


    Twelve species of Triplocania, seven based on male and female specimens and five based on male specimens, are here described and illustrated; nine species are Brazilian, three are Ecuadorian, and one of the latter is shared with Peru. Comments on sexes known and distribution of the species are included.

  19. Portrayal of Life Form in Selected Biographies for Children Eight to Twelve Years of Age. (United States)

    Koch, Shirley Lois

    This study describes and analyzes, in a critical literary manner, selected biographies for children eight to twelve years of age. Biographies of Jane Addams, Cesar Chavez, Mohandas Gandhi, Toyohiko Kagawa, Martin Luther King, Jr., and Albert Schweitzer are viewed from the perspective of a literary criterion based on the principles of design to…

  20. Premarital sex in the last twelve months and its predictors among ...

    African Journals Online (AJOL)

    Premarital sex in the last twelve months and its predictors among students of ... Statistical significance was determined through a 95% confidence level. ... having comprehensive knowledge of HIV [AOR(95% CI)=1.5(1.01-2.10)], alcohol use ...

  1. Portrayal of Life Form in Selected Biographies for Children Eight to Twelve Years of Age. (United States)

    Koch, Shirley Lois

    This study describes and analyzes, in a critical literary manner, selected biographies for children eight to twelve years of age. Biographies of Jane Addams, Cesar Chavez, Mohandas Gandhi, Toyohiko Kagawa, Martin Luther King, Jr., and Albert Schweitzer are viewed from the perspective of a literary criterion based on the principles of design to…

  2. A novel double quad-inverter configuration for multilevel twelve-phase open-winding converter

    DEFF Research Database (Denmark)

    Padmanaban, Sanjeevi Kumar; Blaabjerg, Frede; Wheeler, Patrick William


    This paper describes a novel proposal of double quad-inverter configuration for multilevel twelve-phase open-winding ac converter. Modular power units are developed from reconfigured eight classical three-phase voltage source inverters (VSIs). Each VSI has one additional bi-directional switching ...

  3. Leiden Mutation and the Course of Severe Acute Pancreatitis

    Directory of Open Access Journals (Sweden)

    A. V. Ershov


    Full Text Available Objective: to evaluate the impact of Leiden mutation on the course of severe acute pancreatitis. Subjects and methods. One hundred and twelve people were examined. Group 1 comprised 50 patients diagnosed with severe acute pancreatitis without coagulation factor V (Leiden mutation. Group 2 included 42 patients with severe acute pancreatitis who were found to have Leiden mutation. Acute pancreatitis was first diagnosed in both groups. Group 3 consisted of 20 apparently healthy individuals (a control group. The severity of the underlying disease was determined in accordance with the clinical and laboratory parameters recommended by the I. I. Dzhanelidze Saint Petersburg Research Institute of Emergence Care. Results. This investigation revealed an association of Leiden mutation with trends in the development of acute pancreatitis. Group 2 exhibited a more severe disease: large focal pancreatic necrosis was twice more common and infectious complications developed more frequently; more aggressive and radical treatments were more often used. The patients with Leiden mutation had higher mortality rates (33% in the Leiden mutation group and 24% in the non-mutation group. Conclusion. The findings should be kept in mind in elaborating new diagnostic methods and principles in the treatment of the underlying disease and in the prevention of its complications in patients with severe acute pancreatitis. Key words: acute pancreatitis, Leiden mutation.

  4. Fast capillary electrophoresis-laser induced fluorescence analysis of ligase chain reaction products: human mitochondrial DNA point mutations causing Leber's hereditary optic neuropathy. (United States)

    Muth, J; Williams, P M; Williams, S J; Brown, M D; Wallace, D C; Karger, B L


    High speed capillary electrophoresis-laser-induced fluorescence (CE-LIF) has been used to separate and detect point mutations using the ligase chain reaction (LCR). The method utilizes short capillary columns (7.5 cm effective length) and fields of 400 V/cm to analyze DNA-ethidium bromide complexes using an He/Ne laser. The method was first demonstrated with a commercially available kit for LCR based on a lacI gene fragment inserted in a Bluescript II phagemid. LCR-CE-LIF was then applied to detect point mutations in human mitochondrial DNA, resulting in Leber's hereditary optic neuropathy (LHON). Three severe mutations were analyzed in which the original base is substituted by a thymidine base at positions 3460, 11778 and 14459. Appropriate primers were designed with polyT tails for length discrimination of pooled samples. Successful detection of mutated samples was achieved, with appropriate correction for small amounts of nonspecific ligated product. The method is rapid, easy to implement, and automatable.

  5. AB168. Novel DYM compound heterozygous mutations in a Malaysian boy with Dyggve-Melchior-Clausen syndrome (United States)

    Ong, Winnie Peitee; Md Haniffa, Muzhirah Aisha; Leong, Huey Yin; Chew, Hui Bein; Ch’ng, Gaik Siew; Ngu, Lock Hock; Patel, Nisha; Hashem, Mais Omar; Alkuraya, Fowzan Sami; Keng, Wee Teik


    Background Dyggve-Melchior-Clausen (DMC) syndrome and Smith-McCort Dysplasia (SMC) are rare, progressive, autosomal recessive skeletal dysplasias caused by mutations in the Dymeclin (DYM) gene, mapped to chromosome 18q21.1. These are allelic disorders and share many features including short stature, a barrel-shaped chest, platyspondyly, abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. The distinguishing feature is that individuals with DMC have intellectual disabilities whereas SMC is associated with normal intelligence. Case presentation We present a 6-year-old Malaysian boy, the elder of two children born to a non-consanguineous Chinese couple. He was a term baby but was small and short for gestational age at birth. He initially presented to the paediatric endocrinologist for concerns of short stature and was subsequently referred prior to the age of three for suspicion of mucopolysaccharidosis (MPS) from his vertebral radiological findings. Clinical evaluation revealed that he had short stature, microcephaly and prominent pectus carinatum. He had normal early developmental milestones but on follow-up, it became obvious he had learning difficulties with expressive speech delay. His skeletal radiographs showed platyspondyly with a double hump and anterior breaking, broad ribs, widened metacarpals, abnormally shaped femoral heads and lacy crests of the iliac wings. Molecular testing of the DYM gene identified novel compound heterozygous mutations—a deletion c.242_249del8 in exon 4 was inherited from his father and a single nucleotide duplication c.1917dupT in exon 17 was inherited from his mother. Both these mutations cause a frameshift and result in aberrant mRNA processing. The parents are therefore heterozygous carriers. Our patient was initially thought to have Smith-McCort dysplasia SMC but his diagnosis had since been revised to DMC when it became evident he had speech delay and was faltering with his

  6. Codon Y791F mutations in a large kindred: is prophylactic thyroidectomy always indicated?

    DEFF Research Database (Denmark)

    Vestergaard, Peter; Vestergaard, Else Marie; Brockstedt, Helle


    . Mutation analysis was done by direct bidirectional sequencing of PCR products on an ABI 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). RESULTS: The index person was screened genetically due to goitre at a young age. A total of 27 members of the family underwent genetic testing. Twelve...

  7. Identification of 3 novel VHL germ-line mutations in Danish VHL patients

    Directory of Open Access Journals (Sweden)

    Dandanell Mette


    Full Text Available Abstract Background von Hippel-Lindau (VHL disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene. Methods VHL mutational analysis was carried out by sequencing of the coding sequence and by multiplex ligation-dependent probe amplification analysis. The functional consequence of the variants was investigated using in silico prediction tools. Results A total of 289 probands suspected of having VHL syndrome have been screened for mutations in the VHL gene. Twenty-six different VHL mutations were identified in 36 families including one in-frame duplication, two frame-shift mutations, four nonsense mutations, twelve missense mutations, three intronic mutations and four large genomic rearrangements. Three of these mutations (c.319 C > T, c.342_343dupGGT and c.520_521dupAA were novel. Conclusions In this study we report the VHL germ-line mutations found in Danish families. We found three novel VHL mutations where two were classified as pathogenic and the latter was classified as a variant of unknown significance. Together, our findings contribute to the interpretation of the potential pathogenicity of VHL germ-line mutations.

  8. Anatomical studies on twelve clones of Camellia species with reference to their taxonomic significance

    Directory of Open Access Journals (Sweden)

    Rajanna L


    Full Text Available Anatomical studies of leaf and stem of twelve clones of Camellia were investigated. Cross sections of the stem of all the clones exhibited a typical pattern of arrangement of tissues characteristics of woody plants. Two types of idioblastic sclereids were found in the medullary parenchyma of the taxa studied. While astrosclereids werepresent in 10 of the twelve clones, the vesciculose sclereids were found only in the four clones belonging to C. sinensis. Leaves of the clones show variations in the number of palisade layers. Astro sclereids, brachy sclereids, and dendritic forms were observed in the leaves, their distribution varying in the different clones. A few other micromorphological features are also recorded. Our study forms a basis for answering uncertainties in taxonomic revision in the genus Camellia.

  9. Descriptions of twelve new species of ochyroceratids (Araneae, Ochyroceratidae) from mainland Ecuador. (United States)

    Dupérré, Nadine


    Twelve new species in three different genera from the spider family Ochyroceratidae are described from mainland Ecuador: Speocera bioforestae sp. n., Speocera violacea sp. n., Speocera musgo sp. n., Ochyrocera rinocerotos sp. n., Ochyrocera callaina sp. n., Ochyrocera italoi sp. n., Ochyrocera minotaure sp. n., Ochyrocera losrios sp. n., Ochyrocera zabaleta sp. n., Ochyrocera otonga sp. n., Ochyrocera cashcatotoras sp. n. and Psiloochyrocera tortilis sp. n. Speocera machadoi Gertsch 1977 is transferred to Ochyrocera.

  10. A Hidden Twelve-Dimensional SuperPoincare Symmetry In Eleven Dimensions

    Energy Technology Data Exchange (ETDEWEB)

    Bars, Itzhak; Deliduman, Cemsinan; Pasqua, Andrea; Zumino, Bruno


    First, we review a result in our previous paper, of how a ten-dimensional superparticle, taken off-shell, has a hidden eleven-dimensional superPoincare symmetry. Then, we show that the physical sector is defined by three first-class constraints which preserve the full eleven-dimensional symmetry. Applying the same concepts to the eleven dimensional superparticle, taken off-shell, we discover a hidden twelve dimensional superPoincare symmetry that governs the theory.

  11. Premarital Sex in the Last Twelve Months and Its Predictors among Students of Wollega University, Ethiopia. (United States)

    Regassa, Tesfaye; Chala, Dereje; Adeba, Emiru


    Premarital sex increases the risk of unintended pregnancy and sexually transmitted infections including HIV if unprotected and contraception is not used. Thus, the objective of this study was to assess premarital sex in the last twelve months and its predictors among regular undergraduate students of Wollega University. A cross-sectional survey using pretested, structured questionnaire was conducted on a total of 704 regular undergraduate students of Wollega University from February to March, 2014. We used multistage sampling technique to recruit study participants. Binary and multivariable logistic regressions were performed using SPSS version 20 to assess predictors of premarital sex. Statistical significance was determined through a 95% confidence level. Wollega University youths who had premarital sex in the last twelve months were 28.4%; 55.5% of them did not use condom during last sex while 31.3% engaged in multiple sex. Being male [Adjusted Odds Ratio (AOR)(95% Confidence Interval(CI))=2.7(1.58-4.75)], age 20-24 years [AOR(95%CI)=2.8(1.13-7.20)], training on how to use condom [AOR(95%CI)=1.7(1.17-2.46)], being tested for HIV [AOR(95%CI)=2.3(1.48-3.53)], using social media frequently [AOR(95%CI)=1.8(1.14-2.88)], having comprehensive knowledge of HIV [AOR(95% CI)=1.5(1.01-2.10)], alcohol use [AOR (95%CI)=2.2(1.31-3.56)] were associated with increased odds of premarital sex in the last twelve months. Nearly one-third of regular undergraduate students of the university were engaged in premarital sex in the last twelve months. Being male, using social media frequently and alcohol use were associated with increased odds of premarital sex in the stated period. Thus, higher institutions have to deliver abstinence messages alongside information about self-protection.

  12. Hidden twelve-dimensional super Poincaré symmetry in eleven dimensions

    CERN Document Server

    Bars, Itzhak; Pasqua, A; Zumino, B; Bars, Itzhak; Deliduman, Cemsinan; Pasqua, Andrea; Zumino, Bruno


    First, we review a result in our previous paper, of how a ten-dimensional superparticle, taken off-shell, has a hidden eleven-dimensional superPoincare symmetry. Then, we show that the physical sector is defined by three first-class constraints which preserve the full eleven-dimensional symmetry. Applying the same concepts to the eleven dimensional superparticle, taken off-shell, we discover a hidden twelve dimensional superPoincare symmetry that governs the theory.

  13. Transgenic Animal Mutation Assays

    Institute of Scientific and Technical Information of China (English)

    Tao Chen; Ph.D.D.A.B.T.


    @@ The novel transgenic mouse and rat mutation assays have provided a tool for analyzing in vivo mutation in any tissue, thus permitting the direct comparison of cancer incidence with mutant frequency.

  14. Lack of mutation induction with exposure to 1.5 GHz electromagnetic near fields used for cellular phones in brains of Big Blue mice. (United States)

    Takahashi, Satoru; Inaguma, Shingo; Cho, Young-Man; Imaida, Katsumi; Wang, Jianqing; Fujiwara, Osamu; Shirai, Tomoyuki


    The possible mutagenic potential of exposure to 1.5 GHz electromagnetic near field (EMF) was investigated using brain tissues of Big Blue mice (BBM). Male BBM were locally exposed to EMF in the head region at 2.0, 0.67, and 0 W/kg specific absorption rate for 90 min/day, 5 days/week, for 4 weeks. No gliosis or degenerative lesions were histopathologically noted in brain tissues, and no obvious differences in Ki-67 labeling and apoptotic indices of glial cells were evident among the groups. There was no significant variation in the frequency of independent mutations of the lacI transgene in the brains. G:C to A:T transitions at CpG sites constituted the most prevalent mutations in all groups and at all time points. Deletion mutations were slightly increased in both the high and low EMF exposure groups as compared with the sham-exposed group, but the differences were not statistically significant. These findings suggest that exposure to 1.5 GHz EMF is not mutagenic to mouse brain cells and does not create any increased hazard with regard to brain tumor development.

  15. Maize Mutator transposon

    Institute of Scientific and Technical Information of China (English)

    Yijun WANG; Mingliang XU; Dexiang DENG; Yunlong BIAN


    Transposable elements are widely distributed in eukaryotes. Due to its high copy numbers, high forward mutation rate and preferential insertion into low-copy DNA sequences, among others, the Mutator system has been widely used as a mutagen in genomic research. The discovery, classification, transposition specificity and epige-netic regulation of Mutator transposons were described. The application of Mutator tagging in plant genomic research was also presented. The role of Mu-like elements in genome evolution was briefly depicted. Moreover, the direction of Mutator transposon research in the future was discussed.

  16. Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations. (United States)

    Deb, S; Wong, S Q; Li, J; Do, H; Weiss, J; Byrne, D; Chakrabarti, A; Bosma, T; Fellowes, A; Dobrovic, A; Fox, S B


    Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers. Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes. Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours. This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.

  17. Definition of a Twelve-Point Polygonal SAA Boundaryfor the GLAST Mission

    Energy Technology Data Exchange (ETDEWEB)

    Djomehri, Sabra I.; /UC, Santa Cruz /SLAC


    The Gamma-Ray Large Area Space Telescope (GLAST), set to launch in early 2008, detects gamma rays within a huge energy range of 100 MeV - 300 GeV. Background cosmic radiation interferes with such detection resulting in confusion over distinguishing cosmic from gamma rays encountered. This quandary is resolved by encasing GLAST's Large Area Telescope (LAT) with an Anti-Coincidence Detector (ACD), a device which identifies and vetoes charged particles. The ACD accomplishes this through plastic scintillator tiles; when cosmic rays strike, photons produced induce currents in Photomultiplier Tubes (PMTs) attached to these tiles. However, as GLAST orbits Earth at altitudes {approx}550km and latitudes between -26 degree and 26 degree, it will confront the South Atlantic Anomaly (SAA), a region of high particle flux caused by trapped radiation in the geomagnetic field. Since the SAA flux would degrade the sensitivity of the ACD's PMTs over time, a determined boundary enclosing this region need be attained, signaling when to lower the voltage on the PMTs as a protective measure. The operational constraints on such a boundary require a convex SAA polygon with twelve edges, whose area is minimal ensuring GLAST has maximum observation time. The AP8 and PSB97 models describing the behavior of trapped radiation were used in analyzing the SAA and defining a convex SAA boundary of twelve sides. The smallest possible boundary was found to cover 14.58% of GLAST's observation time. Further analysis of defining a boundary safety margin to account for inaccuracies in the models reveals if the total SAA hull area is increased by {approx}20%, the loss of total observational area is < 5%. These twelve coordinates defining the SAA flux region are ready for implementation by the GLAST satellite.

  18. The correlation between reading and mathematics ability at age twelve has a substantial genetic component. (United States)

    Davis, Oliver S P; Band, Gavin; Pirinen, Matti; Haworth, Claire M A; Meaburn, Emma L; Kovas, Yulia; Harlaar, Nicole; Docherty, Sophia J; Hanscombe, Ken B; Trzaskowski, Maciej; Curtis, Charles J C; Strange, Amy; Freeman, Colin; Bellenguez, Céline; Su, Zhan; Pearson, Richard; Vukcevic, Damjan; Langford, Cordelia; Deloukas, Panos; Hunt, Sarah; Gray, Emma; Dronov, Serge; Potter, Simon C; Tashakkori-Ghanbaria, Avazeh; Edkins, Sarah; Bumpstead, Suzannah J; Blackwell, Jenefer M; Bramon, Elvira; Brown, Matthew A; Casas, Juan P; Corvin, Aiden; Duncanson, Audrey; Jankowski, Janusz A Z; Markus, Hugh S; Mathew, Christopher G; Palmer, Colin N A; Rautanen, Anna; Sawcer, Stephen J; Trembath, Richard C; Viswanathan, Ananth C; Wood, Nicholas W; Barroso, Ines; Peltonen, Leena; Dale, Philip S; Petrill, Stephen A; Schalkwyk, Leonard S; Craig, Ian W; Lewis, Cathryn M; Price, Thomas S; Donnelly, Peter; Plomin, Robert; Spencer, Chris C A


    Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children's ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child's cognitive abilities at age twelve.

  19. New Eyes on the Universe Twelve Cosmic Mysteries and the Tools We Need to Solve Them

    CERN Document Server

    Webb, Stephen


    "New Eyes on the Universe -- Twelve Cosmic Mysteries and the Tools We Need to Solve Them" gives an up-to-date broad overview of some of the key issues in modern astronomy and cosmology. It describes the vast amount of observational data that the new generation of observatories and telescopes are currently producing, and how that data might solve some of the outstanding puzzles inherent in our emerging world view. Included are questions such as: What is causing the Universe to blow itself apart? What could be powering the luminous gamma-ray bursters? Where is all the matter in the Uni


    Institute of Scientific and Technical Information of China (English)


    Direct chromosome analysis and FISH were performed on twelve primary gastric carcinomas. Two of them had simple chromosome changes: 48,XX, +8, +20, and 49, XY, +2, +8, +9, and the others had complicated chromosome changes, which includes much more numerical and structural chromosome aberrations. Frequent structural changes in the complicated types involved chromosome 7, 3, 1, 5 and 12 etc. The del 7q was noted in eight cases. The del (3p) and del (1p) were noted in six and five cases, respectively. The results provide some important clues for isolation of the genes related to gastric cancer.

  1. Developing a learning culture: twelve tips for individuals, teams and organizations. (United States)

    Stinson, Lynn; Pearson, David; Lucas, Beverley


    A culture of learning in providing health services and education for health professionals is a constant challenge for individuals, team and organizations. The importance of such a culture was highlighted by the findings of the Bristol Royal Infirmary Inquiry (2001). This was discussed in the context of the literature on the Learning Organization (Senge, 1990) at the 2004 Association of Medical Education in Europe (AMEE) conference, and reviewed a year later at the 2005 AMEE conference. This paper outlines twelve tips for educational and health service organizations in facilitating a culture of learning for their members and also offers specific advice to individual students and professionals.

  2. Three kinds of mutation

    CERN Document Server

    Buan, Aslak Bakke; Thomas, Hugh


    For a finite dimensional hereditary algebra, we consider: exceptional sequences in the category of finite dimensional modules, silting objects in the bounded derived category, and m-cluster tilting objects in the m-cluster category. There are mutation operations on both the set of m-cluster tilting objects and the set of exceptional sequences. It is also possible to define a mutation operation for silting objects. We compare these three different notions of mutation.

  3. Work environment perceptions following relocation to open-plan offices: A twelve-month longitudinal study. (United States)

    Bergström, Jessica; Miller, Michael; Horneij, Eva


    A workplace's design can have various positive or negative effects on the employees and since the 1970s the advantages and disadvantages of open-plan offices have been discussed. The aim of this study was to investigate perceived health, work environment and self-estimated productivity one month before and at three, six and twelve months after relocation from individual offices to an open-plan office environment. Employees from three departments within the same company group and who worked with relatively similar tasks and who were planned to be relocated from private offices to open-plan offices were invited to participate. Questionnaires comprising items from The Salutogenic Health Indicator Scale, The Work Experience Measurement Scale, the questionnaire by Brennan et al. about perceived performance and one question from the Work Ability Index were sent to participants one month before relocation (baseline) to open-plan offices and then at three, six and twelve months after relocation. At baseline, 82 questionnaires were sent out. The response rate was 85%. At the follow-ups 77-79 questionnaires were sent out and the response-rate was 70%-81%. At follow-ups, perceived health, job satisfaction and performance had generally deteriorated. The results of the study indicate that employees' perception of health, work environment and performance decreased during a 12 month period following relocation from individual offices to open-plan offices.

  4. Approximate analytic method for high-apogee twelve-hour orbits of artificial Earth's satellites (United States)

    Vashkovyaka, M. A.; Zaslavskii, G. S.


    We propose an approach to the study of the evolution of high-apogee twelve-hour orbits of artificial Earth's satellites. We describe parameters of the motion model used for the artificial Earth's satellite such that the principal gravitational perturbations of the Moon and Sun, nonsphericity of the Earth, and perturbations from the light pressure force are approximately taken into account. To solve the system of averaged equations describing the evolution of the orbit parameters of an artificial satellite, we use both numeric and analytic methods. To select initial parameters of the twelve-hour orbit, we assume that the path of the satellite along the surface of the Earth is stable. Results obtained by the analytic method and by the numerical integration of the evolving system are compared. For intervals of several years, we obtain estimates of oscillation periods and amplitudes for orbital elements. To verify the results and estimate the precision of the method, we use the numerical integration of rigorous (not averaged) equations of motion of the artificial satellite: they take into account forces acting on the satellite substantially more completely and precisely. The described method can be applied not only to the investigation of orbit evolutions of artificial satellites of the Earth; it can be applied to the investigation of the orbit evolution for other planets of the Solar system provided that the corresponding research problem will arise in the future and the considered special class of resonance orbits of satellites will be used for that purpose.

  5. Global surface temperature change analysis based on MODIS data in recent twelve years (United States)

    Mao, K. B.; Ma, Y.; Tan, X. L.; Shen, X. Y.; Liu, G.; Li, Z. L.; Chen, J. M.; Xia, L.


    Global surface temperature change is one of the most important aspects in global climate change research. In this study, in order to overcome shortcomings of traditional observation methods in meteorology, a new method is proposed to calculate global mean surface temperature based on remote sensing data. We found that (1) the global mean surface temperature was close to 14.35 °C from 2001 to 2012, and the warmest and coldest surface temperatures of the global in the recent twelve years occurred in 2005 and 2008, respectively; (2) the warmest and coldest surface temperatures on the global land surface occurred in 2005 and 2001, respectively, and on the global ocean surface in 2010 and 2008, respectively; and (3) in recent twelve years, although most regions (especially the Southern Hemisphere) are warming, global warming is yet controversial because it is cooling in the central and eastern regions of Pacific Ocean, northern regions of the Atlantic Ocean, northern regions of China, Mongolia, southern regions of Russia, western regions of Canada and America, the eastern and northern regions of Australia, and the southern tip of Africa. The analysis of daily and seasonal temperature change indicates that the temperature change is mainly caused by the variation of orbit of celestial body. A big data model based on orbit position and gravitational-magmatic change of celestial body with the solar or the galactic system should be built and taken into account for climate and ecosystems change at a large spatial-temporal scale.

  6. Mutation scanning of peach floral genes

    Directory of Open Access Journals (Sweden)

    Wilde H Dayton


    Full Text Available Abstract Background Mutation scanning technology has been used to develop crop species with improved traits. Modifications that improve screening throughput and sensitivity would facilitate the targeted mutation breeding of crops. Technical innovations for high-resolution melting (HRM analysis are enabling the clinic-based screening for human disease gene polymorphism. We examined the application of two HRM modifications, COLD-PCR and QMC-PCR, to the mutation scanning of genes in peach, Prunus persica. The targeted genes were the putative floral regulators PpAGAMOUS and PpTERMINAL FLOWER I. Results HRM analysis of PpAG and PpTFL1 coding regions in 36 peach cultivars found one polymorphic site in each gene. PpTFL1 and PpAG SNPs were used to examine approaches to increase HRM throughput. Cultivars with SNPs could be reliably detected in pools of twelve genotypes. COLD-PCR was found to increase the sensitivity of HRM analysis of pooled samples, but worked best with small amplicons. Examination of QMC-PCR demonstrated that primary PCR products for further analysis could be produced from variable levels of genomic DNA. Conclusions Natural SNPs in exons of target peach genes were discovered by HRM analysis of cultivars from a southeastern US breeding program. For detecting natural or induced SNPs in larger populations, HRM efficiency can be improved by increasing sample pooling and template production through approaches such as COLD-PCR and QMC-PCR. Technical advances developed to improve clinical diagnostics can play a role in the targeted mutation breeding of crops.

  7. Comparative assay of fluorescent antibody test results among twelve European National Reference Laboratories using various anti-rabies conjugates

    DEFF Research Database (Denmark)

    Robardet, E.; Andrieu, S.; Rasmussen, Thomas Bruun


    Twelve National Reference Laboratories (NRLs) for rabies have undertaken a comparative assay to assess the comparison of fluorescent antibody test (FAT) results using five coded commercial anti-rabies conjugates (Biorad, Bioveta, Fujirebio, Millipore, and SIFIN conjugates). Homogenized positive...

  8. Gestational mutations in radiation carcinogenesis (United States)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  9. Lacie Skwarim 移动硬盘

    Institute of Scientific and Technical Information of China (English)


    也许因为生就便是为了携带数据,所以移动硬盘大多在外观上略偏严肃,带点神秘色彩。而Lacie本次推出的Skwarim移动硬盘就另辟蹊径,它由世界知名设计师Karim Rashid亲自操刀设计。

  10. Mutation and premating isolation. (United States)

    Woodruff, R C; Thompson, J N


    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  11. Exploring Content Schemata Influence on L2 Reading: The Hunted Fox and Twelve and Not Stupid

    Directory of Open Access Journals (Sweden)

    Amizura Hanadi Mohd Radzi


    Full Text Available This paper will discuss the aspects of content schemata in second language reading among diploma level students who were taking a reading course in Universiti Teknologi MARA Perlis. In this qualitative case study, the researcher had selected two short stories that are categorized as content-familiar texts, i.e. The Hunted Fox and Twelve and Not Stupid. Six participants were asked to write a 150-word entry response on the short story and a grading criteria was used to assess the participants’ level of comprehension. An in-depth interview was also conducted on each participant. The entry responses and the interview patterns were analyzed to determine whether content schemata had contributed to the learners’ understanding of the text. This study discovered that content schemata had contributed to the learners’ understanding of the text because the learners’ comprehension was facilitated by their background knowledge on the content-familiar texts.

  12. Development and characterization of twelve microsatellite markers for Porphyra linearis Greville. (United States)

    Varela-Álvarez, Elena; Paulino, Cristina; Serrão, Ester A


    The genus Porphyra (and its sister genus Pyropia) contains important red algal species that are cultivated and/or harvested for human consumption, sustaining a billion-dollar aquaculture industry. A vast amount of research has been focused on species of this genus, including studies on genetics and genomics among other areas. Twelve novel microsatellite markers were developed here for Porphyra linearis. Markers were characterized using 32 individuals collected from four natural populations of P. linearis with total heterozygosity varying from 0.098 to 0.916. The number of alleles per locus ranged from 2 to 18. All markers showed cross amplification with Porphyra umbilicalis and/or Porphyra dioica. These polymorphic microsatellite markers are useful for investigating population genetic diversity and differentiation in P. linearis and may become useful for other genetic research on the reproductive biology of this important species.

  13. Proteomic characterization of human milk whey proteins during a twelve-month lactation period. (United States)

    Liao, Yalin; Alvarado, Rudy; Phinney, Brett; Lönnerdal, Bo


    Human milk is a rich source of bioactive proteins that support the early growth and development of the newborn. Although the major components of the protein fraction in human milk have been studied, the expression and relative abundance of minor components have received limited attention. We examined the expression of low-abundance proteins in the whey fraction of human milk and their dynamic changes over a twelve-month lactation period. The low-abundance proteins were enriched by ProteoMiner beads, and protein identification was performed by liquid chromatography tandem mass spectrometry. One hundred and fifteen proteins were identified, thirty-eight of which have not been previously reported in human colostrum or milk. We also for the first time described differences in protein patterns among the low-abundance proteins during lactation. These results enhance our knowledge about the complexity of the human milk proteome, which constitutes part of the advantages to the breast-fed infant.

  14. Fate of the conformal fixed point with twelve massless fermions and SU(3) gauge group

    CERN Document Server

    Fodor, Zoltan; Kuti, Julius; Mondal, Santanu; Nogradi, Daniel; Wong, Chik Him


    We report new results on the conformal properties of an important strongly coupled gauge theory, a building block of composite Higgs models beyond the Standard Model. With twelve massless fermions in the fundamental representation of the SU(3) color gauge group, an infrared fixed point of the $\\beta$-function was recently reported in the theory (Cheng:2014jba) with uncertainty in the location of the critical gauge coupling inside the narrow $[ 6.0

  15. Twelve Years of Education and Public Outreach with the Fermi Gamma-ray Space Telescope

    CERN Document Server

    Cominsky, Lynn; Simonnet, Aurore; Education, the Fermi


    During the past twelve years, NASA's Fermi Gamma-ray Space Telescope has supported a wide range of Education and Public Outreach (E/PO) activities, targeting K-14 students and the general public. The purpose of the Fermi E/PO program is to increase student and public understanding of the science of the high-energy Universe, through inspiring, engaging and educational activities linked to the mission's science objectives. The E/PO program has additional more general goals, including increasing the diversity of students in the Science, Technology, Engineering and Mathematics (STEM) pipeline, and increasing public awareness and understanding of Fermi science and technology. Fermi's multi-faceted E/PO program includes elements in each major outcome category: Higher Education; Elementary and Secondary Education; Informal Education and Public Outreach.

  16. Twelve tips for developing and delivering a massive open online course in medical education. (United States)

    Pickering, James D; Henningsohn, Lars; DeRuiter, Marco C; de Jong, Peter G M; Reinders, Marlies E J


    Massive open online courses (MOOCs) are a novel mode of online learning. They are typically based on higher education courses and can attract a high number of learners, often in the thousands. They are distinct from on-campus education and deliver the learning objectives through a series of short videos, recommended readings and discussion fora, alongside automated assessments. Within medical education the role of MOOCs remains unclear, with recent proposals including continuing professional development, interprofessional education or integration into campus-based blended learning curricula. In this twelve tips article, we aim to provide a framework for readers to use when developing, delivering and evaluating a MOOC within medical education based on the literature and our own experience. Practical advice is provided on how to design the appropriate curriculum, engage with learners on the platform, select suitable assessments, and comprehensively evaluate the impact of your course.

  17. Hepatoprotective activity of twelve novel 7'-hydroxy lignan glucosides from Arctii Fructus. (United States)

    Yang, Ya-Nan; Huang, Xiao-Ying; Feng, Zi-Ming; Jiang, Jian-Shuang; Zhang, Pei-Cheng


    Twelve novel 7'-hydroxy lignan glucosides (1-12), including two benzofuran-type neolignans, two 8-O-4' neolignans, two dibenzylbutyrolactone lignans, and six tetrahydrofuranoid lignans, together with six known lignan glucosides (13-18), were isolated from the fruit of Arctium lappa L. (Asteraceae), commonly known as Arctii Fructus. Their structures were elucidated using spectroscopy (1D and 2D NMR, MS, IR, ORD, and UV) and on the basis of chemical evidence. The absolute configurations of compounds 1-12 were confirmed using rotating frame nuclear overhauser effect spectroscopy (ROESY), the circular dichroic (CD) exciton chirality method, and Rh2(OCOCF3)4-induced CD spectrum analysis. All of the isolated compounds were tested for hepatoprotective effects against D-galactosamine-induced cytotoxicity in HL-7702 hepatic cells. Compounds 1, 2, 7-12, and 17 showed significantly stronger hepatoprotective activity than the positive control bicyclol at a concentration of 1 × 10(-5) M.

  18. Twelve Tips for teaching medical professionalism at all levels of medical education. (United States)

    Al-Eraky, Mohamed Mostafa


    Review of studies published in medical education journals over the last decade reveals that teaching medical professionalism is essential, yet challenging. According to a recent Best Evidence in Medical Education (BEME) guide, there is no consensus on a theoretical or practical model to integrate the teaching of professionalism into medical education. The aim of this article is to outline a practical manual for teaching professionalism at all levels of medical education. Drawing from research literature and author's experience, Twelve Tips are listed and organised in four clusters with relevance to (1) the context, (2) the teachers, (3) the curriculum, and (4) the networking. With a better understanding of the guiding educational principles for teaching medical professionalism, medical educators will be able to teach one of the most challenging constructs in medical education.

  19. Parkinson disease: α-synuclein mutational screening and new clinical insight into the p.E46K mutation. (United States)

    Pimentel, Márcia M G; Rodrigues, Fabíola C; Leite, Marco Antônio A; Campos Júnior, Mário; Rosso, Ana Lucia; Nicaretta, Denise H; Pereira, João S; Silva, Delson José; Della Coletta, Marcus V; Vasconcellos, Luiz Felipe R; Abreu, Gabriella M; Dos Santos, Jussara M; Santos-Rebouças, Cíntia B


    Amongst Parkinson's disease-causing genetic factors, missense mutations and genomic multiplications in the gene encoding α-synuclein are well established causes of the disease, although genetic data in populations with a high degree of admixture, such as the Brazilian one, are still scarce. In this study, we conducted a molecular screening of α-synuclein point mutations and copy number variation in the largest cohort of Brazilian patients with Parkinson's disease (n = 549) and also in twelve Portuguese and one Bolivian immigrants. Genomic DNA was isolated from peripheral blood leukocytes or saliva, and the mutational screening was performed by quantitative and qualitative real-time PCR. The only alteration identified was the p.E46K mutation in a 60-year-old man, born in Bolivia, with a familial history of autosomal dominant Parkinson's disease. This is the second family ever reported, in which this rare pathogenic mutation is segregating. The same mutation was firstly described ten years ago in a Spanish family with a neurodegenerative syndrome combining parkinsonism, dementia and visual hallucinations. The clinical condition of our proband reveals a less aggressive phenotype than previously described and reinforces that marked phenotypic heterogeneity is common among patients with Parkinson's disease, even among those carriers sharing the same mutation. Our findings add new insight into the preexisting information about α-synuclein p.E46K, improving our understanding about the endophenotypes associated to this mutation and corroborate that missense alterations and multiplications in α-synuclein are uncommon among Brazilian patients with Parkinson's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Comparative analysis and supragenome modeling of twelve Moraxella catarrhalis clinical isolates

    Directory of Open Access Journals (Sweden)

    Hermans Peter WM


    Full Text Available Abstract Background M. catarrhalis is a gram-negative, gamma-proteobacterium and an opportunistic human pathogen associated with otitis media (OM and exacerbations of chronic obstructive pulmonary disease (COPD. With direct and indirect costs for treating these conditions annually exceeding $33 billion in the United States alone, and nearly ubiquitous resistance to beta-lactam antibiotics among M. catarrhalis clinical isolates, a greater understanding of this pathogen's genome and its variability among isolates is needed. Results The genomic sequences of ten geographically and phenotypically diverse clinical isolates of M. catarrhalis were determined and analyzed together with two publicly available genomes. These twelve genomes were subjected to detailed comparative and predictive analyses aimed at characterizing the supragenome and understanding the metabolic and pathogenic potential of this species. A total of 2383 gene clusters were identified, of which 1755 are core with the remaining 628 clusters unevenly distributed among the twelve isolates. These findings are consistent with the distributed genome hypothesis (DGH, which posits that the species genome possesses a far greater number of genes than any single isolate. Multiple and pair-wise whole genome alignments highlight limited chromosomal re-arrangement. Conclusions M. catarrhalis gene content and chromosomal organization data, although supportive of the DGH, show modest overall genic diversity. These findings are in stark contrast with the reported heterogeneity of the species as a whole, as wells as to other bacterial pathogens mediating OM and COPD, providing important insight into M. catarrhalis pathogenesis that will aid in the development of novel therapeutic regimens.

  1. Mutation rates among RNA viruses


    Drake, John W.; Holland, John J.


    The rate of spontaneous mutation is a key parameter in modeling the genetic structure and evolution of populations. The impact of the accumulated load of mutations and the consequences of increasing the mutation rate are important in assessing the genetic health of populations. Mutation frequencies are among the more directly measurable population parameters, although the information needed to convert them into mutation rates is often lacking. A previous analysis of mutation rates in RNA viru...

  2. Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency. (United States)

    Péquignot, M O; Dey, R; Zeviani, M; Tiranti, V; Godinot, C; Poyau, A; Sue, C; Di Mauro, S; Abitbol, M; Marsac, C


    Cytochrome c oxidase (COX) deficiency is one of the major causes of Leigh Syndrome (LS), a fatal encephalopathy of infancy or childhood, characterized by symmetrical lesions in the basal ganglia and brainstem. Mutations in the nuclear genes encoding COX subunits have not been found in patients with LS and COX deficiency, but mutations have been identified in SURF1. SURF1 encodes a factor involved in COX biogenesis. To date, 30 different mutations have been reported in 40 unrelated patients. We aim to provide an overview of all known mutations in SURF1, and to propose a common nomenclature. Twelve of the mutations were insertion/deletion mutations in exons 1, 4, 6, 8, and 9; 10 were missense/nonsense mutations in exons 2, 4, 5, 7, and 8; and eight were detected at splicing sites in introns 3 to 7. The most frequent mutation was 312_321del 311_312insAT which was found in 12 patients out of 40. Twenty mutations have been described only once. We also list all polymorphisms discovered to date.

  3. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations (United States)

    Johnston, Jennifer J.; Sapp, Julie C.; Turner, Joyce T.; Amor, David; Aftimos, Salim; Aleck, Kyrieckos A.; Bocian, Maureen; Bodurtha, Joann N.; Cox, Gerald F.; Curry, Cynthia J.; Day, Ruth; Donnai, Dian; Field, Michael; Fujiwara, Ikuma; Gabbett, Michael; Gal, Moran; Graham, John M.; Hedera, Peter; Hennekam, Raoul C.M.; Hersh, Joseph H.; Hopkin, Robert J.; Kayserili, Hülya; Kidd, Alexa M.J.; Kimonis, Virginia; Lin, Angela E.; Lynch, Sally Ann; Maisenbacher, Melissa; Mansour, Sahar; McGaughran, Julie; Mehta, Lakshmi; Murphy, Helen; Raygada, Margarita; Robin, Nathaniel H.; Rope, Alan F.; Rosenbaum, Kenneth N.; Schaefer, G. Bradley; Shealy, Amy; Smith, Wendy; Soller, Maria; Sommer, Annmarie; Stalker, Heather J.; Steiner, Bernhard; Stephan, Mark J.; Tilstra, David; Tomkins, Susan; Trapane, Pamela; Tsai, Anne Chun-Hui; Van Allen, Margot I.; Vasudevan, Pradeep C.; Zabel, Bernhard; Zunich, Janice; Black, Graeme C.M.; Biesecker, Leslie G.


    A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining ninety-three probands here. This includes nineteen probands (twelve mutations) who fulfilled clinical criteria for GCPS or PHS, forty-eight probands (sixteen mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), twenty-one probands (six mutations) with features of PHS or GCPS and oral-facial-digital syndrome and five probands (one mutation) with non-syndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the phenotype-genotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria. PMID:20672375

  4. Mutations in GABRB3

    DEFF Research Database (Denmark)

    Møller, Rikke S; Wuttke, Thomas V; Helbig, Ingo


    OBJECTIVE: To examine the role of mutations in GABRB3 encoding the β3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing...... of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. RESULTS: We identified 22 patients with heterozygous mutations in GABRB3, including 3...... probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies...

  5. AIP mutations and gigantism. (United States)

    Rostomyan, Liliya; Potorac, Iulia; Beckers, Pablo; Daly, Adrian F; Beckers, Albert


    AIP mutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIP mutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIP gene). These data support targeted genetic screening for AIP mutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Mapping Mutations on Phylogenies

    DEFF Research Database (Denmark)

    Nielsen, Rasmus


    This chapter provides a short review of recent methodologies developed for mapping mutations on phylogenies. Mapping of mutations, or character changes in general, using the maximum parsimony principle has been one of the most powerful tools in phylogenetics, and it has been used in a variety...... of different applications, for example, in the detection of correlated evolution and to identify selection acting on DNA sequences. However, many uses of parsimony mappings have been criticized because they focus on only one of many possible mappings and/or because they do not incorporate statistical...... uncertainty in the mapping. Recently developed probabilistic methods can incorporate statistical uncertainty in the character mappings. In these methods, focus is on a probability distribution of mutational mappings instead of a single estimate of the mutational mapping....

  7. PRRT2 gene mutations (United States)

    Gardiner, Alice R.; Bhatia, Kailash P.; Stamelou, Maria; Dale, Russell C.; Kurian, Manju A.; Schneider, Susanne A.; Wali, G.M.; Counihan, Tim; Schapira, Anthony H.; Spacey, Sian D.; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Hélio A.G.; Raskin, Salmo; Sander, Josemir W.; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M.; Wood, Nicholas W.; Hanna, Michael


    ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders. PMID:23077024

  8. Twelve-year cyclic surging episode at Donjek Glacier in Yukon, Canada (United States)

    Furuya, M.; Abe, T.; Sakakibara, D.


    Surge-type glaciers exhibit several-fold to orders-of-magnitude speed-up during the short active phase, resulting in km-scale terminus advance. Although there are many surge-type glaciers near the border of Alaska and the Yukon, the generation mechanisms remain uncertain because of limited and few continuous observations. To better understand the surge dynamics and predict the next event, it is essential to examine the entire surge cycles. Here we use Landsat optical imageries to reveal the long-term evolutions, and report three surging episodes at Donjek Glacier in Yukon, Canada. Using the Landsat images, we found three surging events in 1989, 2001, and 2013. In the 2001 event, the surface speed significantly increased by up to 4.5 m/d; during the quiescent phases it was ~0.5 m/d at the terminus. While the duration of active phase is about 4~5 and 2~3 year in the 2001 and 2013 events, the period in the 1989 event is unclear because of the lack of high temporal resolution data. Remarkably, the surging area is limited to the ~20-km section from the terminus instead of the entire glacier. Moreover, we examined the terminus area changes from 1975 to 2014. Although the area has been secularly decreasing probably due to the tread of global warming, it has also revealed four significant fluctuations during the nearly forty years. Comparing the speed and the area changes, the three speed-up events correspond to the terminus area fluctuations with a few time lags. It turns out that the surge event has been quite regularly repeating every twelve years. Although the behavior is rather similar to that in Svalbard glaciers in terms of maximum speed and unclear initiation season, the recurrence interval is much shorter than other nearby surges. Considering that the surge events seem to have initiated around significantly narrower area than upstream, the strong valley constriction may control the regularity as well as the twelve-year recurrence time.

  9. Changes in mutational status during third-line treatment for metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise Garm; Pallisgaard, Niels; Andersen, Rikke Fredslund


    KRAS and BRAF mutations are responsible for primary resistance to epidermal growth factor receptor (EGFR) MoAbs in metastatic colorectal cancer (mCRC), but it is unknown what causes wildtype (wt) patients to develop resistance during treatment. We measured circulating free DNA (cfDNA), KRAS...... and BRAF in plasma and report the changes during third line treatment with cetuximab and irinotecan. One-hundred-and-eight patients received irinotecan 350 mg/m2 q3w and weekly cetuximab (250 mg/m2) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated KRAS/BRAF alleles in plasma...... different types of mutations detected in the plasma, including synchronous KRAS and BRAF. Twelve patients had a primary KRAS mutant tumor, but wild-type disease according to baseline plasma analysis, eight of these obtained stabilization of disease. In five patients with primary wt disease a mutation...

  10. MECP2 gene mutation analysis in Chinese patients with Rett syndrome

    Institute of Scientific and Technical Information of China (English)

    PanH; WangYP; BaoXH; MengHD; ZhangY; WuXR; ShenY


    Rett syndrome (RTT) is a progressive neurodevelopmental disorder that affects almost exclusively girls. Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) have been found to be a cause. In order to study the spectrum of MECP2 mutations in Chinese patients, we employed PCR and sequencing of the coding region of MECP2 gene in 31 Chinese cases of classical sporadic RTT. Mutations in MECP2 were found in about 55%. Twelve different mutations in exon 3 were identified in 17 of these 31 patients; two of these are novel. A novel missense variant was detected in the C-terminal region in a patient and her father who was normal. In addition, there was a single nucleotide variant in the 3'UTR.

  11. Subquivers of mutation-acyclic quivers are mutation-acyclic

    CERN Document Server

    Warkentin, Matthias


    Quiver mutation plays a crucial role in the definition of cluster algebras by Fomin and Zelevinsky. It induces an equivalence relation on the set of all quivers without loops and two-cycles. A quiver is called mutation-acyclic if it is mutation-equivalent to an acyclic quiver. The aim of this note is to show that full subquivers of mutation-acyclic quivers are mutation-acyclic.

  12. Margalef revisited: A new phytoplankton mandala incorporating twelve dimensions, including nutritional physiology. (United States)

    Glibert, Patricia M


    Building on the classic depiction of the progression from a diatom to a dinoflagellate bloom as a function of nutrients and turbulence, known as the "Margalef mandala", a new conceptual model or mandala is presented here. The new mandala maps twelve response or effects traits, or environmental characteristics, related to different phytoplankton functional types: (1) relative preference for chemically reduced vs chemically oxidized forms of nitrogen; (2) relative availability of inorganic nitrogen and phosphorus; (3) adaptation to high vs low light and the tendency to be autotrophic vs mixotrophic; (4) cell motility; (5) environmental turbulence; (6) pigmentation quality; (7) temperature; (8) cell size; (9) relative growth rate; (10) relative production of bioactive compounds such as toxins or reactive oxygen species (ROS); (11) r vs K strategy; and (12) fate of the production in terms of grazing. The new mandala serves to highlight the differences and trade-offs between traits and/or environmental conditions, and illustrates some traits tend to track each other, a concept that may be helpful in trait-based modeling approaches and in understanding environmental factors associated with harmful algal blooms. It is hoped that this new mandala captures some of our recent insight into phytoplankton physiology and functional traits, and has contemporary relevance in light of anthropogenic changes in nutrient form and ratio. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Margalef revisited: A new phytoplankton mandala incorporating twelve dimensions, including nutrient ratios and forms (United States)

    Glibert, P. M.


    Building on the classic depiction of the progression from a diatom to a dinoflagellate bloom as a function of nutrients and turbulence, known as the "Margalef mandala", a new conceptual model or mandala is presented here. The new mandala maps twelve traits or environmental characteristics related to different phytoplankton functional types: (1) relative preference for chemically reduced vs chemically oxidized forms of nitrogen; (2) relative availability of inorganic nitrogen and phosphorus; (3) adaptation to high vs low light and the tendency to be autotrophic vs mixotrophic; (4) cell motility; (5) environmental turbulence; (6) pigmentation quality; (7) temperature; (8) cell size; (9) relative growth rate; (10) relative production of bioactive compounds such as toxins or reactive oxygen species (ROS); (11) r vs K strategy; and (12) fate of the production in terms of grazing. The new mandala serves to highlight the differences and trade-offs between traits and/or environmental conditions, and illustrates some traits tend to track each other, a concept that may be helpful in trait-based modeling approaches. It is hoped that this new mandala captures some of our recent insight into phytoplankton physiology and functional traits, and has contemporary relevance in light of anthropogenic changes in nutrient form and ratio.

  14. Evolution and potential function of fibrinogen-like domains across twelve Drosophila species

    Directory of Open Access Journals (Sweden)

    Middha Sumit


    Full Text Available Abstract Background The fibrinogen-like (FBG domain consists of approximately 200 amino acid residues, which has high sequence similarity to the C-terminal halves of fibrinogen β and γ chains. Fibrinogen-related proteins (FREPs containing one or more FBG domains are found universally in vertebrates and invertebrates. In invertebrates, FREPs are involved in immune responses and other aspects of physiology. To understand the complexity of this gene family in Drosophila, we analyzed FREPs in twelve Drosophila species. Results Using the genome data from 12 Drosophila species, we identified FBG domains in each species. The results show that the gene numbers in each species vary from 14 genes up to 43 genes. Using sequence profile analysis, we found that FBG domains have high sequence similarity and are highly conserved throughout. By comparison of structure and sequence conservation, some of the FBG domains in Drosophila melanogaster are predicted to function in recognition of carbohydrates and their derivatives on the surface of microorganisms in innate immunity. Conclusion Sequence and structural analyses show that FREP family across 12 Drosophila species contains conserved FBG domains. Expansion of the FREP families in Drosophila is mainly accounted by a major expansion of FBG domains.

  15. Twelve-Year Trends of PM10 and Visibility in the Hefei Metropolitan Area of China

    Directory of Open Access Journals (Sweden)

    Lin Huang


    Full Text Available China has been experiencing severe air pollution and previous studies have mostly focused on megacities and a few hot spot regions. Hefei, the provincial capital city of Anhui province, has a population of near 5 million in its metropolitan area, but its air quality has not been reported in literature. In this study, daily PM10 and visibility data in 2001–2012 were analyzed to investigate the air quality status as well as the twelve-year pollution trends in Hefei. The results reveal that Hefei has been suffering high PM10 pollution and low visibility during the study period. The annual average PM10 concentrations are 2~3 times of the Chinese Ambient Air Quality Standard. PM10 shows fluctuating variation in 2001–2007 and has a slightly decreasing trend after 2008. The annual average visibility range is generally lower than 7 km and shows a worsening trend from 2001 to 2006 followed by an improving trend from 2007 to 2012. Wind speed, precipitation, and relative humidity have negative effects on PM10 concentrations in Hefei, while temperature could positively or negatively affect PM10. The results provide a general understanding of the status and long-term trends of PM10 pollution and visibility in a typical second-tier city in China.

  16. Validation of Twelve Small Kepler Transiting Planets in the Habitable Zone

    CERN Document Server

    Torres, Guillermo; Fressin, Francois; Caldwell, Douglas A; Twicken, Joseph D; Ballard, Sarah; Batalha, Natalie M; Bryson, Stephen T; Ciardi, David R; Henze, Christopher E; Howell, Steve B; Isaacson, Howard T; Jenkins, Jon M; Muirhead, Philip S; Newton, Elisabeth R; Petigura, Erik A; Barclay, Thomas; Borucki, William J; Crepp, Justin R; Everett, Mark E; Horch, Elliott P; Howard, Andrew W; Kolbl, Rea; Marcy, Geoffrey W; McCauliff, Sean; Quintana, Elisa V


    We present an investigation of twelve candidate transiting planets from Kepler with orbital periods ranging from 34 to 207 days, selected from initial indications that they are small and potentially in the habitable zone (HZ) of their parent stars. The expected Doppler signals are too small to confirm them by demonstrating that their masses are in the planetary regime. Here we verify their planetary nature by validating them statistically using the BLENDER technique, which simulates large numbers of false positives and compares the resulting light curves with the Kepler photometry. This analysis was supplemented with new follow-up observations (high-resolution optical and near-infrared spectroscopy, adaptive optics imaging, and speckle interferometry), as well as an analysis of the flux centroids. For eleven of them (KOI-0571.05, 1422.04, 1422.05, 2529.02, 3255.01, 3284.01, 4005.01, 4087.01, 4622.01, 4742.01, and 4745.01) we show that the likelihood they are true planets is far greater than that of a false po...

  17. Measurement and analysis of angular velocity variations of twelve-cylinder diesel engine crankshaft (United States)

    Bulatović, Ž. M.; Štavljanin, M. S.; Tomić, M. V.; Knežević, D. M.; Biočanin, S. Lj.


    This paper presents the procedures for measuring and analyzing the angular velocity variation of twelve-cylinder diesel engine crankshaft on its free end and on the power-output end. In addition, the paper deals with important aspects of the measurement of crankshaft torsional oscillations. The method is based on digital encoders placed at two distances, and one of them is a sensor not inserted directly on the shaft, i.e. a non-contact method with a toothed disc is used. The principle based on toothed disc is also used to measure the actual camshaft angular velocity of in-line compact high-pressure pump the engine is equipped with, and this paper aims to demonstrate the possibility of measuring the actual angular velocity of any rotating shaft in the engine, on which it is physically possible to mount a toothed disc. The method was created completely independently during long-range development and research tests of V46 family engines. This method is specific for its particular adaptability for use on larger engines with extensive vibrations and torsional oscillations. The main purpose of this paper is a practical contribution to all the more interesting research of the use of engine crankshaft angular velocity as a diagnostic tool for identifying the engine irregular running.

  18. Access to oral health services in children under twelve years of age in Peru, 2014

    Directory of Open Access Journals (Sweden)

    Akram Hernández-Vásquez


    Full Text Available The aim of the study was to explore the patterns of dental health services access in children under twelve years of age in Peru. Data from 25,285 children under 12 years who participated in the Demographic and Family Health Survey of 2014 were reviewed. An exploratory spatial analysis was performed to project the proportions of children with access to dental health services, according to national regions, type of health service and urban or rural place of residence. The results show that of the total sample, 26.7% had access to dental health services in the last six months, 39.6% belonged to the age group 0-4 years, 40.6% lived in the Andean region and 58.3% lived in urban areas. The regions of Huancavelica, Apurimac, Ayacucho, Lima and Pasco had the highest percentages of access nationwide. In conclusion, there is low access to dental health services in the population under 12 years of age in Peru. The spatial distribution of access to dental health services allows regions to be identified and grouped according to similar access patterns, in order to better focus public health actions.

  19. Synergy between Seeking Safety and Twelve-Step Affiliation on Substance Use Outcomes for Women (United States)

    Morgan-Lopez, Antonio A.; Saavedra, Lissette M.; Hien, Denise A.; Campbell, Aimee N.; Wu, Elwin; Ruglass, Lesia


    Objective The Recovery Management paradigm provides a conceptual framework for the examination of joint impact of a focal treatment and post-treatment service utilization on substance abuse treatment outcomes. We test this framework by examining the interactive effects of a treatment for comorbid PTSD and substance use, Seeking Safety, and post-treatment Twelve-Step Affiliation (TSA) on alcohol and cocaine use. Method Data from 353 women in a six-site, randomized controlled effectiveness trial within the NIDA Clinical Trials Network were analyzed under latent class pattern mixture modeling. LCPMM was used to model variation in Seeking Safety by TSA interaction effects on alcohol and cocaine use. Results Significant reductions in alcohol use among women in Seeking Safety (compared to Health Education) were observed; women in the Seeking Safety condition who followed up with TSA had the greatest reductions over time in alcohol use. Reductions in cocaine use over time were also observed but did not differ between treatment conditions nor were there interactions with post-treatment TSA. Conclusions Findings advance understanding of the complexities for treatment and continuing recovery processes for women with PTSD and SUDs, and further support the chronic disease model of addiction. PMID:23558158

  20. Coréia aguda na gravidez Acute chorea in pregnancy: comments on twelve consecutive cases

    Directory of Open Access Journals (Sweden)

    Walter C. Pereira


    Full Text Available São apresentados doze casos de coréia aguda observados entre 150.000 gestantes (1/12.500. A maioria dos surtos ocorreu no segundo trimestre da primeira gravidez. A duração média dos sintomas foi de três meses, não tendo sido registrado caso algum de óbito materno. Todos os partos foram espontâneos e normais. Houve apenas um óbito fetal conseqüente a choque hemorrágico. São tecidas considerações a propósito dos aspectos clínico, laboratorial e prognóstico da coréia gravídica, sendo focalizado mais pormenorizadamente o problema fisiopatogênico dessa afecção.Twelve consecutive cases of acute chorea occurring among 150.000 pregnant women (1/12.500 are reported. Most of the cases occurred from the fourth do the sixth month of the first pregnancy. The average duration of the symptoms was of three months and no one case of maternal death was verified in the group. The deliveries were spontaneous and normal in all the patients. Only one case of fetal death occurred in consequence of a hemorragic shock. Comments are made on the clinical, laboratorial and prognostic features of chorea gravidarum, being particulary focused the physiopathogenic problem of this condtion.


    Energy Technology Data Exchange (ETDEWEB)

    Mazeh, Tsevi; Nachmani, Gil; Holczer, Tomer; Sokol, Gil [School of Physics and Astronomy, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978 (Israel); Fabrycky, Daniel C. [Department of Astronomy and Astrophysics, University of Chicago, 5640 Ellis Ave., Chicago, IL 60637 (United States); Ford, Eric B.; Ragozzine, Darin [Astronomy Department, University of Florida, Gainesville, FL 32111 (United States); Sanchis-Ojeda, Roberto [Department of Physics and Kavli Institute for Astrophysics and Space Research, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Rowe, Jason F.; Lissauer, Jack J. [NASA Ames Research Center, Moffett Field, CA 94035 (United States); Zucker, Shay [Department of Geophysical, Atmospheric and Planetary Sciences, Raymond and Beverly Sackler Faculty of Exact Sciences Tel Aviv University, 69978 Tel Aviv (Israel); Agol, Eric [Department of Astronomy, Box 351580, University of Washington, Seattle, WA 98195 (United States); Carter, Joshua A. [Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Quintana, Elisa V. [SETI Institute, 189 Bernardo Ave, Suite 100, Mountain View, CA 94043 (United States); Steffen, Jason H. [Fermilab Center for Particle Astrophysics, P.O. Box 500, MS 127, Batavia, IL 60510 (United States); Welsh, William [Astronomy Department, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182 (United States)


    Following the works of Ford et al. and Steffen et al. we derived the transit timing of 1960 Kepler objects of interest (KOIs) using the pre-search data conditioning light curves of the first twelve quarters of the Kepler data. For 721 KOIs with large enough signal-to-noise ratios, we obtained also the duration and depth of each transit. The results are presented as a catalog for the community to use. We derived a few statistics of our results that could be used to indicate significant variations. Including systems found by previous works, we have found 130 KOIs that showed highly significant times of transit variations (TTVs) and 13 that had short-period TTV modulations with small amplitudes. We consider two effects that could cause apparent periodic TTV—the finite sampling of the observations and the interference with the stellar activity, stellar spots in particular. We briefly discuss some statistical aspects of our detected TTVs. We show that the TTV period is correlated with the orbital period of the planet and with the TTV amplitude.

  2. Peer teaching in medical education: twelve reasons to move from theory to practice. (United States)

    Ten Cate, Olle; Durning, Steven


    To provide an estimation of how often peer teaching is applied in medical education, based on reports in the literature and to summarize reasons that support the use of this form of teaching. We surveyed the 2006 medical education literature and categorised reports of peer teaching according to educational distance between students teaching and students taught, group size, and level of formality of the teaching. Subsequently, we analysed the rationales for applying peer teaching. Most reports were published abstracts in either Medical Education's annual feature 'Really Good Stuff' or the AMEE's annual conference proceedings. We identified twelve distinct reasons to apply peer teaching, including 'alleviating faculty teaching burden', 'providing role models for junior students', 'enhancing intrinsic motivation' and 'preparing physicians for their future role as educators'. Peer teaching appears to be practiced often, but many peer teaching reports do not become full length journal articles. We conclude that specifically 'near-peer teaching' appears beneficial for student teachers and learners as well as for the organisation. The analogy of the 'journeyman', as intermediate between 'apprentice' and 'master', with both learning and teaching tasks, is a valuable but yet under-recognized source of education in the medical education continuum.

  3. Heterochromatic banding patterns on chromosomes of twelve weevil species (Insecta, Coleoptera, Curculionoidea: Apionidae, Curculionidae). (United States)

    Holecová, Milada; Rozek, Maria; Lachowska, Dorota


    The C-banding patterns of twelve weevil species are presented. The obtained results confirm the existence of two groups of species: with a small or large amount of heterochromatin in the karyotype. The first group comprises seven species (Apionidae: Holotrichapion pisi; Curculionidae: Phyllobius urticae, Ph. pyri, Ph. maculicornis, Tanymecus palliatus, Larinodontes turbinatus, Cionus tuberculosus). In weevils with a small amount of heterochromatin, tiny grains on the nucleus in interphase are visible, afterwards in mitotic and meiotic prophase appearing as dark dots. The absence of C-bands does not indicate a lack of heterochromatin but heterochromatic regions are sometimes so small that the condensation is not visible during the cell cycle. The second group comprises five species (Otiorhynchus niger, O. morio, Polydrusus corruscus, Barypeithes chevrolati, Nedyus quadrimaculatus) which possess much larger heteropicnotic parts of chromosomes visible during all nuclear divisions. The species examined have paracentromeric C-bands on autosomes and the sex chromosome X, except for Otiorhynchus niger, which also has an intercalary bands on one pair of autososomes. All the species examined differ in the size of segments of constitutive heterochromatin. The y heterochromosome is dot-like and wholly euchromatic in all the studied species.

  4. In vitro antibacterial and antifungal activities of twelve sponges collected from the Anambas Islands, Indonesia

    Directory of Open Access Journals (Sweden)

    Masteria Yunovilsa Putra


    Full Text Available Objective: To evaluate antimicrobial activities in methanolic extracts of twelve sponges collected from the Anambas Islands, Indonesia. Methods: The antibacterial activity of methanolic extracts was tested against two Grampositive bacteria, viz. Bacillus subtilis (ATCC 6633 and Staphylococcus aureus (ATCC 25923, and two Gram-negative bacteria, viz. Eschericia coli (ATCC 25922 and Vibrio anguillarum (ATCC 19264 using the disk diffusion assay. The antifungal activity was similarly tested against Candida albicans (ATCC 10231 and Aspergillus niger (ATCC 16404. The minimum inhibitory concentrations of promising sponges extracts were determined by the microdilution technique. Results: All the sponge species in this study showed antimicrobial activities against at least one of the test strains. Antibacterial activities were observed in 66.7% of the sponges extracts, while 30.0% of the extracts exhibited antifungal activities. Among them, the extracts of the sponges Stylissa massa and Axinyssa sp. were the most active against four tested bacteria and the yeast Candida albicans. The sponge Theonella swinhoei and two species of Xestospongia also displayed significant activities against two fungal pathogens Candida albicans and Aspergillus niger. Conclusions: Antimicrobial activities were demonstrated in extracts from various marine sponges collected from the Anambas Islands, Indonesia. The most promising sponges among them were Stylissa massa and Axinyssa sp. This is the first report of antimicrobial activity in extracts of marine sponges from the Indonesian Anambas Islands.

  5. The SLUGGS Survey: Kinematics for over 2500 Globular Clusters in Twelve Early-type Galaxies

    CERN Document Server

    Pota, Vincenzo; Romanowsky, Aaron J; Brodie, Jean P; Spitler, Lee R; Strader, Jay; Foster, Caroline; Arnold, Jacob A; Benson, Andrew; Blom, Christina; Hargis, Jonathan R; Rhode, Katherine L; Usher, Christopher


    We present a spectro-photometric survey of 2522 extragalactic globular clusters (GCs) around twelve early-type galaxies, nine of which have not been published previously. Combining space-based and multi-colour wide field ground-based imaging, with spectra from the Keck DEIMOS instrument, we obtain an average of 160 GC radial velocities per galaxy, with a high velocity precision of 15 km/s per GC. After studying the photometric properties of the GC systems, such as their spatial and colour distributions, we focus on the kinematics of metal-poor (blue) and metal-rich (red) GC subpopulations to an average distance of ~8 effective radii from the galaxy centre. Our results show that for some systems the bimodality in GC colour is also present in GC kinematics. The kinematics of the red GC subpopulations are strongly coupled with the host galaxy stellar kinematics. The blue GC subpopulations are more dominated by random motions, especially in the outer regions, and decoupled from the red GCs. Peculiar GC kinematic ...

  6. Whole-Proteome Analysis of Twelve Species of Alphaproteobacteria Links Four Pathogens

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    Yunyun Zhou


    Full Text Available Thousands of whole-genome and whole-proteome sequences have been made available through advances in sequencing technology, and sequences of millions more organisms will become available in the coming years. This wealth of genetic information will provide numerous opportunities to enhance our understanding of these organisms including a greater understanding of relationships among species. Researchers have used 16S rRNA and other gene sequences to study the evolutionary origins of bacteria, but these strategies do not provide insight into the sharing of genes among bacteria via horizontal transfer. In this work we use an open source software program called pClust to cluster proteins from the complete proteomes of twelve species of Alphaproteobacteria and generate a dendrogram from the resulting orthologous protein clusters. We compare the results with dendrograms constructed using the 16S rRNA gene and multiple sequence alignment of seven housekeeping genes. Analysis of the whole proteomes of these pathogens grouped Rickettsia typhi with three other animal pathogens whereas conventional sequence analysis failed to group these pathogens together. We conclude that whole-proteome analysis can give insight into relationships among species beyond their phylogeny, perhaps reflecting the effects of horizontal gene transfer and potentially providing insight into the functions of shared genes by means of shared phenotypes.


    Directory of Open Access Journals (Sweden)

    Adebowale Odeyemi


    Full Text Available The incidence and survival of lipolytic organisms in domestic wastewater and receiving stream were monitored over 12 months. The average total bacterial count in the wastewater samples reduced in April and November by 24.2% and 41.6% respectively. There was also a reduction of 42.3% and 60.1% in the load in the receiving stream in August and July. Subsequently, at 5m downstream from the entry of the wastewater the microbial load reduced in March (19.2% and June (19.2%. However, the occurrence of coliforms was more affected in the months of May (53% to July (87.2%. At 5m and 10m downstream the coliform population reduced by 27.9% and 30.1% respectively. Of the twelve (12 bacterial isolates obtained at the exit of the wastewater into the receiving stream, only four (4 were found to possess lipolytic activity. These include the species of Enterococcus, Klebsiella, Pseudomonas and Staphylococcus. There was no significant difference in the amount of nutrients found in the domestic wastewater and receiving stream during the months. This paper also discusses the implication of disposing large amounts of wastewater effluents into the receiving water and the need to remedy and minimize the overall impact of such pollution on the environment.

  8. Interaction and cooperative effort among scientific societies. Twelve years of COSCE. (United States)

    Martín, Nazario; Andradas, Carlos


    The evolution of knowledge and technology in recent decades has brought profound changes in science policy, not only in the countries but also in the supranational organizations. It has been necessary, therefore, to adapt the scientific institutions to new models in order to achieve a greater and better communication between them and the political counterparts responsible for defining the general framework of relations between science and society. The Federationon of Scientific Societies of Spain (COSCE, Confederación de Sociedades Científicas de España) was founded in October 2003 to respond to the urgent need to interact with the political institutions and foster a better orientation in the process of making decisions about the science policy. Currently COSCE consists of over 70 Spanish scientific societies and more than 40,000 scientists. During its twelve years of active life, COSCE has developed an intense work of awareness of the real situation of science in Spain by launching several initiatives (some of which have joined other organizations) or by joining initiatives proposed from other groups related to science both at the Spanish level and at the European and non-European scenarios. [Int Microbiol 18(4): 245-251 (2015)].

  9. Ecological conversion efficiency and its influencers in twelve species of fish in the Yellow Sea Ecosystem (United States)

    Tang, Qisheng; Guo, Xuewu; Sun, Yao; Zhang, Bo


    The ecological conversion efficiencies in twelve species of fish in the Yellow Sea Ecosystem, i.e., anchovy ( Engraulis japonicus), rednose anchovy ( Thrissa kammalensis), chub mackerel ( Scomber japonicus), halfbeak ( Hyporhamphus sajori), gizzard shad ( Konosirus punctatus), sand lance ( Ammodytes personatus), red seabream ( Pagrus major), black porgy ( Acanthopagrus schlegeli), black rockfish ( Sebastes schlegeli), finespot goby ( Chaeturichthys stigmatias), tiger puffer ( Takifugu rubripes), and fat greenling ( Hexagrammos otakii), were estimated through experiments conducted either in situ or in a laboratory. The ecological conversion efficiencies were significantly different among these species. As indicated, the food conversion efficiencies and the energy conversion efficiencies varied from 12.9% to 42.1% and from 12.7% to 43.0%, respectively. Water temperature and ration level are the main factors influencing the ecological conversion efficiencies of marine fish. The higher conversion efficiency of a given species in a natural ecosystem is acquired only under the moderate environment conditions. A negative relationship between ecological conversion efficiency and trophic level among ten species was observed. Such a relationship indicates that the ecological efficiency in the upper trophic levels would increase after fishing down marine food web in the Yellow Sea ecosystem.

  10. Differences in antimicrobial activity of chlorine against twelve most prevalent poultry-associated Salmonella serotypes. (United States)

    Paul, Narayan C; Sullivan, Tarah S; Shah, Devendra H


    Chlorine is the most widely used carcass sanitizer in poultry processing in the USA. The objective of this study was to determine the effects of varying concentrations of organic matter on the susceptibility of twelve most prevalent poultry-associated Salmonella serotypes (MPPSTs) to chlorine. To mimic the microenvironment of the water used for immersion chilling, we manipulated organic matter contamination levels in pre-chilled (pH∼6, T∼4 °C) chlorinated (50 ppm) water using varying concentrations (0, 1, 2, 3, 4, and 5%) of chicken-meat-extract (CME) produced from frozen chicken carcasses. This CME-based in vitro model was challenged with ∼1 × 10(5) CFUs of each MPPST isolate and the bacterial survival was tested at 5, 30, 60 and 90 min post-challenge. In this model, the decimal reduction time (D90-values) of each MPPST was linearly correlated with the concentration of CME. Significant inter-serotype differences in the D90-values were observed. The results show that the pH, concentration of total- and free-chlorine were also linearly correlated with the presence of CME in a concentration-dependent manner. The findings of this study indicate that the serotype and the levels of organic matter contamination significantly influence Salmonella survival and that both variables should be included in models that predict effectiveness of chlorine treatment in immersion chilling.

  11. Alcoholics Anonymous and twelve-step recovery: a model based on social and cognitive neuroscience. (United States)

    Galanter, Marc


    In the course of achieving abstinence from alcohol, longstanding members of Alcoholics Anonymous (AA) typically experience a change in their addiction-related attitudes and behaviors. These changes are reflective of physiologically grounded mechanisms which can be investigated within the disciplines of social and cognitive neuroscience. This article is designed to examine recent findings associated with these disciplines that may shed light on the mechanisms underlying this change. Literature review and hypothesis development. Pertinent aspects of the neural impact of drugs of abuse are summarized. After this, research regarding specific brain sites, elucidated primarily by imaging techniques, is reviewed relative to the following: Mirroring and mentalizing are described in relation to experimentally modeled studies on empathy and mutuality, which may parallel the experiences of social interaction and influence on AA members. Integration and retrieval of memories acquired in a setting like AA are described, and are related to studies on storytelling, models of self-schema development, and value formation. A model for ascription to a Higher Power is presented. The phenomena associated with AA reflect greater complexity than the empirical studies on which this article is based, and certainly require further elucidation. Despite this substantial limitation in currently available findings, there is heuristic value in considering the relationship between the brain-based and clinical phenomena described here. There are opportunities for the study of neuroscientific correlates of Twelve-Step-based recovery, and these can potentially enhance our understanding of related clinical phenomena. © American Academy of Addiction Psychiatry.

  12. Deathly silence and apocalyptic noise: Observations on the soundscape of the Book of the Twelve

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    Aaron Schart


    Full Text Available This paper proposes a reading of the Book of the Twelve (used interchangeably with �Twelve� and �Book� for convenience that concentrates on the sound that is included in the description of the world of the text. Three onomatopoeic devices are singled out. First, the mourning cry h�y is considered. This interjection is used differently in several of the writings: in Amos (5:18; 6:1 the prophet cries out in compassion with the addressees. By contrast, in Nahum 3:1 and Habakkuk 2:6�19, h�y is uttered in a mood of mockery. In Zechariah 2:10 a third, joyful h�y is used. It appears that the different usages cohere nicely with the overall structure of the Book of the Twelve. Secondly, the interjection has likewise shows different usages. In Amos 6:10 and 8:3, it simulates the last breath of Israelites dying when the land is devastated. By contrast, in Habakkuk 2:20, Zephaniah 1:7 and Zechariah 2:17, the addressees are directed to be silent before YHWH. This command should be perceived as an act of reverence. Again, the sequence of the occurrences coheres with the overall structure of the Book of the Twelve. Of special relevance is that the last three instances build a frame around the Babylonian exile, which lies between Zephaniah and Haggai. The third example is the phrase ham�n�m, ham�n�m in Joel 4:14. The author employs an irregular double plural to construe this place as the loudest spot (�apocalyptic noise� within the Twelve.Setu sa go tiba le modumo wa aphokhaliptiki: Ditemogo ka medumo ya Puku ya ba LesomepediPampiri ye e �i�inya go balwa ga Puku ya ba Lesomepedi (yeo e ka nogo bit�wa �Lesomepedi� goba �Puku� go bebofat�a ditaba ka go gatelela modumo wo o lego ka gare ga tlhaloso ya lefase la go tswala dingwalo t�e. Ditsela t�e tharo t�a onomathopoiki di bewa pepeneng. La mathomo, go �et�wa sello sa mahloko sa h?y. Lelahlelwa le le �omi�wa ka go fapana mo dingwalong t�e mmalwa: go Amosi

  13. Fate of the conformal fixed point with twelve massless fermions and SU(3) gauge group (United States)

    Fodor, Zoltan; Holland, Kieran; Kuti, Julius; Mondal, Santanu; Nogradi, Daniel; Wong, Chik Him


    We report new results on the conformal properties of an important strongly coupled gauge theory, a building block of composite Higgs models beyond the Standard Model. With twelve massless fermions in the fundamental representation of the SU(3) color gauge group, an infrared fixed point (IRFP) of the β -function was recently reported in the theory [A. Cheng, A. Hasenfratz, Y. Liu, G. Petropoulos, and D. Schaich, J. High Energy Phys. 05 (2014) 137] with uncertainty in the location of the critical gauge coupling inside the narrow [6.0 fixed point and scale invariance in the theory with model-building implications. Using the exact same renormalization scheme as the previous study, we show that no fixed point of the β -function exists in the reported interval. Our findings eliminate the only seemingly credible evidence for conformal fixed point and scale invariance in the Nf=12 model whose infrared properties remain unresolved. The implications of the recently completed 5-loop QCD β -function for arbitrary flavor number are discussed with respect to our work.

  14. Twelve tips for creating trigger images for problem-based learning cases. (United States)

    Azer, Samy A


    A trigger is the starting point of problem-based learning (PBL) cases. It is usually in the form of 5-6 text lines that provide the key information about the main character (usually the patient), including 3-4 of patient's presenting problems. In addition to the trigger text, most programs using PBL include a visual trigger. This might be in the form of a single image, a series of images, a video clip, a cartoon, or even one of the patient's investigation results (e.g. chest X-ray, pathology report, or urine sample analysis). The main educational objectives of the trigger image are as follows: (1) to introduce the patient to the students; (2) to enhance students' observation skills; (3) to provide them with new information to add to the cues obtained from the trigger text; and (4) to stimulate students to ask questions as they develop their enquiry plan. When planned and delivered effectively, trigger images should be engaging and stimulate group discussion. Understanding the educational objectives of using trigger images and choosing appropriate images are the keys for constructing successful PBL cases. These twelve tips highlight the key steps in the successful creation of trigger images.

  15. COMP mutations: domain-dependent relationship between abnormal chondrocyte trafficking and clinical PSACH and MED phenotypes. (United States)

    Chen, Tung-Ling L; Posey, Karen L; Hecht, Jacqueline T; Vertel, Barbara M


    Mutations in cartilage oligomeric matrix protein (COMP) produce clinical phenotypes ranging from the severe end of the spectrum, pseudoachondroplasia (PSACH), which is a dwarfing condition, to a mild condition, multiple epiphyseal dysplasia (MED). Patient chondrocytes have a unique morphology characterized by distended rER cisternae containing lamellar deposits of COMP and other extracellular matrix proteins. It has been difficult to determine why different mutations give rise to variable clinical phenotypes. Using our in vitro cell system, we previously demonstrated that the most common PSACH mutation, D469del, severely impedes trafficking of COMP and type IX collagen in chondrocytic cells, consistent with observations from patient cells. Here, we hypothesize that PSACH and MED mutations variably affect the cellular trafficking behavior of COMP and that the extent of defective trafficking correlates with clinical phenotype. Twelve different recombinant COMP mutations were expressed in rat chondrosarcoma cells and the percent cells with ER-retained COMP was assessed. For mutations in type 3 (T3) repeats, trafficking defects correlated with clinical phenotype; PSACH mutations had more cells retaining mutant COMP, while MED mutations had fewer. In contrast, the cellular trafficking pattern observed for mutations in the C-terminal globular domain (CTD) was not predictive of clinical phenotype. The results demonstrate that different COMP mutations in the T3 repeat domain have variable effects on intracellular transport, which correlate with clinical severity, while CTD mutations do not show such a correlation. These findings suggest that other unidentified factors contribute to the effect of the CTD mutations. J. Cell. Biochem. 103: 778-787, 2008. (c) 2007 Wiley-Liss, Inc. Copyright 2007 Wiley-Liss, Inc.

  16. Mutational spectrum drives the rise of mutator bacteria.

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    Alejandro Couce

    Full Text Available Understanding how mutator strains emerge in bacterial populations is relevant both to evolutionary theory and to reduce the threat they pose in clinical settings. The rise of mutator alleles is understood as a result of their hitchhiking with linked beneficial mutations, although the factors that govern this process remain unclear. A prominent but underappreciated fact is that each mutator allele increases only a specific spectrum of mutational changes. This spectrum has been speculated to alter the distribution of fitness effects of beneficial mutations, potentially affecting hitchhiking. To study this possibility, we analyzed the fitness distribution of beneficial mutations generated from different mutator and wild-type Escherichia coli strains. Using antibiotic resistance as a model system, we show that mutational spectra can alter these distributions substantially, ultimately determining the competitive ability of each strain across environments. Computer simulation showed that the effect of mutational spectrum on hitchhiking dynamics follows a non-linear function, implying that even slight spectrum-dependent fitness differences are sufficient to alter mutator success frequency by several orders of magnitude. These results indicate an unanticipated central role for the mutational spectrum in the evolution of bacterial mutation rates. At a practical level, this study indicates that knowledge of the molecular details of resistance determinants is crucial for minimizing mutator evolution during antibiotic therapy.

  17. Improving Comparability Of Survey Results Through Ex-Post Harmonisation A Case Study With Twelve European National Travel Surveys

    DEFF Research Database (Denmark)

    Christensen, Linda; Hubert, Jean-Paul; Järvi, Tuuli

    that reflect behavioural differences rather than methodological ones, in the context of the COST Action SHANTI (Survey Harmonisation with New Technologies Improvement, TUD0804) an ex-post harmonisation approach was developed using microdata from twelve European NTS’s. The paper presents both concept and basic...

  18. Twelve Years of Education and Public Outreach with the Fermi Gamma-ray Space Telescope (United States)

    Cominsky, Lynn R.; McLin, K. M.; Simonnet, A.; Fermi E/PO Team


    During the past twelve years, NASA's Fermi Gamma-ray Space Telescope has supported a wide range of Education and Public Outreach (E/PO) activities, targeting K-14 students and the general public. The purpose of the Fermi E/PO program is to increase student and public understanding of the science of the high-energy Universe, through inspiring, engaging and educational activities linked to the mission’s science objectives. The E/PO program has additional more general goals, including increasing the diversity of students in the Science, Technology, Engineering and Mathematics (STEM) pipeline, and increasing public awareness and understanding of Fermi science and technology. Fermi's multi-faceted E/PO program includes elements in each major outcome category: ● Higher Education: Fermi E/PO promotes STEM careers through the use of NASA data including research experiences for students and teachers (Global Telescope Network), education through STEM curriculum development projects (Cosmology curriculum) and through enrichment activities (Large Area Telescope simulator). ● Elementary and Secondary education: Fermi E/PO links the science objectives of the Fermi mission to well-tested, customer-focused and NASA-approved standards-aligned classroom materials (Black Hole Resources, Active Galaxy Education Unit and Pop-up book, TOPS guides, Supernova Education Unit). These materials have been distributed through (Educator Ambassador and on-line) teacher training workshops and through programs involving under-represented students (after-school clubs and Astro 4 Girls). ● Informal education and public outreach: Fermi E/PO engages the public in sharing the experience of exploration and discovery through high-leverage multi-media experiences (Black Holes planetarium and PBS NOVA shows), through popular websites (Gamma-ray Burst Skymap, Epo's Chronicles), social media (Facebook, MySpace), interactive web-based activities (Space Mysteries, Einstein@Home) and activities by

  19. Relative peripheral refraction in children: twelve-month changes in eyes with different ametropias. (United States)

    Lee, Tsui-Tsui; Cho, Pauline


    To determine the peripheral refraction of children with different types of ametropias and to evaluate the relationship between central refractive changes, baseline relative peripheral refraction (RPR) and changes in RPR over a 12-month monitoring period. Cycloplegic central and peripheral refraction were performed biannually on the right eyes of children aged 6-9 for 12 months, using an open-view autorefractor. Peripheral refraction were measured along 10°, 20° and 30° from central fixation in both nasal and temporal fields. Refractive data were transposed into M, J0 and J45 vectors for analyses. RPR was determined by subtracting the central measurement from each peripheral measurement. Hyperopic eyes showed relative peripheral myopia while myopic eyes had relative hyperopia across the central 60° horizontal field at baseline. Emmetropic eyes had relative myopia within but showed relative hyperopia beyond the central 30° field. However, there was no significant correlation between central refractive changes and baseline RPR or between changes in central refraction and RPR over twelve months in any refractive groups. Correlations between changes in PR and central myopic shift were found mainly in the nasal field in different groups. In the subgroup analysis on the initially emmetropic and the initially myopic groups, the subgroups with faster myopic progression did not have significantly different RPR from the subgroups with slower progression. The RPR pattern of the initially emmetropic and the initially myopic groups became more asymmetric at the end of the study period with a larger increase in relative hyperopia in the temporal field. RPR patterns were different among hyperopic, emmetropic and myopic eyes. However, baseline RPR and changes in RPR cannot predict changes in central refraction over time. Our results did not provide evidence to support the hypothesis of RPR as a causative factor for myopic central refractive changes in children. Ophthalmic

  20. Computational study of the structural and vibrational properties of ten and twelve vertex closo-carboranes

    Energy Technology Data Exchange (ETDEWEB)

    Salam, A.; Deleuze, M.S.; Francois, J.-P


    Calculations using ab initio Hartree-Fock and Density Functional theories, the latter employing the B3LYP functional, in combination with a number of large standard basis sets ranging from 6-31G** to cc-pVDZ, have been performed on a series of ten and twelve vertex closo-carborane isomer species. Results obtained for optimized structural parameters and molecular properties are presented for 1,2-, 1,6- and 1,10-C{sub 2}B{sub 8}H{sub 10} and 1,2-, 1,7- and 1,12-C{sub 2}B{sub 10}H{sub 12} and compared, where possible, with both earlier theoretical data and experiment. Irrespective of the model chemistry chosen, the para-isomer in each class of carborane cluster is found to be the most stable species, corresponding to a structure in which the cage carbon atoms are positioned at diametrically opposed ends of the respective polyhedron. Boron-hydrogen and carbon-hydrogen bond lengths are found to change little on going from isomers of one particular cage size to another, supporting analogous conclusions previously established for small closo-carborane cages possessing five, six and seven vertices. The calculated vibrational spectra of the isomers of both decacarborane and dodecacarborane are seen to be similar to each other and reflect a high degree of rigidity within each cluster. Key polyhedral skeletal breathing modes along with characteristic boron-hydrogen and carbon-hydrogen stretching frequencies are identified in the spectra and compared with experiment. Thermochemical data relating to each species are also analyzed.

  1. Indifference to pain syndrome in a twelve-year-old boy (case report

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    Baghdadi T


    Full Text Available Background: People vary greatly in their response to painful stimuli, from those with a low pain threshold to those with indifference to pain. However, insensitivity to pain is a rare disorder, characterized by the lack of usual subjective and objective responses to noxious stimuli. Patients who have congenital indifference to pain sustain painless injuries beginning in infancy, but have sensory responses that are otherwise normal on examination. Perception of passive movement, joint position, and vibration is normal in these patients, as are tactile thresholds and light touch perception. Case report: A twelve-year-old boy was admitted to the hospital for a painless deformity, degeneration in both knees and a neglected femoral neck fracture that was inappropriately painless. Further examination revealed normal sensory responses, perception of passive movement, joint position, vibration tactile thresholds and light touch perception. Spinal cord and brain MRI were normal as was the electromyography and nerve conduction velocity (EMG/NCV examination. There was no positive family history for this disorder. Conclusion: The deficits present in the different pain insensitivity syndromes provide insight into the complex anatomical and physiological nature of pain perception. Reports on pain asymbolia, in which pain is perceived but does not cause suffering, and related cortical conditions illustrate that there can be losses that independently involve either the sensory-discriminative component or the affective-motivational component of pain perception, thus highlighting their different anatomical localization. The paucity of experience with this entity and the resultant diagnostic problems, the severity of the associated disabling arthropathy and underscore the importance of this case report of indifference to pain.

  2. Removal of trace level amounts of twelve sulfonamides from drinking water by UV-activated peroxymonosulfate. (United States)

    Cui, Changzheng; Jin, Lei; Jiang, Lei; Han, Qi; Lin, Kuangfei; Lu, Shuguang; Zhang, Dong; Cao, Guomin


    Trace levels of residual antibiotics in drinking water may threaten public health and become a serious problem in modern society. In this work, we investigated the degradation of twelve sulfonamides (SAs) at environmentally relevant trace level concentrations by three different methods: ultraviolet (UV) photolysis, peroxymonosulfate (PMS) oxidation, and UV-activated PMS (UV/PMS). Sulfaguanidine, sulfadiazine, sulfamerazine, sulfamethazine, sulfathiazole, sulfamethoxydiazine, and sulfadimethoxine were be effectively removed by direct UV photolysis and PMS oxidation. However, sulfanilamide, sulfamethizole, sulfamethoxazole, sulfisoxazole, and sulfachloropyridazine were not completely degraded, despite prolonging the UV irradiation time to 30min or increasing the PMS concentration to 5.0mg·L(-1). UV/PMS provided more thorough elimination of SAs, as demonstrated by the complete removal of 200ng·L(-1) of all SAs within 5min at an initial PMS concentration of 1.0mg·L(-1). UV/PMS promoted SA decomposition more efficiently than UV photolysis or PMS oxidation alone. Bicarbonate concentration and pH had a negligible effect on SA degradation by UV/PMS. However, humic acid retarded the process. Removal of 200ng·L(-1) of each SA from a sample of sand-filtered effluent from a drinking water treatment plant (DWTPs) was quickly and completely achieved by UV/PMS. Meanwhile, about 41% of the total organic carbon (TOC) was eliminated. Scavenging experiments showed that sulfate radical (SO4(-)) was the predominant species involved in the degradation. It is concluded that UV/PMS is a rapid and efficient method for removing trace-level SAs from drinking water. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. A survey of innovation through duplication in the reduced genomes of twelve parasites.

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    Jeremy D DeBarry

    Full Text Available We characterize the prevalence, distribution, divergence, and putative functions of detectable two-copy paralogs and segmental duplications in the Apicomplexa, a phylum of parasitic protists. Apicomplexans are mostly obligate intracellular parasites responsible for human and animal diseases (e.g. malaria and toxoplasmosis. Gene loss is a major force in the phylum. Genomes are small and protein-encoding gene repertoires are reduced. Despite this genomic streamlining, duplications and gene family amplifications are present. The potential for innovation introduced by duplications is of particular interest. We compared genomes of twelve apicomplexans across four lineages and used orthology and genome cartography to map distributions of duplications against genome architectures. Segmental duplications appear limited to five species. Where present, they correspond to regions enriched for multi-copy and species-specific genes, pointing toward roles in adaptation and innovation. We found a phylum-wide association of duplications with dynamic chromosome regions and syntenic breakpoints. Trends in the distribution of duplicated genes indicate that recent, species-specific duplicates are often tandem while most others have been dispersed by genome rearrangements. These trends show a relationship between genome architecture and gene duplication. Functional analysis reveals: proteases, which are vital to a parasitic lifecycle, to be prominent in putative recent duplications; a pair of paralogous genes in Toxoplasma gondii previously shown to produce the rate-limiting step in dopamine synthesis in mammalian cells, a possible link to the modification of host behavior; and phylum-wide differences in expression and subcellular localization, indicative of modes of divergence. We have uncovered trends in multiple modes of duplicate divergence including sequence, intron content, expression, subcellular localization, and functions of putative recent duplicates that

  4. Characterizing gene-gene interactions in a statistical epistasis network of twelve candidate genes for obesity. (United States)

    De, Rishika; Hu, Ting; Moore, Jason H; Gilbert-Diamond, Diane


    Recent findings have reemphasized the importance of epistasis, or gene-gene interactions, as a contributing factor to the unexplained heritability of obesity. Network-based methods such as statistical epistasis networks (SEN), present an intuitive framework to address the computational challenge of studying pairwise interactions between thousands of genetic variants. In this study, we aimed to analyze pairwise interactions that are associated with Body Mass Index (BMI) between SNPs from twelve genes robustly associated with obesity (BDNF, ETV5, FAIM2, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18). We used information gain measures to identify all SNP-SNP interactions among and between these genes that were related to obesity (BMI > 30 kg/m(2)) within the Framingham Heart Study Cohort; interactions exceeding a certain threshold were used to build an SEN. We also quantified whether interactions tend to occur more between SNPs from the same gene (dyadicity) or between SNPs from different genes (heterophilicity). We identified a highly connected SEN of 709 SNPs and 1241 SNP-SNP interactions. Combining the SEN framework with dyadicity and heterophilicity analyses, we found 1 dyadic gene (TMEM18, P-value = 0.047) and 3 heterophilic genes (KCTD15, P-value = 0.045; SH2B1, P-value = 0.003; and TMEM18, P-value = 0.001). We also identified a lncRNA SNP (rs4358154) as a key node within the SEN using multiple network measures. This study presents an analytical framework to characterize the global landscape of genetic interactions from genome-wide arrays and also to discover nodes of potential biological significance within the identified network.

  5. Thermal environment in eight low-energy and twelve conventional Finnish houses. (United States)

    Kähkönen, Erkki; Salmi, Kari; Holopainen, Rauno; Pasanen, Pertti; Reijula, Kari


    We assessed the thermal environment of eight recently built low-energy houses and twelve conventional Finnish houses. We monitored living room, bedroom and outdoor air temperatures and room air relative humidity from June 2012 to September 2013. Perceived thermal environment was evaluated using a questionnaire survey during the heating, cooling and interim seasons. We compared the measured and perceived thermal environments of the low-energy and conventional houses. The mean air temperature was 22.8 °C (21.9-23.8 °C) in the low-energy houses, and 23.3 °C (21.4-26.5 °C) in the conventional houses during the summer (1. June 2013-31. August 2013). In the winter (1. December 2012-28. February 2013), the mean air temperature was 21.3 °C (19.8-22.5 °C) in the low-energy houses, and 21.6 °C (18.1-26.4 °C) in the conventional houses. The variation of the air temperature was less in the low-energy houses than that in the conventional houses. In addition, the occupants were on average slightly more satisfied with the indoor environment in the low-energy houses. However, there was no statistically significant difference between the mean air temperature and relative humidity of the low-energy and conventional houses. Our measurements and surveys showed that a good thermal environment can be achieved in both types of houses.

  6. Phytochemical screening of twelve species of phytoplankton isolated from Arabian Sea coast

    Directory of Open Access Journals (Sweden)

    Sushanth Vishwanath Rai


    Full Text Available Objective: To analyze the phytochemicals in twelve species of marine phytoplankton. Methods: Total phenolic content of methanol extract was estimated by the Folin-Ciocalteu method. Total flavonoid content of the methanol extarct was determined by aluminium chloride method. Chlorophylls, β-carotene and astaxanthin were estimated by acetone extraction method. Vitamin C was determined by dinitrophenyl-hydrazine method. Phycobiliproteins such as allophycocyanin, phycocyanin and phycoerythrin in the aqueous extracts were determined. Results: Total phenolics varied from 5.41 mg gallic acid equivalents/g dry weight (DW in Phormidium corium (P. corium to 17.37 mg gallic acid equivalents/g DW in Oscillatoria fremyii (O. fremyii. Total flavonoids ranged between 0.74 mg quercetin equivalent/g DW in P. corium and 9.87 mg quercetin equivalent/g DW in Nannochloropsis oceanica. Chlorophyll-a pigment was high in Chaetoceros calcitrans (C. calcitrans (15.51 mg/g DW and low in P. corium (1.08 mg/g DW. Chlorophyll-c ranged between 0.07 mg/g DW in Nannochloropsis oceanica and 4.62 mg/g DW in C. calcitrans. High contents of β-carotene and astaxanthin were found in C. calcitrans and low in P. corium which ranged from 0.33 to 10.03 mg/g DW and 0.18 to 3.85 mg/g DW, respectively. Vitamin C content varied from 0.50 mg/g DW in C. calcitrans to 1.51 mg/g DW in Phormidium tenue. O. fremyii showed highest total phycobiliproteins of 317.05 mg/g DW. High contents of allophycocyanin and phycocyanin were found in O. fremyii, whereas high contents of phycoerythrin were found in Oscillatoria sancta. All the three phycobiliproteins were low in Chroococcus turgidus. Conclusions: Marine phytoplankton are one of the natural sources providing novel biologically active compounds with potential for pharmaceutical applications.

  7. Androgen receptor gene mutations in hormone-refractory prostate cancer. (United States)

    Wallén, M J; Linja, M; Kaartinen, K; Schleutker, J; Visakorpi, T


    Prostate cancer is considered to be one of the most hormone-dependent human malignancies. As a key mediator of hormonal response, the androgen receptor (AR) is believed to have an important role in the progression of prostate cancer. Mutations in the coding region of the AR gene have been found in both untreated and hormone-refractory prostate cancer, but the frequency of such mutations at different stages of the disease is poorly documented and even contradictory results have been published. In the present study, the frequency of AR gene mutations was determined in 30 locally recurrent and two metastatic hormone-refractory prostate tumours using the polymerase chain reaction (PCR), non-radioactive single strand conformation polymorphism (SSCP), and sequencing. The length of the polymorphic CAG repeat, which is inversely correlated with the ability of the AR to activate transcription, was also analysed as well as the GGC repeat. Twelve samples were known to contain an AR gene amplification. Altogether, one point mutation (Gly(674)-->Ala) and one microsatellite mutation (CAG(20)-->CAG(18)) were found, both in cancers containing the AR gene amplification. The mean lengths of the polymorphic CAG and GGC repeats were similar to those observed in the normal population. These results favour the view that mutations in the AR gene are rare in hormone-refractory prostate cancer and do not play an important role, at least, in local relapse. Instead, the amplification and consequent overexpression of the wild-type AR gene seem to be the most common alteration involving the AR in hormone-refractory prostate cancer.

  8. Silting mutation in triangulated categories

    CERN Document Server

    Aihara, Takuma


    In representation theory of algebras the notion of `mutation' often plays important roles, and two cases are well known, i.e. `cluster tilting mutation' and `exceptional mutation'. In this paper we focus on `tilting mutation', which has a disadvantage that it is often impossible, i.e. some of summands of a tilting object can not be replaced to get a new tilting object. The aim of this paper is to take away this disadvantage by introducing `silting mutation' for silting objects as a generalization of `tilting mutation'. We shall develope a basic theory of silting mutation. In particular, we introduce a partial order on the set of silting objects and establish the relationship with `silting mutation' by generalizing the theory of Riedmann-Schofield and Happel-Unger. We show that iterated silting mutation act transitively on the set of silting objects for local, hereditary or canonical algebras. Finally we give a bijection between silting subcategories and certain t-structures.


    DEFF Research Database (Denmark)


    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder. The ...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....


    DEFF Research Database (Denmark)


    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  11. Are There Mutator Polymerases?

    Directory of Open Access Journals (Sweden)

    Miguel Garcia-Diaz


    Full Text Available DNA polymerases are involved in different cellular events, including genome replication and DNA repair. In the last few years, a large number of novel DNA polymerases have been discovered, and the biochemical analysis of their properties has revealed a long list of intriguing features. Some of these polymerases have a very low fidelity and have been suggested to play mutator roles in different processes, like translesion synthesis or somatic hypermutation. The current view of these processes is reviewed, and the current understanding of DNA polymerases and their role as mutator enzymes is discussed.

  12. Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II. (United States)

    Hühn, R; Stoermer, H; Klingele, B; Bausch, E; Fois, A; Farnetani, M; Di Rocco, M; Boué, J; Kirk, J M; Coleman, R; Scherer, G


    Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disorder of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in hepatic tyrosine aminotransferase (TAT). We have previously described one deletion and six different point mutations in four RHS patients. We have now analyzed the TAT genes in a further seven unrelated RHS families from Italy, France, the United Kingdom, and the United States. We have established PCR conditions for the amplification of all twelve TAT exons and have screened the products for mutations by direct sequence analysis or by first performing single-strand conformation polymorphism analysis. We have thus identified the presumably pathological mutations in eight RHS alleles, including two nonsense mutations (R57X, E411X) and four amino acid substitutions (R119W, L201R, R433Q, R433W). Only the R57X mutation, which was found in one Scottish and two Italian families, has been previously reported in another Italian family. Haplotype analysis indicates that this mutation, which involves a CpG dinucleotide hot spot, has a common origin in the three Italian families but arose independently in the Scottish family. Two polymorphisms have also been detected, viz., a protein polymorphism, P15S, and a silent substitution S103S (TCG-->TCA). Expression of R433Q and R433W demonstrate reduced activity of the mutant proteins. In all, twelve different TAT gene mutations have now been identified in tyrosinemia type II.

  13. Msx1 Mutations (United States)

    Wang, Y.; Kong, H.; Mues, G.; D’Souza, R.


    Mutations in the transcription factors PAX9 and MSX1 cause selective tooth agenesis in humans. In tooth bud mesenchyme of mice, both proteins are required for the expression of Bmp4, which is the key signaling factor for progression to the next step of tooth development. We have previously shown that Pax9 can transactivate a 2.4-kb Bmp4 promoter construct, and that most tooth-agenesis-causing PAX9 mutations impair DNA binding and Bmp4 promoter activation. We also found that Msx1 by itself represses transcription from this proximal Bmp4 promoter, and that, in combination with Pax9, it acts as a potentiator of Pax9-induced Bmp4 transactivation. This synergism of Msx1 with Pax9 is significant, because it is currently the only documented mechanism for Msx1-mediated activation of Bmp4. In this study, we investigated whether the 5 known tooth-agenesis-causing MSX1 missense mutations disrupt this Pax9-potentiation effect, or if they lead to deficiencies in protein stability, protein-protein interactions, nuclear translocation, and DNA-binding. We found that none of the studied molecular mechanisms yielded a satisfactory explanation for the pathogenic effects of the Msx1 mutations, calling for an entirely different approach to the investigation of this step of odontogenesis on the molecular level. PMID:21297014

  14. Phytochemical screening of twelve species of phytoplankton isolated from Arabian Sea coast

    Institute of Scientific and Technical Information of China (English)

    Sushanth Vishwanath Rai; Madaiah Rajashekhar


    Objective:To analyze the phytochemicals in twelve species of marine phytoplankton. Methods: Total phenolic content of methanol extract was estimated by the Folin-Ciocalteu method. Total flavonoid content of the methanol extarct was determined by aluminium chloride method. Chlorophylls,β-carotene and astaxanthin were estimated by acetone extraction method. Vitamin C was determined by dinitrophenyl-hydrazine method. Phycobiliproteins such as allophycocyanin, phycocyanin and phycoerythrin in the aqueous extracts were determined. Results: Total phenolics varied from 5.41 mg gallic acid equivalents/g dry weight (DW) in Phormidium corium (P. corium) to 17.37 mg gallic acid equivalents/g DW inOscillatoria fremyii(O. fremyii). Total flavonoids ranged between 0.74 mg quercetin equivalent/g DW inP. corium and 9.87 mg quercetin equivalent/g DW inNannochloropsis oceanica. Chlorophyll-a pigment was high inChaetoceros calcitrans(C. calcitrans)(15.51 mg/g DW) and low inP. corium (1.08 mg/g DW). Chlorophyll-c ranged between 0.07 mg/g DW inNannochloropsis oceanica and 4.62 mg/g DW inC. calcitrans. High contents ofβ-carotene and astaxanthin were found inC. calcitrans and low inP. corium which ranged from 0.33 to 10.03 mg/g DW and 0.18 to 3.85 mg/g DW, respectively. Vitamin C content varied from 0.50 mg/g DW inC. calcitrans to 1.51 mg/g DW inPhormidium tenue.O. fremyii showed highest total phycobiliproteins of 317.05 mg/g DW. High contents of allophycocyanin and phycocyanin were found inO. fremyii, whereas high contents of phycoerythrin were found inOscillatoria sancta. All the three phycobiliproteins were low inChroococcus turgidus. Conclusions: Marine phytoplankton are one of the natural sources providing novel biologically active compounds with potential for pharmaceutical applications.

  15. Nutrient Contents per Serving of Twelve Varieties of Cooked Rice Marketed in Jordan

    Directory of Open Access Journals (Sweden)

    Jafar M. El-Qudah


    Full Text Available Jordan imports rice from different countries without any quality preferences. Twelve varieties of cooked rice marketed in Jordan were analyzed. The content per serving of these varieties were computed for energy, protein, carbohydrates, fat, calcium, sodium, potassium, magnesium, manganese, copper, iron and phosphorous. The protein content per serving found to range from 0.49 g for La Cigala rice to 6.2 g for Harvest rice. The fat content for all rice brands was less than 0.37 g per serving. The energy content ranged from 172.12 g/serving for Basmati rice to 212.25 g/serving for Sun White rice. Generally, all rice varieties contain significant amounts of minerals per serving. Ruzzana found to contain the highest level of calcium (38.2 mg/serving and Amber the lowest calcium content (6.7 mg/serving. Magnesium content found to range from 5.7 mg/serving for Royal Umberella rice to 16.3 mg/serving for Ruzzana rice. Consumption of one serving of Harvest cooked rice will cover 13.5% of the daily requirement of protein for females and 11.1% for males. Manganese content of one serving of Harvest, Sun White, Abu bent and La Cigala will cover 22.2% of the daily requirements for females and 14.7% for males, while consumption of one of Basmati, Sos rice or Amber will cover only 11.1% and 8.75 of requirement for females and males respectively. Planning a healthful diet is not a simple task. Dietary Reference Intake planning and assessing the diets of individuals or groups of healthy individuals according to their stage of life and sex. Food choice is a function of many factors, including personal preferences, habits, ethnic heritage and tradition. Dietary guidelines for Americans, consider whole grain products like rice are among the food groups that form the basis of a healthy diet. Including rice as part of a healthy, balanced diet can be linked to overall healthier eating patterns. Rice eaters are more likely to eat a diet consistent with the 2005 Dietary

  16. Risk factors for chronic noncontiguous diseases: Twelve-week prospective study

    Directory of Open Access Journals (Sweden)

    Lapčević Mirjana


    basis of RF number and combination for genesis and development of CND in our sample, 74.7% of variability (development or risk may be accounted for angina pectoris (AP, 74.2% for DM+HTA, 70.0% for DM, 79.9% for HTA, 80.8% for myocardial infarction (Ml, and 85.8% of variability (development or risk for cerebrovascular insult (CVI. Twelve-week intervention resulted in reduction of HTA, HLP, glucose, and PC (p<0.001 levels as well as lower BMI and PA (p<0.5. To accomplish the aforementioned goals, continuous mutual activity of an individual, his/her family, health service and community is required, along with occasional evaluation of the obtained results.

  17. Experiencing a constructivist museum exhibit: A case study of twelve children and their families (United States)

    Hill, Martha Anne Leech


    The American Association for the Advancement of Science and the National Research Council have called for the creation of a scientifically literate populace and introduced science standards and guidelines to direct this process. Science education in traditional school settings plays a key role in reaching this goal, but individuals over their lifetimes will have more exposure to science ideas through informal science experiences such as visits to museums and through diverse media sources. The purpose of this study was to explore the role museums play in this journey to science literacy. This qualitative collective case study examined the experience of 12 children and their families in a children's museum as they interacted with an exhibit designed along the tenets of constructivist theory to introduce children to ideas of science. Twelve children and their families were videotaped interacting with a model of a watershed that included the stream, surrounding land, gravel, and dam building and erosion abatement manipulatives. Children were interviewed to ascertain their stream-related ideas and conceptual understanding prior to and after using the exhibit. Parents completed demographic and post-exhibit experience questionnaires. Two museum staff members who played key roles in the development of the exhibit and surrounding gallery were also interviewed. Individual and cross-case analyses were done to describe the experience of each child and family, and to elucidate the commonalities of these experiences to describe the phenomenon of using a constructivist-based science exhibit. Results of the study indicate (1) the type of experience children and families had at the exhibit depended on child and parent interactions and roles each assumed, and (2) experience with the exhibit encouraged children to think more deeply about water topics, past experiences, and ideas they had previously constructed. Implications of this research include (1) parents should engage children

  18. [Risk factors for chronic noncontiguous diseases: twelve-week prospective study]. (United States)

    Lapcević, Mirjana; Vuković, Mira


    RF number and combination for genesis and development of CND in our sample, 74.7% of variability (development or risk) may be accounted for angina pectoris (AP), 74.2% for DM+HTA, 70.0% for DM, 79.9% for HTA, 80.8% for myocardial infarction (MI), and 85.8% of variability (development or risk) for cerebrovascular insult (CVI). Twelve-week intervention resulted in reduction of HTA, HLP, glucose, and PC (p<0.001) levels as well as lower BMI and PA (p<0.5). To accomplish the aforementioned goals, continuous mutual activity of an individual, his/her family, health service and community is required, along with occasional evaluation of the obtained results.

  19. Mutations in galactosemia

    Energy Technology Data Exchange (ETDEWEB)

    Reichardt, J.K.V. [Univ. of Southern California School of Medicine, Los Angeles, CA (United States)


    This Letter raises four issues concerning two papers on galactosemia published in the March 1995 of the Journal. First, table 2 in the paper by Elsas et al. incorrectly attributes seven galactose-l-phosphate uridyl transferase (GALT) mutations (S135L, L195P, K285N, N314D, R333W, R333G, and K334R). The table also fails to mention that others have reported the same two findings attributed to {open_quotes}Leslie et al.; Elsas et al. and in press{close_quotes} and {open_quotes}Leslie et al.; Elsas et al.{close_quotes} The first finding on the prevalence of the Q188R galactosemia mutation in the G/G Caucasian population has also been described by Ng et al., and the second finding on the correlation of the N314D GALT mutation with the Duarte variant was reported by Lin et al. Second, Elsas et al. suggest that the E203K and N314D mutations may {open_quotes}produce intra-allelic complementation when in cis{close_quotes}. This speculation is supported by the activity data of individual III-2 but is inconsistent with the activities of three other individuals I-1, II-1, and III-1 of the same pedigree. The GALT activity measured in these three individuals suggests a dominant negative effect of E203K in E203K-N314D chromosomes, since they all have less than normal activity. Thus, the preponderance of the data in this paper is at odds with the authors speculation. It is worth recalling that Lin et al. also identified four N314D GALT mutations on 95 galactosemic chromosomes examined. A similar situation also appears to be the case in proband III-1 (with genotype E203K-N314D/IVSC) in the Elsas et al. paper. 9 refs.

  20. Commentary on "tissue-specific mutagenesis by N-butyl-N-(4-hydroxybutyl) nitrosamine as the basis for urothelial cell carcinogenesis." He Z, Kosinska W, Zhao ZL, Wu XR, Guttenplan JB, Department of Basic Science, New York University Dental College, NY, USA.: Mutat Res 2012;742(1-2):92-5 [Epub 2011 Dec 4]. (United States)

    Scherr, Douglas S


    Bladder cancer is one of the few cancers that have been linked to carcinogens in the environment and tobacco smoke. Of the carcinogens tested in mouse chemical carcinogenesis models, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) is one that reproducibly causes high-grade, invasive cancers in the urinary bladder, but not in any other tissues. However, the basis for such a high-level tissue-specificity has not been explored. Using mutagenesis in lacI (Big Blue™) mice, we show here that BBN is a potent mutagen and it causes high-level of mutagenesis specifically in the epithelial cells (urothelial) of the urinary bladder. After a 2-6-week treatment of 0.05% BBN in the drinking water, mutagenesis in urothelial cells of male and female mice was about two orders of magnitude greater than the spontaneous mutation background. In contrast, mutagenesis in smooth muscle cells of the urinary bladder was about five times lower than in urothelial tissue. No appreciable increase in mutagenesis was observed in kidney, ureter, liver or forestomach. In lacI (Big Blue™) rats, BBN mutagenesis was also elevated in urothelial cells, albeit not nearly as profoundly as in mice. This provides a potential explanation as to why rats are less prone than mice to the formation of aggressive form of bladder cancer induced by BBN. Our results suggest that the propensity to BBN-triggered mutagenesis of urothelial cells underlies its heightened susceptibility to this carcinogen and that mutagenesis induced by BBN represents a novel model for initiation of bladder carcinogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Evolutionary Stability Against Multiple Mutations

    CERN Document Server

    Ghatak, Anirban; Shaiju, A J


    It is known (see e.g. Weibull (1995)) that ESS is not robust against multiple mutations. In this article, we introduce robustness against multiple mutations and study some equivalent formulations and consequences.

  2. BRAF mutations in conjunctival melanoma

    DEFF Research Database (Denmark)

    Larsen, Ann-Cathrine; Dahl, Christina; Dahmcke, Christina M.


    Purpose: To investigate incidence, clinicopathological features and prognosis of BRAF-mutated conjunctival melanoma in Denmark. Furthermore, to determine BRAF mutations in paired premalignant lesions and evaluate immunohistochemical BRAF V600E oncoprotein detection. Methods: Data from 139 patients...

  3. Independent Peer Evaluation of the Large Area Crop Inventory Experiment (LACIE): The LACIE Symposium (United States)


    Yield models and crop estimate accuracy are discussed within the Large Area Crop Inventory Experiment. The wheat yield estimates in the United States, Canada, and U.S.S.R. are emphasized. Experimental results design, system implementation, data processing systems, and applications were considered.

  4. The Impact of the Financial Crisis on the Content of Twelve Bestselling US Principles of Economics Textbooks

    DEFF Research Database (Denmark)

    Madsen, Poul Thøis


    How have authors of twelve bestselling introductory US textbooks in economics responded to the traumatizing financial crisis? In general the financial crisis is described with a couple of lines here and there or it is dealt with in boxes, separate sections, or specific isolated chapters. Some...... of the textbooks distinguish themselves by also having made some modest qualitative changes of content as a reaction to the financial crisis (especially Colander 2010 and Krugman and Wells 2013). Applying my general analysis of the changes being made already in the twelve textbooks seen as a whole, I discuss how...... any introductory textbook could integrate the financial crisis more adequately into the general presentation, thereby hopefully contributing to enhancing the interest of the students....


    Directory of Open Access Journals (Sweden)

    Luis Vaz


    Full Text Available The aim of the current study was to identify the Rugby game- related statistics that discriminated between winning and losing teams in IRB and S12 close games. Archival data reported to game-related statistics from 120 IRB games and 204 Super Twelve games played between 2003 and 2006. Afterwards, a cluster analysis was conducted to establish, according to game final score differences, three different match groups. Only the close games group was selected for further analysis (IRB n = 64 under 15 points difference and Super Twelve n = 95 under 11 points difference. An analysis to the structure coefficients (SC obtained through a discriminant analysis allowed to identify the most powerful game-related statistics in discriminating between winning and losing teams. The discriminant functions were statistically significant for Super Twelve games (Chi-square = 33.8, p < 0.01, but not for IRB games (Chi- square = 9.4, p = n.s.. In the first case, winners and losers were discriminated by possessions kicked (SC = 0.48, tackles made (SC = 0.45, rucks and pass (SC = -0.40, passes completed (SC = 0. 39, mauls won (SC = -0.36, turnovers won (SC = -0.33, kicks to touch (SC = 0.32 and errors made (SC = -0.32. The minus sign denotes higher values in losing teams. Rugby game-related statistics were able to discriminate between winners and losers in Super Twelve close games and suggest that a kicking based game supported by an effective defensive structure is more likely to win matches than a possession based one

  6. Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations

    Directory of Open Access Journals (Sweden)

    Tiede Henning


    Full Text Available Abstract Background Mutations in the bone morphogenetic protein receptor 2 (BMPR2 gene can lead to idiopathic pulmonary arterial hypertension (IPAH. This study prospectively screened for BMPR2 mutations in a large cohort of PAH-patients and compared clinical features between BMPR2 mutation carriers and non-carriers. Methods Patients have been assessed by right heart catheterization and genetic testing. In all patients a detailed family history and pedigree analysis have been obtained. We compared age at diagnosis and hemodynamic parameters between carriers and non-carriers of BMPR2 mutations. In non-carriers with familial aggregation of PAH further genes/gene regions as the BMPR2 promoter region, the ACVRL1, Endoglin, and SMAD8 genes have been analysed. Results Of the 231 index patients 22 revealed a confirmed familial aggregation of the disease (HPAH, 209 patients had sporadic IPAH. In 49 patients (86.3% of patients with familial aggregation and 14.3% of sporadic IPAH mutations of the BMPR2 gene have been identified. Twelve BMPR2 mutations and 3 unclassified sequence variants have not yet been described before. Mutation carriers were significantly younger at diagnosis than non-carriers (38.53 ± 12.38 vs. 45.78 ± 11.32 years, p Conclusion This study identified in a large prospectively assessed cohort of PAH- patients new BMPR2 mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening for BMPR2 mutations may be clinically useful.

  7. Radicular anatomy of twelve representatives of the Catasetinae subtribe (Orchidaceae: Cymbidieae

    Directory of Open Access Journals (Sweden)

    Cristiano Pedroso-de-Moraes


    Full Text Available Considering that the root structure of the Brazilian genera belonging to the Catasetinae subtribe is poorly known, we describe the roots of twelve representatives from this subtribe. For anatomical analysis, the roots were fixed in FAA 50, preserved in ethanol 70% and sectioned at its medium region using razor blades. The sections were stained with 0.05% astra blue and safranin and mounted in glycerin. For the identification of starch we used Lugol's solution; for lignin, floroglucin chloridric; for lipids, Sudan III, and for flavanoids, potassium hydroxide. The relevant aspects were registered using a digital camera joined with an Olympus microspope (BX51 model. The structural similarities of all roots support the placement of the subtribe Catasetinae into the monophyletic tribe Cymbidieae. Some root features are restricted to one or two taxa and can be useful in the systematics of the subtribe. For example, the occurrence of flavonoidic crystals characterizes the genera Catasetum and Cychnodes, and the number of the velamen layers and the shape of the epivelamen cells are useful to confirm the taxonomic position of Clowesia amazonica. The presence of velamen and flavonoidic crystals was interpreted as an adaptation to the epiphytic habit.Considerando que a estrutura das raízes de gêneros brasileiros pertencentes à subtribo Catasetinae é pouco conhecida, descrevemos as raízes de doze representantes desta subtribo. Para análise anatômica, as raízes foram fixadas em FAA 50, preservadas em álcool 70% e seccionadas na sua região média usando lâminas de barbear. Os cortes foram corados com astra blue e Safrablau 0,05% e montados em glicerina. Para a identificação do amido, utilizou-se a solução de Lugol; da lignina, floroglucina clorídrica, dos lipídios, Sudan III e dos flavonóides, hidróxido de potássio. Os aspectos relevantes foram registrados usando câmera digital acoplada a um microscópio Olympus (modelo BX51. As semelhan

  8. Kin Selection - Mutation Balance

    DEFF Research Database (Denmark)

    Dyken, J. David Van; Linksvayer, Timothy Arnold; Wade, Michael J.


    Abstract Social conflict, in the form of intraspecific selfish "cheating" has been observed in a number of natural systems. However, a formal, evolutionary genetic theory of social cheating that provides an explanatory, predictive framework for these observations is lacking. Here we derive the kin...... selection-mutation balance, which provides an evolutionary null hypothesis for the statics and dynamics of cheating. When social interactions have linear fitness effects and Hamilton´s rule is satisfied, selection is never strong enough to eliminate recurrent cheater mutants from a population, but cheater...... lineages are transient and do not invade. Instead, cheating lineages are eliminated by kin selection but are constantly reintroduced by mutation, maintaining a stable equilibrium frequency of cheaters. The presence of cheaters at equilibrium creates a "cheater load" that selects for mechanisms of cheater...

  9. Mutation of Auslander generators

    CERN Document Server

    Lada, Magdalini


    Let $\\Lambda$ be an artin algebra with representation dimension equal to three and $M$ an Auslander generator of $\\Lambda$. We show how, under certain assumptions, we can mutate $M$ to get a new Auslander generator whose endomorphism ring is derived equivalent to the endomorphism ring of $M$. We apply our results to selfinjective algebras with radical cube zero of infinite representation type, where we construct an infinite set of Auslander generators.

  10. Sex and deleterious mutations. (United States)

    Gordo, Isabel; Campos, Paulo R A


    The evolutionary advantage of sexual reproduction has been considered as one of the most pressing questions in evolutionary biology. While a pluralistic view of the evolution of sex and recombination has been suggested by some, here we take a simpler view and try to quantify the conditions under which sex can evolve given a set of minimal assumptions. Since real populations are finite and also subject to recurrent deleterious mutations, this minimal model should apply generally to all populations. We show that the maximum advantage of recombination occurs for an intermediate value of the deleterious effect of mutations. Furthermore we show that the conditions under which the biggest advantage of sex is achieved are those that produce the fastest fitness decline in the corresponding asexual population and are therefore the conditions for which Muller's ratchet has the strongest effect. We also show that the selective advantage of a modifier of the recombination rate depends on its strength. The quantification of the range of selective effects that favors recombination then leads us to suggest that, if in stressful environments the effect of deleterious mutations is enhanced, a connection between sex and stress could be expected, as it is found in several species.

  11. Septin mutations in human cancers

    Directory of Open Access Journals (Sweden)

    Elias T Spiliotis


    Full Text Available Septins are GTP-binding proteins that are evolutionarily and structurally related to the RAS oncogenes. Septin expression levels are altered in many cancers and new advances point to how abnormal septin expression may contribute to the progression of cancer. In contrast to the RAS GTPases, which are frequently mutated and actively promote tumorigenesis, little is known about the occurrence and role of septin mutations in human cancers. Here, we review septin missense mutations that are currently in the Catalog of Somatic Mutations in Cancer (COSMIC database. The majority of septin mutations occur in tumors of the large intestine, skin, endometrium and stomach. Over 25% of the annotated mutations in SEPT2, SEPT4 and SEPT9 belong to large intestine tumors. From all septins, SEPT9 and SEPT14 exhibit the highest mutation frequencies in skin, stomach and large intestine cancers. While septin mutations occur with frequencies lower than 3%, recurring mutations in several invariant and highly conserved amino acids are found across different septin paralogs and tumor types. Interestingly, a significant number of these mutations occur in the GTP-binding pocket and septin dimerization interfaces. Future studies may determine how these somatic mutations affect septin structure and function, whether they contribute to the progression of specific cancers and if they could serve as tumor-specific biomarkers.

  12. Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations. (United States)

    Wang, Zheng; Zhang, Weimin; Wang, Yun; Meng, Yan; Su, Liang; Shi, Huiping; Huang, Shangzhi


    Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) and transmitted as an autosomal recessive trait. This is the first systematic mutation screen in Chinese MPS IVA patients. Mutation detections in 24 unrelated Chinese MPS IVA patients were performed by PCR and direct sequencing of exons or the mRNA of GALNS. A total of 42 mutant alleles were identified, belonging to 27 different mutations. Out of the 27 mutations, 16 were novel, including 2 splicing mutations (c.567-1G>T and c.634-1G>A), 2 nonsense mutations (p.W325X and p.Q422X) and 12 missense mutations (p.T88I, p.H142R, p.P163H, p.G168L, p.H236D, p.N289S, p.T312A, p.G316V, p.A324E, p.L366P, p.Q422K and p.F452L). p.G340D was found to be a common mutation in the Chinese MPS IVA patients, accounting for 16.7% of the total number of mutant alleles. The results show that the mutations in Chinese MPS IVA patients are also family specific but have a different mutation spectrum as compared to those of other populations.

  13. Calreticulin Mutations in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Noa Lavi


    Full Text Available With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph− myeloproliferative neoplasms (MPNs in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET and primary myelofibrosis (PMF. At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations and recurrent 5-bp insertions (type 2 mutations in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review.

  14. Occurrence of weak mutators among avian pathogenic Escherichia coli (APEC) isolates causing salpingitis and peritonitis in broiler breeders

    DEFF Research Database (Denmark)

    Pires dos Santos, Teresa M S; Bisgaard, Magne; Kyvsgaard, Niels Christian


    A collection of 46 avian pathogenic Escherichia coli (APEC) isolates was examined for the presence of mutators by determining the rate of mutation to rifampicin resistance. The collection included 34 E. coli isolates obtained in pure culture from chronic lesions of salpingitis and peritonitis in 34...... broiler breeders, of which 12 were associated with the development of secondary septicemia. Twelve additional isolates were obtained from a clonal outbreak (ST95) of E. coli peritonitis syndrome (EPS), the lesions of which changed gradually over time into a subacute/chronic form. The hypothesis...

  15. Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification (United States)

    Hsu, Sandy Chan; Sears, Renee L.; Lemos, Roberta R.; Quintáns, Beatriz; Huang, Alden; Spiteri, Elizabeth; Nevarez, Lisette; Mamah, Catherine; Zatz, Mayana; Pierce, Kerrie D.; Fullerton, Janice M.; Adair, John C.; Berner, Jon E.; Bower, Matthew; Brodaty, Henry; Carmona, Olga; Dobricić, Valerija; Fogel, Brent L.; García-Estevez, Daniel; Goldman, Jill; Goudreau, John L.; Hopfer, Suellen; Janković, Milena; Jaumà, Serge; Jen, Joanna C.; Kirdlarp, Suppachok; Klepper, Joerg; Kostić, Vladimir; Lang, Anthony E.; Linglart, Agnès; Maisenbacher, Melissa K.; Manyam, Bala V.; Mazzoni, Pietro; Miedzybrodzka, Zofia; Mitarnun, Witoon; Mitchell, Philip B.; Mueller, Jennifer; Novaković, Ivana; Paucar, Martin; Paulson, Henry; Simpson, Sheila A.; Svenningsson, Per; Tuite, Paul; Vitek, Jerrold; Wetchaphanphesat, Suppachok; Williams, Charles; Yang, Michele; Schofield, Peter R.; de Oliveira, João R. M.; Sobrido, María-Jesús


    Familial idiopathic basal ganglia calcification (IBGC) or Fahr’s disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient’s disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation. PMID:23334463

  16. In silico investigation of molecular effects caused by missense mutations in creatine transporter protein (United States)

    Zhang, Zhe; Schwatz, Charles; Alexov, Emil


    Creatine transporter (CT) protein, which is encoded by SLC6A8 gene, is essential for taking up the creatine in the cell, which in turn plays a key role in the spatial and temporal maintenance of energy in skeletal and cardiac muscle cells. It was shown that some missense mutations in CT cause mental retardation, while others are harmless non-synonymous single nucleoside polymorphism (nsSNP). Currently fifteen missense mutations in CT are known, among which twelve are disease-causing. Sequence analysis reveals that there is no clear trend distinguishing disease-causing from harmless missense mutations. Because of that, we built 3D model of the CT using highly homologous template and use the model to investigate the effects of mutations of CT stability and hydrogen bond network. It is demonstrated that disease-causing mutations affect the folding free energy and ionization states of titratable group in much greater extend as compared with harmless mutations. Supported by grants from NLM, NIH, grant numbers 1R03LM009748 and 1R03LM009748-S1.

  17. A single mutation in the core domain of the lac repressor reduces leakiness

    NARCIS (Netherlands)

    Gatti-Lafranconi, Pietro; Dijkman, Willem; Devenish, Sean RA; Hollfelder, Florian


    The lac operon provides cells with the ability to switch from glucose to lactose metabolism precisely when necessary. This metabolic switch is mediated by the lac repressor (LacI), which in the absence of lactose binds to the operator DNA sequence to inhibit transcription. Allosteric rearrangements

  18. No mutation was detected in the LMNA gene among sporadic Charcot-Marie-Tooth patients%在散发型腓骨肌萎缩症患者中未检测出LMNA基因突变

    Institute of Scientific and Technical Information of China (English)

    宋书娟; 章远志; 陈彪; 王曼捷; 王越英; 张远锦; 闫明; Nanbert ZHONG


    Objective: To intensively investigate sporadic CMT patients, we have analyzed the LMNA gene in this study in a series of 32 unrelated CMT patients. Methods: Twelve exons of the LMNA gene were amplified from genetomic DNA. PCR products of each exon were analyzed by single strand conformational polymorphism (SSCP). Results: No abnormal SSCP pattern, suggesting no mutation in our CMT patients, was detected. Conclusion: The CMT diseases resulted from the mutations of LMNA gene were rare.

  19. Ocular hypotensive effect, preservation of visual fields, and safety of adding dorzolamide to prostaglandin therapy for twelve months

    Directory of Open Access Journals (Sweden)

    Kenji Inoue


    Full Text Available Kenji Inoue1,3, Mieko Masumoto1,3, Masato Wakakura1, Goji Tomita2, On behalf of the Ochanomizu Ophthalmology Study Group31Inouye Eye Hospital, Tokyo, Japan; 2Department of Ophthalmology, Toho University School of Medicine, Tokyo, Japan; 3Ochanomizu Ophthalmology, Tokyo, JapanPurpose: To prospectively evaluate the safety, hypotensive effect, and preservation of visual fields of dorzolamide when added to latanoprost.Subjects and methods: This study included 46 patients (46 eyes with primary open-angle glaucoma who had been treated with latanoprost. Dorzolamide (1% was added to latanoprost, and the intraocular pressure (IOP was monitored before and after 3, 6, and 12 months. The mean deviation shown by Humphrey perimetry was compared before and after twelve months of treatment. Adverse reactions were monitored over the 12-month study period.Results: The mean baseline IOP was 17.2 ± 3.0 mmHg while those after 3, 6 and 12 months of treatment were 14.9 ± 3.0 mmHg, 14.5 ± 3.2 mmHg, and 14.6 ± 2.6 mmHg respectively (P < 0.0001, 1-ß(power = 0.9999571. The absolute reduction of IOP and the percent reduction were similar after 3, 6, and 12 months of treatment. The mean deviation on Humphrey perimetry was similar before and after twelve months of treatment. Three patients discontinued dorzolamide therapy due to elevation of IOP and one patient discontinued it because of adverse reactions.Conclusion: Dorzolamide is safe and effective when used for twelve months as add-on therapy to latanoprost for open-angle glaucoma.Keywords: dorzolamide, primary open-angle glaucoma, latanoprost 

  20. Do supervised weekly exercise programs maintain functional exercise capacity and quality of life, twelve months after pulmonary rehabilitation in COPD?

    Directory of Open Access Journals (Sweden)

    Alison Jennifer A


    Full Text Available Abstract Background Pulmonary rehabilitation programs have been shown to increase functional exercise capacity and quality of life in COPD patients. However, following the completion of pulmonary rehabilitation the benefits begin to decline unless the program is of longer duration or ongoing maintenance exercise is followed. Therefore, the aim of this study is to determine if supervised, weekly, hospital-based exercise compared to home exercise will maintain the benefits gained from an eight-week pulmonary rehabilitation program in COPD subjects to twelve months. Methods Following completion of an eight-week pulmonary rehabilitation program, COPD subjects will be recruited and randomised (using concealed allocation in numbered envelopes into either the maintenance exercise group (supervised, weekly, hospital-based exercise or the control group (unsupervised home exercise and followed for twelve months. Measurements will be taken at baseline (post an eight-week pulmonary rehabilitation program, three, six and twelve months. The exercise measurements will include two six-minute walk tests, two incremental shuttle walk tests, and two endurance shuttle walk tests. Oxygen saturation, heart rate and dyspnoea will be monitored during all these tests. Quality of life will be measured using the St George's Respiratory Questionnaire and the Hospital Anxiety and Depression Scale. Participants will be excluded if they require supplemental oxygen or have neurological or musculoskeletal co-morbidities that will prevent them from exercising independently. Discussion Pulmonary rehabilitation plays an important part in the management of COPD and the results from this study will help determine if supervised, weekly, hospital-based exercise can successfully maintain functional exercise capacity and quality of life following an eight-week pulmonary rehabilitation program in COPD subjects in Australia.

  1. Filaggrin mutations and the skin

    Directory of Open Access Journals (Sweden)

    Dipankar De


    Full Text Available Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.

  2. Muller's ratchet with compensatory mutations

    CERN Document Server

    Pfaffelhuber, Peter; Wakolbinger, Anton


    We consider an infinite dimensional system of stochastic differential equations which describes the evolution of type frequencies in a large population. Random reproduction is modeled by a Wright-Fisher noise whose inverse diffusion coefficient $N$ corresponds to the total population size. The type of an individual is the number $k$ of deleterious mutations it carries. We assume that fitness of individuals carrying $k$ mutations is decreased by $\\alpha k$ for some $\\alpha >0$. Along the individual lines of descent, (new) mutations accumulate at rate $\\lambda$ per generation, and each of these mutations has a small probability $\\gamma$ per generation to disappear. While the case $\\gamma =0 $ is known as (the Fleming-Viot version of) {\\em Muller's ratchet}, the case $\\gamma > 0$ is referred to as that of {\\em compensatory mutations} in the biological literature. In the former case ($\\gamma=0$), an ever increasing number of mutations is accumulated over time, while in the latter ($\\gamma > 0$) this is prevented ...

  3. Filaggrin mutations and the skin. (United States)

    De, Dipankar; Handa, Sanjeev


    Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.

  4. The myrmicine ant genus Metapone Forel (Hymenoptera: Formicidae): a global taxonomic review with descriptions of twelve new species. (United States)

    Taylor, Robert W; Alpert, Gary D


    The 28 known species of Metapone are monographed and illustrated. Twelve are described as new: M. africana, Gabon; M. balinensis, Bali, Indonesia; M. enigmatica, northeast New Guinea; M. hoelldobleri, northeast Queensland, Australia; M. javana, Java, Indonesia; M. manni, Viti Levu, Fiji; M. mathinnae, Flinders Island, Tasmania, Australia; M. philwardi, northeast New Guinea; M. salomonis, Guadalcanal, Solomon Islands; M. tecklini, northeast Queensland; M. titan, New Ireland, Papua New Guinea; M. wallaceana, Lombok, Indonesia; spp.n. New synonymies include M. greeni Forel = M. johni Karavaiev (Sri Lanka) syn.n, and M. jacobsoni Crawley (Sumatra) = M. nicobarensis Tiwari & Jonathan (Great Nicobar Island) syn.n.

  5. Mutations induced in plant breeding

    Energy Technology Data Exchange (ETDEWEB)

    Barriga B, P. (Universidad Austral de Chile, Valdivia. Inst. de Produccion y Sanidad Vegetal)


    The most significant aspects of the use of ionizing radiations in plant breeding are reviewed. Aspects such as basic principles of mutation, expression and selection in obtention of mutants, methods for using induced mutations and sucess achieved with this methodology in plant breeding are reviewed. Results obtained in a program of induced mutation on wheat for high content of protein and lysine at the Universidad Austral de Chile are presented.

  6. Haplotype Analysis of Norwegian and Swedish Patients with Acute Intermittent Porphyria (AIP: Extreme Haplotype Heterogeneity for the Mutation R116W

    Directory of Open Access Journals (Sweden)

    Kjersti Tjensvoll


    Full Text Available Acute intermittent porphyria (AIP, the most common of the acute porphyrias, is caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS also called porphobilinogen deaminase (PBGD. The mutation spectrum in the HMBS gene is characterized by a majority of family specific mutations. Among the exceptions are R116W and W198X, with high prevalence in both the Dutch and Swedish populations. These two mutations were also detected in unrelated Norwegian patients. Thus, Norwegian and Swedish patients were haplotyped using closely linked flanking microsatellites and intragenic single nucleotide polymorphisms (SNPs to see if the high frequency of these two mutations is due to a founder effect. Twelve intragenic SNPs were determined by a method based on fluorescent restriction enzyme fingerprinting single-strand conformation polymorphism (F-REF-SSCP.

  7. Hepatic gene mutations induced in Big Blue rats by both the potent rat liver azo-carcinogen 6BT and its reported noncarcinogenic analogue 5BT. (United States)

    Fletcher, K; Soames, A R; Tinwell, H; Lefevre, P A; Ashby, J


    The potent rat liver carcinogen 6-p-dimethylaminophenylazobenzthiazole (6BT) and its reported noncarcinogenic analogue 5-p-dimethylaminophenylazobenzthiazole (5BT; evaluated for carcinogenicity under the similar limited bioassay conditions used for 6BT) have been studied in order to seek an explanation for their different carcinogenic activities. Both compounds act as DNA-damaging agents to the rat liver, and both have now been shown to induce lacI (-) gene mutations in the liver of Big Blue(trade mark) transgenic rats. Both compounds were mutagenic following ten daily gavage doses or following administration in diet for 10 days. Neither chemical induced cell proliferation in the liver following repeat gavage administrations. In contrast, dietary administration of 6BT, and to a lesser extent of 5BT, induced hepatic cell proliferation. The carcinogen 6BT, but not the noncarcinogen 5BT, caused proliferation of oval stem cells in the livers by both routes of administration. It is possible that mutations induced in oval cells by 6BT are responsible for its potent carcinogenicity, and that the comparative absence of these cells in 5BT-treated livers may account for the carcinogenic inactivity of 5BT. Equally, the proliferation of the oval cells may reflect changes in liver homeostasis associated with the liver toxicity observed at the dose level of 6BT used (which was, nonetheless, the dose level used in the positive cancer bioassays). It is concluded that the new data presented cannot explain the differing carcinogenic activities of 5BT and 6BT, and that the reported noncarcinogen 5BT may also be carcinogenic when adequately assessed for this activity.

  8. Mutations in the coding regions of the hepatocyte nuclear factor 4 alpha in Iranian families with maturity onset diabetes of the young

    Directory of Open Access Journals (Sweden)

    Tavakolafshari Jalil


    Full Text Available Abstract Hepatocyte nuclear factor 4α (HNF4α is a nuclear receptor involved in glucose homeostasis and is required for normal β cell function. Mutations in the HNF4α gene are associated with maturity onset diabetes of the young type 1 (MODY1. The aim of the present study was to determine the prevalence and nature of mutations in HNF4α gene in Iranian patients with a clinical diagnosis of MODY and their family members. Twelve families including 30 patients with clinically MODY diagnosis and 21 members of their family were examined using PCR-RFLP method and in case of mutation confirmed by sequencing techniques. Fifty age and sex matched subjects with normal fasting blood sugar (FBS and Glucose tolerance test (GTT were constituted the control group and investigated in the similar pattern. Single mutation of V255M in the HNF4α gene was detected. This known mutation was found in 8 of 30 patients and 3 of 21 individuals in relatives. Fifty healthy control subjects did not show any mutation. Here, it is indicated that the prevalence of HNF4α mutation among Iranian patients with clinical MODY is considerable. This mutation was present in 26.6% of our patients, but nothing was found in control group. In the family members, 3 subjects with the age of ≤25 years old carried this mutation. Therefore, holding this mutation in this range of age could be a predisposing factor for developing diabetes in future.

  9. The Effect o f Twelve - Week Recreation Act i v ities on the Anxiety Level of Female Pri soners

    Directory of Open Access Journals (Sweden)

    Zekiye B AŞARAN


    Full Text Available T h e a i m o f t h e s t u d y w a s to examine the effect of twelve - weeks recreation activities on the trait anxiety level of female prisoners in the prisons. The sampling of this study consists of 45 female prisoners who are in the Open Prison in Kandira, 22 of whom are in the experimental group and 23 of whom are in the control group. Different activities, such as music, dance, meditatio n, sportive activities, movies and videos, fun and entertainment activities and competitions, were performed one and half hours a day and two days a week. This lasted for twelve weeks. The data were collected by pre - tests and post - tests that were given bo th at the beginning and at the end of this program. Personal information form and Spielberger anxiety inventory were used as the data collecting tool. The reliability coefficient (Cronbach Alpha was calculated as ,873. The data were analysed with SPSS Win dows 18 programme. Descriptive statistics and Wilcoxon test were conducted. A si gnificant statistical correlation was determined between the prisoners’ pre - tests and post - tests scores in the experimental group (p <0.05. A s c o n c l u s i o n , a positive impact on trait anxiety levels of prisoners w a s f o u n d a f t e r 12 weeks o f recreational activities.

  10. Risk assessment of K basin twelve-inch drain valve failure from a postulated seismic initiating event

    Energy Technology Data Exchange (ETDEWEB)

    MORGAN, R.G.


    The Spent Nuclear Fuel (SNF) Project will transfer metallic SNF from the Hanford 105 K-East and 105 K-West Basins to safe interim storage in the Canister Storage Building in the 200 Area. The initial basis for design, fabrication, installation, and operation of the fuel removal systems was that the basin leak rates which could result from a postulated accident condition would not be excessive relative to reasonable recovery operations. However, an additional potential K Basin water leak path is through the K Basin drain valves. Three twelve-inch drain valves are located in the main basin bays along the north wall. The sumps containing the valves are filled with concrete which covers the drain valve body. Visual observations suggest that only the valve's bonnet and stem are exposed above the basin concrete floor. It was recognized, however, that damage of the drain valve bonnet or stem during a seismic initiating event could provide a potential K Basin water leak path. The objectives of this activity are to: (1) evaluate the risk of damaging the three twelve-inch drain valves located along the north wall of the main basin from a seismic initiating event, and (2) determine the associated potential leak rate from a damaged valve.

  11. Twelve new species and fifty-three new provincial distribution records of Aleocharinae rove beetles of Saskatchewan, Canada (Coleoptera, Staphylinidae). (United States)

    Klimaszewski, Jan; Larson, David J; Labrecque, Myriam; Bourdon, Caroline


    One hundred twenty species of aleocharine beetles (Staphylinidae) are recognized in the province of Saskatchewan. Sixty-five new provincial records, including twelve new species and one new North American record, are presented. Oligota inflata (Mannerheim), a Palearctic species, is newly recorded for North America. The following twelve species are described as new to science: Acrotona pseudopygmaea Klimaszewski & Larson, sp. n., Agaricomorpha pulchra Klimaszewski & Larson, sp. n. (new genus record for Canadian fauna), Aleochara elisabethae Klimaszewski & Larson, sp. n., Atheta (Dimetrota) larsonae Klimaszewski & Larson, sp. n., Atheta (Microdota) pseudopittionii Klimaszewski & Larson, sp. n., Atheta (Microdota) spermathecorum Klimaszewski & Larson, sp. n., Atheta (sensu lato) richardsoni Klimaszewski & Larson, sp. n., Brachyusa saskatchewanae Klimaszewski & Larson, sp. n., Dochmonota langori Klimaszewski & Larson, sp. n., Dochmonota simulans Klimaszewski & Larson, sp. n., Dochmonota websteri Klimaszewski & Larson, sp. n., and Oxypoda domestica Klimaszewski & Larson, sp. n. Colour images of habitus and black and white images of the median lobe of the aedeagus, spermatheca, and tergite and sternite VIII are presented for all new species, Oligota inflata Mannerheim and Dochmonota rudiventris (Eppelsheim). A new synonymy is established: Tetralina filitarsus Casey, syn. n. = Tetralina helenae Casey, now placed in the genus Brachyusa Mulsant & Rey.

  12. Risk assessment of K basin twelve-inch drain valve failure from a postulated seismic initiating event

    Energy Technology Data Exchange (ETDEWEB)

    MORGAN, R.G.


    The Spent Nuclear Fuel (SNF) Project will transfer metallic SNF from the Hanford 105 K-East and 105 K-West Basins to safe interim storage in the Canister Storage Building in the 200 Area. The initial basis for design, fabrication, installation, and operation of the fuel removal systems was that the basin leak rates which could result from a postulated accident condition would not be excessive relative to reasonable recovery operations. However, an additional potential K Basin water leak path is through the K Basin drain valves. Three twelve-inch drain valves are located in the main basin bays along the north wall. The sumps containing the valves are filled with concrete which covers the drain valve body. Visual observations suggest that only the valve's bonnet and stem are exposed above the basin concrete floor. It was recognized, however, that damage of the drain valve bonnet or stem during a seismic initiating event could provide a potential K Basin water leak path. The objectives of this activity are to: (1) evaluate the risk of damaging the three twelve-inch drain valves located along the north wall of the main basin from a seismic initiating event, and (2) determine the associated potential leak rate from a damaged valve.

  13. A class III archaeological survey of twelve region wide fencing upgrade locations in Eagle, Grand, Gunnison, Jackson, Moffat, Pitkin, and Routt counties, Colorado (United States)

    US Fish and Wildlife Service, Department of the Interior — The Colorado Department of Transportation proposes to upgrade existing right-of-way fencing along roadways at twelve separate locations in northwestern Colorado. To...

  14. MPL mutations in myeloproliferative disorders

    DEFF Research Database (Denmark)

    Beer, Philip A.; Campbell, Peter J.; Scott, Linda M.


    Activating mutations of MPL exon 10 have been described in a minority of patients with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET), but their prevalence and clinical significance are unclear. Here we demonstrate that MPL mutations outside exon 10 are uncommon in platelet cDNA...

  15. The Extension of The Twelve-Point Sphere Theorem for a Tetrahedron%四面体的十二点二次曲面

    Institute of Scientific and Technical Information of China (English)

    王奇志; 王东生


    垂心四面体中四条高的垂足,四个面的重心及从各顶点与四面体的垂心连线的三等分点,共十二个点共球.试图把垂心改为四面体内的任意点,相应地把四条高线改换为过该点与每个顶点连线的共点直线组时,则将把垂心四面体的十二点球有趣地推广为四面体的十二点二次曲面.%The four feet of four altitudes for an orthocenter tetrahedron, the centers of gravity of the four faces, the trisection of the line segments from the orthocenter to four summits, total twelve points lie on same sphere, which is known as twelve-point sphere. If the orthocenter can be changed into any point within a tetrahedron in this paper, and corresponding the four perpendiculars also can be changed into the four lines segment passing through the given point to the summits of the tetrahedron, the twelve-point sphere can be changed into twelve-point quadric surface. Twelve point sphere of an orthocenter tetrahedron can be generalized to the twelve-point quadratic surface of a tetrahedron.

  16. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

    LENUS (Irish Health Repository)

    Davidson, G L


    The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1\\/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1\\/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

  17. Novel mutations of TCOF1 gene in European patients with treacher Collins syndrome

    Directory of Open Access Journals (Sweden)

    Rinaldi Fabrizio


    Full Text Available Abstract Background Treacher Collins syndrome (TCS is one of the most severe autosomal dominant congenital disorders of craniofacial development and shows variable phenotypic expression. TCS is extremely rare, occurring with an incidence of 1 in 50.000 live births. The TCS distinguishing characteristics are represented by down slanting palpebral fissures, coloboma of the eyelid, micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic arches, and macrostomia. Conductive hearing loss and cleft palate are often present. TCS results from mutations in the TCOF1 gene located on chromosome 5, which encodes a serine/alanine-rich nucleolar phospho-protein called Treacle. However, alterations in the TCOF1 gene have been implicated in only 81-93% of TCS cases. Methods In this study, the entire coding regions of the TCOF1 gene, including newly described exons 6A and 16A, were sequenced in 46 unrelated subjects suspected of TCS clinical indication. Results Fifteen mutations were reported, including twelve novel and three already described in 14 sporadic patients and in 3 familial cases. Moreover, seven novel polymorphisms were also described. Most of the mutations characterised were microdeletions spanning one or more nucleotides, in addition to an insertion of one nucleotide in exon 18 and a stop mutation. The deletions and the insertion described cause a premature termination of translation, resulting in a truncated protein. Conclusion This study confirms that almost all the TCOF1 pathogenic mutations fall in the coding region and lead to an aberrant protein.

  18. Mutational meltdown in laboratory yeast populations

    NARCIS (Netherlands)

    Zeyl, C.; Mizesko, M.; Visser, de J.A.G.M.


    In small or repeatedly bottlenecked populations, mutations are expected to accumulate by genetic drift, causing fitness declines. In mutational meltdown models, such fitness declines further reduce population size, thus accelerating additional mutation accumulation and leading to extinction. Because

  19. Twelve reasons to refuse the nuclear in the MDP; Douze raisons pour refuser le nucleaire dans le MDP

    Energy Technology Data Exchange (ETDEWEB)

    Bonduelle, A


    The author presents twelve reasons which show that the nuclear energy has not a place in the MDP Mechanism of Clean Development: a main loophole for the developed countries, the doubtful ''additionality'' of the nuclear, the treaty ratification is more difficult with the nuclear, the domestic energy conservation is more efficient in Europe than the nuclear development, the nuclear white elephants facing the South debts, the technology transfers are doubtful, the developing countries and the sustainable development policies are evicted from the MDP, some options are more powerful in the South, the reactors and transport networks size are unsuited, the absence of democratic control, the nuclear proliferation, the nuclear safety and the wastes. (A.L.B.)

  20. Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4). (United States)

    Piscosquito, Giuseppe; Saveri, Paola; Magri, Stefania; Ciano, Claudia; Gandioli, Claudia; Morbin, Michela; Bella, Daniela D; Moroni, Isabella; Taroni, Franco; Pareyson, Davide


    Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive (AR) demyelinating neuropathy associated to SH3TC2 mutations, characterized by early onset, spine deformities, and cranial nerve involvement. We screened 43 CMT4 patients (36 index cases) with AR inheritance, demyelinating nerve conductions, and negative testing for PMP22 duplication, GJB1 and MPZ mutations, for SH3TC2 mutations. Twelve patients (11 index cases) had CMT4C as they carried homozygous or compound heterozygous mutations in SH3TC2. We found six mutations: three nonsense (p.R1109*, p.R954*, p.Q892*), one splice site (c.805+2T>C), one synonymous variant (p.K93K) predicting altered splicing, and one frameshift (p.F491Lfs*32) mutation. The splice site and the frameshift mutations are novel. Mean onset age was 7 years (range: 1-14). Neuropathy was moderate-to-severe. Scoliosis was present in 11 patients (severe in 4), and cranial nerve deficits in 9 (hearing loss in 7). Scoliosis and cranial nerve involvement are frequent features of this CMT4 subtype, and their presence should prompt the clinician to look for SH3TC2 gene mutations. In our series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR-CMT type.

  1. Minisequencing mitochondrial DNA pathogenic mutations

    Directory of Open Access Journals (Sweden)

    Carracedo Ángel


    Full Text Available Abstract Background There are a number of well-known mutations responsible of common mitochondrial DNA (mtDNA diseases. In order to overcome technical problems related to the analysis of complete mtDNA genomes, a variety of different techniques have been proposed that allow the screening of coding region pathogenic mutations. Methods We here propose a minisequencing assay for the analysis of mtDNA mutations. In a single reaction, we interrogate a total of 25 pathogenic mutations distributed all around the whole mtDNA genome in a sample of patients suspected for mtDNA disease. Results We have detected 11 causal homoplasmic mutations in patients suspected for Leber disease, which were further confirmed by standard automatic sequencing. Mutations m.11778G>A and m.14484T>C occur at higher frequency than expected by change in the Galician (northwest Spain patients carrying haplogroup J lineages (Fisher's Exact test, P-value Conclusion We here developed a minisequencing genotyping method for the screening of the most common pathogenic mtDNA mutations which is simple, fast, and low-cost. The technique is robust and reproducible and can easily be implemented in standard clinical laboratories.

  2. HNPCC: Six new pathogenic mutations

    Directory of Open Access Journals (Sweden)

    Epplen Joerg T


    Full Text Available Abstract Background Hereditary non-polyposis colorectal cancer (HNPCC is an autosomal dominant disease with a high risk for colorectal and endometrial cancer caused by germline mutations in DNA mismatch-repair genes (MMR. HNPCC accounts for approximately 2 to 5% of all colorectal cancers. Here we present 6 novel mutations in the DNA mismatch-repair genes MLH1, MSH2 and MSH6. Methods Patients with clinical diagnosis of HNPCC were counselled. Tumor specimen were analysed for microsatellite instability and immunohistochemistry for MLH1, MSH2 and MSH6 protein was performed. If one of these proteins was not detectable in the tumor mutation analysis of the corresponding gene was carried out. Results We identified 6 frameshift mutations (2 in MLH1, 3 in MSH2, 1 in MSH6 resulting in a premature stop: two mutations in MLH1 (c.2198_2199insAACA [p.N733fsX745], c.2076_2077delTG [p.G693fsX702], three mutations in MSH2 (c.810_811delGT [p.C271fsX282], c.763_766delAGTGinsTT [p.F255fsX282], c.873_876delGACT [p.L292fsX298] and one mutation in MSH6 (c.1421_1422dupTG [p.C475fsX480]. All six tumors tested for microsatellite instability showed high levels of microsatellite instability (MSI-H. Conclusions HNPCC in families with MSH6 germline mutations may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations.

  3. Radiation mutation breeding

    Energy Technology Data Exchange (ETDEWEB)

    Song, Hi Sup; Kim, Jae Sung; Kim, Jin Kyu; Shin, In Chul; Lim, Young Taek


    In order to develop an advanced technical knowledge for the selection of better mutants, some of the crops were irradiated and the mutation rate, the survival rate and the method for selction of a mutant were studied. Furthermore, this study aimed to obtain basic data applicable to the development of genetic resources by evaluation and analysis the specific character for selection of the superior mutant and its plant breeding. 1. selection of the mutant with a superior resistance against environment in the principal crops 1) New varieties of mutant rices such as Wonpyeongbyeo, Wongwangbyeo, Winmibyeo, and heogseon chalbeyeo (sticky forma) were registered in the national variety list and made an application to crop variety protection right. They are under review now. 2) We also keep on studying on the number of a grain of 8 lines of excellent mutant rice for the purpose of improvement of breeding . 3) We selected 3 lines which have a resistance to pod and stem blight in large soybean, 31 lines with small grain size and higher yield, 112 lines of soybean of cooking, 7 lines of low lipoxygenase content, and 12 lines with decreased phytic acid content by 20 % compared to the previous level. 2. Selection of advanced Mugunwha (Rose of Sharon) mutant 1) Bagseul, a new variety of mutant, was developed and 30 plantlets of it are being proliferated. 2) Fifty-three lines of a mutant having a various morphologies were selected.

  4. Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma

    Directory of Open Access Journals (Sweden)

    Bardeesy Nabeel


    Full Text Available Abstract Background The genetics of advanced biliary tract cancers (BTC, which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. Methods To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases. Results Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%. KRAS mutations were identified in 3 (13% intra-hepatic cholangiocarcinomas and 1 (33% perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma. Conclusions The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.

  5. Markov models for accumulating mutations

    CERN Document Server

    Beerenwinkel, Niko


    We introduce and analyze a waiting time model for the accumulation of genetic changes. The continuous time conjunctive Bayesian network is defined by a partially ordered set of mutations and by the rate of fixation of each mutation. The partial order encodes constraints on the order in which mutations can fixate in the population, shedding light on the mutational pathways underlying the evolutionary process. We study a censored version of the model and derive equations for an EM algorithm to perform maximum likelihood estimation of the model parameters. We also show how to select the maximum likelihood poset. The model is applied to genetic data from different cancers and from drug resistant HIV samples, indicating implications for diagnosis and treatment.

  6. Dynamical Mutation of Dark Energy

    CERN Document Server

    Abramo, L R; Liberato, L; Rosenfeld, R


    We discuss the intriguing possibility that dark energy may change its equation of state in situations where large dark energy fluctuations are present. We show indications of this dynamical mutation in some generic models of dark energy.

  7. PPARγ mutations, lipodystrophy and diabetes. (United States)

    Astapova, Olga; Leff, Todd


    The focus of this review is the lipodystrophy syndrome caused by mutation in the PPARγ nuclear receptor - partial familial lipodystrophy FPLD3. To provide a broader context for how these mutations act to generate the clinical features of partial lipodystrophy we will review the basic biology of PPARγ and also survey the set PPARγ genetic variants that do not cause lipodystrophy, but are nonetheless associated with clinically related syndromes, specifically type 2 diabetes.

  8. Gene mutations in hepatocellular adenomas

    DEFF Research Database (Denmark)

    Raft, Marie B; Jørgensen, Ernö N; Vainer, Ben


    is associated with bi-allelic mutations in the TCF1 gene and morphologically has marked steatosis. β-catenin activating HCA has increased activity of the Wnt/β-catenin pathway and is associated with possible malignant transformation. Inflammatory HCA is characterized by an oncogene-induced inflammation due....... This review offers an overview of the reported gene mutations associated with hepatocellular adenomas together with a discussion of the diagnostic and prognostic value....

  9. Mutations causative of familial hypercholesterolaemia

    DEFF Research Database (Denmark)

    Benn, Marianne; Watts, Gerald F; Tybjærg-Hansen, Anne


    AIMS: Ideally, familial hypercholesterolaemia (FH) is diagnosed by testing for mutations that decrease the catabolism of low-density lipoprotein (LDL) cholesterol; however, genetic testing is not universally available. The aim of the present study was to assess the frequency and predictors of FH....... The prevalence of the four FH mutations was 0.18% (1:565), suggesting a total prevalence of FH mutations of 0.46% (1:217). Using the Dutch Lipid Clinic Network (DLCN) criteria, odds ratios for an FH mutation were 439 (95% CI: 170-1 138) for definite FH, 90 (53-152) for probable FH, and 18 (13-25) for possible FH......-cholesterol concentration to discriminate between mutation carriers and non-carriers was 4.4 mmol/L. CONCLUSION: Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population and are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria...

  10. Changes in lipids over twelve months after initiating protease inhibitor therapy among persons treated for HIV/AIDS

    Directory of Open Access Journals (Sweden)

    Hogg Robert S


    Full Text Available Abstract Background Protease inhibitors are known to alter the lipid profiles in subjects treated for HIV/AIDS. However, the magnitude of this effect on plasma lipoproteins and lipids has not been adequately quantified. Objective To estimate the changes in plasma lipoproteins and triglycerides occurring within 12 months of initiating PI-based antiretroviral therapy among HIV/AIDS afflicted subjects. Methods We included all antiretroviral naïve HIV-infected persons treated at St-Paul's Hospital, British Columbia, Canada, who initiated therapy with protease inhibitor antiretroviral (ARV drugs between August 1996 and January 2002 and who had at least one plasma lipid measurement. Longitudinal associations between medication use and plasma lipids were estimated using mixed effects models that accounted for repeated measures on the same subjects and were adjusted for age, sex, time dependent CD4+ T-cell count, and time dependent cumulative use of non-nucleoside reverse transcriptase inhibitors and adherence. The cumulative number of prescriptions filled for PIs was considered time dependent. We estimated the changes in the 12 months following any initiation of a PI based regimen. Results A total of 679 eligible subjects were dispensed nucleoside analogues and PI at the initiation of therapy. Over a median 47 months of follow-up (interquartile range (IQR: 29–62, subjects had a median of 3 (IQR: 1–6 blood lipid measurements. Twelve months after treatment initiation of PI use, there was an estimated 20% (95% confidence interval: 17% – 24% increase in total cholesterol and 22% (12% – 33% increase in triglycerides. Conclusions Twelve months after treatment initiation with PIs, statistically significant increases in total cholesterol and triglycerides levels were observed in HIV-infected patients under conditions of standard treatment. Our results contribute to the growing body of evidence implicating PIs in the development of blood lipid

  11. Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome. (United States)

    Xu, Xiaojing; Yang, Xiaoxu; Wu, Qixi; Liu, Aijie; Yang, Xiaoling; Ye, Adam Yongxin; Huang, August Yue; Li, Jiarui; Wang, Meng; Yu, Zhe; Wang, Sheng; Zhang, Zhichao; Wu, Xiru; Wei, Liping; Zhang, Yuehua


    The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered "de novo" by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low-level mosaicism in parents of families with seemingly "de novo" mutations will allow for better informed genetic counseling.

  12. A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. (United States)

    Ingre, Caroline; Landers, John E; Rizik, Naji; Volk, Alexander E; Akimoto, Chizuru; Birve, Anna; Hübers, Annemarie; Keagle, Pamela J; Piotrowska, Katarzyna; Press, Rayomand; Andersen, Peter Munch; Ludolph, Albert C; Weishaupt, Jochen H


    Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have very recently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, we performed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporal dementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenic relevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260 sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United States were screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. In a German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which was absent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recently described p.Gln117Gly sequence variant was found in another familial ALS patient from the United States. The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overt cognitive involvement. PFN1 mutations were absent in patients with motor neuron disease and dementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the "classic" ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proof-of-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motor neuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization by phosphorylation of profilin 1 might be necessary for motor neuron survival.

  13. 5S rDNA characterization in twelve Sciaenidae fish species (Teleostei, Perciformes: depicting gene diversity and molecular markers

    Directory of Open Access Journals (Sweden)

    Fernanda A. Alves-Costa


    Full Text Available In order to extend the genetic data on the Sciaenidae fish family, the present study had the purpose to characterize PCR-generated 5S rDNA repeats of twelve species of this group through PAGE (Polyacrylamide Gel Electrophoresis analysis. The results showed the occurrence of at least two different 5S rDNA size classes in all the species. Moreover, 5S rDNA repeats of one of the studied species - Isopisthus parvipinnis - were cloned and subjected to nucleotide sequencing and Southern blot membrane hybridization analyses, which permitted to confirm the existence of two major 5S rDNA classes. Phylogenetic analysis based on the nucleotide sequences of different 5S rDNA repeats of I. parvipinnis lead to their separation into two major clusters. These results may reflect the high dynamism that rules the evolution rate of 5S rDNA repeats. The obtained data suggest that 5S rDNA can be useful in genetic analyses to identify species-specific markers and determine relationships among species of the Sciaenidae group.

  14. Uptake of radionuclide thorium by twelve native plants grown in uranium mill tailings soils from south part of China

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Xun, E-mail:


    Highlights: • Screen dominant plants grown in uranium mill tailings soils. • Quantify the content of {sup 232}Th of soil samples from uranium mill tailings. • Quantify the transfer factor, bioconcentration factor and phytoremediation factor. • Screen out the plant species capable of remediating radionuclide contaminated soils. • Guide the reuse of study area in future. - Abstract: The concentrations of thorium ({sup 232}Th) in soil from a uranium mill tailings repository in South China were analyzed. The results showed that all the soil samples were acidic and the concentrations of {sup 232}Th in all the soil samples were more than the natural radionuclide content in soil of China. Through the field investigation, twelve kinds of dominant plants were discovered. The total quantity of {sup 232}Th in the whole plant is highest in rice flat sedge. We also found that Miscanthus floridulus has the greatest transfer factor (TF) for {sup 232}Th, rice flat sedge has the greatest bioconcentration factor (BF) for {sup 232}Th. At the mean time, M. floridulus has the greatest phytoremediation factor (PF) for {sup 232}Th. On the basis of the above conclusions and the definition for hyperaccumulator, rice flat sedge and M. floridulus could be the candidates of phytoremediation for radionuclide {sup 232}Th in the soil.

  15. Videofluoroscopy of the oral phase of swallowing in eight to twelve years old children with dental malocclusion. (United States)

    Junqueira, Patricia; Costa, Milton Melciades


    The objective of this study was to describe the oral phase of swallowing in individuals with dental malocclusion and to generate data that would contribute to the rehabilitation of those patients. The study was based on the evaluation of the swallowing system through videofluoroscopy on thirty-four children of both genders, aged eight to twelve years old who present with Angle Class II and III dental malocclusions. Thirteen children of similar age and gender presenting normal dental occlusion formed the control group. The results indicated that the oral phase of swallowing is different between individuals with normal occlusion and malocclusion. Dental occlusion types Angle Class II and III did not present a swallowing pattern, independently of the amount of liquid ingested. The swallowing appeared effective in the oral phase of individuals with dental malocclusion, even though adaptations were identified. The outcome, in the absence of a single pattern and the efficiency of the adapted swallowing demonstrates, first a need for additional research investigating orofacial myofunctional treatment for patients with malocclusion and second how such analyses should focus on contributing positively to the rehabilitation of these patients.

  16. Advanced LIGO Two-Stage Twelve-Axis Vibration Isolation and Positioning Platform. Part 2: Experimental Investigation and Tests Results

    CERN Document Server

    Matichard, Fabrice; Mason, Kenneth; Mittleman, Richard; Abbott, Benjamin; Abbott, Samuel; Allwine, Eric; Barnum, Samuel; Birch, Jeremy; Biscans, Sebastien; Clark, Daniel; Coyne, Dennis; DeBra, Dan; DeRosa, Ryan; Foley, Stephany; Fritschel, Peter; Giaime, Joseph A; Gray, Corey; Grabeel, Gregory; Hanson, Joe; Hillard, Michael; Kissel, Jeffrey; Kucharczyk, Christopher; Roux, Adrien Le; Lhuillier, Vincent; Macinnis, Myron; OReilly, Brian; Ottaway, David; Paris, Hugo; Puma, Michael; Radkins, Hugh; Ramet, Celine; Robinson, Mitchell; Ruet, Laurent; Sareen, Pradeep; Shoemaker, Daivid; Stein, Andy; Thomas, Jeremy; Vargas, Michael; Warner, Jimmy


    This paper presents the results of the past seven years of experimental investigation and testing done on the two-stage twelve-axis vibration isolation platform for Advanced LIGO gravity waves observatories. This five-ton two-and-half-meter wide system supports more than a 1000 kg of very sensitive equipment. It provides positioning capability and seismic isolation in all directions of translation and rotation. To meet the very stringent requirements of Advanced LIGO, the system must provide more than three orders of magnitude of isolation over a very large bandwidth. It must bring the motion below 10^(-11) m/(Hz)^0.5 at 1 Hz and 10^(-12) m/(Hz)^0.5 at 10 Hz. A prototype of this system has been built in 2006. It has been extensively tested and analyzed during the following two years. This paper shows how the experimental results obtained with the prototype were used to engineer the final design. It highlights how the engineering solutions implemented not only improved the isolation performance but also greatl...

  17. Twelve-month safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing

    DEFF Research Database (Denmark)

    Bisgaard, Hans; Allen, David; Milanowski, Janusz;


    : There was no significant difference in mean adjusted growth rates between the 2 groups: 84.0 mm/year in the FP group versus 86.4 mm/year in the SCG group (difference FP-SCG: -2.4 mm/year; 95% confidence interval: -6.6 to 1.8). Growth comparisons were independent of age, gender, previous use of steroid, or whether measured......, exacerbations, and requirements for oral steroid treatment and more symptom-free days and days without use of rescue treatment. CONCLUSIONS: Twelve months of treatment with inhaled FP (100 microg twice daily) in preschool children aged 1 to 3 years with recurrent wheeze has no effect on growth and no other......OBJECTIVE: Our aim was to compare the 12-month safety and efficacy of fluticasone propionate (FP) and sodium cromoglycate (SCG) in children aged 1 to 3 years with mild to moderate recurrent wheeze. METHODS: The study was a randomized, parallel-group, open-label multicenter study of 625 children...

  18. A First Assessment of Mycobacterium tuberculosis Genetic Diversity and Drug-Resistance Patterns in Twelve Caribbean Territories

    Directory of Open Access Journals (Sweden)

    Julie Millet


    Full Text Available With the exception of some French-speaking islands, data on tuberculosis (TB in the Caribbean are scarce. In this study, we report a first assessment of genetic diversity of a convenience sample of Mycobacterium tuberculosis strains received from twelve Caribbean territories by spoligotyping and describe their drug-resistance patterns. Of the 480 isolates, 40 (8.3% isolates showed resistance to at least one anti-TB drug. The proportion of drug-resistant strains was significantly higher in The Bahamas (21.4%; P=0.02, and Guyana (27.5%; P<0.0001, while it was significantly lower in Jamaica (2.4%; P=0.03 than in other countries of the present study. Regarding genetic diversity, 104 distinct spoligotype patterns were observed: 49 corresponded to clustered strains (2 to 93 strains per cluster, while 55 remained unclustered among which 16 patterns were not reported previously. Combining the study results with regional data retrieved from the international SITVIT2 database underlined a connection between frequency of certain M. tuberculosis phylogenetic lineages and the language spoken, suggesting historical (colonial and ongoing links (trade, tourism, and migratory flows with European countries with which they shared a common past.

  19. Measuring performance in off-patent drug markets: a methodological framework and empirical evidence from twelve EU Member States. (United States)

    Kanavos, Panos


    This paper develops a methodological framework to help evaluate the performance of generic pharmaceutical policies post-patent expiry or after loss of exclusivity in non-tendering settings, comprising five indicators (generic availability, time delay to and speed of generic entry, number of generic competitors, price developments, and generic volume share evolution) and proposes a series of metrics to evaluate performance. The paper subsequently tests this framework across twelve EU Member States (MS) by using IMS data on 101 patent expired molecules over the 1998-2010 period. Results indicate that significant variation exists in generic market entry, price competition and generic penetration across the study countries. Size of a geographical market is not a predictor of generic market entry intensity or price decline. Regardless of geographic or product market size, many off patent molecules lack generic competitors two years after loss of exclusivity. The ranges in each of the five proposed indicators suggest, first, that there are numerous factors--including institutional ones--contributing to the success of generic entry, price decline and market penetration and, second, MS should seek a combination of supply and demand-side policies in order to maximise cost-savings from generics. Overall, there seems to be considerable potential for faster generic entry, uptake and greater generic competition, particularly for molecules at the lower end of the market.

  20. Chemical Abundances in Twelve Red Giants of the Large Magellanic Cloud from High-Resolution Infrared Spectroscopy

    CERN Document Server

    Smith, V V; Cunha, K; Plez, B; Lambert, D L; Pilachowski, C A; Barbuy, B; Melendez, J; Balachandran, S C; Bessell, M S; Geisler, D; Hesser, J E; Winge, C


    High-resolution infrared spectra (R=50,000) have been obtained for twelve red-giant members of the LMC with the Gemini South 8.3-meter telescope plus Phoenix spectrometer. Quantitative chemical abundances of carbon-12, carbon-13, nitrogen-14, and oxygen-16 were derived from molecular lines of CO, CN, and OH, while sodium, scandium, titanium, and iron abundances were derived from neutral atomic lines. The LMC giants have masses from about 1 to 4 solar masses and span a metallicity range from [Fe/H]= -1.1 to -0.3. The program red giants all show evidence of first dredge-up mixing, with low 12C/13C ratios, and low 12C correlated with high 14N abundances. Comparisons of the oxygen-to-iron ratios in the LMC and the Galaxy indicate that the trend of [O/Fe] versus [Fe/H] in the LMC falls about 0.2 dex below the Galactic trend. Such an offset can be modeled as due to an overall lower rate of supernovae per unit mass in the LMC relative to the Galaxy, as well as a slightly lower ratio of supernovae of type II to super...

  1. Common Β- Thalassaemia Mutations in

    Directory of Open Access Journals (Sweden)

    P Azarfam


    Full Text Available Introduction: β –Thalassaemia was first explained by Thomas Cooly as Cooly’s anaemia in 1925. The β- thalassaemias are hereditary autosomal disorders with decreased or absent β-globin chain synthesis. The most common genetic defects in β-thalassaemias are caused by point mutations, micro deletions or insertions within the β-globin gene. Material and Methods: In this research , 142 blood samples (64 from childrens hospital of Tabriz , 15 samples from Shahid Gazi hospital of Tabriz , 18 from Urumia and 45 samples from Aliasghar hospital of Ardebil were taken from thalassaemic patients (who were previously diagnosed .Then 117 non-familial samples were selected . The DNA of the lymphocytes of blood samples was extracted by boiling and Proteinase K- SDS procedure, and mutations were detected by ARMS-PCR methods. Results: From the results obtained, eleven most common mutations,most of which were Mediterranean mutations were detected as follows; IVS-I-110(G-A, IVS-I-1(G-A ،IVS-I-5(G-C ,Frameshift Codon 44 (-C,( codon5(-CT,IVS-1-6(T-C, IVS-I-25(-25bp del ,Frameshift 8.9 (+G ,IVS-II-1(G-A ,Codon 39(C-T, Codon 30(G-C the mutations of the samples were defined. The results showed that Frameshift 8.9 (+G, IVS-I-110 (G-A ,IVS-II-I(G-A, IVS-I-5(G-C, IVS-I-1(G-A , Frameshift Codon 44(-C , codon5(-CT , IVS-1-6(T-C , IVS-I-25(-25bp del with a frequency of 29.9%, 25.47%,17.83%, 7.00%, 6.36% , 6.63% , 3.8% , 2.5% , 0.63% represented the most common mutations in North - west Iran. No mutations in Codon 39(C-T and Codon 30(G-C were detected. Cunclusion: The frequency of the same mutations in patients from North - West of Iran seems to be different as compared to other regions like Turkey, Pakistan, Lebanon and Fars province of Iran. The pattern of mutations in this region is more or less the same as in the Mediterranean region, but different from South west Asia and East Asia.

  2. [Founder mutation in Lynch syndrome]. (United States)

    Cajal, Andrea R; Piñero, Tamara A; Verzura, Alicia; Santino, Juan Pablo; Solano, Angela R; Kalfayan, Pablo G; Ferro, Alejandra; Vaccaro, Carlos


    Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase). The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments.

  3. SQSTM1 Mutations and Glaucoma.

    Directory of Open Access Journals (Sweden)

    Todd E Scheetz

    Full Text Available Glaucoma is the most common cause of irreversible blindness worldwide. One subset of glaucoma, normal tension glaucoma (NTG occurs in the absence of high intraocular pressure. Mutations in two genes, optineurin (OPTN and TANK binding kinase 1 (TBK1, cause familial NTG and have known roles in the catabolic cellular process autophagy. TKB1 encodes a kinase that phosphorylates OPTN, an autophagy receptor, which ultimately activates autophagy. The sequestosome (SQSTM1 gene also encodes an autophagy receptor and also is a target of TBK1 phosphorylation. Consequently, we hypothesized that mutations in SQSTM1 may also cause NTG. We tested this hypothesis by searching for glaucoma-causing mutations in a cohort of NTG patients (n = 308 and matched controls (n = 157 using Sanger sequencing. An additional 1098 population control samples were also analyzed using whole exome sequencing. A total of 17 non-synonymous mutations were detected which were not significantly skewed between cases and controls when analyzed separately, or as a group (p > 0.05. These data suggest that SQSTM1 mutations are not a common cause of NTG.

  4. Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer. (United States)

    Castellanos, Emily; Feld, Emily; Horn, Leora


    EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being increasingly understood. Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design.

  5. Clinical Relevance of CHEK2 And NBN Mutations in the Macedonian Population

    Directory of Open Access Journals (Sweden)

    Maleva Kostovska I.


    Full Text Available Clinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delС, I157T and del5395 and NBN (R215W and 657del5 gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR assay. We have found that mutations were more frequent in breast cancer patients (n = 13, 4.3% than in controls (n = 5, 1.8%, although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations (NBN R215W and CHEK2 I157T. The most frequent variant was I157T, found in 10 patients and four controls (p = 0.176 and was found to be associated with familial breast cancer (p = 0.041. CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population.

  6. Rapid generation of hypomorphic mutations (United States)

    Arthur, Laura L.; Chung, Joyce J.; Jankirama, Preetam; Keefer, Kathryn M.; Kolotilin, Igor; Pavlovic-Djuranovic, Slavica; Chalker, Douglas L.; Grbic, Vojislava; Green, Rachel; Menassa, Rima; True, Heather L.; Skeath, James B.; Djuranovic, Sergej


    Hypomorphic mutations are a valuable tool for both genetic analysis of gene function and for synthetic biology applications. However, current methods to generate hypomorphic mutations are limited to a specific organism, change gene expression unpredictably, or depend on changes in spatial-temporal expression of the targeted gene. Here we present a simple and predictable method to generate hypomorphic mutations in model organisms by targeting translation elongation. Adding consecutive adenosine nucleotides, so-called polyA tracks, to the gene coding sequence of interest will decrease translation elongation efficiency, and in all tested cell cultures and model organisms, this decreases mRNA stability and protein expression. We show that protein expression is adjustable independent of promoter strength and can be further modulated by changing sequence features of the polyA tracks. These characteristics make this method highly predictable and tractable for generation of programmable allelic series with a range of expression levels. PMID:28106166

  7. Neutral Evolution of Mutational Robustness

    CERN Document Server

    Van Nimwegen, E; Huynen, M; Nimwegen, Erik van; Crutchfield, James P.; Huynen, Martijn


    We introduce and analyze a general model of a population evolving over a network of selectively neutral genotypes. We show that the population's limit distribution on the neutral network is solely determined by the network topology and given by the principal eigenvector of the network's adjacency matrix. Moreover, the average number of neutral mutant neighbors per individual is given by the matrix spectral radius. This quantifies the extent to which populations evolve mutational robustness: the insensitivity of the phenotype to mutations. Since the average neutrality is independent of evolutionary parameters---such as, mutation rate, population size, and selective advantage---one can infer global statistics of neutral network topology using simple population data available from {\\it in vitro} or {\\it in vivo} evolution. Populations evolving on neutral networks of RNA secondary structures show excellent agreement with our theoretical predictions.

  8. Mutations in ANKH cause chondrocalcinosis. (United States)

    Pendleton, Adrian; Johnson, Michelle D; Hughes, Anne; Gurley, Kyle A; Ho, Andrew M; Doherty, Michael; Dixey, Josh; Gillet, Pierre; Loeuille, Damien; McGrath, Rodney; Reginato, Antonio; Shiang, Rita; Wright, Gary; Netter, Patrick; Williams, Charlene; Kingsley, David M


    Chondrocalcinosis (CC) is a common cause of joint pain and arthritis that is caused by the deposition of calcium-containing crystals within articular cartilage. Although most cases are sporadic, rare familial forms have been linked to human chromosomes 8 (CCAL1) or 5p (CCAL2) (Baldwin et al. 1995; Hughes et al. 1995; Andrew et al. 1999). Here, we show that two previously described families with CCAL2 have mutations in the human homolog of the mouse progressive ankylosis gene (ANKH). One of the human mutations results in the substitution of a highly conserved amino acid residue within a predicted transmembrane segment. The other creates a new ATG start site that adds four additional residues to the ANKH protein. Both mutations segregate completely with disease status and are not found in control subjects. In addition, 1 of 95 U.K. patients with sporadic CC showed a deletion of a single codon in the ANKH gene. The same change was found in a sister who had bilateral knee replacement for osteoarthritis. Each of the three human mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro. All three of the human mutations showed significantly more activity than a previously described nonsense mutation that causes severe hydroxyapatite mineral deposition and widespread joint ankylosis in mice. These results suggest that small sequence changes in ANKH are one cause of CC and joint disease in humans. Increased ANK activity may explain the different types of crystals commonly deposited in human CCAL2 families and mutant mice and may provide a useful pharmacological target for treating some forms of human CC.

  9. Mutations determining mitomycin resistance in Bacillus subtilis. (United States)

    Iyer, V N


    Iyer, V. N. (Microbiology Research Institute, Canada Department of Agriculture, Ottawa, Canada). Mutations determining mitomycin resistance in Bacillus subtilis. J. Bacteriol. 92:1663-1669. 1966.-The pattern of development of genetic resistance in Bacillus subtilis to mitomycin C was studied, and spontaneous single and multistep mutants were obtained. The transmission and expression of these mutations in sensitive strains proved possible by means of genetic transformation. The mutations were genetically studied in relation to a chromosomal mutation, mac-1, which confers resistance to the macrolide antibiotic erythromycin and which has been previously localized in the early-replicating segment of the B. subtilis chromosome. The results indicate that all of three primary mutations studied in this manner, as well as a secondary and tertiary mutation derived from one of the primary mutations, are clustered in this early-replicating segment. It appears that the secondary and tertiary mutations enhance the resistance conferred by the primary mutation, apparently without themselves conferring any resistance.

  10. 12 Daghem: Beskrivning av uppfostringsklimat och sociala relationer (Twelve Day Care Centers: A Multisite Comparison of Day-Care Climate and Social Relations). (United States)

    Ekholm, Bodil; Hedin, Anna

    Twelve day care centers in a Swedish commune were systematically observed. Centers were selected on the basis of responses to a questionnaire on attitudes about upbringing which was answered by all the personnel at the 104 day care centers in the commune. Four of the selected centers represented a so-called "present-focused" upbringing…

  11. Dual-resolution Raman spectroscopy for measurements of temperature and twelve species in hydrocarbon–air flames

    Energy Technology Data Exchange (ETDEWEB)

    Magnotti, Gaetano; Barlow, Robert S.


    This study introduces dual-resolution Raman spectroscopy as a novel diagnostics approach for measurements of temperature and species in flames where multiple hydrocarbons are present. Simultaneous measurement of multiple hydrocarbons is challenging because their vibrational Raman spectra in the C–H stretch region are closely overlapped and are not well known over the range of temperature encountered in flames. Overlap between the hydrocarbon spectra is mitigated by adding a second spectrometer, with a higher dispersion grating, to collect the Raman spectra in the C–H stretch region. A dual-resolution Raman spectroscopy instrument has been developed and optimized for measurements of major species (N2, O2, H2O, CO2, CO, H2, DME) and major combustion intermediates (CH4, CH2O, C2H2, C2H4 and C2H6) in DME–air flames. The temperature dependences of the hydrocarbon Raman spectra over fixed spectral regions have been determined through a series of measurements in laminar Bunsen-burner flames, and have been used to extend a library of previously acquired Raman spectra up to flame temperature. The paper presents the first Raman measurements of up to twelve species in hydrocarbon flames, and the first quantitative Raman measurements of formaldehyde in flames. Lastly, the accuracy and precision of the instrument are determined from measurements in laminar flames and the applicability of the instrument to turbulent DME–air flames is discussed.

  12. [Effect of broken black tea on the formation of dental enamel and the contents of twelve kinds of chemical elements]. (United States)

    Cao, Jin; Yao, Zhigang; Yi, Juan; Zhao, Yan; Zhong, Jie; Yuan, Huabing


    The aim of this study was to investigate the effect of broken black tea with slightly hyper-normal fluoride content which was near the level of people tea-drinking habits on enamel morphological structure and its content of chemical elements. Thirty six rats were divided randomly into 3 groups: one was control group and another two groups fed with broken black tea infusion with F- content of 8.2 mg/l and 16.4 mg/l, respectively. After 360 days, collected 144 teeth, observed their morphological structure by electron micrograph, Scanning electron micrographs (SEM) and also analyzed concentrations of several chemical elements in tooth by x-ray fluorescence spectrometry (XRF). Chronic dental fluorosis in rats was induced by treatment with broken black tea with slightly hyper-normal fluoride content. Hyper-calcification and hypo-calcification appeared in enamel of those teeth from both broken black tea treated groups in dose-dependent manner. Twelve kinds of chemical elements, such as Ca, Mg, P, Al, Cl were examined. The contents of Ca, P, Mg were reduced and that of Al and Cl were increased significantly. Compared with control group, the levels of Si, S, Fe were lower in those teeth from treated group (broken black tea with the F- content of 8.2 mg/l), while higher in those teeth from treated group (broken black tea with the F- content of 16.4 mg/l). Long-term drinking broken black tea with hyper-normal fluoride content could cause chronic dental fluorosis, and its injury in enamel was related with Hyper-calcification and hypo-calcification mainly. Those changes of several chemical elements level in enamel, such as Ca, P, Al, Cl, were suggested that these chemical elements have influences on the development and mineralization of enamel.

  13. Monitoring field susceptibility to imidacloprid in the cat flea: a world-first initiative twelve years on. (United States)

    Kopp, Steven; Blagburn, Byron; Coleman, Glen; Davis, Wendell; Denholm, Ian; Field, Chris; Hostetler, Joe; Mencke, Norbert; Rees, Robert; Rust, Michael; Schroeder, Iris; Tetzner, Kathrin; Williamson, Martin


    In 2001, an international surveillance initiative was established, utilising a validated larval development inhibition assay to track the susceptibility of cat flea isolates to imidacloprid. In 2009, an Australian node was incorporated into the programme, joining laboratories in the United States and Europe. Field isolates of Ctenocephalides felis eggs were submitted to participating laboratories and, where egg quantity and quality was sufficient, were placed in the imidacloprid discriminating dose bioassay for evaluation. Between 2002 and 2012, a total of 2,307 cat flea isolates were received across all sites; 1,685 submissions (73 %) were suitable for placement into the bioassay. In the Northern Hemisphere, isolate submission rate was influenced by season, with highest numbers submitted between June and October. In Australia, pets with flea infestations could be sourced year-round, and submission rate was largely influenced by programme factors and not climate. A total of 1,367 valid assays were performed between 2002 and 2012 (assay validity data was not recorded in 2001); adult flea emergence 5 % or greater at 3 ppm imidacloprid was observed in 38 of these assays (2.8 %). For these isolates that reached the threshold for further investigation, re-conduct of the assay using either a repeat challenge dose of 3 ppm of imidacloprid or a dose response probit analysis confirmed their susceptibility to imidacloprid. From 2009 to 2012, the Australian node performed valid assays on 97 field isolates from a total of 136 submissions, with no adult emergence observed at the 3-ppm imidacloprid discriminating dose. In addition to reviewing the data generated by this twelve-year initiative, this paper discusses lessons learned from the coordination and evolution of a complex project across geographically dispersed laboratories on three continents.

  14. Functional roles and substrate specificities of twelve cytochromes P450 belonging to CYP52 family in n-alkane assimilating yeast Yarrowia lipolytica. (United States)

    Iwama, Ryo; Kobayashi, Satoshi; Ishimaru, Chiaki; Ohta, Akinori; Horiuchi, Hiroyuki; Fukuda, Ryouichi


    Yarrowia lipolytica possesses twelve ALK genes, which encode cytochromes P450 in the CYP52 family. In this study, using a Y. lipolytica strain from which all twelve ALK genes had been deleted, strains individually expressing each of the ALK genes were constructed and their roles and substrate specificities were determined by observing their growth on n-alkanes and analyzing fatty acid metabolism. The results suggested that the twelve Alk proteins can be categorized into four groups based on their substrate specificity: Alk1p, Alk2p, Alk9p, and Alk10p, which have significant activities to hydroxylate n-alkanes; Alk4p, Alk5p, and Alk7p, which have significant activities to hydroxylate the ω-terminal end of dodecanoic acid; Alk3p and Alk6p, which have significant activities to hydroxylate both n-alkanes and dodecanoic acid; and Alk8p, Alk11p, and Alk12p, which showed faint or no activities to oxidize these substrates. The involvement of Alk proteins in the oxidation of fatty alcohols and fatty aldehydes was also analyzed by measuring viability of the mutant deleted for twelve ALK genes in medium containing dodecanol and by observing growth on dodecanal of a mutant strain, in which twelve ALK genes were deleted along with four fatty aldehyde dehydrogenase genes. It was suggested that ALK gene(s) is/are involved in the detoxification of dodecanol and the assimilation of dodecanal. These results imply that genes encoding CYP52-family P450s have undergone multiplication and diversification in Y. lipolytica for assimilation of various hydrophobic compounds.

  15. Familial Mediterranean fever gene mutations in the inner northern region of Turkey and genotype-phenotype correlation in children. (United States)

    Yilmaz, Resul; Ozer, Samet; Ozyurt, Huseyin; Erkorkmaz, Unal; Sahin, Semsettin


    Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterised by recurrent episodes of fever, polyserositis and rash. The aim of this study was to determine the most common mutations and clinical features, and their relationships. The medical records of 78 patients were evaluated retrospectively. All of the patients had been diagnosed with FMF according to Tel Hashomer criteria between January 2005 and May 2008 in general paediatric clinics of the School of Medicine at Gaziosmanpasa University. Twelve mutations were detected in the 78 patients by polymerase chain reaction-enzyme-linked immunosorbent assay. The patients were classified into three groups according to allele status. The most prominent clinical symptoms were abdominal pain (95%), fever (90%), arthritis (33%) and pleuritis (31%). Seventeen different genotypes were identified. The mutations were homozygous in 25 (32%) patients, compound heterozygous in 28 (36%) patients and heterozygous in 22 (28%) patients. No mutation was detected in three (4%) patients. The most frequent mutations were M694V (55%), M680I (16%), E148Q (10%) and P369S (4%). The mean symptom severity score was highest in the homozygous group, and high levels of C-reactive protein were also detected in this group. In addition to clinical criteria, molecular studies for detecting disease-causing mutations are needed to establish the diagnosis of FMF. FMF patients who were homozygous for MEFV gene mutations had a higher symptom severity score and higher incidence of appendectomy. The broad spectrum of mutations may reflect intercultural interactions of ethnic groups in Anatolia. Nation-wide studies may help to determine the relationships among demographic, clinical and genetic features of FMF.

  16. Isocitrate dehydrogenase mutations in gliomas. (United States)

    Waitkus, Matthew S; Diplas, Bill H; Yan, Hai


    Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified in the vast majority of progressive gliomas and secondary glioblastomas (GBMs). IDH enzymes normally catalyze the decarboxylation of isocitrate to generate α-ketoglutarate (αKG), but recurrent mutations at Arg(132) of IDH1 and Arg(172) of IDH2 confer a neomorphic enzyme activity that catalyzes reduction of αKG into the putative oncometabolite D-2-hydroxyglutate (D2HG). D2HG inhibits αKG-dependent dioxygenases and is thought to create a cellular state permissive to malignant transformation by altering cellular epigenetics and blocking normal differentiation processes. Herein, we discuss the relevant literature on mechanistic studies of IDH1/2 mutations in gliomas, and we review the potential impact of IDH1/2 mutations on molecular classification and glioma therapy.

  17. LMNA mutations in progeroid syndromes. (United States)

    Huang, Shurong; Kennedy, Brian K; Oshima, Junko


    Segmental progeroid syndromes are disorders in which affected individuals. present various features that suggest accelerated ageing. The two best-known examples are Hutchinson-Gilford progeria syndrome (HGPS, 'Progeria of childhood') and Werner syndrome (WS, 'Progeria of the adult'). A novel, recurrent de novo mutation in the LMNA gene, responsible for the majority of HGPS cases, results in an in-frame deletion of 50 amino acids, including endoproteolytic sites required for processing of prelamin A to mature lamin A protein. Another mutation results in a 35 amino acid in-frame deletion with a milder HGPS phenotype. WRN, the gene responsible for the majority of WS cases, encodes a multifunctional nuclear protein with exonuclease and helicase activities and may participate in optimizing DNA repair/recombination. A subset of WS patients do not show mutations at the WRN locus (atypical WS), but show heterozygous amino acid substitutions in the heptad repeat region of lamin A. Structural analysis suggests that mutations in atypical WS may interfere with protein-protein interactions. When compared to WRN-mutant WS, LMNA-mutant atypical WS patients appear to show earlier onset and possibly more severe ageing-related symptoms.

  18. Mutations in RARS cause hypomyelination

    NARCIS (Netherlands)

    Wolf, Nicole I.; Salomons, Gajja S.; Rodenburg, Richard J.; Pouwels, Petra J. W.; Schieving, Jolanda H.; Derks, Terry G. J.; Fock, Johanna M.; Rump, Patrick; van Beek, Daphne M.; van der Knaap, Marjo S.; Waisfisz, Quinten


    Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients

  19. Mutations in RARS cause hypomyelination

    NARCIS (Netherlands)

    Wolf, Nicole I.; Salomons, Gajja S.; Rodenburg, Richard J.; Pouwels, Petra J. W.; Schieving, Jolanda H.; Derks, Terry G. J.; Fock, Johanna M.; Rump, Patrick; van Beek, Daphne M.; van der Knaap, Marjo S.; Waisfisz, Quinten

    Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients

  20. Mutations in RARS cause hypomyelination

    NARCIS (Netherlands)

    Wolf, N.I.; Salomons, G.S.; Rodenburg, R.J.; Pouwels, P.J.; Schieving, J.H.; Derks, T.G.; Fock, J.M.; Rump, P.; Beek, D.M. van; Knaap, M.S. van der; Waisfisz, Q.


    Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients

  1. IDH mutations in acute myeloid leukemia. (United States)

    Rakheja, Dinesh; Konoplev, Sergej; Medeiros, L Jeffrey; Chen, Weina


    Acute myeloid leukemia is a heterogeneous group of diseases. Mutations of the isocitrate dehydrogenase (IDH) genes represent a novel class of point mutations in acute myeloid leukemia. These mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate and confer novel enzymatic activity, facilitating the reduction of α-ketoglutarate to d-2-hydroxyglutarate, a putative oncometabolite. IDH1/IDH2 mutations are heterozygous, and their combined frequency is approximately 17% in unselected acute myeloid leukemia cases, 27% in cytogenetically normal acute myeloid leukemia cases, and up to 67% in acute myeloid leukemia cases with cuplike nuclei. These mutations are largely mutually exclusive. Despite many similarities of IDH1 and IDH2 mutations, it is possible that they represent distinct molecular or clinical subgroups of acute myeloid leukemia. All known mutations involve arginine (R), in codon 132 of IDH1 or codon 140 or 172 of IDH2. IDH1(R132) and IDH2(R140) mutations are frequently accompanied by normal cytogenetics and NPM1 mutation, whereas IDH2(R172) is frequently the only mutation detected in acute myeloid leukemia. There is increasing evidence that the prognostic impact of IDH1/2 mutations varies according to the specific mutation and also depends on the context of concurrent mutations of other genes. IDH1(R132) mutation may predict poor outcome in a subset of patients with molecular low-risk acute myeloid leukemia, whereas IDH2(R172) mutations confer a poor prognosis in patients with acute myeloid leukemia. Expression of IDH1/2 mutants induces an increase in global DNA hypermethylation and inhibits TET2-induced cytosine 5-hydroxymethylation, DNA demethylation. These data suggest that IDH1/2 mutations constitute a distinct mutational class in acute myeloid leukemia, which affects the epigenetic state, an important consideration for the development of therapeutic agents.

  2. Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome

    Directory of Open Access Journals (Sweden)

    María E. Teresa-Rodrigo


    Full Text Available Cornelia de Lange syndrome (CdLS is a congenital developmental disorder characterized by distinctive craniofacial features, growth retardation, cognitive impairment, limb defects, hirsutism, and multisystem involvement. Mutations in five genes encoding structural components (SMC1A, SMC3, RAD21 or functionally associated factors (NIPBL, HDAC8 of the cohesin complex have been found in patients with CdLS. In about 60% of the patients, mutations in NIPBL could be identified. Interestingly, 17% of them are predicted to change normal splicing, however, detailed molecular investigations are often missing. Here, we report the first systematic study of the physiological splicing of the NIPBL gene, that would reveal the identification of four new splicing isoforms ΔE10, ΔE12, ΔE33,34, and B’. Furthermore, we have investigated nine mutations affecting splice-sites in the NIPBL gene identified in twelve CdLS patients. All mutations have been examined on the DNA and RNA level, as well as by in silico analyses. Although patients with mutations affecting NIPBL splicing show a broad clinical variability, the more severe phenotypes seem to be associated with aberrant transcripts resulting in a shift of the reading frame.

  3. Tilting mutation of Brauer tree algebras

    CERN Document Server

    Aihara, T


    We define tilting mutations of symmetric algebras as the endomorphism algebras of Okuyama-Rickard complexes. For Brauer tree algebras, we give an explicit description of the change of Brauer trees under mutation.

  4. Identifying driver mutations in sequenced cancer genomes

    DEFF Research Database (Denmark)

    Raphael, Benjamin J; Dobson, Jason R; Oesper, Layla


    High-throughput DNA sequencing is revolutionizing the study of cancer and enabling the measurement of the somatic mutations that drive cancer development. However, the resulting sequencing datasets are large and complex, obscuring the clinically important mutations in a background of errors, noise......, and random mutations. Here, we review computational approaches to identify somatic mutations in cancer genome sequences and to distinguish the driver mutations that are responsible for cancer from random, passenger mutations. First, we describe approaches to detect somatic mutations from high-throughput DNA...... sequencing data, particularly for tumor samples that comprise heterogeneous populations of cells. Next, we review computational approaches that aim to predict driver mutations according to their frequency of occurrence in a cohort of samples, or according to their predicted functional impact on protein...

  5. Inactivating CUX1 mutations promote tumorigenesis



    A major challenge for cancer genetics is to determine which low frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers to identify novel drivers and find inactivating mutations in the homeodomain transcription factor CUX1 (cut-like homeobox 1) in ~1-5% of tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical si...

  6. A retrospective evaluation of the quality of malaria case management at twelve health facilities in four districts in Zambia

    Institute of Scientific and Technical Information of China (English)

    Pascalina Chanda-Kapata; Emmanuel Chanda; Freddie Masaninga; Annette Habluetzel; Felix Masiye; Ibrahima Soce Fall


    Objective: To establish the appropriateness of malaria case management at health facility level in four districts in Zambia. Methods: This study was a retrospective evaluation of the quality of malaria case management at health facilities in four districts conveniently sampled to represent both urban and rural settings in different epidemiological zones and health facility coverage. The review period was from January to December 2008. The sample included twelve lower level health facilities from four districts. The Pearson Chi-square test was used to identify characteristics which affected the quality of case management.Results:Out of 4891 suspected malaria cases recorded at the 12 health facilities, more than 80% of the patients had a temperature taken to establish their fever status. About 67% (CI95 66.1-68.7) were tested for parasitemia by either rapid diagnostic test or microscopy, whereas the remaining 22.5% (CI95 21.3.1-23.7) were not subjected to any malaria test. Of the 2247 malaria cases reported (complicated and uncomplicated), 71% were parasitologically confirmed while 29% were clinically diagnosed (unconfirmed). About 56% (CI95 53.9-58.1) of the malaria cases reported were treated with artemether-lumefantrine (AL), 35% (CI95 33.1-37.0) with sulphadoxine-pyrimethamine, 8% (CI95 6.9-9.2) with quinine and 1% did not receive any anti-malarial. Approximately 30% of patients WHO were found negative for malaria parasites were still prescribed an anti-malarial, contrary to the guidelines. There were marked inter-district variations in the proportion of patients in WHOm a diagnostic tool was used, and in the choice of anti-malarials for the treatment of malaria confirmed cases. Association between health worker characteristics and quality of case malaria management showed that nurses performed better than environmental health technicians and clinical officers on the decision whether to use the rapid diagnostic test or not. Gender, in service training on malaria

  7. Plastome Mutations and Recombination Events in Barley Chloroplast Mutator Seedlings. (United States)

    Landau, Alejandra; Lencina, Franco; Pacheco, María G; Prina, Alberto R


    The barley chloroplast mutator (cpm) is an allele of a nuclear gene that when homozygous induces several types of cytoplasmically inherited chlorophyll deficiencies. In this work, a plastome Targeting Induced Local Lesions in Genomes (TILLING) strategy based on mismatch digestion was used on families that carried the cpm genotype through many generations. Extensive scanning of 33 plastome genes and a few intergenic regions was conducted. Numerous polymorphisms were detected on both genic and intergenic regions. The detected polymorphisms can be accounted for by at least 61 independent mutational events. The vast majority of the polymorphisms originated in substitutions and small indels (insertions/deletions) in microsatellites. The rpl23 and the rps16 genes were the most polymorphic. Interestingly, the variation observed in the rpl23 gene consisted of several combinations of 5 different one nucleotide polymorphisms. Besides, 4 large indels that have direct repeats at both ends were also observed, which appear to be originated from recombinational events. The cpm mutation spectrum suggests that the CPM gene product is probably involved in plastome mismatch repair. The numerous subtle molecular changes that were localized in a wide range of plastome sites show the cpm as a valuable source of plastome variability for plant research and/or plant breeding. Moreover, the cpm mutant appears to be an interesting experimental material for investigating the mechanisms responsible for maintaining the stability of plant organelle DNA.

  8. Biological evolution model with conditional mutation rates (United States)

    Saakian, David B.; Ghazaryan, Makar; Bratus, Alexander; Hu, Chin-Kun


    We consider an evolution model, in which the mutation rates depend on the structure of population: the mutation rates from lower populated sequences to higher populated sequences are reduced. We have applied the Hamilton-Jacobi equation method to solve the model and calculate the mean fitness. We have found that the modulated mutation rates, directed to increase the mean fitness.

  9. Lacie phase 1 Classification and Mensuration Subsystem (CAMS) rework experiment (United States)

    Chhikara, R. S.; Hsu, E. M.; Liszcz, C. J.


    An experiment was designed to test the ability of the Classification and Mensuration Subsystem rework operations to improve wheat proportion estimates for segments that had been processed previously. Sites selected for the experiment included three in Kansas and three in Texas, with the remaining five distributed in Montana and North and South Dakota. The acquisition dates were selected to be representative of imagery available in actual operations. No more than one acquisition per biophase were used, and biophases were determined by actual crop calendars. All sites were worked by each of four Analyst-Interpreter/Data Processing Analyst Teams who reviewed the initial processing of each segment and accepted or reworked it for an estimate of the proportion of small grains in the segment. Classification results, acquisitions and classification errors and performance results between CAMS regular and ITS rework are tabulated.

  10. TCOF1 mutation database: novel mutation in the alternatively spliced exon 6A and update in mutation nomenclature. (United States)

    Splendore, Alessandra; Fanganiello, Roberto D; Masotti, Cibele; Morganti, Lucas S C; Passos-Bueno, M Rita


    Recently, a novel exon was described in TCOF1 that, although alternatively spliced, is included in the major protein isoform. In addition, most published mutations in this gene do not conform to current mutation nomenclature guidelines. Given these observations, we developed an online database of TCOF1 mutations in which all the reported mutations are renamed according to standard recommendations and in reference to the genomic and novel cDNA reference sequences ( We also report in this work: 1) results of the first screening for large deletions in TCOF1 by Southern blot in patients without mutation detected by direct sequencing; 2) the identification of the first pathogenic mutation in the newly described exon 6A; and 3) statistical analysis of pathogenic mutations and polymorphism distribution throughout the gene.

  11. Anaerobically Grown Escherichia coli Has an Enhanced Mutation Rate and Distinct Mutational Spectra (United States)

    Shewaramani, Sonal; Finn, Thomas J.; Kassen, Rees; Rainey, Paul B.


    Oxidative stress is a major cause of mutation but little is known about how growth in the absence of oxygen impacts the rate and spectrum of mutations. We employed long-term mutation accumulation experiments to directly measure the rates and spectra of spontaneous mutation events in Escherichia coli populations propagated under aerobic and anaerobic conditions. To detect mutations, whole genome sequencing was coupled with methods of analysis sufficient to identify a broad range of mutational classes, including structural variants (SVs) generated by movement of repetitive elements. The anaerobically grown populations displayed a mutation rate nearly twice that of the aerobic populations, showed distinct asymmetric mutational strand biases, and greater insertion element activity. Consistent with mutation rate and spectra observations, genes for transposition and recombination repair associated with SVs were up-regulated during anaerobic growth. Together, these results define differences in mutational spectra affecting the evolution of facultative anaerobes. PMID:28103245

  12. PAX6 mutations: genotype-phenotype correlations

    Directory of Open Access Journals (Sweden)

    Hanson Isabel M


    Full Text Available Abstract Background The PAX6 protein is a highly conserved transcriptional regulator that is important for normal ocular and neural development. In humans, heterozygous mutations of the PAX6 gene cause aniridia (absence of the iris and related developmental eye diseases. PAX6 mutations are archived in the Human PAX6 Allelic Variant Database, which currently contains 309 records, 286 of which are mutations in patients with eye malformations. Results We examined the records in the Human PAX6 Allelic Variant Database and documented the frequency of different mutation types, the phenotypes associated with different mutation types, the contribution of CpG transitions to the PAX6 mutation spectrum, and the distribution of chain-terminating mutations in the open reading frame. Mutations that introduce a premature termination codon into the open reading frame are predominantly associated with aniridia; in contrast, non-aniridia phenotypes are typically associated with missense mutations. Four CpG dinucleotides in exons 8, 9, 10 and 11 are major mutation hotspots, and transitions at these CpG's account for over half of all nonsense mutations in the database. Truncating mutations are distributed throughout the PAX6 coding region, except for the last half of exon 12 and the coding part of exon 13, where they are completely absent. The absence of truncating mutations in the 3' part of the coding region is statistically significant and is consistent with the idea that nonsense-mediated decay acts on PAX6 mutant alleles. Conclusion The PAX6 Allelic Variant Database is a valuable resource for studying genotype-phenotype correlations. The consistent association of truncating mutations with the aniridia phenotype, and the distribution of truncating mutations in the PAX6 open reading frame, suggests that nonsense-mediated decay acts on PAX6 mutant alleles.

  13. Mutation Clusters from Cancer Exome. (United States)

    Kakushadze, Zura; Yu, Willie


    We apply our statistically deterministic machine learning/clustering algorithm *K-means (recently developed in to 10,656 published exome samples for 32 cancer types. A majority of cancer types exhibit a mutation clustering structure. Our results are in-sample stable. They are also out-of-sample stable when applied to 1389 published genome samples across 14 cancer types. In contrast, we find in- and out-of-sample instabilities in cancer signatures extracted from exome samples via nonnegative matrix factorization (NMF), a computationally-costly and non-deterministic method. Extracting stable mutation structures from exome data could have important implications for speed and cost, which are critical for early-stage cancer diagnostics, such as novel blood-test methods currently in development.

  14. Structural analysis of the genome of breast cancer cell line ZR-75-30 identifies twelve expressed fusion genes

    Directory of Open Access Journals (Sweden)

    Schulte Ina


    Full Text Available Abstract Background It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements. Results We first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing—55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads. From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer—in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator. Conclusions This is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports

  15. Tailoring the metabolism against mutations (United States)

    Gulbahce, Natali; Motter, Adilson E.; Almaas, Eivind; Barabasi, Albert Laszlo


    In the post-genomic era, organisms can be modelled at the whole-cell level in silico via steady state methods to describe their metabolic capabilities. We use two such methods, Flux Balance Analysis and Minimization of Metabolic Adjustment to explore the behavior of cells (of E. coli and S. cerevisiae) after severe mutations. We propose experimentally feasible ways of modifying the underlying biochemical reaction network of a mutant cell such that cell functionality, in particular growth rate, is significantly improved.

  16. Ancestral origins of the prion protein gene D178N mutation in the Basque Country. (United States)

    Rodríguez-Martínez, Ana B; Barreau, Christian; Coupry, Isabelle; Yagüe, Jordi; Sánchez-Valle, Raquel; Galdós-Alcelay, Luis; Ibáñez, Agustín; Digón, Antón; Fernández-Manchola, Ignacio; Goizet, Cyril; Castro, Azucena; Cuevas, Nerea; Alvarez-Alvarez, Maite; de Pancorbo, Marian M; Arveiler, Benoît; Zarranz, Juan J


    Fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD) are familial prion diseases with autosomal dominant inheritance of the D178N mutation. FFI has been reported in at least 27 pedigrees around the world. Twelve apparently unrelated FFI and fCJD pedigrees with the characteristic D178N mutation have been reported in the Prion Diseases Registry of the Basque Country since 1993. The high incidence of familial prion diseases in this region may reflect a unique ancestral origin of the chromosome carrying this mutation. In order to investigate this putative founder effect, we developed "happy typing", a new approach to the happy mapping method, which consists of the physical isolation of large haploid genomic DNA fragments and their analysis by the Polymerase Chain Reaction in order to perform haplotypic analysis instead of pedigree analysis. Six novel microsatellite markers, located in a 150-kb genomic segment flanking the PRNP gene were characterized for typing haploid DNA fragments of 285 kb in size. A common haplotype was found in patients from the Basque region, strongly suggesting a founder effect. We propose that "happy typing" constitutes an efficient method for determining disease-associated haplotypes, since the analysis of a single affected individual per pedigree should provide sufficient evidence.

  17. Pathogenic mutations in Parkinson disease. (United States)

    Tan, Eng-King; Skipper, Lisa M


    Parkinson disease (PD; Parkinson's) is the second most common neurodegenerative disease, characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies. Increasing evidence suggests that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system (UPS) dysfunction may represent the principal molecular pathways that commonly underlie the pathogenesis. The relative role of genetic and environmental factors has been the focus of research and debate. The recent discovery of a number of disease-causing genes (SNCA, Parkin/PARK2, UCHL1, PINK1, DJ1/PARK7, and LRRK2) in familial and sporadic forms of PD has provided considerable insights into the pathophysiology of this complex disorder. The frequency of these gene mutations may vary according to ethnicity and to the specific gene. A gene dosage effect is observed in some cases, and the phenotype of some of the mutation carriers closely resembles typical PD. Penetrance of some of the recurrent mutations is incomplete and may vary with age. Further research to unravel the etiopathology could identify biochemical or genetic markers for potential neuroprotective trials. (c) 2007 Wiley-Liss, Inc.

  18. LHON: Mitochondrial Mutations and More. (United States)

    Kirches, E


    Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells (RGCs). The primary cause of the disease is usually a mutation of the mitochondrial genome (mtDNA) causing a single amino acid exchange in one of the mtDNA-encoded subunits of NADH:ubiquinone oxidoreductase, the first complex of the electron transport chain. It was thus obvious to accuse neuronal energy depletion as the most probable mediator of neuronal death. The group of Valerio Carelli and other authors have nicely shown that energy depletion shapes the cell fate in a LHON cybrid cell model. However, the cybrids used were osteosarcoma cells, which do not fully model neuronal energy metabolism. Although complex I mutations may cause oxidative stress, a potential pathogenetic role of the latter was less taken into focus. The hypothesis of bioenergetic failure does not provide a simple explanation for the relatively late disease onset and for the incomplete penetrance, which differs remarkably between genders. It is assumed that other genetic and environmental factors are needed in addition to the 'primary LHON mutations' to elicit RGC death. Relevant nuclear modifier genes have not been identified so far. The review discusses the unresolved problems of a pathogenetic hypothesis based on ATP decline and/or ROS-induced apoptosis in RGCs.

  19. Discussion the Theory of "Shi's Twelve Word Life Cultivation Skill"%“施氏十二字养生功”的基础理论探讨

    Institute of Scientific and Technical Information of China (English)

    胡志俊; 王世伟; 施杞; 叶秀兰; 唐占英


    目的:探讨施氏十二字养生功理论渊源及作用原理.方法:通过发掘古代医学文献对导引的论述并结合现代医学理论来探讨施氏十二字养生功的作用机理.结果:施氏十二字养生功是在中医传统导引理论指导下通过长期的临床实践创建的养生功,对以颈椎病为主的骨退行性病变引起的疼痛不适等有良好疗效.结论:施氏十二字养生功是防治颈椎病有效方法之一.%Objective: Discussion the origin of "Shi's twelve word life cultivation skill " theory and principle. Methods: To explore the ancient medical literature through the discussion on the guidance and combined with modern medical theory of health work Discussion the theory of "Shi's twelve word life cultivation skill" and it's mechanism. Results: "Shi's twelve word life cultivation skill" is guided in the theory of traditional Chinese medicine under the guidance of clinical practice through long-term work to create the health of the cervical degenerative bone disease mainly caused such pain and discomfort have a good effect. Conclusion: "Shi's twelve-word life-cultivation skill" is an effective method for prevention and treatment of cervical spondylosis.

  20. Flies from L.A., The Sequel: A further twelve new species of Megaselia (Diptera: Phoridae) from the BioSCAN Project in Los Angeles (California, USA)


    Hartop, Emily; Brown, Brian; Disney,R. Henry


    Presented are continued results from the BioSCAN Project, an urban biodiversity study sampling primarily from private backyards in Los Angeles, California (USA). Presented are continued results from the BioSCAN Project, an urban biodiversity study sampling primarily from private backyards in Los Angeles, California (USA). Twelve new species of Megaselia (Diptera: Phoridae) are described: M. baileyae, M. friedrichae, M. gonzalezorum, M. joanneae, M. losangelensis, M. phyllissunae, M. p...

  1. The Twelve Promises of Alcoholics Anonymous: psychometric measure validation and mediational testing as a 12-step specific mechanism of behavior change. (United States)

    Kelly, John F; Greene, M Claire


    Empirical support for the recovery utility of 12-step mutual-help organizations (MHOs) has led to increased investigation of how such organizations confer benefit. The Twelve Promises of Alcoholics Anonymous (AA) feature prominently in 12-step philosophy and culture and are one of the few documented explications of the cognitive, affective, and behavioral benefits that members might accrue. This study investigated the psychometric properties of a measure of AA's Twelve Promises and examined whether it mediated the effect of 12-step participation on abstinence. Young adults (N=302, M age 20.4 [1.6], range 18-25; 27% female; 95% White) enrolled in an addiction treatment effectiveness study completed assessments at intake and 3-, 6-, and 12-months post treatment including a 26-item, Twelve Promises Scale (TPS). Factor analyses examined the TPS' psychometrics and lagged mediational analyses tested the TPS as a mechanism of behavior change. Robust principal axis factoring extraction with Varimax rotation revealed a 2-factor solution explaining 45-58% of the variance across three administrations ("Psychological Wellbeing"=26-39%; "Freedom from Craving=17-21%); internal consistency was high (alpha=.83-.93). Both factors were found to increase in relation to greater 12-step participation, but significant mediation was found only for the Freedom from Craving factor explaining 21-34% of the effect of 12-step participation in increasing abstinence. The TPS shows potential as a conceptually relevant, and psychometrically sound measure and may be useful in helping elucidate the extent to which the Twelve Promises emerge as an independent benefit of 12-step participation and/or explain SUD remission and recovery. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Ultra pressure liquid chromatography-negative electrospray ionization mass spectrometry determination of twelve halobenzoquinones at ng/L levels in drinking water. (United States)

    Huang, Rongfu; Wang, Wei; Qian, Yichao; Boyd, Jessica M; Zhao, Yuli; Li, Xing-Fang


    We report here the characterization of twelve halobenzoquinones (HBQs) using electrospray ionization (ESI) high resolution quadrupole time-of-flight mass spectrometry. The high resolution negative ESI spectra of the twelve HBQs formed two parent ions, [M + H(+) + 2e(-)], and the radical M(-•). The intensities of these two parent ions are dependent on their chemical structures and on instrumental parameters such as the source temperature and flow rate. The characteristic ions of the HBQs were used to develop an ultra pressure liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. At the UPLC flow rate (400 μL/min) and under the optimized ESI conditions, eleven HBQs showed the stable and abundant transitions [M + H(+) + 2e(-)] → X(-) (X(-) representing Cl(-), Br(-), or I(-)), while dibromo-dimethyl-benzoquinone (DBDMBQ) showed only the transition of M(-•) → Br(-). The UPLC efficiently separates all HBQs including some HBQ isomers, while the MS/MS offers exquisite limits of detection (LODs) at subng/mL levels for all HBQs except DBDMBQ. Combined with solid phase extraction (SPE), the method LOD is down to ng/L. The results from analysis of authentic samples demonstrated that the SPE-UPLC-MS/MS method is reliable, fast, and sensitive for the identification and quantification of the twelve HBQs in drinking water.

  3. Blood-letting punctures at twelve Jing-Well points of the hand can treat cerebral ischemia in a similar manner to mannitol

    Institute of Scientific and Technical Information of China (English)

    Xuan Lu; Zelin Chen; Yi Guo; Liang Gao; Liyuan Jiang; Zhongzheng Li; Jianqiao Fang


    A rat model of middle cerebral artery permanent occlusion was established using the modified Longa method. Successfully established model animals were treated by blood-letting puncture at twelve Jing-Well points of the hand, and/or by injecting mannitol into the caudal vein twice daily. Brain tissue was collected at 24, 48 and 72 hours after modeling, and blood was collected through the retinal vein before Evans blue was injected, approximately 1 hour prior to harvesting of brain tissue. Results showed that Evans blue leakage into brain tissue and serum nitric oxide synthase activity were significantly increased in model rats. Treatment with blood-letting punctures at twelve Jing-Well points of the hand and/or injection of mannitol into the caudal vein reduced the amount of Evans blue leakage into the brain tissue and serum nitric oxide synthase activity to varying degrees. There was no significant difference between single treatment and combined treatment. Experimental findings indicate that blood-letting punctures at twelve Jing-Well points of the hand can decrease blood-brain barrier permeability and serum nitric oxide synthase activity in rats following middle cerebral artery occlusion, and its effect is similar to that of mannitol injection alone and Jing-Well points plus mannitol injection.

  4. Effect of Blood-letting Puncture at Twelve Well-Points of Hand on Consciousness and Heart Rate in Patients with Apoplexy

    Institute of Scientific and Technical Information of China (English)

    Guo Yi; Wang Xiuyun; Xu Tangping; Dai Zhihua; Li Yunchen


    Objective: To observe the effect of blood-letting puncture at Twelve Well-Points of Hand on consciousness and heart rate in patients with early apoplexy. Method: Under observation were patients with disturbance of consciousness within 3 days after the apoplectic seizure. The patients were divided into a large injury team, a moderate injury team and a mild injury team. Each team was again randomly divided into a puncture group and a control group, with routine treatment in both groups but bloodletting puncture only in the puncture group. Quantitative changes in consciousness, blood pressure and heart rate of the patients were observed. Result: Blood-letting puncture at Twelve Well-Points of Hand can improve the consciousness and raise the systolic pressure in patients of the mild injury team, and accelerate the heart rate in all the patients in the puncture group. Conclusion: Blood-letting puncture at Twelve Well-Points of Hand can improve the consciousness of patients with brain injury in small area.

  5. A Comparison of the Twelve Core Values of Thai People Defined by the Head of the National Council for Peace and Order (NCPO) Found in Thai Private and Public University Students (United States)

    Ngammuk, Patariya


    This study aims to examine the twelve core values of Thai people found in Thai university students. The twelve values consist of the following attributes: 1.Upholding the nation, the religions and the Monarchy 2. Being honest, sacrificial and patient with positive attitude for the common good of the public 3. Being grateful to the parents,…

  6. Mutation induction by ion beams in plants

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Atsushi [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment


    The effect of ion beams such as C, He, and Ne ions was investigated on the mutation induction in plants with the expectation that ion beams of high linear energy transfer (LET) can frequently produce large DNA alternation such as inversion, translocation and large deletion rather than point mutation. Mutation frequency was investigated using Arabidopsis visible phenotype loci and was 8 to 33 fold higher for 220 MeV carbon ions than for electrons. Mutation spectrum was investigated on the flower color of chrysanthemum cv to find that flower mutants induced by ion beams show complex and stripe types rather than single color. Polymerase chain reaction analysis was performed to investigate DNA alteration of mutations. In conclusion, the characteristics of ion beams for the mutation induction are 1) high frequency, 2) broad mutation spectrum, and 3) novel mutants. (S. Ohno)

  7. Androgen receptor gene mutation, rearrangement, polymorphism. (United States)

    Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E; Wang, Zhou


    Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.

  8. Review of the Spirobolida on Madagascar, with descriptions of twelve new genera, including three genera of 'fire millipedes' (Diplopoda

    Directory of Open Access Journals (Sweden)

    Thomas Wesener


    Full Text Available Twelve new genera and 37 new species of Spirobolida are described: Corallobolus cruentus gen. n., sp. n., Sanguinobolus maculosus gen. n., sp. n., Colossobolus semicyclus gen. n., sp. n., C. oblongopedus sp. n., C. giganteus sp. n., C. minor sp. n., C. litoralis sp. n., C. aculeatus sp. n., C. pseudoaculeatus sp. n., Zehntnerobolus gen. n., Flagellobolus pauliani gen. n., sp. n., Riotintobolus mandenensis gen. n., sp. n., R. minutus sp. n., R. aridus sp. n., R. anomalus sp. n., Pseudocentrobolus aureus gen. n., sp. n., P. vohibasiensis sp. n., Granitobolus endemicus gen. n., sp. n., G. andohahelensis sp. n., Caprobolus andringitra gen. n., sp. n., Alluviobolus laticlavius gen. n., sp. n., A. tsimelahy sp. n., A. antanosy sp. n., Ostinobolus rufus gen. n., sp. n., O. stellaris sp. n., O. montanus sp. n., O. subterraneus sp. n., and Hylekobolus brachiosauroides gen. n., sp. n., H. rufus sp. n., H. griseus sp. n., H. albicollaris sp. n., H. goodmani sp. n., H. montanus sp. n., H. analavelona sp. n., H. latifrons sp. n., H. andasibensis sp. n., H. marojejy sp. n., H. anjanaharibe sp. n. All genera and species are endemic to Madagascar. Hylekobolus belongs to the family Spirobolellidae, while all other Malagasy genera of Spirobolida belong to the Pachybolidae. Among them, only Zehntnerobolus gen. n. is based on a previously described species: Spirobolus rubripes de Saussure & Zehntner, 1897, whereas the remaining 11 new genera altogether contain (a total of 37 new species. Three of the new genera are large-bodied “fire millipedes” (>100 mm long with striking red/black colour patterns. The new discoveries increase the number of endemic Malagasy genera of Spirobolida more than fivefold (from 3 to 15. The number of endemic species recorded from Madagascar has more than doubled (to 61. Body length of the new species varies greatly (between 23 and 170 mm. Keys to all Malagasy Spirobolida families, genera, as well as the newly described species

  9. Oncogene mutational profile in nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Zhang ZC


    Full Text Available Zi-Chen Zhang,1,* Sha Fu,1,* Fang Wang,1 Hai-Yun Wang,1 Yi-Xin Zeng,2 Jian-Yong Shao11Department of Molecular Diagnostics, 2Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China *These authors contributed equally to this work Abstract: Nasopharyngeal carcinoma (NPC is a common tumor in Southern China, but the oncogene mutational status of NPC patients has not been clarified. Using time-of-flight mass spectrometry, 238 mutation hotspots in 19 oncogenes were examined in 123 NPC patients. The relationships between mutational status and clinical data were assessed with a χ2 or Fisher's exact test. Survival analysis was performed using the Kaplan–Meier method with the log-rank test. In 123 patients, 21 (17.1% NPC tumors were positive for mutations in eight oncogenes: six patients had PIK3CA mutations (4.9%, five NRAS mutations (4.1%, four KIT mutations (3.3%, two PDGFRA mutations (1.6%, two ABL mutations (1.6%, and one with simultaneous mutations in HRAS, EGFR, and BRAF (1%. Patients with mutations were more likely to relapse or develop metastasis than those with wild-type alleles (P=0.019. No differences or correlations were found in other clinical characteristics or in patient survival. No mutations were detected in oncogenes AKT1, AKT2, CDK, ERBB2, FGFR1, FGFR3, FLT3, JAK2, KRAS, MET, and RET. These results demonstrate an association between NPC and mutations in NRAS, KIT, PIK3CA, PDGFRA, and ABL, which are associated with patient relapse and metastasis. Keywords: NPC, oncogene, mutation

  10. CHEK2∗1100delC Mutation and Risk of Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Victoria Hale


    Full Text Available Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer. CHEK2 plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, of CHEK2 on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussed CHEK2∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18 for unselected cases and 3.39 (1.78–6.47 for familial cases, indicating that CHEK2∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer.

  11. Effects of mutations at the stambh A locus of Drosophila melanogaster

    Indian Academy of Sciences (India)

    M. Kumar; Minu Joseph; Shanti Chandrashekaran


    We report novel findings on the cytogenetic location, functional complexity and maternal and germline roles of the stambh A locus of Drosophila melanogaster. stmA is localized to polytene bands 44D1.2 on 2R. stmA mutations are of two types: temperature-sensitive (ts) adult and larval paralytic or unconditional embryonic or larval lethal. Twelve alleles reported in this study fall into two intragenic complementing groups suggesting that stmA is a complex locus with more than one functional domain. Some unconditional embryonic lethal alleles show a ‘neurogenic’ phenotype of cuticle loss accompanied by neural hypertrophy. It is shown that embryos of ts paralytic alleles also show mild neural hypertrophy at permissive temperatures while short exposure to heat induces severe cuticle loss in these embryos. stmA exerts a maternal influence over heat-induced cuticle loss. Unconditional embryonic lethal alleles of stmA are also germline lethal.

  12. [TP53 mutations and molecular epidemiology]. (United States)

    Otsuka, Kazunori; Ishioka, Chikashi


    Tumor suppressor p53 protein is activated by a variety of cellular stresses through several pathways and transactivates its downstream genes, including regulators of cell cycle, apoptosis and DNA repair. The loss of p53 function by TP53 gene mutations therefore fails to activate these genes and is thought to be a critical cause of carcinogenesis and/or tumor progression. TP53 is one of the most frequently mutated genes in human cancer. TP53 mutations are found in about 50% of human cancers, although the frequency of TP53 mutations differs among tumor types. However, the degree of functional disorder of mutant p53 varies according to the type of TP53 mutation. And the effects of p53 on cancer formation and/or progression are influenced by the degree of p53 dysfunction. So it is important to analyze the effects of TP53 mutations carefully according to the oncogenicity of each mutation from the molecular epidemiological point of view. Here, together with some cautions needed for analyzing and interpreting the significance of TP53 gene mutations, we present some examples of the identified specific mutation spectrum and the correlation between the prognosis and TP53 mutation in some cancers.

  13. Evaluation of CFTR gene mutations in Adana

    Directory of Open Access Journals (Sweden)

    Ozlem Goruroglu Ozturk


    Full Text Available ABSTRACT Objective: Cystic fibrosis is the most common autosomal recessive inherited disorder seen in the white populations. It develops in result of mutations of cystic fibrosis transmembrane regulator (CFTR gene. Rate of these mutations vary in different geographical regions. In this study, we aimed to determine the frequency of CFTR gene mutations in Adana. Methods: DNA samples of 63 subjects (21 women, 42 men who were diagnosed as cystic fibrosis at Balcali Hospital of Cukurova University, were studied for 19 different CFTR mutations by the strip assay method which is based on reverse hybridization. Results: In cystic fibrosis diagnosed patients, 19 mutations were observed of which 9 were homozygous and 10 were heterozygous. ∆F508 frequency was found as 11.9%, and rate of homozygous was found as 66.7%. Mutation frequencies of W1282X and N1303K were found as 2.40% and 4.80% respectively and rate of homozygous mutations were 50% for both. I148T mutation frequency was found as 3.20% and all were heterozygous. For the whole 19 mutations, frequency of mutation in 63 subjects was 22.3%. Conclusion: Detection of CFTR gene mutations by the strip assay method by reverse hybridization is an easy, fast and informative method. However, due to improvability of the common mutations in probable cystic fibrosis patients because of heterogenity in this region, it is still a major problem and does not exclude cystic fibrosis diagnosis. But this problematic issue can be overcome by evaluating the whole exons of CFTR mutations by advanced molecular tecniques. Key words: CFTR, cystic fibrosis, molecular diagnosis, reverse hibridisation [Cukurova Med J 2013; 38(2.000: 202-208

  14. A Simple Oligonucleotide Biochip Capable of Rapidly Detecting Known Mitochondrial DNA Mutations in Chinese Patients with Leber’S Hereditary Optic Neuropathy (LHON

    Directory of Open Access Journals (Sweden)

    Wei-Dong Du


    Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G > A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases. The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis.

  15. A simple oligonucleotide biochip capable of rapidly detecting known mitochondrial DNA mutations in Chinese patients with Leber's hereditary optic neuropathy (LHON). (United States)

    Du, Wei-Dong; Chen, Gang; Cao, Hui-Min; Jin, Qing-Hui; Liao, Rong-Feng; He, Xiang-Cheng; Chen, Da-Ben; Huang, Shu-Ren; Zhao, Hui; Lv, Yong-Mei; Tang, Hua-Yang; Tang, Xian-Fa; Wang, Yong-Qing; Sun, Song; Zhao, Jian-Long; Zhang, Xue-Jun


    Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases). The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis.

  16. Lattices, graphs, and Conway mutation

    CERN Document Server

    Greene, Joshua Evan


    The d-invariant of an integral, positive definite lattice L records the minimal norm of a characteristic covector in each equivalence class mod 2L. We prove that the 2-isomorphism type of a connected graph is determined by the d-invariant of its lattice of integral cuts (or flows). As an application, we prove that a reduced, alternating link diagram is determined up to mutation by the Heegaard Floer homology of the link's branched double-cover. Thus, alternating links with homeomorphic branched double-covers are mutants.

  17. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a

    Energy Technology Data Exchange (ETDEWEB)

    Chou, J.Y.; Lei, K.J.; Shelly, L.L. [National Institutes of Health, Bethesda, MD (United States)


    Glycogen storage disease (GSD) type la (von Gierke disease) is caused by the deficiency of glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. The disease presents with clinical manifestations of severe hypoglycemia, hepatomegaly, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia. We have succeeded in isolating a murine G6Pase cDNA from a normal mouse liver cDNA library by differentially screening method. We then isolated the human G6Pase cDNA and gene. To date, we have characterized the G6Pase genes of twelve GSD type la patients and uncovered a total of six different mutations. The mutations are comprised of R83C (an Arg at codon 83 to a Cys), Q347X (a Gly at codon 347 to a stop codon), 459insTA (a two basepair insertion at nucleotide 459 yielding a truncated G6Pase of 129 residues), R295C (an Arg at codon 295 to a Cys), G222R (a Gly at codon 222 to an Arg) and {delta}F327 (a codon deletion for Phe-327 at nucleotides 1058 to 1060). The relative incidences of these mutations are 37.5% (R83C), 33.3% (Q347X), 16.6% (459insTA), 4.2% (G222R), 4.2% (R295C) and 4.2% ({delta}F327). Site-directed mutagenesis and transient expression assays demonstrated that the R83C, Q347X, R295C, and {delta}F327 mutations abolished whereas the G222R mutation greatly reduced G6Pase activity. We further characterized the structure-function requirements of amino acids 83, 222, and 295 in G6Pase catalysis. The identification of mutations in GSD type la patients has unequivocally established the molecular basis of the type la disorder. Knowledge of the mutations may be applied to prenatal diagnosis and opens the way for developing and evaluating new therapeutic approaches.

  18. Mutation, Witten Index, and Quiver Invariant

    CERN Document Server

    Kim, Heeyeon; Yi, Piljin


    We explore Seiberg-like dualities, or mutations, for ${\\cal N}=4$ quiver quantum mechanics in the context of wall-crossing. In contrast to higher dimensions, the 1d Seiberg-duality must be performed with much care. With fixed Fayet-Iliopoulos constants, at most two nodes can be mutated, one left and the other right, mapping a chamber of a quiver into a chamber of a mutated quiver. We delineate this complex pattern for triangle quivers and show how the Witten indices are preserved under such finely chosen mutations. On the other hand, the quiver invariants, or wall-crossing-safe part of supersymmetric spectra, mutate more straightforwardly, whereby a quiver is mapped to a quiver. The mutation rule that preserves the quiver invariant is different from the usual one, however, which we explore and confirm numerically.

  19. Somatic mutations in aging, cancer and neurodegeneration. (United States)

    Kennedy, Scott R; Loeb, Lawrence A; Herr, Alan J


    The somatic mutation theory of aging posits that the accumulation of mutations in the genetic material of somatic cells as a function of time results in a decrease in cellular function. In particular, the accumulation of random mutations may inactivate genes that are important for the functioning of the somatic cells of various organ systems of the adult, result in a decrease in organ function. When the organ function decreases below a critical level, death occurs. A significant amount of research has shown that somatic mutations play an important role in aging and a number of age related pathologies. In this review, we explore evidence for increases in somatic nuclear mutation burden with age and the consequences for aging, cancer, and neurodegeneration. We then review evidence for increases in mitochondrial mutation burden and the consequences for dysfunction in the disease processes.

  20. Identification of six new Gaucher disease mutations

    Energy Technology Data Exchange (ETDEWEB)

    Beutler, E.; Gelbart, T.; West, C. (Scripps Research Institute, La Jolla, CA (United States))


    The four most common mutations account for 97% of the Gaucher disease-producing alleles in Jewish patients and 75% of the alleles in non-Jewish patients. Although at least 15 other mutations and some examples of gene conversion and/or fusion genes have been described, a number of mutations remain unidentified. We have now identified six new mutations, a deletion of a C at the 72 position of the cDNA, a 481C[yields]T mutation (122p[sup Gly[yields]Ser]), a 751T [yields] C (212 [sup Tyr[yields]His]), a 1549G [yields] A (478[sup Gly[yields]Ser]), a 1604G [yields] A (496 [sup Arg[yields]His]), and a 55-bp deletion. All but one of these were found in single families. The 1604A mutation, however, was observed in four unrelated individuals. 7 refs., 2 tabs.

  1. How mutation affects evolutionary games on graphs. (United States)

    Allen, Benjamin; Traulsen, Arne; Tarnita, Corina E; Nowak, Martin A


    Evolutionary dynamics are affected by population structure, mutation rates and update rules. Spatial or network structure facilitates the clustering of strategies, which represents a mechanism for the evolution of cooperation. Mutation dilutes this effect. Here we analyze how mutation influences evolutionary clustering on graphs. We introduce new mathematical methods to evolutionary game theory, specifically the analysis of coalescing random walks via generating functions. These techniques allow us to derive exact identity-by-descent (IBD) probabilities, which characterize spatial assortment on lattices and Cayley trees. From these IBD probabilities we obtain exact conditions for the evolution of cooperation and other game strategies, showing the dual effects of graph topology and mutation rate. High mutation rates diminish the clustering of cooperators, hindering their evolutionary success. Our model can represent either genetic evolution with mutation, or social imitation processes with random strategy exploration.

  2. Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome. (United States)

    Mian, Syed A; Smith, Alexander E; Kulasekararaj, Austin G; Kizilors, Aytug; Mohamedali, Azim M; Lea, Nicholas C; Mitsopoulos, Konstantinos; Ford, Kevin; Nasser, Erick; Seidl, Thomas; Mufti, Ghulam J


    The recent identification of acquired mutations in key components of the spliceosome machinery strongly implicates abnormalities of mRNA splicing in the pathogenesis of myelodysplastic syndromes. However, questions remain as to how these aberrations functionally combine with the growing list of mutations in genes involved in epigenetic modification and cell signaling/transcription regulation identified in these diseases. In this study, amplicon sequencing was used to perform a mutation screen in 154 myelodysplastic syndrome patients using a 22-gene panel, including commonly mutated spliceosome components (SF3B1, SRSF2, U2AF1, ZRSR2), and a further 18 genes known to be mutated in myeloid cancers. Sequencing of the 22-gene panel revealed that 76% (n=117) of the patients had mutations in at least one of the genes, with 38% (n=59) having splicing gene mutations and 49% (n=75) patients harboring more than one gene mutation. Interestingly, single and specific epigenetic modifier mutations tended to coexist with SF3B1 and SRSF2 mutations (P<0.03). Furthermore, mutations in SF3B1 and SRSF2 were mutually exclusive to TP53 mutations both at diagnosis and at the time of disease transformation. Moreover, mutations in FLT3, NRAS, RUNX1, CCBL and C-KIT were more likely to co-occur with splicing factor mutations generally (P<0.02), and SRSF2 mutants in particular (P<0.003) and were significantly associated with disease transformation (P<0.02). SF3B1 and TP53 mutations had varying impacts on overall survival with hazard ratios of 0.2 (P<0.03, 95% CI, 0.1-0.8) and 2.1 (P<0.04, 95% CI, 1.1-4.4), respectively. Moreover, patients with splicing factor mutations alone had a better overall survival than those with epigenetic modifier mutations, or cell signaling/transcription regulator mutations with and without coexisting mutations of splicing factor genes, with worsening prognosis (P<0.001). These findings suggest that splicing factor mutations are maintained throughout disease

  3. Mutational analysis of Bloom helicase. (United States)

    Xi, Xu Guang


    DNA helicases are biomolecular motors that convert the chemical energy derived from the hydrolysis of nucleotide triphosphate (usually ATP) into mechanical energy to unwind double-stranded DNA. The unwinding of double-stranded DNA is an essential process for DNA replication, repair, recombination, and transcription. Mutations in human RecQ helicases result in inherent human disease including Bloom's syndrome, Werner's syndrome, and Rothmund-Thomson syndrome. Bloom's syndrome (BS) is a rare human autosomal recessive disorder characterized by a strong predisposition to a wide range of cancers commonly affecting the general population. In order to understand the molecular basis of BS pathology and the mechanism underlying the function of Bloom helicase, we have analyzed BS-causing missense mutations by a combination of structural modeling, site-directed mutagenesis, and biochemical and biophysical approaches. Here, we describe the methods and protocols for measuring ATPase, ATP and DNA binding, DNA strand annealing, and DNA unwinding activities of Bloom protein and its mutant variants. These approaches should be applicable and useful for studying other helicases.

  4. Definition of mutations in polyautoimmunity. (United States)

    Johar, Angad; Sarmiento-Monroy, Juan C; Rojas-Villarraga, Adriana; Silva-Lara, Maria F; Patel, Hardip R; Mantilla, Ruben D; Velez, Jorge I; Schulte, Klaus-Martin; Mastronardi, Claudio; Arcos-Burgos, Mauricio; Anaya, Juan-Manuel


    Familial autoimmunity and polyautoimmunity represent extreme phenotypes ideal for identifying major genomic variants contributing to autoimmunity. Whole exome sequencing (WES) and linkage analysis are well suited for this purpose due to its strong resolution upon familial segregation patterns of functional protein coding and splice variants. The primary objective of this study was to identify potentially autoimmune causative variants using WES data from extreme pedigrees segregating polyautoimmunity phenotypes. DNA of 47 individuals across 10 extreme pedigrees, ascertained from probands affected with polyautoimmunity and familial autoimmunity, were selected for WES. Variant calls were obtained through Genome Analysis Toolkit. Filtration and prioritization framework to identify mutation(s) were applied, and later implemented for genetic linkage analysis. Sanger sequencing corroborated variants with significant linkage. Novel and mostly rare variants harbored in SRA1, MLL4, ABCB8, DHX34 and PLAUR showed significant linkage (LOD scores are >3.0). The strongest signal was in SRA1, with a LOD score of 5.48. Network analyses indicated that SRA1, PLAUR and ABCB8 contribute to regulation of apoptotic processes. Novel and rare variants in genetic linkage with polyautoimmunity were identified throughout WES. Genes harboring these variants might be major players of autoimmunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Mutation detection using Surveyor nuclease. (United States)

    Qiu, Peter; Shandilya, Harini; D'Alessio, James M; O'Connor, Kevin; Durocher, Jeffrey; Gerard, Gary F


    We have developed a simple and flexible mutation detection technology for the discovery and mapping of both known and unknown mutations. This technology is based on a new mismatch-specific DNA endonuclease from celery, Surveyor nuclease, which is a member of the CEL nuclease family of plant DNA endonucleases. Surveyor nuclease cleaves with high specificity at the 3' side of any mismatch site in both DNA strands, including all base substitutions and insertion/deletions up to at least 12 nucleotides. Surveyor nuclease technology involves four steps: (i) PCR to amplify target DNA from both mutant and wild-type reference DNA; (ii) hybridization to form heteroduplexes between mutant and wild-type reference DNA; (iii) treatment of annealed DNA with Surveyor nuclease to cleave heteroduplexes; and (iv) analysis of digested DNA products using the detection/separation platform of choice. The technology is highly sensitive, detecting rare mutants present at as low as 1 in 32 copies. Unlabeled Surveyor nuclease digestion products can be analyzed using conventional gel electrophoresis or high-performance liquid chromatography (HPLC), while end labeled digestion products are suitable for analysis by automated gel or capillary electrophoresis. The entire protocol can be performed in less than a day and is suitable for automated and high-throughput procedures.

  6. Activating GNAS mutations in parosteal osteosarcoma. (United States)

    Carter, Jodi M; Inwards, Carrie Y; Jin, Long; Evers, Barbara; Wenger, Doris E; Oliveira, Andre M; Fritchie, Karen J


    Parosteal osteosarcoma is a surface-based osteosarcoma that often exhibits deceptively bland cytologic features, hindering diagnosis in small biopsies or when correlative radiologic imaging is not readily available. A number of benign and malignant fibro-osseous lesions, including fibrous dysplasia (FD) and low-grade central osteosarcoma, fall within the morphologic differential diagnosis of parosteal osteosarcoma. Somatic mutations in GNAS, encoding the α-subunit of the heterotrimeric G protein complex (Gsα), occur in FD and McCune-Albright syndrome but have not been reported in parosteal osteosarcoma. We evaluated GNAS mutational status in parosteal osteosarcoma and several of its histologic mimics to determine its utility in differentiating these entities. Eleven of 14 (79%) FD cases had GNAS mutations within codon 201 (5 R201C and 6 R201H mutations). GNAS mutations were not detected in any cases of adamantinoma or osteofibrous dysplasia. Direct sequencing of 9 parosteal osteosarcomas, including 3 of low grade and 6 with dedifferentiation, revealed activating GNAS mutations in 5 cases (55%), distributed as 4 R201C-mutated tumors and 1 tumor with an R201H mutation. GNAS codon 227 mutations were not detected in any of the cases. There was no association between GNAS mutational status and patient demographics, histologic dedifferentiation, or clinical outcome. To our knowledge, we report the first series of parosteal osteosarcomas harboring activating GNAS mutations. Our data suggest that GNAS mutational status may have limited utility as an ancillary technique in differentiating benign and malignant fibro-osseous lesions of the bone.

  7. The Mutational Robustness of Influenza A Virus (United States)

    McCrone, John T.; Lauring, Adam S.


    A virus’ mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16) than in the other 6 segments (0.78 ± 0.24), and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects. PMID:27571422

  8. The inheritance of pathogenic mitochondrial DNA mutations


    Cree, L.M.; Samuels, D.C.; Chinnery, P F


    Abstract Mitochondrial DNA mutations cause disease in >1 in 5000 of the population, and ~1 in 200 of the population are asymptomatic carriers of a pathogenic mtDNA mutation. Many patients with these pathogenic mtDNA mutations present with a progressive, disabling neurological syndrome that leads to major disability and premature death. There is currently no effective treatment for mitochondrial disorders, placing great emphasis on preventing the transmission of these diseases. An e...

  9. The Mutational Robustness of Influenza A Virus.

    Directory of Open Access Journals (Sweden)

    Elisa Visher


    Full Text Available A virus' mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16 than in the other 6 segments (0.78 ± 0.24, and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects.

  10. Emerging patterns of somatic mutations in cancer


    Watson, Ian R.; Takahashi, Koichi; Futreal, P. Andrew; Chin, Lynda


    The advance in technological tools for massively parallel, high-throughput sequencing of DNA has enabled the comprehensive characterization of somatic mutations in large number of tumor samples. Here, we review recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates, s...

  11. Somatic mutations of calreticulin in myeloproliferative neoplasms. (United States)

    Klampfl, Thorsten; Gisslinger, Heinz; Harutyunyan, Ashot S; Nivarthi, Harini; Rumi, Elisa; Milosevic, Jelena D; Them, Nicole C C; Berg, Tiina; Gisslinger, Bettina; Pietra, Daniela; Chen, Doris; Vladimer, Gregory I; Bagienski, Klaudia; Milanesi, Chiara; Casetti, Ilaria Carola; Sant'Antonio, Emanuela; Ferretti, Virginia; Elena, Chiara; Schischlik, Fiorella; Cleary, Ciara; Six, Melanie; Schalling, Martin; Schönegger, Andreas; Bock, Christoph; Malcovati, Luca; Pascutto, Cristiana; Superti-Furga, Giulio; Cazzola, Mario; Kralovics, Robert


    Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients. We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms. Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2. Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F

  12. Computational Analysis of PTEN Gene Mutation

    Directory of Open Access Journals (Sweden)

    Siew-Kien Mah


    Full Text Available Post-genomic data can be efficiently analyzed using computational tools. It has the advantage over the biochemical and biophysical methods in term of higher coverage. In this research, we adopted a computational analysis on PTEN gene mutation.  Mutation in PTEN is responsible for many human diseases. The results of this research provide insights into the protein domains of PTEN and the distribution of mutation.

  13. Methods for detection of ataxia telangiectasia mutations

    Energy Technology Data Exchange (ETDEWEB)

    Gatti, Richard A.


    The present invention is directed to a method of screening large, complex, polyexonic eukaryotic genes such as the ATM gene for mutations and polymorphisms by an improved version of single strand conformation polymorphism (SSCP) electrophoresis that allows electrophoresis of two or three amplified segments in a single lane. The present invention also is directed to new mutations and polymorphisms in the ATM gene that are useful in performing more accurate screening of human DNA samples for mutations and in distinguishing mutations from polymorphisms, thereby improving the efficiency of automated screening methods.

  14. Mutation rate analysis at 19 autosomal microsatellites. (United States)

    Qian, Xiao-Qin; Yin, Cai-Yong; Ji, Qiang; Li, Kai; Fan, Han-Ting; Yu, Yan-Fang; Bu, Fan-Li; Hu, Ling-Li; Wang, Jian-Wen; Mu, Hao-Fang; Haigh, Steven; Chen, Feng


    Previous studies have demonstrated that a large sample size is needed to reliably estimate population- and locus-specific microsatellite mutation rates. Therefore, we conducted a long-term collaboration study and performed a comprehensive analysis on the mutation characteristics of 19 autosomal short tandem repeat (STR) loci. The STR loci located on 15 of 22 autosomal chromosomes were analyzed in a total of 21,106 samples (11,468 parent-child meioses) in a Chinese population. This provided 217,892 allele transfers at 19 STR loci. An overall mutation rate of 1.20 × 10(-3) (95% CI, 1.06-1.36 × 10(-3) ) was observed in the populations across 18 of 19 STR loci, except for the TH01 locus with no mutation found. Most STR mutations (97.7%) were single-step mutations, and only a few mutations (2.30%) comprised two and multiple steps. Interestingly, approximately 93% of mutation events occur in the male germline. The mutation ratios increased with the paternal age at child birth (r = 0.99, ptesting, kinship analysis, and population genetics.

  15. The mutational spectrum in Waardenburg syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Read, A.P.; Tassabehji, M.; Liu, X.Z. [and others


    101 individuals or families with Waardenburg syndrome (WS) or related abnormalities have been screened for mutations in the PAX3 gene. PAX3 mutations were seen in 19 of 35 individuals or families with features of Type I Waardenburg syndrome. None of the 47 Type 2 WS families showed any PAX3 mutation, nor did any of 19 individuals with other neural crest syndromes or pigmentary disturbances. PAX3 mutations included substitutions of highly conserved amino acids, splice site mutations, nonsense mutations and frameshifting deletions or insertions. One patient (with Type 1 WS, mental retardation and growth retardation) had a chromosomal deletion of 7-8 Mb encompassing the PAX3 gene. Mutations were seen in each of exons 2-6, with a concentration in the 5{prime} part of the paired box (exon 2) and the 3{prime} part of the homeobox (exon 6). There was no evident relation between the molecular change and the clinical manifestations in mutation carriers. We conclude that PAX3 dosage effects very specifically produce dystopia canthorum, the distinguishing feature of Type 1 WS, and variably produce the other features of Type 1 WS depending on genetic background or chance events. Two of the Type 2 families showed linkage to markers from 3p14, the location of the MITF gene. MITF encodes a basic helix-loop-helix-zipper protein which is the homologue of the mouse microphthalmia gene product. It is likely that mutations in MITF cause some but not all Type 2 WS.

  16. Novel PORCN mutations in focal dermal hypoplasia. (United States)

    Froyen, G; Govaerts, K; Van Esch, H; Verbeeck, J; Tuomi, M-L; Heikkilä, H; Torniainen, S; Devriendt, K; Fryns, J-P; Marynen, P; Järvelä, I; Ala-Mello, S


    Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.

  17. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. (United States)

    Friedrich, Katrin; Lee, Lin; Leistritz, Dru F; Nürnberg, Gudrun; Saha, Bidisha; Hisama, Fuki M; Eyman, Daniel K; Lessel, Davor; Nürnberg, Peter; Li, Chumei; Garcia-F-Villalta, María J; Kets, Carolien M; Schmidtke, Joerg; Cruz, Vítor Tedim; Van den Akker, Peter C; Boak, Joseph; Peter, Dincy; Compoginis, Goli; Cefle, Kivanc; Ozturk, Sukru; López, Norberto; Wessel, Theda; Poot, Martin; Ippel, P F; Groff-Kellermann, Birgit; Hoehn, Holger; Martin, George M; Kubisch, Christian; Oshima, Junko


    Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.

  18. The clinical importance of myeloid antigen coexpression and TEL-AML1 mutation in patients with childhood acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Ayşen Türedi Yıldırım


    Full Text Available Objective: In this study, we aim to investigate the relationship,if any, between clinical features, prognosis, and thecoexpressions and TEL-AML1 mutation in patients withacute lymphoblastic leukemia (ALL.Methods: Eigthy-three patients with acute lymphoblasticleukemia were retrospectively examined. Age, gender,White blood cell count, hemoglobin level, platelet count,ALL subtypei (B or T ALL, risk groups, surface antigensdeteceted by flow cytometry, existence of TEL-AML1 mutations,response, remission and relapse status at 8., 33. Days of treatment were recorded and analyzed.Results: 15 (18% out of 83 were identified with aberrantantigen expression. Of these patients, twelve (14.4%had myeloid antigen coexpression (CD13 and/or CD33,two with B cell ALL had CD2 and CD7 coexpressions respectively,one with T cell ALL had CD19 coexpression.No significant differences were found between patientswith and without myeloid antigen coexpression in terms ofhemoglobin levels, white blood cells and platelet counts,responses given on the 8th, 15th, and 30th days on the treatment,risk groups, and relapse (p>0.05. Myeloid antigencoexpression was found in 4 of 13 patients who were identifiedwith TEL-AML1 mutation. No significant relationshipwas found between this mutation and coexpressions. Norelapse and exitus were observed in four patients with coexpressionand TEL-AML1.Conclusion: The prognosis and clinical features showsno statistically significant relationship with the presence ofneither Myeloid antigen expression nor TEL-AML1 mutation.We believe, however, the future studies involving biggersample sizes will prove to be useful in terms of moreconvincing results. J Clin Exp Invest 2013; 4(1: 90-94Key words: Acute lenfoblastic leukemia, coexpression,TEL-AML1 mutation, prognosis

  19. A frequent splicing mutation and novel missense mutations color the updated mutational spectrum of classic galactosemia in Portugal. (United States)

    Coelho, Ana I; Ramos, Ruben; Gaspar, Ana; Costa, Cláudia; Oliveira, Anabela; Diogo, Luísa; Garcia, Paula; Paiva, Sandra; Martins, Esmeralda; Teles, Elisa Leão; Rodrigues, Esmeralda; Cardoso, M Teresa; Ferreira, Elena; Sequeira, Sílvia; Leite, Margarida; Silva, Maria João; de Almeida, Isabel Tavares; Vicente, João B; Rivera, Isabel


    Classic galactosemia is an autosomal recessive disorder caused by deficient galactose-1-phosphate uridylyltransferase (GALT) activity. Patients develop symptoms in the neonatal period, which can be ameliorated by dietary restriction of galactose. Many patients develop long-term complications, with a broad range of clinical symptoms whose pathophysiology is poorly understood. The high allelic heterogeneity of GALT gene that characterizes this disorder is thought to play a determinant role in biochemical and clinical phenotypes. We aimed to characterize the mutational spectrum of GALT deficiency in Portugal and to assess potential genotype-phenotype correlations. Direct sequencing of the GALT gene and in silico analyses were employed to evaluate the impact of uncharacterized mutations upon GALT functionality. Molecular characterization of 42 galactosemic Portuguese patients revealed a mutational spectrum comprising 14 nucleotide substitutions: ten missense, two nonsense and two putative splicing mutations. Sixteen different genotypic combinations were detected, half of the patients being p.Q188R homozygotes. Notably, the second most frequent variation is a splicing mutation. In silico predictions complemented by a close-up on the mutations in the protein structure suggest that uncharacterized missense mutations have cumulative point effects on protein stability, oligomeric state, or substrate binding. One splicing mutation is predicted to cause an alternative splicing event. This study reinforces the difficulty in establishing a genotype-phenotype correlation in classic galactosemia, a monogenic disease whose complex pathogenesis and clinical features emphasize the need to expand the knowledge on this "cloudy" disorder.

  20. Mutation specific functions of EGFR result in a mutation-specific downstream pathway activation

    NARCIS (Netherlands)

    L. Eraslan-Erdem (Lale); Y. Gao; N.K. Kloosterhof (Nanne); Y. Atlasi (Yaser); J.A.A. Demmers (Jeroen); A. Sacchetti (Andrea); J.M. Kros (Johan); P.A.E. Sillevis Smitt (Peter); J.G.J.V. Aerts (Joachim); P.J. French (Pim)


    markdownabstractBackground: Epidermal growth factor receptor (EGFR) is frequently mutated in various types of cancer. Although all oncogenic mutations are considered activating, different tumour types have different mutation spectra. It is possible that functional differences underlie this tumour-ty

  1. TERT promoter mutations in thyroid cancer. (United States)

    Liu, Rengyun; Xing, Mingzhao


    The 2013 discovery of Telomerase reverse transcriptase (TERT) promoter mutations chr5, 1,295,228 C>T (C228T) and 1,295,250 C>T (C250T) in thyroid cancer represents an important event in the thyroid cancer field and much progress has occurred since then. This article provides a comprehensive review of this exciting new thyroid cancer field. The oncogenic role of TERT promoter mutations involves their creation of consensus binding sites for E-twenty-six transcriptional factors. TERT C228T is far more common than TERT C250T and their collective prevalence is, on average, 0, 11.3, 17.1, 43.2 and 40.1% in benign thyroid tumors, papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer, respectively, displaying an association with aggressive types of thyroid cancer. TERT promoter mutations are associated with aggressive thyroid tumor characteristics, tumor recurrence and patient mortality as well as BRAF V600E mutation. Coexisting BRAF V600E and TERT promoter mutations have a robust synergistic impact on the aggressiveness of PTC, including a sharply increased tumor recurrence and patient mortality, while either mutation alone has a modest impact. Thus, TERT with promoter mutations represents a prominent new oncogene in thyroid cancer and the mutations are promising new diagnostic and prognostic genetic markers for thyroid cancer, which, in combination with BRAF V600E mutation or other genetic markers (e.g. RAS mutations), are proving to be clinically useful for the management of thyroid cancer. Future studies will specifically define such clinical utilities, elucidate the biological mechanisms and explore the potential as therapeutic targets of TERT promoter mutations in thyroid cancer.

  2. Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib

    Directory of Open Access Journals (Sweden)

    Marcelo Paschoalete Carlin


    Full Text Available Glycogen storage disease (GSD comprises a group of autosomal recessive disorders characterized by deficiency of the enzymes that regulate the synthesis or degradation of glycogen. Types Ia and Ib are the most prevalent; while the former is caused by deficiency of glucose-6-phosphatase (G6Pase, the latter is associated with impaired glucose-6-phosphate transporter, where the catalytic unit of G6Pase is located. Over 85 mutations have been reported since the cloning of G6PC and SLC37A4 genes. In this study, twelve unrelated patients with clinical symptoms suggestive of GSDIa and Ib were investigated by using genetic sequencing of G6PC and SLC37A4 genes, being three confirmed as having GSD Ia, and two with GSD Ib. In seven of these patients no mutations were detected in any of the genes. Five changes were detected in G6PC, including three known point mutations (p.G68R, p.R83C and p.Q347X and two neutral mutations (c.432G > A and c.1176T > C. Four changes were found in SLC37A4: a known point mutation (p.G149E, a novel frameshift insertion (c.1338_1339insT, and two neutral mutations (c.1287G > A and c.1076-28C > T. The frequency of mutations in our population was similar to that observed in the literature, in which the mutation p.R83C is also the most frequent one. Analysis of both genes should be considered in the investigation of this condition. An alternative explanation to the negative results in this molecular study is the possibility of a misdiagnosis. Even with a careful evaluation based on laboratory and clinical findings, overlap with other types of GSD is possible, and further molecular studies should be indicated.

  3. Finite mutation classes of coloured quivers

    CERN Document Server

    Torkildsen, Hermund André


    We consider the general notion of coloured quiver mutation and show that the mutation class of a coloured quiver $Q$, arising from an $m$-cluster tilting object associated with $H$, is finite if and only if $H$ is of finite or tame representation type, or it has at most 2 simples. This generalizes a result known for 1-cluster categories.

  4. Silting mutation for self-injective algebras

    CERN Document Server

    Aihara, Takuma


    We study `silting mutaion' for self-injective algebras. In particular we focus on `tilting mutation' and show that iterated irreducible `silting mutation' transitively act on the set of silting objects for representation-finite symmetric algebras. Moreover we give some sufficient conditions for `Bongartz-type Lemma' on silting objects.

  5. MT-CYB mutations in hypertrophic cardiomyopathy

    DEFF Research Database (Denmark)

    Hagen, Christian M; Aidt, Frederik H; Havndrup, Ole


    Mitochondrial dysfunction is a characteristic of heart failure. Mutations in mitochondrial DNA, particularly in MT-CYB coding for cytochrome B in complex III (CIII), have been associated with isolated hypertrophic cardiomyopathy (HCM). We hypothesized that MT-CYB mutations might play an important...

  6. Inverse PCR for Point Mutation Introduction. (United States)

    Silva, Diogo; Santos, Gustavo; Barroca, Mário; Collins, Tony


    Inverse PCR is a powerful tool for the rapid introduction of desired mutations at desired positions in a circular double-stranded DNA sequence. Here, custom-designed mutant primers oriented in the inverse direction are used to amplify the entire circular template with incorporation of the required mutation(s). By careful primer design it can be used to perform such diverse modifications as the introduction of point mutations and multiple mutations, the insertion of new sequences, and even sequence deletions. Three primer formats are commonly used; nonoverlapping, partially overlapping and fully overlapping primers, and here we describe the use of nonoverlapping primers for introduction of a point mutation. Use of such a primer setup in the PCR reaction, with one of the primers containing the desired mismatch mutation, results in the amplification of a linear, double-stranded, mutated product. Methylated template DNA is removed from the nonmethylated PCR product by DpnI digestion and the PCR product is then phosphorylated by polynucleotide kinase treatment before being recircularized by ligation, and transformed to E. coli. This relatively simple site-directed mutagenesis procedure is of major importance in biology and biotechnology today where it is commonly employed for the study and engineering of DNA, RNA, and proteins.

  7. KRAS and BRAF mutations in anal carcinoma

    DEFF Research Database (Denmark)

    Serup-Hansen, Eva; Linnemann, Dorte; Høgdall, Estrid


    the frequency and the prognostic value of KRAS and BRAF mutations in a large cohort of patients with anal cancer. One hundred and ninety-three patients with T1-4N0-3M0-1 anal carcinoma were included in the study. Patients were treated with curative (92%) or palliative intent (8%) between January 2000...... and January 2010. KRAS mutations were detected using Therascreen(®)KRAS real-time PCR assay (Qiagen) and V600E or V600D/K BRAF mutations were uncovered using Pyrosequencing. The frequency of KRAS and BRAF mutations was low; KRAS mutations were detected in 1.6% and BRAF mutations in 4.7% of the biopsies....... No impact of KRAS or BRAF status on survival was found. In conclusion, both KRAS and BRAF mutations are rare in anal cancer. The low frequency of KRAS mutations support protocols exploring EGFR-targeted therapy in patients with metastatic anal cancer, while treatment with BRAF inhibitors might be relevant...

  8. KRAS mutation testing in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Cong Tan; Xiang Du


    The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers,and KRAS mutational status testing has been highlighted in recent years.The most frequent mutations in this gene,point substitutions in codons 12 and 13,were validated as negative predictors of response to anti-epidermal growth factor receptor antibodies.Therefore,determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers.Currently,a variety of detection methods have been established to analyze the mutation status in the key regions of the KRAS gene; however,several challenges remain related to standardized and uniform testing,including the selection of tumor samples,tumor sample processing and optimal testing methods.Moreover,new testing strategies,in combination with the mutation analysis of BRAF,PIK3CA and loss of PTEN proposed by many researchers and pathologists,should be promoted.In addition,we recommend that microsatellite instability,a prognostic factor,be added to the abovementioned concomitant analysis.This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing.This review also addresses other aspects of status testing for determining the appropriate treatment and offers insight into the potential drawbacks of mutational testing.

  9. Mutational analysis of TARDBP in Parkinson's disease

    NARCIS (Netherlands)

    Blitterswijk, M. van; Es, M.A. van; Verbaan, D.; Hilten, J.J. van; Scheffer, H.; Warrenburg, B.P.C. van de; Veldink, J.H.; Berg, L.H. van den


    Mutations in TAR DNA-binding protein (TARDBP) are associated with heterogenic phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease. In this study, we investigated the presence of TARDBP mutations in a cohort of 429 Dutch patients with Parkinson's dise

  10. Abetalipoproteinemia: A novel mutation of microsomal triglyceride ...

    African Journals Online (AJOL)

    Hager Barakizou


    Jan 25, 2016 ... molecular genetics in a Tunisian child having a novel mutation of MTP gene. 2. ... ABL is caused by MTP gene frameshift, non-sense and splice site mutations which ... and its variations could be associated with central obesity, ele- vated liver enzymes, and alcoholic fatty liver disease [5]. It has recently been ...

  11. Analyzing effects of naturally occurring missense mutations. (United States)

    Zhang, Zhe; Miteva, Maria A; Wang, Lin; Alexov, Emil


    Single-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will produce an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This paper focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein and how to assess their effects on protein wild-type characteristics. The existing methods and approaches for predicting the effects of mutation on protein stability, structure, and dynamics are outlined and discussed with respect to their underlying principles. Available resources, either as stand-alone applications or webservers, are pointed out as well. It is emphasized that understanding the molecular mechanisms behind these effects due to these missense mutations is of critical importance for detecting disease-causing mutations. The paper provides several examples of the application of 3D structure-based methods to model the effects of protein stability and protein-protein interactions caused by missense mutations as well.

  12. Molecular methods for the detection of mutations. (United States)

    Monteiro, C; Marcelino, L A; Conde, A R; Saraiva, C; Giphart-Gassler, M; De Nooij-van Dalen, A G; Van Buuren-van Seggelen, V; Van der Keur, M; May, C A; Cole, J; Lehmann, A R; Steinsgrimsdottir, H; Beare, D; Capulas, E; Armour, J A


    We report the results of a collaborative study aimed at developing reliable, direct assays for mutation in human cells. The project used common lymphoblastoid cell lines, both with and without mutagen treatment, as a shared resource to validate the development of new molecular methods for the detection of low-level mutations in the presence of a large excess of normal alleles. As the "gold standard, " hprt mutation frequencies were also measured on the same samples. The methods under development included i) the restriction site mutation (RSM) assay, in which mutations lead to the destruction of a restriction site; ii) minisatellite length-change mutation, in which mutations lead to alleles containing new numbers of tandem repeat units; iii) loss of heterozygosity for HLA epitopes, in which antibodies can be used to direct selection for mutant cells; iv) multiple fluorescence-based long linker arm nucleotides assay (mf-LLA) technology, for the detection of substitutional mutations; v) detection of alterations in the TP53 locus using a (CA) array as the target for the screening; and vi) PCR analysis of lymphocytes for the presence of the BCL2 t(14:18) translocation. The relative merits of these molecular methods are discussed, and a comparison made with more "traditional" methods.

  13. Mutation update for the PORCN gene

    DEFF Research Database (Denmark)

    Lombardi, Maria Paola; Bulk, Saskia; Celli, Jacopo


    Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then, several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum,...

  14. Increased strength of the scapular stabilizer and lumbar muscles after twelve weeks of Pilates training using the Reformer machine: A pilot study. (United States)

    Dos Santos, Núbia Tomain Otoni; Raimundo, Karoline Cipriano; da Silva, Sheila Aparecida; Souza, Lara Andrade; Ferreira, Karoline Carregal; Borges Santo Urbano, Zuleika Ferreira; Gasparini, Andréa Licre Pessina; Bertoncello, Dernival


    The aim of this work was to analyze muscle strength in Pilates novices who used the Reformer equipment during twelve training sessions. Twenty-four healthy young female volunteers, who were non-smokers and did not exercise regularly, were split into a control group (mean age 28 ± 4 years and BMI 24.55 ± 3.21 kg/m(2)) and a training group (mean age 29 ± 4 years and BMI 22.69 ± 2.87 kgm(2)). The data were checked for normality using the Kolmogorov-Smirnov test, and were then analyzed using the t-test (p Pilates group). The corresponding values for the lumbar muscles were 53.83 ± 11.66/53.28 ± 11.14 (control group) and 54.75 ± 10.27/64.80 ± 10.20 (Pilates group). After twelve sessions of Pilates with the Reformer equipment, there were improvements in lumbar extensor and scapular stabilizer strength. Several benefits are reported by practitioners of Pilates, but until now, there has been limited scientific evidence of the improvement of strength in the trunk and limbs after application of the technique. Published by Elsevier Ltd.

  15. Mechanisms of action in integrated cognitive-behavioral treatment versus twelve-step facilitation for substance-dependent adults with comorbid major depression. (United States)

    Glasner-Edwards, Suzette; Tate, Susan R; McQuaid, John R; Cummins, Kevin; Granholm, Eric; Brown, Sandra A


    In a population of veterans with co-occurring substance use disorders and concomitant major depressive disorder, the current study compared mechanisms of change and therapeutic effects relevant to both disorders between integrated, dual disorder-specific cognitive behavioral therapy (ICBT) and twelve-step facilitation (TSF). Veterans (N = 148) were given standard pharmacotherapy for depression and were randomly assigned to receive 24 weeks of either TSF or ICBT. Process measures were selected to quantify (1) changes in self-efficacy in ICBT, (2) changes in ability to terminate negative affect in ICBT, (3) twelve-step affiliation (TSA) in TSF, and (4) changes in social support in both conditions. Measures of depression and substance use were administered to all participants before treatment, during treatment, and at the end of treatment. Self-efficacy increased among both TSF and ICBT participants during treatment, whereas self-reported ability to regulate negative affect did not change. Consistent with predictions, TSF participants increased community TSA during treatment, whereas those receiving ICBT reduced TSA. Changes in self-efficacy and TSA were associated with improvement in substance use outcomes at the end of treatment. Hypothesized changes in social support were not supported. Both ICBT and TSF produce improvements in self-efficacy, and these changes are related to substance use outcomes for depressed substance abusers. In TSF, intervention-specific changes in TSA occur during the course of treatment and are related to substance use outcomes.

  16. Effects of dietary crude protein on the growth performance, carcass characteristics and serum biochemical indexes of Lueyang black-boned chickens from seven to twelve weeks of age

    Directory of Open Access Journals (Sweden)

    SK Liu


    Full Text Available This study was undertaken to assess dietary crude protein (CP concentration for optimum growth performance and carcass characteristics of Lueyang black-boned chicken. In total, six hundred 42-day-old Lueyang black-boned chicks were randomly assigned to five treatments, each with six replicate pens with ten males and ten females. The birds fed experimental diets with different levels of protein concentration of 120, 140, 160, 180 and 200 g kg-1 from seven to twelve weeks of age respectively. On day of 84, weight gain, feed intake, and feed:gain ratio were measured, and two chickens (one male and one female close to the average weight of all birds in each treatment were selected from each pen and sacrificed to evaluate carcass traits and selected serum biochemical indexes. Dietary CP concentration did not have any significant influence on feed intake (p>0.05. The birds fed the diet with 180 or 160 g kg-1 CP concentration exhibited greater (p<0.05 growth rate, better feed conversion ratio, relative breast weight and albumin concentration in serum than that of those fed other dietary CP concentrations. According to the results of regression analysis, the CP requirements of Lueyang black-boned chicken from seven to twelve weeks of age for optimal weight gain and feed:gain ratio were 174 and 170 g kg-1, respectively.

  17. Mutations in the human TWIST gene. (United States)

    Gripp, K W; Zackai, E H; Stolle, C A


    Saethre-Chotzen syndrome is a relatively common craniosynostosis disorder with autosomal dominant inheritance. Mutations in the TWIST gene have been identified in patients with Saethre-Chotzen syndrome. The TWIST gene product is a transcription factor with DNA binding and helix-loop-helix domains. Numerous missense and nonsense mutations cluster in the functional domains, without any apparent mutational hot spot. Two novel point mutations and one novel polymorphism are included in this review. Large deletions including the TWIST gene have been identified in some patients with learning disabilities or mental retardation, which are not typically part of the Saethre-Chotzen syndrome. Comprehensive studies in patients with the clinical diagnosis of Saethre-Chotzen syndrome have demonstrated a TWIST gene abnormality in about 80%, up to 37% of which may be large deletions [Johnson et al., 1998]. The gene deletions and numerous nonsense mutations are suggestive of haploinsufficiency as the disease-causing mechanism. No genotype phenotype correlation was apparent.

  18. Hypomyelinating Leukodystrophy due to HSPD1 Mutations

    DEFF Research Database (Denmark)

    Schioldan Kusk, Maria; Damgaard, Bodil; Risom, Lotte


    The hypomyelinating leukodystrophies (HMLs) encompass the X-linked Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations and known as the classical form of HML as well as Pelizaeus-Merzbacher-like disease (PMLD) (Online Mendelian Inheritance in Man [OMIM] 608804 and OMIM 260600) due to GJC2...... mutations. In addition, mutations in at least 10 other genes are known to cause HMLs. In 2008, an Israeli family with clinical and neuroimaging findings similar to those found in PMD was reported. The patients were found to have a homozygous missense mutation in HSPD1, encoding the mitochondrial heat......-shock protein 60 (Hsp60), and the disorder was defined as the autosomal recessive mitochondrial Hsp60 chaperonopathy (MitCHAP-60) disease. We here report the first case of this severe neurodegenerative disease since it was first described. Given the fact that the families carried the same mutation our patient...

  19. Mutation studies in ascidians: a review. (United States)

    Crocetta, Fabio; Marino, Rita; Cirino, Paola; Macina, Alberto; Staiano, Leopoldo; Esposito, Rosaria; Pezzotti, Maria Rosa; Racioppi, Claudia; Toscano, Francesco; De Felice, Elena; Locascio, Annamaria; Ristoratore, Filomena; Spagnuolo, Antonietta; Zanetti, Laura; Branno, Margherita; Sordino, Paolo


    Historically, mutations have had a significant impact on the study of developmental processes and phenotypic evolution. Lesions in DNA are created by artificial methods or detected by natural genetic variation. Random mutations are then ascribed to genetic change by direct sequencing or positional cloning. Tunicate species of the ascidian genus Ciona represent nearly fully realized model systems in which gene function can be investigated in depth. Additionally, tunicates are valuable organisms for the study of naturally occurring mutations due to the capability to exploit genetic variation down to the molecular level. Here, we summarize the available information about how mutations are studied in ascidians with examples of insights that have resulted from these applications. We also describe notions and methodologies that might be useful for the implementation of easy and tight procedures for mutations studies in Ciona.

  20. Mutations affecting gyrase in Haemophilus influenzae

    Energy Technology Data Exchange (ETDEWEB)

    Setlow, J.K.; Cabrera-Juarez, E.; Albritton, W.L.; Spikes, D.; Mutschler, A.


    Mutants separately resistant to novobiocin, coumermycin, nalidixic acid, and oxolinic acid contained gyrase activity as measured in vitro that was resistant to the antibiotics, indicating that the mutations represented structural alterations of the enzyme. One Novr mutant contained an altered B subunit of the enzyme, as judged by the ability of a plasmid, pNov1, containing the mutation to complement a temperature-sensitive gyrase B mutation in Escherichia coli and to cause novobiocin resistance in that strain. Three other Novr mutations did not confer antibiotic resistance to the gyrase but appeared to increase the amount of active enzyme in the cell. One of these, novB1, could only act in cis, whereas a new mutation, novC, could act in trans. An RNA polymerase mutation partially substituted for the novB1 mutation, suggesting that novB1 may be a mutation in a promoter region for the B subunit gene. Growth responses of strains containing various combinations of mutations on plasmids or on the chromosome indicated that low-level resistance to novobiocin or coumermycin may have resulted from multiple copies of wild-type genes coding for the gyrase B subunit, whereas high-level resistance required a structural change in the gyrase B gene and was also dependent on alteration in a regulatory region. When there was mismatch at the novB locus, with the novB1 mutation either on a plasmid or the chromosome, and the corresponding wild-type gene present in trans, chromosome to plasmid recombination during transformation was much higher than when the genes matched, probably because plasmid to chromosome recombination, eliminating the plasmid, was inhibited by the mismatch.

  1. Science Letters: Screen p53 mutations in hepatocellular carcinoma by FASAY: A novel splicing mutation

    Institute of Scientific and Technical Information of China (English)

    WU Xiao-mo; FU Jing-geng; GE Wang-zhong; ZHU Jiang-yan; WANG Jun-yong; ZHANG Wei; QIAN Wei; HUO Ke-ke


    Objective: To establish a routine procedure for the detection of p53 mutations in hepatocellular carcinoma (HCC)surgical resections using the FASAY (functional analysis of separated alleles of p53 on yeast) procedure. Methods: p53 status was analyzed by FASAY and cDNA sequencing in 50 cases of HCC. After the extraction of RNA from the frozen tumor and corresponding normal tissues, reverse transcription RT-PCR was carried out using these samples. The assay can detect mutations of p53mRNA between codons 67 and 347 by the DNA-binding activity of the protein and reveal them as red colonies. Results: Of the 50specimens, 29 (58%) were positive (mutant) by FASAY. Sequencing analysis confirmed that all 29 FASAY positive tumors harbored mutations, and that no mutations were detectable in any FASAY negative tumors. In 29 p53 mutations, 22 mutations were point missense mutation, 5 were deletions and 2 were splicing mutations. A novel splice mutation on splice donor of intron 6was reported, which could produce two different mRNAs, respectively using the nearest upstream and downstream recessive splice donor sites. Conclusion: FASAY is a sensitive method for detecting the various types of p53 mutations in HCC, suggesting that the yeast functional assay for the detection of p53 mutations may be essential for elucidating their clinical significance.

  2. MutationFinder: a high-performance system for extracting point mutation mentions from text. (United States)

    Caporaso, J Gregory; Baumgartner, William A; Randolph, David A; Cohen, K Bretonnel; Hunter, Lawrence


    Discussion of point mutations is ubiquitous in biomedical literature, and manually compiling databases or literature on mutations in specific genes or proteins is tedious. We present an open-source, rule-based system, MutationFinder, for extracting point mutation mentions from text. On blind test data, it achieves nearly perfect precision and a markedly improved recall over a baseline. MutationFinder, along with a high-quality gold standard data set, and a scoring script for mutation extraction systems have been made publicly available. Implementations, source code and unit tests are available in Python, Perl and Java. MutationFinder can be used as a stand-alone script, or imported by other applications.

  3. Software Mutational Robustness: Bridging The Gap Between Mutation Testing and Evolutionary Biology

    CERN Document Server

    Schulte, Eric; Fast, Ethan; Forrest, Stephanie; Weimer, Westley


    In the mutation testing paradigm, test suite quality is measured by its ability to detect variant programs generated through application of random changes to an original program. In evolutionary biology however, neutral mutations that leave fitness unchanged are considered to be beneficial---improving the system's robustness and ability to discover evolutionary improvements. In this paper, we generate a population of variant programs from an original program by applying lightweight random mutations. We adopt biological terminology and refer to undetected variants as neutral, and the percentage of all variants that are neutral as mutational robustness. Although they are related to equivalent mutants in mutation testing, which are viewed as problematic, we show positive properties of neutral variants which are easily generated and can be used to protect software against unknown defects. Even when mutations are restricted to statements executed by the test suit, we find that mutational robustness is high: 36.75%...

  4. Risk of Budd-Chiari syndrome associated with factor V Leiden and G20210A prothrombin mutation: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Peijin Zhang

    Full Text Available BACKGROUND: Various studies have demonstrated that factor V Leiden (FVL and G20210A prothrombin mutation contribute to the risk of Budd-Chiari syndrome (BCS, while other studies provided conflicting findings. In order to derive more precise estimations of the relationships, a meta-analysis was performed. METHODS: Eligible articles were identified through search of databases including Pubmed, Chinese Biomedical Database (CBM, Chinese, and Chinese National Knowledge Infrastructure (CNKI, Chinese. Odd ratios (ORs with 95% confidence intervals (CIs were calculated using random- or fixed- model. RESULTS: Finally, twelve studies were included for FVL and nine studies were included for G20210A prothrombin mutation. With respect to FVL, significantly increased BCS risk was found in the overall population (OR = 6.29, 95%CI = 4.23-9.36. Subgroup analyses suggested that FVL was associated with an increased risk of BCS in the population with high background mutation prevalence (>1% in the normal population. No significant association was found between BCS and G20210A prothrombin mutation (OR = 1.78, 95%CI = 0.77-4.11. CONCLUSION: The presence of FVL should be evaluated in patients with BCS. Conversely, G20210A prothrombin mutation is not significantly associated with risk of BCS. Large-scale well designed studies are necessary to be conducted to further confirm or refute the observed association.


    Directory of Open Access Journals (Sweden)

    S. Etemad Ahari


    Full Text Available ObjectiveMitochondrial DNA (mtDNA is considered a candidate modifier factor for neuro-degenerative disorders. The most common type of ataxia is Friedreich’s ataxia (FA. The aim of this study was to investigate different parts of mtDNA in 20 Iranian FA patients and 80 age-matched controls by polymerase chain reaction (PCR and automated DNA sequencing methods to find any probable point mutations involved in the pathogenesis of FA. Materials and MethodsWe identified 13 nucleotide substitutions including A3505G, T3335C, G3421A, G8251A, A8563G, A8563G, G8584A, T8614C, T8598C, C8684T, A8701G, G8994A and A9024G. ResultsTwelve of 13 nucleotide substitutions had already been reported as polymorphism. One of the nucleotide substitutions (A9024G had not been reported before. The A9024G nucleotide substitution does not change its amino acid. The controls were also investigated for this polymorphism which was found in two of them (2.5%. ConclusionNone of the mutations found in this study can affect the clinical manifestations of FA. This survey also provides evidence that the mtDNA A9024G allele is a new nonpathogenic polymorphism. We suggest follow-up studies for this polymorphism in different populations.

  6. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. (United States)

    Bonne, G; Mercuri, E; Muchir, A; Urtizberea, A; Bécane, H M; Recan, D; Merlini, L; Wehnert, M; Boor, R; Reuner, U; Vorgerd, M; Wicklein, E M; Eymard, B; Duboc, D; Penisson-Besnier, I; Cuisset, J M; Ferrer, X; Desguerre, I; Lacombe, D; Bushby, K; Pollitt, C; Toniolo, D; Fardeau, M; Schwartz, K; Muntoni, F


    Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease

  7. Mutational robustness of gene regulatory networks.

    Directory of Open Access Journals (Sweden)

    Aalt D J van Dijk

    Full Text Available Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor-target gene interactions but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive. In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence.

  8. Benchmarking infrastructure for mutation text mining (United States)


    Background Experimental research on the automatic extraction of information about mutations from texts is greatly hindered by the lack of consensus evaluation infrastructure for the testing and benchmarking of mutation text mining systems. Results We propose a community-oriented annotation and benchmarking infrastructure to support development, testing, benchmarking, and comparison of mutation text mining systems. The design is based on semantic standards, where RDF is used to represent annotations, an OWL ontology provides an extensible schema for the data and SPARQL is used to compute various performance metrics, so that in many cases no programming is needed to analyze results from a text mining system. While large benchmark corpora for biological entity and relation extraction are focused mostly on genes, proteins, diseases, and species, our benchmarking infrastructure fills the gap for mutation information. The core infrastructure comprises (1) an ontology for modelling annotations, (2) SPARQL queries for computing performance metrics, and (3) a sizeable collection of manually curated documents, that can support mutation grounding and mutation impact extraction experiments. Conclusion We have developed the principal infrastructure for the benchmarking of mutation text mining tasks. The use of RDF and OWL as the representation for corpora ensures extensibility. The infrastructure is suitable for out-of-the-box use in several important scenarios and is ready, in its current state, for initial community adoption. PMID:24568600

  9. Predicting Resistance Mutations Using Protein Design Algorithms

    Energy Technology Data Exchange (ETDEWEB)

    Frey, K.; Georgiev, I; Donald, B; Anderson, A


    Drug resistance resulting from mutations to the target is an unfortunate common phenomenon that limits the lifetime of many of the most successful drugs. In contrast to the investigation of mutations after clinical exposure, it would be powerful to be able to incorporate strategies early in the development process to predict and overcome the effects of possible resistance mutations. Here we present a unique prospective application of an ensemble-based protein design algorithm, K*, to predict potential resistance mutations in dihydrofolate reductase from Staphylococcus aureus using positive design to maintain catalytic function and negative design to interfere with binding of a lead inhibitor. Enzyme inhibition assays show that three of the four highly-ranked predicted mutants are active yet display lower affinity (18-, 9-, and 13-fold) for the inhibitor. A crystal structure of the top-ranked mutant enzyme validates the predicted conformations of the mutated residues and the structural basis of the loss of potency. The use of protein design algorithms to predict resistance mutations could be incorporated in a lead design strategy against any target that is susceptible to mutational resistance.

  10. New mutations in CMT 1 and HNPP

    Energy Technology Data Exchange (ETDEWEB)

    Vandenberghe, A.; Boucherat, M. [Faculty of Pharmacy, Lyon (France); Bonnebouche, C. [Hopital de l`Antiquaille, Lyon (France)] [and others


    The majority of mutations in CMT 1 (Charcot-Marie-Tooth disease type 1) are due to a duplication of a 1.5 Mb fragment from chromosome 17 containing the PMP22 myelin gene. In addition, micromutations are found in the genes for PMP22 and myelin Po. We collected data from over one hundred families with a duplication in 17p11.2. In about 10% of these families, a de novo mutation was observed. All parents were clinically examined as normal and correct paternity was confirmed. Some families were informative for polymorphic probes located in the duplicated region, and we could deduce a majority of new mutations to be from paternal origin. HNPP (hereditary neuropathy with liability to pressure palsies) is believed to be the reciprocal product of an unequal crossing over underlying the CMT 1 mutation and is due to a deletion of the 1.5 Mb fragment. One new HNPP mutation was found among 7 deleted HNPP families. This mutation is of paternal origin. Clinically assigned CMT 1 patients without a duplication are screened for micromutations applying the SSCP technique. In one family, a de novo mutation was found in the gene for Po.

  11. Significance of duon mutations in cancer genomes (United States)

    Yadav, Vinod Kumar; Smith, Kyle S.; Flinders, Colin; Mumenthaler, Shannon M.; de, Subhajyoti


    Functional mutations in coding regions not only affect the structure and function of the protein products, but may also modulate their expression in some cases. This class of mutations, recently dubbed “duon mutations” due to their dual roles, can potentially have major impacts on downstream pathways. However their significance in diseases such as cancer remain unclear. In a survey covering 4606 samples from 19 cancer types, and integrating allelic expression, overall mRNA expression, regulatory motif perturbation, and chromatin signatures in one composite index called REDACT score, we identified potential duon mutations. Several such mutations are detected in known cancer genes in multiple cancer types. For instance a potential duon mutation in TP53 is associated with increased expression of the mutant allelic gene copy, thereby possibly amplifying the functional effects on the downstream pathways. Another potential duon mutation in SF3B1 is associated with abnormal splicing and changes in angiogenesis and matrix degradation related pathways. Our findings emphasize the need to interrogate the mutations in coding regions beyond their obvious effects on protein structures.

  12. Inherited cardiomyopathies caused by troponin mutations

    Institute of Scientific and Technical Information of China (English)

    Qun-Wei Lu; Xiao-Yan Wu; Sachio Morimoto


    Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca2+-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca2+ sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.

  13. Risk assessment of K Basin twelve-inch and four-inch drain valve failure from a postulated seismic initiating event

    Energy Technology Data Exchange (ETDEWEB)

    MORGAN, R.G.


    The Spent Nuclear Fuel (SNF) Project will transfer metallic SNF from the Hanford 105 K-East and 105 K-West Basins to safe interim storage in the Canister Storage Building in the 200 Area. The initial basis for design, fabrication, installation, and operation of the fuel removal systems was that the basin leak rate which could result from a postulated accident condition would not be excessive relative to reasonable recovery operations. However, an additional potential K Basin water leak path is through the K Basin drain valves. Three twelve-inch drain valves are located in the main basin bays along the north wall. Five four-inch drain valves are located in the north and south loadout pits (NLOP and SLOP), the weasel pit, the technical viewing pit, and the discharge chute pit. The sumps containing the valves are filled with concrete which covers the drain valve body. Visual observations indicate that only the valve's bonnet and stem are exposed above the basin concrete floor for the twelve-inch drain valve and that much less of the valve's bonnet and stem are exposed above the basin concrete floor for the five four-inch drain valves. It was recognized, however, that damage of the drain valve bonnet or stem during a seismic initiating event could provide a potential K Basin water leak path. The objectives of this analysis are to: (1) evaluate the likelihood of damaging the three twelve-inch drain valves located along the north wall of the main basin and the five four-inch drain valves located in the pits from a seismic initiating event, and (2) determine the likelihood of exceeding a specific consequence (initial leak rate) from a damaged valve. The analysis process is a risk-based uncertainty analysis where each variable is modeled using available information and engineering judgement. The uncertainty associated with each variable is represented by a probability distribution (probability density function). Uncertainty exists because of the inherent

  14. Mitochondrial DNA Mutations Associated with Aminoglycoside Ototoxicity

    Institute of Scientific and Technical Information of China (English)

    GUAN Min-Xin


    The mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of all the mutations, the homoplasmic A1555G and C1494T mutations at a highly conserved decoding region in the 12S rRNA have been associated with aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. The A1555G or C1494T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the secondary structure of this RNA more closely resemble the corresponding region of bacterial 16S rRNA. Thus, the new U - A or G-C pair in 12S rRNA created by the C1494T or A1555G transition facilitates the binding of aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying these mutations. Furthermore, the growth defect and impairment of mitochondrial translation were observed in cell lines carrying the A1555G or C1494T mutation in the presence of high concentration of aminoglycosides. In addition, nuclear modifier genes and mitochondrial haplotypes modulate the phenotypic manifestation of the A1555G and C1494T mutations. These observations provide the direct genetic and biochemical evidences that the A1555G or C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and nonsyndromic hearing loss. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.

  15. TERT promoter mutations in melanoma survival. (United States)

    Nagore, Eduardo; Heidenreich, Barbara; Rachakonda, Sívaramakrishna; Garcia-Casado, Zaida; Requena, Celia; Soriano, Virtudes; Frank, Christoph; Traves, Victor; Quecedo, Esther; Sanjuan-Gimenez, Josefa; Hemminki, Kari; Landi, Maria Teresa; Kumar, Rajiv


    Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.

  16. Energy parasites trigger oncogene mutation. (United States)

    Pokorný, Jiří; Pokorný, Jan; Jandová, Anna; Kobilková, Jitka; Vrba, Jan; Vrba, Jan


    Cancer initialization can be explained as a result of parasitic virus energy consumption leading to randomized genome chemical bonding. Analysis of experimental data on cell-mediated immunity (CMI) containing about 12,000 cases of healthy humans, cancer patients and patients with precancerous cervical lesions disclosed that the specific cancer and the non-specific lactate dehydrogenase-elevating (LDH) virus antigen elicit similar responses. The specific antigen is effective only in cancer type of its origin but the non-specific antigen in all examined cancers. CMI results of CIN patients display both healthy and cancer state. The ribonucleic acid (RNA) of the LDH virus parasitizing on energy reduces the ratio of coherent/random oscillations. Decreased effect of coherent cellular electromagnetic field on bonding electrons in biological macromolecules leads to elevating probability of random genome reactions. Overlapping of wave functions in biological macromolecules depends on energy of the cellular electromagnetic field which supplies energy to bonding electrons for selective chemical bonds. CMI responses of cancer and LDH virus antigens in all examined healthy, precancerous and cancer cases point to energy mechanism in cancer initiation. Dependence of the rate of biochemical reactions on biological electromagnetic field explains yet unknown mechanism of genome mutation.

  17. Melanoma: from mutations to medicine (United States)

    Tsao, Hensin; Chin, Lynda; Garraway, Levi A.; Fisher, David E.


    Melanoma is often considered one of the most aggressive and treatment-resistant human cancers. It is a disease that, due to the presence of melanin pigment, was accurately diagnosed earlier than most other malignancies and that has been subjected to countless therapeutic strategies. Aside from early surgical resection, no therapeutic modality has been found to afford a high likelihood of curative outcome. However, discoveries reported in recent years have revealed a near avalanche of breakthroughs in the melanoma field—breakthroughs that span fundamental understanding of the molecular basis of the disease all the way to new therapeutic strategies that produce unquestionable clinical benefit. These discoveries have been born from the successful fruits of numerous researchers working in many—sometimes-related, although also distinct—biomedical disciplines. Discoveries of frequent mutations involving BRAF(V600E), developmental and oncogenic roles for the microphthalmia-associated transcription factor (MITF) pathway, clinical efficacy of BRAF-targeted small molecules, and emerging mechanisms underlying resistance to targeted therapeutics represent just a sample of the findings that have created a striking inflection in the quest for clinically meaningful progress in the melanoma field. PMID:22661227

  18. Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations. (United States)

    Sampieri, Katia; Hadjistilianou, Theodora; Mari, Francesca; Speciale, Caterina; Mencarelli, Maria Antonietta; Cetta, Francesco; Manoukian, Siranoush; Peissel, Bernard; Giachino, Daniela; Pasini, Barbara; Acquaviva, Antonio; Caporossi, Aldo; Frezzotti, Renato; Renieri, Alessandra; Bruttini, Mirella


    Retinoblastoma (RB, OMIM#180200) is the most common intraocular tumour in infancy and early childhood. Constituent mutations in the RB1 gene predispose individuals to RB development. We performed a mutational screening of the RB1 gene in Italian patients affected by RB referred to the Medical Genetics of the University of Siena. In 35 unrelated patients, we identified germline RB1 mutations in 6 out of 9 familial cases (66%) and in 7 out of 26 with no family history of RB (27%). Using the single-strand conformational polymorphism (SSCP) technique, 11 novel mutations were detected, including 3 nonsense, 5 frameshift and 4 splice-site mutations. Only two of these mutations (1 splice site and 1 missense) were previously reported. The mutation spectrum reflects the published literature, encompassing predominately nonsense or frameshift and splicing mutations. RB1 germline mutation was detected in 37% of our cases. Gross rearrangements outside the investigated region, altered DNA methylation, or mutations in non-coding regions, may be the cause of disease in the remainder of the patients. Some cases, e.g. a case of incomplete penetrance, or variable expressivity ranging from retinoma to multiple tumours, are discussed in detail. In addition, a case of pre-conception genetic counselling resolved by rescue of banked cordonal blood of the affected deceased child is described.

  19. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics. (United States)

    Akiyama, M


    Filaggrin is a key protein involved in skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris and have been shown to be major predisposing factors for atopic eczema (AE), initially in European populations. Subsequently, FLG mutations were identified in Japanese, Chinese, Taiwanese and Korean populations. It was demonstrated that FLG mutations are closely associated with AE in the Japanese population. Notably, the same FLG mutations identified in the European population were rarely found in Asians. These results exemplify differences in filaggrin population genetics between Europe and Asia. For mutation screening, background information needs to be obtained on prevalent FLG mutations for each geographical population. It is therefore important to establish the global population genetics maps for FLG mutations. Mutations at any site within FLG, even mutations in C-terminal imperfect filaggrin repeats, cause significant reductions in amounts of profilaggrin/filaggrin peptide in patient epidermis as the C-terminal region is essential for proper processing of profilaggrin into filaggrin. Thus, no genotype-phenotype correlation has been observed in patients with FLG mutations. A restoration of the barrier function seems a feasible and promising strategy for treatment and prevention in individuals with filaggrin deficiency.

  20. MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer. (United States)

    Gauthier, Nicholas Paul; Reznik, Ed; Gao, Jianjiong; Sumer, Selcuk Onur; Schultz, Nikolaus; Sander, Chris; Miller, Martin L


    The MutationAligner web resource, available at, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  1. Ophthalmic manifestations in a Chinese family with familial amyloid polyneuropathy due to a TTR Gly83Arg mutation. (United States)

    Liu, T; Zhang, B; Jin, X; Wang, W; Lee, J; Li, J; Yuan, H; Cheng, X


    To describe the characteristic ophthalmic phenotypes of a large Chinese family with familial amyloid polyneuropathy due to a missense mutation in transthyretin (TTR) (c.307 C>G). Twenty-seven individuals (12 affected, 15 unaffected) from a five-generation Chinese family underwent general medical examination and comprehensive ophthalmic examination, including best correct visual acuity, intraocular pressure measurements, Schirmer test, slitlamp examination, fundoscopy, and ocular ultrasonography. Histological examination of vitreous biopsies using Congo red staining and immunohistochemistry was performed. Cardiovascular magnetic resonance (CMR), electrocardiogram, and echocardiogram were used to evaluate cardiac amyloidosis. Electromyography was used to evaluate nerve function. All four exons of TTR were amplified by PCR, sequenced using a Bigdye terminator v3.1 cycle sequencing kit and analyzed on an ABI 3700XL Genetic Analyzer. All 12 affected individuals in the family had ocular manifestations, including severe vitreous opacities, secondary glaucoma, xerophthalmia, dyscoria, and attenuated retinal arteries. Congo red staining demonstrated amyloid deposits in the vitreous, and immunohistochemical staining confirmed the deposition of TTR proteins in the vitreous. Twelve individuals had polyneuropathy, and electromyography detected functional damage in peripheral nerves. One individual was diagnosed with cardiac amyloidosis by CMR. Direct sequencing revealed the heterozygous missense mutation in TTR (c.307 C>G p.Gly83Arg) in all 12 affected individuals. The mutation co-segregated with the disease phenotype and was absent in 100 normal controls. Vitreous opacity is very common in patients with the TTR Gly83Arg mutation; other clinical characteristics associated with the mutation include polyneuropathy and cardiac amyloidosis.

  2. Particle Swarm Optimization with Adaptive Mutation

    Institute of Scientific and Technical Information of China (English)

    LU Zhen-su; HOU Zhi-rong; DU Juan


    A new adaptive mutation particle swarm optimizer,which is based on the variance of the population's fitness,is presented in this paper.During the rtmning time,the mutation probability for the current best particle is determined by two factors:the variance of the population's fitness and the current optimal solution.The ability of particle swarm optimization (PSO) algorithm to break away from the local optimum is greatly improved by the mutation.The experimental results show that the new algorithm not only has great advantage of convergence property over genetic algorithm and PSO,but can also avoid the premature convergence problem effectively.

  3. Prevalent mutations in fatty acid oxidation disorders

    DEFF Research Database (Denmark)

    Gregersen, N; Andresen, B S; Bross, P


    UNLABELLED: The mutational spectrum in a given disease-associated gene is often comprised of a large number of different mutations, of which a single or a few are present in a large proportion of diseased individuals. Such prevalent mutations are known in four genes of the fatty acid oxidation: t...... of the disease in question and determination of the carrier frequency in the general population may help in elucidating the penetrance of the genotype. This is exemplified in disorders of mitochondrial fatty acid oxidation....

  4. Inconel 718十二角头螺栓制造工艺技术研究%Study on Manufacturing Technology for Inconel 718 Twelve-Point Bolt

    Institute of Scientific and Technical Information of China (English)

    王玉凤; 刘风雷; 庄宝潼


    The material and structure features of Inconel 718 twelve-point bolt are introduced, and key manufacturing technologies, such as hot heading, heat treatment, warm rolling, etc. are analyzed, and optimal technological parameters are obtained. Dimensional in-spection and qualiifcation tests are carried out. The results show that technology designing is rational..%介绍了Inconel 718十二角头螺栓的材料和结构特点,分析了关键制造加工技术,如热镦锻、热处理、滚压螺纹等,确定了合理的工艺参数,并对研制件的尺寸和性能进行了评估,结果表明工艺技术设计合理。

  5. Molecular phylogenetic systematics of twelve species of Acipenseriformes based on mtDNA ND4L -ND4 gene sequence analysis

    Institute of Scientific and Technical Information of China (English)

    张四明; 张亚平; 郑向忠; 陈永久; 邓怀; 汪登强; 危起伟; 张云武; 聂龙; 吴清江


    Acipenseriformes is an endangered primitive fish group, which occupies a special place in the history of ideas concerning fish evolution, even in vertebrate evolution. However, the classification and evolution of the fishes have been debated. The mitochondrial DMA (mtDNA) ND4L and partial A7D4 genes were first sequenced in twelve species of the order Acipenseriformes, including endemic Chinese species. The following points were drawn from DNA sequences analysis: (i) the two species of Huso can be ascribed to Acipenser; (ii) A. dabryanus is the mostly closely related to A. sinensis, and most likely the landlocked form of A. sinensis; (iii) genus Acipenser in trans-Pacific region might have a common origin; (iv) mtDNA ND4L and ND4 genes are the ideal genetic markers for phylogenetic analysis of the order Acipenseriformes.

  6. Molecular phylogenetic systematics of twelve species of Acipenseriformes based on mtDNA ND4L -ND4 gene sequence analysis

    Institute of Scientific and Technical Information of China (English)


    Acipenseriformes is an endangered primitive fish group, which occupies a special place in the history of ideas concerning fish evolution, even in vertebrate evolution. However, the classification and evolution of the fishes have been debated. The mitochondrial DNA (mtDNA) ND4L and partial ND4 genes were first sequenced in twelve species of the order Acipenseriformes, including endemic Chinese species. The following points were drawn from DNA sequences analysis: (i) the two species of Huso can be ascribed to Acipenser; (ii) A. dabryanus is the mostly closely related to A. sinensis, and most likely the landlocked form of A. sinensis; (iii) genus Acipenser in trans-Pacific region might have a common origin; (iv) mtDNA ND4L and ND4 genes are the ideal genetic markers for phylogenetic analysis of the order Acipenseriformes.

  7. Analyses of Twelve New Whole Genome Sequences of Cassava Brown Streak Viruses and Ugandan Cassava Brown Streak Viruses from East Africa: Diversity, Supercomputing and Evidence for Further Speciation.

    Directory of Open Access Journals (Sweden)

    Joseph Ndunguru

    Full Text Available Cassava brown streak disease is caused by two devastating viruses, Cassava brown streak virus (CBSV and Ugandan cassava brown streak virus (UCBSV which are frequently found infecting cassava, one of sub-Saharan Africa's most important staple food crops. Each year these viruses cause losses of up to $100 million USD and can leave entire families without their primary food source, for an entire year. Twelve new whole genomes, including seven of CBSV and five of UCBSV were uncovered in this research, doubling the genomic sequences available in the public domain for these viruses. These new sequences disprove the assumption that the viruses are limited by agro-ecological zones, show that current diagnostic primers are insufficient to provide confident diagnosis of these viruses and give rise to the possibility that there may be as many as four distinct species of virus. Utilizing NGS sequencing technologies and proper phylogenetic practices will rapidly increase the solution to sustainable cassava production.

  8. A miniature condition in Brahman cattle is associated with a single nucleotide mutation within the growth hormone gene. (United States)

    McCormack, B L; Chase, C C; Olson, T A; Elsasser, T H; Hammond, A C; Welsh, T H; Jiang, H; Randel, R D; Okamura, C A; Lucy, M C


    Miniature Brahman cattle at the USDA ARS Subtropical Agriculture Research Station in Brooksville, FL have normal proportioned growth but are approximately 70% of mature height and weight when compared with Brahman cattle in the same herd. Pedigree analyses suggest that the condition is inherited through a recessive allele. The miniature Brahman cattle in the Brooksville herd have been used for studies of growth and reproduction, but the underlying causative mutation is unknown. Presumably, the miniature condition could arise from a mutation in the GH gene. The objective, therefore, was to clone the GH cDNA from Brooksville miniature Brahman cattle, compare its sequence to normal Brahman cattle, and test the biological activity of the native GH protein. Messenger RNA was isolated from the pituitary, and a cDNA for the protein coding region of the GH gene was amplified by reverse-transcription polymerase chain reaction (PCR) from each of 2 miniature Brahman bulls. The cDNA were cloned into plasmid vectors, and top and bottom strands were sequenced by automated DNA sequencing. The sequence of both cDNA clones derived from miniature cattle differed from Bos indicus GH (GenBank AF034386) at base number 641 because there was a cytosine (C) instead of a thymine (T). The C to T change encoded a mutation (threonine to methionine) at amino acid 200 (T200M mutation). The mutation was confirmed by sequencing of an additional 2 miniature cattle and comparing their sequence to 2 normal cattle. The threonine is located in the fourth alpha helix of GH and is 1 of 8 amino acids that participate in binding of GH to the GH receptor. Twelve miniature Brahman and 9 normal Brahman cattle were tested by using a restriction fragment length polymorphism analysis that employed the BsmBI restriction enzyme (specific for the mutated nucleotide). The 12 miniature Brahman cattle were homozygous for the mutation (-/-). Seven of the normal Brahman cattle were homozygous for the wild-type allele

  9. Age Distribution of Influenza Like Illness Cases during Post-Pandemic A(H3N2): Comparison with the Twelve Previous Seasons, in France (United States)

    Turbelin, Clément; Souty, Cécile; Pelat, Camille; Hanslik, Thomas; Sarazin, Marianne; Blanchon, Thierry; Falchi, Alessandra


    In France, the 2011–2012 influenza epidemic was characterized by the circulation of antigenically drifted influenza A(H3N2) viruses and by an increased disease severity and mortality among the elderly, with respect to the A(H1N1)pdm09 pandemic and post-pandemic outbreaks. Whether the epidemiology of influenza in France differed between the 2011–2012 epidemic and the previous outbreaks is unclear. Here, we analyse the age distribution of influenza like illness (ILI) cases attended in general practice during the 2011–2012 epidemic, and compare it with that of the twelve previous epidemic seasons. Influenza like illness data were obtained through a nationwide surveillance system based on sentinel general practitioners. Vaccine effectiveness was also estimated. The estimated number of ILI cases attended in general practice during the 2011–2012 was lower than that of the past twelve epidemics. The age distribution was characteristic of previous A(H3N2)-dominated outbreaks: school-age children were relatively spared compared to epidemics (co-)dominated by A(H1N1) and/or B viruses (including the 2009 pandemic and post-pandemic outbreaks), while the proportion of adults over 30 year-old was higher. The estimated vaccine effectiveness (54%, 95% CI (48, 60)) was in the lower range for A(H3N2) epidemics. In conclusion, the age distribution of ILI cases attended in general practice seems to be not different between the A(H3N2) pre-pandemic and post-pandemic epidemics. Future researches including a more important number of ILI epidemics and confirmed virological data of influenza and other respiratory pathogens are necessary to confirm these results. PMID:23755294

  10. Multifunctional adaptive NS1 mutations are selected upon human influenza virus evolution in the mouse.

    Directory of Open Access Journals (Sweden)

    Nicole E Forbes

    Full Text Available The role of the NS1 protein in modulating influenza A virulence and host range was assessed by adapting A/Hong Kong/1/1968 (H3N2 (HK-wt to increased virulence in the mouse. Sequencing the NS genome segment of mouse-adapted variants revealed 11 mutations in the NS1 gene and 4 in the overlapping NEP gene. Using the HK-wt virus and reverse genetics to incorporate mutant NS gene segments, we demonstrated that all NS1 mutations were adaptive and enhanced virus replication (up to 100 fold in mouse cells and/or lungs. All but one NS1 mutant was associated with increased virulence measured by survival and weight loss in the mouse. Ten of twelve NS1 mutants significantly enhanced IFN-β antagonism to reduce the level of IFN β production relative to HK-wt in infected mouse lungs at 1 day post infection, where 9 mutants induced viral yields in the lung that were equivalent to or significantly greater than HK-wt (up to 16 fold increase. Eight of 12 NS1 mutants had reduced or lost the ability to bind the 30 kDa cleavage and polyadenylation specificity factor (CPSF30 thus demonstrating a lack of correlation with reduced IFN β production. Mutant NS1 genes resulted in increased viral mRNA transcription (10 of 12 mutants, and protein production (6 of 12 mutants in mouse cells. Increased transcription activity was demonstrated in the influenza mini-genome assay for 7 of 11 NS1 mutants. Although we have shown gain-of-function properties for all mutant NS genes, the contribution of the NEP mutations to phenotypic changes remains to be assessed. This study demonstrates that NS1 is a multifunctional virulence factor subject to adaptive evolution.

  11. Multiple mutations and mutation combinations in the sodium channel of permethrin resistant mosquitoes, Culex quinquefasciatus (United States)

    Li, Ting; Zhang, Lee; Reid, William R.; Xu, Qiang; Dong, Ke; Liu, Nannan


    A previous study identified 3 nonsynonymous and 6 synonymous mutations in the entire mosquito sodium channel of Culex quinquefasciatus, the prevalence of which were strongly correlated with levels of resistance and increased dramatically following insecticide selection. However, it is unclear whether this is unique to this specific resistant population or is a common mechanism in field mosquito populations in response to insecticide pressure. The current study therefore further characterized these mutations and their combinations in other field and permethrin selected Culex mosquitoes, finding that the co-existence of all 9 mutations was indeed correlated with the high levels of permethrin resistance in mosquitoes. Comparison of mutation combinations revealed several common mutation combinations presented across different field and permethrin selected populations in response to high levels of insecticide resistance, demonstrating that the co-existence of multiple mutations is a common event in response to insecticide resistance across different Cx. quinquefasciatus mosquito populations.

  12. Spontaneous mutation parameters for Arabidopsis thaliana measured in the wild. (United States)

    Rutter, Matthew T; Shaw, Frank H; Fenster, Charles B


    Mutations are the ultimate source of genetic diversity and their contributions to evolutionary process depend critically on their rate and their effects on traits, notably fitness. Mutation rate and mutation effect can be measured simultaneously through the use of mutation accumulation lines, and previous mutation accumulation studies measuring these parameters have been performed in laboratory conditions. However, estimation of mutation parameters for fitness in wild populations requires assays in environments where mutations are exposed to natural selection and natural environmental variation. Here we quantify mutation parameters in both the wild and greenhouse environments using 100 25th generation Arabidopsis thaliana mutation accumulation lines. We found significantly greater mutational variance and a higher mutation rate for fitness under field conditions relative to greenhouse conditions. However, our field estimates were low when scaled to natural environmental variation. Many of the mutation accumulation lines have increased fitness, counter to the expectation that nearly all mutations decrease fitness. A high mutation rate and a low mutational contribution to phenotypic variation may explain observed levels of natural genetic variation. Our findings indicate that mutation parameters are not fixed, but are variables whose values may reflect the specific environment in which mutations are tested.

  13. Mutations in ANTXR1 Cause GAPO Syndrome

    NARCIS (Netherlands)

    Stranecky, V.; Hoischen, A.; Hartmannova, H.; Zaki, M.S.; Chaudhary, A.; Zudaire, E.; Noskova, L.; Baresova, V.; Pristoupilova, A.; Hodanova, K.; Sovova, J.; Hulkova, H.; Piherova, L.; Hehir-Kwa, J.Y.; Silva, D. De; Senanayake, M.P.; Farrag, S.; Zeman, J.; Martasek, P.; Baxova, A.; Afifi, H.H.; Croix, B. St.; Brunner, H.G.; Temtamy, S.; Kmoch, S.


    The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. We studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262C>T [

  14. Mutation screening in Rett syndrome patients

    National Research Council Canada - National Science Library

    Xiang, F; Buervenich, S; Nicolao, P; Bailey, M E; Zhang, Z; Anvret, M


    Rett syndrome (RTT) was first described in 1966. Its biological and genetic foundations were not clear until recently when Amir et al reported that mutations in the MECP2 gene were detected in around 50% of RTT patients...

  15. Recorded Step Directional Mutation for Faster Convergence

    CERN Document Server

    Dunning, Ted


    Two meta-evolutionary optimization strategies described in this paper accelerate the convergence of evolutionary programming algorithms while still retaining much of their ability to deal with multi-modal problems. The strategies, called directional mutation and recorded step in this paper, can operate independently but together they greatly enhance the ability of evolutionary programming algorithms to deal with fitness landscapes characterized by long narrow valleys. The directional mutation aspect of this combined method uses correlated meta-mutation but does not introduce a full covariance matrix. These new methods are thus much more economical in terms of storage for problems with high dimensionality. Additionally, directional mutation is rotationally invariant which is a substantial advantage over self-adaptive methods which use a single variance per coordinate for problems where the natural orientation of the problem is not oriented along the axes.

  16. Early mutation bursts in colorectal tumors (United States)

    Salomon, Matthew P.; Shibata, Darryl; Curtis, Christina; Siegmund, Kimberly; Marjoram, Paul


    Tumor growth is an evolutionary process involving accumulation of mutations, copy number alterations, and cancer stem cell (CSC) division and differentiation. As direct observation of this process is impossible, inference regarding when mutations occur and how stem cells divide is difficult. However, this ancestral information is encoded within the tumor itself, in the form of intratumoral heterogeneity of the tumor cell genomes. Here we present a framework that allows simulation of these processes and estimation of mutation rates at the various stages of tumor development and CSC division patterns for single-gland sequencing data from colorectal tumors. We parameterize the mutation rate and the CSC division pattern, and successfully retrieve their posterior distributions based on DNA sequence level data. Our approach exploits Approximate Bayesian Computation (ABC), a method that is becoming widely-used for problems of ancestral inference. PMID:28257429


    Institute of Scientific and Technical Information of China (English)

    ZENG Ji-bin; SONG Yue; WANG Yi; SHI Yu-yuan


    @@ Genetic alternations, such as mutations caused inactivities of tumor suppressor gene, have been identified in a wide variety of tumors, including osteosarcoma. Osteosarcoma is the most frequent primary malignant bone tumor that occurs in the extremities of young adolescents in most cases. Because of the high frequent occurrence of this type of tumor in hereditary retinoblastoma patients, involvement of the Rb1 gene mutations was suspected in the development of osteosarcoma, and a few reports have shown alternations of the Rb1 gene in osteosarcoma. We studied Rb1 gene mutations in 9 osteosarcoma samples and one cell line (OS 732) to explore the types and mechanism of Rb1 gene mutations in osteosarcoma.

  18. IFITM5 mutations and osteogenesis imperfecta. (United States)

    Hanagata, Nobutaka


    Interferon-induced transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein that has been shown to be a positive regulatory factor for mineralization in vitro. However, Ifitm5 knockout mice do not exhibit serious bone abnormalities, and thus the function of IFITM5 in vivo remains unclear. Recently, a single point mutation (c.-14C>T) in the 5' untranslated region of IFITM5 was identified in patients with osteogenesis imperfecta type V (OI-V). Furthermore, a single point mutation (c.119C>T) in the coding region of IFITM5 was identified in OI patients with more severe symptoms than patients with OI-V. Although IFITM5 is not directly involved in the formation of bone in vivo, the reason why IFITM5 mutations cause OI remains a major mystery. In this review, the current state of knowledge of OI pathological mechanisms due to IFITM5 mutations will be reviewed.

  19. Mutation analysis of Australasian Gaucher disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, P.V.; Carey, W.F.; Morris, C.P.; Lewis, B.D. [Women`s and Children`s Hospital, North Adelaide, South Australia (Australia)


    We have previously reported phenotype and genotype analyses in 28 Australasian Gaucher patients who were screened for several of the common Gaucher mutations: N370S, L444P, 84GG, and R463C. Horowitz and Zimran have reported that the complex alleles recNciI and recTL, which contain several point mutations including L444P, are relatively common, especially in non-Jewish Gaucher patients. Zimran and Horowitz have also stated that these recombinant alleles could easily be missed by laboratories testing only for the common Gaucher point mutations. Failure to correctly identify these mutations would influence any attempt to correlate genotype with phenotype. We have therefore retested our Gaucher patients for recNciI (L444P, A456P, and V46OV) and recTL (D409H, L444P, A456P, and V46OV) by PCR amplification, followed by hybridization with allele-specific oligonucleotides. 4 refs.

  20. Emerging patterns of somatic mutations in cancer. (United States)

    Watson, Ian R; Takahashi, Koichi; Futreal, P Andrew; Chin, Lynda


    Recent advances in technological tools for massively parallel, high-throughput sequencing of DNA have enabled the comprehensive characterization of somatic mutations in a large number of tumour samples. In this Review, we describe recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep-sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates and spectra, as well as the roles of environmental insults that influence these processes. We highlight the developing statistical approaches that are used to identify significantly mutated genes, and discuss the emerging biological and clinical insights from such analyses, as well as the future challenges of translating these genomic data into clinical impacts.

  1. Febrile Episodic Ataxia with Novel Mutation

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap


    Full Text Available An episodic ataxia type 2 (EA2 kindred with ataxic spells induced by fever or high environmental temperature and a novel CACNA1A mutation were identified and reported from the Universities of Mississippi and Minnesota.

  2. Mutational analysis of yeast profilin. (United States)

    Haarer, B K; Petzold, A S; Brown, S S


    We have mutated two regions within the yeast profilin gene in an effort to functionally dissect the roles of actin and phosphatidylinositol 4,5-bisphosphate (PIP2) binding in profilin function. A series of truncations was carried out at the C terminus of profilin, a region that has been implicated in actin binding. Removal of the last three amino acids nearly eliminated the ability of profilin to bind polyproline in vitro but had no dramatic in vivo effects. Thus, the extreme C terminus is implicated in polyproline binding, but the physiological relevance of this interaction is called into question. More extensive truncation, of up to eight amino acids, had in vivo effects of increasing severity and resulted in changes in conformation and expression level of the mutant profilins. However, the ability of these mutants to bind actin in vitro was not eliminated, suggesting that this region cannot be solely responsible for actin binding. We also mutagenized a region of profilin that we hypothesized might be involved in PIP2 binding. Alteration of basic amino acids in this region produced mutant profilins that functioned well in vivo. Many of these mutants, however, were unable to suppress the loss of adenylate cyclase-associated protein (Cap/Srv2p [A. Vojtek, B. Haarer, J. Field, J. Gerst, T. D. Pollard, S. S. Brown, and M. Wigler, Cell 66:497-505, 1991]), indicating that a defect could be demonstrated in vivo. In vitro assays demonstrated that the inability to suppress loss of Cap/Srv2p correlated with a defect in the interaction with actin, independently of whether PIP2 binding was reduced. Since our earlier studies of Acanthamoeba profilins suggested the importance of PIP2 binding for suppression, we conclude that both activities are implicated and that an interplay between PIP2 binding and actin binding may be important for profilin function.

  3. Mutational Analysis of Cell Types in TSC (United States)


    associated with epilepsy and autism . The generation of two new model systems permits more in-depth analysis of the developmental pathogenesis of TSC and...disability, and autism . TSC1/TSC2 gene mutations lead to developmental alterations in brain structure known as tubers in over 80% of TSC patients. Loss of...that is associated with epilepsy, cognitive disability, and autism . TSC1/TSC2 gene mutations lead to developmental alterations in brain structure

  4. Noise-mean relationship in mutated promoters. (United States)

    Hornung, Gil; Bar-Ziv, Raz; Rosin, Dalia; Tokuriki, Nobuhiko; Tawfik, Dan S; Oren, Moshe; Barkai, Naama


    Gene expression depends on the frequency of transcription events (burst frequency) and on the number of mRNA molecules made per event (burst size). Both processes are encoded in promoter sequence, yet their dependence on mutations is poorly understood. Theory suggests that burst size and frequency can be distinguished by monitoring the stochastic variation (noise) in gene expression: Increasing burst size will increase mean expression without changing noise, while increasing burst frequency will increase mean expression and decrease noise. To reveal principles by which promoter sequence regulates burst size and frequency, we randomly mutated 22 yeast promoters chosen to span a range of expression and noise levels, generating libraries of hundreds of sequence variants. In each library, mean expression (m) and noise (coefficient of variation, η) varied together, defining a scaling curve: η(2) = b/m + η(ext)(2). This relation is expected if sequence mutations modulate burst frequency primarily. The estimated burst size (b) differed between promoters, being higher in promoter containing a TATA box and lacking a nucleosome-free region. The rare variants that significantly decreased b were explained by mutations in TATA, or by an insertion of an out-of-frame translation start site. The decrease in burst size due to mutations in TATA was promoter-dependent, but independent of other mutations. These TATA box mutations also modulated the responsiveness of gene expression to changing conditions. Our results suggest that burst size is a promoter-specific property that is relatively robust to sequence mutations but is strongly dependent on the interaction between the TATA box and promoter nucleosomes.

  5. (Somatic mutations in nuclear and mitochondrial DNA)

    Energy Technology Data Exchange (ETDEWEB)


    The study is concerned the design of new assays that may detect rare somatic mutations in nuclear and mitochondrial DNA, which may increase upon exposure to mutagens, and thus become a marker of human exposure to such mutagens. Two assays for somatic mutation were presented, one for mitochondrial DNA deletions which was developed by the author, and one for deletions of the ADA gene which resides in the nucleus.

  6. Mutation spectra of complex environmental mixtures

    Energy Technology Data Exchange (ETDEWEB)

    DeMarini, D.M. [EPA, Research Triangle Park, NC (United States)


    Bioassay-directed chemical analysis of complex environmental mixtures has indicated that much of the genotoxic activity of mixtures is due to the presence of one or a few classes or chemicals within the mixture. We have extended this observation to the molecular level by using colony probe hybridization and PCR/DNA sequence analysis to determine the mutation spectra of {approximately}8,000 revertants induced by a variety of complex mixtures and their chemical fractions in TA100 and TA98 of Salmonella. For urban air, >80% of mutagenic activity was due to a base/neutral fraction that contained primarily PAHs. The mutation spectrum induced by unfractionated urban air was not significantly different from that produced by a model PAH, B(a)P. The mutation spectrum induced by organic extracts of chlorinated drinking water were similar to those produced by the chlorinated furanone MX, which accounted for {approximately}20% of the mutagenic activity of the samples. The base/neutral fraction of municipal waste incinerator emissions accounted for the primary class of mutations induced by the emissions, and a polar neutral fraction accounted for the secondary class of mutations induced by the emissions. The primary class of mutations induced by cigarette smoke condensate in TA100 (GC {yields} TA) is also the primary class of mutations in the p53 gene of lung tumors of cigarette smokers. These results confirm at the molecular level that the mutations induced by a complex mixture reflect the dominance of one or a few classes of chemicals within the mixture.

  7. Clinical features and mismatch repair gene mutation screening in Chinese patients with hereditary nonpolyposis colorectal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Shan-Run Liu; Bo Zhao; Zhen-Jun Wang; Yuan-Lian Wan; Yan-Ting Huang


    metachronous CRCs within 10 years after operation. Eight hMSH2 or hMLH1 genesequence variations were found in twelve families, including the first Mongolian kindred with a hMSH2 gene mutation. CONCLUSION: HNPCC is characterized by an early-age onset, proximal predominance of CRC, multiple metachronous CRCs, and an excess of extra-colonic cancers. Frequent gastric cancer occurrence and less synchronous CRCs are the remarkable features in Chinese HNPCC patients. DHPLCis a powerful tool in hMSH2 and hMLH1 gene mutationscreening. hMLH1 gene mutations, especially of the first nine exons, have been found more common than hMSH2 gene mutations in Chinese patients. Three of seven mutations have been found to be novel, and the germline G204X nonsense mutation in the third exon of hMSH2 hasbecome the first MMR gene mutation found in Chinese Mongolian people.

  8. RELN Mutations in Autism Spectrum Disorder. (United States)

    Lammert, Dawn B; Howell, Brian W


    RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, null mutations lead to lissencephaly with cerebellar hypoplasia (LCH), accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD). RELN maps to the AUTS1 locus on 7q22, and at this time over 40 distinct mutations have been identified that would alter the protein sequence, four of which are de novo. The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats. Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis.

  9. RELN mutations in autism spectrum disorder

    Directory of Open Access Journals (Sweden)

    Dawn B. Lammert


    Full Text Available RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, null mutations lead to lissencephaly with cerebellar hypoplasia, accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD. RELN maps to the AUTS1 locus on 7q22, and at this time over 40 distinct mutations have been identified that would alter the protein sequence, four of which are de novo. The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein, and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats. Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis.

  10. The Mutations Associated with Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Ruti Parvari


    Full Text Available Cardiomyopathy is an important cause of heart failure and a major indication for heart transplantation in children and adults. This paper describes the state of the genetic knowledge of dilated cardiomyopathy (DCM. The identification of the causing mutation is important since presymptomatic interventions of DCM have proven value in preventing morbidity and mortality. Additionally, as in general in genetic studies, the identification of the mutated genes has a direct clinical impact for the families and population involved. Identifying causative mutations immediately amplifies the possibilities for disease prevention through carrier screening and prenatal testing. This often lifts a burden of social isolation from affected families, since healthy family members can be assured of having healthy children. Identification of the mutated genes holds the potential to lead to the understanding of disease etiology, pathophysiology, and therefore potential therapy. This paper presents the genetic variations, or disease-causing mutations, contributing to the pathogenesis of hereditary DCM, and tries to relate these to the functions of the mutated genes.

  11. TOX3 mutations in breast cancer.

    Directory of Open Access Journals (Sweden)

    James Owain Jones

    Full Text Available TOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs in six primary tumours, corresponding to an overall mutation frequency of 4.5%. One potentially deleterious missense mutation in exon 3 (Leu129Phe was identified in one tumour (genomic DNA and cDNA. Whilst copy number changes of 16q12 are common in breast cancer, our data show that mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology.

  12. Frequent MAGE mutations in human melanoma.

    Directory of Open Access Journals (Sweden)

    Otavia L Caballero

    Full Text Available BACKGROUND: Cancer/testis (CT genes are expressed only in the germ line and certain tumors and are most frequently located on the X-chromosome (the CT-X genes. Amongst the best studied CT-X genes are those encoding several MAGE protein families. The function of MAGE proteins is not well understood, but several have been shown to potentially influence the tumorigenic phenotype. METHODOLOGY/PRINCIPAL FINDINGS: We undertook a mutational analysis of coding regions of four CT-X MAGE genes, MAGEA1, MAGEA4, MAGEC1, MAGEC2 and the ubiquitously expressed MAGEE1 in human melanoma samples. We first examined cell lines established from tumors and matching blood samples from 27 melanoma patients. We found that melanoma cell lines from 37% of patients contained at least one mutated MAGE gene. The frequency of mutations in the coding regions of individual MAGE genes varied from 3.7% for MAGEA1 and MAGEA4 to 14.8% for MAGEC2. We also examined 111 fresh melanoma samples collected from 86 patients. In this case, samples from 32% of the patients exhibited mutations in one or more MAGE genes with the frequency of mutations in individual MAGE genes ranging from 6% in MAGEA1 to 16% in MAGEC1. SIGNIFICANCE: These results demonstrate for the first time that the MAGE gene family is frequently mutated in melanoma.

  13. A DSPP mutation causing dentinogenesis imperfecta and characterization of the mutational effect. (United States)

    Lee, Sook-Kyung; Lee, Kyung-Eun; Song, Su Jeong; Hyun, Hong-Keun; Lee, Sang-Hoon; Kim, Jung-Wook


    Mutations in the DSPP gene have been identified in nonsyndromic hereditary dentin defects, but the genotype-phenotype correlations are not fully understood. Recently, it has been demonstrated that the mutations of DSPP affecting the IPV leader sequence result in mutant DSPP retention in rough endoplasmic reticulum (ER). In this study, we identified a Korean family with dentinogenesis imperfecta type III. To identify the disease causing mutation in this family, we performed mutational analysis based on candidate gene sequencing. Exons and exon-intron boundaries of DSPP gene were sequenced, and the effects of the identified mutation on the pre-mRNA splicing and protein secretion were investigated. Candidate gene sequencing revealed a mutation (c.50C > T, p.P17L) in exon 2 of the DSPP gene. The splicing assay showed that the mutation did not influence pre-mRNA splicing. However, the mutation interfered with protein secretion and resulted in the mutant protein remaining largely in the ER. These results suggest that the mutation affects ER-to-Golgi apparatus export and results in the reduction of secreted DSPP and ER overload. This may induce cell stress and damage processing and/or transport of dentin matrix proteins or other critical proteins.

  14. A DSPP Mutation Causing Dentinogenesis Imperfecta and Characterization of the Mutational Effect

    Directory of Open Access Journals (Sweden)

    Sook-Kyung Lee


    Full Text Available Mutations in the DSPP gene have been identified in nonsyndromic hereditary dentin defects, but the genotype-phenotype correlations are not fully understood. Recently, it has been demonstrated that the mutations of DSPP affecting the IPV leader sequence result in mutant DSPP retention in rough endoplasmic reticulum (ER. In this study, we identified a Korean family with dentinogenesis imperfecta type III. To identify the disease causing mutation in this family, we performed mutational analysis based on candidate gene sequencing. Exons and exon-intron boundaries of DSPP gene were sequenced, and the effects of the identified mutation on the pre-mRNA splicing and protein secretion were investigated. Candidate gene sequencing revealed a mutation (c.50C > T, p.P17L in exon 2 of the DSPP gene. The splicing assay showed that the mutation did not influence pre-mRNA splicing. However, the mutation interfered with protein secretion and resulted in the mutant protein remaining largely in the ER. These results suggest that the mutation affects ER-to-Golgi apparatus export and results in the reduction of secreted DSPP and ER overload. This may induce cell stress and damage processing and/or transport of dentin matrix proteins or other critical proteins.

  15. Dominant cataract mutations and specific-locus mutations in mice induced by radiation or ethylnitrosourea

    Energy Technology Data Exchange (ETDEWEB)

    Ehling, U.H.; Favor, J.; Kratochvilova, J.; Neuhaeuser-Klaus, A. (Gesellschaft fuer Strahlen- und Umweltforschung m.b.H. Muenchen, Neuherberg (Germany, F.R.). Inst. fuer Genetik)


    In a combined experiment, dominant cataract mutations and specific-locus mutations were scored in the same offspring. In radiation experiments, a total of 15 dominant cataract and 38 specific-locus mutations was scored in 29396 offspring. In experiments with ethylnitrosourea (ENU), a total of 12 dominant cataracts and 54 specific-locus mutations was observed in 12712 offspring. The control frequency for dominant cataracts was 0 in 9954 offspring and for specific-locus mutations 11 in 169955 offspring. The two characteristic features of radiation-induced specific-locus mutations - the augmenting effect of dose fractionation and the quantitative differences in the mutation rates between spermatogonial and post-spermatogonial stages - can also be demonstrated for the induction of dominant cataracts. The dominant cataract mutations recovered can be categorized into 7 phenotypic classes. The only noteworthy difference observed between the radiation- and ENU-induced mutations recovered was that, of the 2 radiation-induced total lens opacities, both were associated with an iris anomaly and microphthalmia whereas the ENU-induced total opacities were not.

  16. On the mutation rate of herpes simplex virus type 1. (United States)

    Drake, John W; Hwang, Charles B C


    All seven DNA-based microbes for which carefully established mutation rates and mutational spectra were previously available displayed a genomic mutation rate in the neighborhood of 0.003 per chromosome replication. The pathogenic mammalian DNA virus herpes simplex type 1 has an estimated genomic mutation rate compatible with that value.

  17. Contributions of the measles virus nucleocapsid gene and the SQSTM1/p62(P392L) mutation to Paget's disease. (United States)

    Kurihara, Noriyoshi; Hiruma, Yuko; Yamana, Kei; Michou, Laëtitia; Rousseau, Côme; Morissette, Jean; Galson, Deborah L; Teramachi, Jumpei; Zhou, Hua; Dempster, David W; Windle, Jolene J; Brown, Jacques P; Roodman, G David


    Paget's disease (PD) is characterized by abnormal osteoclasts (OCL) that secrete high IL-6 levels and induce exuberant bone formation. Because measles virus nucleocapsid gene (MVNP) and the p62(P392L) mutation are implicated in PD, marrows from 12 PD patients harboring p62(P392L) and eight normals were tested for MVNP expression and pagetic OCL formation. Eight out of twelve patients expressed MVNP and formed pagetic OCL in vitro, which were inhibited by antisense-MVNP. Four out of twelve patients lacked MVNP and formed normal OCL that were hyperresponsive to RANKL but unaffected by antisense-MVNP. Similarly, mice expressing only p62(P394L) formed normal OCL, while mice expressing MVNP in OCL, with or without p62(P394L), developed pagetic OCL and expressed high IL-6 levels dependent on p38MAPK activation. IL-6 deficiency in MVNP mice abrogated pagetic OCL development in vitro. Mice coexpressing MVNP and p62(P394L) developed dramatic Paget's-like bone lesions. These results suggest that p62(P394L) and IL-6 induction by MVNP play key roles in PD.

  18. Cluster algebras of finite mutation type via unfoldings

    CERN Document Server

    Felikson, Anna; Tumarkin, Pavel


    We complete classification of mutation-finite cluster algebras by extending the technique derived by Fomin, Shapiro, and Thurston to skew-symmetrizable case. We show that every mutation-finite skew-symmetrizable matrix admits an unfolding which embeds the mutation class of mutation-finite skew-symmetrizable matrix to the mutation class of some mutation-finite skew-symmetric matrix. In particular, this establishes a correspondence between almost all skew-symmetrizable mutation-finite cluster algebras and triangulated marked bordered surfaces.

  19. The three faces of riboviral spontaneous mutation: spectrum, mode of genome replication, and mutation rate.

    Directory of Open Access Journals (Sweden)

    Libertad García-Villada

    Full Text Available Riboviruses (RNA viruses without DNA replication intermediates are the most abundant pathogens infecting animals and plants. Only a few riboviral infections can be controlled with antiviral drugs, mainly because of the rapid appearance of resistance mutations. Little reliable information is available concerning i kinds and relative frequencies of mutations (the mutational spectrum, ii mode of genome replication and mutation accumulation, and iii rates of spontaneous mutation. To illuminate these issues, we developed a model in vivo system based on phage Qß infecting its natural host, Escherichia coli. The Qß RT gene encoding the Read-Through protein was used as a mutation reporter. To reduce uncertainties in mutation frequencies due to selection, the experimental Qß populations were established after a single cycle of infection and selection against RT(- mutants during phage growth was ameliorated by plasmid-based RT complementation in trans. The dynamics of Qß genome replication were confirmed to reflect the linear process of iterative copying (the stamping-machine mode. A total of 32 RT mutants were detected among 7,517 Qß isolates. Sequencing analysis of 45 RT mutations revealed a spectrum dominated by 39 transitions, plus 4 transversions and 2 indels. A clear template•primer mismatch bias was observed: A•C>C•A>U•G>G•U> transversion mismatches. The average mutation rate per base replication was ≈9.1×10(-6 for base substitutions and ≈2.3×10(-7 for indels. The estimated mutation rate per genome replication, μ(g, was ≈0.04 (or, per phage generation, ≈0.08, although secondary RT mutations arose during the growth of some RT mutants at a rate about 7-fold higher, signaling the possible impact of transitory bouts of hypermutation. These results are contrasted with those previously reported for other riboviruses to depict the current state of the art in riboviral mutagenesis.

  20. Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer (United States)

    Yu, Jun; Wu, William K K; Li, Xiangchun; He, Jun; Li, Xiao-Xing; Ng, Simon S M; Yu, Chang; Gao, Zhibo; Yang, Jie; Li, Miao; Wang, Qiaoxiu; Liang, Qiaoyi; Pan, Yi; Tong, Joanna H; To, Ka F; Wong, Nathalie; Zhang, Ning; Chen, Jie; Lu, Youyong; Lai, Paul B S; Chan, Francis K L; Li, Yingrui; Kung, Hsiang-Fu; Yang, Huanming; Wang, Jun; Sung, Joseph J Y


    Background Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication. Objective To identify recurrent somatic mutations with prognostic significance in patients with CRC. Method Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases. Results Seven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (6–14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study. Conclusions The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging. PMID:24951259

  1. Twelve lectures on structural dynamics

    CERN Document Server

    Preumont, André


    This text addresses the modeling of vibrating systems with the perspective of finding the model of minimum complexity which accounts for the physics of the phenomena at play. The first half of the book (Ch.1-6) deals with the dynamics of discrete and continuous mechanical systems; the classical approach emphasizes the use of Lagrange's equations. The second half of the book (Ch.7-12) deals with more advanced topics, rarely encountered in the existing literature: seismic excitation, random vibration (including fatigue), rotor dynamics, vibration isolation and dynamic vibration absorbers; the final chapter is an introduction to active control of vibrations. The first part of this text may be used as a one semester course for 3rd year students in Mechanical, Aerospace or Civil Engineering. The second part of the text is intended for graduate classes. A set of problems is provided at the end of every chapter. The author has a 35 years experience in various aspects of Structural dynamics, both in industry (nuclea...

  2. Family Textbooks Twelve Years Later (United States)

    Glenn, Norval D.


    In 1996 the author conducted an intensive study of twenty current family textbooks published in the United States, the results of which appeared in an academic journal article and a nonacademic report in 1997. The study included practical "functionalist" marriage and family textbooks and more academic sociology of the family books; these…

  3. The Twelve Days of Shengdan

    Institute of Scientific and Technical Information of China (English)



    On the first day of Christmas,China gaveto me A bird that can say ni hao A partridge in a pear tree has nothing on a caged bird that will greet me in Chinese as I pass by—although I worry that one day I’ll try to engage the bird in conversation and find out it speaks better Chinese than I do.

  4. Purging deleterious mutations under self fertilization: paradoxical recovery in fitness with increasing mutation rate in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Levi T Morran

    Full Text Available BACKGROUND: The accumulation of deleterious mutations can drastically reduce population mean fitness. Self-fertilization is thought to be an effective means of purging deleterious mutations. However, widespread linkage disequilibrium generated and maintained by self-fertilization is predicted to reduce the efficacy of purging when mutations are present at multiple loci. METHODOLOGY/PRINCIPAL FINDINGS: We tested the ability of self-fertilizing populations to purge deleterious mutations at multiple loci by exposing obligately self-fertilizing populations of Caenorhabditis elegans to a range of elevated mutation rates and found that mutations accumulated, as evidenced by a reduction in mean fitness, in each population. Therefore, purging in obligate selfing populations is overwhelmed by an increase in mutation rate. Surprisingly, we also found that obligate and predominantly self-fertilizing populations exposed to very high mutation rates exhibited consistently greater fitness than those subject to lesser increases in mutation rate, which contradicts the assumption that increases in mutation rate are negatively correlated with fitness. The high levels of genetic linkage inherent in self-fertilization could drive this fitness increase. CONCLUSIONS: Compensatory mutations can be more frequent under high mutation rates and may alleviate a portion of the fitness lost due to the accumulation of deleterious mutations through epistatic interactions with deleterious mutations. The prolonged maintenance of tightly linked compensatory and deleterious mutations facilitated by self-fertilization may be responsible for the fitness increase as linkage disequilibrium between the compensatory and deleterious mutations preserves their epistatic interaction.

  5. The risk of extinction - the mutational meltdown or the overpopulation


    Malarz, K.


    The phase diagrams survival-extinction for the Penna model with parameters: (mutations rate)-(birth rate), (mutation rate)-(harmful mutations threshold), (harmful mutation threshold)-(minimal reproduction age) are presented. The extinction phase may be caused by either mutational meltdown or overpopulation. When the Verhulst factor is responsible for removing only newly born babies and does not act on adults the overpopulation is avoided and only genetic factors may lead to species extinction.

  6. Resistance assessment for oxathiapiprolin in Phytophthora capsici and the detection of a point mutation (G769W in PcORP1 that confers resistance

    Directory of Open Access Journals (Sweden)

    Jianqiang eMiao


    Full Text Available The potential for oxathiapiprolin resistance in Phytophthora capsici was evaluated. The baseline sensitivities of 175 isolates to oxathiapiprolin were initially determinated and found to conform to a unimodal curve with a mean EC50 value of 5.61×10-4 μg/ml. Twelve stable oxathiapiprolin-resistant mutants were generated by fungicide adaption in two sensitive isolates, LP3 and HNJZ10. The fitness of the LP3-mutants was found to be similar to or better than that of the parental isolate LP3, while the HNJZ10-mutants were found to have lost the capacity to produce zoospores. Taken together these results suggest that the risk of P. capsici developing resistance to oxathiapiprolin is moderate. Comparison of the PcORP1 genes in the LP3-mutants and wild-type parental isolate, which encode the target protein of oxathiapiprolin, revealed that a heterozygous mutation caused the amino acid substitution G769W. Transformation and expression of the mutated PcORP1-769W allele in the sensitive wild-type isolate BYA5 confirmed that the mutation in PcORP1 was responsible for the observed oxathiapiprolin resistance. Finally diagnostic tests including As-PCR and CAPs were developed to detect the oxathiapiprolin resistance resulting from the G769W point mutation in field populations of P. capsici.

  7. Rapid detection of medium chain acyl-CoA dehydrogenase gene mutations by non-radioactive, single strand conformation polymorphism minigels. (United States)

    Iolascon, A; Parrella, T; Perrotta, S; Guardamagna, O; Coates, P M; Sartore, M; Surrey, S; Fortina, P


    Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a common inherited metabolic disorder affecting fatty acid beta oxidation. Identification of carriers is important since the disease can be fatal and is readily treatable once diagnosed. Twelve molecular defects have been identified in the MCAD gene; however, a single highly prevalent mutation, A985G, accounts for > 90% of mutant alleles in the white population. In order to facilitate the molecular diagnosis of MCAD deficiency, oligonucleotide primers were designed to amplify the exon regions encompassing the 12 mutations enzymatically, and PCR products were then screened with a single strand conformation polymorphism (SSCP) based method. Minigels were used allowing much faster run times, and silver staining was used after gel electrophoresis to eliminate the need for radioisotopic labelling strategies. Our non-radioactive, minigel SSCP approach showed that normals can be readily distinguished from heterozygotes and homozygotes for all three of the 12 known MCAD mutations which were detected in our sampling of 48 persons. In addition, each band pattern is characteristic for a specific mutation, including those mapping in the same PCR product like A985G and T1124C. When necessary, the molecular defect was confirmed using either restriction enzyme digestion of PCR products or by direct DNA sequence analysis or both. This rapid, non-radioactive approach can become routine for molecular diagnosis of MCAD deficiency and other genetic disorders.

  8. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location

    NARCIS (Netherlands)

    P. Nieminen; L. Papagiannoulis-Lascarides; J. Waltimo-Siren; P. Ollila; S. Karjalainen; S. Arte; J. Veerkamp; V. Tallon Walton; E. Chimenos Küstner; T. Siltanen; H. Holappa; P.L. Lukinmaa; S. Alaluusua


    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic fea

  9. Mutation analysis and prenatal diagnosis of EXT1 gene mutations in Chinese patients with multiple osteochondromas

    Institute of Scientific and Technical Information of China (English)

    ZHU Hai-yan; HU Ya-li; YANG Ying; WU Xing; ZHU Rui-fang; ZHU Xiang-yu; DUAN Hong-lei; ZHANG Ying; ZHOU Jin-yong


    Background Multiple osteochondromas (MO), an inherited autosomal dominant disorder, is characterized by the presence of multiple exostoses on the long bones. MO is caused by mutations in the EXT1 or EXT2 genes which encode glycosyltransferases implicated in heparin sulfate biosynthesis.Methods In this study, efforts were made to identify the underlying disease-causing mutations in patients from two MO families in China.Results Two novel EXT1 gene mutations were identified and no mutation was found in EXT2 gene. The mutation c.497T>A in exon 1 of the EXT1 gene was cosegregated with the disease phenotype in family 1 and formed a stop codon at amino acid site 166. The fetus of the proband was diagnosed negative. In family 2, the mutation c. 1430-1431delCC in exon 6 of the EXT1 gene would cause frameshift and introduce a premature stop codon after the reading frame being open for 42 amino acids. The fetus of this family inherited this mutation from the father.Conclusions Mutation analysis of two MO families in this study demonstrates its further application in MO genetic counseling and prenatal diagnosis.

  10. Evaluation of twelve maize (Zea mays L. cultivars for silage Avaliação de doze cultivares de milho (Zea mays L. para silagem

    Directory of Open Access Journals (Sweden)

    Maria Celina Jorge Leme


    Full Text Available The experiment was conducted to evaluate the agronomic characteristics and chemical composition of different maize cultivars for ensiling of the plant. Twelve maize cultivar were analyzed in a completely randomized block design, with three block, twelve treatments and three replication. The plot with three lines of six meters long and spacing of 0.8 m were used in all trials. The cycle of the plants of the planting to harvest varied from 105 to 114 days. The height average differed among (P 0.05 for ear by plant number (0.9 to 1.1, dry matter (33.2 to 38.2 %, ether extract (1.9 to 2.5 % and neutral detergent fiber (49.1 to 56.2 %. The dry matter production differed (P O experimento foi realizado com o objetivo de avaliar as características agronômicas e químico-bromatológica de diferentes cultivares de milho para ensilagem. Foram avaliados doze cultivares de milho em delineamento experimental em blocos casualizados, com três blocos, 12 tratamentos e três repetições. As parcelas foram constituídas por três linhas de seis metros de comprimento e espaçamento de 0,8 m entre linhas. O ciclo das plantas, do plantio à colheita, variou de 105 a 114 dias. A altura média diferiu entre os cultivares (P 0,05 entre os cultivares para número de espigas por planta (0,9 a 1,1, teores de matéria seca (33,2 a 38,2 %, de extrato etéreo (1,9 a 2,5 % e de fibra em detergente neutro (49,1 a 56,2 %. A produção de matéria seca diferiu (P < 0,05 entre o cultivar TORK (20,6 t/ha e os cultivares CD-302 (16,4 t/ha e TRAKTOR (15,7 t/ha. O AGN-3150 apresentou o menor teor de fibra em detergente ácido (24,2 % e maior digestibilidade (80,7 %. Todas as cultivares apresentaram características agronômicas e qualitativas adequadas para produção de silagem, destacando-se os cultivares TORK e AGN-3150.

  11. Volatility of Mutator Phenotypes at Single Cell Resolution.

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    Scott R Kennedy


    Full Text Available Mutator phenotypes accelerate the evolutionary process of neoplastic transformation. Historically, the measurement of mutation rates has relied on scoring the occurrence of rare mutations in target genes in large populations of cells. Averaging mutation rates over large cell populations assumes that new mutations arise at a constant rate during each cell division. If the mutation rate is not constant, an expanding mutator population may contain subclones with widely divergent rates of evolution. Here, we report mutation rate measurements of individual cell divisions of mutator yeast deficient in DNA polymerase ε proofreading and base-base mismatch repair. Our data are best fit by a model in which cells can assume one of two distinct mutator states, with mutation rates that differ by an order of magnitude. In error-prone cell divisions, mutations occurred on the same chromosome more frequently than expected by chance, often in DNA with similar predicted replication timing, consistent with a spatiotemporal dimension to the hypermutator state. Mapping of mutations onto predicted replicons revealed that mutations were enriched in the first half of the replicon as well as near termination zones. Taken together, our findings show that individual genome replication events exhibit an unexpected volatility that may deepen our understanding of the evolution of mutator-driven malignancies.

  12. PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers.

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    Filip Janku

    Full Text Available BACKGROUND: Oncogenic mutations of PIK3CA, RAS (KRAS, NRAS, and BRAF have been identified in various malignancies, and activate the PI3K/AKT/mTOR and RAS/RAF/MEK pathways, respectively. Both pathways are critical drivers of tumorigenesis. METHODS: Tumor tissues from 504 patients with diverse cancers referred to the Clinical Center for Targeted Therapy at MD Anderson Cancer Center starting in October 2008 were analyzed for PIK3CA, RAS (KRAS, NRAS, and BRAF mutations using polymerase chain reaction-based DNA sequencing. RESULTS: PIK3CA mutations were found in 54 (11% of 504 patients tested; KRAS in 69 (19% of 367; NRAS in 19 (8% of 225; and BRAF in 31 (9% of 361 patients. PIK3CA mutations were most frequent in squamous cervical (5/14, 36%, uterine (7/28, 25%, breast (6/29, 21%, and colorectal cancers (18/105, 17%; KRAS in pancreatic (5/9, 56%, colorectal (49/97, 51%, and uterine cancers (3/20, 15%; NRAS in melanoma (12/40, 30%, and uterine cancer (2/11, 18%; BRAF in melanoma (23/52, 44%, and colorectal cancer (5/88, 6%. Regardless of histology, KRAS mutations were found in 38% of patients with PIK3CA mutations compared to 16% of patients with wild-type (wtPIK3CA (p = 0.001. In total, RAS (KRAS, NRAS or BRAF mutations were found in 47% of patients with PIK3CA mutations vs. 24% of patients wtPIK3CA (p = 0.001. PIK3CA mutations were found in 28% of patients with KRAS mutations compared to 10% with wtKRAS (p = 0.001 and in 20% of patients with RAS (KRAS, NRAS or BRAF mutations compared to 8% with wtRAS (KRAS, NRAS or wtBRAF (p = 0.001. CONCLUSIONS: PIK3CA, RAS (KRAS, NRAS, and BRAF mutations are frequent in diverse tumors. In a wide variety of tumors, PIK3CA mutations coexist with RAS (KRAS, NRAS and BRAF mutations.

  13. Novel progranulin mutation: screening for PGRN mutations in a Portuguese series of FTD/CBS cases. (United States)

    Guerreiro, Rita Joao; Santana, Isabel; Bras, Jose Miguel; Revesz, Tamas; Rebelo, Olinda; Ribeiro, Maria Helena; Santiago, Beatriz; Oliveira, Catarina Resende; Singleton, Andrew; Hardy, John


    Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD) in many families. Different frequencies of these genetic changes have been reported in diverse populations leading us to determine if these mutations were a major cause of FTD in the Portuguese population. The entire coding sequence plus exon 0 of PGRN were sequenced in a consecutive series of 46 FTD/CBS Portuguese patients. Two mutations were found: a novel pathogenic insertion (p.Gln300GlnfsX61) and a previously described point variant (p.T182M) of unclear pathogenicity. Pathogenic mutations in the PGRN gene were found in one of the 36 probands studied (3% of the probands in our series) who had a corticobasal syndrome presentation, indicating that in the Portuguese population, mutations in this gene are not a major cause of FTD.

  14. Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria;


    Background: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA...... repair and is associated with treatment outcome in ovarian cancer. Methods and Results: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous...... ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated...

  15. The clinical efficacy of Colgate Total Plus Whitening Toothpaste containing a special grade of silica and Colgate Total Toothpaste for controlling breath odor twelve hours after toothbrushing: a single-use clinical study. (United States)

    Sharma, Naresh C; Galustians, H Jack; Qaqish, Jimmy; Galustians, Ana; Petrone, Margaret E; Rustogi, Kedar N; Zhang, Yun Po; DeVizio, William; Volpe, Anthony R


    The objective of this double-blind clinical study, conducted in harmony with American Dental Association guidelines, was to compare a new dentifrice formulation variant of Colgate Total Toothpaste containing a special grade of silica (Colgate Total Plus Whitening Toothpaste) to the commercially available, ADA-Accepted and clinically proven Colgate Total Toothpaste for controlling breath odor twelve hours after brushing the teeth. Breath odor was evaluated by a panel of three examiners using a nine-point hedonic scale. Following a baseline evaluation of breath odor, prospective study subjects who scored above the threshold value for unpleasant breath odor were stratified by score and randomized into two treatment groups. Subjects were provided with a soft-bristled toothbrush, and brushed their teeth thoroughly in their regular and customary manner with their assigned dentifrice. Subjects refrained from dental hygiene, breath mints or mounthrinses for the next twelve hours, after which they were again evaluated for breath odor. Eighty-three (83) adult male and female subjects from the Mississauga, Ontario, Canada area participated in the study. At twelve hours after brushing their teeth, subjects in both dentifrice treatment groups presented mean breath odor scores which were statistically significantly lower than the mean scores observed at baseline. Importantly, there was no statistical difference between the two dentifrices of the mean twelve-hour breath odor scores. The mean twelve-hour breath scores for the Colgate Total Plus Whitening Toothpaste group and the Colgate Total Toothpaste group were 4.89 and 4.67, respectively, which are within the range of values corresponding to pleasant breath odor. Thus, the results of this double-blind clinical study, conducted according to a protocol which had been approved by the Council on Scientific Affairs of the American Dental Association, support the conclusion that Colgate Total Plus Whitening Toothpaste and Colgate

  16. 试述十二律结合四气理论防治五脏疾病%Prevention and Treatment of Five Zang-organs Diseases with Twelve Temperaments Combining with Siqi Theory

    Institute of Scientific and Technical Information of China (English)

    贺海辉; 雷磊; 吴子明


    The study and treatment of the music therapy is very popular in Europe and America. While the Chi-nese traditional music therapy is still in the stage of excavation, both the theory and clinical practice are waiting for exploration and development. Through the formation of twelve temperaments and twelve temperaments system, this article discussed the twelve temperaments which reflect the yin and yang of twelve months, and the five in-ternal organs reflect the yin and yang of the four season . The author thinks that the twelve temperaments can pre-vent and treat diseases of five zang-organs, and puts forward the train of thought of prevention and treatment of five zang-organs diseases with twelve temperaments combining with Siqi theory.%目前音乐疗法在欧美的研究和治疗应用非常普遍,而我国中医音乐疗法还处于挖掘整理阶段,无论是基础理论还是临床实践都有待进一步的探索和发展。本文通过论述十二律的形成和十二律吕制度表明十二律反映十二月阴阳,以及五脏通应自然界四时阴阳,认为十二律能够防治五脏疾病,并提出十二律结合四气防治疾病的思路。

  17. BRAF mutation in hairy cell leukemia

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    Ahmad Ahmadzadeh


    Full Text Available BRAF is a serine/threonine kinase with a regulatory role in the mitogen-activated protein kinase (MAPK signaling pathway. A mutation in the RAF gene, especially in BRAF protein, leads to an increased stimulation of this cascade, causing uncontrolled cell division and development of malignancy. Several mutations have been observed in the gene coding for this protein in a variety of human malignancies, including hairy cell leukemia (HCL. BRAF V600E is the most common mutation reported in exon15 of BRAF, which is observed in almost all cases of classic HCL, but it is negative in other B-cell malignancies, including the HCL variant. Therefore it can be used as a marker to differentiate between these B-cell disorders. We also discuss the interaction between miRNAs and signaling pathways, including MAPK, in HCL. When this mutation is present, the use of BRAF protein inhibitors may represent an effective treatment. In this review we have evaluated the role of the mutation of the BRAF gene in the pathogenesis and progression of HCL.

  18. BRCA1 mutations in Brazilian patients

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    Juliano Javert Lourenço


    Full Text Available BRCA1 mutations are known to be responsible for the majority of hereditary breast and ovarian cancers in women with early onset and a family history of the disease. In this paper we present a mutational survey conducted in 47 Brazilian patients with breast/ovarian cancer, selected based on age at diagnosis, family history, tumor laterality, and presence of breast cancer in male patients. All 22 coding exons and intron-exon junctions were sequenced. Constitutional mutations were found in seven families, consisting of one insertion (insC5382 in exon 20 (four patients, one four base-pair deletion (3450-3453delCAAG in exon 11 resulting in a premature stop codon (one patient, one transition (IVS17+2T> C in intron 17 affecting a mRNA splicing site (one patient, and a C> T transition resulting in a stop-codon (Q1135X in exon 11 (one patient. The identification of these mutations which are associated to hereditary breast and ovarian cancers will contribute to the characterization of the mutational spectrum of BRCA1 and to the improvement of genetic counseling for familial breast/ovarian cancer patients in Brazil.

  19. Urinary Tract Effects of HPSE2 Mutations (United States)

    Stuart, Helen M.; Roberts, Neil A.; Hilton, Emma N.; McKenzie, Edward A.; Daly, Sarah B.; Hadfield, Kristen D.; Rahal, Jeffery S.; Gardiner, Natalie J.; Tanley, Simon W.; Lewis, Malcolm A.; Sites, Emily; Angle, Brad; Alves, Cláudia; Lourenço, Teresa; Rodrigues, Márcia; Calado, Angelina; Amado, Marta; Guerreiro, Nancy; Serras, Inês; Beetz, Christian; Varga, Rita-Eva; Silay, Mesrur Selcuk; Darlow, John M.; Dobson, Mark G.; Barton, David E.; Hunziker, Manuela; Puri, Prem; Feather, Sally A.; Goodship, Judith A.; Goodship, Timothy H.J.; Lambert, Heather J.; Cordell, Heather J.; Saggar, Anand; Kinali, Maria; Lorenz, Christian; Moeller, Kristina; Schaefer, Franz; Bayazit, Aysun K.; Weber, Stefanie; Newman, William G.


    Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS. PMID:25145936

  20. High frequency of the c.3207CA (p.H1069Q) mutation in A TP7B gene of Lithuanian patients with hepatic presentation of Wilson's disease

    Institute of Scientific and Technical Information of China (English)

    Laimutis Kucinskas; Jolanta Jeroch; Astra Vitkauskiene; Raimundas Sakalauskas; Vitalija Petrenkiene; Vaidutis Kucinskas; Rima Naginiene; Hartmut Schmidt; Limas Kupcinskas


    AIM: To investigate the prevalence of the ATP7B gene mutation in patients with hepatic presentation of Wilson's disease (WD) in Lithuania.METHODS: Eleven unrelated Lithuanian families, including 13 WD patients were tested. Clinically WD diagnosis was established in accordance to the Leipzig scoring system. Genomic DNA was extracted from whole venous blood using a salt precipitation method. Firstly, the semi-nested polymerase chain reaction (PCR) technique was used to detect the c.3207CA (p.H1069Q) mutation. Patients not homozygous for the c.3207CA (p.H1069Q) mutation were further analyzed. The 21 exons of the WD gene were amplified in a thermal cycler (Biometra T3 Thermocycler, G6ttingen, Germany). Direct sequencing of the amplified PCR products was performed by cycle sequencing using fluorescent dye terminators in an automatic sequencer (Applied Biosystems, Darmstadt, Germany).RESULTS: Total of 13 WD patients (mean age 26.4 years; range 17-40; male/female 3/10) presented with hepatic disorders and 16 their first degree relatives (including 12 siblings) were studied. Some of WD patients, in addition to hepatic symptoms, have had extrahepatic disorders (hemolytic anemia 3; Fanconi syndrome 1; neurophsychiatric and behavioural disorder 2). Liver biopsy specimens were available in all of 13 WD patients (8 had cirrhosis; 1-chronic hepatitis; 3-acute liver failure, l-liver steatosis). Twelve of 13 (92.3%) WD patients had the c.3207CA (p.H1069Q) mutation, 6 of them in both chromosomes, 6 were presented as compound heterozygotes with additional c.3472-82delGGTTTAACCAT, c.3402delC, c.3121CT (p.R1041W) or unknown mutations. For one patient with liver cirrhosis and psychiatric disorder (Leipzig score 6), no mutations were found. Out of 16 first degree WD relatives, 11 (68.7%) were heterozygous for the c.3207CA (p.H1069Q) mutation. Two patients with fulminant WD died from acute liver failure and 11 are in full remission under penicillamine or zinc acetate treatment. Three

  1. Clinical Outcomes and Co-Occurring Mutations in Patients with RUNX1-Mutated Acute Myeloid Leukemia. (United States)

    Khan, Maliha; Cortes, Jorge; Kadia, Tapan; Naqvi, Kiran; Brandt, Mark; Pierce, Sherry; Patel, Keyur P; Borthakur, Gautam; Ravandi, Farhad; Konopleva, Marina; Kornblau, Steven; Kantarjian, Hagop; Bhalla, Kapil; DiNardo, Courtney D


    (1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2) We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5.1% of younger patients and 15.9% of older patients, and were significantly associated with increasing age (p = 0.01) as well as intermediate-risk cytogenetics including normal karyotype (p = 0.02) in the elderly cohort, and with lower lactate dehydrogenase (LDH; p = 0.02) and higher platelet count (p = 0.012) overall. Identified co-occurring mutations were primarily ASXL1 mutations in older patients and RAS mutations in younger patients; FLT3-ITD and IDH1/2 co-mutations were also frequent. Younger mRUNX1 AML patients treated with intensive chemotherapy experienced inferior treatment outcomes. In older patients with AML treated with hypomethylating agent (HMA) therapy, response and survival was independent of RUNX1 status. Older mRUNX1 patients with prior myelodysplastic syndrome or myeloproliferative neoplasms (MDS/MPN) had particularly dismal outcome. Future studies should focus on the prognostic implications of RUNX1 mutations relative to other co-occurring mutations, and the potential role of hypomethylating agents for this molecularly-defined group.

  2. SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila. (United States)

    Praveen, Kavita; Wen, Ying; Gray, Kelsey M; Noto, John J; Patlolla, Akash R; Van Duyne, Gregory D; Matera, A Gregory


    Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.

  3. SMA-causing missense mutations in survival motor neuron (Smn display a wide range of phenotypes when modeled in Drosophila.

    Directory of Open Access Journals (Sweden)

    Kavita Praveen


    Full Text Available Mutations in the human survival motor neuron 1 (SMN gene are the primary cause of spinal muscular atrophy (SMA, a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs, core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.

  4. Knock-in Mice Harboring a Ca2+ Desensitizing Mutation in Cardiac Troponin C Develop Early Onset Dilated Cardiomyopathy

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    Bradley K McConnell


    Full Text Available The physiological consequences of aberrant Ca2+ binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca2+ sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca2+ sensitivity of reconstituted thin filaments by increasing the rate of Ca2+ dissociation. In addition, the D73N mutation drastically blunted the extent of Ca2+ desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca2+ sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was twelve weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction and fractional shortening, were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to β-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM. In conclusion, our results suggest that decreasing Ca2+ sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM.

  5. 11p13 deletions can be more frequent than the PAX6 gene point mutations in Polish patients with aniridia. (United States)

    Wawrocka, Anna; Sikora, Agata; Kuszel, Lukasz; Krawczynski, Maciej R


    Aniridia is a rare, bilateral, congenital ocular disorder causing incomplete formation of the iris, usually characterized by iris aplasia/hypoplasia. It can also appear with other ocular anomalies, such as cataracts, glaucoma, corneal pannus, optic nerve hypoplasia, macular hypoplasia, or ectopia lentis. In the majority of cases, it is caused by mutation in the PAX6 gene, but it can also be caused by microdeletions that involve the 11p13 region. Twelve unrelated patients of Polish origin with a clinical diagnosis of aniridia were screened for the presence of microdeletions in the 11p13 region by means of multiplex ligation probe amplification (MLPA). Additionally, the coding regions of the PAX6 gene were sequenced in all probands. MLPA examination revealed different size deletions of the 11p13 region in five patients. In three cases, deletions encompassed the entire PAX6 gene and a few adjacent genes. In one case, a fragment of the PAX6 gene was deleted only. In the final case, the deletion did not include any PAX6 sequence. Our molecular findings provide further evidence of the existence of the distant 3' regulatory elements in the downstream region of the PAX6 gene, which is known from other studies to influence the level of protein expression. Sequence analysis of the PAX6 gene revealed the three different point mutations in the remaining four patients with aniridia. All the detected mutations were reported earlier. Based on accomplished results, the great diversity of the molecular basis of aniridia was found. It varies from point mutations to different size deletions in the 11p13 region which encompass partly or completely the PAX6 gene or cause a position effect.

  6. Stress, burnout and doctors' attitudes to work are determined by personality and learning style: a twelve year longitudinal study of UK medical graduates. (United States)

    McManus, I C; Keeling, A; Paice, E


    The study investigated the extent to which approaches to work, workplace climate, stress, burnout and satisfaction with medicine as a career in doctors aged about thirty are predicted by measures of learning style and personality measured five to twelve years earlier when the doctors were applicants to medical school or were medical students. Prospective study of a large cohort of doctors. The participants were first studied when they applied to any of five UK medical schools in 1990. Postal questionnaires were sent to all doctors with a traceable address on the current or a previous Medical Register. The current questionnaire included measures of Approaches to Work, Workplace Climate, stress (General Health Questionnaire), burnout (Maslach Burnout Inventory), and satisfaction with medicine as a career and personality (Big Five). Previous questionnaires had included measures of learning style (Study Process Questionnaire) and personality. Doctors' approaches to work were predicted by study habits and learning styles, both at application to medical school and in the final year. How doctors perceive their workplace climate and workload is predicted both by approaches to work and by measures of stress, burnout and satisfaction with medicine. These characteristics are partially predicted by trait measures of personality taken five years earlier. Stress, burnout and satisfaction also correlate with trait measures of personality taken five years earlier. Differences in approach to work and perceived workplace climate seem mainly to reflect stable, long-term individual differences in doctors themselves, reflected in measures of personality and learning style.

  7. Phenolic Composition and Antioxidant and Antiproliferative Activities of the Extracts of Twelve Common Bean (Phaseolus vulgaris L. Endemic Ecotypes of Southern Italy before and after Cooking

    Directory of Open Access Journals (Sweden)

    Maria Neve Ombra


    Full Text Available Beans are important dietary components with versatile health benefits. We analysed the extracts of twelve ecotypes of Phaseolus vulgaris in order to determine their phenolic profiles, antioxidant activity, and the in vitro antiproliferative activity. Ultra-performance liquid chromatography with diode array detector (UPLC-DAD admitted us to detect and quantify some known polyphenols, such as gallic acid, chlorogenic acid, epicatechin, myricetin, formononetin, caffeic acid, and kaempferol. The antioxidant activity (AA ranged from 1.568 ± 0.041 to 66.572 ± 3.197 mg necessary to inhibit the activity of the 2,2-diphenyl-1-picrylhydrazyl (DPPH radical by 50% (EC50. The extracts, except those obtained from the nonpigmented samples, were capable of inhibiting the proliferation of the human epithelial colorectal adenocarcinoma (Caco-2 cells, human breast cancer cells MCF-7, and A549 NSCLC cell line. Cultivars differed in composition and concentration of polyphenols including anthocyanins; cooking affected the antioxidant activity only marginally. Qualitative and quantitative differences in phenolic composition between the groups of beans influenced the biological activities; on the other hand, we did not find significant differences on the biological activities within the same variety, before and after cooking.

  8. Efficacy of disulfiram and Twelve Step Facilitation in cocaine-dependent individuals maintained on methadone: A randomized placebo-controlled trial (United States)

    Carroll, Kathleen M.; Nich, Charla; Shi, Julia M.; Eagan, Dorothy; Ball, Samuel A.


    Background Cocaine use remains a major problem within methadone maintenance programs. Disulfiram’s efficacy in reducing cocaine use has been demonstrated in several trials, but its relative efficacy among individuals who use versus abstain from alcohol remains unclear Treatment approaches which seek to enhance substance users’ involvement in self-help activities (Twelve Step Facilitation, TSF) have been associated with better outcomes among alcohol and cocaine users, but have rarely been evaluated among methadone-maintained cocaine-opioid users. Methods We conducted a randomized, placebo controlled, double blind (for medication condition), factorial (2×2) trial with 4 treatment conditions: Disulfiram plus TSF, disulfiram plus standard counseling only, placebo plus TSF, and placebo plus standard counseling in the context of a community-based methadone maintenance program. Participants (N=112) received either disulfiram (250 mg/d) or placebo in conjunction with daily methadone maintenance. Results Assignment to TSF was associated with less cocaine use throughout treatment and a higher number of cocaine-negative urines. While there were no significant main effects of disulfiram versus placebo, individuals without an alcohol use disorder demonstrated greater reductions in cocaine use over time when assigned to disulfiram. Conclusions TSF appears feasible in this methadone maintenance program and was associated with modest reductions in cocaine use, an often intractable problem in this setting. Support for the efficacy of disulfiram was weaker, as it appeared effective only for those without a current alcohol use disorder for this sample. PMID:22695473

  9. Polymorphisms in twelve candidate genes are associated with growth, muscle lipid profile and meat quality traits in eleven European cattle breeds. (United States)

    Sevane, N; Armstrong, E; Wiener, P; Pong Wong, R; Dunner, S


    Current customers' demands focus on the nutritional and sensory quality of cattle meat. Candidate gene approach allows identification of genetic polymorphisms that have a measurable effect on traits of interest. The aim of this work is to identify new molecular markers for beef production through an association study using 27 candidate genes and 314 purebred bulls from 11 European cattle breeds. Twelve genes were found associated with different lipid and meat quality traits, and among these stand out the considerable effect of CAST on fatness score, CGGBP1 on growth traits, HSPB1 on the percentage of lauric acid (12:0) and phospholipid docosahexaenoic acid (DHA 22:6 n - 3), RORA on the ratio of light absorption (K) to light scattering (S) (K/S), and TNFA on lightness (L*). Most of these traits are related to post-mortem muscle biochemical changes, which are key factors controlling meat quality and consumers' acceptance. Also, the variations produced on muscle fatty acid profiles, such as those of AANAT, CRH, CSN3, HSPB1, and TNFA, give insights into the genetic networks controlling these complex traits and the possibility of future improvement of meat nutritional quality.

  10. Twelve weeks of BodyBalance® training improved balance and functional task performance in middle-aged and older adults

    Directory of Open Access Journals (Sweden)

    Nicholson VP


    Full Text Available Vaughan P Nicholson, Mark R McKean, Brendan J Burkett School of Health and Sport Sciences, University of the Sunshine Coast, Sunshine Coast, QLD, Australia Purpose: The purpose of the study was to evaluate the effect of BodyBalance® training on balance, functional task performance, fear of falling, and health-related quality of life in adults aged over 55 years.Participants and methods: A total of 28 healthy, active adults aged 66±5 years completed the randomized controlled trial. Balance, functional task performance, fear of falling, and self-reported quality of life were assessed at baseline and after 12 weeks. Participants either undertook two sessions of BodyBalance per week for 12 weeks (n=15 or continued with their normal activities (n=13.Results: Significant group-by-time interactions were found for the timed up and go (P=0.038, 30-second chair stand (P=0.037, and mediolateral center-of-pressure range in narrow stance with eyes closed (P=0.017. There were no significant effects on fear of falling or self-reported quality of life.Conclusion: Twelve weeks of BodyBalance training is effective at improving certain balance and functional based tasks in healthy older adults. Keywords: postural control, yoga, tai chi, center of pressure, exercise

  11. Theory of the “New Music” Expressionism Based on Schoenberg’ s Twelve-Tone Music%论“新音乐”的表现主义

    Institute of Scientific and Technical Information of China (English)



    The Western music of the 20th century, due to the social change, the influence of the economic recovery and cultural ideological trend, produced extremely complex and changeful music form and cultural form.This article, through the innovation of the 20th century Western new music composing techniques, taking Schoenberg and expressionist music representative of twelve-tone music as an example, discusses the“new music” under the influence of the ideological trend of expressionist music, as well as the“tradition” in the leading position of expressionist music.%20世纪的西方音乐,由于受到社会变动、经济复苏和文化思潮的影响,产生了极其复杂多变的音乐形式和文化形态。本文将借20世纪西方新音乐作曲技法的创新,并以表现主义音乐代表人物勋伯格的十二音音乐为例进行分析,论述了“新音乐”思潮影响下的表现主义音乐,以及“反传统”思想在表现主义音乐中的主导地位。

  12. Barley husk carbon as the fiber coating for the solid-phase microextraction of twelve pesticides in vegetables prior to gas chromatography-mass spectrometric detection. (United States)

    Liang, Weiqian; Wang, Juntao; Zang, Xiaohuan; Dong, Wenhuan; Wang, Chun; Wang, Zhi


    In this work, a barley husk biomaterial was successfully carbonized by hydrothermal method. The carbon had a high specific surface area and good stability. It was coated onto a stainless steel wire through sol-gel technique to prepare a solid-phase microextraction fiber for the extraction of trace levels of twelve pesticides (tsumacide, fenobucarb, indoxacarb, diethofencarb, thimet, terbufos, malathion, thiamethoxam, imidacloprid, buprofezin, acetamiprid, thiamethoxam) from vegetable samples prior to gas chromatography-mass spectrometric (GC-MS) detection. The main experimental parameters that could influence the extraction efficiency such as extraction time, extraction temperature, sample pH, sample salinity, stirring rate, desorption temperature and desorption time, were investigated. Under the optimized conditions, the linearity was observed in the range of 0.2-75.0μgkg(-1) for tomato samples, and 0.3-60.0μgkg(-1) for cucumber samples, with the correlation coefficients (r) ranging from 0.9959 to 0.9983. The limits of detection of the method were 0.01-0.05μgkg(-1) for tomato samples, and 0.03-0.10μgkg(-1) for cucumber samples. The recoveries of the analytes for the method from spiked samples were in the range of 76%-104%, and the precision, expressed as the relative standard deviations, was less than 12%. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Discussion on the Rhetoric of Libretto in Twelve Muqam%浅谈《十二木卡姆》唱词的修辞性

    Institute of Scientific and Technical Information of China (English)



    木卡姆语言的佳妙,除了配合歌腔旋律的演唱外,还表现出了其驾驭文字的艺术手法。论文从不同木卡姆剧本中搜寻出最常用的修辞格,并例举若干例子分别说明这些修辞格在作品中的作用及其相关的问题,试图从修辞立场来研读木卡姆语言的艺术成果。%Twelve Muqam’s libretto showed the writing art, excepting with the song melody singing cavity. We searched most commonly used figures of speech from the script of a different Maqam, and cited a number of examples to illustrate the role of rhetorical devices in his works and their associated problems. We will try to study Muqam language art achievements from from the perspective of rhetoric.

  14. Transfer of eleven species of the genus Burkholderia to the genus Paraburkholderia and proposal of Caballeronia gen. nov. to accommodate twelve species of the genera Burkholderia and Paraburkholderia. (United States)

    Dobritsa, Anatoly P; Samadpour, Mansour


    It has been proposed to split the genus Burkholderia into two genera according to phylogenetic clustering: (1) a genus retaining this name and consisting mainly of animal and plant pathogens and (2) the genus Paraburkholderia including so-called environmental bacteria. The latter genus name has been validly published recently. During the period between the effective and valid publications of the genus name Paraburkholderia, 16 novel species of the genus Burkholderiawere described, but only two of them can be classified as members of this genus based on the emended genus description. Analysis of traits and phylogenetic positions of the other 11 species shows that they belong to the genus Paraburkholderia, and we propose to transfer them to this genus. The reclassified species names are proposed as Paraburkholderia dipogonis comb. nov., Paraburkholderia ginsengiterrae comb. nov., Paraburkholderia humisilvae comb. nov., Paraburkholderia insulsa comb. nov., Paraburkholderia kirstenboschensis comb. nov., Paraburkholderia metalliresistens comb. nov., Paraburkholderia monticola comb. nov., Paraburkholderia panaciterrae comb. nov., Paraburkholderia rhizosphaerae comb. nov., Paraburkholderia solisilvae comb. nov. and Paraburkholderia susongensis comb. nov. The remaining three species are transferred to the new genus Caballeronia gen. nov. proposed to accommodate twelve species of the genera Burkholderia and Paraburkholderia forming a distinctive clade in phylogenetic trees. The new genus members are Caballeronia choica comb. nov., Caballeronia cordobensis comb. nov., Caballeronia glathei comb. nov., Caballeronia grimmiae comb. nov., Caballeronia humi comb. nov., Caballeronia megalochromosomata comb. nov., Caballeronia jiangsuensis comb. nov., Caballeronia sordidicola comb. nov., Caballeronia telluris comb. nov., Caballeronia terrestris comb. nov., Caballeronia udeis comb. nov., and Caballeronia zhejiangensis comb. nov.

  15. Phenolic Composition and Antioxidant and Antiproliferative Activities of the Extracts of Twelve Common Bean (Phaseolus vulgaris L.) Endemic Ecotypes of Southern Italy before and after Cooking. (United States)

    Ombra, Maria Neve; d'Acierno, Antonio; Nazzaro, Filomena; Riccardi, Riccardo; Spigno, Patrizia; Zaccardelli, Massimo; Pane, Catello; Maione, Mena; Fratianni, Florinda


    Beans are important dietary components with versatile health benefits. We analysed the extracts of twelve ecotypes of Phaseolus vulgaris in order to determine their phenolic profiles, antioxidant activity, and the in vitro antiproliferative activity. Ultra-performance liquid chromatography with diode array detector (UPLC-DAD) admitted us to detect and quantify some known polyphenols, such as gallic acid, chlorogenic acid, epicatechin, myricetin, formononetin, caffeic acid, and kaempferol. The antioxidant activity (AA) ranged from 1.568 ± 0.041 to 66.572 ± 3.197 mg necessary to inhibit the activity of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical by 50% (EC50). The extracts, except those obtained from the nonpigmented samples, were capable of inhibiting the proliferation of the human epithelial colorectal adenocarcinoma (Caco-2) cells, human breast cancer cells MCF-7, and A549 NSCLC cell line. Cultivars differed in composition and concentration of polyphenols including anthocyanins; cooking affected the antioxidant activity only marginally. Qualitative and quantitative differences in phenolic composition between the groups of beans influenced the biological activities; on the other hand, we did not find significant differences on the biological activities within the same variety, before and after cooking.

  16. Challenge of goodness: twelve humanitarian proposals based on the experience of 1991-1995 wars in Croatia and Bosnia and Herzegovina. (United States)

    Lang, S


    Based on the 1991-1995 war experience of peoples of Croatia and Bosnia and Herzegovina, I made twelve proposals regarding the following aspects of health, humanitarian work, and human rights: 1. Broadening of the WHO definition of health by including spiritual well-being (absence of hatred) in it, 2. Inclusion of the term genocide into the Index Medicus (MeSH), 3. Establishment of concepts of prevention of hate, 4. Right to a home, 5. Right of civilians to participate in defense and renewal, 6. Right to deliberation from enslavement and right to find out the fate of missing persons, 7. Global hospital, 8. Monitoring of prisoner-of-war camps, 9. Refugee camps, 10. Providing of care for the abandoned - a new category of people suffering in war, 11. Introduction of the Helping Hand concept, 12. Organization of the Red Cross Forum after the cessation of hostilities. The fundamental objective was to establish the legitimacy of honesty in practice, regulative social mechanisms, and science.

  17. A Randomized Controlled Trial of Puncturing and Bloodletting at Twelve Hand Jing Points to Treat Acute Carbon Monoxide Poisoning as Adjunct to First Aid Treatment: A Study Protocol

    Directory of Open Access Journals (Sweden)

    Ying Yue


    Full Text Available Background. Acute carbon monoxide poisoning (ACOP is a significant cause of morbidity and mortality in many countries. Twelve Hand Jing Points (THJP have been believed to be effective to treat all kinds of emergency calls in traditional Chinese medicine (TCM for more than 3000 years. This randomized controlled trial (RCT is designed to evaluate the effectiveness of THJP in curing acute carbon monoxide poisoning in first aid treatment. This paper reports the protocol of the trial. Methods/Design. This RCT is a multicenter, randomized, controlled study undergoing in China. The compliant patients are divided into the bloodletting group and standard of care group. With first aid treatments given to both of the groups, the bloodletting group is bleeding at THJP upon being hospitalized. Primary outcomes and secondary outcomes will be measured and compared between these two groups. Before treatment, immediately after treatment, and 30 minutes, 1 hour, and 4 hours after treatment, patients’ basic vital signs and state of consciousness were observed. Before treatment and 1 and 4 hours after treatment, carboxyhemoglobin concentration in venous blood samples was detected. Discussion. The objective of this study is to provide convincing evidence to clarify the efficacy and safety of THJP for early treatment of acute carbon monoxide poisoning.

  18. Mutation screening of the EYA1, SIX1, and SIX5 genes in an East Asian cohort with branchio-oto-renal syndrome. (United States)

    Wang, Shih-Hao; Wu, Chen-Chi; Lu, Ying-Chang; Lin, Yin-Hung; Su, Yi-Ning; Hwu, Wuh-Liang; Yu, I-Shing; Hsu, Chuan-Jen


    To explore the genetic characteristics of branchio-oto-renal (BOR) syndrome in an East Asian population. Prospective clinical genetic study. Twelve families (total of 18 patients) who fulfilled the criteria for BOR syndrome were enrolled in this study. Mutation screening of the EYA1, SIX1, and SIX5 genes was performed by direct sequencing and quantitative polymerase chain reaction, and genotype-phenotype correlation was investigated. Two novel EYA1 variants, c.466C>T (p.Q156X) and c.1735delG (p.D579fs), were identified in two multiplex families. The c.466C>T variant resulted in a truncated EYA1 protein, whereas the c.1735delG variant was predicted to encode an EYA1 protein with an abnormal C terminal. Neither variant was identified in a panel of 100 normal controls, and both were cosegregated with the BOR phenotype in the pedigrees, indicating that they were pathogenic mutations. No SIX1 and SIX5 mutations were detected in members of the remaining 10 families. Analysis of the genotype-phenotype correlation revealed a high phenotypic variability between and within BOR families. Two novel EYA1 mutations (c.466C>T and c.1735delG) were identified in two families with BOR syndrome. SIX1 and SIX5 mutations were not detected in the present study. Further investigation is warranted regarding the contribution of SIX1 and SIX5 mutations to BOR syndrome in East Asian populations. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

  19. Reverse mutations in the fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Brown, W.T.; Houck, G.E. Jr.; Ding, Xiaohua [New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States)


    Three females were identified who have apparent reversal of fragile X premutations. Based on haplotype analysis of nearby markers, they were found to have inherited a fragile X chromosome from their premutation carrier mothers, and yet had normal size FMR1 repeat alleles. The changes in repeat sizes from mother to daughter was 95 to 35 in the first, 145 to 43 in the second, and 82 to 33 in the third. In the first family, mutations of the nearby microsatellites FRAXAC2 and DXS548 were also observed. In the other two, only mutations involving the FMR1 repeats were found. We suggest differing mutational mechanisms such as gene conversion versus DNA replication slippage may underlie such reversions. We estimate that such revertants may occur among 1% or less of premutation carrier offspring. Our results indicate that women identified to be carriers by linkage should be retested by direct DNA analysis. 35 refs., 5 figs.

  20. The entropy characters of point mutation

    Institute of Scientific and Technical Information of China (English)

    MA GuoJi; LIANG LiJing; FAN YanHui; WANG WenJuan; DAI JiaQing; YUAN ZhiFa


    The biological diversity, which depends on the genetic material DNA, is the foundation for a species to survive and evolve. The entropy is the best measurement of biological diversity. Based on the sin-gle-parameter and the two-parameter models, here we established some differential equations about the point mutation of a DNA sequence with finite length, as well as some functions describing the processes of the variation in quantities of 4 kinds of bases (A, T, G and C) in the DNA sequence. At the molecular level, we discussed the entropy characteristics of point mutation. The results proved that a species maintained its entropy and evolved in the direction of the increasing biological diversity. In order to testify the theoretical results, we did a series of computer simulations of random point muta-tion in Matlab environment. The results were well consistent with the theoretical researches.

  1. Radiation induced dynamic mutations and transgenerational effects. (United States)

    Niwa, Ohtsura


    Many studies have confirmed that radiation can induce genomic instability in whole body systems. Although the molecular mechanisms underlying induced genomic instability are not known at present, this interesting phenomenon could be the manifestation of a cellular fail-safe system in which fidelity of repair and replication is down-regulated to tolerate DNA damage. Two features of genomic instability namely, delayed mutation and untargeted mutation, require two mechanisms of ;damage memory' and ;damage sensing, signal transduction and execution' to induce mutations at a non damaged-site. In this report, the phenomenon of transgenerational genomic instability and possible mechanisms are discussed using mouse data collected in our laboratory as the main bases.

  2. Radiation-induced mutations and plant breeding

    Energy Technology Data Exchange (ETDEWEB)

    Naqvi, S.H.M.


    Ionizing radiation could cause genetic changes in an organism and could modify gene linkages. The induction of mutation through radiation is random and the probability of getting the desired genetic change is low but can be increased by manipulating different parameters such as dose rate, physical conditions under which the material has been irradiated, etc. Induced mutations have been used as a supplement to conventional plant breeding, particularly for creating genetic variability for specific characters such as improved plant structure, pest and disease resistance, and desired changes in maturity period; more than 200 varieties of crop plants have been developed by this technique. The Pakistan Atomic Energy Commission has used this technique fruitfully to evolve better germplasm in cotton, rice, chickpea, wheat and mungbean; some of the mutants have become popular commercial varieties. This paper describes some uses of radiation induced mutations and the results achieved in Pakistan so far.

  3. Effect of Mutations on HP Lattice Proteins (United States)

    Shi, Guangjie; Vogel, Thomas; Landau, David; Li, Ying; Wüst, Thomas


    Using Wang-Landau sampling with approriate trial moves[2], we investigate the effect of different types of mutations on lattice proteins in the HP model. While exact studies have been carried out for short HP proteins[3], the systems we investigate are of much larger size and hence not accessible for exact enumerations. Based on the estimated density of states, we systematically analyse the changes in structure and degeneracy of ground states of particular proteins and measure thermodynamic quantities like the stability of ground states and the specific heat, for example. Both, neutral mutations, which do not change the structure and stability of ground states, as well as critical mutations, which do change the thermodynamic behavior qualitatively, have been observed. Research supported by NSF

  4. Selection-Mutation Dynamics of Signaling Games

    Directory of Open Access Journals (Sweden)

    Josef Hofbauer


    Full Text Available We study the structure of the rest points of signaling games and their dynamic behavior under selection-mutation dynamics by taking the case of three signals as our canonical example. Many rest points of the replicator dynamics of signaling games are not isolated and, therefore, not robust under perturbations. However, some of them attract open sets of initial conditions. We prove the existence of certain rest points of the selection-mutation dynamics close to Nash equilibria of the signaling game and show that all but the perturbed rest points close to strict Nash equilibria are dynamically unstable. This is an important result for the evolution of signaling behavior, since it shows that the second-order forces that are governed by mutation can increase the chances of successful signaling.

  5. Constraints on mutational pathways of hemoglobin evolution

    DEFF Research Database (Denmark)

    Kumar, Amit; Natarajan, Chandrasekhar; Moriyama, Hideaki


    When an evolutionary transition in protein function involves multiple mutational steps, a number of important questions can be addressed by experimentally examining the full set of possible intermediate genotypes that connect the ancestral starting point and the evolved endpoint. For example......, if the functional effects of mutations depend on the sequential order in which they occur, then evolution may be more likely to follow some pathways (those involving onotonic increases in fitness) rather than others (those involving low-fitness intermediates). Here we report an experimental analysis of multiple...... nightjar Hb, we used a combinatorial protein engineering approach to synthesize genotypes representing each of the 16 possible multi-site combinations.We discovered that all possible mutational pathways connecting the high-affinity ancestor and the low-affinity, wild-type Hb may not be equally accessible...

  6. Replicative DNA polymerase mutations in cancer. (United States)

    Heitzer, Ellen; Tomlinson, Ian


    Three DNA polymerases - Pol α, Pol δ and Pol ɛ - are essential for DNA replication. After initiation of DNA synthesis by Pol α, Pol δ or Pol ɛ take over on the lagging and leading strand respectively. Pol δ and Pol ɛ perform the bulk of replication with very high fidelity, which is ensured by Watson-Crick base pairing and 3'exonuclease (proofreading) activity. Yeast models have shown that mutations in the exonuclease domain of Pol δ and Pol ɛ homologues can cause a mutator phenotype. Recently, we identified germline exonuclease domain mutations (EDMs) in human POLD1 and POLE that predispose to 'polymerase proofreading associated polyposis' (PPAP), a disease characterised by multiple colorectal adenomas and carcinoma, with high penetrance and dominant inheritance. Moreover, somatic EDMs in POLE have also been found in sporadic colorectal and endometrial cancers. Tumors with EDMs are microsatellite stable and show an 'ultramutator' phenotype, with a dramatic increase in base substitutions.

  7. Fitness cost of chromosomal drug resistance-conferring mutations. (United States)

    Sander, Peter; Springer, Burkhard; Prammananan, Therdsak; Sturmfels, Antje; Kappler, Martin; Pletschette, Michel; Böttger, Erik C


    To study the cost of chromosomal drug resistance mutations to bacteria, we investigated the fitness cost of mutations that confer resistance to different classes of antibiotics affecting bacterial protein synthesis (aminocyclitols, 2-deoxystreptamines, macrolides). We used a model system based on an in vitro competition assay with defined Mycobacterium smegmatis laboratory mutants; selected mutations were introduced by genetic techniques to address the possibility that compensatory mutations ameliorate the resistance cost. We found that the chromosomal drug resistance mutations studied often had only a small fitness cost; compensatory mutations were not involved in low-cost or no-cost resistance mutations. When drug resistance mutations found in clinical isolates were considered, selection of those mutations that have little or no fitness cost in the in vitro competition assay seems to occur. These results argue against expectations that link decreased levels of antibiotic consumption with the decline in the level of resistance.

  8. The spectrum of mutation produced by low dose radiation

    Energy Technology Data Exchange (ETDEWEB)

    Morley,Alexander,A; Turner, David,R


    Inherited mutations are the basis of evolution and acquired mutations in humans are important in ageing, cancer and possibly various forms of tissue degeneration. Mutations are responsible for many of the long-term effects of radiation. However, sensitive direct detection of mutations in humans has been difficult. The aims of the project were to develop methods for the sensitive enumeration of mutations in DNA, to measure mutation frequencies in a wide variety of tissue types and to quantify the mutational effect of direct oxidative damage produced by radiation, at both high and low doses. The project was successful in developing a sensitive method which could detect mutations directly in the genetic material, DNA at a sensitivity of 1 mutated molecule in 1000000000 unmutated molecules. However a number of methodological problems had to be overcome and lack of ongoing funding made it impossible to fulfill all of the aims of the project

  9. Profile of TP53 gene mutations in sinonasal cancer

    DEFF Research Database (Denmark)

    Holmila, Reetta; Bornholdt, Jette; Suitiala, Tuula


    %) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C-->T transition (43/125; 34% of base changes in the coding region). G-->T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation...... not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations.......Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC...


    Institute of Scientific and Technical Information of China (English)

    卞留贯; 孙青芳; 沈建康; 赵卫国; 罗其中


    Objective To analyze the mutation of NF2 gene (exon 2,4,6 and 13) in schwannomas. Methods The NF2 gene mutation in 36 schwannomas were observed by PCR-SSCP and DNA sequence. The proliferative index of schwannoma was detected by immunohistochemistry. Results We found 13 mutations in 36 schwannomas, including 6 deletion or insertion resulting in a frameshift, 2 nonsense mutations, 2 missense mutations, and 3 alterations affecting acceptor or donor of splicing sites in E4,E6,E13. The proliferative index of schwannomas with mutation were significantly higher than those without mutation (P< 0.05). Conclusion NF2 gene mutation is the frequent event in the tumorigenesis of schwannomas, and there is some correlation between the mutation and clinical behavior(tumor proliferation).

  11. Splice Site Mutations in the ATP7A Gene

    DEFF Research Database (Denmark)

    Skjørringe, Tina; Tümer, Zeynep; Møller, Lisbeth Birk


    Menkes disease (MD) is caused by mutations in the ATP7A gene. We describe 33 novel splice site mutations detected in patients with MD or the milder phenotypic form, Occipital Horn Syndrome. We review these 33 mutations together with 28 previously published splice site mutations. We investigate 12...... mutations for their effect on the mRNA transcript in vivo. Transcriptional data from another 16 mutations were collected from the literature. The theoretical consequences of splice site mutations, predicted with the bioinformatics tool Human Splice Finder, were investigated and evaluated in relation...... to in vivo results. Ninety-six percent of the mutations identified in 45 patients with classical MD were predicted to have a significant effect on splicing, which concurs with the absence of any detectable wild-type transcript in all 19 patients investigated in vivo. Sixty-seven percent of the mutations...

  12. Confidence-based somatic mutation evaluation and prioritization.

    Directory of Open Access Journals (Sweden)

    Martin Löwer

    Full Text Available Next generation sequencing (NGS has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR, to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence and 44 mutations assigned a high FDR (low confidence. All of the high confidence somatic mutations validated (50 of 50, none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set.

  13. Multiple oncogenic mutations related to targeted therapy in nasopharyngeal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jian-Wei Zhang; Hong-Yuan Zhao; Yu-Xiang Ma; Zhi-Huang Hu; Pei-Yu Huang; Li Zhang; Tao Qin; Shao-Dong Hong; Jing Zhang; Wen-Feng Fang; Yuan-Yuan Zhao; Yun-Peng Yang; Cong Xue; Yan Huang


    Introduction:An increasing number of targeted drugs have been tested for the treatment of nasopharyngeal carcinoma (NPC). However, targeted therapy-related oncogenic mutations have not been fully evaluated. This study aimed to detect targeted therapy-related oncogenic mutations in NPC and to determine which targeted therapy might be potentially effective in treating NPC. Methods:By using the SNaPshot assay, a rapid detection method, 19 mutation hotspots in 6 targeted therapy-related oncogenes were examined in 70 NPC patients. The associations between oncogenic mutations and clinicopathologic factors were analyzed. Results:Among 70 patients, 12 (17.1%) had mutations in 5 oncogenes:7 (10.0%) had v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutation, 2 (2.8%) had epidermal growth factor receptor (EGFR) mutation, 1 (1.4%) had phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, 1 (1.4%) had Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and 1 (1.4%) had simultaneous EGFR and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations. No significant differences were observed between oncogenic mutations and clinicopathologic characteristics. Additionally, these oncogenic mutations were not associated with tumor recurrence and metastasis. Conclusions:Oncogenic mutations are present in NPC patients. The efficacy of targeted drugs on patients with the related oncogenic mutations requires further validation.

  14. The study of human mutation rates

    Energy Technology Data Exchange (ETDEWEB)

    Neel, J.V.


    We will describe recent developments regarding the question of induced mutations in the survivors of the atomic bombings of Hiroshima and Nagasaki. As part of that work we, describe some developments with respect to the Amerindian blood samples collected under DoE sponsorship between 1964 and 1982. Then developments regarding the application of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) to the study of genetic variation and mutation affecting protein characteristics. In particular, we will report on the identification and isolation of genes of especial interest as reflected in the behavior of the proteins which they encode.

  15. Suppressors of Recb Mutations in Salmonella Typhimurium


    Benson, N. R.; Roth, J.


    Using a screen that directly assesses transductional proficiency, we have isolated suppressors of recB mutations in Salmonella typhimurium. The alleles of sbcB reported here are phenotypically distinct from those isolated in Escherichia coli in that they restore recombination proficiency (Rec(+)), resistance to ultraviolet light (UV(R)), and mitomycin C resistance (MC(R)) in the absence of an accompanying sbcCD mutation. In addition the sbcB alleles reported here are co-dominant to sbcB(+). W...

  16. Confirmation of the mitochondrial ND1 gene mutation G3635A as a primary LHON mutation. (United States)

    Yang, Juhua; Zhu, Yihua; Tong, Yi; Chen, Lu; Liu, Lijuan; Zhang, Zhiqiang; Wang, Xiaoyan; Huang, Dinggou; Qiu, Wentong; Zhuang, Shuliu; Ma, Xu


    We report the clinical and genetic characterization of two Chinese LHON families who do not carry the primary LHON-mutations. Mitochondrial genome sequence analysis revealed the presence of a homoplasmic ND1 G3635A mutation in both families. In Family LHON-001, 31 other variants belonging to the East Asian haplogroup R11a were identified and in Family LHON-019, 37 other variants belonging to the East Asian haplogroup D4g were determined. The ND1 G3635A mutation changes the conversed serine110 residue to asparagine. This mutation has been previously described in a single Russian LHON family and has been suggested to contribute to increased LHON expressivity. In addition, a mutation in cytochrome c oxidase subunit II at C7868T (COII/L95F) may act in synergy with G3635A, increasing LHON expressivity in Family LHON-001, which had a higher level of LHON penetrance than Family LHON-019. In summary, the G3635A mutation is confirmed as a rare primary pathogenic mutation for LHON.

  17. Molecular evaluation of a novel missense mutation & an insertional truncating mutation in SUMF1 gene

    Directory of Open Access Journals (Sweden)

    Udhaya H Kotecha


    Full Text Available Background & objectives: Multiple suphphatase deficiency (MSD is an autosomal recessive disorder affecting the post translational activation of all enzymes of the sulphatase family. To date, approximately 30 different mutations have been identified in the causative gene, sulfatase modifying factor 1 (SUMF1. We describe here the mutation analysis of a case of MSD. Methods: The proband was a four year old boy with developmental delay followed by neuroregression. He had coarse facies, appendicular hypertonia, truncal ataxia and ichthyosis limited to both lower limbs. Radiographs showed dysostosis multiplex. Clinical suspicion of MSD was confirmed by enzyme analysis of four enzymes of the sulphatase group. Results: The patient was compound heterozygote for a c.451A>G (p.K151E substitution in exon 3 and a single base insertion mutation (c.690_691 InsT in exon 5 in the SUMF1 gene. The bioinformatic analysis of the missense mutation revealed no apparent effect on the overall structure. However, the mutated 151-amino acid residue was found to be adjacent to the substrate binding and the active site residues, thereby affecting the substrate binding and/or catalytic activity, resulting in almost complete loss of enzyme function. Conclusions: The two mutations identified in the present case were novel. This is perhaps the first report of an insertion mutation in SUMF1 causing premature truncation of the protein.

  18. High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients. (United States)

    van den Hurk, Karin; Balint, Balazs; Toomey, Sinead; O'Leary, Patrick C; Unwin, Louise; Sheahan, Kieran; McDermott, Enda W; Murphy, Ian; van den Oord, Joost J; Rafferty, Mairin; FitzGerald, Dara M; Moran, Julie; Cummins, Robert; MacEneaney, Owen; Kay, Elaine W; O'Brien, Cathal P; Finn, Stephen P; Heffron, Cynthia C B B; Murphy, Michelle; Yela, Ruben; Power, Derek G; Regan, Padraic J; McDermott, Clodagh M; O'Keeffe, Allan; Orosz, Zsolt; Donnellan, Paul P; Crown, John P; Hennessy, Bryan T; Gallagher, William M


    Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (PBRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.

  19. Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis.

    Directory of Open Access Journals (Sweden)

    Yasushi Ogawa


    Full Text Available When two mutations, one dominant pathogenic and the other "confining" nonsense, coexist in the same allele, theoretically, reversion of the latter may elicit a disease, like the opening of Pandora's box. However, cases of this hypothetical pathogenic mechanism have never been reported. We describe a lethal form of keratitis-ichthyosis-deafness (KID syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient's mother had the identical misssense mutation which was confined by the nonsense mutation. The biological relationship between the parents and the child was confirmed by genotyping of 15 short tandem repeat loci. Haplotype analysis using 40 SNPs spanning the >39 kbp region surrounding the GJB2 gene and an extended SNP microarray analysis spanning 83,483 SNPs throughout chromosome 13 in the family showed that an allelic recombination event involving the maternal allele carrying the mutations generated the pathogenic allele unique to the patient, although the possibility of coincidental accumulation of spontaneous point mutations cannot be completely excluded. Previous reports and our mutation screening support that p.Gly45Glu is in complete linkage disequilibrium with p.Tyr136X in the Japanese population. Estimated from statisitics in the literature, there may be approximately 11,000 p.Gly45Glu carriers in the Japanese population who have this second-site confining mutation, which acts as natural genetic protection from the lethal disease. The reversion-triggered onset of the disesase shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance.

  20. Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. (United States)

    Martelotto, Luciano G; Ng, Charlotte Ky; De Filippo, Maria R; Zhang, Yan; Piscuoglio, Salvatore; Lim, Raymond S; Shen, Ronglai; Norton, Larry; Reis-Filho, Jorge S; Weigelt, Britta


    Massively parallel sequencing studies have led to the identification of a large number of mutations present in a minority of cancers of a given site. Hence, methods to identify the likely pathogenic mutations that are worth exploring experimentally and clinically are required. We sought to compare the performance of 15 mutation effect prediction algorithms and their agreement. As a hypothesis-generating aim, we sought to define whether combinations of prediction algorithms would improve the functional effect predictions of specific mutations. Literature and database mining of single nucleotide variants (SNVs) affecting 15 cancer genes was performed to identify mutations supported by functional evidence or hereditary disease association to be classified either as non-neutral (n = 849) or neutral (n = 140) with respect to their impact on protein function. These SNVs were employed to test the performance of 15 mutation effect prediction algorithms. The accuracy of the prediction algorithms varies considerably. Although all algorithms perform consistently well in terms of positive predictive value, their negative predictive value varies substantially. Cancer-specific mutation effect predictors display no-to-almost perfect agreement in their predictions of these SNVs, whereas the non-cancer-specific predictors showed no-to-moderate agreement. Combinations of predictors modestly improve accuracy and significantly improve negative predictive values. The information provided by mutation effect predictors is not equivalent. No algorithm is able to predict sufficiently accurately SNVs that should be taken forward for experimental or clinical testing. Combining algorithms aggregates orthogonal information and may result in improvements in the negative predictive value of mutation effect predictions.

  1. Germline met mutations in mice reveal mutation- and background-associated differences in tumor profiles.

    Directory of Open Access Journals (Sweden)

    Carrie R Graveel

    Full Text Available BACKGROUND: The receptor tyrosine kinase Met is involved in the progression and metastasis of numerous human cancers. Although overexpression and autocrine activation of the Met signaling pathway are commonly found in human cancers, mutational activation of Met has been observed in small cell and non-small cell lung cancers, lung adenocarcinomas, renal carcinomas, and mesotheliomas. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the influence of mutationally activated Met in tumorigenesis, we utilized a novel mouse model. Previously, we observed that various Met mutations developed unique mutation-specific tumor spectra on a C57BL/6 background. Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met. For this purpose, we created congenic knock-in lines of the Met mutations D1226N, M1248T, and Y1228C on the FVB/N background. Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background. However, on the FVB/N background most developed a high incidence of mammary carcinomas with diverse histopathologies. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that on two distinct mouse backgrounds, Met is able to initiate tumorigenesis in multiple cell types, including epithelial, hematopoietic, and endothelial. Furthermore, these observations emphasize that even a modest increase in Met activation can initiate tumorigenesis with both the Met mutational spectra and host background having profound influence on the type of tumor generated. Greater insight into the interaction of genetic modifiers and Met signaling will significantly enhance our ability to tailor combination therapies for Met-driven cancers.

  2. Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis.

    Directory of Open Access Journals (Sweden)

    Yasushi Ogawa


    Full Text Available When two mutations, one dominant pathogenic and the other "confining" nonsense, coexist in the same allele, theoretically, reversion of the latter may elicit a disease, like the opening of Pandora's box. However, cases of this hypothetical pathogenic mechanism have never been reported. We describe a lethal form of keratitis-ichthyosis-deafness (KID syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient's mother had the identical misssense mutation which was confined by the nonsense mutation. The biological relationship between the parents and the child was confirmed by genotyping of 15 short tandem repeat loci. Haplotype analysis using 40 SNPs spanning the >39 kbp region surrounding the GJB2 gene and an extended SNP microarray analysis spanning 83,483 SNPs throughout chromosome 13 in the family showed that an allelic recombination event involving the maternal allele carrying the mutations generated the pathogenic allele unique to the patient, although the possibility of coincidental accumulation of spontaneous point mutations cannot be completely excluded. Previous reports and our mutation screening support that p.Gly45Glu is in complete linkage disequilibrium with p.Tyr136X in the Japanese population. Estimated from statisitics in the literature, there may be approximately 11,000 p.Gly45Glu carriers in the Japanese population who have this second-site confining mutation, which acts as natural genetic protection from the lethal disease. The reversion-triggered onset of the disesase shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance.

  3. Recurrent APC gene mutations in Polish FAP families

    Directory of Open Access Journals (Sweden)

    Pławski Andrzej


    Full Text Available Abstract The molecular diagnostics of genetically conditioned disorders is based on the identification of the mutations in the predisposing genes. Hereditary cancer disorders of the gastrointestinal tracts are caused by mutations of the tumour suppressor genes or the DNA repair genes. Occurrence of recurrent mutation allows improvement of molecular diagnostics. The mutation spectrum in the genes causing hereditary forms of colorectal cancers in the Polish population was previously described. In the present work an estimation of the frequency of the recurrent mutations of the APC gene was performed. Eight types of mutations occurred in 19.4% of our FAP families and these constitute 43% of all Polish diagnosed families.

  4. Positive mutations and mutation-dependent Verhulst factor in Penna ageing model (United States)

    Moss de Oliveira, S.; Stauffer, D.; de Oliveira, P. M. C.; Sá Martins, J. S.


    We modify twice the Penna model for biological ageing. First, we introduce back (good) mutations and a memory for them into the model. It allows us to observe an improvement of the species fitness over long-time scales as well as punctuated equilibrium. Second, we adopt a food/space competition factor that depends on the number of accumulated mutations in the individuals genomes, and get rid of the fixed limiting number of allowed mutations. Besides reproducing the main results of the standard model, we also observe a mortality maximum for the oldest old.

  5. Mutations in Escherichia coli that relieve catabolite repression of tryptophanase synthesis. Tryptophanase promoter-like mutations. (United States)

    Ward, D F; Yudkin, M D


    From a strain lacking adenyl cyclase and the catabolite-sensitive gene activator protein, two mutants were isolated that can synthesize tryptophanase. Each mutation is extremely closely linked to the tryptophanase structural gene. The mutations differ from one another in the rate of synthesis of tryptophanase that they permit in the genetic background in which they were isolated; they differ from one another and also from the wild type in the maximum rate of synthesis of tryptophanase that they permit in a genetic background with intact adenyl cyclase and catabolite-sensitive gene activator protein. Both mutations appear to lie in the tryptophanase promoter.

  6. Asymptotics of steady states of a selection–mutation equation for small mutation rate

    KAUST Repository

    Calsina, Àngel


    We consider a selection-mutation equation for the density of individuals with respect to a continuous phenotypic evolutionary trait. We assume that the competition term for an individual with a given trait depends on the traits of all the other individuals, therefore giving an infinite-dimensional nonlinearity. Mutations are modelled by means of an integral operator. We prove existence of steady states and show that, when the mutation rate goes to zero, the asymptotic profile of the population is a Cauchy distribution. © Royal Society of Edinburgh 2013.

  7. Novel ATM mutations with ataxia-telangiectasia. (United States)

    Liu, Xiao-Li; Wang, Tian; Huang, Xiao-Jun; Zhou, Hai-Yan; Luan, Xing-Hua; Shen, Jun-Yi; Chen, Sheng-Di; Cao, Li


    Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia-telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. KIT mutation analysis in mast cell neoplasms

    DEFF Research Database (Denmark)

    Arock, M; Sotlar, K; Akin, C;


    Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in various cells and tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT...

  9. Caveolin-3 Mutations in Rippling Muscle Disease

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap


    Full Text Available Two unrelated patients with novel homozygous missense mutations (L86P and A92T in caveolin-3 gene (CAV3, presenting with a severe form of rippling muscle disease (RMD, are reported from the University of Bonn, and other centers in Germany.

  10. New mutation type in pseudohypoparathyroidism type Ia. (United States)

    Fernandez-Rebollo, Eduardo; Barrio, Raquel; Pérez-Nanclares, Gustavo; Carcavilla, Atilano; Garin, Intza; Castaño, Luis; de Nanclares, Guiomar Pérez


    The GNAS gene encodes the alpha-subunit of the stimulatory G proteins, which play a crucial role in intracellular signal transduction of peptide and neurotransmitter receptors. Heterozygous inactivating maternally inherited mutations of GNAS (including translation initiation mutations, amino acid substitutions, nonsense mutations, splice site mutations and small insertions or deletions) lead to a phenotype in which Albright hereditary osteodystrophy is associated with pseudohypoparathyroidism type Ia. We sought to identify the molecular defect in a patient who was thought to have PHP-Ia. The GNAS gene of a 5-year-old boy with brachydactily, mental retardation, pseudohypoparathyroidism and congenital hypothyroidism was investigated. We found a heterozygous inversion of exon 2 and part of intron 1 of de novo origin. Molecular studies of cDNA from blood RNA demonstrated that both the normal and the mutant variants were stable and that new splice-sites were generated. This report demonstrates the first evidence for an inversion at the GNAS gene responsible of pseudohypoparathyroidism type Ia.

  11. Mutation Rates of STR Systems in Danes

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Bøttcher, Susanne Gammelgaard; Christensen, Susanne

    Danish paternity cases in the period 1999 to 2005 were investigated regarding mutation rates in STR loci. STR-typing was performed by the Applied Biosystems AmplfStr Profiler Plus kit in the period 1999 to early 2005, hereafter named the PP9, and by Applied Biosystems AmplfStr Identifier kit...

  12. Research Discovers Frequent Mutations of Chromatin

    Institute of Scientific and Technical Information of China (English)


    With the support of National Natural Science Foundation of China, BGI, the largest genomics organization in the world, and Peking University Shenzhen Hospital, published online in Nature Geneticsics that the study on frequent mutations of chromatin remodeling genes in transitional cell carcinoma (TCC) of thebladder on August 8th, 2011. Their study provides a valuable genetic basis for future studies on TCC,

  13. Mutations in connexin genes and disease. (United States)

    Pfenniger, Anna; Wohlwend, Annelise; Kwak, Brenda R


    Connexins are a family of transmembrane proteins that are widely expressed in the human body. Connexins play an important role in cell-cell communication and homeostasis in various tissues by forming gap junction channels, which enable a direct passage of ions or metabolites from one cell to another. Twenty-one different connexins are expressed in humans, each having distinct expression patterns and regulation properties. Knowledge on this family of proteins can be gained by making an inventory of mutations and associated diseases in human. PubMed and other relevant databases were searched. In addition, key review articles were screened for relevant original publications. Sections of representative organs were photographed and annotated. The crucial role of connexins is highlighted by the discovery of mutations in connexin genes which cause a variety of disorders such as myelin-related diseases, skin disorders, hearing loss, congenital cataract, or more complex syndromes such as the oculodendrodigital dysplasia. This review systematically addresses current knowledge on mutations in connexin genes and disease, focusing on the correlation between genetic defects, cellular phenotypes and clinical manifestations. The review of diseases caused by mutations in connexin genes highlights the essential nature of connexin function and intercellular communication in tissue homeostasis. © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

  14. EGFR mutation frequency and effectiveness of erlotinib

    DEFF Research Database (Denmark)

    Weber, Britta; Hager, Henrik; Sorensen, Boe S;


    OBJECTIVES: In 2008, we initiated a prospective study to explore the frequency and predictive value of epidermal growth factor receptor (EGFR) mutations in an unselected population of Danish patients with non-small cell lung cancer offered treatment with erlotinib, mainly in second-line. MATERIALS...

  15. Seven functional classes of Barth syndrome mutation (United States)

    Whited, Kevin; Baile, Matthew G.; Currier, Pamela; Claypool, Steven M.


    Patients with Barth syndrome (BTHS), a rare X-linked disease, suffer from skeletal and cardiomyopathy and bouts of cyclic neutropenia. The causative gene encodes tafazzin, a transacylase, which is the major determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, CL. In addition to numerous frame shift and splice-site mutations, 36 missense mutations have been associated with BTHS. Previously, we established a BTHS-mutant panel in the yeast Saccharomyces cerevisiae that successfully models 18/21 conserved pathogenic missense mutations and defined the loss-of-function mechanism associated with a subset of the mutant tafazzins. Here, we report the biochemical and cell biological characterization of the rest of the yeast BTHS-mutant panel and in so doing identify three additional modes of tafazzin dysfunction. The largest group of mutant tafazzins is catalytically null, two mutants encode hypomorphic alleles, and another two mutants are temperature sensitive. Additionally, we have expanded the defects associated with previously characterized matrix-mislocalized-mutant tafazzins to include the rapid degradation of aggregation-prone polypeptides that correctly localize to the mitochondrial IMS. In sum, our in-depth characterization of the yeast BTHS-mutant panel has identified seven functional classes of BTHS mutation. PMID:23100323

  16. Mutational profiling of kinases in glioblastoma

    NARCIS (Netherlands)

    F.E. Bleeker (Fonnet); S. Lamba (Simona); C. Zanon (Carlo); R.J. Molenaar (Remco J.); T. Hulsebos (Theo); D. Troost (Dirk); A.A.G. van Tilborg (Angela); W.P. Vandertop (Peter); S. Leenstra (Sieger); C.J.F. van Noorden (Cornelis); A. Bardelli (Alberto)


    textabstractBackground: Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma.Methods: Database mining and a literature search identified 76 kinases that have been found to

  17. Targeted gene mutation in Phytophthora spp.

    NARCIS (Netherlands)

    Lamour, K.H.; Finley, L.; Hurtado-Gonzales, O.; Gobena, D.; Tierney, M.; Meijer, H.J.G.


    The genus Phytophthora belongs to the oomycetes and is composed of plant pathogens. Currently, there are no strategies to mutate specific genes for members of this genus. Whole genome sequences are available or being prepared for Phytophthora sojae, P. ramorum, P. infestans, and P. capsici and the d

  18. The mutational landscape of adenoid cystic carcinoma

    NARCIS (Netherlands)

    Ho, A.S.; Kannan, K.; Roy, D.M.; Morris, L.G.T.; Ganly, I.; Katabi, N.; Ramaswami, D.; Walsh, L.A.; Eng, S.; Huse, J.T.; Zhang, J.; Dolgalev, I.; Huberman, K.; Heguy, A.; Viale, A.; Drobnjak, M.; Leversha, M.A.; Rice, C.E.; Singh, B.; Iyer, N.G.; Leemans, C.R.; Bloemena, E.; Ferris, R.L.; Seethala, R.R.; Gross, B.E.; Liang, Y.; Sinha, R.; Peng, L.; Raphael, B.J.; Turcan, S.; Gong, Y.; Schultz, N.; Kim, S.; Chiosea, S.; Shah, J.P.; Sander, C.; Lee, W.; Chan, T.A.


    Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exo

  19. Mutational Analysis of Merkel Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Erstad, Derek J. [Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (United States); Cusack, James C. Jr., E-mail: [Division of Surgical Oncology, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (United States)


    Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge.

  20. De novo mutations in epileptic encephalopathies

    NARCIS (Netherlands)

    Allen, Andrew S.; Berkovic, Samuel F.; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E.; Epstein, Michael P.; Glauser, Tracy; Goldstein, David B.; Han, Yujun; Heinzen, Erin L.; Hitomi, Yuki; Howell, Katherine B.; Johnson, Michael R.; Kuzniecky, Ruben; Lowenstein, Daniel H.; Lu, Yi-Fan; Madou, Maura R. Z.; Marson, Anthony G.; Mefford, Heather C.; Nieh, Sahar Esmaeeli; O'Brien, Terence J.; Ottman, Ruth; Petrovski, Slave; Poduri, Annapurna; Ruzzo, Elizabeth K.; Scheffer, Ingrid E.; Sherr, Elliott H.; Yuskaitis, Christopher J.; Abou-Khalil, Bassel; Alldredge, Brian K.; Bautista, Jocelyn F.; Berkovic, Samuel F.; Boro, Alex; Cascino, Gregory D.; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael P.; Fiol, Miguel; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel; Geller, Eric B.; Glauser, Tracy; Glynn, Simon; Haut, Sheryl R.; Hayward, Jean; Helmers, Sandra L.; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E.; Knowlton, Robert C.; Kossoff, Erich; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H.; McGuire, Shannon M.; Motika, Paul V.; Novotny, Edward J.; Ottman, Ruth; Paolicchi, Juliann M.; Parent, Jack M.; Park, Kristen; Poduri, Annapurna; Scheffer, Ingrid E.; Shellhaas, Renee A.; Sherr, Elliott H.; Shih, Jerry J.; Singh, Rani; Sirven, Joseph; Smith, Michael C.; Sullivan, Joseph; Thio, Liu Lin; Venkat, Anu; Vining, Eileen P. G.; Von Allmen, Gretchen K.; Weisenberg, Judith L.; Widdess-Walsh, Peter; Winawer, Melodie R.


    Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown(1). Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115)

  1. Genetic mutations associated with status epilepticus. (United States)

    Bhatnagar, M; Shorvon, S


    This paper reports the results of a preliminary search of the literature aimed at identifying the genetic mutations reported to be strongly associated with status epilepticus. Genetic mutations were selected for inclusion if status epilepticus was specifically mentioned as a consequence of the mutation in standard genetic databases or in a case report or review article. Mutations in 122 genes were identified. The genetic mutations identified were found in only rare conditions (sometimes vanishingly rare) and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. There are no identified 'pure status epilepticus genes'. The range of genes underpinning status epilepticus differs in many ways from the range of genes underpinning epilepsy, which suggests that the processes underpinning status epilepticus differ from those underpinning epilepsy. It has been frequently postulated that status epilepticus is the result of a failure of 'seizure termination mechanisms', but the wide variety of genes affecting very diverse biochemical pathways identified in this survey makes any unitary cause unlikely. The genetic influences in status epilepticus are likely to involve a wide range of mechanisms, some related to development, some to cerebral energy production, some to diverse altered biochemical pathways, some to transmitter and membrane function, and some to defects in networks or systems. The fact that many of the identified genes are involved with cerebral development suggests that status epilepticus might often be a system or network phenomenon. To date, there are very few genes identified which are associated with adult-onset status epilepticus (except in those with preexisting neurological damage), and this is disappointing as the cause of many adult

  2. Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability.

    Directory of Open Access Journals (Sweden)

    Cristina Medina-Trillo

    Full Text Available Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3% were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG or hypomorphic (p.I126S alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability.

  3. Cubitene: an irregular twelve-membered-ring diterpene from a termite soldier. [1,5-dimethyl-8,10-bis(isopropenyl)cyclododeca-1,5-diene

    Energy Technology Data Exchange (ETDEWEB)

    Prestwich, G.D. (International Centre of Insect Physiology and Ecology, Nairobi, Kenya); Wiemer, D.F.; Meinwald, J.; Clardy, J.


    Cubitene was isolated from the hexane extract of C. umbratus soldier heads by chromatography over Florisil followed by preparative GLC. High resolution mass spectroscopy indicated the formula of cubitene to be C/sub 20/H/sub 32/. Mass spectra of catalytically hydrogenated cubitene products showed peaks at m/rho 279, consistent with their formulation as substituted cycloalkanes of the composition C/sub 20/H/sub 40/. Cubitene is therefore a monocyclic hydrocarbon with four centers of unsaturation. the /sup 1/H NMR spectral data revealed the presence of two 1,1-disubstituted double bonds, and two additional olefinic protons. Four methyl groups attached to double bonds are also observed. The /sup 13/C NMR spectrum indicated the presence of two tribsubstituted double bonds. Fortunately, cubitene could be obtained in crystalline form (mp 34.5-35/sup 0/C) from cold methanol, allowing a single-crystal x-ray diffraction analysis. It crystallized in the monoclinic crystal class. Lattice parameters were: a = 15.963 (5), b = 6.799 (2), c = 17.038 (5) A; theta = 96.99 (2)/sup 0/. Evidence shows cubitene to be 1,5-dimethyl-8,10-bis(isopropenyl)cyclododeca-1,5-diene, a structure in which one isoprene unit is irregularly joined to three others. It appears to be the first example of a diterpene hydrocarbon based on a twelve-membered carbocyclic ring. Its biosynthesis poses interesting problems. Two possible biosynthetic routes are suggested. An even more basic question remains....whether termite soldiers synthesize cubitene at all, or whether they simply sequester it (or a closely related precursor) from their food.

  4. Mitochondrial mutations in subjects with psychiatric disorders.

    Directory of Open Access Journals (Sweden)

    Adolfo Sequeira

    Full Text Available A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C. Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.

  5. Reverse mutation in fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Antinolo, G.; Borrego, S.; Cabeza, J.C. [Hospital Universitario, Sevilla (Spain)] [and others


    The fragile X syndrome is the most common cause of familial mental retardation, with an incidence of {approximately}1/1,500 in males and 1/2,500 in females. The clinical expression includes moderate to severe mental retardation, macroorchidism, dysmorphic facial features and behavior disturbances. In 1991, the FMR-1 gene was isolated from the region of the fragile X site. The fragile X phenotype has been found, in most cases, to be characterized at the molecular level by expansion of a (CGG){sub n} repeat and hypermethylation of a CpG island identified in the 5{prime}-UTR of the FMR-1 gene. It has been proposed, and some evidence has been shown, that germ cells carry only premutation alleles and that expansion occurs at a postzygotic stage. A few cases of reduction of the (CGG){sub n} repeat in fragile X syndrome have been reported. These reductions were from a larger premutation to a smaller premutation, in female-to-male transmission, from full mutation to a mosaic pattern, reduction from mosaic full-mutation/premutation females or regression from premutation to normal. We present here the novel observation of a phenotypically normal female carrying a nonmosaic full-mutation allele in somatic cells who transmits a premutation allele to her daughter. This daughter has three mosaic offspring with the full mutation and the premutation. Two of them are monozygotic (MZ) twins sharing a concordant mutation pattern. They are monoamniotic monochorionic, which indicates a late form of twinning. 20 refs., 1 fig.

  6. The Wilson disease gene: Haplotypes and mutations

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G.R.; Roberts, E.A.; Cox, D.W. [Hospital for Sick Children, Toronto (Canada); Walshe, J.M. [Middlesex Hospital, London (United Kingdom)


    Wilson disease (WND) is an autosomal recessive defect of copper transport. The gene involved in WND, located on chromosome 13, has recently been shown to be a putative copper transporting P-type ATPase, designated ATP7B. The gene is highly similar to ATP7A, located on the X chromosome, which is defective in Menkes disease, another disorder of copper transport. We have available for study WND families from Canada (34 families), the United Kingdom (32 families), Japan (4 families), Iceland (3 families) and Hong Kong (2 families). We have utilized four highly polymorphic CA repeat markers (D13S296, D13S301, D13S314 and D13S316) surrounding the ATP7B locus to construct haplotypes in these families. Analysis indicates that there are many unique WND haplotypes not present on normal chromosomes and that there may be a large number of different WND mutations. We have screened the WND patients for mutations in the ATP7B gene. Fifty six patients, representing all of the identified haplotypes, have been screened using single strand conformational polymorphism (SSCP), followed by selective sequencing. To date, 19 mutations and 12 polymorphisms have been identified. All of the changes are nucleotide substitutions or small insertions/deletions and there is no evidence for larger deletions as seen in the similar gene on the X chromosome, ATP7A. Haplotypes of close markers and the ability to detect some of the mutations present in the gene allow for more reliable molecular diagnosis of presymptomatic sibs of WND patients. A reassessment of individuals previously diagnosed in the presymptomatic phase is now required, as we have have identified some heterozygotes who are biochemically indistinguishable from affected homozygotes. The identification of specific mutations will soon allow direct diagnosis of WND patients with a high level of certainty.

  7. AChR deficiency due to epsilon-subunit mutations : two common mutations in the Netherlands

    NARCIS (Netherlands)

    Faber, Catharina G.; Molenaar, Peter C.; Vles, Johannes S. H.; Bonifati, Domenic M.; Verschuuren, Jan J. G. M.; van Doorn, Pieter A.; Kuks, Jan B. M.; Wokke, John H. J.; Beeson, David; De Baets, Marc


    Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) epsilon-subunit gene underlying congenital myasthenic syndromes in nine patients

  8. AChR deficiency due to ε-subunit mutations: Two common mutations in the Netherlands

    NARCIS (Netherlands)

    C.G. Faber (Carin); P.C. Molenaar (Peter); J.S.H. Vles (Johannes); D.M. Bonifati (Domenic); J.J. Verschuuren (Jan); P.A. van Doorn (Pieter); J.B.M. Kuks (Jan); J.H.J. Wokke (John); D. Beeson (David); M.H. de Baets (Marc)


    textabstractCongenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) ε-subunit gene underlying congenital myasthenic syndromes in nine

  9. AChR deficiency due to ε-subunit mutations: Two common mutations in the Netherlands

    NARCIS (Netherlands)

    C.G. Faber (Carin); P.C. Molenaar (Peter); J.S.H. Vles (Johannes); D.M. Bonifati (Domenic); J.J. Verschuuren (Jan); P.A. van Doorn (Pieter); J.B.M. Kuks (Jan); J.H.J. Wokke (John); D. Beeson (David); M.H. de Baets (Marc)


    textabstractCongenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) ε-subunit gene underlying congenital myasthenic syndromes in nine patie

  10. AChR deficiency due to epsilon-subunit mutations : two common mutations in the Netherlands

    NARCIS (Netherlands)

    Faber, Catharina G.; Molenaar, Peter C.; Vles, Johannes S. H.; Bonifati, Domenic M.; Verschuuren, Jan J. G. M.; van Doorn, Pieter A.; Kuks, Jan B. M.; Wokke, John H. J.; Beeson, David; De Baets, Marc


    Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) epsilon-subunit gene underlying congenital myasthenic syndromes in nine patients (s

  11. AChR deficiency due to epsilon-subunit mutations : two common mutations in the Netherlands

    NARCIS (Netherlands)

    Faber, Catharina G.; Molenaar, Peter C.; Vles, Johannes S. H.; Bonifati, Domenic M.; Verschuuren, Jan J. G. M.; van Doorn, Pieter A.; Kuks, Jan B. M.; Wokke, John H. J.; Beeson, David; De Baets, Marc


    Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) epsilon-subunit gene underlying congenital myasthenic syndromes in nine patients (s

  12. Association of TERT Promoter Mutation, But Not BRAF Mutation, With Increased Mortality in PTC. (United States)

    George, Jonathan R; Henderson, Ying C; Williams, Michelle D; Roberts, Dianna B; Hei, Hu; Lai, Stephen Y; Clayman, Gary L


    Papillary thyroid carcinoma (PTC) carrying the BRAF mutation has been reported to be associated with high recurrence and potentially increased mortality. PTC carrying the TERT promoter mutation has been associated with older age, recurrence, and aggressive disease. The objective of this study was to determine the association of BRAF and TERT promoter gene alterations with recurrence and survival in a high-risk population. Genomic DNA was analyzed for the BRAF mutation from 256 persistent/recurrent PTC (p/rPTC; 202 new, 54 previously reported) and for the TERT promoter mutation and polymorphism (242 p/rPTC). Two-tailed Fisher exact tests or the Pearson χ(2) test were performed for the associations between mutations and other variables. Overall and disease-free survivals were compared by log rank tests on Kaplan-Meier plots and by Cox regression analysis. TERT promoter constructs were tested in PTC cell lines to determine their activities in these cells. BRAF V600E mutation was identified in 235 of 256 (91.8%), TERT promoter mutation at -124 was detected in 77 of 242 (31.8%), and TERT promoter polymorphism at -245 was found in 113 of 242 (46.7%) p/rPTC patients. A significant difference in survival was found in p/rPTC patients with the TERT promoter mutation, which also displayed increased activity in vitro as compared to the nonmutated promoter sequence. No association was noted between the BRAF mutation or TERT promoter polymorphism and recurrence or survival. A drawback of our study could be the limited number of patients with nonmutated BRAF (21 of 256 [8.2%]). Mutation in the TERT promoter, but not in BRAF, was associated with decreased survival in 19 (24.7%) p/rPTC patients who died of disease and in 38 (49.4%) p/rPTC patients who died at last contact. The presence or absence of the BRAF mutation and TERT promoter polymorphism, however, was not significantly correlated with survival.

  13. Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development.

    Directory of Open Access Journals (Sweden)

    Takayuki Mito

    Full Text Available Mitochondrial DNA (mtDNA mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ(0 mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.

  14. An MRPS12 mutation modifies aminoglycoside sensitivity caused by 12S rRNA mutations

    Directory of Open Access Journals (Sweden)

    Sonia eEmperador


    Full Text Available Several homoplasmic pathologic mutations in mitochondrial DNA, such as those causing Leber hereditary optic neuropathy or non-syndromic hearing loss, show incomplete penetrance. Therefore, other elements must modify their pathogenicity. Discovery of these modifying factors is not an easy task because in multifactorial diseases conventional genetic approaches may not always be informative.Here, we have taken an evolutionary approach to unmask putative modifying factors for a particular homoplasmic pathologic mutation causing aminoglycoside-induced and non-syndromic hearing loss, the m.1494C>T transition in the mitochondrial DNA. The mutation is located in the decoding site of the mitochondrial ribosomal RNA. We first looked at mammalian species that had fixed the human pathologic mutation. These mutations are called compensated pathogenic deviations because an organism carrying one must also have another that suppresses the deleterious effect of the first. We found that species from the primate family Cercopithecidae (old world monkeys harbor the m.1494T allele even if their auditory function is normal.In humans the m.1494T allele increases the susceptibility to aminoglycosides. However, in primary fibroblasts from a Cercopithecidae species, aminoglycosides do not impair cell growth, respiratory complex IV activity and quantity or the mitochondrial protein synthesis. Interestingly, these species also carry a fixed mutation in the mitochondrial ribosomal protein S12. We show that the expression of this variant in a human m.1494T cell line reduces its susceptibility to aminoglycosides. Because several mutations in this human protein have been described, they may possibly explain the absence of pathologic phenotype in some pedigree members with the most frequent pathologic mutations in mitochondrial ribosomal RNA.

  15. Illness perceptions, risk perception and worry in SDH mutation carriers

    NARCIS (Netherlands)

    Hulsteijn, L.T. van; Kaptein, A.A.; Louisse, A.; Biermasz, N.R.; Smit, J.W.; Corssmit, E.P.


    Succinate dehydrogenase (SDH) mutation carriers are predisposed for developing paragangliomas. This study aimed to explore illness perceptions, risk perception and disease-related worry in these individuals. All consecutive SDHB and SDHD mutation carriers followed at the Department of Endocrinology

  16. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

    NARCIS (Netherlands)

    M. Remke (Marc); E.A. Ramaswamy; M. Peacock (Munro); D.J.H. Shih (David J.); C. Koelsche (Christian); P.A. Northcott (Paul A.); N. Hill (Nadia); S. Cavalli (Silvia); M. Kool (Marcel); X. Wang (Xin); S. Mack (Stephen); M. Barszczyk (Mark); A.S. Morrissy (A. Sorana); X. Wu (Xiaochong); S. Agnihotri (Sameer); P. Luu (Phan); D. Jones (David); L. Garzia (Livia); A.M. Dubuc (Adrian); N. Zhukova (Nataliya); R. Vanner (Robert); J.M. Kros (Johan); P.J. French (Pim); E.G. van Meir (Erwin); R. Vibhakar (Rajeev); K. Zitterbart (Karel); J.A. Chan (Jennifer); L. Bognár (László); A. Klekner (Almos); B. Lach (Boleslaw); S. Jung (Shin); F. Saad (Fred); L.M. Liau (Linda); S. Albrecht (Steffen); M. Zollo (Maurizio); M.K. Cooper (Michael); R.C. Thompson (Reid); O. Delattre (Olivier); F. Bourdeaut (Franck); F.F. Doz (François); M. Garami (Miklós); P. Hauser (Peter); C.G. Carlotti (Carlos); T.E. Van Meter (Timothy); L. Massimi (Luca); D. Fults (Daniel); L.W. Pomeroy (Laura); T. Kumabe (Toshiro); Y.S. Ra (Young Shin); J.R. Leonard (Jeffrey); S.K. Elbabaa (Samer); J. Mora (Jaume); J.B. Rubin (Joshua); Y.-J. Cho (Yoon-Jae); R.E. McLendon (Roger); D.D. Bigner (Darell); C.G. Eberhart (Charles); M. Fouladi (Maryam); R.J. Wechsler-Reya (Robert); R. Faria (Rui); S.E. Croul (Sidney); A. Huang (Anding); E. Bouffet (Eric); C.E. Hawkins (Cynthia); M. Dirks (Maaike); W.A. Weiss (William); U. Schüller (Ulrich); A. Pollack (Aaron); P. Rutkowski (Piotr); D. Meyronet (David); A. Jouvet (Anne); M. Fèvre-Montange (Michelle); N. Jabado (Nada); M. Perek-Polnik (Marta); W.A. Grajkowska (Wieslawa); S.-K. Kim (Seung-Ki); J.T. Rutka (James); E. Malkin (Elissa); U. Tabori (Uri); S.M. Pfister (Stefan); A. Korshunov (Andrey); A. von Deimling (Andreas); M.D. Taylor (Michael)


    textabstractTelomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought

  17. Ebola Virus Mutated to Become More Infectious, Scientists Say (United States)

    ... Ebola Virus Mutated to Become More Infectious, Scientists Say Virologists ... 3, 2016 (HealthDay News) -- Mutations in the Ebola virus boosted its ability to infect people during the ...

  18. Rare and unexpected beta thalassemic mutations in Qazvin ...

    African Journals Online (AJOL)



    Jan 4, 2010 ... Key words: Rare thalassemia mutations, beta globin gene, Qazvin, direct sequencing. INTRODUCTION ... Degree of incidence of various mutations in beta thalassemia major patients of ..... prevention and treatment. Leiden ...

  19. Modelling mutational landscapes of human cancers in vitro (United States)

    Olivier, Magali; Weninger, Annette; Ardin, Maude; Huskova, Hana; Castells, Xavier; Vallée, Maxime P.; McKay, James; Nedelko, Tatiana; Muehlbauer, Karl-Rudolf; Marusawa, Hiroyuki; Alexander, John; Hazelwood, Lee; Byrnes, Graham; Hollstein, Monica; Zavadil, Jiri


    Experimental models that recapitulate mutational landscapes of human cancers are needed to decipher the rapidly expanding data on human somatic mutations. We demonstrate that mutation patterns in immortalised cell lines derived from primary murine embryonic fibroblasts (MEFs) exposed in vitro to carcinogens recapitulate key features of mutational signatures observed in human cancers. In experiments with several cancer-causing agents we obtained high genome-wide concordance between human tumour mutation data and in vitro data with respect to predominant substitution types, strand bias and sequence context. Moreover, we found signature mutations in well-studied human cancer driver genes. To explore endogenous mutagenesis, we used MEFs ectopically expressing activation-induced cytidine deaminase (AID) and observed an excess of AID signature mutations in immortalised cell lines compared to their non-transgenic counterparts. MEF immortalisation is thus a simple and powerful strategy for modelling cancer mutation landscapes that facilitates the interpretation of human tumour genome-wide sequencing data.

  20. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma

    NARCIS (Netherlands)

    Burnichon, N.; Cascon, A.; Schiavi, F.; Morales, N.P.; Comino-Mendez, I.; Abermil, N.; Inglada-Perez, L.; Cubas, A.A. de; Amar, L.; Barontini, M.; Quiros, S.B. de; Bertherat, J.; Bignon, Y.J.; Blok, M.J.; Bobisse, S.; Borrego, S.; Castellano, M.; Chanson, P.; Chiara, M.D.; Corssmit, E.P.; Giacche, M.; Krijger, R.R. de; Ercolino, T.; Girerd, X.; Gomez-Garcia, E.B.; Gomez-Grana, A.; Guilhem, I.; Hes, F.J.; Honrado, E.; Korpershoek, E.; Lenders, J.W.; Leton, R.; Mensenkamp, A.R.; Merlo, A.; Mori, L.; Murat, A.; Pierre, P.; Plouin, P.F.; Prodanov, T.; Quesada-Charneco, M.; Qin, N.; Rapizzi, E.; Raymond, V.; Reisch, N.; Roncador, G.; Ruiz-Ferrer, M.; Schillo, F.; Stegmann, A.P.; Suarez, C.; Taschin, E.; Timmers, H.J.L.M.; Tops, C.M.; Urioste, M.; Beuschlein, F.; Pacak, K.; Mannelli, M.; Dahia, P.L.; Opocher, G.; Eisenhofer, G.; Gimenez-Roqueplo, A.P.; Robledo, M.


    PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations