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Sample records for novo designed 4-alpha-helix

  1. Monolayers of a De Novo Designed 4-Alpha-Helix Bundle Carboprotein and Partial Structures on Au(111)-Surfaces

    DEFF Research Database (Denmark)

    Brask, Jesper; Wackerbarth, Hainer; Jensen, Knud Jørgen

    2002-01-01

    on a galactopyranoside derivative with a thiol anchor aglycon suitable for surface immobilization on gold. The galactopyranoside with thiol anchor and the thiol anchor alone were prepared for comparison. Voltammetry of the three molecules on Au(111) showed reductive desorption peaks caused by monolayer adsorption via...... thiolate-Au bonding. In situ STM of the thiol anchor disclosed an ordered adlayer with clear domains and molecular features. This holds promise, broadly for single-molecule voltammetry and the SPM and scanning tunnelling microscopy (STM) of natural and synthetic proteins....

  2. Monolayer Assemblies of a De Novo Designed 4-alpha-Helix Bundle Carboprotein and Its Sulfur Anchor Fragment on Au(111) Surfaces Addressed by Voltammetry and In Situ Scanning Tunneling Microscopy

    DEFF Research Database (Denmark)

    Brask, Jesper; Wackerbarth, Hainer; Jensen, Knud J.

    2003-01-01

    carboprotein without thiol anchor have been prepared and investigated for comparison. Cyclic and differential pulse voltammetry (DPV) of the proteins show desorption peaks around -750 mV (SCE), whereas the thiol anchor desorption peak is at -685 mV. The peaks are by far the highest for thiol monomeric 4-R...

  3. de novo computational enzyme design.

    Science.gov (United States)

    Zanghellini, Alexandre

    2014-10-01

    Recent advances in systems and synthetic biology as well as metabolic engineering are poised to transform industrial biotechnology by allowing us to design cell factories for the sustainable production of valuable fuels and chemicals. To deliver on their promises, such cell factories, as much as their brick-and-mortar counterparts, will require appropriate catalysts, especially for classes of reactions that are not known to be catalyzed by enzymes in natural organisms. A recently developed methodology, de novo computational enzyme design can be used to create enzymes catalyzing novel reactions. Here we review the different classes of chemical reactions for which active protein catalysts have been designed as well as the results of detailed biochemical and structural characterization studies. We also discuss how combining de novo computational enzyme design with more traditional protein engineering techniques can alleviate the shortcomings of state-of-the-art computational design techniques and create novel enzymes with catalytic proficiencies on par with natural enzymes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. De Novo Construction of Redox Active Proteins.

    Science.gov (United States)

    Moser, C C; Sheehan, M M; Ennist, N M; Kodali, G; Bialas, C; Englander, M T; Discher, B M; Dutton, P L

    2016-01-01

    Relatively simple principles can be used to plan and construct de novo proteins that bind redox cofactors and participate in a range of electron-transfer reactions analogous to those seen in natural oxidoreductase proteins. These designed redox proteins are called maquettes. Hydrophobic/hydrophilic binary patterning of heptad repeats of amino acids linked together in a single-chain self-assemble into 4-alpha-helix bundles. These bundles form a robust and adaptable frame for uncovering the default properties of protein embedded cofactors independent of the complexities introduced by generations of natural selection and allow us to better understand what factors can be exploited by man or nature to manipulate the physical chemical properties of these cofactors. Anchoring of redox cofactors such as hemes, light active tetrapyrroles, FeS clusters, and flavins by His and Cys residues allow cofactors to be placed at positions in which electron-tunneling rates between cofactors within or between proteins can be predicted in advance. The modularity of heptad repeat designs facilitates the construction of electron-transfer chains and novel combinations of redox cofactors and new redox cofactor assisted functions. Developing de novo designs that can support cofactor incorporation upon expression in a cell is needed to support a synthetic biology advance that integrates with natural bioenergetic pathways. © 2016 Elsevier Inc. All rights reserved.

  5. Antimicrobial peptide capsids of de novo design.

    Science.gov (United States)

    De Santis, Emiliana; Alkassem, Hasan; Lamarre, Baptiste; Faruqui, Nilofar; Bella, Angelo; Noble, James E; Micale, Nicola; Ray, Santanu; Burns, Jonathan R; Yon, Alexander R; Hoogenboom, Bart W; Ryadnov, Maxim G

    2017-12-22

    The spread of bacterial resistance to antibiotics poses the need for antimicrobial discovery. With traditional search paradigms being exhausted, approaches that are altogether different from antibiotics may offer promising and creative solutions. Here, we introduce a de novo peptide topology that-by emulating the virus architecture-assembles into discrete antimicrobial capsids. Using the combination of high-resolution and real-time imaging, we demonstrate that these artificial capsids assemble as 20-nm hollow shells that attack bacterial membranes and upon landing on phospholipid bilayers instantaneously (seconds) convert into rapidly expanding pores causing membrane lysis (minutes). The designed capsids show broad antimicrobial activities, thus executing one primary function-they destroy bacteria on contact.

  6. Generative Recurrent Networks for De Novo Drug Design.

    Science.gov (United States)

    Gupta, Anvita; Müller, Alex T; Huisman, Berend J H; Fuchs, Jens A; Schneider, Petra; Schneider, Gisbert

    2018-01-01

    Generative artificial intelligence models present a fresh approach to chemogenomics and de novo drug design, as they provide researchers with the ability to narrow down their search of the chemical space and focus on regions of interest. We present a method for molecular de novo design that utilizes generative recurrent neural networks (RNN) containing long short-term memory (LSTM) cells. This computational model captured the syntax of molecular representation in terms of SMILES strings with close to perfect accuracy. The learned pattern probabilities can be used for de novo SMILES generation. This molecular design concept eliminates the need for virtual compound library enumeration. By employing transfer learning, we fine-tuned the RNN's predictions for specific molecular targets. This approach enables virtual compound design without requiring secondary or external activity prediction, which could introduce error or unwanted bias. The results obtained advocate this generative RNN-LSTM system for high-impact use cases, such as low-data drug discovery, fragment based molecular design, and hit-to-lead optimization for diverse drug targets. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  7. De-novo design of antimicrobial peptides for plant protection.

    Directory of Open Access Journals (Sweden)

    Benjamin Zeitler

    Full Text Available This work describes the de-novo design of peptides that inhibit a broad range of plant pathogens. Four structurally different groups of peptides were developed that differ in size and position of their charged and hydrophobic clusters and were assayed for their ability to inhibit bacterial growth and fungal spore germination. Several peptides are highly active at concentrations between 0,1 and 1 µg/ml against plant pathogenic bacteria, such as Pseudomonas syringae, Pectobacterium carotovorum, and Xanthomonas vesicatoria. Importantly, no hemolytic activity could be detected for these peptides at concentrations up to 200 µg/ml. Moreover, the peptides are also active after spraying on the plant surface demonstrating a possible way of application. In sum, our designed peptides represent new antimicrobial agents and with the increasing demand for antimicrobial compounds for production of "healthy" food, these peptides might serve as templates for novel antibacterial and antifungal agents.

  8. Massively parallel de novo protein design for targeted therapeutics

    KAUST Repository

    Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Ferná ndez-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

    2017-01-01

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

  9. Massively parallel de novo protein design for targeted therapeutics

    KAUST Repository

    Chevalier, Aaron

    2017-09-26

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

  10. Massively parallel de novo protein design for targeted therapeutics

    Science.gov (United States)

    Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Fernández-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

    2018-01-01

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. PMID:28953867

  11. Application of Generative Autoencoder in De Novo Molecular Design.

    Science.gov (United States)

    Blaschke, Thomas; Olivecrona, Marcus; Engkvist, Ola; Bajorath, Jürgen; Chen, Hongming

    2018-01-01

    A major challenge in computational chemistry is the generation of novel molecular structures with desirable pharmacological and physiochemical properties. In this work, we investigate the potential use of autoencoder, a deep learning methodology, for de novo molecular design. Various generative autoencoders were used to map molecule structures into a continuous latent space and vice versa and their performance as structure generator was assessed. Our results show that the latent space preserves chemical similarity principle and thus can be used for the generation of analogue structures. Furthermore, the latent space created by autoencoders were searched systematically to generate novel compounds with predicted activity against dopamine receptor type 2 and compounds similar to known active compounds not included in the trainings set were identified. © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  12. De Novo Design of Bioactive Small Molecules by Artificial Intelligence.

    Science.gov (United States)

    Merk, Daniel; Friedrich, Lukas; Grisoni, Francesca; Schneider, Gisbert

    2018-01-01

    Generative artificial intelligence offers a fresh view on molecular design. We present the first-time prospective application of a deep learning model for designing new druglike compounds with desired activities. For this purpose, we trained a recurrent neural network to capture the constitution of a large set of known bioactive compounds represented as SMILES strings. By transfer learning, this general model was fine-tuned on recognizing retinoid X and peroxisome proliferator-activated receptor agonists. We synthesized five top-ranking compounds designed by the generative model. Four of the compounds revealed nanomolar to low-micromolar receptor modulatory activity in cell-based assays. Apparently, the computational model intrinsically captured relevant chemical and biological knowledge without the need for explicit rules. The results of this study advocate generative artificial intelligence for prospective de novo molecular design, and demonstrate the potential of these methods for future medicinal chemistry. © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  13. A Pareto Algorithm for Efficient De Novo Design of Multi-functional Molecules.

    Science.gov (United States)

    Daeyaert, Frits; Deem, Micheal W

    2017-01-01

    We have introduced a Pareto sorting algorithm into Synopsis, a de novo design program that generates synthesizable molecules with desirable properties. We give a detailed description of the algorithm and illustrate its working in 2 different de novo design settings: the design of putative dual and selective FGFR and VEGFR inhibitors, and the successful design of organic structure determining agents (OSDAs) for the synthesis of zeolites. We show that the introduction of Pareto sorting not only enables the simultaneous optimization of multiple properties but also greatly improves the performance of the algorithm to generate molecules with hard-to-meet constraints. This in turn allows us to suggest approaches to address the problem of false positive hits in de novo structure based drug design by introducing structural and physicochemical constraints in the designed molecules, and by forcing essential interactions between these molecules and their target receptor. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Programming peptidomimetic syntheses by translating genetic codes designed de novo.

    Science.gov (United States)

    Forster, Anthony C; Tan, Zhongping; Nalam, Madhavi N L; Lin, Hening; Qu, Hui; Cornish, Virginia W; Blacklow, Stephen C

    2003-05-27

    Although the universal genetic code exhibits only minor variations in nature, Francis Crick proposed in 1955 that "the adaptor hypothesis allows one to construct, in theory, codes of bewildering variety." The existing code has been expanded to enable incorporation of a variety of unnatural amino acids at one or two nonadjacent sites within a protein by using nonsense or frameshift suppressor aminoacyl-tRNAs (aa-tRNAs) as adaptors. However, the suppressor strategy is inherently limited by compatibility with only a small subset of codons, by the ways such codons can be combined, and by variation in the efficiency of incorporation. Here, by preventing competing reactions with aa-tRNA synthetases, aa-tRNAs, and release factors during translation and by using nonsuppressor aa-tRNA substrates, we realize a potentially generalizable approach for template-encoded polymer synthesis that unmasks the substantially broader versatility of the core translation apparatus as a catalyst. We show that several adjacent, arbitrarily chosen sense codons can be completely reassigned to various unnatural amino acids according to de novo genetic codes by translating mRNAs into specific peptide analog polymers (peptidomimetics). Unnatural aa-tRNA substrates do not uniformly function as well as natural substrates, revealing important recognition elements for the translation apparatus. Genetic programming of peptidomimetic synthesis should facilitate mechanistic studies of translation and may ultimately enable the directed evolution of small molecules with desirable catalytic or pharmacological properties.

  15. Metal stabilization of collagen and de novo designed mimetic peptides

    OpenAIRE

    Parmar, Avanish S.; Xu, Fei; Pike, Douglas H.; Belure, Sandeep V.; Hasan, Nida F.; Drzewiecki, Kathryn E.; Shreiber, David I.; Nanda, Vikas

    2015-01-01

    We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacen...

  16. Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides.

    Science.gov (United States)

    Parmar, Avanish S; Xu, Fei; Pike, Douglas H; Belure, Sandeep V; Hasan, Nida F; Drzewiecki, Kathryn E; Shreiber, David I; Nanda, Vikas

    2015-08-18

    We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo- and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal-specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix.

  17. Adopting De Novo Programming Approach on IC Design Service Firms Resources Integration

    Directory of Open Access Journals (Sweden)

    James K. C. Chen

    2014-01-01

    Full Text Available The semiconductor industry has very important position in computer industry, ICT field, and new electronic technology developing. The IC design service is one of key factor of semiconductor industry development. There are more than 365 IC design service firms have been established around Hsinchu Science Park in Taiwan. Building an efficient planning model for IC design service firm resources integrating is very interest issue. This study aims to construct a planning model for IC design service firm implementation resources integration. This study uses the De Novo programming as an approach of criteria alternative to achieve optimal resource allocation on IC design firm. Results show the IC design service firm should conduct open innovation concept and utilizes design outsourcing obtains cost down and enhance IC design service business performance. This plan model of De Novo programming is not only for IC design service firm and also can apply to the other industrial implementation strategic alliance/integrating resource. This plan model is a universal model for the others industries field.

  18. A de novo designed monomeric, compact three helix bundle protein on a carbohydrate template

    DEFF Research Database (Denmark)

    Malik, Leila; Nygård, Jesper; Christensen, Niels Johan

    2015-01-01

    De novo design and chemical synthesis of proteins and of other artificial structures, which mimic them, is a central strategy for understanding protein folding and for accessing proteins with novel functions. We have previously described carbohydrates as templates for the assembly of artificial...... the template could facilitate protein folding. Here we report the design and synthesis of 3-helix bundle carboproteins on deoxy-hexopyranosides. The carboproteins were analyzed by CD, AUC, SAXS, and NMR, which revealed the formation of the first compact, and folded monomeric carboprotein distinctly different...

  19. Concept of combinatorial de novo design of drug-like molecules by particle swarm optimization.

    Science.gov (United States)

    Hartenfeller, Markus; Proschak, Ewgenij; Schüller, Andreas; Schneider, Gisbert

    2008-07-01

    We present a fast stochastic optimization algorithm for fragment-based molecular de novo design (COLIBREE, Combinatorial Library Breeding). The search strategy is based on a discrete version of particle swarm optimization. Molecules are represented by a scaffold, which remains constant during optimization, and variable linkers and side chains. Different linkers represent virtual chemical reactions. Side-chain building blocks were obtained from pseudo-retrosynthetic dissection of large compound databases. Here, ligand-based design was performed using chemically advanced template search (CATS) topological pharmacophore similarity to reference ligands as fitness function. A weighting scheme was included for particle swarm optimization-based molecular design, which permits the use of many reference ligands and allows for positive and negative design to be performed simultaneously. In a case study, the approach was applied to the de novo design of potential peroxisome proliferator-activated receptor subtype-selective agonists. The results demonstrate the ability of the technique to cope with large combinatorial chemistry spaces and its applicability to focused library design. The technique was able to perform exploitation of a known scheme and at the same time explorative search for novel ligands within the framework of a given molecular core structure. It thereby represents a practical solution for compound screening in the early hit and lead finding phase of a drug discovery project.

  20. The Folding of de Novo Designed Protein DS119 via Molecular Dynamics Simulations

    Directory of Open Access Journals (Sweden)

    Moye Wang

    2016-04-01

    Full Text Available As they are not subjected to natural selection process, de novo designed proteins usually fold in a manner different from natural proteins. Recently, a de novo designed mini-protein DS119, with a βαβ motif and 36 amino acids, has folded unusually slowly in experiments, and transient dimers have been detected in the folding process. Here, by means of all-atom replica exchange molecular dynamics (REMD simulations, several comparably stable intermediate states were observed on the folding free-energy landscape of DS119. Conventional molecular dynamics (CMD simulations showed that when two unfolded DS119 proteins bound together, most binding sites of dimeric aggregates were located at the N-terminal segment, especially residues 5–10, which were supposed to form β-sheet with its own C-terminal segment. Furthermore, a large percentage of individual proteins in the dimeric aggregates adopted conformations similar to those in the intermediate states observed in REMD simulations. These results indicate that, during the folding process, DS119 can easily become trapped in intermediate states. Then, with diffusion, a transient dimer would be formed and stabilized with the binding interface located at N-terminals. This means that it could not quickly fold to the native structure. The complicated folding manner of DS119 implies the important influence of natural selection on protein-folding kinetics, and more improvement should be achieved in rational protein design.

  1. Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets.

    Science.gov (United States)

    Allen, William J; Fochtman, Brian C; Balius, Trent E; Rizzo, Robert C

    2017-11-15

    De novo design can be used to explore vast areas of chemical space in computational lead discovery. As a complement to virtual screening, from-scratch construction of molecules is not limited to compounds in pre-existing vendor catalogs. Here, we present an iterative fragment growth method, integrated into the program DOCK, in which new molecules are built using rules for allowable connections based on known molecules. The method leverages DOCK's advanced scoring and pruning approaches and users can define very specific criteria in terms of properties or features to customize growth toward a particular region of chemical space. The code was validated using three increasingly difficult classes of calculations: (1) Rebuilding known X-ray ligands taken from 663 complexes using only their component parts (focused libraries), (2) construction of new ligands in 57 drug target sites using a library derived from ∼13M drug-like compounds (generic libraries), and (3) application to a challenging protein-protein interface on the viral drug target HIVgp41. The computational testing confirms that the de novo DOCK routines are robust and working as envisioned, and the compelling results highlight the potential utility for designing new molecules against a wide variety of important protein targets. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  2. De novo peptide design and experimental validation of histone methyltransferase inhibitors.

    Directory of Open Access Journals (Sweden)

    James Smadbeck

    Full Text Available Histones are small proteins critical to the efficient packaging of DNA in the nucleus. DNA–protein complexes, known as nucleosomes, are formed when the DNA winds itself around the surface of the histones. The methylation of histone residues by enhancer of zeste homolog 2 (EZH2 maintains gene repression over successive cell generations. Overexpression of EZH2 can silence important tumor suppressor genes leading to increased invasiveness of many types of cancers. This makes the inhibition of EZH2 an important target in the development of cancer therapeutics. We employed a three-stage computational de novo peptide design method to design inhibitory peptides of EZH2. The method consists of a sequence selection stage and two validation stages for fold specificity and approximate binding affinity. The sequence selection stage consists of an integer linear optimization model that was solved to produce a rank-ordered list of amino acid sequences with increased stability in the bound peptide-EZH2 structure. These sequences were validated through the calculation of the fold specificity and approximate binding affinity of the designed peptides. Here we report the discovery of novel EZH2 inhibitory peptides using the de novo peptide design method. The computationally discovered peptides were experimentally validated in vitro using dose titrations and mechanism of action enzymatic assays. The peptide with the highest in vitro response, SQ037, was validated in nucleo using quantitative mass spectrometry-based proteomics. This peptide had an IC50 of 13.5 mM, demonstrated greater potency as an inhibitor when compared to the native and K27A mutant control peptides, and demonstrated competitive inhibition versus the peptide substrate. Additionally, this peptide demonstrated high specificity to the EZH2 target in comparison to other histone methyltransferases. The validated peptides are the first computationally designed peptides that directly inhibit EZH2

  3. De novo peptide design and experimental validation of histone methyltransferase inhibitors.

    Directory of Open Access Journals (Sweden)

    James Smadbeck

    Full Text Available Histones are small proteins critical to the efficient packaging of DNA in the nucleus. DNA-protein complexes, known as nucleosomes, are formed when the DNA winds itself around the surface of the histones. The methylation of histone residues by enhancer of zeste homolog 2 (EZH2 maintains gene repression over successive cell generations. Overexpression of EZH2 can silence important tumor suppressor genes leading to increased invasiveness of many types of cancers. This makes the inhibition of EZH2 an important target in the development of cancer therapeutics. We employed a three-stage computational de novo peptide design method to design inhibitory peptides of EZH2. The method consists of a sequence selection stage and two validation stages for fold specificity and approximate binding affinity. The sequence selection stage consists of an integer linear optimization model that was solved to produce a rank-ordered list of amino acid sequences with increased stability in the bound peptide-EZH2 structure. These sequences were validated through the calculation of the fold specificity and approximate binding affinity of the designed peptides. Here we report the discovery of novel EZH2 inhibitory peptides using the de novo peptide design method. The computationally discovered peptides were experimentally validated in vitro using dose titrations and mechanism of action enzymatic assays. The peptide with the highest in vitro response, SQ037, was validated in nucleo using quantitative mass spectrometry-based proteomics. This peptide had an IC50 of 13.5 [Formula: see text]M, demonstrated greater potency as an inhibitor when compared to the native and K27A mutant control peptides, and demonstrated competitive inhibition versus the peptide substrate. Additionally, this peptide demonstrated high specificity to the EZH2 target in comparison to other histone methyltransferases. The validated peptides are the first computationally designed peptides that directly

  4. Functional tuning of the catalytic residue pKa in a de novo designed esterase.

    Science.gov (United States)

    Hiebler, Katharina; Lengyel, Zsófia; Castañeda, Carlos A; Makhlynets, Olga V

    2017-09-01

    AlleyCatE is a de novo designed esterase that can be allosterically regulated by calcium ions. This artificial enzyme has been shown to hydrolyze p-nitrophenyl acetate (pNPA) and 4-nitrophenyl-(2-phenyl)-propanoate (pNPP) with high catalytic efficiency. AlleyCatE was created by introducing a single-histidine residue (His 144 ) into a hydrophobic pocket of calmodulin. In this work, we explore the determinants of catalytic properties of AlleyCatE. We obtained the pK a value of the catalytic histidine using experimental measurements by NMR and pH rate profile and compared these values to those predicted from electrostatics pK a calculations (from both empirical and continuum electrostatics calculations). Surprisingly, the pK a value of the catalytic histidine inside the hydrophobic pocket of calmodulin is elevated as compared to the model compound pK a value of this residue in water. We determined that a short-range favorable interaction with Glu 127 contributes to the elevated pK a of His 144 . We have rationally modulated local electrostatic potential in AlleyCatE to decrease the pK a of its active nucleophile, His 144 , by 0.7 units. As a direct result of the decrease in the His 144 pK a value, catalytic efficiency of the enzyme increased by 45% at pH 6. This work shows that a series of simple NMR experiments that can be performed using low field spectrometers, combined with straightforward computational analysis, provide rapid and accurate guidance to rationally improve catalytic efficiency of histidine-promoted catalysis. Proteins 2017; 85:1656-1665. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  5. Anti-plasmodial action of de novo-designed, cationic, lysine-branched, amphipathic, helical peptides

    Directory of Open Access Journals (Sweden)

    Kaushik Naveen K

    2012-08-01

    Full Text Available Abstract Background A lack of vaccine and rampant drug resistance demands new anti-malarials. Methods In vitro blood stage anti-plasmodial properties of several de novo-designed, chemically synthesized, cationic, amphipathic, helical, antibiotic peptides were examined against Plasmodium falciparum using SYBR Green assay. Mechanistic details of anti-plasmodial action were examined by optical/fluorescence microscopy and FACS analysis. Results Unlike the monomeric decapeptides {(Ac-GXRKXHKXWA-NH2 (X = F,ΔF (Fm, ΔFm IC50 >100 μM}, the lysine-branched,dimeric versions showed far greater potency {IC50 (μM Fd 1.5 , ΔFd 1.39}. The more helical and proteolytically stable ΔFd was studied for mechanistic details. ΔFq, a K-K2 dendrimer of ΔFm and (ΔFm2 a linear dimer of ΔFm showed IC50 (μM of 0.25 and 2.4 respectively. The healthy/infected red cell selectivity indices were >35 (ΔFd, >20 (ΔFm2 and 10 (ΔFq. FITC-ΔFd showed rapid and selective accumulation in parasitized red cells. Overlaying DAPI and FITC florescence suggested that ΔFd binds DNA. Trophozoites and schizonts incubated with ΔFd (2.5 μM egressed anomalously and Band-3 immunostaining revealed them not to be associated with RBC membrane. Prematurely egressed merozoites from peptide-treated cultures were found to be invasion incompetent. Conclusion Good selectivity (>35, good resistance index (1.1 and low cytotoxicity indicate the promise of ΔFd against malaria.

  6. De novo design of an RNA tile that self-assembles into a homo-octameric nanoprism

    Science.gov (United States)

    Yu, Jinwen; Liu, Zhiyu; Jiang, Wen; Wang, Guansong; Mao, Chengde

    2015-01-01

    Rational, de novo design of RNA nanostructures can potentially integrate a wide array of structural and functional diversities. Such nanostructures have great promises in biomedical applications. Despite impressive progress in this field, all RNA building blocks (or tiles) reported so far are not geometrically well defined. They are generally flexible and can only assemble into a mixture of complexes with different sizes. To achieve defined structures, multiple tiles with different sequences are needed. In this study, we design an RNA tile that can homo-oligomerize into a uniform RNA nanostructure. The designed RNA nanostructure is characterized by gel electrophoresis, atomic force microscopy and cryogenic electron microscopy imaging. We believe that development along this line would help RNA nanotechnology to reach the structural control that is currently associated with DNA nanotechnology.

  7. NOVO DESIGN PARA A REDE FEDERAL DE EDUCAÇÃO TECNOLÓGICA

    Directory of Open Access Journals (Sweden)

    Francisco das Chagas Mariz Fernandes

    2009-03-01

    Full Text Available RESUMO A partir do ano de 2003, o Governo Lula iniciou ações voltadas à democratização da oferta da educação técnica no país, através de um plano estruturante de expansão da Rede Federal de Educação Profissional e Tecnológica. A primeira fase do plano compreendeu a construção de 64 novas Unidades de Ensino para somar às 140 que já existiam. Ao mesmo tempo, o Ministério da Educação logo deu início à segunda fase do projeto, para a implantação de mais 150 novas Escolas, devendo totalizar, até 2010, a meta de 354 instituições. Nesse contexto, surge a proposta de constituição de 38 Institutos Federais de Educação, Ciência e Tecnologia para integrar, a partir do exercício de 2009, essas Unidades de Ensino, bem como constituir a Rede Federal de Educação Profissional, Científica e Tecnológica. Cada Instituto Federal é estruturado com uma Reitoria e vários Campi, com gestão interdependente entre ambos. Territorialmente, à Reitoria competirá a função estratégica de definição de políticas, supervisão e controle. Para tanto, necessita de uma estrutura administrativa que congregue, além do gabinete, pró-reitorias e diretorias de atuação sistêmica, cabendo a esses órgãos a função de trabalhar matricialmente vinculados às unidades afins dos Campi. Cada Campus, por sua vez, responsável pela execução dos objetivos finalísticos institucionais, necessita de uma estruturação híbrida, através da associação da departamentalização funcional e a matricial – para viabilizar o diálogo e interação dos departamentos da área acadêmica com as unidades operacionais dos demais departamentos das áreas de administração, de apoio ao ensino, de extensão e de pesquisa. Na realidade, o arranjo situacional dos Institutos Federais é novo e caracteriza-se como próprio de uma estrutura em rede, para integrar sistemicamente diversas organizações de ensino através de um núcleo central – no

  8. Protein design and engineering of a de novo pathway for microbial production of 1,3-propanediol from glucose.

    Science.gov (United States)

    Chen, Zhen; Geng, Feng; Zeng, An-Ping

    2015-02-01

    Protein engineering to expand the substrate spectrum of native enzymes opens new possibilities for bioproduction of valuable chemicals from non-natural pathways. No natural microorganism can directly use sugars to produce 1,3-propanediol (PDO). Here, we present a de novo route for the biosynthesis of PDO from sugar, which may overcome the mentioned limitations by expanding the homoserine synthesis pathway. The accomplishment of pathway from homoserine to PDO is achieved by protein engineering of glutamate dehydrogenase (GDH) and pyruvate decarboxylase to sequentially convert homoserine to 4-hydroxy-2-ketobutyrate and 3-hydroxypropionaldehyde. The latter is finally converted to PDO by using a native alcohol dehydrogenase. In this work, we report on experimental accomplishment of this non-natural pathway, especially by protein engineering of GDH for the key step of converting homoserine to 4-hydroxy-2-ketobutyrate. These results show the feasibility and significance of protein engineering for de novo pathway design and overproduction of desired industrial products. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Apoprotein Structure and Metal Binding Characterization of a de Novo Designed Peptide, α3DIV, that Sequesters Toxic Heavy Metals.

    Science.gov (United States)

    Plegaria, Jefferson S; Dzul, Stephen P; Zuiderweg, Erik R P; Stemmler, Timothy L; Pecoraro, Vincent L

    2015-05-12

    De novo protein design is a biologically relevant approach that provides a novel process in elucidating protein folding and modeling the metal centers of metalloproteins in a completely unrelated or simplified fold. An integral step in de novo protein design is the establishment of a well-folded scaffold with one conformation, which is a fundamental characteristic of many native proteins. Here, we report the NMR solution structure of apo α3DIV at pH 7.0, a de novo designed three-helix bundle peptide containing a triscysteine motif (Cys18, Cys28, and Cys67) that binds toxic heavy metals. The structure comprises 1067 NOE restraints derived from multinuclear multidimensional NOESY, as well as 138 dihedral angles (ψ, φ, and χ1). The backbone and heavy atoms of the 20 lowest energy structures have a root mean square deviation from the mean structure of 0.79 (0.16) Å and 1.31 (0.15) Å, respectively. When compared to the parent structure α3D, the substitution of Leu residues to Cys enhanced the α-helical content of α3DIV while maintaining the same overall topology and fold. In addition, solution studies on the metalated species illustrated metal-induced stability. An increase in the melting temperatures was observed for Hg(II), Pb(II), or Cd(II) bound α3DIV by 18-24 °C compared to its apo counterpart. Further, the extended X-ray absorption fine structure analysis on Hg(II)-α3DIV produced an average Hg(II)-S bond length at 2.36 Å, indicating a trigonal T-shaped coordination environment. Overall, the structure of apo α3DIV reveals an asymmetric distorted triscysteine metal binding site, which offers a model for native metalloregulatory proteins with thiol-rich ligands that function in regulating toxic heavy metals, such as ArsR, CadC, MerR, and PbrR.

  10. A de novo designed 11 kDa polypeptide: model for amyloidogenic intrinsically disordered proteins.

    Science.gov (United States)

    Topilina, Natalya I; Ermolenkov, Vladimir V; Sikirzhytski, Vitali; Higashiya, Seiichiro; Lednev, Igor K; Welch, John T

    2010-07-01

    A de novo polypeptide GH(6)[(GA)(3)GY(GA)(3)GE](8)GAH(6) (YE8) has a significant number of identical weakly interacting beta-strands with the turns and termini functionalized by charged amino acids to control polypeptide folding and aggregation. YE8 exists in a soluble, disordered form at neutral pH but is responsive to changes in pH and ionic strength. The evolution of YE8 secondary structure has been successfully quantified during all stages of polypeptide fibrillation by deep UV resonance Raman (DUVRR) spectroscopy combined with other morphological, structural, spectral, and tinctorial characterization. The YE8 folding kinetics at pH 3.5 are strongly dependent on polypeptide concentration with a lag phase that can be eliminated by seeding with a solution of folded fibrillar YE8. The lag phase of polypeptide folding is concentration dependent leading to the conclusion that beta-sheet folding of the 11-kDa amyloidogenic polypeptide is completely aggregation driven.

  11. Voltammetry and In Situ Scanning Tunnelling Microscopy of De Novo Designed Heme Protein Monolayers on Au(111)-Electrode Surfaces

    DEFF Research Database (Denmark)

    Albrecht, Tim; Li, Wu; Haehnel, Wolfgang

    2006-01-01

    to the tunnelling current, apparently due to slow electron transfer kinetics. As a consequence, STM images of heme-containing and heme-free MOP-C did not reveal any notable differences in apparent height or physical extension. The apparent height of heme-containing MOP-C did not show any dependence on the substrate...... potential being varied around the redox potential of the protein. The mere presence of an accessible molecular energy level is not sufficient to result in detectable tunnelling current modulation. (c) 2006 Elsevier B.V. All rights reserved.......In the present work, we report the electrochemical characterization and in situ scanning tunnelling microscopy (STM) studies of monolayers of an artificial de novo designed heme protein MOP-C, covalently immobilized on modified Au(111) surfaces. The protein forms closely packed monolayers, which...

  12. OptMAVEn--a new framework for the de novo design of antibody variable region models targeting specific antigen epitopes.

    Directory of Open Access Journals (Sweden)

    Tong Li

    Full Text Available Antibody-based therapeutics provides novel and efficacious treatments for a number of diseases. Traditional experimental approaches for designing therapeutic antibodies rely on raising antibodies against a target antigen in an immunized animal or directed evolution of antibodies with low affinity for the desired antigen. However, these methods remain time consuming, cannot target a specific epitope and do not lead to broad design principles informing other studies. Computational design methods can overcome some of these limitations by using biophysics models to rationally select antibody parts that maximize affinity for a target antigen epitope. This has been addressed to some extend by OptCDR for the design of complementary determining regions. Here, we extend this earlier contribution by addressing the de novo design of a model of the entire antibody variable region against a given antigen epitope while safeguarding for immunogenicity (Optimal Method for Antibody Variable region Engineering, OptMAVEn. OptMAVEn simulates in silico the in vivo steps of antibody generation and evolution, and is capable of capturing the critical structural features responsible for affinity maturation of antibodies. In addition, a humanization procedure was developed and incorporated into OptMAVEn to minimize the potential immunogenicity of the designed antibody models. As case studies, OptMAVEn was applied to design models of neutralizing antibodies targeting influenza hemagglutinin and HIV gp120. For both HA and gp120, novel computational antibody models with numerous interactions with their target epitopes were generated. The observed rates of mutations and types of amino acid changes during in silico affinity maturation are consistent with what has been observed during in vivo affinity maturation. The results demonstrate that OptMAVEn can efficiently generate diverse computational antibody models with both optimized binding affinity to antigens and reduced

  13. PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores.

    Science.gov (United States)

    Waszkowycz, B; Clark, D E; Frenkel, D; Li, J; Murray, C W; Robson, B; Westhead, D R

    1994-11-11

    A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.

  14. Transferable coarse-grained potential for de novo protein folding and design.

    Directory of Open Access Journals (Sweden)

    Ivan Coluzza

    Full Text Available Protein folding and design are major biophysical problems, the solution of which would lead to important applications especially in medicine. Here we provide evidence of how a novel parametrization of the Caterpillar model may be used for both quantitative protein design and folding. With computer simulations it is shown that, for a large set of real protein structures, the model produces designed sequences with similar physical properties to the corresponding natural occurring sequences. The designed sequences require further experimental testing. For an independent set of proteins, previously used as benchmark, the correct folded structure of both the designed and the natural sequences is also demonstrated. The equilibrium folding properties are characterized by free energy calculations. The resulting free energy profiles not only are consistent among natural and designed proteins, but also show a remarkable precision when the folded structures are compared to the experimentally determined ones. Ultimately, the updated Caterpillar model is unique in the combination of its fundamental three features: its simplicity, its ability to produce natural foldable designed sequences, and its structure prediction precision. It is also remarkable that low frustration sequences can be obtained with such a simple and universal design procedure, and that the folding of natural proteins shows funnelled free energy landscapes without the need of any potentials based on the native structure.

  15. De novo design, synthesis and characterisation of MP3, a new catalytic four-helix bundle hemeprotein.

    Science.gov (United States)

    Faiella, Marina; Maglio, Ornella; Nastri, Flavia; Lombardi, Angela; Lista, Liliana; Hagen, Wilfred R; Pavone, Vincenzo

    2012-12-07

    A new artificial metalloenzyme, MP3 (MiniPeroxidase 3), designed by combining the excellent structural properties of four-helix bundle protein scaffolds with the activity of natural peroxidases, was synthesised and characterised. This new hemeprotein model was developed by covalently linking the deuteroporphyrin to two peptide chains of different compositions to obtain an asymmetric helix-loop-helix/heme/helix-loop-helix sandwich arrangement, characterised by 1) a His residue on one chain that acts as an axial ligand to the iron ion; 2) a vacant distal site that is able to accommodate exogenous ligands or substrates; and 3) an Arg residue in the distal site that should assist in hydrogen peroxide activation to give an HRP-like catalytic process. MP3 was synthesised and characterised as its iron complex. CD measurements revealed the high helix-forming propensity of the peptide, confirming the appropriateness of the model procedure; UV/Vis, MCD and EPR experiments gave insights into the coordination geometry and the spin state of the metal. Kinetic experiments showed that Fe(III)-MP3 possesses peroxidase-like activity comparable to R38A-hHRP, highlighting the possibility of mimicking the functional features of natural enzymes. The synergistic application of de novo design methods, synthetic procedures, and spectroscopic characterisation, described herein, demonstrates a method by which to implement and optimise catalytic activity for an enzyme mimetic. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Electrochemical and spectroscopic investigations of immobilized de novo designed heme proteins on metal electrodes

    DEFF Research Database (Denmark)

    Albrecht, Tim; Li, WW; Ulstrup, Jens

    2005-01-01

    On the basis of rational design principles, template-assisted four-helix-bundle proteins that include two histidines for coordinative binding of a heme were synthesized. Spectroscopic and thermodynamic characterization of the proteins in solution reveals the expected bis-histidine coordinated heme...

  17. Shape-specific nanostructured protein mimics from de novo designed chimeric peptides.

    Science.gov (United States)

    Jiang, Linhai; Yang, Su; Lund, Reidar; Dong, He

    2018-01-30

    Natural proteins self-assemble into highly-ordered nanoscaled architectures to perform specific functions. The intricate functions of proteins have provided great impetus for researchers to develop strategies for designing and engineering synthetic nanostructures as protein mimics. Compared to the success in engineering fibrous protein mimetics, the design of discrete globular protein-like nanostructures has been challenging mainly due to the lack of precise control over geometric packing and intermolecular interactions among synthetic building blocks. In this contribution, we report an effective strategy to construct shape-specific nanostructures based on the self-assembly of chimeric peptides consisting of a coiled coil dimer and a collagen triple helix folding motif. Under salt-free conditions, we showed spontaneous self-assembly of the chimeric peptides into monodisperse, trigonal bipyramidal-like nanoparticles with precise control over the stoichiometry of two folding motifs and the geometrical arrangements relative to one another. Three coiled coil dimers are interdigitated on the equatorial plane while the two collagen triple helices are located in the axial position, perpendicular to the coiled coil plane. A detailed molecular model was proposed and further validated by small angle X-ray scattering experiments and molecular dynamics (MD) simulation. The results from this study indicated that the molecular folding of each motif within the chimeric peptides and their geometric packing played important roles in the formation of discrete protein-like nanoparticles. The peptide design and self-assembly mechanism may open up new routes for the construction of highly organized, discrete self-assembling protein-like nanostructures with greater levels of control over assembly accuracy.

  18. De novo design and engineering of functional metal and porphyrin-binding protein domains

    Science.gov (United States)

    Everson, Bernard H.

    In this work, I describe an approach to the rational, iterative design and characterization of two functional cofactor-binding protein domains. First, a hybrid computational/experimental method was developed with the aim of algorithmically generating a suite of porphyrin-binding protein sequences with minimal mutual sequence information. This method was explored by generating libraries of sequences, which were then expressed and evaluated for function. One successful sequence is shown to bind a variety of porphyrin-like cofactors, and exhibits light- activated electron transfer in mixed hemin:chlorin e6 and hemin:Zn(II)-protoporphyrin IX complexes. These results imply that many sophisticated functions such as cofactor binding and electron transfer require only a very small number of residue positions in a protein sequence to be fixed. Net charge and hydrophobic content are important in determining protein solubility and stability. Accordingly, rational modifications were made to the aforementioned design procedure in order to improve its overall success rate. The effects of these modifications are explored using two `next-generation' sequence libraries, which were separately expressed and evaluated. Particular modifications to these design parameters are demonstrated to effectively double the purification success rate of the procedure. Finally, I describe the redesign of the artificial di-iron protein DF2 into CDM13, a single chain di-Manganese four-helix bundle. CDM13 acts as a functional model of natural manganese catalase, exhibiting a kcat of 0.08s-1 under steady-state conditions. The bound manganese cofactors have a reduction potential of +805 mV vs NHE, which is too high for efficient dismutation of hydrogen peroxide. These results indicate that as a high-potential manganese complex, CDM13 may represent a promising first step toward a polypeptide model of the Oxygen Evolving Complex of the photosynthetic enzyme Photosystem II.

  19. d-Cysteine Ligands Control Metal Geometries within De Novo Designed Three-Stranded Coiled Coils

    DEFF Research Database (Denmark)

    Ruckthong, Leela; Peacock, Anna F.A.; Pascoe, Cherilyn E.

    2017-01-01

    Although metal ion binding to naturally occurring l-amino acid proteins is well documented, understanding the impact of the opposite chirality (d-)amino acids on the structure and stereochemistry of metals is in its infancy. We examine the effect of a d-configuration cysteine within a designed l......-amino acid three-stranded coiled coil in order to enforce a precise coordination number on a metal center. The d chirality does not alter the native fold, but the side-chain re-orientation modifies the sterics of the metal binding pocket. l-Cys side chains within the coiled-coil structure have previously...... by comparison of the structure of ZnIICl(CSL16DC)3 2- to the published structure of ZnII(H2O)(GRAND-CSL12AL16LC)3 -. Moreover, spectroscopic analysis indicates that the CdII geometry observed by using l-Cys ligands (a mixture of three- and four-coordinate CdII) is altered to a single four-coordinate species...

  20. iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan.

    Science.gov (United States)

    Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

    2011-06-01

    The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

  1. iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan

    Science.gov (United States)

    Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

    2011-06-01

    The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

  2. De novo molecular design

    CERN Document Server

    Schneider, Gisbert

    2013-01-01

    Systematically examining current methods and strategies, this ready reference covers a wide range of molecular structures, from organic-chemical drugs to peptides, Proteins and nucleic acids, in line with emerging new drug classes derived from biomacromolecules. A leader in the field and one of the pioneers of this young discipline has assembled here the most prominent experts from across the world to provide first-hand knowledge. While most of their methods and examples come from the area of pharmaceutical discovery and development, the approaches are equally applicable for chemical probes an

  3. De novo design, synthesis, and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.

    Science.gov (United States)

    Potin, Dominique; Launay, Michele; Nicolai, Eric; Fabreguette, Maud; Malabre, Patrice; Caussade, François; Besse, Dominique; Skala, Stacey; Stetsko, Dawn K; Todderud, Gordon; Beno, Brett R; Cheney, Daniel L; Chang, Chiehying J; Sheriff, Steven; Hollenbaugh, Diane L; Barrish, Joel C; Iwanowicz, Edwin J; Suchard, Suzanne J; Dhar, T G Murali

    2005-02-15

    LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.

  4. A de novo NADPH generation pathway for improving lysine production of Corynebacterium glutamicum by rational design of the coenzyme specificity of glyceraldehyde 3-phosphate dehydrogenase.

    Science.gov (United States)

    Bommareddy, Rajesh Reddy; Chen, Zhen; Rappert, Sugima; Zeng, An-Ping

    2014-09-01

    Engineering the cofactor availability is a common strategy of metabolic engineering to improve the production of many industrially important compounds. In this work, a de novo NADPH generation pathway is proposed by altering the coenzyme specificity of a native NAD-dependent glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to NADP, which consequently has the potential to produce additional NADPH in the glycolytic pathway. Specifically, the coenzyme specificity of GAPDH of Corynebacterium glutamicum is systematically manipulated by rational protein design and the effect of the manipulation for cellular metabolism and lysine production is evaluated. By a combinatorial modification of four key residues within the coenzyme binding sites, different GAPDH mutants with varied coenzyme specificity were constructed. While increasing the catalytic efficiency of GAPDH towards NADP enhanced lysine production in all of the tested mutants, the most significant improvement of lysine production (~60%) was achieved with the mutant showing similar preference towards both NAD and NADP. Metabolic flux analysis with (13)C isotope studies confirmed that there was no significant change of flux towards the pentose phosphate pathway and the increased lysine yield was mainly attributed to the NADPH generated by the mutated GAPDH. The present study highlights the importance of protein engineering as a key strategy in de novo pathway design and overproduction of desired products. Copyright © 2014 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  5. Synergistic Integration of Experimental and Simulation Approaches for the de Novo Design of Silk-Based Materials.

    Science.gov (United States)

    Huang, Wenwen; Ebrahimi, Davoud; Dinjaski, Nina; Tarakanova, Anna; Buehler, Markus J; Wong, Joyce Y; Kaplan, David L

    2017-04-18

    Tailored biomaterials with tunable functional properties are crucial for a variety of task-specific applications ranging from healthcare to sustainable, novel bio-nanodevices. To generate polymeric materials with predictive functional outcomes, exploiting designs from nature while morphing them toward non-natural systems offers an important strategy. Silks are Nature's building blocks and are produced by arthropods for a variety of uses that are essential for their survival. Due to the genetic control of encoded protein sequence, mechanical properties, biocompatibility, and biodegradability, silk proteins have been selected as prototype models to emulate for the tunable designs of biomaterial systems. The bottom up strategy of material design opens important opportunities to create predictive functional outcomes, following the exquisite polymeric templates inspired by silks. Recombinant DNA technology provides a systematic approach to recapitulate, vary, and evaluate the core structure peptide motifs in silks and then biosynthesize silk-based polymers by design. Post-biosynthesis processing allows for another dimension of material design by controlled or assisted assembly. Multiscale modeling, from the theoretical prospective, provides strategies to explore interactions at different length scales, leading to selective material properties. Synergy among experimental and modeling approaches can provide new and more rapid insights into the most appropriate structure-function relationships to pursue while also furthering our understanding in terms of the range of silk-based systems that can be generated. This approach utilizes nature as a blueprint for initial polymer designs with useful functions (e.g., silk fibers) but also employs modeling-guided experiments to expand the initial polymer designs into new domains of functional materials that do not exist in nature. The overall path to these new functional outcomes is greatly accelerated via the integration of

  6. Computational design and elaboration of a de novo heterotetrameric alpha-helical protein that selectively binds an emissive abiological (porphinato)zinc chromophore.

    Science.gov (United States)

    Fry, H Christopher; Lehmann, Andreas; Saven, Jeffery G; DeGrado, William F; Therien, Michael J

    2010-03-24

    The first example of a computationally de novo designed protein that binds an emissive abiological chromophore is presented, in which a sophisticated level of cofactor discrimination is pre-engineered. This heterotetrameric, C(2)-symmetric bundle, A(His):B(Thr), uniquely binds (5,15-di[(4-carboxymethyleneoxy)phenyl]porphinato)zinc [(DPP)Zn] via histidine coordination and complementary noncovalent interactions. The A(2)B(2) heterotetrameric protein reflects ligand-directed elements of both positive and negative design, including hydrogen bonds to second-shell ligands. Experimental support for the appropriate formulation of [(DPP)Zn:A(His):B(Thr)](2) is provided by UV/visible and circular dichroism spectroscopies, size exclusion chromatography, and analytical ultracentrifugation. Time-resolved transient absorption and fluorescence spectroscopic data reveal classic excited-state singlet and triplet PZn photophysics for the A(His):B(Thr):(DPP)Zn protein (k(fluorescence) = 4 x 10(8) s(-1); tau(triplet) = 5 ms). The A(2)B(2) apoprotein has immeasurably low binding affinities for related [porphinato]metal chromophores that include a (DPP)Fe(III) cofactor and the zinc metal ion hemin derivative [(PPIX)Zn], underscoring the exquisite active-site binding discrimination realized in this computationally designed protein. Importantly, elements of design in the A(His):B(Thr) protein ensure that interactions within the tetra-alpha-helical bundle are such that only the heterotetramer is stable in solution; corresponding homomeric bundles present unfavorable ligand-binding environments and thus preclude protein structural rearrangements that could lead to binding of (porphinato)iron cofactors.

  7. Biological effects of a de novo designed myxoma virus peptide analogue: evaluation of cytotoxicity on tumor cells.

    Directory of Open Access Journals (Sweden)

    Taghrid S Istivan

    Full Text Available BACKGROUND: The Resonant Recognition Model (RRM is a physico-mathematical model that interprets protein sequence linear information using digital signal processing methods. In this study the RRM concept was employed for structure-function analysis of myxoma virus (MV proteins and the design of a short bioactive therapeutic peptide with MV-like antitumor/cytotoxic activity. METHODOLOGY/PRINCIPAL FINDINGS: The analogue RRM-MV was designed by RRM as a linear 18 aa 2.3 kDa peptide. The biological activity of this computationally designed peptide analogue against cancer and normal cell lines was investigated. The cellular cytotoxicity effects were confirmed by confocal immunofluorescence microscopy, by measuring the levels of cytoplasmic lactate dehydrogenase (LDH and by Prestoblue cell viability assay for up to 72 hours in peptide treated and non-treated cell cultures. Our results revealed that RRM-MV induced a significant dose and time-dependent cytotoxic effect on murine and human cancer cell lines. Yet, when normal murine cell lines were similarly treated with RRM-MV, no cytotoxic effects were observed. Furthermore, the non-bioactive RRM designed peptide RRM-C produced negligible cytotoxic effects on these cancer and normal cell lines when used at similar concentrations. The presence/absence of phosphorylated Akt activity in B16F0 mouse melanoma cells was assessed to indicate the possible apoptosis signalling pathway that could be affected by the peptide treatment. So far, Akt activity did not seem to be significantly affected by RRM-MV as is the case for the original viral protein. CONCLUSIONS/SIGNIFICANCE: Our findings indicate the successful application of the RRM concept to design a bioactive peptide analogue (RRM-MV with cytotoxic effects on tumor cells only. This 2.345 kDa peptide analogue to a 49 kDa viral protein may be suitable to be developed as a potential cancer therapeutic. These results also open a new direction to the rational

  8. Inducible Expression of the De-Novo Designed Antimicrobial Peptide SP1-1 in Tomato Confers Resistance to Xanthomonas campestris pv. vesicatoria.

    Directory of Open Access Journals (Sweden)

    Areli Herrera Diaz

    Full Text Available Antimicrobial peptides (AMPs are small peptides with less than 50 amino acids and are part of the innate immune response in almost all organisms, including bacteria, vertebrates, invertebrates and plants. AMPs are active against a broad-spectrum of pathogens. The inducible expression of AMPs in plants is a promising approach to combat plant pathogens with minimal negative side effects, such as phytotoxicity or infertility. In this study, inducible expression of the de-novo designed AMP SP1-1 in Micro Tom tomato protected tomato fruits against bacterial spot disease caused by Xanthomonas campestris pv. vesicatoria. The peptide SP1-1 was targeted to the apoplast which is the primary infection site for plant pathogens, by fusing SP1-1 peptide to the signal peptide RsAFP1 of radish (Raphanus sativus. The pathogen inducibility of the expression was enabled by using an optimized inducible 4XW2/4XS promoter. As a result, the tomato fruits of independently generated SP1-1 transgenic lines were significantly more resistant to X. campestris pv. vesicatoria than WT tomato fruits. In transgenic lines, bacterial infection was reduced up to 65% in comparison to the infection of WT plants. Our study demonstrates that the combination of the 4XW2/4XS cis-element from parsley with the synthetic antimicrobial peptide SP1-1 is a good alternative to protect tomato fruits against infections with X. campestris pv. vesicatoria.

  9. Membrane interaction and secondary structure of de novo designed arginine-and tryptophan peptides with dual function

    KAUST Repository

    Rydberg, Hanna A.

    2012-10-01

    Cell-penetrating peptides and antimicrobial peptides are two classes of positively charged membrane active peptides with several properties in common. The challenge is to combine knowledge about the membrane interaction mechanisms and structural properties of the two classes to design peptides with membrane-specific actions, useful either as transporters of cargo or as antibacterial substances. Membrane active peptides are commonly rich in arginine and tryptophan. We have previously designed a series of arg/trp peptides and investigated how the position and number of tryptophans affect cellular uptake. Here we explore the antimicrobial properties and the interaction with lipid model membranes of these peptides, using minimal inhibitory concentrations assay (MIC), circular dichroism (CD) and linear dichroism (LD). The results show that the arg/trp peptides inhibit the growth of the two gram positive strains Staphylococcus aureus and Staphylococcus pyogenes, with some individual variations depending on the position of the tryptophans. No inhibition of the gram negative strains Proteus mirabilis or Pseudomonas aeruginosa was noticed. CD indicated that when bound to lipid vesicles one of the peptides forms an α-helical like structure, whereas the other five exhibited rather random coiled structures. LD indicated that all six peptides were somehow aligned parallel with the membrane surface. Our results do not reveal any obvious connection between membrane interaction and antimicrobial effect for the studied peptides. By contrast cell-penetrating properties can be coupled to both the secondary structure and the degree of order of the peptides. © 2012 Elsevier Inc.

  10. De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities.

    Science.gov (United States)

    Murugan, Ravichandran N; Jacob, Binu; Ahn, Mija; Hwang, Eunha; Sohn, Hoik; Park, Hyo-Nam; Lee, Eunjung; Seo, Ji-Hyung; Cheong, Chaejoon; Nam, Ky-Youb; Hyun, Jae-Kyung; Jeong, Ki-Woong; Kim, Yangmee; Shin, Song Yub; Bang, Jeong Kyu

    2013-01-01

    Much attention has been focused on the design and synthesis of potent, cationic antimicrobial peptides (AMPs) that possess both antimicrobial and anti-inflammatory activities. However, their development into therapeutic agents has been limited mainly due to their large size (12 to 50 residues in length) and poor protease stability. In an attempt to overcome the issues described above, a set of ultra-short, His-derived antimicrobial peptides (HDAMPs) has been developed for the first time. Through systematic tuning of pendant hydrophobic alkyl tails at the N(π)- and N(τ)-positions on His, and the positive charge of Arg, much higher prokaryotic selectivity was achieved, compared to human AMP LL-37. Additionally, the most potent HDAMPs showed promising dual antimicrobial and anti-inflammatory activities, as well as anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and proteolytic resistance. Our results from transmission electron microscopy, membrane depolarization, confocal laser-scanning microscopy, and calcein-dye leakage experiments propose that HDAMP-1 kills microbial cells via dissipation of the membrane potential by forming pore/ion channels on bacterial cell membranes. The combination of the ultra-short size, high-prokaryotic selectivity, potent anti-MRSA activity, anti-inflammatory activity, and proteolytic resistance of the designed HDAMP-1, -3, -5, and -6 makes these molecules promising candidates for future antimicrobial therapeutics.

  11. De novo design of RNA-binding proteins with a prion-like domain related to ALS/FTD proteinopathies.

    Science.gov (United States)

    Mitsuhashi, Kana; Ito, Daisuke; Mashima, Kyoko; Oyama, Munenori; Takahashi, Shinichi; Suzuki, Norihiro

    2017-12-04

    Aberrant RNA-binding proteins form the core of the neurodegeneration cascade in spectrums of disease, such as amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Six ALS-related molecules, TDP-43, FUS, TAF15, EWSR1, heterogeneous nuclear (hn)RNPA1 and hnRNPA2 are RNA-binding proteins containing candidate mutations identified in ALS patients and those share several common features, including harboring an aggregation-prone prion-like domain (PrLD) containing a glycine/serine-tyrosine-glycine/serine (G/S-Y-G/S)-motif-enriched low-complexity sequence and rich in glutamine and/or asparagine. Additinally, these six molecules are components of RNA granules involved in RNA quality control and become mislocated from the nucleus to form cytoplasmic inclusion bodies (IBs) in the ALS/FTD-affected brain. To reveal the essential mechanisms involved in ALS/FTD-related cytotoxicity associated with RNA-binding proteins containing PrLDs, we designed artificial RNA-binding proteins harboring G/S-Y-G/S-motif repeats with and without enriched glutamine residues and nuclear-import/export-signal sequences and examined their cytotoxicity in vitro. These proteins recapitulated features of ALS-linked molecules, including insoluble aggregation, formation of cytoplasmic IBs and components of RNA granules, and cytotoxicity instigation. These findings indicated that these artificial RNA-binding proteins mimicked features of ALS-linked molecules and allowed the study of mechanisms associated with gain of toxic functions related to ALS/FTD pathogenesis.

  12. Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C82(OH)22 and its implication for de novo design of nanomedicine

    Energy Technology Data Exchange (ETDEWEB)

    Kang, S. -g.; Zhou, G.; Yang, P.; Liu, Y.; Sun, B.; Huynh, T.; Meng, H.; Zhao, L.; Xing, G.; Chen, C.; Zhao, Y.; Zhou, R.

    2012-09-18

    Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C82(OH)22 can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C82(OH)22 effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Enzyme activity assays also show Gd@C82(OH)22 not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C82(OH)22–MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C82(OH)22 inhibits MMP-9 mainly via an exocite interaction, whereas the well-known zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C82(OH)22 exhibits specific binding modes near the ligand-specificity loop S1', thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific binding mode make Gd@C82(OH)22 a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Finally, our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.

  13. in silico Whole Genome Sequencer & Analyzer (iWGS): a computational pipeline to guide the design and analysis of de novo genome sequencing studies

    Science.gov (United States)

    The availability of genomes across the tree of life is highly biased toward vertebrates, pathogens, human disease models, and organisms with relatively small and simple genomes. Recent progress in genomics has enabled the de novo decoding of the genome of virtually any organism, greatly expanding it...

  14. Pb(II) and Hg(II) binding to $\\textit{de novo}$ designed proteins studied by $^{204m}$Pb- and $^{199m}$Hg-Perturbed Angular Correlation of $\\gamma$-rays (PAC) spectroscopy : Clues to heavy metal toxicity

    CERN Multimedia

    2002-01-01

    $\\textit{De novo}$ design of proteins combined with PAC spectroscopy offers a unique and powerful approach to the study of fundamental chemistry of heavy metal-protein interactions, and thus of the mechanisms underlying heavy metal toxicity. In this project we focus on Pb(II) and Hg(II) binding to designed three stranded coiled coil proteins with one or two binding sites, mimicking a variety of naturally occurring thiolate-rich metal ion binding sites in proteins. The $^{204m}$Pb- and $^{199m}$Hg-PAC experiments will complement data already recorded with EXAFS, NMR, UV-Vis and CD spectroscopies.

  15. Modular Engineering Concept at Novo Nordisk Engineering

    DEFF Research Database (Denmark)

    Moelgaard, Gert; Miller, Thomas Dedenroth

    1997-01-01

    This report describes the concept of a new engineering method at Novo Nordisk Engineering: Modular Engineering (ME). Three tools are designed to support project phases with different levels of detailing and abstraction. ME supports a standard, cross-functional breakdown of projects that facilitates...

  16. De Novo Glutamine Synthesis

    Science.gov (United States)

    He, Qiao; Shi, Xinchong; Zhang, Linqi; Yi, Chang; Zhang, Xuezhen

    2016-01-01

    Purpose: The aim of this study was to investigate the role of de novo glutamine (Gln) synthesis in the proliferation of C6 glioma cells and its detection with 13N-ammonia. Methods: Chronic Gln-deprived C6 glioma (0.06C6) cells were established. The proliferation rates of C6 and 0.06C6 cells were measured under the conditions of Gln deprivation along with or without the addition of ammonia or glutamine synthetase (GS) inhibitor. 13N-ammonia uptake was assessed in C6 cells by gamma counting and in rats with C6 and 0.06C6 xenografts by micro–positron emission tomography (PET) scanning. The expression of GS in C6 cells and xenografts was assessed by Western blotting and immunohistochemistry, respectively. Results: The Gln-deprived C6 cells showed decreased proliferation ability but had a significant increase in GS expression. Furthermore, we found that low concentration of ammonia was sufficient to maintain the proliferation of Gln-deprived C6 cells, and 13N-ammonia uptake in C6 cells showed Gln-dependent decrease, whereas inhibition of GS markedly reduced the proliferation of C6 cells as well as the uptake of 13N-ammoina. Additionally, microPET/computed tomography exhibited that subcutaneous 0.06C6 xenografts had higher 13N-ammonia uptake and GS expression in contrast to C6 xenografts. Conclusion: De novo Gln synthesis through ammonia–glutamate reaction plays an important role in the proliferation of C6 cells. 13N-ammonia can be a potential metabolic PET tracer for Gln-dependent tumors. PMID:27118759

  17. Design and rationale of the HITTS randomized controlled trial: Effect of High-intensity Interval Training in de novo Heart Transplant Recipients in Scandinavia.

    Science.gov (United States)

    Nytrøen, Kari; Yardley, Marianne; Rolid, Katrine; Bjørkelund, Elisabeth; Karason, Kristjan; Wigh, Julia Philip; Dall, Christian Have; Arora, Satish; Aakhus, Svend; Lunde, Ketil; Solberg, Ole Geir; Gustafsson, Finn; Prescott, Eva Irene Bossano; Gullestad, Lars

    2016-02-01

    There is no consensus on how, when, and at what intensity exercise should be performed and organized after heart transplantation (HTx). Most rehabilitation programs are conducted in HTx centers, which might be impractical and costly. We have recently shown that high-intensity interval training (HIT) is safe, well tolerated, and efficacious in maintenance HTx recipients, but there are no studies among de novo patients, and whether HIT is feasible and superior to moderate training in HTx recipients is unclear. A total of 120 clinically stable HTx recipients older than 18 years will be recruited from 3 Scandinavian HTx centers. Participants are randomized to HIT or moderate training, shortly after surgery. All exercises are supervised in the patients' local communities. Testing at baseline and follow-up includes the following: VO2peak (primary end point), muscle strength, body composition, quality of life, myocardial performance, endothelial function, biomarkers, and progression of cardiac allograft vasculopathy. A subgroup (n = 90) will also be tested at 3-year follow-up to assess long-term effects of exercise. So far, the HIT intervention is well tolerated, without any serious adverse events. We aim to test whether decentralized HIT is feasible, safe, and superior to moderate training, and whether it will lead to significant improvement in exercise capacity and less long-term complications. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. De novo design of chiral organotin cancer drug candidates: validation of enantiopreferential binding to molecular target DNA and 5'-GMP by UV-visible, fluorescence, (1)H and (31)P NMR.

    Science.gov (United States)

    Arjmand, Farukh; Sharma, Girish Chandra; Sayeed, Fatima; Muddassir, Mohd; Tabassum, Sartaj

    2011-12-02

    N,N-bis[(R-/S-)-1-benzyl-2-ethoxyethane] tin (IV) complexes were synthesized by applying de novo design strategy by the condensation reaction of (R-/S-)2-amino-2-phenylethanol and dibromoethane in presence of dimethyltin dichloride and thoroughly characterized by elemental analysis, conductivity measurements, IR, ESI-MS, (1)H, (13)C and (119)Sn, multinuclear NMR spectroscopy and XRD study. Enantioselective and specific binding profile of R-enantiomer 1 in comparison to S-enantiomer 2 with ultimate molecular target CT-DNA was validated by UV-visible, fluorescence, circular dichroism, (1)H and (31)P NMR techniques. This was further corroborated well by interaction of 1 and 2 with 5'-GMP. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Extreme-Scale De Novo Genome Assembly

    Energy Technology Data Exchange (ETDEWEB)

    Georganas, Evangelos [Intel Corporation, Santa Clara, CA (United States); Hofmeyr, Steven [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Joint Genome Inst.; Egan, Rob [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Computational Research Division; Buluc, Aydin [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Joint Genome Inst.; Oliker, Leonid [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Joint Genome Inst.; Rokhsar, Daniel [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Computational Research Division; Yelick, Katherine [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Joint Genome Inst.

    2017-09-26

    De novo whole genome assembly reconstructs genomic sequence from short, overlapping, and potentially erroneous DNA segments and is one of the most important computations in modern genomics. This work presents HipMER, a high-quality end-to-end de novo assembler designed for extreme scale analysis, via efficient parallelization of the Meraculous code. Genome assembly software has many components, each of which stresses different components of a computer system. This chapter explains the computational challenges involved in each step of the HipMer pipeline, the key distributed data structures, and communication costs in detail. We present performance results of assembling the human genome and the large hexaploid wheat genome on large supercomputers up to tens of thousands of cores.

  20. Contribuições do design estratégico para o desenvolvimento de novos modelos de negócios no contexto de empresas startups

    OpenAIRE

    Almada, Viviane da Silva

    2015-01-01

    As organizações, especialmente as empresas startups, estão inseridas em mercados onde a necessidade de um olhar direcionado para a resolução de problemas complexos e a busca de inovação é cada vez mais crescente. Neste contexto destaca-se o design estratégico, uma abordagem que permite a expansão do espaço do problema a ser resolvido, do mesmo modo que aumenta as possibilidades de inovação e traz uma dimensão projetual de constante experimentação. Esta pesquisa tem como objetivo fornece...

  1. De Novo Design of Boron-Based Host Materials for Highly Efficient Blue and White Phosphorescent OLEDs with Low Efficiency Roll-Off.

    Science.gov (United States)

    Xue, Miao-Miao; Huang, Chen-Chao; Yuan, Yi; Cui, Lin-Song; Li, Yong-Xi; Wang, Bo; Jiang, Zuo-Quan; Fung, Man-Keung; Liao, Liang-Sheng

    2016-08-10

    Borane is an excellent electron-accepting species, and its derivatives have been widely used in a variety of fields. However, the use of borane derivatives as host materials in OLEDs has rarely reported because the device performance is generally not satisfactory. In this work, two novel spiro-bipolar hosts with incorporated borane were designed and synthesized. The strategies used in preparing these materials were to increase the spatial separation of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) in the molecules, tune the connecting positions of functional groups, and incorporate specific functional groups with desirable thermal stability. Based on these designs, phosphorescent OLEDs with borane derivatives as hosts and with outstanding device performances were obtained. In particular, devices based on SAF-3-DMB/FIrpic exhibited an external quantum efficiency (EQE) of >25%. More encouragingly, the device was found to have quite a low efficiency roll-off, giving an efficiency of >20% even at a high brightness of 10000 cd/m(2). Furthermore, the EQE of the three-color-based (R + G + B) white OLED employing SAF-3-DMB as a host was also as high as 22.9% with CIE coordinates of (x, y) = (0.40, 0.48). At a brightness of 5000 cd/m(2), there was only a 3% decrease in EQE from its maximum value, implying a very low efficiency roll-off.

  2. Engineering out motion: introduction of a de novo disulfide bond and a salt bridge designed to close a dynamic cleft on the surface of cytochrome b5.

    Science.gov (United States)

    Storch, E M; Daggett, V; Atkins, W M

    1999-04-20

    A previous molecular dynamics (MD) simulation of cytochrome b5 (cyt b5) at 25 degrees C displayed localized dynamics on the surface of the protein giving rise to the periodic formation of a cleft that provides access to the heme through a protected hydrophobic channel [Storch and Daggett (1995) Biochemistry 34, 9682]. Here we describe the production and testing of mutants designed to prevent the cleft from opening using a combination of experimental and theoretical techniques. Two mutants have been designed to close the surface cleft: S18D to introduce a salt bridge and S18C:R47C to incorporate a disulfide bond. The putative cleft forms between two separate cores of the protein: one is structural in nature and can be monitored through the fluorescence of Trp 22, and the other binds the heme prosthetic group and can be tracked via heme absorbance. An increase in motion localized to the cleft region was observed for each protein, except for the disulfide-containing variant, in MD simulations at 50 degrees C compared to simulations at 25 degrees C. For the disulfide-containing variant, the cleft remained closed. Both urea and temperature denaturation curves were nearly identical for wild-type and mutant proteins when heme absorbance was monitored. In contrast, fluorescence studies revealed oxidized S18C:R47C to be considerably more stable based on the midpoints of the denaturation transitions, Tm and U1/2. Moreover, the fluorescence changes for each protein were complete at approximately 50 degrees C and a urea concentration of approximately 3.9 M, significantly below the temperature and urea concentration (62 degrees C, 5 M urea) required to observe heme release. In addition, solvent accessibility based on acrylamide quenching of Trp 22 was lower in the S18C:R47C mutant, particularly at 50 degrees C, before heme release [presented in the accompanying paper (58)]. The results suggest that a constraining disulfide bond can be designed to inhibit dynamic cleft formation

  3. NovoPen Echo® insulin delivery device

    Directory of Open Access Journals (Sweden)

    Hyllested-Winge J

    2016-01-01

    Full Text Available Jacob Hyllested-Winge,1 Thomas Sparre,2 Line Kynemund Pedersen2 1Novo Nordisk Pharma Ltd, Tokyo, Japan; 2Novo Nordisk A/S, Søborg, Denmark Abstract: The introduction of insulin pen devices has provided easier, well-tolerated, and more convenient treatment regimens for patients with diabetes mellitus. When compared with vial and syringe regimens, insulin pens offer a greater clinical efficacy, improved quality of life, and increased dosing accuracy, particularly at low doses. The portable and discreet nature of pen devices reduces the burden on the patient, facilitates adherence, and subsequently contributes to the improvement in glycemic control. NovoPen Echo® is one of the latest members of the NovoPen® family that has been specifically designed for the pediatric population and is the first to combine half-unit increment (=0.5 U of insulin dosing with a simple memory function. The half-unit increment dosing amendments and accurate injection of 0.5 U of insulin are particularly beneficial for children (and insulin-sensitive adults/elders, who often require small insulin doses. The memory function can be used to record the time and amount of the last dose, reducing the fear of double dosing or missing a dose. The memory function also provides parents with extra confidence and security that their child is taking insulin at the correct doses and times. NovoPen Echo is a lightweight, durable insulin delivery pen; it is available in two different colors, which may help to distinguish between different types of insulin, providing more confidence for both users and caregivers. Studies have demonstrated a high level of patient satisfaction, with 80% of users preferring NovoPen Echo to other pediatric insulin pens. Keywords: NovoPen Echo®, memory function, half-unit increment dosing, adherence, children, adolescents 

  4. A prospective evaluation of the safety and efficacy of the TAXUS Element paclitaxel-eluting coronary stent system for the treatment of de novo coronary artery lesions: Design and statistical methods of the PERSEUS clinical program

    Directory of Open Access Journals (Sweden)

    Wehrenberg Scott

    2010-01-01

    Full Text Available Abstract Background Paclitaxel-eluting stents decrease angiographic and clinical restenosis following percutaneous coronary intervention compared to bare metal stents. TAXUS Element is a third-generation paclitaxel-eluting stent which incorporates a novel, thinner-strut, platinum-enriched metal alloy platform. The stent is intended to have enhanced radiopacity and improved deliverability compared to other paclitaxel-eluting stents. The safety and efficacy of the TAXUS Element stent are being evaluated in the pivotal PERSEUS clinical trials. Methods/Design The PERSEUS trials include two parallel studies of the TAXUS Element stent in single, de novo coronary atherosclerotic lesions. The PERSEUS Workhorse study is a prospective, randomized (3:1, single-blind, non-inferiority trial in subjects with lesion length ≤28 mm and vessel diameter ≥2.75 mm to ≤4.0 mm which compares TAXUS Element to the TAXUS Express2 paclitaxel-eluting stent system. The Workhorse study employs a novel Bayesian statistical approach that uses prior information to limit the number of study subjects exposed to the investigational device and thus provide a safer and more efficient analysis of the TAXUS Element stent. PERSEUS Small Vessel is a prospective, single-arm, superiority trial in subjects with lesion length ≤20 mm and vessel diameter ≥2.25 mm to Discussion The TAXUS PERSEUS clinical trial program uses a novel statistical approach to evaluate whether design and metal alloy iterations in the TAXUS Element stent platform provide comparable safety and improved procedural performance compared to the previous generation Express stent. PERSEUS trial enrollment is complete and primary endpoint data are expected in 2010. PERSEUS Workhorse and Small Vessel are registered at http://www.clinicaltrials.gov, identification numbers NCT00484315 and NCT00489541.

  5. New design of logistics for export of ethanol: a long-term vision; Novo desenho logistico para exportacao de etanol: uma visao de longo prazo

    Energy Technology Data Exchange (ETDEWEB)

    Scandiffio, Mirna Ivonne Gaya [Universidade Estadual de Campinas (NIPE/UNICAMP), SP (Brazil). Nucleo Interdisciplinar de Planejamento Energetico], e-mail: mirna@fem.unicamp.br; Leal, Manoel Regis Lima Verde [Centro de Energias Alternativas e Meio Ambiente - CENEA, Fortaleza, CE (Brazil)], e-mail: regislv@energiabr.org.br

    2008-07-01

    Production of ethanol from sugarcane, in Brazil, has presented continued expansion. Estimates of harvest from season 2007-2008 show a production of near 27 million m3 of ethanol, 20% over the previous season. Internal market responded, in 2005, for close to eighty five percent of national supply and the remaining 3.5 million m3 were sent abroad. A prospective study from NIPE-UNICAMP projects an increase in exports to reach 105 million m3 by 2025. All that projected growth, whether for internal consumption or exports, is not reflected in the very small amounts of investment in infrastructure in the last decades, pointing out the fragility and distortion of the transportation matrix of the country. Above sixty percent of national cargo is made by roads. Transportation of ethanol using pipelines represented, in the Eighties, close to 13% and hydro ways were responsible for 22% of its flow. Nowadays, ethanol dedicated pipelines respond only for 2%. Ethanol transportation by pipes seems to be the more competitive way of transporting when considering cost, time and delivery credibility, plus its positive environmental impact due to the substitution of diesel use. The experience of 30 years, since the launch of the National Program of Alcohol PROALCOOL, gives the country a solid knowledge, not only regarding the agricultural area and ethanol production, but also in logistics transporting by pipelines. The objective of this article is to analyze a new logistic design for transporting ethanol supported by a long term view, up to 2025. (author)

  6. Airline Maintenance Manpower Optimization from the De Novo Perspective

    Science.gov (United States)

    Liou, James J. H.; Tzeng, Gwo-Hshiung

    Human resource management (HRM) is an important issue for today’s competitive airline marketing. In this paper, we discuss a multi-objective model designed from the De Novo perspective to help airlines optimize their maintenance manpower portfolio. The effectiveness of the model and solution algorithm is demonstrated in an empirical study of the optimization of the human resources needed for airline line maintenance. Both De Novo and traditional multiple objective programming (MOP) methods are analyzed. A comparison of the results with those of traditional MOP indicates that the proposed model and solution algorithm does provide better performance and an improved human resource portfolio.

  7. Engineering and introduction of de novo disulphide bridges in ...

    Indian Academy of Sciences (India)

    The engineeringof de novo disulphide bridges has been explored as a means to increase the thermal stability of enzymes in the rationalmethod of protein engineering. In this study, Disulphide by Design software, homology modelling and moleculardynamics simulations were used to select appropriate amino acid pairs for ...

  8. Towards accurate de novo assembly for genomes with repeats

    NARCIS (Netherlands)

    Bucur, Doina

    2017-01-01

    De novo genome assemblers designed for short k-mer length or using short raw reads are unlikely to recover complex features of the underlying genome, such as repeats hundreds of bases long. We implement a stochastic machine-learning method which obtains accurate assemblies with repeats and

  9. Pesquisa de novos elementos Pesquisa de novos elementos

    Directory of Open Access Journals (Sweden)

    Gil Mário de Macedo Grassi

    1978-11-01

    Full Text Available The present study deals with the discovery of new elements synthesized by man. The introduction discusses in general the theories about nuclear transmutation, which is the method employed in these syntheses. The study shows the importance of the Periodical Table since it is through this table that one can reach a prevision of new elements and its, properties. The discoveries of the transuranic elements, together wich the data of their first preparations are also tabulated The stability of these elements is also discussed, and future speculations are showedNeste trabalho estuda-se, teoricamente, a descoberta de novos elementos sintetizados pelo homem Na introdução apresentamos um apanhado geral sobre as teorias a respeito da transmutação nuclear, que é o método utilizado nestas sínteses. Em seguida, mostramos a importância da Tabela Periódica, pois é através dela que se chega à previsão dos novos elementos e de suas propriedades. As descobertas dos transurânicos, Já realizadas com êxito, juntamente com os dados de suas primeiras preparações são tabelados. A estabilidade destes novos elementos também é discutida, e apresentadas futuras especulações.

  10. A Public Trial De Novo

    DEFF Research Database (Denmark)

    Vedel, Jane Bjørn; Gad, Christopher

    2011-01-01

    This article addresses the concept of “industrial interests” and examines its role in a topical controversy about a large research grant from a private foundation, the Novo Nordisk Foundation, to the University of Copenhagen. The authors suggest that the debate took the form of a “public trial” w.......” The article ends with a discussion of some implications of the analysis, including that policy making, academic research, and public debates might benefit from more detailed accounts of interests and stakes.......This article addresses the concept of “industrial interests” and examines its role in a topical controversy about a large research grant from a private foundation, the Novo Nordisk Foundation, to the University of Copenhagen. The authors suggest that the debate took the form of a “public trial......” where the grant and close(r) intermingling between industry and public research was prosecuted and defended. First, the authors address how the grant was framed in the media. Second, they redescribe the case by introducing new “evidence” that, because of this framing, did not reach “the court...

  11. UniNovo: a universal tool for de novo peptide sequencing.

    Science.gov (United States)

    Jeong, Kyowon; Kim, Sangtae; Pevzner, Pavel A

    2013-08-15

    Mass spectrometry (MS) instruments and experimental protocols are rapidly advancing, but de novo peptide sequencing algorithms to analyze tandem mass (MS/MS) spectra are lagging behind. Although existing de novo sequencing tools perform well on certain types of spectra [e.g. Collision Induced Dissociation (CID) spectra of tryptic peptides], their performance often deteriorates on other types of spectra, such as Electron Transfer Dissociation (ETD), Higher-energy Collisional Dissociation (HCD) spectra or spectra of non-tryptic digests. Thus, rather than developing a new algorithm for each type of spectra, we develop a universal de novo sequencing algorithm called UniNovo that works well for all types of spectra or even for spectral pairs (e.g. CID/ETD spectral pairs). UniNovo uses an improved scoring function that captures the dependences between different ion types, where such dependencies are learned automatically using a modified offset frequency function. The performance of UniNovo is compared with PepNovo+, PEAKS and pNovo using various types of spectra. The results show that the performance of UniNovo is superior to other tools for ETD spectra and superior or comparable with others for CID and HCD spectra. UniNovo also estimates the probability that each reported reconstruction is correct, using simple statistics that are readily obtained from a small training dataset. We demonstrate that the estimation is accurate for all tested types of spectra (including CID, HCD, ETD, CID/ETD and HCD/ETD spectra of trypsin, LysC or AspN digested peptides). UniNovo is implemented in JAVA and tested on Windows, Ubuntu and OS X machines. UniNovo is available at http://proteomics.ucsd.edu/Software/UniNovo.html along with the manual.

  12. Biophysical characterization of a de novo elastin

    Science.gov (United States)

    Greenland, Kelly Nicole

    Natural human elastin is found in tissue such as the lungs, arteries, and skin. This protein is formed at birth with no mechanism present to repair or supplement the initial quantity formed. As a result, the functionality and durability of elastin's elasticity is critically important. To date, the mechanics of this ability to stretch and recoil is not fully understood. This study utilizes de novo protein design to create a small library of simplistic versions of elastin-like proteins, demonstrate the elastin-like proteins, maintain elastin's functionality, and inquire into its structure using solution nuclear magnetic resonance (NMR). Elastin is formed from cross-linked tropoelastin. Therefore, the first generation of designed proteins consisted of one protein that utilized homogony of interspecies tropoelastin by using three common domains, two hydrophobic and one cross-linking domains. Basic modifications were made to open the hydrophobic region and also to make the protein easier to purify and characterize. The designed protein maintained its functionality, self-aggregating as the temperature increased. Uniquely, the protein remained self-aggregated as the temperature returned below the critical transition temperature. Self-aggregation was additionally induced by increasing salt concentrations and by modifying the pH. The protein appeared to have little secondary structure when studied with solution NMR. These results fueled a second generation of designed elastin-like proteins. This generation contained variations designed to study the cross-linking domain, one specific hydrophobic domain, and the effect of the length of the elastin-like protein. The cross-linking domain in one variation has been significantly modified while the flanking hydrophobic domains have remained unchanged. This characterization of this protein will answer questions regarding the specificity of the homologous nature of the cross-linking domain of tropoelastin across species. A second

  13. de novo'' aneurysms following endovascular procedures

    International Nuclear Information System (INIS)

    Briganti, F.; Cirillo, S.; Caranci, F.; Esposito, F.; Maiuri, F.

    2002-01-01

    Two personal cases of ''de novo'' aneurysms of the anterior communicating artery (ACoA) occurring 9 and 4 years, respectively, after endovascular carotid occlusion are described. A review of the 30 reported cases (including our own two) of ''de novo'' aneurysms after occlusion of the major cerebral vessels has shown some features, including a rather long time interval after the endovascular procedure of up to 20-25 years (average 9.6 years), a preferential ACoA (36.3%) and internal carotid artery-posterior communicating artery (ICA-PCoA) (33.3%) location of the ''de novo'' aneurysms, and a 10% rate of multiple aneurysms. These data are compared with those of the group of reported spontaneous ''de novo'' aneurysms after SAH or previous aneurysm clipping. We agree that the frequency of ''de novo'' aneurysms after major-vessel occlusion (two among ten procedures in our series, or 20%) is higher than commonly reported (0 to 11%). For this reason, we suggest that patients who have been submitted to endovascular major-vessel occlusion be followed up for up to 20-25 years after the procedure, using non-invasive imaging studies such as MR angiography and high-resolution CT angiography. On the other hand, periodic digital angiography has a questionable risk-benefit ratio; it may be used when a ''de novo'' aneurysm is detected or suspected on non-invasive studies. The progressive enlargement of the ACoA after carotid occlusion, as described in our case 1, must be considered a radiological finding of risk for ''de novo'' aneurysm formation. (orig.)

  14. Neointimal Healing Evaluated by Optical Coherence Tomography after Drug-Eluting Absorbable Metal Scaffold Implantation in de novo Native Coronary Lesions: Rationale and Design of the Magmaris-OCT Study.

    Science.gov (United States)

    Karjalainen, Pasi; Paana, Tuomas; Sia, Jussi; Nammas, Wail

    We sought to explore neointimal healing assessed by optical coherence tomography (OCT) following implantation of the Magmaris sirolimus-eluting absorbable metal scaffold. The Magmaris-OCT is a prospective, multicenter, single-arm observational clinical study, intended to enrol 60 consecutive patients with up to 2 de novo native coronary lesions, each located in different major epicardial vessels, with a reference vessel diameter of 2.5-3.5 mm, and a maximum lesion length of 20 mm. Patients will undergo Magmaris scaffold implantation in the target lesion, according to the standard practice. Clinical follow-up will take place at 30 days, and at 3, 6, 9, and 12 months. For invasive-imaging follow-up, patients will be classified into 3 groups: cohort A will be scheduled for follow-up at 3 months, cohort B at 6 months, and cohort C at 12 months. Invasive imaging will include quantitative coronary angiography, OCT evaluation, and coronary flow reserve measurement. The primary end point will be the percentage of uncovered scaffold struts assessed by OCT at the prespecified follow-up. This study will provide insight into the short- and mid-term healing properties following Magmaris scaffold implantation, with special emphasis on the neointimal coverage of scaffold struts. © 2017 S. Karger AG, Basel.

  15. Web Access to Digitised Content of the Exhibition Novo Mesto 1848-1918 at the Dolenjska Museum, Novo Mesto

    Directory of Open Access Journals (Sweden)

    Majda Pungerčar

    2013-09-01

    Full Text Available EXTENDED ABSTRACTFor the first time, the Dolenjska museum Novo mesto provided access to digitised museum resources when they took the decision to enrich the exhibition Novo mesto 1848-1918 by adding digital content. The following goals were identified: the digital content was created at the time of exhibition planning and design, it met the needs of different age groups of visitors, and during the exhibition the content was accessible via touch screen. As such, it also served for educational purposes (content-oriented lectures or problem solving team work. In the course of exhibition digital content was accessible on the museum website http://www.novomesto1848-1918.si. The digital content was divided into the following sections: the web photo gallery, the quiz and the game. The photo gallery was designed in the same way as the exhibition and the print catalogue and extended by the photos of contemporary Novo mesto and accompanied by the music from the orchestron machine. The following themes were outlined: the Austrian Empire, the Krka and Novo mesto, the town and its symbols, images of the town and people, administration and economy, social life and Novo mesto today followed by digitised archive materials and sources from that period such as the Commemorative book of the Uniformed Town Guard, the National Reading Room Guest Book, the Kazina guest book, the album of postcards and the Diploma of Honoured Citizen Josip Gerdešič. The Web application was also a tool for a simple and on line selection of digitised material and the creation of new digital content which proved to be much more convenient for lecturing than Power Point presentations. The quiz consisted of 40 questions relating to the exhibition theme and the catalogue. Each question offered a set of three answers only one of them being correct and illustrated by photography. The application auto selected ten questions and valued the answers immediately. The quiz could be accessed

  16. DeNovoGUI: an open source graphical user interface for de novo sequencing of tandem mass spectra.

    Science.gov (United States)

    Muth, Thilo; Weilnböck, Lisa; Rapp, Erdmann; Huber, Christian G; Martens, Lennart; Vaudel, Marc; Barsnes, Harald

    2014-02-07

    De novo sequencing is a popular technique in proteomics for identifying peptides from tandem mass spectra without having to rely on a protein sequence database. Despite the strong potential of de novo sequencing algorithms, their adoption threshold remains quite high. We here present a user-friendly and lightweight graphical user interface called DeNovoGUI for running parallelized versions of the freely available de novo sequencing software PepNovo+, greatly simplifying the use of de novo sequencing in proteomics. Our platform-independent software is freely available under the permissible Apache2 open source license. Source code, binaries, and additional documentation are available at http://denovogui.googlecode.com .

  17. De novo assembly of highly diverse viral populations

    Directory of Open Access Journals (Sweden)

    Yang Xiao

    2012-09-01

    Full Text Available Abstract Background Extensive genetic diversity in viral populations within infected hosts and the divergence of variants from existing reference genomes impede the analysis of deep viral sequencing data. A de novo population consensus assembly is valuable both as a single linear representation of the population and as a backbone on which intra-host variants can be accurately mapped. The availability of consensus assemblies and robustly mapped variants are crucial to the genetic study of viral disease progression, transmission dynamics, and viral evolution. Existing de novo assembly techniques fail to robustly assemble ultra-deep sequence data from genetically heterogeneous populations such as viruses into full-length genomes due to the presence of extensive genetic variability, contaminants, and variable sequence coverage. Results We present VICUNA, a de novo assembly algorithm suitable for generating consensus assemblies from genetically heterogeneous populations. We demonstrate its effectiveness on Dengue, Human Immunodeficiency and West Nile viral populations, representing a range of intra-host diversity. Compared to state-of-the-art assemblers designed for haploid or diploid systems, VICUNA recovers full-length consensus and captures insertion/deletion polymorphisms in diverse samples. Final assemblies maintain a high base calling accuracy. VICUNA program is publicly available at: http://www.broadinstitute.org/scientific-community/science/projects/viral-genomics/ viral-genomics-analysis-software. Conclusions We developed VICUNA, a publicly available software tool, that enables consensus assembly of ultra-deep sequence derived from diverse viral populations. While VICUNA was developed for the analysis of viral populations, its application to other heterogeneous sequence data sets such as metagenomic or tumor cell population samples may prove beneficial in these fields of research.

  18. Wegener's granulomatosis occurring de novo during pregnancy.

    Science.gov (United States)

    Alfhaily, F; Watts, R; Leather, A

    2009-01-01

    Wegener's granulomatosis (WG) is rarely diagnosed during the reproductive years and uncommonly manifests for the first time during pregnancy. We report a case of de novo WG presenting at 30 weeks gestation with classical symptoms of WG (ENT, pulmonary). The diagnosis was confirmed by radiological, laboratory, and histological investigations. With a multidisciplinary approach, she had a successful vaginal delivery of a healthy baby. She was treated successfully by a combination of steroids, azathioprine and intravenous immunoglobulin in the active phase of disease for induction of remission and by azathioprine and steroids for maintenance of remission. The significant improvement in her symptoms allowed us to continue her pregnancy to 37 weeks when delivery was electively induced. Transplacental transmission of PR3-ANCA occurred but the neonate remained well. This case of de novo WG during pregnancy highlights the seriousness of this disease and the challenge in management of such patients.

  19. MRUniNovo: an efficient tool for de novo peptide sequencing utilizing the hadoop distributed computing framework.

    Science.gov (United States)

    Li, Chuang; Chen, Tao; He, Qiang; Zhu, Yunping; Li, Kenli

    2017-03-15

    Tandem mass spectrometry-based de novo peptide sequencing is a complex and time-consuming process. The current algorithms for de novo peptide sequencing cannot rapidly and thoroughly process large mass spectrometry datasets. In this paper, we propose MRUniNovo, a novel tool for parallel de novo peptide sequencing. MRUniNovo parallelizes UniNovo based on the Hadoop compute platform. Our experimental results demonstrate that MRUniNovo significantly reduces the computation time of de novo peptide sequencing without sacrificing the correctness and accuracy of the results, and thus can process very large datasets that UniNovo cannot. MRUniNovo is an open source software tool implemented in java. The source code and the parameter settings are available at http://bioinfo.hupo.org.cn/MRUniNovo/index.php. s131020002@hnu.edu.cn ; taochen1019@163.com. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  20. Study on Strategic Planning of Road and Bridge Infrastructure Development in City Planning: Taking Porto-novo City of Benin Republic as Example

    Directory of Open Access Journals (Sweden)

    Boko-haya Dossa Didier

    2018-01-01

    Full Text Available Concern about the townlet infrastructure construction in developing country is one of the crucial part of county town planning and development. By taking the overall planning and design in a case study of Porto-novo city at Republic of Benin, this paper analyzes the characteristics and opportunities of Porto-novo city and puts forward corresponding infrastructure construction strategy. In the end, the paper comes up with specific plan of planning and design under the background of Porto-novo's planning of development strategy.

  1. De novo malignancy after pancreas transplantation in Japan.

    Science.gov (United States)

    Tomimaru, Y; Ito, T; Marubashi, S; Kawamoto, K; Tomokuni, A; Asaoka, T; Wada, H; Eguchi, H; Mori, M; Doki, Y; Nagano, H

    2015-04-01

    Long-term immunosuppression is associated with an increased risk of cancer. Especially, the immunosuppression in pancreas transplantation is more intensive than that in other organ transplantation because of its strong immunogenicity. Therefore, it suggests that the risk of post-transplant de novo malignancy might increase in pancreas transplantation. However, there have been few studies of de novo malignancy after pancreas transplantation. The aim of this study was to analyze the incidence of de novo malignancy after pancreas transplantation in Japan. Post-transplant patients with de novo malignancy were surveyed and characterized in Japan. Among 107 cases receiving pancreas transplantation in Japan between 2001 and 2010, de novo malignancy developed in 9 cases (8.4%): post-transplant lymphoproliferative disorders in 6 cases, colon cancer in 1 case, renal cancer in 1 case, and brain tumor in 1 case. We clarified the incidence of de novo malignancy after pancreas transplantation in Japan. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. De novo design of peptide immunogens that mimic the coiled coil region of human T-cell leukemia virus type-1 glycoprotein 21 transmembrane subunit for induction of native protein reactive neutralizing antibodies.

    Science.gov (United States)

    Sundaram, Roshni; Lynch, Marcus P; Rawale, Sharad V; Sun, Yiping; Kazanji, Mirdad; Kaumaya, Pravin T P

    2004-06-04

    Peptide vaccines able to induce high affinity and protective neutralizing antibodies must rely in part on the design of antigenic epitopes that mimic the three-dimensional structure of the corresponding region in the native protein. We describe the design, structural characterization, immunogenicity, and neutralizing potential of antibodies elicited by conformational peptides derived from the human T-cell leukemia virus type 1 (HTLV-1) gp21 envelope glycoprotein spanning residues 347-374. We used a novel template design and a unique synthetic approach to construct two peptides (WCCR2T and CCR2T) that would each assemble into a triple helical coiled coil conformation mimicking the gp21 crystal structure. The peptide B-cell epitopes were grafted onto the epsilon side chains of three lysyl residues on a template backbone construct consisting of the sequence acetyl-XGKGKGKGCONH2 (where X represents the tetanus toxoid promiscuous T cell epitope (TT) sequence 580-599). Leucine substitutions were introduced at the a and d positions of the CCR2T sequence to maximize helical character and stability as shown by circular dichroism and guanidinium hydrochloride studies. Serum from an HTLV-1-infected patient was able to recognize the selected epitopes by enzyme-linked immunosorbent assay (ELISA). Mice immunized with the wild-type sequence (WCCR2T) and the mutant sequence (CCR2T) elicited high antibody titers that were capable of recognizing the native protein as shown by flow cytometry and whole virus ELISA. Sera and purified antibodies from immunized mice were able to reduce the formation of syncytia induced by the envelope glycoprotein of HTLV-1, suggesting that antibodies directed against the coiled coil region of gp21 are capable of disrupting cell-cell fusion. Our results indicate that these peptides represent potential candidates for use in a peptide vaccine against HTLV-1.

  3. Novos paradigmas literários

    Directory of Open Access Journals (Sweden)

    Denise Azevedo Duarte Guimarães

    2005-12-01

    Full Text Available O artigo estuda a emergência de novos paradigmas literários, procurando refletir acerca das textualidades contemporâneas. Focaliza os hipertextos informatizados e a poesia multimídia, com o intuito de desvendar como estão sendo criados novos procedimentos expressivos e em que medida eles podem ser identificados com reflexões teóricas anteriores acerca do texto literário impresso. Remete a questões ligadas à leitura dos diferentes tipos de signos e aos modos como eles se integram para a constituição dessas novíssimas linguagens híbridas em novos suportes.El artículo estudia la emergencia de nuevos paradigmas literarios, procurando reflejar acerca de las textualidades contemporáneas. Enfoca los hipertextos informatizados y la poesía multimedia, intentando desvendar cómo están siendo creados nuevos procedimientos expresivos y en qué medida ellos pueden ser identificados a reflexiones teóricas anteriores acerca del texto literario impreso. Remite a cuestiones ligadas a la lectura de los diferentes tipos de signos y a los modos cómo ellos se interaccionan para la constitución de los novísimos lenguajes híbridos en nuevos supuestos.This article investigates the emergence of new literary paradigms as it tries to understand new contemporary textualities. It analyses some hypertexts and multimedia poetry trying to trace how new expressive procedures are being created. How can these new languages be identified and what are their relations to previous theories which dealt with the literary printed text? This study approaches questions linked to the reading of different types of signs and the modes they function towards the fabrication of these new hybrid languages.

  4. De novo autoimmune hepatitis after liver transplantation.

    Science.gov (United States)

    Lohse, Ansgar W; Weiler-Norman, Christina; Burdelski, Martin

    2007-10-01

    The Kings College group was the first to describe a clinical syndrome similar to autoimmune hepatitis in children and young adults transplanted for non-immune mediated liver diseases. They coined the term "de novo autoimmune hepatitis". Several other liver transplant centres confirmed this observation. Even though the condition is uncommon, patients with de novo AIH are now seen in most of the major transplant centres. The disease is usually characterized by features of acute hepatitis in otherwise stable transplant recipients. The most characteristic laboratory hallmark is a marked hypergammaglobulinaemia. Autoantibodies are common, mostly ANA. We described also a case of LKM1-positivity in a patients transplanted for Wilson's disease, however this patients did not develop clinical or histological features of AIH. Development of SLA/LP-autoantibodies is also not described. Therefore, serologically de novo AIH appears to correspond to type 1 AIH. Like classical AIH patients respond promptly to treatment with increased doses of prednisolone and azathioprine, while the calcineurin inhibitors cyclosporine or tacrolimus areof very limited value - which is not surprising, as almost all patients develop de novo AIH while receiving these drugs. Despite the good response to treatment, most patients remain a clinical challenge as complete stable remissions are uncommon and flares, relapses and chronic disease activity can often occur. Pathogenetically this syndrome is intriguing. It is not clear, if the immune response is directed against allo-antigens, neo-antigens in the liver, or self-antigens, possibly shared by donor and host cells. It is very likely that the inflammatory milieu due to alloreactive cells in the transplanted organ contribute to the disease process. Either leading to aberrant antigen presentation, or providing co-stimulatory signals leading to the breaking of self-tolerance. The development of this disease in the presence of treatment with calcineurin

  5. Efficient assembly of de novo human artificial chromosomes from large genomic loci

    Directory of Open Access Journals (Sweden)

    Stromberg Gregory

    2005-07-01

    Full Text Available Abstract Background Human Artificial Chromosomes (HACs are potentially useful vectors for gene transfer studies and for functional annotation of the genome because of their suitability for cloning, manipulating and transferring large segments of the genome. However, development of HACs for the transfer of large genomic loci into mammalian cells has been limited by difficulties in manipulating high-molecular weight DNA, as well as by the low overall frequencies of de novo HAC formation. Indeed, to date, only a small number of large (>100 kb genomic loci have been reported to be successfully packaged into de novo HACs. Results We have developed novel methodologies to enable efficient assembly of HAC vectors containing any genomic locus of interest. We report here the creation of a novel, bimolecular system based on bacterial artificial chromosomes (BACs for the construction of HACs incorporating any defined genomic region. We have utilized this vector system to rapidly design, construct and validate multiple de novo HACs containing large (100–200 kb genomic loci including therapeutically significant genes for human growth hormone (HGH, polycystic kidney disease (PKD1 and ß-globin. We report significant differences in the ability of different genomic loci to support de novo HAC formation, suggesting possible effects of cis-acting genomic elements. Finally, as a proof of principle, we have observed sustained ß-globin gene expression from HACs incorporating the entire 200 kb ß-globin genomic locus for over 90 days in the absence of selection. Conclusion Taken together, these results are significant for the development of HAC vector technology, as they enable high-throughput assembly and functional validation of HACs containing any large genomic locus. We have evaluated the impact of different genomic loci on the frequency of HAC formation and identified segments of genomic DNA that appear to facilitate de novo HAC formation. These genomic loci

  6. Automated de novo phasing and model building of coiled-coil proteins.

    Science.gov (United States)

    Rämisch, Sebastian; Lizatović, Robert; André, Ingemar

    2015-03-01

    Models generated by de novo structure prediction can be very useful starting points for molecular replacement for systems where suitable structural homologues cannot be readily identified. Protein-protein complexes and de novo-designed proteins are examples of systems that can be challenging to phase. In this study, the potential of de novo models of protein complexes for use as starting points for molecular replacement is investigated. The approach is demonstrated using homomeric coiled-coil proteins, which are excellent model systems for oligomeric systems. Despite the stereotypical fold of coiled coils, initial phase estimation can be difficult and many structures have to be solved with experimental phasing. A method was developed for automatic structure determination of homomeric coiled coils from X-ray diffraction data. In a benchmark set of 24 coiled coils, ranging from dimers to pentamers with resolutions down to 2.5 Å, 22 systems were automatically solved, 11 of which had previously been solved by experimental phasing. The generated models contained 71-103% of the residues present in the deposited structures, had the correct sequence and had free R values that deviated on average by 0.01 from those of the respective reference structures. The electron-density maps were of sufficient quality that only minor manual editing was necessary to produce final structures. The method, named CCsolve, combines methods for de novo structure prediction, initial phase estimation and automated model building into one pipeline. CCsolve is robust against errors in the initial models and can readily be modified to make use of alternative crystallographic software. The results demonstrate the feasibility of de novo phasing of protein-protein complexes, an approach that could also be employed for other small systems beyond coiled coils.

  7. De novo pathway-based biomarker identification

    DEFF Research Database (Denmark)

    Alcaraz, Nicolas; List, Markus; Batra, Richa

    2017-01-01

    in a large cohort of breast cancer samples from The Cancer Genome Atlas (TCGA) revealed that MGs are considerably more stable than SG models, while also providing valuable insight into the cancer hallmarks that drive them. In addition, when tested on an independent benchmark non-TCGA dataset, MG features......Gene expression profiles have been extensively discussed as an aid to guide the therapy by predicting disease outcome for the patients suffering from complex diseases, such as cancer. However, prediction models built upon single-gene (SG) features show poor stability and performance on independent...... on their molecular subtypes can provide a detailed view of the disease and lead to more personalized therapies. We propose and discuss a novel MG approach based on de novo pathways, which for the first time have been used as features in a multi-class setting to predict cancer subtypes. Comprehensive evaluation...

  8. Spaced Seed Data Structures for De Novo Assembly

    Directory of Open Access Journals (Sweden)

    Inanç Birol

    2015-01-01

    Full Text Available De novo assembly of the genome of a species is essential in the absence of a reference genome sequence. Many scalable assembly algorithms use the de Bruijn graph (DBG paradigm to reconstruct genomes, where a table of subsequences of a certain length is derived from the reads, and their overlaps are analyzed to assemble sequences. Despite longer subsequences unlocking longer genomic features for assembly, associated increase in compute resources limits the practicability of DBG over other assembly archetypes already designed for longer reads. Here, we revisit the DBG paradigm to adapt it to the changing sequencing technology landscape and introduce three data structure designs for spaced seeds in the form of paired subsequences. These data structures address memory and run time constraints imposed by longer reads. We observe that when a fixed distance separates seed pairs, it provides increased sequence specificity with increased gap length. Further, we note that Bloom filters would be suitable to implicitly store spaced seeds and be tolerant to sequencing errors. Building on this concept, we describe a data structure for tracking the frequencies of observed spaced seeds. These data structure designs will have applications in genome, transcriptome and metagenome assemblies, and read error correction.

  9. Los "intelectuales" y el Estado Novo

    Directory of Open Access Journals (Sweden)

    Luís REIS TORGAL

    2010-02-01

    Full Text Available RESUMEN: El concepto de “intelectual” es difícil de definir y sin duda se debate constantemente. Sin embargo, es importante reflexionar sobre él a fin de comprender su significado y los problemas que implica. Sea como fuere, a un Estado autoritario “moderno” se le supone una única ideología que tiene que difundirse por medio de una propaganda bien organizada, proceso en el que los intelectuales desempeñan un papel significativo. El “Nuevo Estado” de Salazar encaja en esta categoría y sin duda el conocimiento acerca de sus “intelectuales” es fundamental. En este artículo, el objetivo es proporcionar algunos ejemplos interesantes de “intelectuales” o de simples “funcionarios políticos” con inclinación intelectual a fin de indicar el sentido y complejidad de un estudio con una dimensión distinta sobre este asunto. A este fin han sido seleccionadas tres personalidades responsables de la actividad ideológica y cultural de gran relieve en el Estado de Salazar: António Ferro, João Ameal y Costa Brochado. Palabras clave: Estado Novo; Authotitarianism; Salazar, António de Oliveira; Intellectuals; Ferro, António; Brochado, Idalino da Costa; Ameal, João. ABSTRACT: The concept of the “intellectual” is difficult to define and undoubtedly constantly debated. It is nevertheless important to reflect on it in order to understand its meaning and the problems involved with it. Be that as it may, a “modern” authoritarian State presumes a single ideology which has to be diffused by means of well-organised propaganda, in which process “intellectuals” play a significant role. Salazar’s “New State” fits this category and, undoubtedly, knowledge about its “intellectuals” is fundamental. The objective in this article is to provide some interesting examples of “intellectuals” or simple “political functionar- ies” with an intellectual bent so as to indicate the sense and complexity of a study of a

  10. Icarus: visualizer for de novo assembly evaluation.

    Science.gov (United States)

    Mikheenko, Alla; Valin, Gleb; Prjibelski, Andrey; Saveliev, Vladislav; Gurevich, Alexey

    2016-11-01

    : Data visualization plays an increasingly important role in NGS data analysis. With advances in both sequencing and computational technologies, it has become a new bottleneck in genomics studies. Indeed, evaluation of de novo genome assemblies is one of the areas that can benefit from the visualization. However, even though multiple quality assessment methods are now available, existing visualization tools are hardly suitable for this purpose. Here, we present Icarus-a novel genome visualizer for accurate assessment and analysis of genomic draft assemblies, which is based on the tool QUAST. Icarus can be used in studies where a related reference genome is available, as well as for non-model organisms. The tool is available online and as a standalone application. http://cab.spbu.ru/software/icarus CONTACT: aleksey.gurevich@spbu.ruSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. [Diagnosis and management of de novo epilepsy].

    Science.gov (United States)

    Louise, Tyvaert

    2018-03-01

    The diagnosis of de novo epilepsy is complex. An accurate diagnostic approach has to be followed based on specific key steps. Epileptic seizure or non-epileptic malaise: risk of diagnosis error around 20%. Facing a first unprovoked seizure, the practitioner has to know the risk factors specifically linked to an increase risk of seizure recurrence. In presence of these factors, an antiepileptic drug would be indicated. The first antiepileptic drug has to be highly selected according to the epilepsy type and causes but also to the patient characteristics (sex, age, comorbidities, associated drugs, profession, and way of life…) An exhaustive patient Education needs to support the first antiepileptic drug prescription: (sleep and nutritional advices, benefit of observance, antiepileptic drugs features and side effects, follow-up, prognosis…) A regular follow-up is essential to control the observance, tolerability and efficacy of the antiepileptic drug, and to control also the good acceptance of the disease. A systematic research of common comorbidities may be also performed. Electroencephalogram and antiepileptic drugs levels are unnecessary in the classical follow up of known epileptic patients (except specific cases). Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. De novo origin of human protein-coding genes.

    Directory of Open Access Journals (Sweden)

    Dong-Dong Wu

    2011-11-01

    Full Text Available The de novo origin of a new protein-coding gene from non-coding DNA is considered to be a very rare occurrence in genomes. Here we identify 60 new protein-coding genes that originated de novo on the human lineage since divergence from the chimpanzee. The functionality of these genes is supported by both transcriptional and proteomic evidence. RNA-seq data indicate that these genes have their highest expression levels in the cerebral cortex and testes, which might suggest that these genes contribute to phenotypic traits that are unique to humans, such as improved cognitive ability. Our results are inconsistent with the traditional view that the de novo origin of new genes is very rare, thus there should be greater appreciation of the importance of the de novo origination of genes.

  13. De Novo Origin of Human Protein-Coding Genes

    Science.gov (United States)

    Wu, Dong-Dong; Irwin, David M.; Zhang, Ya-Ping

    2011-01-01

    The de novo origin of a new protein-coding gene from non-coding DNA is considered to be a very rare occurrence in genomes. Here we identify 60 new protein-coding genes that originated de novo on the human lineage since divergence from the chimpanzee. The functionality of these genes is supported by both transcriptional and proteomic evidence. RNA–seq data indicate that these genes have their highest expression levels in the cerebral cortex and testes, which might suggest that these genes contribute to phenotypic traits that are unique to humans, such as improved cognitive ability. Our results are inconsistent with the traditional view that the de novo origin of new genes is very rare, thus there should be greater appreciation of the importance of the de novo origination of genes. PMID:22102831

  14. Identifying wrong assemblies in de novo short read primary ...

    Indian Academy of Sciences (India)

    2016-08-05

    Aug 5, 2016 ... Most of these assemblies are done using some de novo short read assemblers and other related approaches. .... benchmarking projects like Assemblathon 1, Assemblathon ... from a large insert library (at least 1000 bases).

  15. Arginine de novo and nitric oxide production in disease states

    OpenAIRE

    Luiking, Yvette C.; Ten Have, Gabriella A. M.; Wolfe, Robert R.; Deutz, Nicolaas E. P.

    2012-01-01

    Arginine is derived from dietary protein intake, body protein breakdown, or endogenous de novo arginine production. The latter may be linked to the availability of citrulline, which is the immediate precursor of arginine and limiting factor for de novo arginine production. Arginine metabolism is highly compartmentalized due to the expression of the enzymes involved in arginine metabolism in various organs. A small fraction of arginine enters the NO synthase (NOS) pathway. Tetrahydrobiopterin ...

  16. De Novo Collapsing Glomerulopathy in a Renal Allograft Recipient

    Directory of Open Access Journals (Sweden)

    Kanodia K

    2008-01-01

    Full Text Available Collapsing glomerulopathy (CG, characterized histologically by segmental/global glomerular capillary collapse, podocyte hypertrophy and hypercellularity and tubulo-interstitial injury; is characterized clinically by massive proteinuria and rapid progressive renal failure. CG is known to recur in renal allograft and rarely de novo. We report de novo CG 3 years post-transplant in a patient who received renal allograft from haplo-identical type donor.

  17. Language and national identity in Novo Cinema Galego

    Directory of Open Access Journals (Sweden)

    Brais ROMERO SUÁREZ

    2015-12-01

    Full Text Available The talk of town since its inception in 2010, the Cinema Novo Galego has been successful in all competitions and festivals that has been present. From the FIPRESCI prize in Cannes to the Best Emerging Director at Locarno, this new wave of cinema places Galicia in the world film stage. But does Novo Cinema Galego an accurate representation of Galicia? What's the role of Galicia in this movement?

  18. Radioisotope devices at Novo-Krivorozhskij-ore-enrichment plant

    International Nuclear Information System (INIS)

    Levitskij, V.Ya.; Kucher, V.G.; Ministerstvo Chernoj Metallurgii Ukrainskoj SSR, Dnepropetrovsk, Bazovaya Opytno-Konstruktorskaya Izotopnaya lab.)

    1975-01-01

    Use of the ''Ferrite'' analyzers, AZhR and PAZh-1 and the GR-7 gamma relay in different engineering areas of the Novo-Krivorozh ore-enrichment plant is evaluated. The ''Ferrite'' radioisotopic analyzer was designed for rapid roentgeno-radiometric determination of the total iron and iron group element contents in powdered samples of ores and products of their treatment. From the density of the flux of the characteristic radiation it is possible to determine quantitatively the content of the element of interest in the analyzed material. The radioisotpic analyzer AZhR-1 is distinguished by its high efficiency in the analysis for total iron on products of processing of iron ore raw materials. The use of this apparatus allows complete replacement of the chemical method for rapid analysis of concentrates by the roentgeno-radiometric method, which decreases the total analytical work on determination of total iron and speeds up output of information on concentrate quality. The radioisotopic gamma analyzer PAZh-1 is designed for automatic and either continuous or discrete measurement of the total iron content in iron ore materials ground to 50 mm, carried on a conveyor, without selection or preparation of the samples for analysis. The analyzer operates on the principle of measuring the average frequency of impingement on a detector of gamma quanta back-scattered by the analyzed material. This frequency is determined by the percentage content of total iron in the material. The apparatus operates continuously. The mean square deviation of the apparatus values from chemical data is 0.93% Fesub(total). Use of the apparatus greatly increases the operativeness of the control and decreases the laboriousness of raw material sampling in an engineering stream. The radioisotopic data units GR-7 are designed for control of the level of materials in hoppers for recovery and burning of agglomerates. Use of this apparatus showed its great advantage over data units of other types

  19. Clinicopathologic factors associated with de novo metastatic breast cancer.

    Science.gov (United States)

    Shen, Tiansheng; Siegal, Gene P; Wei, Shi

    2016-12-01

    While breast cancers with distant metastasis at presentation (de novo metastasis) harbor significantly inferior clinical outcomes, there have been limited studies analyzing the clinicopathologic characteristics in this subset of patients. In this study, we analyzed 6126 breast cancers diagnosed between 1998 and 2013 to identify factors associated with de novo metastatic breast cancer. When compared to patients without metastasis at presentation, race, histologic grade, estrogen/progesterone receptor (ER/PR) and HER2 statuses were significantly associated with de novo metastasis in the entire cohort, whereas age, histologic grade, PR and HER2 status were the significant parameters in the subset of patients with locally advanced breast cancer (Stage IIB/III). The patients with de novo metastatic breast cancer had a significant older mean age and a lower proportion of HER2-positive tumors when compared to those with metastatic recurrence. Further, the HER2-rich subtype demonstrated a drastically higher incidence of de novo metastasis when compared to the luminal and triple-negative breast cancers in the entire cohort [odds ratio (OR)=5.68 and 2.27, respectively] and in the patients with locally advanced disease (OR=4.02 and 2.12, respectively), whereas no significant difference was seen between de novo metastatic cancers and those with metastatic recurrence. Moreover, the luminal and HER2-rich subtypes showed bone-seeking (OR=1.92) and liver-homing (OR=2.99) characteristics, respectively, for the sites of de novo metastasis, while the latter was not observed in those with metastatic recurrence. Our data suggest that an algorithm incorporating clinicopathologic factors, especially histologic grade and receptor profile, remains of significant benefit during decision making in newly diagnosed breast cancer in the pursuit of precision medicine. Copyright © 2016 Elsevier GmbH. All rights reserved.

  20. De novo status epilepticus with isolated aphasia.

    Science.gov (United States)

    Flügel, Dominique; Kim, Olaf Chan-Hi; Felbecker, Ansgar; Tettenborn, Barbara

    2015-08-01

    Sudden onset of aphasia is usually due to stroke. Rapid diagnostic workup is necessary if reperfusion therapy is considered. Ictal aphasia is a rare condition but has to be excluded. Perfusion imaging may differentiate acute ischemia from other causes. In dubious cases, EEG is required but is time-consuming and laborious. We report a case where we considered de novo status epilepticus as a cause of aphasia without any lesion even at follow-up. A 62-year-old right-handed woman presented to the emergency department after nurses found her aphasic. She had undergone operative treatment of varicosis 3 days earlier. Apart from hypertension and obesity, no cardiovascular risk factors and no intake of medication other than paracetamol were reported. Neurological examination revealed global aphasia and right pronation in the upper extremity position test. Computed tomography with angiography and perfusion showed no abnormalities. Electroencephalogram performed after the CT scan showed left-sided slowing with high-voltage rhythmic 2/s delta waves but no clear ictal pattern. Intravenous lorazepam did improve EEG slightly, while aphasia did not change. Lumbar puncture was performed which likely excluded encephalitis. Magnetic resonance imaging showed cortical pathological diffusion imaging (restriction) and cortical hyperperfusion in the left parietal region. Intravenous anticonvulsant therapy under continuous EEG resolved neurological symptoms. The patient was kept on anticonvulsant therapy. Magnetic resonance imaging after 6 months showed no abnormalities along with no clinical abnormalities. Magnetic resonance imaging findings were only subtle, and EEG was without clear ictal pattern, so the diagnosis of aphasic status remains with some uncertainty. However, status epilepticus can mimic stroke symptoms and has to be considered in patients with aphasia even when no previous stroke or structural lesions are detectable and EEG shows no epileptic discharges. Epileptic origin is

  1. Purine biosynthesis de novo by lymphocytes in gout

    International Nuclear Information System (INIS)

    Kamoun, P.; Chanard, J.; Brami, M.; Funck-Brentano, J.L.

    1978-01-01

    A method of measurement in vitro of purine biosynthesis de novo in human circulating blood lymphocytes is proposed. The rate of early reactions of purine biosynthesis de novo was determined by the incorporation of [ 14 C]formate into N-formyl glycinamide ribonucleotide when the subsequent reactions of the metabolic pathway were completely inhibited by the antibiotic azaserine. Synthesis of 14 C-labelled N-formyl glycinamide ribonucleotide by lymphocytes was measured in healthy control subjects and patients with primary gout or hyperuricaemia secondary to renal failure, with or without allopurinol therapy. The average synthesis was higher in gouty patients without therapy than in control subjects, but the values contained overlap the normal range. In secondary hyperuricaemia the synthesis was at same value as in control subjects. These results are in agreement with the inconstant acceleration of purine biosynthesis de novo in gouty patients as seen by others with measurement of [ 14 C]glycine incorporation into urinary uric acid. (author)

  2. De novo transcriptome assembly associated with fumonisin production by the rice pathogen Fusarium fujikuroi

    Directory of Open Access Journals (Sweden)

    Keerthi S. Guruge

    2018-06-01

    Full Text Available The present study employed a next-generation sequencing method to assemble a de novo transcriptome database designed to distinguish gene expression changes exhibited by the fumonisin-producing fungus Fusarium fujikuroi when grown under ‘fumonisin-producing’ compared to ‘non-fumonisin-producing’ conditions. The raw data of this study have been deposited at DNA Data Bank of Japan (DDBJ under the accession ID DRA006146. Keywords: Fusarium fujikuroi, Fumonisin, Next-generation sequencing, Transcriptome, Gene-expression

  3. Persistent hyperthyroidism and de novo Graves' ophthalmopathy after total thyroidectomy.

    Science.gov (United States)

    Tay, Wei Lin; Loh, Wann Jia; Lee, Lianne Ai Ling; Chng, Chiaw Ling

    2017-01-01

    We report a patient with Graves' disease who remained persistently hyperthyroid after a total thyroidectomy and also developed de novo Graves' ophthalmopathy 5 months after surgery. She was subsequently found to have a mature cystic teratoma containing struma ovarii after undergoing a total hysterectomy and salpingo-oophorectomy for an incidental ovarian lesion. It is important to investigate for other causes of primary hyperthyroidism when thyrotoxicosis persists after total thyroidectomy.TSH receptor antibody may persist after total thyroidectomy and may potentially contribute to the development of de novo Graves' ophthalmopathy.

  4. Demanda dos principais metais e novos materiais : analise de tendencias

    OpenAIRE

    Wilson Trigueiro de Sousa

    1990-01-01

    Resumo: Neste trabalho são analisadas algumas tendências na área de novos materiais na tentativa de obter um melhor entendimento das repercussões das atuais inovações tecnológicas para o setor mineral. Inicialmente são revisados os principais estudos sobre as mudanças ocorridas por volta de 1972/74 no comportamento da demanda dos metais mais importantes. Entre as possíveis causas, está o progresso técnico, que tornou possível o surgimento de novos materiais e o aperfeiçoamento de outros em us...

  5. Engineering a de Novo Transport Tunnel

    Czech Academy of Sciences Publication Activity Database

    Březovský, J.; Babková, P.; Degtjarik, Oksana; Fořtová, A.; Gora, A.; Iermak, Iuliia; Řezáčová, Pavlína; Dvořák, P.; Kutá Smatanová, Ivana; Prokop, Z.; Chaloupková, R.; Damborský, J.

    2016-01-01

    Roč. 6, č. 11 (2016), s. 7597-7610 ISSN 2155-5435 Institutional support: RVO:61388971 ; RVO:68378050 Keywords : transport tunnel * protein engineering * protein design Subject RIV: EE - Microbiology, Virology Impact factor: 10.614, year: 2016

  6. Engineering a de Novo Transport Tunnel

    Czech Academy of Sciences Publication Activity Database

    Březovský, J.; Babková, P.; Degtjarik, O.; Fořtová, A.; Gora, A.; Iermak, I.; Řezáčová, Pavlína; Dvořák, P.; Kutá Smatanová, I.; Prokop, Z.; Chaloupková, R.; Damborský, J.

    2016-01-01

    Roč. 6, č. 11 (2016), s. 7597-7610 ISSN 2155-5435 Institutional support: RVO:61388963 Keywords : transport tunnel * protein engineering * protein design * activity * specificity Subject RIV: CE - Biochemistry Impact factor: 10.614, year: 2016

  7. Model-Based GUI Testing Using Uppaal at Novo Nordisk

    DEFF Research Database (Denmark)

    H. Hjort, Ulrik; Rasmussen, Jacob Illum; Larsen, Kim Guldstrand

    2009-01-01

    This paper details a collaboration between Aalborg University and Novo Nordiskin developing an automatic model-based test generation tool for system testing of the graphical user interface of a medical device on an embedded platform. The tool takes as input an UML Statemachine model and generates...

  8. De novo synthesis of milk triglycerides in humans

    Science.gov (United States)

    Mammary gland (MG) de novo lipogenesis contributes significantly to milk fat in animals but little is known in humans. Objective: To test the hypothesis that the incorporation of 13C carbons from [U-13C]glucose into fatty acids (FA) and glycerol in triglycerides (TG) will be greater: 1) in milk tha...

  9. Response monitoring in de novo patients with Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Rita Willemssen

    Full Text Available BACKGROUND: Parkinson's disease (PD is accompanied by dysfunctions in a variety of cognitive processes. One of these is error processing, which depends upon phasic decreases of medial prefrontal dopaminergic activity. Until now, there is no study evaluating these processes in newly diagnosed, untreated patients with PD ("de novo PD". METHODOLOGY/PRINCIPAL FINDINGS: Here we report large changes in performance monitoring processes using event-related potentials (ERPs in de novo PD-patients. The results suggest that increases in medial frontal dopaminergic activity after an error (Ne are decreased, relative to age-matched controls. In contrast, neurophysiological processes reflecting general motor response monitoring (Nc are enhanced in de novo patients. CONCLUSIONS/SIGNIFICANCE: It may be hypothesized that the Nc-increase is at costs of dopaminergic activity after an error; on a functional level errors may not always be detected and correct responses sometimes be misinterpreted as errors. This pattern differs from studies examining patients with a longer history of PD and may reflect compensatory processes, frequently occurring in pre-manifest stages of PD. From a clinical point of view the clearly attenuated Ne in the de novo PD patients may prove a useful additional tool for the early diagnosis of basal ganglia dysfunction in PD.

  10. Foldability of a Natural De Novo Evolved Protein.

    Science.gov (United States)

    Bungard, Dixie; Copple, Jacob S; Yan, Jing; Chhun, Jimmy J; Kumirov, Vlad K; Foy, Scott G; Masel, Joanna; Wysocki, Vicki H; Cordes, Matthew H J

    2017-11-07

    The de novo evolution of protein-coding genes from noncoding DNA is emerging as a source of molecular innovation in biology. Studies of random sequence libraries, however, suggest that young de novo proteins will not fold into compact, specific structures typical of native globular proteins. Here we show that Bsc4, a functional, natural de novo protein encoded by a gene that evolved recently from noncoding DNA in the yeast S. cerevisiae, folds to a partially specific three-dimensional structure. Bsc4 forms soluble, compact oligomers with high β sheet content and a hydrophobic core, and undergoes cooperative, reversible denaturation. Bsc4 lacks a specific quaternary state, however, existing instead as a continuous distribution of oligomer sizes, and binds dyes indicative of amyloid oligomers or molten globules. The combination of native-like and non-native-like properties suggests a rudimentary fold that could potentially act as a functional intermediate in the emergence of new folded proteins de novo. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. On the performance of de novo pathway enrichment

    DEFF Research Database (Denmark)

    Batra, Richa; Alcaraz, Nicolas; Gitzhofer, Kevin

    2017-01-01

    De novo pathway enrichment is a powerful approach to discover previously uncharacterized molecular mechanisms in addition to already known pathways. To achieve this, condition-specific functional modules are extracted from large interaction networks. Here, we give an overview of the state...

  12. De Novo Coding Variants Are Strongly Associated with Tourette Disorder

    DEFF Research Database (Denmark)

    Willsey, A Jeremy; Fernandez, Thomas V; Yu, Dongmei

    2017-01-01

    Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 ...

  13. Illumina-based de novo transcriptome sequencing and analysis

    Indian Academy of Sciences (India)

    In the present study, we used Illumina HiSeq technology to perform de novo assembly of heart and musk gland transcriptomes from the Chinese forest musk deer. A total of 239,383 transcripts and 176,450 unigenes were obtained, of which 37,329 unigenes were matched to known sequences in the NCBI nonredundant ...

  14. De novo structural modeling and computational sequence analysis ...

    African Journals Online (AJOL)

    Different bioinformatics tools and machine learning techniques were used for protein structural classification. De novo protein modeling was performed by using I-TASSER server. The final model obtained was accessed by PROCHECK and DFIRE2, which confirmed that the final model is reliable. Until complete biochemical ...

  15. Direct Visualization of De novo Lipogenesis in Single Living Cells

    Science.gov (United States)

    Li, Junjie; Cheng, Ji-Xin

    2014-10-01

    Increased de novo lipogenesis is being increasingly recognized as a hallmark of cancer. Despite recent advances in fluorescence microscopy, autoradiography and mass spectrometry, direct observation of de novo lipogenesis in living systems remains to be challenging. Here, by coupling stimulated Raman scattering (SRS) microscopy with isotope labeled glucose, we were able to trace the dynamic metabolism of glucose in single living cells with high spatial-temporal resolution. As the first direct visualization, we observed that glucose was largely utilized for lipid synthesis in pancreatic cancer cells, which occurs at a much lower rate in immortalized normal pancreatic epithelial cells. By inhibition of glycolysis and fatty acid synthase (FAS), the key enzyme for fatty acid synthesis, we confirmed the deuterium labeled lipids in cancer cells were from de novo lipid synthesis. Interestingly, we also found that prostate cancer cells exhibit relatively lower level of de novo lipogenesis, but higher fatty acid uptake compared to pancreatic cancer cells. Together, our results demonstrate a valuable tool to study dynamic lipid metabolism in cancer and other disorders.

  16. Particulated articular cartilage: CAIS and DeNovo NT.

    Science.gov (United States)

    Farr, Jack; Cole, Brian J; Sherman, Seth; Karas, Vasili

    2012-03-01

    Cartilage Autograft Implantation System (CAIS; DePuy/Mitek, Raynham, MA) and DeNovo Natural Tissue (NT; ISTO, St. Louis, MO) are novel treatment options for focal articular cartilage defects in the knee. These methods involve the implantation of particulated articular cartilage from either autograft or juvenile allograft donor, respectively. In the laboratory and in animal models, both CAIS and DeNovo NT have demonstrated the ability of the transplanted cartilage cells to "escape" from the extracellular matrix, migrate, multiply, and form a new hyaline-like cartilage tissue matrix that integrates with the surrounding host tissue. In clinical practice, the technique for both CAIS and DeNovo NT is straightforward, requiring only a single surgery to affect cartilage repair. Clinical experience is limited, with short-term studies demonstrating both procedures to be safe, feasible, and effective, with improvements in subjective patient scores, and with magnetic resonance imaging evidence of good defect fill. While these treatment options appear promising, prospective randomized controlled studies are necessary to refine the indications and contraindications for both CAIS and DeNovo NT.

  17. A gestão de design na concepção de novos produtos: uma ferramenta de integração do processo de gestão e inovação MANAGEMENT OF DESIGN IN CONCEPTION OF NEW PRODUCTS: A TOOL FOR INTEGRATION OF CASE MANAGEMENT AND INNOVATION

    Directory of Open Access Journals (Sweden)

    Silvana Saionara Gollo

    2010-12-01

    Full Text Available O artigo tem como objetivo o desenvolvimento de um framework de gestão de design focado na maximização do fluxo de informações no desenvolvimento de produtos inovadores em organizações competitivas. A metodologia utilizada no estudo baseou-se na teoria levantada por meio de revisão bibliográfica, delineando uma pesquisa qualitativa, de caráter exploratório, através de estudo de caso. As variáveis trabalhadas permitiram a análise, identificação e classificação do processo de desenvolvimento de produtos em quatro empresas de diferentes ramos de atividade industrial. O trabalho partiu do pressuposto de que o design, incorporado na estrutura organizacional de uma empresa por meio da gestão de design e integrado com as demais unidades de negócios, fortalece a estratégia das organizações. Normal 0 21 false false false PT-BR X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabela normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} The article aims at developing a framework for the management of design focused on maximizing the flow of information in the development of innovative products at competitive organizations. The methodology used in the study was based on the theory raised by means of literature review, outlining a qualitative research, exploratory in nature, through case study. The variables worked led the analysis

  18. Seaside, ícone do novo urbanismo

    Directory of Open Access Journals (Sweden)

    Adilson Costa Macedo

    2011-10-01

    Full Text Available The town of Seaside case study brings home to questions related to the Congress for the new urbanism, founded in 1993. This town, the second designed by the architects Andres Duany and Elizabeth Plater Zyberk is based upon revising partterns of the traditional way to build small communities in America. Both, the urban tissues and the building prototypes have been considered. Following the process used by the architectural firms to conceptualize, develop and implement urban design projects the plan for Seaside is analysed. The town was carefully programmed, designed and built. Thus, the present paper describes the interactions between the developer, the architects and the community involved, concluding that the good interaction among them is the clue for the success of any project. As a matter of contolling the urban development a code was created in a first version. Afterwards this code is unfolded to urban design more generic elements in order to fit different situations. It is denominated smar code and up to now it reached the ninth version. The plan for Seaside emphasizes the importance of the triangle drama binding the developer, architect and community to achieve a high quality project. Being successful Seaside stimulated many other initiatives along side the Gulf of Mexico panhandle.

  19. Genome-wide patterns and properties of de novo mutations in humans

    NARCIS (Netherlands)

    Francioli, Laurent C.; Polak, Paz P.; Koren, Amnon; Menelaou, Androniki; Chun, Sung; Renkens, Ivo; van Duijn, Cornelia M.; Swertz, Morris; Wijmenga, Cisca; van Ommen, Gertjan; Slagboom, P. Eline; Boomsma, Dorret I.; Ye, Kai; Guryev, Victor; Arndt, Peter F.; Kloosterman, Wigard P.; de Bakker, Paul I. W.; Sunyaev, Shamil R.

    Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect(1-10). Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring

  20. Genome-wide patterns and properties of de novo mutations in humans

    NARCIS (Netherlands)

    Francioli, L.C.; Polak, P.P.; Koren, A.; Menelaou, A.; Chun, S.; Renkens, I.; van Duijn, C.M.; Swertz, M.A.; Wijmenga, C.; van Ommen, G.J.; Slagboom, P.E.; Boomsma, D.I.; Ye, K.; Guryev, V.; Arndt, P.F.; Kloosterman, W.P.; Bakker, P.I.W.; Sunyaev, S.R.; Dijk, F.; Neerincx, P.B.T.; Pulit, S.L.; Deelen, P.; Elbers, C.C.; Palamara, P.F.; Pe'er, I.; Abdellaoui, A.; van Oven, M.; Vermaat, M.; Li, M.; Laros, J.F.J.; Stoneking, M.; de Knijff, P.; Kayser, M.; Veldink, J.H.; Van den Berg, L.H.; Byelas, H.; den Dunnen, J.T.; Dijkstra, M.; Amin, N.; van der Velde, K.J.; Hottenga, J.J.; van Setten, J.; van Leeuwen, E.M.; Kanterakis, A.; Kattenberg, V.M.; Karssen, L.C.; van Schaik, B.D.C.; Bot, J.; Nijman, I.J.; van Enckevort, D.; Mei, H.; Koval, V.; Estrada, K.; Medina-Gomez, C.; Lameijer, E.W.; Moed, M.H.; Hehir-Kwa, J.Y.; Handsaker, R.E.; McCarroll, S.A.; Vuzman, D.; Sohail, M.; Hormozdiari, F.; Marschall, T.; Schönhuth, A.; Beekman, M.; de Craen, A.J.; Suchiman, H.E.D.; Hofman, A.; Oostra, B.; Isaacs, A.; Rivadeneira, F.; Uitterlinden, A.G.; Willemsen, G.; Platteel, M.; Pitts, S.J.; Potluri, S.; Sundar, P.; Cox, D.R.; Li, Q.; Li, Y.; Du, Y.; Chen, R.; Cao, H.; Li, N.; Cao, S.; Wang, J.; Bovenberg, J.A.; Brandsma, M.

    2015-01-01

    Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect. Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of

  1. ChemTS: an efficient python library for de novo molecular generation

    Science.gov (United States)

    Yang, Xiufeng; Zhang, Jinzhe; Yoshizoe, Kazuki; Terayama, Kei; Tsuda, Koji

    2017-12-01

    Automatic design of organic materials requires black-box optimization in a vast chemical space. In conventional molecular design algorithms, a molecule is built as a combination of predetermined fragments. Recently, deep neural network models such as variational autoencoders and recurrent neural networks (RNNs) are shown to be effective in de novo design of molecules without any predetermined fragments. This paper presents a novel Python library ChemTS that explores the chemical space by combining Monte Carlo tree search and an RNN. In a benchmarking problem of optimizing the octanol-water partition coefficient and synthesizability, our algorithm showed superior efficiency in finding high-scoring molecules. ChemTS is available at https://github.com/tsudalab/ChemTS.

  2. Sensitivity-Informed De Novo Programming for Many-Objective Water Portfolio Planning Under Uncertainty

    Science.gov (United States)

    Kasprzyk, J. R.; Reed, P. M.; Kirsch, B. R.; Characklis, G. W.

    2009-12-01

    Risk-based water supply management presents severe cognitive, computational, and social challenges to planning in a changing world. Decision aiding frameworks must confront the cognitive biases implicit to risk, the severe uncertainties associated with long term planning horizons, and the consequent ambiguities that shape how we define and solve water resources planning and management problems. This paper proposes and demonstrates a new interactive framework for sensitivity informed de novo programming. The theoretical focus of our many-objective de novo programming is to promote learning and evolving problem formulations to enhance risk-based decision making. We have demonstrated our proposed de novo programming framework using a case study for a single city’s water supply in the Lower Rio Grande Valley (LRGV) in Texas. Key decisions in this case study include the purchase of permanent rights to reservoir inflows and anticipatory thresholds for acquiring transfers of water through optioning and spot leases. A 10-year Monte Carlo simulation driven by historical data is used to provide performance metrics for the supply portfolios. The three major components of our methodology include Sobol globoal sensitivity analysis, many-objective evolutionary optimization and interactive tradeoff visualization. The interplay between these components allows us to evaluate alternative design metrics, their decision variable controls and the consequent system vulnerabilities. Our LRGV case study measures water supply portfolios’ efficiency, reliability, and utilization of transfers in the water supply market. The sensitivity analysis is used interactively over interannual, annual, and monthly time scales to indicate how the problem controls change as a function of the timescale of interest. These results have been used then to improve our exploration and understanding of LRGV costs, vulnerabilities, and the water portfolios’ critical reliability constraints. These results

  3. When less is more: 'slicing' sequencing data improves read decoding accuracy and de novo assembly quality.

    Science.gov (United States)

    Lonardi, Stefano; Mirebrahim, Hamid; Wanamaker, Steve; Alpert, Matthew; Ciardo, Gianfranco; Duma, Denisa; Close, Timothy J

    2015-09-15

    As the invention of DNA sequencing in the 70s, computational biologists have had to deal with the problem of de novo genome assembly with limited (or insufficient) depth of sequencing. In this work, we investigate the opposite problem, that is, the challenge of dealing with excessive depth of sequencing. We explore the effect of ultra-deep sequencing data in two domains: (i) the problem of decoding reads to bacterial artificial chromosome (BAC) clones (in the context of the combinatorial pooling design we have recently proposed), and (ii) the problem of de novo assembly of BAC clones. Using real ultra-deep sequencing data, we show that when the depth of sequencing increases over a certain threshold, sequencing errors make these two problems harder and harder (instead of easier, as one would expect with error-free data), and as a consequence the quality of the solution degrades with more and more data. For the first problem, we propose an effective solution based on 'divide and conquer': we 'slice' a large dataset into smaller samples of optimal size, decode each slice independently, and then merge the results. Experimental results on over 15 000 barley BACs and over 4000 cowpea BACs demonstrate a significant improvement in the quality of the decoding and the final assembly. For the second problem, we show for the first time that modern de novo assemblers cannot take advantage of ultra-deep sequencing data. Python scripts to process slices and resolve decoding conflicts are available from http://goo.gl/YXgdHT; software Hashfilter can be downloaded from http://goo.gl/MIyZHs stelo@cs.ucr.edu or timothy.close@ucr.edu Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Design

    DEFF Research Database (Denmark)

    Volf, Mette

    This publication is unique in its demystification and operationalization of the complex and elusive nature of the design process. The publication portrays the designer’s daily work and the creative process, which the designer is a part of. Apart from displaying the designer’s work methods...... and design parameters, the publication shows examples from renowned Danish design firms. Through these examples the reader gets an insight into the designer’s reality....

  5. De Novo generation of molecular structures using optimization to select graphs on a given lattice

    DEFF Research Database (Denmark)

    Bywater, R.P.; Poulsen, Thomas Agersten; Røgen, Peter

    2004-01-01

    A recurrent problem in organic chemistry is the generation of new molecular structures that conform to some predetermined set of structural constraints that are imposed in an endeavor to build certain required properties into the newly generated structure. An example of this is the pharmacophore...... model, used in medicinal chemistry to guide de novo design or selection of suitable structures from compound databases. We propose here a method that efficiently links up a selected number of required atom positions while at the same time directing the emergent molecular skeleton to avoid forbidden...... positions. The linkage process takes place on a lattice whose unit step length and overall geometry is designed to match typical architectures of organic molecules. We use an optimization method to select from the many different graphs possible. The approach is demonstrated in an example where crystal...

  6. Melhoramento do cafeeiro: IV - Café Mundo Novo

    Directory of Open Access Journals (Sweden)

    A. Carvalho

    1952-06-01

    Full Text Available Em um conjunto de cafeeiros existentes em Mundo Novo, hoje Urupês, na região Araraquarense do Estado de São Paulo, foram feitas seleções de vários cafeeiros baseando-se no seu aspecto vegetativo, na produção existente na época da seleção e na provável produção do ano seguinte. Estudou-se a origem da plantação inicial desse café, tanto em Urupês como em Jaú, chegando-se à conclusão de que é provavelmente originário desta última localidade. Progênies do café "Mundo Novo", anteriormente conhecido por "Sumatra" e derivado de plantas selecionadas em Urupês e Jaú, acham-se em estudo em seis localidades do Estado : Campinas, Ribeirão Prêto, Pindorama, Mococa, Jaú e Monte Alegre do Sul. No presente trabalho são apenas aproveitados dados referentes à variabilidade morfológica e característicos da produção das progênies dos primeiros cafeeiros selecionados em Urupês e estudados em Campinas, Jaú, Pindorama e Mococa. Em tôdas as localidades, observou-se variação nos caracteres morfológicos das progênies, verificando-se a ocorrência de plantas quase improdutivas. A maioria das progênies, no entanto, se caracteriza por acentuado vigor vegetativo. Foram estudadas as produções totais das progénies e das plantas, no período 1946-1951, notando-se que algumas progénies se salientaram pela elevada produção em tôdas as localidades. Os tipos de sementes "moca", "concha" e "chato" foram determinados em amostras de tôdas as plantas, por um período de três anos, notando-se que a variação ocorrida é da mesma ordem que a encontrada em outros cafeeiros em seleção. Procurou-se eliminar, pela seleção, cafeeiros com elevada produção de frutos sem sementes em uma ou duas lojas, característico êsse que parece ser hereditário. Os resultados obtidos de cruzamento entre os melhores cafeeiros "Mundo Novo" de Campinas e plantas da variedade murta, indicaram que esses cafeeiros são do tipo bourbon. Provavelmente

  7. Recurrence risk in de novo structural chromosomal rearrangements.

    Science.gov (United States)

    Röthlisberger, Benno; Kotzot, Dieter

    2007-08-01

    According to the textbook of Gardner and Sutherland [2004], the standard on genetic counseling for chromosome abnormalities, the recurrence risk of de novo structural or combined structural and numeric chromosome rearrangements is less than 0.5-2% and takes into account recurrence by chance, gonadal mosaicism, and somatic-gonadal mosaicism. However, these figures are roughly estimated and neither any systematic study nor exact or evidence-based risk calculations are available. To address this question, an extensive literature search was performed and surprisingly only 29 case reports of recurrence of de novo structural or combined structural and numeric chromosomal rearrangements were found. Thirteen of them were with a trisomy 21 due to an i(21q) replacing one normal chromosome 21. In eight of them low-level mosaicism in one of the parents was found either in fibroblasts or in blood or in both. As a consequence of the low number of cases and theoretical considerations (clinical consequences, mechanisms of formation, etc.), the recurrence risk should be reduced to less than 1% for a de novo i(21q) and to even less than 0.3% for all other de novo structural or combined structural and numeric chromosomal rearrangements. As the latter is lower than the commonly accepted risk of approximately 0.3% for indicating an invasive prenatal diagnosis and as the risk of abortion of a healthy fetus after chorionic villous sampling or amniocentesis is higher than approximately 0.5%, invasive prenatal investigation in most cases is not indicated and should only be performed if explicitly asked by the parents subsequent to appropriate genetic counseling. (c) 2007 Wiley-Liss, Inc.

  8. Novos encontros de anofelíneos em recipientes artificiais

    Directory of Open Access Journals (Sweden)

    Oswaldo Paulo Forattini

    1998-12-01

    Full Text Available Assinalam-se novos encontros de anofelíneos em recipientes artificiais. Um deles diz respeito a formas imaturas de Anopheles bellator em criadouros experimentais e outro é concernente ao achado de An. albitarsis l.s., em recipiente abandonado. Tecem-se considerações sobre a pressão seletiva representada pela produção, cada vez maior, de objetos descartáveis.

  9. Infant Mortality in Novo Hamburgo: Associated Factors and Cardiovascular Causes

    Energy Technology Data Exchange (ETDEWEB)

    Brum, Camila de Andrade [Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC), Porto Alegre, RS (Brazil); Stein, Airton Tetelbom [Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS (Brazil); Grupo Hospitalar Conceição (GHC), Porto Alegre, RS (Brazil); Universidade Luterana do Brasil (ULBRA), Porto Alegre, RS (Brazil); Pellanda, Lucia Campos, E-mail: luciapell.pesquisa@cardiologia.org.br [Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC), Porto Alegre, RS (Brazil); Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS (Brazil)

    2015-04-15

    Infant mortality has decreased in Brazil, but remains high as compared to that of other developing countries. In 2010, the Rio Grande do Sul state had the lowest infant mortality rate in Brazil. However, the municipality of Novo Hamburgo had the highest infant mortality rate in the Porto Alegre metropolitan region. To describe the causes of infant mortality in the municipality of Novo Hamburgo from 2007 to 2010, identifying which causes were related to heart diseases and if they were diagnosed in the prenatal period, and to assess the access to healthcare services. This study assessed infants of the municipality of Novo Hamburgo, who died, and whose data were collected from the infant death investigation records. Of the 157 deaths in that period, 35.3% were reducible through diagnosis and early treatment, 25% were reducible through partnership with other sectors, 19.2% were non-preventable, 11.5% were reducible by means of appropriate pregnancy monitoring, 5.1% were reducible through appropriate delivery care, and 3.8% were ill defined. The major cause of death related to heart disease (13.4%), which was significantly associated with the variables ‘age at death’, ‘gestational age’ and ‘birth weight’. Regarding access to healthcare services, 60.9% of the pregnant women had a maximum of six prenatal visits. It is mandatory to enhance prenatal care and newborn care at hospitals and basic healthcare units to prevent infant mortality.

  10. Infant Mortality in Novo Hamburgo: Associated Factors and Cardiovascular Causes

    Directory of Open Access Journals (Sweden)

    Camila de Andrade Brum

    2015-04-01

    Full Text Available Background: Infant mortality has decreased in Brazil, but remains high as compared to that of other developing countries. In 2010, the Rio Grande do Sul state had the lowest infant mortality rate in Brazil. However, the municipality of Novo Hamburgo had the highest infant mortality rate in the Porto Alegre metropolitan region. Objective: To describe the causes of infant mortality in the municipality of Novo Hamburgo from 2007 to 2010, identifying which causes were related to heart diseases and if they were diagnosed in the prenatal period, and to assess the access to healthcare services. Methods: This study assessed infants of the municipality of Novo Hamburgo, who died, and whose data were collected from the infant death investigation records. Results: Of the 157 deaths in that period, 35.3% were reducible through diagnosis and early treatment, 25% were reducible through partnership with other sectors, 19.2% were non-preventable, 11.5% were reducible by means of appropriate pregnancy monitoring, 5.1% were reducible through appropriate delivery care, and 3.8% were ill defined. The major cause of death related to heart disease (13.4%, which was significantly associated with the variables ‘age at death’, ‘gestational age’ and ‘birth weight’. Regarding access to healthcare services, 60.9% of the pregnant women had a maximum of six prenatal visits. Conclusion: It is mandatory to enhance prenatal care and newborn care at hospitals and basic healthcare units to prevent infant mortality.

  11. Infant Mortality in Novo Hamburgo: Associated Factors and Cardiovascular Causes

    International Nuclear Information System (INIS)

    Brum, Camila de Andrade; Stein, Airton Tetelbom; Pellanda, Lucia Campos

    2015-01-01

    Infant mortality has decreased in Brazil, but remains high as compared to that of other developing countries. In 2010, the Rio Grande do Sul state had the lowest infant mortality rate in Brazil. However, the municipality of Novo Hamburgo had the highest infant mortality rate in the Porto Alegre metropolitan region. To describe the causes of infant mortality in the municipality of Novo Hamburgo from 2007 to 2010, identifying which causes were related to heart diseases and if they were diagnosed in the prenatal period, and to assess the access to healthcare services. This study assessed infants of the municipality of Novo Hamburgo, who died, and whose data were collected from the infant death investigation records. Of the 157 deaths in that period, 35.3% were reducible through diagnosis and early treatment, 25% were reducible through partnership with other sectors, 19.2% were non-preventable, 11.5% were reducible by means of appropriate pregnancy monitoring, 5.1% were reducible through appropriate delivery care, and 3.8% were ill defined. The major cause of death related to heart disease (13.4%), which was significantly associated with the variables ‘age at death’, ‘gestational age’ and ‘birth weight’. Regarding access to healthcare services, 60.9% of the pregnant women had a maximum of six prenatal visits. It is mandatory to enhance prenatal care and newborn care at hospitals and basic healthcare units to prevent infant mortality

  12. Identification of optimum sequencing depth especially for de novo genome assembly of small genomes using next generation sequencing data.

    Science.gov (United States)

    Desai, Aarti; Marwah, Veer Singh; Yadav, Akshay; Jha, Vineet; Dhaygude, Kishor; Bangar, Ujwala; Kulkarni, Vivek; Jere, Abhay

    2013-01-01

    Next Generation Sequencing (NGS) is a disruptive technology that has found widespread acceptance in the life sciences research community. The high throughput and low cost of sequencing has encouraged researchers to undertake ambitious genomic projects, especially in de novo genome sequencing. Currently, NGS systems generate sequence data as short reads and de novo genome assembly using these short reads is computationally very intensive. Due to lower cost of sequencing and higher throughput, NGS systems now provide the ability to sequence genomes at high depth. However, currently no report is available highlighting the impact of high sequence depth on genome assembly using real data sets and multiple assembly algorithms. Recently, some studies have evaluated the impact of sequence coverage, error rate and average read length on genome assembly using multiple assembly algorithms, however, these evaluations were performed using simulated datasets. One limitation of using simulated datasets is that variables such as error rates, read length and coverage which are known to impact genome assembly are carefully controlled. Hence, this study was undertaken to identify the minimum depth of sequencing required for de novo assembly for different sized genomes using graph based assembly algorithms and real datasets. Illumina reads for E.coli (4.6 MB) S.kudriavzevii (11.18 MB) and C.elegans (100 MB) were assembled using SOAPdenovo, Velvet, ABySS, Meraculous and IDBA-UD. Our analysis shows that 50X is the optimum read depth for assembling these genomes using all assemblers except Meraculous which requires 100X read depth. Moreover, our analysis shows that de novo assembly from 50X read data requires only 6-40 GB RAM depending on the genome size and assembly algorithm used. We believe that this information can be extremely valuable for researchers in designing experiments and multiplexing which will enable optimum utilization of sequencing as well as analysis resources.

  13. Design

    DEFF Research Database (Denmark)

    Volf, Mette

    Design - proces & metode iBog®  er enestående i sit fokus på afmystificering og operationalisering af designprocessens flygtige og komplekse karakter. Udgivelsen går bag om designerens daglige arbejde og giver et indblik i den kreative skabelsesproces, som designeren er en del af. Udover et bredt...... indblik i designerens arbejdsmetoder og designparametre giver Design - proces & metode en række eksempler fra anerkendte designvirksomheder, der gør det muligt at komme helt tæt på designerens virkelighed....

  14. Design

    Science.gov (United States)

    Buchanan, Richard; Cross, Nigel; Durling, David; Nelson, Harold; Owen, Charles; Valtonen, Anna; Boling, Elizabeth; Gibbons, Andrew; Visscher-Voerman, Irene

    2013-01-01

    Scholars representing the field of design were asked to identify what they considered to be the most exciting and imaginative work currently being done in their field, as well as how that work might change our understanding. The scholars included Richard Buchanan, Nigel Cross, David Durling, Harold Nelson, Charles Owen, and Anna Valtonen. Scholars…

  15. Historical outline of 16th century signets: including examples from the Franciscan monastery in Novo mesto

    Directory of Open Access Journals (Sweden)

    Ines Jerele

    2006-01-01

    Full Text Available The library of the Franciscan Monastery in Novo mesto keeps 224 early prints from the 16th century in which 175 printers’ and publishers’ devices were recorded. These were printed between 1501 and 1600 in 88 printers’ workshops across Europe. Printers’ and publishers’ devices, also called signets, were used in the 16th century as trademarks of respective printers and publishers. Spiritual and cultural ideas of the 16th century and intellectual goals of their owners are reflected in the complex humanistic motifs of signets. Most of the 16th century signets can be compared to impresas; they include a symbolic image and a short motto in Latin. This text presents some of the main characteristics of signets registered in Slovenia, such as the meaning, design features and motifs, dating from the early development of print culture in Europe.

  16. Uncovering Clinical Features of De Novo Philadelphia Positive Myelodysplasia.

    Science.gov (United States)

    Armas, Aristides; Chen, Chen; Mims, Martha; Rivero, Gustavo

    2017-01-01

    Myelodysplastic syndrome (MDS) is cytogenetically heterogeneous and retains variable risk for acute myeloid leukemia transformation. Though not yet fully understood, there is an association between genetic abnormalities and defects in gene expression. The functional role for infrequent cytogenetic alteration remains unclear. An uncommon chromosomic abnormality is the presence of the Philadelphia (Ph) chromosome. Here, we report a patient with Ph+ MDS treated with low dose Dasatinib who achieved hematologic response for 7 months. In addition, we also examined the English literature on all de novo Ph + MDS cases between 1996 and 2015 to gain insight into clinical features and outcome.

  17. Perspective on Biotransformation and De Novo Biosynthesis of Licorice Constituents.

    Science.gov (United States)

    Zhao, Yujia; Lv, Bo; Feng, Xudong; Li, Chun

    2017-12-27

    Licorice, an important herbal medicine, is derived from the dried roots and rhizomes of Glycyrrhiza genus plants. It has been widely used in food, pharmaceutical, tobacco, and cosmetics industries with high economic value. However, overexploitation of licorice resources has severely destroyed the local ecology. Therefore, producing bioactive compounds of licorice through the biotransformation and bioengineering methods is a hot spot in recent years. In this perspective, we comprehensively summarize the biotransformation of licorice constituents into high-value-added derivatives by biocatalysts. Furthermore, successful cases and the strategies for de novo biosynthesizing compounds of licorice in microbes have been summarized. This paper will provide new insights for the further research of licorice.

  18. De Novo and Recurrence of Nonalcoholic Steatohepatitis After Liver Transplantation.

    Science.gov (United States)

    Kappus, Matthew; Abdelmalek, Manal

    2017-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developing countries. Approximately 25% of patients with NAFLD develop nonalcoholic steatohepatitis (NASH). NASH-related cirrhosis is now a leading listing indication for liver transplantation in the United States. Although posttransplant survival for NASH-related cirrhosis is comparable with that of other liver diseases, many patients have features of metabolic syndrome, which can contribute to a recurrence of NAFLD or NASH. This article reviews the epidemiology, pathophysiology, and treatment of de novo and recurrence of NASH after liver transplantation. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. The historical town core and traffic in Novo mesto

    Directory of Open Access Journals (Sweden)

    Lilijana Jankovič

    2001-01-01

    Full Text Available The historical town core of Novo mesto is subject to intolerable traffic conditions. Individual car use is suffocating the town core, but simultaneously good access is essential for shopkeepers and other inhabitants since buses don’t go there. The project proposes changes to the traffic regime, its basic goals are to redesign the town square into a pedestrian place and to eliminate transitory traffic by rerouting vehicles to less burdened side roads. It introduces short-term parking, smaller parking garages in the core and larger parking spaces on the edge and routes the buses through the town core.

  20. Model-Based GUI Testing Using Uppaal at Novo Nordisk

    Science.gov (United States)

    Hjort, Ulrik H.; Illum, Jacob; Larsen, Kim G.; Petersen, Michael A.; Skou, Arne

    This paper details a collaboration between Aalborg University and Novo Nordiskin developing an automatic model-based test generation tool for system testing of the graphical user interface of a medical device on an embedded platform. The tool takes as input an UML Statemachine model and generates a test suite satisfying some testing criterion, such as edge or state coverage, and converts the individual test case into a scripting language that can be automatically executed against the target. The tool has significantly reduced the time required for test construction and generation, and reduced the number of test scripts while increasing the coverage.

  1. Catalysis by a de novo zinc-mediated protein interface: implications for natural enzyme evolution and rational enzyme engineering.

    Science.gov (United States)

    Der, Bryan S; Edwards, David R; Kuhlman, Brian

    2012-05-08

    Here we show that a recent computationally designed zinc-mediated protein interface is serendipitously capable of catalyzing carboxyester and phosphoester hydrolysis. Although the original motivation was to design a de novo zinc-mediated protein-protein interaction (called MID1-zinc), we observed in the homodimer crystal structure a small cleft and open zinc coordination site. We investigated if the cleft and zinc site at the designed interface were sufficient for formation of a primitive active site that can perform hydrolysis. MID1-zinc hydrolyzes 4-nitrophenyl acetate with a rate acceleration of 10(5) and a k(cat)/K(M) of 630 M(-1) s(-1) and 4-nitrophenyl phosphate with a rate acceleration of 10(4) and a k(cat)/K(M) of 14 M(-1) s(-1). These rate accelerations by an unoptimized active site highlight the catalytic power of zinc and suggest that the clefts formed by protein-protein interactions are well-suited for creating enzyme active sites. This discovery has implications for protein evolution and engineering: from an evolutionary perspective, three-coordinated zinc at a homodimer interface cleft represents a simple evolutionary path to nascent enzymatic activity; from a protein engineering perspective, future efforts in de novo design of enzyme active sites may benefit from exploring clefts at protein interfaces for active site placement.

  2. Novo-desenvolvimento, capital social e desigualdade social

    Directory of Open Access Journals (Sweden)

    Ana Cristina de Oliveira Oliveira

    2012-03-01

    Full Text Available Este artigo aborda a tendência de enfrentamento da desigualdade social a partir, no campo econômico, da versão do novo-desenvolvimentismo e, no campo político e ideológico, a partir da noção de capital social, na tentativa de realizar um "capitalismo com face mais humana". Discutiremos duas ordens de questões, considerando a especificidade da formação social brasileira de capitalismo dependente: 1 a “construção de Estados fortes” para

    assegurar as condições de acumulação do capital, ampliando as margens do mercado de consumo, aliviando a pobreza e controlando possíveis tensões políticas e 2 a difusão da necessidade de construir uma sociedade em harmonia, que se traduz na incorporação da ética empreendedora dos empresários em todas as esferas sociais. Entendemos que este escopo político-econômico revela uma nova pedagogia da hegemonia, sustentada numa suposta alternativa
    de gerenciamento das novas expressões da “questão social”, voltada para educar o conformismo e ocultar o conflito de classes.
    Palavras-chave:  questão social; novo-desenvolvimentismo; capital social; inclusão forçada

  3. De novo biosynthesis of anthocyanins in Saccharomyces cerevisiae.

    Science.gov (United States)

    Eichenberger, Michael; Hansson, Anders; Fischer, David; Dürr, Lara; Naesby, Michael

    2018-06-01

    Anthocyanins (ACNs) are plant secondary metabolites responsible for most of the red, purple and blue colors of flowers, fruits and vegetables. They are increasingly used in the food and beverage industry as natural alternative to artificial colorants. Production of these compounds by fermentation of microorganisms would provide an attractive alternative. In this study, Saccharomyces cerevisiae was engineered for de novo production of the three basic anthocyanins, as well as the three main trans-flavan-3-ols. Enzymes from different plant sources were screened and efficient variants found for most steps of the biosynthetic pathway. However, the anthocyanidin synthase was identified as a major obstacle to efficient production. In yeast, this enzyme converts the majority of its natural substrates leucoanthocyanidins into the off-pathway flavonols. Nonetheless, de novo biosynthesis of ACNs was shown for the first time in yeast and for the first time in a single microorganism. It provides a framework for optimizing the activity of anthocyanidin synthase and represents an important step towards sustainable industrial production of these highly relevant molecules in yeast.

  4. Origins of De Novo Genes in Human and Chimpanzee.

    Science.gov (United States)

    Ruiz-Orera, Jorge; Hernandez-Rodriguez, Jessica; Chiva, Cristina; Sabidó, Eduard; Kondova, Ivanela; Bontrop, Ronald; Marqués-Bonet, Tomàs; Albà, M Mar

    2015-12-01

    The birth of new genes is an important motor of evolutionary innovation. Whereas many new genes arise by gene duplication, others originate at genomic regions that did not contain any genes or gene copies. Some of these newly expressed genes may acquire coding or non-coding functions and be preserved by natural selection. However, it is yet unclear which is the prevalence and underlying mechanisms of de novo gene emergence. In order to obtain a comprehensive view of this process, we have performed in-depth sequencing of the transcriptomes of four mammalian species--human, chimpanzee, macaque, and mouse--and subsequently compared the assembled transcripts and the corresponding syntenic genomic regions. This has resulted in the identification of over five thousand new multiexonic transcriptional events in human and/or chimpanzee that are not observed in the rest of species. Using comparative genomics, we show that the expression of these transcripts is associated with the gain of regulatory motifs upstream of the transcription start site (TSS) and of U1 snRNP sites downstream of the TSS. In general, these transcripts show little evidence of purifying selection, suggesting that many of them are not functional. However, we find signatures of selection in a subset of de novo genes which have evidence of protein translation. Taken together, the data support a model in which frequently-occurring new transcriptional events in the genome provide the raw material for the evolution of new proteins.

  5. A simple method suitable to study de novo root organogenesis

    Directory of Open Access Journals (Sweden)

    Xiaodong eChen

    2014-05-01

    Full Text Available De novo root organogenesis is the process in which adventitious roots regenerate from detached or wounded plant tissues or organs. In tissue culture, appropriate types and concentrations of plant hormones in the medium are critical for inducing adventitious roots. However, in natural conditions, regeneration from detached organs is likely to rely on endogenous hormones. To investigate the actions of endogenous hormones and the molecular mechanisms guiding de novo root organogenesis, we developed a simple method to imitate natural conditions for adventitious root formation by culturing Arabidopsis thaliana leaf explants on B5 medium without additive hormones. Here we show that the ability of the leaf explants to regenerate roots depends on the age of the leaf and on certain nutrients in the medium. Based on these observations, we provide examples of how this method can be used in different situations, and how it can be optimized. This simple method could be used to investigate the effects of various physiological and molecular changes on the regeneration of adventitious roots. It is also useful for tracing cell lineage during the regeneration process by differential interference contrast observation of -glucuronidase staining, and by live imaging of proteins labeled with fluorescent tags.

  6. De novo transcriptome assembly of Setatria italica variety Taejin

    Directory of Open Access Journals (Sweden)

    Yeonhwa Jo

    2016-06-01

    Full Text Available Foxtail millet (Setaria italica belonging to the family Poaceae is an important millet that is widely cultivated in East Asia. Of the cultivated millets, the foxtail millet has the longest history and is one of the main food crops in South India and China. Moreover, foxtail millet is a model plant system for biofuel generation utilizing the C4 photosynthetic pathway. In this study, we carried out de novo transcriptome assembly for the foxtail millet variety Taejin collected from Korea using next-generation sequencing. We obtained a total of 8.676 GB raw data by paired-end sequencing. The raw data in this study can be available in NCBI SRA database with accession number of SRR3406552. The Trinity program was used to de novo assemble 145,332 transcripts. Using the TransDecoder program, we predicted 82,925 putative proteins. BLASTP was performed against the Swiss-Prot protein sequence database to annotate the functions of identified proteins, resulting in 20,555 potentially novel proteins. Taken together, this study provides transcriptome data for the foxtail millet variety Taejin by RNA-Seq.

  7. De novo transcriptome assembly of the mycoheterotrophic plant Monotropa hypopitys

    Directory of Open Access Journals (Sweden)

    Alexey V. Beletsky

    2017-03-01

    Full Text Available Monotropa hypopitys (pinesap is a non-photosynthetic obligately mycoheterotrophic plant of the family Ericaceae. It obtains the carbon and other nutrients from the roots of surrounding autotrophic trees through the associated mycorrhizal fungi. In order to understand the evolutionary changes in the plant genome associated with transition to a heterotrophic lifestyle, we performed de novo transcriptomic analysis of M. hypopitys using next-generation sequencing. We obtained the RNA-Seq data from flowers, flower bracts and roots with haustoria using Illumina HiSeq2500 platform. The raw data obtained in this study can be available in NCBI SRA database with accession number of SRP069226. A total of 10.3 GB raw sequence data were obtained, corresponding to 103,357,809 raw reads. A total of 103,025,683 reads were filtered after removing low-quality reads and trimming the adapter sequences. The Trinity program was used to de novo assemble 98,349 unigens with an N50 of 1342 bp. Using the TransDecoder program, we predicted 43,505 putative proteins. 38,416 unigenes were annotated in the Swiss-Prot protein sequence database using BLASTX. The obtained transcriptomic data will be useful for further studies of the evolution of plant genomes upon transition to a non-photosynthetic lifestyle and the loss of photosynthesis-related functions.

  8. Design

    DEFF Research Database (Denmark)

    Jensen, Ole B.; Pettiway, Keon

    2017-01-01

    In this chapter, Ole B. Jensen takes a situational approach to mobilities to examine how ordinary life activities are structured by technology and design. Using “staging mobilities” as a theoretical approach, Jensen considers mobilities as overlapping, actions, interactions and decisions by desig...... by providing ideas about future research for investigating mobilities in situ as a kind of “staging,” which he notes is influenced by the “material turn” in social sciences....... with a brief description of how movement is studied within social sciences after the “mobilities turn” versus the idea of physical movement in transport geography and engineering. He then explains how “mobilities design” was derived from connections between traffic and architecture. Jensen concludes...

  9. Os novos horizontes da narrativa publicitária: haiku ou (r)evolução?

    OpenAIRE

    Alves, Márcia Renata Queirós da Silva

    2014-01-01

    Relatório de atividade profissional de mestrado em Ciências da Comunicação A publicidade foi acompanhando os novos estilos de vida e hábitos do universo do consumo, tornando-se mais imediata, concisa e intuitiva. Vivemos na era dos elevator pitch ou elevator speech 1, como também são conhecidos, dos igniting talks (eventos de apresentação com regras rígidas de duração – 5 minutos/20 slides), do easy-friendly (expressão em voga transversal ao design, à arquitetura e à arquitetura d...

  10. Designing the molecular future

    OpenAIRE

    Schneider Gisbert

    2011-01-01

    Approximately 25 years ago the first computer applications were conceived for the purpose of automated 'de novo' drug design prominent pioneering tools being ALADDIN CAVEAT GENOA and DYLOMMS. Many of these early concepts were enabled by innovative techniques for ligand receptor interaction modeling like GRID MCSS DOCK and CoMFA which still provide the theoretical framework for several more recently developed molecular design algorithms. After a first wave of software tools and groundbreaking ...

  11. Improved protein quality in transgenic soybean expressing a de novo synthetic protein, MB-16.

    Science.gov (United States)

    Zhang, Yunfang; Schernthaner, Johann; Labbé, Natalie; Hefford, Mary A; Zhao, Jiping; Simmonds, Daina H

    2014-06-01

    To improve soybean [Glycine max (L.) Merrill] seed nutritional quality, a synthetic gene, MB-16 was introduced into the soybean genome to boost seed methionine content. MB-16, an 11 kDa de novo protein enriched in the essential amino acids (EAAs) methionine, threonine, lysine and leucine, was originally developed for expression in rumen bacteria. For efficient seed expression, constructs were designed using the soybean codon bias, with and without the KDEL ER retention sequence, and β-conglycinin or cruciferin seed specific protein storage promoters. Homozygous lines, with single locus integrations, were identified for several transgenic events. Transgene transmission and MB-16 protein expression were confirmed to the T5 and T7 generations, respectively. Quantitative RT-PCR analysis of developing seed showed that the transcript peaked in growing seed, 5-6 mm long, remained at this peak level to the full-sized green seed and then was significantly reduced in maturing yellow seed. Transformed events carrying constructs with the rumen bacteria codon preference showed the same transcription pattern as those with the soybean codon preference, but the transcript levels were lower at each developmental stage. MB-16 protein levels, as determined by immunoblots, were highest in full-sized green seed but the protein virtually disappeared in mature seed. However, amino acid analysis of mature seed, in the best transgenic line, showed a significant increase of 16.2 and 65.9 % in methionine and cysteine, respectively, as compared to the parent. This indicates that MB-16 elevated the sulfur amino acids, improved the EAA seed profile and confirms that a de novo synthetic gene can enhance the nutritional quality of soybean.

  12. A human-specific de novo protein-coding gene associated with human brain functions.

    Directory of Open Access Journals (Sweden)

    Chuan-Yun Li

    2010-03-01

    Full Text Available To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203. Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706's mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimer's brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions.

  13. Combined "de novo" and "ex novo" lipid fermentation in a mix-medium of corncob acid hydrolysate and soybean oil by Trichosporon dermatis.

    Science.gov (United States)

    Huang, Chao; Luo, Mu-Tan; Chen, Xue-Fang; Qi, Gao-Xiang; Xiong, Lian; Lin, Xiao-Qing; Wang, Can; Li, Hai-Long; Chen, Xin-De

    2017-01-01

    Microbial oil is one important bio-product for its important function in energy, chemical, and food industry. Finding suitable substrates is one key issue for its industrial application. Both hydrophilic and hydrophobic substrates can be utilized by oleaginous microorganisms with two different bio-pathways (" de novo " lipid fermentation and " ex novo " lipid fermentation). To date, most of the research on lipid fermentation has focused mainly on only one fermentation pathway and little work was carried out on both " de novo " and " ex novo " lipid fermentation simultaneously; thus, the advantages of both lipid fermentation cannot be fulfilled comprehensively. In this study, corncob acid hydrolysate with soybean oil was used as a mix-medium for combined " de novo " and " ex novo " lipid fermentation by oleaginous yeast Trichosporon dermatis . Both hydrophilic and hydrophobic substrates (sugars and soybean oil) in the medium can be utilized simultaneously and efficiently by T. dermatis . Different fermentation modes were compared and the batch mode was the most suitable for the combined fermentation. The influence of soybean oil concentration, inoculum size, and initial pH on the lipid fermentation was evaluated and 20 g/L soybean oil, 5% inoculum size, and initial pH 6.0 were suitable for this bioprocess. By this technology, the lipid composition of extracellular hydrophobic substrate (soybean oil) can be modified. Although adding emulsifier showed little beneficial effect on lipid production, it can modify the intracellular lipid composition of T. dermatis . The present study proves the potential and possibility of combined " de novo " and " ex novo " lipid fermentation. This technology can use hydrophilic and hydrophobic sustainable bio-resources to generate lipid feedstock for the production of biodiesel or other lipid-based chemical compounds and to treat some special wastes such as oil-containing wastewater.

  14. Interplay between De Novo Biosynthesis and Sequestration of Cyanogenic Glucosides in Arthropods

    DEFF Research Database (Denmark)

    Fürstenberg-Hägg, Joel

    (Zygaenidae, Lepidoptera) both sequester (take up and accumulate) the CNglcs linamarin and lotaustralin from their food plants (Fabacea) and biosynthesize them de novo from valine and isoleucine. The presented research demonstrates that de novo biosynthesis of CNglcs in Z. filipendulae is dependent...

  15. 76 FR 68767 - Draft Guidance for Industry and Food and Drug Administration Staff; De Novo Classification...

    Science.gov (United States)

    2011-11-07

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0689] Draft Guidance for Industry and Food and Drug Administration Staff; De Novo Classification Process... for Industry and Food and Drug Administration Staff; De Novo Classification Process (Evaluation of...

  16. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder

    DEFF Research Database (Denmark)

    Hamilton, P J; Campbell, N G; Sharma, S

    2013-01-01

    De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution...

  17. Improved outcome with novel device for low-pressure PTCA in de novo and in-stent lesions

    International Nuclear Information System (INIS)

    Ischinger, Thomas A.; Solar, Ronald J.; Hitzke, Evelyn

    2003-01-01

    Purpose: Complex lesion morphology requiring the use of high pressure to effect lumen expansion and in-stent restenosis (ISR) remain two indications that challenge conventional PTCA balloons. We report on a new PTCA device that is designed to provide precise, low-pressure dilatation of both de novo and in-stent lesions. Methods: The FX miniRAIL catheter (FX) has an integral wire positioned external to a dilating balloon and a short, 12-mm guidewire lumen distal to the balloon. The balloon inflates against the guidewire and the external wire to prevent slippage and to introduce high focal longitudinal stresses at low inflation pressures. In this initial study, the FX was used in 37 lesions (25 de novo, 12 in-stent; vessel reference diameter=2.73±0.49 mm) in 30 patients. A stepwise inflation protocol and QCA were used to determine the balloon pressure at which the stenosis was resolved (stenosis resolution pressure, SRP). Results: All lesions (100%) were easily reached, crossed and dilated without complication. The SRP was 4.5±2.9 atm, and no balloon slippage was observed. Residual stenosis after FX was 26.39±13.29%. Minor dissections (Types A and B) were observed in eight lesions (21.6%). Target lesion revascularization (TLR) and target vessel revascularization (TVR) at follow-up (8.1±1.5 months) were 8.3% and 12.5%, respectively. Conclusion: The design of the FX is versatile and appears to provide for a safe, effective and improved low-pressure PTCA technique in de novo and in-stent lesions

  18. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies

    DEFF Research Database (Denmark)

    2014-01-01

    in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p...... = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have...... analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1...

  19. Genes from scratch--the evolutionary fate of de novo genes.

    Science.gov (United States)

    Schlötterer, Christian

    2015-04-01

    Although considered an extremely unlikely event, many genes emerge from previously noncoding genomic regions. This review covers the entire life cycle of such de novo genes. Two competing hypotheses about the process of de novo gene birth are discussed as well as the high death rate of de novo genes. Despite the high death rate, some de novo genes are retained and remain functional, even in distantly related species, through their integration into gene networks. Further studies combining gene expression with ribosome profiling in multiple populations across different species will be instrumental for an improved understanding of the evolutionary processes operating on de novo genes. Copyright © 2015 The Author. Published by Elsevier Ltd.. All rights reserved.

  20. Peptide de novo sequencing of mixture tandem mass spectra

    DEFF Research Database (Denmark)

    Gorshkov, Vladimir; Hotta, Stéphanie Yuki Kolbeck; Braga, Thiago Verano

    2016-01-01

    they decrease the identification performance using database search engines. De novo sequencing approaches are expected to be even more sensitive to the reduction in mass spectrum quality resulting from peptide precursor co-isolation and thus prone to false identifications. The deconvolution approach matched...... complementary b-, y-ions to each precursor peptide mass, which allowed the creation of virtual spectra containing sequence specific fragment ions of each co-isolated peptide. Deconvolution processing resulted in equally efficient identification rates but increased the absolute number of correctly sequenced...... peptides. The improvement was in the range of 20–35% additional peptide identifications for a HeLa lysate sample. Some correct sequences were identified only using unprocessed spectra; however, the number of these was lower than those where improvement was obtained by mass spectral deconvolution. Tight...

  1. Herpes simplex virus 1 induces de novo phospholipid synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Sutter, Esther [Electron Microscopy, Institute of Veterinary Anatomy, University of Zuerich (Switzerland); Oliveira, Anna Paula de; Tobler, Kurt [Electron microscopy, Institute of Virology, University of Zuerich (Switzerland); Schraner, Elisabeth M. [Electron Microscopy, Institute of Veterinary Anatomy, University of Zuerich (Switzerland); Sonda, Sabrina [Institute of Parasitology, University of Zuerich (Switzerland); Kaech, Andres [Center for Microscopy and Image Analysis, University of Zuerich (Switzerland); Lucas, Miriam S. [Electron Microscopy ETH Zuerich (EMEZ), Swiss Federal Institute of Technology, Zuerich (Switzerland); Ackermann, Mathias [Electron microscopy, Institute of Virology, University of Zuerich (Switzerland); Wild, Peter, E-mail: pewild@access.uzh.ch [Electron Microscopy, Institute of Veterinary Anatomy, University of Zuerich (Switzerland)

    2012-08-01

    Herpes simplex virus type 1 capsids bud at nuclear membranes and Golgi membranes acquiring an envelope composed of phospholipids. Hence, we measured incorporation of phospholipid precursors into these membranes, and quantified changes in size of cellular compartments by morphometric analysis. Incorporation of [{sup 3}H]-choline into both nuclear and cytoplasmic membranes was significantly enhanced upon infection. [{sup 3}H]-choline was also part of isolated virions even grown in the presence of brefeldin A. Nuclei expanded early in infection. The Golgi complex and vacuoles increased substantially whereas the endoplasmic reticulum enlarged only temporarily. The data suggest that HSV-1 stimulates phospholipid synthesis, and that de novo synthesized phospholipids are inserted into nuclear and cytoplasmic membranes to i) maintain membrane integrity in the course of nuclear and cellular expansion, ii) to supply membrane constituents for envelopment of capsids by budding at nuclear membranes and Golgi membranes, and iii) to provide membranes for formation of transport vacuoles.

  2. De novo SOX11 mutations cause Coffin-Siris syndrome.

    Science.gov (United States)

    Tsurusaki, Yoshinori; Koshimizu, Eriko; Ohashi, Hirofumi; Phadke, Shubha; Kou, Ikuyo; Shiina, Masaaki; Suzuki, Toshifumi; Okamoto, Nobuhiko; Imamura, Shintaro; Yamashita, Michiaki; Watanabe, Satoshi; Yoshiura, Koh-ichiro; Kodera, Hirofumi; Miyatake, Satoko; Nakashima, Mitsuko; Saitsu, Hirotomo; Ogata, Kazuhiro; Ikegawa, Shiro; Miyake, Noriko; Matsumoto, Naomichi

    2014-06-02

    Coffin-Siris syndrome (CSS) is a congenital disorder characterized by growth deficiency, intellectual disability, microcephaly, characteristic facial features and hypoplastic nails of the fifth fingers and/or toes. We previously identified mutations in five genes encoding subunits of the BAF complex, in 55% of CSS patients. Here we perform whole-exome sequencing in additional CSS patients, identifying de novo SOX11 mutations in two patients with a mild CSS phenotype. sox11a/b knockdown in zebrafish causes brain abnormalities, potentially explaining the brain phenotype of CSS. SOX11 is the downstream transcriptional factor of the PAX6-BAF complex, highlighting the importance of the BAF complex and SOX11 transcriptional network in brain development.

  3. De novo transcriptome assembly of shrimp Palaemon serratus

    Directory of Open Access Journals (Sweden)

    Alejandra Perina

    2017-03-01

    Full Text Available The shrimp Palaemon serratus is a coastal decapod crustacean with a high commercial value. It is harvested for human consumption. In this study, we used Illumina sequencing technology (HiSeq 2000 to sequence, assemble and annotate the transcriptome of P. serratus. RNA was isolated from muscle of adults individuals and, from a pool of larvae. A total number of 4 cDNA libraries were constructed, using the TruSeq RNA Sample Preparation Kit v2. The raw data in this study was deposited in NCBI SRA database with study accession number of SRP090769. The obtained data were subjected to de novo transcriptome assembly using Trinity software, and coding regions were predicted by TransDecoder. We used Blastp and Sma3s to annotate the identified proteins. The transcriptome data could provide some insight into the understanding of genes involved in the larval development and metamorphosis.

  4. De novo assembly of a haplotype-resolved human genome.

    Science.gov (United States)

    Cao, Hongzhi; Wu, Honglong; Luo, Ruibang; Huang, Shujia; Sun, Yuhui; Tong, Xin; Xie, Yinlong; Liu, Binghang; Yang, Hailong; Zheng, Hancheng; Li, Jian; Li, Bo; Wang, Yu; Yang, Fang; Sun, Peng; Liu, Siyang; Gao, Peng; Huang, Haodong; Sun, Jing; Chen, Dan; He, Guangzhu; Huang, Weihua; Huang, Zheng; Li, Yue; Tellier, Laurent C A M; Liu, Xiao; Feng, Qiang; Xu, Xun; Zhang, Xiuqing; Bolund, Lars; Krogh, Anders; Kristiansen, Karsten; Drmanac, Radoje; Drmanac, Snezana; Nielsen, Rasmus; Li, Songgang; Wang, Jian; Yang, Huanming; Li, Yingrui; Wong, Gane Ka-Shu; Wang, Jun

    2015-06-01

    The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should aid in translating genotypes to phenotypes for the development of personalized medicine.

  5. De novo development of artistic creativity in Alzheimer's disease.

    Science.gov (United States)

    Chakravarty, Ambar

    2011-10-01

    The case of an 82-year-old female with probable Alzheimer's disease (AD), who developed unusual artistic creativity after development of her disease, is described. The possible pathogenetic mechanism is discussed. The patient showed no inclination toward visual arts during her premorbid years. However, 4 years after development of AD suggestive symptoms she started painting beautiful pictures rather impulsively. Some such paintings have been appreciated even by a qualified art expert. Such de novo development of artistic creativity had been described earlier in subjects with the semantic form of fronto-temporal dementia (FTD), but not in AD. The prevailing concept of lateralized compromise and paradoxical functional facilitation, proposed in connection with FTD subjects, may not be applicable in AD subjects where the affection is more diffuse and more posterior in the brain. Hence, the likely pathogenetic mechanism involved in the case described may remain uncertain. Possibilities are discussed.

  6. Novo teste para diagnóstico das afasias

    Directory of Open Access Journals (Sweden)

    José G. Albernaz

    1953-06-01

    Full Text Available Um novo teste para diagnóstico e contrôle do tratamento das diferentes formas de afasia, especialmente adaptado para a língua portuguêsa, é apresentado e descrito em detalhe. O teste, que será de valor para clínicos e psicólogos interessados no tratamento e reabilitação de pacientes afásicos, se executa em cêrca de 30 minutos, interpreta-se fàcilmente e fornece os elementos necessários para o planejamento da reeducação da linguagem. Além disso, a repetição do teste de tempos em tempos indicará os progressos do paciente e sugerirá modificações do plano de tratamento no momento oportuno.

  7. De novo identification of viral pathogens from cell culture hologenomes

    Directory of Open Access Journals (Sweden)

    Patowary Ashok

    2012-01-01

    Full Text Available Abstract Background Fast, specific identification and surveillance of pathogens is the cornerstone of any outbreak response system, especially in the case of emerging infectious diseases and viral epidemics. This process is generally tedious and time-consuming thus making it ineffective in traditional settings. The added complexity in these situations is the non-availability of pure isolates of pathogens as they are present as mixed genomes or hologenomes. Next-generation sequencing approaches offer an attractive solution in this scenario as it provides adequate depth of sequencing at fast and affordable costs, apart from making it possible to decipher complex interactions between genomes at a scale that was not possible before. The widespread application of next-generation sequencing in this field has been limited by the non-availability of an efficient computational pipeline to systematically analyze data to delineate pathogen genomes from mixed population of genomes or hologenomes. Findings We applied next-generation sequencing on a sample containing mixed population of genomes from an epidemic with appropriate processing and enrichment. The data was analyzed using an extensive computational pipeline involving mapping to reference genome sets and de-novo assembly. In depth analysis of the data generated revealed the presence of sequences corresponding to Japanese encephalitis virus. The genome of the virus was also independently de-novo assembled. The presence of the virus was in addition, verified using standard molecular biology techniques. Conclusions Our approach can accurately identify causative pathogens from cell culture hologenome samples containing mixed population of genomes and in principle can be applied to patient hologenome samples without any background information. This methodology could be widely applied to identify and isolate pathogen genomes and understand their genomic variability during outbreaks.

  8. The limits of de novo DNA motif discovery.

    Directory of Open Access Journals (Sweden)

    David Simcha

    Full Text Available A major challenge in molecular biology is reverse-engineering the cis-regulatory logic that plays a major role in the control of gene expression. This program includes searching through DNA sequences to identify "motifs" that serve as the binding sites for transcription factors or, more generally, are predictive of gene expression across cellular conditions. Several approaches have been proposed for de novo motif discovery-searching sequences without prior knowledge of binding sites or nucleotide patterns. However, unbiased validation is not straightforward. We consider two approaches to unbiased validation of discovered motifs: testing the statistical significance of a motif using a DNA "background" sequence model to represent the null hypothesis and measuring performance in predicting membership in gene clusters. We demonstrate that the background models typically used are "too null," resulting in overly optimistic assessments of significance, and argue that performance in predicting TF binding or expression patterns from DNA motifs should be assessed by held-out data, as in predictive learning. Applying this criterion to common motif discovery methods resulted in universally poor performance, although there is a marked improvement when motifs are statistically significant against real background sequences. Moreover, on synthetic data where "ground truth" is known, discriminative performance of all algorithms is far below the theoretical upper bound, with pronounced "over-fitting" in training. A key conclusion from this work is that the failure of de novo discovery approaches to accurately identify motifs is basically due to statistical intractability resulting from the fixed size of co-regulated gene clusters, and thus such failures do not necessarily provide evidence that unfound motifs are not active biologically. Consequently, the use of prior knowledge to enhance motif discovery is not just advantageous but necessary. An implementation of

  9. Cinema utópico: a construção de um novo homem e um novo mundo

    OpenAIRE

    Erika Savernini Lopes

    2011-01-01

    O cinema, desde seus primórdios, prefigurou o espaço cibernético como um novo espaço imaterial construído coletivamente. A concepção desse outro lugar não físico para o qual o homem poderia migrar estabelece para o cinema e para o ciberespaço uma relação direta com as utopias. Na acepção do romance filosófico de Thomas More, a Utopia define-se como um outro espaço não-existente, irrealizável e ideal que diagnostica o atual. O cinema carregaria caracteres fundamentais da Utopia tanto no que se...

  10. Memetic algorithms for de novo motif-finding in biomedical sequences.

    Science.gov (United States)

    Bi, Chengpeng

    2012-09-01

    The objectives of this study are to design and implement a new memetic algorithm for de novo motif discovery, which is then applied to detect important signals hidden in various biomedical molecular sequences. In this paper, memetic algorithms are developed and tested in de novo motif-finding problems. Several strategies in the algorithm design are employed that are to not only efficiently explore the multiple sequence local alignment space, but also effectively uncover the molecular signals. As a result, there are a number of key features in the implementation of the memetic motif-finding algorithm (MaMotif), including a chromosome replacement operator, a chromosome alteration-aware local search operator, a truncated local search strategy, and a stochastic operation of local search imposed on individual learning. To test the new algorithm, we compare MaMotif with a few of other similar algorithms using simulated and experimental data including genomic DNA, primary microRNA sequences (let-7 family), and transmembrane protein sequences. The new memetic motif-finding algorithm is successfully implemented in C++, and exhaustively tested with various simulated and real biological sequences. In the simulation, it shows that MaMotif is the most time-efficient algorithm compared with others, that is, it runs 2 times faster than the expectation maximization (EM) method and 16 times faster than the genetic algorithm-based EM hybrid. In both simulated and experimental testing, results show that the new algorithm is compared favorably or superior to other algorithms. Notably, MaMotif is able to successfully discover the transcription factors' binding sites in the chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) data, correctly uncover the RNA splicing signals in gene expression, and precisely find the highly conserved helix motif in the transmembrane protein sequences, as well as rightly detect the palindromic segments in the primary micro

  11. On the Origin of De Novo Genes in Arabidopsis thaliana Populations.

    Science.gov (United States)

    Li, Zi-Wen; Chen, Xi; Wu, Qiong; Hagmann, Jörg; Han, Ting-Shen; Zou, Yu-Pan; Ge, Song; Guo, Ya-Long

    2016-08-03

    De novo genes, which originate from ancestral nongenic sequences, are one of the most important sources of protein-coding genes. This origination process is crucial for the adaptation of organisms. However, how de novo genes arise and become fixed in a population or species remains largely unknown. Here, we identified 782 de novo genes from the model plant Arabidopsis thaliana and divided them into three types based on the availability of translational evidence, transcriptional evidence, and neither transcriptional nor translational evidence for their origin. Importantly, by integrating multiple types of omics data, including data from genomes, epigenomes, transcriptomes, and translatomes, we found that epigenetic modifications (DNA methylation and histone modification) play an important role in the origination process of de novo genes. Intriguingly, using the transcriptomes and methylomes from the same population of 84 accessions, we found that de novo genes that are transcribed in approximately half of the total accessions within the population are highly methylated, with lower levels of transcription than those transcribed at other frequencies within the population. We hypothesized that, during the origin of de novo gene alleles, those neutralized to low expression states via DNA methylation have relatively high probabilities of spreading and becoming fixed in a population. Our results highlight the process underlying the origin of de novo genes at the population level, as well as the importance of DNA methylation in this process. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  12. Glucagon infusion increases rate of purine synthesis de novo in rat liver

    International Nuclear Information System (INIS)

    Itakura, Mitsuo; Maeda, Noriaki; Tsuchiya, Masami; Yamashita, Kamejiro

    1987-01-01

    Based on the parallel increases of glucagon, the second peak of hepatic cAMP, and the rate of purine synthesis de novo in the prereplicative period in regenerating rate liver after a 70% hepatectomy, it was hypothesized that glucagon is responsible for the increased rate of purine synthesis de novo. To test this hypothesis, the effect of glucagon or dibutyryl cAMP infusion on the rate of purine synthesis de novo in rat liver was studied. Glucagon infusion but not insulin or glucose infusion increased the rate of purine synthesis de novo, which was assayed by [ 14 C]glycine or [ 14 C]formate incorporation, by 2.7- to 4.3-fold. Glucagon infusion increased cAMP concentrations by 4.9-fold and 5-phosphoribosyl-1-pyrophosphate concentrations by 1.5-fold in liver but did not change the specific activity of amidophosphoribosyltransferase or purine ribonucleotide concentrations. Dibutyryl cAMP infusion also increased the rate of purine synthesis de novo by 2.2- to 4.0-fold. Because glucagon infusion increased the rate of purine synthesis de novo in the presence of unchanged purine ribonucleotide concentrations, it is concluded that glucagon after infusion or in animals after a 70% hepatectomy is playing an anabolic role to increase the rate of purine synthesis de novo by increasing cAMP and 5-phosphoribosyl-1-pyrophosphate concentrations

  13. Role of de novo biosynthesis in ecosystem scale monoterpene emissions from a boreal Scots pine forest

    Directory of Open Access Journals (Sweden)

    R. Taipale

    2011-08-01

    Full Text Available Monoterpene emissions from Scots pine have traditionally been assumed to originate as evaporation from specialized storage pools. More recently, the significance of de novo emissions, originating directly from monoterpene biosynthesis, has been recognized. To study the role of biosynthesis at the ecosystem scale, we measured monoterpene emissions from a Scots pine dominated forest in southern Finland using the disjunct eddy covariance method combined with proton transfer reaction mass spectrometry. The interpretation of the measurements was based on a correlation analysis and a hybrid emission algorithm describing both de novo and pool emissions. During the measurement period May–August 2007, the monthly medians of daytime emissions were 200, 290, 180, and 200 μg m−2 h−1. The emissions were partly light dependent, probably due to de novo biosynthesis. The emission potential for both de novo and pool emissions exhibited a decreasing summertime trend. The ratio of the de novo emission potential to the total emission potential varied between 30 % and 46 %. Although the monthly changes were not significant, the ratio always differed statistically from zero, suggesting that the role of de novo biosynthesis was observable. Given the uncertainties in this study, we conclude that more accurate estimates of the contribution of de novo emissions are required for improving monoterpene emission algorithms for Scots pine dominated forests.

  14. Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme.

    Science.gov (United States)

    Watkins, Daniel W; Jenkins, Jonathan M X; Grayson, Katie J; Wood, Nicola; Steventon, Jack W; Le Vay, Kristian K; Goodwin, Matthew I; Mullen, Anna S; Bailey, Henry J; Crump, Matthew P; MacMillan, Fraser; Mulholland, Adrian J; Cameron, Gus; Sessions, Richard B; Mann, Stephen; Anderson, J L Ross

    2017-08-25

    Although catalytic mechanisms in natural enzymes are well understood, achieving the diverse palette of reaction chemistries in re-engineered native proteins has proved challenging. Wholesale modification of natural enzymes is potentially compromised by their intrinsic complexity, which often obscures the underlying principles governing biocatalytic efficiency. The maquette approach can circumvent this complexity by combining a robust de novo designed chassis with a design process that avoids atomistic mimicry of natural proteins. Here, we apply this method to the construction of a highly efficient, promiscuous, and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H 2 O 2 . The maquette exhibits kinetics that match and even surpass those of certain natural peroxidases, retains its activity at elevated temperature and in the presence of organic solvents, and provides a simple platform for interrogating catalytic intermediates common to natural heme-containing enzymes.Catalytic mechanisms of enzymes are well understood, but achieving diverse reaction chemistries in re-engineered proteins can be difficult. Here the authors show a highly efficient and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H 2 O 2 .

  15. Sequencing and de novo assembly of 150 genomes from Denmark as a population reference

    DEFF Research Database (Denmark)

    Maretty, Lasse; Jensen, Jacob Malte; Petersen, Bent

    2017-01-01

    or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high......-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set...

  16. Eculizumab for drug-induced de novo posttransplantation thrombotic microangiopathy: A case report.

    Science.gov (United States)

    Safa, Kassem; Logan, Merranda S; Batal, Ibrahim; Gabardi, Steven; Rennke, Helmut G; Abdi, Reza

    2015-02-01

    De novo thrombotic microangiopathy (TMA) following renal transplantation is a severe complication associated with high rates of allograft failure. Several immunosuppressive agents are associated with TMA. Conventional approaches to managing this entity, such as withdrawal of the offending agent and/or plasmapheresis, often offer limited help, with high rates of treatment failure and graft loss. We herein report a case of drug induced de novo TMA successfully treated using the C5a inhibitor eculizumab in a renal transplant patient. This report highlights a potentially important role for eculizumab in settings where drug-induced de novo TMA is refractory to conventional therapies.

  17. De novo assembly and phasing of a Korean human genome.

    Science.gov (United States)

    Seo, Jeong-Sun; Rhie, Arang; Kim, Junsoo; Lee, Sangjin; Sohn, Min-Hwan; Kim, Chang-Uk; Hastie, Alex; Cao, Han; Yun, Ji-Young; Kim, Jihye; Kuk, Junho; Park, Gun Hwa; Kim, Juhyeok; Ryu, Hanna; Kim, Jongbum; Roh, Mira; Baek, Jeonghun; Hunkapiller, Michael W; Korlach, Jonas; Shin, Jong-Yeon; Kim, Changhoon

    2016-10-13

    Advances in genome assembly and phasing provide an opportunity to investigate the diploid architecture of the human genome and reveal the full range of structural variation across population groups. Here we report the de novo assembly and haplotype phasing of the Korean individual AK1 (ref. 1) using single-molecule real-time sequencing, next-generation mapping, microfluidics-based linked reads, and bacterial artificial chromosome (BAC) sequencing approaches. Single-molecule sequencing coupled with next-generation mapping generated a highly contiguous assembly, with a contig N50 size of 17.9 Mb and a scaffold N50 size of 44.8 Mb, resolving 8 chromosomal arms into single scaffolds. The de novo assembly, along with local assemblies and spanning long reads, closes 105 and extends into 72 out of 190 euchromatic gaps in the reference genome, adding 1.03 Mb of previously intractable sequence. High concordance between the assembly and paired-end sequences from 62,758 BAC clones provides strong support for the robustness of the assembly. We identify 18,210 structural variants by direct comparison of the assembly with the human reference, identifying thousands of breakpoints that, to our knowledge, have not been reported before. Many of the insertions are reflected in the transcriptome and are shared across the Asian population. We performed haplotype phasing of the assembly with short reads, long reads and linked reads from whole-genome sequencing and with short reads from 31,719 BAC clones, thereby achieving phased blocks with an N50 size of 11.6 Mb. Haplotigs assembled from single-molecule real-time reads assigned to haplotypes on phased blocks covered 89% of genes. The haplotigs accurately characterized the hypervariable major histocompatability complex region as well as demonstrating allele configuration in clinically relevant genes such as CYP2D6. This work presents the most contiguous diploid human genome assembly so far, with extensive investigation of

  18. De novo transcriptome assembly of mangosteen (Garcinia mangostana L. fruit

    Directory of Open Access Journals (Sweden)

    Deden Derajat Matra

    2016-12-01

    Full Text Available Garcinia mangostana L. (Mangosteen, of the family Clusiaceae, is one of the economically important tropical fruits in Indonesia. In the present study, we performed de novo transcriptomic analysis of Garcinia mangostana L. through RNA-Seq technology. We obtained the raw data from 12 libraries through Ion Proton System. Clean reads of 191,735,809 were obtained from 307,634,890 raw reads. The raw data obtained in this study can be accessible in DDBJ database with accession number of DRA005014 with bioproject accession number of PRJDB5091. We obtained 268,851 transcripts as well as 155,850 unigenes, having N50 value of 555 and 433 bp, respectively. Transcript/unigene length ranged from 201 to 5916 bp. The unigenes were annotated with two main databases from NCBI and UniProtKB, respectively having annotated-sequences of 73,287 and 73,107, respectively. These transcriptomic data will be beneficial for studying transcriptome of Garcinia mangostana L.

  19. Sequencing and De Novo Transcriptome Assembly of Brachypodium sylvaticum (Poaceae

    Directory of Open Access Journals (Sweden)

    Samuel E. Fox

    2013-03-01

    Full Text Available Premise of the study: We report the de novo assembly and characterization of the transcriptomes of Brachypodium sylvaticum (slender false-brome accessions from native populations of Spain and Greece, and an invasive population west of Corvallis, Oregon, USA. Methods and Results: More than 350 million sequence reads from the mRNA libraries prepared from three B. sylvaticum genotypes were assembled into 120,091 (Corvallis, 104,950 (Spain, and 177,682 (Greece transcript contigs. In comparison with the B. distachyon Bd21 reference genome and GenBank protein sequences, we estimate >90% exome coverage for B. sylvaticum. The transcripts were assigned Gene Ontology and InterPro annotations. Brachypodium sylvaticum sequence reads aligned against the Bd21 genome revealed 394,654 single-nucleotide polymorphisms (SNPs and >20,000 simple sequence repeat (SSR DNA sites. Conclusions: To our knowledge, this is the first report of transcriptome sequencing of invasive plant species with a closely related sequenced reference genome. The sequences and identified SNP variant and SSR sites will provide tools for developing novel genetic markers for use in genotyping and characterization of invasive behavior of B. sylvaticum.

  20. LESSONS IN DE NOVO PEPTIDE SEQUENCING BY TANDEM MASS SPECTROMETRY

    Science.gov (United States)

    Medzihradszky, Katalin F.; Chalkley, Robert J.

    2015-01-01

    Mass spectrometry has become the method of choice for the qualitative and quantitative characterization of protein mixtures isolated from all kinds of living organisms. The raw data in these studies are MS/MS spectra, usually of peptides produced by proteolytic digestion of a protein. These spectra are “translated” into peptide sequences, normally with the help of various search engines. Data acquisition and interpretation have both been automated, and most researchers look only at the summary of the identifications without ever viewing the underlying raw data used for assignments. Automated analysis of data is essential due to the volume produced. However, being familiar with the finer intricacies of peptide fragmentation processes, and experiencing the difficulties of manual data interpretation allow a researcher to be able to more critically evaluate key results, particularly because there are many known rules of peptide fragmentation that are not incorporated into search engine scoring. Since the most commonly used MS/MS activation method is collision-induced dissociation (CID), in this article we present a brief review of the history of peptide CID analysis. Next, we provide a detailed tutorial on how to determine peptide sequences from CID data. Although the focus of the tutorial is de novo sequencing, the lessons learned and resources supplied are useful for data interpretation in general. PMID:25667941

  1. De novo transcriptome assembly of a sour cherry cultivar, Schattenmorelle

    Directory of Open Access Journals (Sweden)

    Yeonhwa Jo

    2015-12-01

    Full Text Available Sour cherry (Prunus cerasus in the genus Prunus in the family Rosaceae is one of the most popular stone fruit trees worldwide. Of known sour cherry cultivars, the Schattenmorelle is a famous old sour cherry with a high amount of fruit production. The Schattenmorelle was selected before 1650 and described in the 1800s. This cultivar was named after gardens of the Chateau de Moreille in which the cultivar was initially found. In order to identify new genes and to develop genetic markers for sour cherry, we performed a transcriptome analysis of a sour cherry. We selected the cultivar Schattenmorelle, which is among commercially important cultivars in Europe and North America. We obtained 2.05 GB raw data from the Schattenmorelle (NCBI accession number: SRX1187170. De novo transcriptome assembly using Trinity identified 61,053 transcripts in which N50 was 611 bp. Next, we identified 25,585 protein coding sequences using TransDecoder. The identified proteins were blasted against NCBI's non-redundant database for annotation. Based on blast search, we taxonomically classified the obtained sequences. As a result, we provide the transcriptome of sour cherry cultivar Schattenmorelle using next generation sequencing.

  2. De novo protein structure generation from incomplete chemical shift assignments

    Energy Technology Data Exchange (ETDEWEB)

    Shen Yang [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States); Vernon, Robert; Baker, David [University of Washington, Department of Biochemistry and Howard Hughes Medical Institute (United States); Bax, Ad [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States)], E-mail: bax@nih.gov

    2009-02-15

    NMR chemical shifts provide important local structural information for proteins. Consistent structure generation from NMR chemical shift data has recently become feasible for proteins with sizes of up to 130 residues, and such structures are of a quality comparable to those obtained with the standard NMR protocol. This study investigates the influence of the completeness of chemical shift assignments on structures generated from chemical shifts. The Chemical-Shift-Rosetta (CS-Rosetta) protocol was used for de novo protein structure generation with various degrees of completeness of the chemical shift assignment, simulated by omission of entries in the experimental chemical shift data previously used for the initial demonstration of the CS-Rosetta approach. In addition, a new CS-Rosetta protocol is described that improves robustness of the method for proteins with missing or erroneous NMR chemical shift input data. This strategy, which uses traditional Rosetta for pre-filtering of the fragment selection process, is demonstrated for two paramagnetic proteins and also for two proteins with solid-state NMR chemical shift assignments.

  3. De novo transcriptome assembly of Sorghum bicolor variety Taejin

    Directory of Open Access Journals (Sweden)

    Yeonhwa Jo

    2016-06-01

    Full Text Available Sorghum (Sorghum bicolor, also known as great millet, is one of the most popular cultivated grass species in the world. Sorghum is frequently consumed as food for humans and animals as well as used for ethanol production. In this study, we conducted de novo transcriptome assembly for sorghum variety Taejin by next-generation sequencing, obtaining 8.748 GB of raw data. The raw data in this study can be available in NCBI SRA database with accession number of SRX1715644. Using the Trinity program, we identified 222,161 transcripts from sorghum variety Taejin. We further predicted coding regions within the assembled transcripts by the TransDecoder program, resulting in a total of 148,531 proteins. We carried out BLASTP against the Swiss-Prot protein sequence database to annotate the functions of the identified proteins. To our knowledge, this is the first transcriptome data for a sorghum variety derived from Korea, and it can be usefully applied to the generation of genetic markers.

  4. De novo malignancy is associated with renal transplant tourism.

    Science.gov (United States)

    Tsai, Meng-Kun; Yang, Ching-Yao; Lee, Chih-Yuan; Yeh, Chi-Chuan; Hu, Rey-Heng; Lee, Po-Huang

    2011-04-01

    Despite the objections to transplant tourism raised by the transplant community, many patients continue travel to other countries to receive commercial transplants. To evaluate some long-term complications, we reviewed medical records of 215 Taiwanese patients (touring group) who received commercial cadaveric renal transplants in China and compared them with those of 321 transplant recipients receiving domestic cadaveric renal transplants (domestic group) over the same 20-year period. Ten years after transplant, the graft and patient survival rates of the touring group were 55 and 81.5%, respectively, compared with 60 and 89.3%, respectively, of the domestic group. The difference between the two groups was not statistically significant. The 10-year cumulative cancer incidence of the touring group (21.5%) was significantly higher than that of the domestic group (6.8%). Univariate and multivariate stepwise regression analyses (excluding time on immunosuppression, an uncontrollable factor) indicated that transplant tourism was associated with significantly higher cancer incidence. Older age at transplantation was associated with a significantly increased cancer risk; however, the risk of de novo malignancy significantly decreased with longer graft survival. Thus, renal transplant tourism may be associated with a higher risk of post-transplant malignancy, especially in patients of older age at transplantation. © 2011 International Society of Nephrology

  5. Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.

    Science.gov (United States)

    Boyden, Lynn M; Kam, Chen Y; Hernández-Martín, Angela; Zhou, Jing; Craiglow, Brittany G; Sidbury, Robert; Mathes, Erin F; Maguiness, Sheilagh M; Crumrine, Debra A; Williams, Mary L; Hu, Ronghua; Lifton, Richard P; Elias, Peter M; Green, Kathleen J; Choate, Keith A

    2016-01-15

    Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. De novo Biosynthesis of "Non-Natural" Thaxtomin Phytotoxins.

    Science.gov (United States)

    Winn, Michael; Francis, Daniel; Micklefield, Jason

    2018-03-30

    Thaxtomins are diketopiperazine phytotoxins produced by Streptomyces scabies and other actinobacterial plant pathogens that inhibit cellulose biosynthesis in plants. Due to their potent bioactivity and novel mode of action there has been considerable interest in developing thaxtomins as herbicides for crop protection. To address the need for more stable derivatives, we have developed a new approach for structural diversification of thaxtomins. Genes encoding the thaxtomin NRPS from S. scabies, along with genes encoding a promiscuous tryptophan synthase (TrpS) from Salmonella typhimurium, were assembled in a heterologous host Streptomyces albus. Upon feeding indole derivatives to the engineered S. albus strain, tryptophan intermediates with alternative substituents are biosynthesized and incorporated by the NRPS to deliver a series of thaxtomins with different functionalities in place of the nitro group. The approach described herein, demonstrates how genes from different pathways and different bacterial origins can be combined in a heterologous host to create a de novo biosynthetic pathway to "non-natural" product target compounds. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. De novo DNA methylation during monkey pre-implantation embryogenesis.

    Science.gov (United States)

    Gao, Fei; Niu, Yuyu; Sun, Yi Eve; Lu, Hanlin; Chen, Yongchang; Li, Siguang; Kang, Yu; Luo, Yuping; Si, Chenyang; Yu, Juehua; Li, Chang; Sun, Nianqin; Si, Wei; Wang, Hong; Ji, Weizhi; Tan, Tao

    2017-04-01

    Critical epigenetic regulation of primate embryogenesis entails DNA methylome changes. Here we report genome-wide composition, patterning, and stage-specific dynamics of DNA methylation in pre-implantation rhesus monkey embryos as well as male and female gametes studied using an optimized tagmentation-based whole-genome bisulfite sequencing method. We show that upon fertilization, both paternal and maternal genomes undergo active DNA demethylation, and genome-wide de novo DNA methylation is also initiated in the same period. By the 8-cell stage, remethylation becomes more pronounced than demethylation, resulting in an increase in global DNA methylation. Promoters of genes associated with oxidative phosphorylation are preferentially remethylated at the 8-cell stage, suggesting that this mode of energy metabolism may not be favored. Unlike in rodents, X chromosome inactivation is not observed during monkey pre-implantation development. Our study provides the first comprehensive illustration of the 'wax and wane' phases of DNA methylation dynamics. Most importantly, our DNA methyltransferase loss-of-function analysis indicates that DNA methylation influences early monkey embryogenesis.

  8. A crise financeira global e depois: um novo capitalismo?

    Directory of Open Access Journals (Sweden)

    Luiz Carlos Bresser-Pereira

    2010-03-01

    Full Text Available A crise financeira global de 2008 foi conseqüência do processo de financeirização, a criação maciça de riqueza financeira fictícia iniciada da década de 1980, e da hegemonia de uma ideologia reacionária, o neoliberalismo, baseada em mercados auto-regulados e eficientes. Dessa crise emergirá um novo capitalismo, embora sua natureza seja de difícil previsão. Não será financeirizado, mas serão retomadas as tendências presentes nos trinta anos dourados em direção ao capitalismo global e baseado no conhecimento, além da tendência de expansão da democracia, tornando-a mais social e participativa.The 2008 global financial crisis was a consequence of the processes of financialization, the massive creation of fictitious financial wealth which began in the 1980's, and of the hegemony of a reactionary ideology, neoliberalism, based on the belief of the self-regulating capacity and efficiency of markets. From this crisis a new capitalism will emerge, althought its chacarteristics are hard to foresee. It will not be financial, but the tendencies of the 30 "golden years" toward global and knowledge-based capitalism, and the tendency of expansion of democracy will be among them.

  9. Enzyme-like replication de novo in a microcontroller environment.

    Science.gov (United States)

    Tangen, Uwe

    2010-01-01

    The desire to start evolution from scratch inside a computer memory is as old as computing. Here we demonstrate how viable computer programs can be established de novo in a Precambrian environment without supplying any specific instantiation, just starting with random bit sequences. These programs are not self-replicators, but act much more like catalysts. The microcontrollers used in the end are the result of a long series of simplifications. The objective of this simplification process was to produce universal machines with a human-readable interface, allowing software and/or hardware evolution to be studied. The power of the instruction set can be modified by introducing a secondary structure-folding mechanism, which is a state machine, allowing nontrivial replication to emerge with an instruction width of only a few bits. This state-machine approach not only attenuates the problems of brittleness and encoding functionality (too few bits available for coding, and too many instructions needed); it also enables the study of hardware evolution as such. Furthermore, the instruction set is sufficiently powerful to permit external signals to be processed. This information-theoretic approach forms one vertex of a triangle alongside artificial cell research and experimental research on the creation of life. Hopefully this work helps develop an understanding of how information—in a similar sense to the account of functional information described by Hazen et al.—is created by evolution and how this information interacts with or is embedded in its physico-chemical environment.

  10. Genome-wide prediction models that incorporate de novo GWAS are a powerful new tool for tropical rice improvement

    Science.gov (United States)

    Spindel, J E; Begum, H; Akdemir, D; Collard, B; Redoña, E; Jannink, J-L; McCouch, S

    2016-01-01

    To address the multiple challenges to food security posed by global climate change, population growth and rising incomes, plant breeders are developing new crop varieties that can enhance both agricultural productivity and environmental sustainability. Current breeding practices, however, are unable to keep pace with demand. Genomic selection (GS) is a new technique that helps accelerate the rate of genetic gain in breeding by using whole-genome data to predict the breeding value of offspring. Here, we describe a new GS model that combines RR-BLUP with markers fit as fixed effects selected from the results of a genome-wide-association study (GWAS) on the RR-BLUP training data. We term this model GS + de novo GWAS. In a breeding population of tropical rice, GS + de novo GWAS outperformed six other models for a variety of traits and in multiple environments. On the basis of these results, we propose an extended, two-part breeding design that can be used to efficiently integrate novel variation into elite breeding populations, thus expanding genetic diversity and enhancing the potential for sustainable productivity gains. PMID:26860200

  11. Transcriptome sequencing and de novo assembly in arecanut, Areca catechu L elucidates the secondary metabolite pathway genes

    Directory of Open Access Journals (Sweden)

    Ramaswamy Manimekalai

    2018-03-01

    Full Text Available Areca catechu L. belongs to the Arecaceae family which comprises many economically important palms. The palm is a source of alkaloids and carotenoids. The lack of ample genetic information in public databases has been a constraint for the genetic improvement of arecanut. To gain molecular insight into the palm, high throughput RNA sequencing and de novo assembly of arecanut leaf transcriptome was undertaken in the present study. A total 56,321,907 paired end reads of 101 bp length consisting of 11.343 Gb nucleotides were generated. De novo assembly resulted in 48,783 good quality transcripts, of which 67% of transcripts could be annotated against NCBI non – redundant database. The Gene Ontology (GO analysis with UniProt database identified 9222 biological process, 11268 molecular function and 7574 cellular components GO terms. Large scale expression profiling through Fragments per Kilobase per Million mapped reads (FPKM showed major genes involved in different metabolic pathways of the plant. Metabolic pathway analysis of the assembled transcripts identified 124 plant related pathways. The transcripts related to carotenoid and alkaloid biosynthetic pathways had more number of reads and FPKM values suggesting higher expression of these genes. The arecanut transcript sequences generated in the study showed high similarity with coconut, oil palm and date palm sequences retrieved from public domains. We also identified 6853 genic SSR regions in the arecanut. The possible primers were designed for SSR detection and this would simplify the future efforts in genetic characterization of arecanut.

  12. Proposal of a new method for effectiveness evaluation in the product design and development process Proposta de um novo método para a avaliação da eficácia do processo de projeto e desenvolvimento do produto

    Directory of Open Access Journals (Sweden)

    Adherbal Caminada Netto

    2011-09-01

    Full Text Available This paper addresses the subject of product design process evaluation from the designer's point of view. Based on the results of a preliminary research phase a comprehensive questionnaire is drawn up, and applied to a selected group of designers in the automotive industry, comprising Brazilian plants of two major car manufacturers, two Tier 1 suppliers and one lorry and bus manufacturer. Data provided by the answers are compiled, presented and discussed within each organizational environment. A combined analysis is then carried out in order to identify those management actions that are considered by the automotive industry as being more important for both assuring and evaluating the effectiveness of the product design and development process. Management actions are classified according to criteria supplied by the ISO quality management standards. Finally, based on the evaluation, management action indicators are defined and a single and flexible effectiveness index is proposed, which can be calculated using both company and industry data for evaluation and benchmark purposes.Este artigo aborda a avaliação do processo de projeto do produto do ponto de vista do projetista de nível superior. Com base nos resultados de uma fase de pesquisa preliminar, elabora-se um questionário de pesquisa abrangente, que é submetido a um grupo de projetistas de nível superior do setor automotivo, compreendendo as operações brasileiras de duas grandes montadoras, de dois fornecedores diretos (Tier 1 das montadoras e de uma montadora de caminhões e ônibus. Os dados obtidos através das respostas ao questionário são compilados, apresentados e discutidos dentro de cada ambiente organizacional. Faz-se então uma análise conjunta, a fim de identificar aquelas ações gerenciais consideradas pelo setor automotivo como sendo mais importantes, tanto para garantir, quanto para avaliar a eficácia do processo de projeto e desenvolvimento do produto. Classifica

  13. Rapid centriole assembly in Naegleria reveals conserved roles for both de novo and mentored assembly.

    Science.gov (United States)

    Fritz-Laylin, Lillian K; Levy, Yaron Y; Levitan, Edward; Chen, Sean; Cande, W Zacheus; Lai, Elaine Y; Fulton, Chandler

    2016-03-01

    Centrioles are eukaryotic organelles whose number and position are critical for cilia formation and mitosis. Many cell types assemble new centrioles next to existing ones ("templated" or mentored assembly). Under certain conditions, centrioles also form without pre-existing centrioles (de novo). The synchronous differentiation of Naegleria amoebae to flagellates represents a unique opportunity to study centriole assembly, as nearly 100% of the population transitions from having no centrioles to having two within minutes. Here, we find that Naegleria forms its first centriole de novo, immediately followed by mentored assembly of the second. We also find both de novo and mentored assembly distributed among all major eukaryote lineages. We therefore propose that both modes are ancestral and have been conserved because they serve complementary roles, with de novo assembly as the default when no pre-existing centriole is available, and mentored assembly allowing precise regulation of number, timing, and location of centriole assembly. © 2016 Wiley Periodicals, Inc.

  14. De Novo Human Cardiac Myocytes for Medical Research: Promises and Challenges

    Directory of Open Access Journals (Sweden)

    Veronique Hamel

    2017-01-01

    Full Text Available The advent of cellular reprogramming technology has revolutionized biomedical research. De novo human cardiac myocytes can now be obtained from direct reprogramming of somatic cells (such as fibroblasts, from induced pluripotent stem cells (iPSCs, which are reprogrammed from somatic cells, and from human embryonic stem cells (hESCs. Such de novo human cardiac myocytes hold great promise for in vitro disease modeling and drug screening and in vivo cell therapy of heart disease. Here, we review the technique advancements for generating de novo human cardiac myocytes. We also discuss several challenges for the use of such cells in research and regenerative medicine, such as the immature phenotype and heterogeneity of de novo cardiac myocytes obtained with existing protocols. We focus on the recent advancements in addressing such challenges.

  15. Novel de novo BRCA2 mutation in a patient with a family history of breast cancer

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Bisgaard, Marie Luise; Jønson, Lars

    2008-01-01

    whole blood. The paternity was determined by single nucleotide polymorphism (SNP) microarray analysis. Parental origin of the de novo mutation was determined by establishing mutation-SNP haplotypes by variant specific PCR, while de novo and mosaic status was investigated by sequencing of DNA from......BACKGROUND: BRCA2 germ-line mutations predispose to breast and ovarian cancer. Mutations are widespread and unclassified splice variants are frequently encountered. We describe the parental origin and functional characterization of a novel de novo BRCA2 splice site mutation found in a patient...... and synthesis of a truncated BRCA2 protein. The aberrant splicing was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient. The mutation was not found in any of the patient's parents or in the mother's carcinoma, showing it is a de novo mutation. Variant specific PCR indicates...

  16. Spontaneous de novo vaginal adenosis resembling Bartholin’s ...

    African Journals Online (AJOL)

    Adebayo Alade Adewole

    Spontaneous de novo vaginal adenosis resembling Bartholin's cyst: A case report ... 6 by 5 cm. The cervix, uterus, adnexa and Pouch of Douglas (POD) were normal. .... of vaginal cancer.2–4 Although, DES exposed daughters have an.

  17. The NOVO Network: the original scientific basis for its establishment and our R&D vision

    OpenAIRE

    Winkel, Jørgen; Edwards, Kasper; Dellve, L.; Schiller, B.; Westgaard, Rolf H.

    2017-01-01

    The NOVO network is a Nordic non-governmental professional association whose aims are to foster the scientific progress, knowledge and development of the working environment within Healthcare as an integrated part of production system development. The vision is a “Nordic Model for Sustainable Systems” in the healthcare sector. It was founded in 2006 in Copenhagen and was financially supported by the Nordic Council of Ministers from 2007 to 2015. The motivation to establish the NOVO Network ar...

  18. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

    DEFF Research Database (Denmark)

    Hoischen, Alexander; van Bon, Bregje W M; Rodríguez-Santiago, Benjamín

    2011-01-01

    Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which...... is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous....

  19. Selecting Superior De Novo Transcriptome Assemblies: Lessons Learned by Leveraging the Best Plant Genome.

    Directory of Open Access Journals (Sweden)

    Loren A Honaas

    Full Text Available Whereas de novo assemblies of RNA-Seq data are being published for a growing number of species across the tree of life, there are currently no broadly accepted methods for evaluating such assemblies. Here we present a detailed comparison of 99 transcriptome assemblies, generated with 6 de novo assemblers including CLC, Trinity, SOAP, Oases, ABySS and NextGENe. Controlled analyses of de novo assemblies for Arabidopsis thaliana and Oryza sativa transcriptomes provide new insights into the strengths and limitations of transcriptome assembly strategies. We find that the leading assemblers generate reassuringly accurate assemblies for the majority of transcripts. At the same time, we find a propensity for assemblers to fail to fully assemble highly expressed genes. Surprisingly, the instance of true chimeric assemblies is very low for all assemblers. Normalized libraries are reduced in highly abundant transcripts, but they also lack 1000s of low abundance transcripts. We conclude that the quality of de novo transcriptome assemblies is best assessed through consideration of a combination of metrics: 1 proportion of reads mapping to an assembly 2 recovery of conserved, widely expressed genes, 3 N50 length statistics, and 4 the total number of unigenes. We provide benchmark Illumina transcriptome data and introduce SCERNA, a broadly applicable modular protocol for de novo assembly improvement. Finally, our de novo assembly of the Arabidopsis leaf transcriptome revealed ~20 putative Arabidopsis genes lacking in the current annotation.

  20. De novo FBXO11 mutations are associated with intellectual disability and behavioural anomalies.

    Science.gov (United States)

    Fritzen, Daniel; Kuechler, Alma; Grimmel, Mona; Becker, Jessica; Peters, Sophia; Sturm, Marc; Hundertmark, Hela; Schmidt, Axel; Kreiß, Martina; Strom, Tim M; Wieczorek, Dagmar; Haack, Tobias B; Beck-Wödl, Stefanie; Cremer, Kirsten; Engels, Hartmut

    2018-05-01

    Intellectual disability (ID) has an estimated prevalence of 1.5-2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.

  1. De novo giant A2 aneurysm following anterior communicating artery occlusion.

    Science.gov (United States)

    Ibrahim, Tarik F; Hafez, Ahmad; Andrade-Barazarte, Hugo; Raj, Rahul; Niemela, Mika; Lehto, Hanna; Numminen, Jussi; Jarvelainen, Juha; Hernesniemi, Juha

    2015-01-01

    De novo intracranial aneurysms are reported to occur with varying incidence after intracranial aneurysm treatment. They are purported to be observed, however, with increased incidence after Hunterian ligation; particularly in cases of carotid artery occlusion for giant or complex aneurysms deemed unclippable. We report a case of right-sided de novo giant A2 aneurysm 6 years after an anterior communicating artery (ACoA) aneurysm clipping. We believe this de novo aneurysm developed in part due to patient-specific risk factors but also a significant change in cerebral hemodynamics. The ACoA became occluded after surgery that likely altered the cerebral hemodynamics and contributed to the de novo aneurysm. We believe this to be the first reported case of a giant de novo aneurysm in this location. Following parent vessel occlusion (mostly of the carotid artery), there are no reports of any de novo aneurysms in the pericallosal arteries let alone a giant one. The patient had a dominant right A1 and the sudden increase in A2 blood flow likely resulted in increased wall shear stress, particularly in the medial wall of the A2 where the aneurysm occurred 2 mm distal to the A1-2 junction. ACoA preservation is a key element of aneurysm surgery in this location. Suspected occlusion of this vessel may warrant closer radiographic follow-up in patients with other risk factors for aneurysm development.

  2. Sequencing and De Novo Assembly of the Toxicodendron radicans (Poison Ivy) Transcriptome.

    Science.gov (United States)

    Weisberg, Alexandra J; Kim, Gunjune; Westwood, James H; Jelesko, John G

    2017-11-10

    Contact with poison ivy plants is widely dreaded because they produce a natural product called urushiol that is responsible for allergenic contact delayed-dermatitis symptoms lasting for weeks. For this reason, the catchphrase most associated with poison ivy is "leaves of three, let it be", which serves the purpose of both identification and an appeal for avoidance. Ironically, despite this notoriety, there is a dearth of specific knowledge about nearly all other aspects of poison ivy physiology and ecology. As a means of gaining a more molecular-oriented understanding of poison ivy physiology and ecology, Next Generation DNA sequencing technology was used to develop poison ivy root and leaf RNA-seq transcriptome resources. De novo assembled transcriptomes were analyzed to generate a core set of high quality expressed transcripts present in poison ivy tissue. The predicted protein sequences were evaluated for similarity to SwissProt homologs and InterProScan domains, as well as assigned both GO terms and KEGG annotations. Over 23,000 simple sequence repeats were identified in the transcriptome, and corresponding oligo nucleotide primer pairs were designed. A pan-transcriptome analysis of existing Anacardiaceae transcriptomes revealed conserved and unique transcripts among these species.

  3. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation.

    Science.gov (United States)

    Tedesco-Silva, Helio; Pescovitz, Mark D; Cibrik, Diane; Rees, Michael A; Mulgaonkar, Shamkant; Kahan, Barry D; Gugliuzza, Kristene K; Rajagopalan, P R; Esmeraldo, Ronaldo de M; Lord, Hélène; Salvadori, Maurizio; Slade, Jennifer M

    2006-12-27

    Phase II trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings. This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. The primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12. FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. The FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min. While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. The associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.

  4. Structural and functional properties of designed globins

    Indian Academy of Sciences (India)

    De novo design of artificial proteins is an essential approach to elucidate the principles of protein architecture and to understand specific functions of natural proteins and also to yield novel molecules for medical and industrial aims. We have designed artificial sequences of 153 amino acids to fit the main-chain framework of ...

  5. Engineering and introduction of de novo disulphide bridges in organophosphorus hydrolase enzyme for thermostability improvement.

    Science.gov (United States)

    Farnoosh, Gholamreza; Khajeh, Khosro; Latifi, Ali Mohammad; Aghamollaei, Hossein

    2016-12-01

    The organophosphorus hydrolase (OPH) has been used to degrade organophosphorus chemicals, as one of the most frequently used decontamination methods. Under chemical and thermal denaturing conditions, the enzyme has been shown to unfold. To utilize this enzyme in various applications, the thermal stability is of importance. The engineering of de novo disulphide bridges has been explored as a means to increase the thermal stability of enzymes in the rational method of protein engineering. In this study, Disulphide by Design software, homology modelling and molecular dynamics simulations were used to select appropriate amino acid pairs for the introduction of disulphide bridge to improve protein thermostability. The thermostability of the wild-type and three selected mutant enzymes were evaluated by half-life, delta G inactivation (ΔGi) and structural studies (fluorescence and far-UV CD analysis). Data analysis showed that half-life of A204C/T234C and T128C/E153C mutants were increased up to 4 and 24 min, respectively; however, for the G74C/A78C mutant, the half-life was decreased up to 9 min. For the T128C/E124C mutant, both thermal stability and Catalytic efficiency (kcat) were also increased. The half-life and ΔGi results were correlated to the obtained information from structural studies by circular dichroism (CD) spectrometry and extrinsic fluorescence experiments; as rigidity increased in A204C/T2234C and T128C/E153C mutants, half-life and ΔGi also increased. For G74C/A78C mutant, these parameters decreased due to its higher flexibility. The results were submitted a strong evidence for the possibility to improve the thermostability of OPH enzyme by introducing a disulphide bridge after bioinformatics design, even though this design would not be always successful.

  6. De novo ORFs in Drosophila are important to organismal fitness and evolved rapidly from previously non-coding sequences.

    Directory of Open Access Journals (Sweden)

    Josephine A Reinhardt

    Full Text Available How non-coding DNA gives rise to new protein-coding genes (de novo genes is not well understood. Recent work has revealed the origins and functions of a few de novo genes, but common principles governing the evolution or biological roles of these genes are unknown. To better define these principles, we performed a parallel analysis of the evolution and function of six putatively protein-coding de novo genes described in Drosophila melanogaster. Reconstruction of the transcriptional history of de novo genes shows that two de novo genes emerged from novel long non-coding RNAs that arose at least 5 MY prior to evolution of an open reading frame. In contrast, four other de novo genes evolved a translated open reading frame and transcription within the same evolutionary interval suggesting that nascent open reading frames (proto-ORFs, while not required, can contribute to the emergence of a new de novo gene. However, none of the genes arose from proto-ORFs that existed long before expression evolved. Sequence and structural evolution of de novo genes was rapid compared to nearby genes and the structural complexity of de novo genes steadily increases over evolutionary time. Despite the fact that these genes are transcribed at a higher level in males than females, and are most strongly expressed in testes, RNAi experiments show that most of these genes are essential in both sexes during metamorphosis. This lethality suggests that protein coding de novo genes in Drosophila quickly become functionally important.

  7. The NordiNet® International Outcome Study and NovoNet® ANSWER Program®: rationale, design, and methodology of two international pharmacoepidemiological registry-based studies monitoring long-term clinical and safety outcomes of growth hormone therapy (Norditropin®).

    Science.gov (United States)

    Höybye, Charlotte; Sävendahl, Lars; Christesen, Henrik Thybo; Lee, Peter; Pedersen, Birgitte Tønnes; Schlumpf, Michael; Germak, John; Ross, Judith

    2013-01-01

    Randomized controlled trials have shown that growth hormone (GH) therapy has effects on growth, metabolism, and body composition. GH therapy is prescribed for children with growth failure and adults with GH deficiency. Carefully conducted observational study of GH treatment affords the opportunity to assess long-term treatment outcomes and the clinical factors and variables affecting those outcomes, in patients receiving GH therapy in routine clinical practice. The NordiNet® International Outcome Study (IOS) and the American Norditropin® Web Enabled Research (ANSWER Program®) are two complementary, non-interventional, observational studies that adhere to current guidelines for pharmacoepidemiological data. The studies include pediatric and adult patients receiving Norditropin®, as prescribed by their physicians. The studies gather long-term data on the safety and effectiveness of reallife treatment with the recombinant human GH, Norditropin®. We describe the origins, aims, objectives, and design methodology of the studies, as well as their governance and validity, strengths, and limitations. The NordiNet® IOS and ANSWER Program® studies will provide valid insights into the effectiveness and safety of GH treatment across a diverse and large patient population treated in accordance with real-world clinical practice and following the Good Pharmacoepidemiological Practice and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.

  8. Internet e Cultura: um novo olhar, veloz e voraz

    Directory of Open Access Journals (Sweden)

    Wilson de Oliveira Souza

    1999-01-01

    Full Text Available Em cada piscadela que damos, um novo mundo enxergamos. Com a globalização, o modo de ver o mundo muda radicalmente, principalmente devido ao complexo ritmo ditado pelas relações entre o meio ambiente e seus usuários. De forma sintetizada, podemos explicar que a globalização é resultado da terceira revolução tecnológica (tecnologias ligadas à busca, processamento, difusão e transmissão de informações; inteligência artificial; engenharia genética, da formação de áreas de livre comércio e blocos econômicos interligados (como o Mercosul, a União Européia e o Nafta e da crescente interligação e interdependência dos mercados físicos e financeiros em escala planetária. Essa trinca é responsável pela alteração, principalmente, da nova forma de enxergarmos a cultura, aceitando que a mundialização da cultura é um processo em curso, não concluído ainda, na qual as formas culturais nacionais ou locais entram em contato rapidamente. Com isso, quedam as barreiras territoriais, forçam as mediações e criam, no dizer de Featherstone, a "terceira cultura", entendendo como "um conjunto de práticas, conhecimentos, convenções e estilos de vida que se desenvolvem de modo a se tornar cada vez mais independente dos Estados-Nação".

  9. Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis.

    Science.gov (United States)

    Pisithkul, Tippapha; Jacobson, Tyler B; O'Brien, Thomas J; Stevenson, David M; Amador-Noguez, Daniel

    2015-09-01

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using (13)C-labeled sugars and [(15)N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. Copyright © 2015, Pisithkul et al.

  10. Potencial forrageiro de novos clones de capim-elefante

    Directory of Open Access Journals (Sweden)

    Botrel Milton de Andrade

    2000-01-01

    Full Text Available O objetivo deste trabalho foi avaliar o comportamento de novos clones selecionados de capim-elefante. O experimento foi realizado na Embrapa Gado de Leite, em Coronel Pacheco -- MG, por um período de dois anos. Foi avaliado o potencial forrageiro de 20 clones de capim-elefante, obtidos pelo programa de melhoramento, e mais duas cultivares tradicionais (Cameroon e Taiwan A-146 usadas como testemunhas. O delineamento experimental foi o de blocos ao acaso com quatro repetições. As adubações para estabelecimento e manutenção foram realizadas de acordo com a análise do solo, visando suprir as exigências nutricionais do capim-elefante. Observaram-se diferenças significativas entre os clones, quanto ao potencial para produção de forragem, à relação folha/colmo e ao perfilhamento aéreo e basal. A maioria dos clones avaliados apresentou maior produção de matéria seca que as cultivares tradicionais, Cameroon e Taiwan A-146, durante o período seco e chuvoso. Não houve diferença significativa no teor de proteína bruta da matéria seca das cultivares controles (Cameroon e Taiwan A-146 e dos clones avaliados, em ambas as estações (águas e seca. O clone F 27-01, lançado pela Embrapa Gado de Leite com o nome de cultivar Pioneiro, destacou-se para quase todas as características agronômicas estudadas.

  11. Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis

    Science.gov (United States)

    Pisithkul, Tippapha; Jacobson, Tyler B.; O'Brien, Thomas J.; Stevenson, David M.

    2015-01-01

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using 13C-labeled sugars and [15N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. PMID:26070680

  12. Estimadores de componentes de variância em delineamento de blocos aumentados com tratamentos novos de uma ou mais populações Estimators of variance components in the augmented block design with new treatments from one or more populations

    Directory of Open Access Journals (Sweden)

    João Batista Duarte

    2001-09-01

    Full Text Available O objetivo do trabalho foi comparar, por meio de simulação, as estimativas de componentes de variância produzidas pelos métodos ANOVA (análise da variância, ML (máxima verossimilhança, REML (máxima verossimilhança restrita e MIVQUE(0 (estimador quadrático não viesado de variância mínima, no delineamento de blocos aumentados com tratamentos adicionais (progênies de uma ou mais procedências (cruzamentos. Os resultados indicaram superioridade relativa do método MIVQUE(0. O método ANOVA, embora não tendencioso, apresentou as estimativas de menor precisão. Os métodos de máxima verossimilhança, sobretudo ML, tenderam a subestimar a variância do erro experimental ( e a superestimar as variâncias genotípicas (, em especial nos experimentos de menor tamanho (n/>0,5. Contudo, o método produziu as piores estimativas de variâncias genotípicas quando as progênies vieram de diferentes cruzamentos e os experimentos foram pequenos.This work compares by simulation estimates of variance components produced by the ANOVA (analysis of variance, ML (maximum likelihood, REML (restricted maximum likelihood, and MIVQUE(0 (minimum variance quadratic unbiased estimator methods for augmented block design with additional treatments (progenies stemming from one or more origins (crosses. Results showed the superiority of the MIVQUE(0 estimation. The ANOVA method, although unbiased, showed estimates with lower precision. The ML and REML methods produced downwards biased estimates for error variance (, and upwards biased estimates for genotypic variances (, particularly the ML method. Biases for the REML estimation became negligible when progenies were derived from a single cross, and experiments were of larger size with ratios />0.5. This method, however, provided the worst estimates for genotypic variances when progenies were derived from several crosses and the experiments were of small size (n<120 observations.

  13. ''de novo'' aneurysms following endovascular procedures

    Energy Technology Data Exchange (ETDEWEB)

    Briganti, F.; Cirillo, S.; Caranci, F. [Department of Neurological Sciences, Services of Neuroradiology, ' ' Federico II' ' University, Naples (Italy); Esposito, F.; Maiuri, F. [Department of Neurological Sciences, Services of Neurosurgery, ' ' Federico II' ' University, Naples (Italy)

    2002-07-01

    Two personal cases of ''de novo'' aneurysms of the anterior communicating artery (ACoA) occurring 9 and 4 years, respectively, after endovascular carotid occlusion are described. A review of the 30 reported cases (including our own two) of ''de novo'' aneurysms after occlusion of the major cerebral vessels has shown some features, including a rather long time interval after the endovascular procedure of up to 20-25 years (average 9.6 years), a preferential ACoA (36.3%) and internal carotid artery-posterior communicating artery (ICA-PCoA) (33.3%) location of the ''de novo'' aneurysms, and a 10% rate of multiple aneurysms. These data are compared with those of the group of reported spontaneous ''de novo'' aneurysms after SAH or previous aneurysm clipping. We agree that the frequency of ''de novo'' aneurysms after major-vessel occlusion (two among ten procedures in our series, or 20%) is higher than commonly reported (0 to 11%). For this reason, we suggest that patients who have been submitted to endovascular major-vessel occlusion be followed up for up to 20-25 years after the procedure, using non-invasive imaging studies such as MR angiography and high-resolution CT angiography. On the other hand, periodic digital angiography has a questionable risk-benefit ratio; it may be used when a ''de novo'' aneurysm is detected or suspected on non-invasive studies. The progressive enlargement of the ACoA after carotid occlusion, as described in our case 1, must be considered a radiological finding of risk for ''de novo'' aneurysm formation. (orig.)

  14. Sequencing and de novo assembly of the transcriptome of the glassy-winged sharpshooter (Homalodisca vitripennis.

    Directory of Open Access Journals (Sweden)

    Raja Sekhar Nandety

    Full Text Available BACKGROUND: The glassy-winged sharpshooter Homalodisca vitripennis (Hemiptera: Cicadellidae, is a xylem-feeding leafhopper and important vector of the bacterium Xylella fastidiosa; the causal agent of Pierce's disease of grapevines. The functional complexity of the transcriptome of H. vitripennis has not been elucidated thus far. It is a necessary blueprint for an understanding of the development of H. vitripennis and for designing efficient biorational control strategies including those based on RNA interference. RESULTS: Here we elucidate and explore the transcriptome of adult H. vitripennis using high-throughput paired end deep sequencing and de novo assembly. A total of 32,803,656 paired-end reads were obtained with an average transcript length of 624 nucleotides. We assembled 32.9 Mb of the transcriptome of H. vitripennis that spanned across 47,265 loci and 52,708 transcripts. Comparison of our non-redundant database showed that 45% of the deduced proteins of H. vitripennis exhibit identity (e-value ≤1(-5 with known proteins. We assigned Gene Ontology (GO terms, Kyoto Encyclopedia of Genes and Genomes (KEGG annotations, and potential Pfam domains to each transcript isoform. In order to gain insight into the molecular basis of key regulatory genes of H. vitripennis, we characterized predicted proteins involved in the metabolism of juvenile hormone, and biogenesis of small RNAs (Dicer and Piwi sequences from the transcriptomic sequences. Analysis of transposable element sequences of H. vitripennis indicated that the genome is less expanded in comparison to many other insects with approximately 1% of the transcriptome carrying transposable elements. CONCLUSIONS: Our data significantly enhance the molecular resources available for future study and control of this economically important hemipteran. This transcriptional information not only provides a more nuanced understanding of the underlying biological and physiological mechanisms that

  15. A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT

    Directory of Open Access Journals (Sweden)

    Lorf Thomas

    2010-04-01

    Full Text Available Abstract Background Immunosuppression with calcineurin inhibitors (CNI increases the risk of renal dysfunction after orthotopic liver transplantation (OLT. Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation. Methods/Design A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate, liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT, treatment failure, (i. e., re-introduction of CNI, incidence of adverse events, and mortality up to one year after OLT. Discussion This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation of this phase III trial. Trial registration number NCT00890253 (clinicaltrials.gov

  16. Coccidioidomicose: novo caso brasileiro Coccidiodomycosis: a new Brazilian case

    Directory of Open Access Journals (Sweden)

    Mário A.P. Moraes

    1998-12-01

    Full Text Available É descrito um caso de coccidioidomicose pulmonar oriundo da zona rural de Bertolínia, PI. A manifestação clínica principal consistiu em dor torácica e o diagnóstico teve por base o achado do agente3/4Coccidioides immitis3/4em cortes histológicos. Formas teciduais do microrganismo3/4esférulas imaturas e maduras3/4estavam presentes nas lesões observadas em fragmento pulmonar removido do paciente por biópsia a céu aberto. Este novo caso autóctone da doença, como os outros anteriormente descritos no Brasil, procedia do interior semi-árido da Região Nordeste. O ambiente quente e seco do sertão nordestino oferece, sem dúvida, condições propícias ao desenvolvimento de C. immitis, um habitante do solo. As pessoas e animais do local devem adquirir a infecção ao revolver a terra, ato que os expõe à poeira contendo os propágulos do fungo.A case of pulmonary coccidioidomycosis from the rural zone of Bertolinia, PI, is reported. The patient, a farm worker, attributed his illness to the dust inhaled while digging a water well during the dry season of the year, some weeks before the onset of the clinical manifestations. The main symptoms of the disease were severe chest pain and moderate fever. The diagnosis was made histopathologically: tissue phase fungal organisms3/4immature spherules and spherules with endospores3/4were observed in histological sections of a lung fragment obtained by open chest biopsy. This is the twelfth autochthonous case of coccidioidomycosis found so far in Brazil. All of them involved native inhabitants of the semi-arid part of Northeastern Brazil. The hot and dry environment of the region seems to favor the development of C. immitis in the soil. Humans and animals probably acquire the infection by digging the soil, when they become exposed to the conidium-bearing dust raised by this activity.

  17. High frequencies of de novo CNVs in bipolar disorder and schizophrenia.

    LENUS (Irish Health Repository)

    Malhotra, Dheeraj

    2011-12-22

    While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.

  18. NOVO DESIGN PARA A REDE FEDERAL DE EDUCAÇÃO TECNOLÓGICA

    OpenAIRE

    Francisco das Chagas Mariz Fernandes

    2009-01-01

    RESUMO A partir do ano de 2003, o Governo Lula iniciou ações voltadas à democratização da oferta da educação técnica no país, através de um plano estruturante de expansão da Rede Federal de Educação Profissional e Tecnológica. A primeira fase do plano compreendeu a construção de 64 novas Unidades de Ensino para somar às 140 que já existiam. Ao mesmo tempo, o Ministério da Educação logo deu início à segunda fase do projeto, para a implantação de mais 150 novas Escolas, devendo totalizar, at...

  19. Design automóvel : novo conceito para um modelo no grupo Volkswagen

    OpenAIRE

    Duarte, Nuno Miguel Oliveira, 1984-

    2015-01-01

    This study intends to present a new concept to a model in the Volkswagen Group, a niche market where the brand isn’t present but has the potential to strengthen the goal of becoming the number one automotive manufacturer. To introduce is important to addresses the automotive history since the birth until today, where we understand which models were important and for what reasons. We also understand that in Portugal in spite of the great amount of auto enthusiasts the tradition of automotive p...

  20. De novo design of alpha-amylase inhibitor: A small linear mimetic of macromolecular proteinaceous ligands

    Czech Academy of Sciences Publication Activity Database

    Marešová, Lucie; Pavlík, Manfred; Horn, Martin; Mareš, Michael

    2005-01-01

    Roč. 12, č. 12 (2005), 1349-1357 ISSN 1074-5521 R&D Projects: GA ČR(CZ) GP203/02/P081; GA MŠk(CZ) OC D16.001 Institutional research plan: CEZ:AV0Z40550506 Keywords : amylase * peptide inhibitor * combinatorial chemistry Subject RIV: CE - Biochemistry Impact factor: 6.138, year: 2005

  1. De novo design and engineering of non-ribosomal peptide synthetases

    Science.gov (United States)

    Bozhüyük, Kenan A. J.; Fleischhacker, Florian; Linck, Annabell; Wesche, Frank; Tietze, Andreas; Niesert, Claus-Peter; Bode, Helge B.

    2018-03-01

    Peptides derived from non-ribosomal peptide synthetases (NRPSs) represent an important class of pharmaceutically relevant drugs. Methods to generate novel non-ribosomal peptides or to modify peptide natural products in an easy and predictable way are therefore of great interest. However, although the overall modular structure of NRPSs suggests the possibility of adjusting domain specificity and selectivity, only a few examples have been reported and these usually show a severe drop in production titre. Here we report a new strategy for the modification of NRPSs that uses defined exchange units (XUs) and not modules as functional units. XUs are fused at specific positions that connect the condensation and adenylation domains and respect the original specificity of the downstream module to enable the production of the desired peptides. We also present the use of internal condensation domains as an alternative to other peptide-chain-releasing domains for the production of cyclic peptides.

  2. De Novo Discovery of Structured ncRNA Motifs in Genomic Sequences

    DEFF Research Database (Denmark)

    Ruzzo, Walter L; Gorodkin, Jan

    2014-01-01

    De novo discovery of "motifs" capturing the commonalities among related noncoding ncRNA structured RNAs is among the most difficult problems in computational biology. This chapter outlines the challenges presented by this problem, together with some approaches towards solving them, with an emphas...... on an approach based on the CMfinder CMfinder program as a case study. Applications to genomic screens for novel de novo structured ncRNA ncRNA s, including structured RNA elements in untranslated portions of protein-coding genes, are presented.......De novo discovery of "motifs" capturing the commonalities among related noncoding ncRNA structured RNAs is among the most difficult problems in computational biology. This chapter outlines the challenges presented by this problem, together with some approaches towards solving them, with an emphasis...

  3. Defining the maize transcriptome de novo using deep RNA-Seq

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Jeffrey; Gross, Stephen; Choi, Cindy; Zhang, Tao; Lindquist, Erika; Wei, Chia-Lin; Wang, Zhong

    2011-06-01

    De novo assembly of the transcriptome is crucial for functional genomics studies in bioenergy research, since many of the organisms lack high quality reference genomes. In a previous study we successfully de novo assembled simple eukaryote transcriptomes exclusively from short Illumina RNA-Seq reads [1]. However, extensive alternative splicing, present in most of the higher eukaryotes, poses a significant challenge for current short read assembly processes. Furthermore, the size of next-generation datasets, often large for plant genomes, presents an informatics challenge. To tackle these challenges we present a combined experimental and informatics strategy for de novo assembly in higher eukaryotes. Using maize as a test case, preliminary results suggest our approach can resolve transcript variants and improve gene annotations.

  4. Defining the maize transcriptome de novo using deep RNA-Seq

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Jeffrey; Gross, Stephen; Choi, Cindy; Zhang, Tao; Lindquist, Erika; Wei, Chia-Lin; Wang, Zhong

    2011-06-02

    De novo assembly of the transcriptome is crucial for functional genomics studies in bioenergy research, since many of the organisms lack high quality reference genomes. In a previous study we successfully de novo assembled simple eukaryote transcriptomes exclusively from short Illumina RNA-Seq reads [1]. However, extensive alternative splicing, present in most of the higher eukaryotes, poses a significant challenge for current short read assembly processes. Furthermore, the size of next-generation datasets, often large for plant genomes, presents an informatics challenge. To tackle these challenges we present a combined experimental and informatics strategy for de novo assembly in higher eukaryotes. Using maize as a test case, preliminary results suggest our approach can resolve transcript variants and improve gene annotations.

  5. Sequencing and de novo assembly of 150 genomes from Denmark as a population reference

    DEFF Research Database (Denmark)

    Maretty, Lasse; Jensen, Jacob Malte; Petersen, Bent

    2017-01-01

    Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits. Genetic variation is identified mainly by mapping short reads to the reference genome......-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set...... or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high...

  6. Sequencing and de novo assembly of 150 genomes from Denmark as a population reference

    DEFF Research Database (Denmark)

    Maretty, Lasse; Jensen, Jacob Malte; Petersen, Bent

    2017-01-01

    Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits. Genetic variation is identified mainly by mapping short reads to the reference genome...... or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high......-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set...

  7. De novo synthesis of purine nucleotides in different fiber types of rat skeletal muscle

    International Nuclear Information System (INIS)

    Tullson, P.C.; John-Alder, H.; Hood, D.A.; Terjung, R.L.

    1986-01-01

    The contribution of de novo purine nucleotide synthesis to nucleotide metabolism in skeletal muscles is not known. The authors have determined rates of de novo synthesis in soleus (slow-twitch red), red gastrocnemius (fast-twitch red), and white gastrocnemius (fast-twitch white) using the perfused rat hindquarter. 14 C glycine incorporation into ATP was linear after 1 and 2 hours of perfusion with 0.2 mM added glycine. The intracellular (I) and extracellular (E) specific activity of 14 C glycine was determined by HPLC of phenylisothiocyanate derivatives of neutralized PCA extracts. The rates of de novo synthesis when expressed relative to muscle ATP content show slow and fast-twitch red muscles to be similar and about twice as great as fast-twitch white muscles. This could represent a greater turnover of the adenine nucleotide pool in more oxidative red muscle types

  8. A Terra em Transe: o cosmopolitismo às avessas do cinema novo

    Directory of Open Access Journals (Sweden)

    Angela Prysthon

    2008-11-01

    Full Text Available Usando como referencial teórico os estudos culturais, este artigo analisa o cinema novo brasileiro como parte de uma estratégia terceiro mundista de conceber a cultura. A partir da emergência do conceito de terceiro mundo e das lutas de descolonização nos anos 1950 e 1960, a ideologia cosmopolita foi sendo vista pelos intelectuais de esquerda como a versão cultural da aliança com as forças hegemônicas da Europa e dos Estados Unidos. O projeto do cinema novo chama a atenção por suas afinidades ideológicas com o terceiro mundismo, mas, paradoxalmente, trazendo à tona uma polí­tica cosmopolita da periferia. Palavras-chave cinema novo, identidade, cultura brasileira, terceiro mundismo, estudos culturais. Abstract Using the cultural studies theoretical framework, this paper analyzes the cinema novo movement in Brazil as a part of the Third World conception of culture. Following the creation of the term "Third World" and the international politics of colonial independence of the 1950s and 1960s, a cosmopolitan attitude was seen by the intellectuals of the left as a cultural version of the alliance with the hegemonic forces of Europe and North America. Even though the cinema novo project can be associated with the ideology of an united Third World ,it brings about, paradoxically, a very cosmopolitan politics of the periphery. Key words cinema novo, identity, Brazilian culture, third world, cultural studies.

  9. Precise detection of de novo single nucleotide variants in human genomes.

    Science.gov (United States)

    Gómez-Romero, Laura; Palacios-Flores, Kim; Reyes, José; García, Delfino; Boege, Margareta; Dávila, Guillermo; Flores, Margarita; Schatz, Michael C; Palacios, Rafael

    2018-05-07

    The precise determination of de novo genetic variants has enormous implications across different fields of biology and medicine, particularly personalized medicine. Currently, de novo variations are identified by mapping sample reads from a parent-offspring trio to a reference genome, allowing for a certain degree of differences. While widely used, this approach often introduces false-positive (FP) results due to misaligned reads and mischaracterized sequencing errors. In a previous study, we developed an alternative approach to accurately identify single nucleotide variants (SNVs) using only perfect matches. However, this approach could be applied only to haploid regions of the genome and was computationally intensive. In this study, we present a unique approach, coverage-based single nucleotide variant identification (COBASI), which allows the exploration of the entire genome using second-generation short sequence reads without extensive computing requirements. COBASI identifies SNVs using changes in coverage of exactly matching unique substrings, and is particularly suited for pinpointing de novo SNVs. Unlike other approaches that require population frequencies across hundreds of samples to filter out any methodological biases, COBASI can be applied to detect de novo SNVs within isolated families. We demonstrate this capability through extensive simulation studies and by studying a parent-offspring trio we sequenced using short reads. Experimental validation of all 58 candidate de novo SNVs and a selection of non-de novo SNVs found in the trio confirmed zero FP calls. COBASI is available as open source at https://github.com/Laura-Gomez/COBASI for any researcher to use. Copyright © 2018 the Author(s). Published by PNAS.

  10. Imparting functionality to biocatalysts via embedding enzymes into nanoporous materials by a de novo approach: size-selective sheltering of catalase in metal-organic framework microcrystals.

    Science.gov (United States)

    Shieh, Fa-Kuen; Wang, Shao-Chun; Yen, Chia-I; Wu, Chang-Cheng; Dutta, Saikat; Chou, Lien-Yang; Morabito, Joseph V; Hu, Pan; Hsu, Ming-Hua; Wu, Kevin C-W; Tsung, Chia-Kuang

    2015-04-08

    We develop a new concept to impart new functions to biocatalysts by combining enzymes and metal-organic frameworks (MOFs). The proof-of-concept design is demonstrated by embedding catalase molecules into uniformly sized ZIF-90 crystals via a de novo approach. We have carried out electron microscopy, X-ray diffraction, nitrogen sorption, electrophoresis, thermogravimetric analysis, and confocal microscopy to confirm that the ~10 nm catalase molecules are embedded in 2 μm single-crystalline ZIF-90 crystals with ~5 wt % loading. Because catalase is immobilized and sheltered by the ZIF-90 crystals, the composites show activity in hydrogen peroxide degradation even in the presence of protease proteinase K.

  11. A botulinum toxin A treatment algorithm for de novo management of torticollis and laterocollis

    Science.gov (United States)

    Kupsch, Andreas; Müngersdorf, Martina; Paus, Sebastian; Stenner, Andrea; Jost, Wolfgang

    2011-01-01

    Objectives Few studies have investigated the injection patterns for botulinum toxin type A for the treatment of heterogeneous forms of cervical dystonia (CD). This large, prospective, open-label, multicentre study aimed to evaluate the effectiveness and safety of 500 U botulinum toxin A for the initial treatment according to a standardised algorithm of the two most frequent forms of CD, predominantly torticollis and laterocollis. Design Patients (aged ≥18 years) with CD not previously treated with botulinum neurotoxin therapy were given one treatment with 500 U Dysport, according to a defined intramuscular injection algorithm based on clinical assessment of direction of head deviation, occurrence of shoulder elevation, occurrence of tremor (all evaluated using the Tsui rating scale) and hypertrophy of the sternocleidomastoid muscle. Results In this study, 516 patients were enrolled, the majority of whom (95.0%) completed treatment. Most patients had torticollis (78.1%). At week 4, mean Tsui scores had significantly decreased by −4.01, −3.76 and −4.09 points in the total, torticollis and laterocollis populations, respectively. Symptom improvement was equally effective between groups. Tsui scores remained significantly below baseline at week 12 in both groups. Treatment was well tolerated; the most frequent adverse events were muscular weakness (13.8%), dysphagia (9.9%) and neck pain (6.6%). Conclusions Dysport 500 U is effective and well tolerated for the de novo management of a range of heterogeneous forms of CD, when using a standardised regimen that allows tailored dosing based on individual symptom assessment. Clinical trials information (NCT00447772; clinicaltrials.gov) PMID:22021883

  12. De novo transcriptome analysis and molecular marker development of two Hemarthria species

    Directory of Open Access Journals (Sweden)

    Xiu eHuang

    2016-04-01

    Full Text Available Hemarthria R. Br. is an important genus of perennial forage grasses that is widely used in subtropical and tropical regions. Hemarthria grasses have made remarkable contributions to the development of animal husbandry and agro-ecosystem maintenance; however, there is currently a lack of comprehensive genomic data available for these species. In this study, we used Illumina high-throughput deep sequencing to characterize of two agriculturally important Hemarthria materials, H. compressa ‘Yaan’ and H. altissima ‘1110.’ Sequencing runs that used each of four normalized RNA samples from the leaves or roots of the two materials yielded more than 24 million high-quality reads. After de novo assembly, 137,142 and 77,150 unigenes were obtained for ‘Yaan’ and ‘1110’, respectively. In addition, a total of 86,731 ‘Yaan’ and 48,645 ‘1110’ unigenes were successfully annotated. After consolidating the unigenes for both materials, 42,646 high-quality SNPs were identified in 10,880 unigenes and 10,888 SSRs were identified in 8,330 unigenes. To validate the identified markers, high quality PCR primers were designed for both SNPs and SSRs. We randomly tested 16 of the SNP primers and 54 of the SSR primers and found that the majority of these primers successfully amplified the desired PCR product. In addition, high cross-species transferability (61.11%-87.04% of SSR markers was achieved for four other Poaceae species. The amount of RNA sequencing data that was generated for these two Hemarthria species greatly increases the amount of genomic information available for Hemarthria and the SSR and SNP markers identified in this study will facilitate further advancements in genetic and molecular studies of the Hemarthria genus.

  13. A de novo expression profiling of Anopheles funestus, malaria vector in Africa, using 454 pyrosequencing.

    Directory of Open Access Journals (Sweden)

    Richard Gregory

    2011-02-01

    Full Text Available Anopheles funestus is one of the major malaria vectors in Africa and yet there are few genomic tools available for this species compared to An. gambiae. To start to close this knowledge gap, we sequenced the An. funestus transcriptome using cDNA libraries developed from a pyrethroid resistant laboratory strain and a pyrethroid susceptible field strain from Mali.Using a pool of life stages (pupae, larvae, adults: females and males for each strain, 454 sequencing generated 375,619 reads (average length of 182 bp. De novo assembly generated 18,103 contigs with average length of 253 bp. The average depth of coverage of these contigs was 8.3. In total 20.8% of all reads were novel when compared to reference databases. The sequencing of the field strain generated 204,758 reads compared to 170,861 from the insecticide resistant laboratory strain. The contigs most differentially represented in the resistant strain belong to the P450 gene family and cuticular genes which correlates with previous studies implicating both of these gene families in pyrethroid resistance. qPCR carried out on six contigs indicates that these ESTs could be suitable for gene expression studies such as microarray. 31,000 sites were estimated to contain Single Nucleotide Polymorphisms (SNPs and analysis of SNPs from 20 contigs suggested that most of these SNPs are likely to be true SNPs. Gene conservation analysis confirmed the close phylogenetic relationship between An. funestus and An. gambiae.This study represents a significant advance for the genetics and genomics of An. funestus since it provides an extensive set of both Expressed Sequence Tags (ESTs and SNPs which can be readily adopted for the design of new genomic tools such as microarray or SNP platforms.

  14. Computational Protein Design

    DEFF Research Database (Denmark)

    Johansson, Kristoffer Enøe

    Proteins are the major functional group of molecules in biology. The impact of protein science on medicine and chemical productions is rapidly increasing. However, the greatest potential remains to be realized. The fi eld of protein design has advanced computational modeling from a tool of support...... to a central method that enables new developments. For example, novel enzymes with functions not found in natural proteins have been de novo designed to give enough activity for experimental optimization. This thesis presents the current state-of-the-art within computational design methods together...... with a novel method based on probability theory. With the aim of assembling a complete pipeline for protein design, this work touches upon several aspects of protein design. The presented work is the computational half of a design project where the other half is dedicated to the experimental part...

  15. The Strategic Design Perspective

    DEFF Research Database (Denmark)

    Rasmussen, Jørgen

    2006-01-01

    In this article I argue, and exemplify, that designers working in close relation with industry, can have significant influence on the nature and the quality of the products (or services) produced by the companies. In order to achieve this, the designer must become one of the decisive factors...... in the strategic framework of the company. This is done by taking the design process to the business floor of the company and using the design competence to innovate, not only products, but the fundamental concepts for product selection. Using design as a strategic tool will cause entirely new products to emerge...... and will make entire groups of products change into services. In this way new markets will appear to benefit the innovative companies, and if designers do their job well, the focus will be on the users, and thereby benefiting them as well. An example of this process is Novo Nordisk. This pharmaceutical company...

  16. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

    DEFF Research Database (Denmark)

    Heinzen, Erin L; Swoboda, Kathryn J; Hitomi, Yuki

    2012-01-01

    and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation...... affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3....

  17. NovoTTF™-100A System (Tumor Treating Fields) transducer array layout planning for glioblastoma: a NovoTAL™ system user study.

    Science.gov (United States)

    Chaudhry, Aafia; Benson, Laura; Varshaver, Michael; Farber, Ori; Weinberg, Uri; Kirson, Eilon; Palti, Yoram

    2015-11-11

    Optune™, previously known as the NovoTTF-100A System™, generates Tumor Treating Fields (TTFields), an effective anti-mitotic therapy for glioblastoma. The system delivers intermediate frequency, alternating electric fields to the supratentorial brain. Patient therapy is personalized by configuring transducer array layout placement on the scalp to the tumor site using MRI measurements and the NovoTAL System. Transducer array layout mapping optimizes therapy by maximizing electric field intensity to the tumor site. This study evaluated physician performance in conducting transducer array layout mapping using the NovoTAL System compared with mapping performed by the Novocure in-house clinical team. Fourteen physicians (7 neuro-oncologists, 4 medical oncologists, and 3 neurosurgeons) evaluated five blinded cases of recurrent glioblastoma and performed head size and tumor location measurements using a standard Digital Imaging and Communications in Medicine reader. Concordance with Novocure measurement and intra- and inter-rater reliability were assessed using relevant correlation coefficients. The study criterion for success was a concordance correlation coefficient (CCC) >0.80. CCC for each physician versus Novocure on 20 MRI measurements was 0.96 (standard deviation, SD ± 0.03, range 0.90-1.00), indicating very high agreement between the two groups. Intra- and inter-rater reliability correlation coefficients were similarly high: 0.83 (SD ±0.15, range 0.54-1.00) and 0.80 (SD ±0.18, range 0.48-1.00), respectively. This user study demonstrated an excellent level of concordance between prescribing physicians and Novocure in-house clinical teams in performing transducer array layout planning. Intra-rater reliability was very high, indicating reproducible performance. Physicians prescribing TTFields, when trained on the NovoTAL System, can independently perform transducer array layout mapping required for the initiation and maintenance of patients on TTFields

  18. De novo transcriptome assembly of the calanoid copepod Neocalanus flemingeri: A new resource for emergence from diapause.

    Science.gov (United States)

    Roncalli, Vittoria; Cieslak, Matthew C; Sommer, Stephanie A; Hopcroft, Russell R; Lenz, Petra H

    2018-02-01

    Copepods, small planktonic crustaceans, are key links between primary producers and upper trophic levels, including many economically important fishes. In the subarctic North Pacific, the life cycle of copepods like Neocalanus flemingeri includes an ontogenetic migration to depth followed by a period of diapause (a type of dormancy) characterized by arrested development and low metabolic activity. The end of diapause is marked by the production of the first brood of eggs. Recent temperature anomalies in the North Pacific have raised concerns about potential negative effects on N. flemingeri. Since diapause is a developmental program, its progress can be tracked using through global gene expression. Thus, a reference transcriptome was developed as a first step towards physiological profiling of diapausing females using high-throughput Illumina sequencing. The de novo transcriptome, the first for this species was designed to investigate the diapause period. RNA-Seq reads were obtained for dormant to reproductive N. flemingeri females. A high quality de novo transcriptome was obtained by first assembling reads from each individual using Trinity software followed by clustering with CAP3 Assembly Program. This assembly consisted of 140,841transcripts (contigs). Bench-marking universal single-copy orthologs analysis identified 85% of core eukaryotic genes, with 79% predicted to be complete. Comparison with other calanoid transcriptomes confirmed its quality and degree of completeness. Trinity assembly of reads originating from multiple individuals led to fragmentation. Thus, the workflow applied here differed from the one recommended by Trinity, but was required to obtain a good assembly. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Illumina–based de novo transcriptome sequencing and analysis of ...

    Indian Academy of Sciences (India)

    Administrator

    2017-10-25

    Oct 25, 2017 ... (Shanghai, China) following manufacturer's protocols (Illumina, San .... suggests that pathways involved in musk production are expressed at a ..... Strickler S. R., Aureliano B. and Mueller L. A. 2012 Designing a transcriptome.

  20. Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease

    DEFF Research Database (Denmark)

    Paludan-Müller, Christian; Ahlberg, Gustav; Ghouse, Jonas

    2017-01-01

    BACKGROUND: De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study...... sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database. METHODS AND RESULTS: We performed a literature search for previous publications on de novo variants associated with severe arrhythmias...... trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ≈844 expected cases in Ex...

  1. Long-read sequencing and de novo assembly of a Chinese genome

    Science.gov (United States)

    Short-read sequencing has enabled the de novo assembly of several individual human genomes, but with inherent limitations in characterizing repeat elements. Here we sequence a Chinese individual HX1 by single-molecule real-time (SMRT) long-read sequencing, construct a physical map by NanoChannel arr...

  2. A De novo Mutation in Dystrophin Causing Muscular Dystrophy in a Female Patient

    Directory of Open Access Journals (Sweden)

    Hao Yu

    2017-01-01

    Conclusions: We identified two novel de novo mutations of DMD gene in two Chinese pedigrees, one of which caused a female patient with muscular dystrophy. The mutational analysis is important for DMD patients and carriers in the absence of a family history. The NGS can help detect the mutations in MLPA-negative patients.

  3. Effect of haemodilution, acidosis, and hypothermia on the activity of recombinant factor VIIa (NovoSeven)

    DEFF Research Database (Denmark)

    Viuff, D.; Lauritzen, B.; Pusateri, A.E.

    2008-01-01

    BACKGROUND: A range of plasma volume expanders is used clinically, often in settings where haemostasis may already be impaired. The haemostatic agent, recombinant activated factor VII (rFVIIa, NovoSeven), may be used to improve haemostasis but potential interactions with different volume expanders...

  4. Optimization of treatment protocols to prevent de novo development of antibiotic resistance in Pseudomonas aeruginosa

    NARCIS (Netherlands)

    Feng, Yanfang

    2016-01-01

    The ever-increasing rate of drug resistant bacteria has been one of the most challenging problem worldwide. This thesis studied the following subjects with mostly the clinically leading pathogen, P. aeruginosa, as the model strain: de novo development of antibiotic resistance in patient during the

  5. Norgal: Extraction and de novo assembly of mitochondrial DNA from whole-genome sequencing data

    DEFF Research Database (Denmark)

    Al-Nakeeb, Kosai Ali Ahmed; Petersen, Thomas Nordahl; Sicheritz-Pontén, Thomas

    2017-01-01

    and performing a de novo assembly on a subset of reads that contains these k-mers. The method was applied to WGS data from a panda, brown algae seaweed, butterfly and filamentous fungus. We were able to extract full circular mitochondrial genomes and obtained sequence identities to the reference sequences...

  6. 76 FR 61103 - Draft Guidance for Industry and Food and Drug Administration Staff; De Novo Classification...

    Science.gov (United States)

    2011-10-03

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0689] Draft Guidance for Industry and Food and Drug Administration Staff; De Novo Classification Process... appropriate, and other forms of information technology. Draft Guidance for Industry and Food and Drug...

  7. De novo post-pollen mitosis II tobacco pollen tube transcriptome

    Czech Academy of Sciences Publication Activity Database

    Hafidh, Said; Breznenová, Katarína; Honys, David

    2012-01-01

    Roč. 7, č. 8 (2012), s. 918-921 ISSN 1559-2316 R&D Projects: GA ČR GPP501/11/P321; GA ČR GA522/09/0858 Institutional research plan: CEZ:AV0Z50380511 Keywords : de novo pollen tube transcriptome * male gametophyte development * pollen tube growth Subject RIV: ED - Physiology

  8. De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy

    NARCIS (Netherlands)

    de Lange, Iris M; Helbig, Katherine L; Weckhuysen, Sarah; Møller, Rikke S; Velinov, Milen; Dolzhanskaya, Natalia; Marsh, Eric; Helbig, Ingo; Devinsky, Orrin; Tang, Sha; Mefford, Heather C; Myers, Candace T; van Paesschen, Wim; Striano, Pasquale; van Gassen, Koen; van Kempen, Marjan; de Kovel, Carolien G F; Piard, Juliette; Minassian, Berge A; Nezarati, Marjan M; Pessoa, André; Jacquette, Aurelia; Maher, Bridget; Balestrini, Simona; Sisodiya, Sanjay; Warde, Marie Therese Abi; De St Martin, Anne; Chelly, Jamel; van 't Slot, Ruben; Van Maldergem, Lionel; Brilstra, Eva H; Koeleman, Bobby P C

    2016-01-01

    BACKGROUND: Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual

  9. Inflammatory bowel disease after liver transplantation : Risk factors for recurrence and De novo disease

    NARCIS (Netherlands)

    Verdonka, RC; Dijkstra, G; Haagsma, EB; Shostrom, VK; Van den Berg, AP; Kleibeuker, JH

    Inflammatory bowel disease (IBD) is associated with primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) and can recur or develop de novo after orthotopic liver transplantation (OLT). The aim of this study was to investigate the incidence and severity of IBD after liver

  10. Drug-Eluting Balloons in the Treatment of Coronary De Novo Lesions

    DEFF Research Database (Denmark)

    Richelsen, Rasmus Kapalu Broge; Overvad, Thure Filskov; Jensen, Svend Eggert

    2016-01-01

    Drug-eluting balloons (DEBs) have emerged as a new application in percutaneous coronary intervention. DEBs have proven successful in the treatment of in-stent restenosis, but their role in de novo lesions is less clear. This paper provides a review of the current studies where DEBs have been used...

  11. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation

    DEFF Research Database (Denmark)

    Michaelson, Jacob J.; Shi, Yujian; Gujral, Madhusudan

    2012-01-01

    De novo mutation plays an important role in autism spectrum disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution hot spots. We...

  12. The Key Drivers behind Novo Nordisk’s Growth in the Diabetes Market in China

    Directory of Open Access Journals (Sweden)

    Hind Louiza CHITOUR

    2013-12-01

    Full Text Available To enter the Chinese Pharmaceutical market, “Big Pharma” has adopted different strategies to tackle the challenges specific to the country in terms of size, demographics, specific sales channels and logistics adjustments. While the majority of Global Pharmaceutical players have opted for an aggressive M&A approach to penetrate the Chinese market and gain local insight; the Danish Novo Nordisk has instead chosen a strategy focusing on innovation and developing its R&D structure to capitalize on the local talent pool. To illustrate Novo Nordisk’s growth strategy in the Mainland, we analyzed its competitiveness in the diabetes market by demonstrating the key drivers behind this success. We applied a various set of tools for this research: Novo Nordisk, Dong Bao Pharmaceutical executives’ interviews and personal observations accounting for the primary data, we also reviewed secondary data to perform a PEST analysis in addition to Porter’s competitive advantage model in order to extract the reasons behind Novo Nordisk’s marching success in the Mainland.

  13. A glance at quality score: implication for de novo transcriptome reconstruction of Illumina reads

    Directory of Open Access Journals (Sweden)

    Stanley Kimbung Mbandi

    2014-02-01

    Full Text Available Downstream analyses of short-reads from next-generation sequencing platforms are often preceded by a pre-processing step that removes uncalled and wrongly called bases. Standard approaches rely on their associated base quality scores to retain the read or a portion of it when the score is above a predefined threshold. It is difficult to differentiate sequencing error from biological variation without a reference using quality scores. The effects of quality score based trimming have not been systematically studied in de novo transcriptome assembly. Using RNA-Seq data produced from Illumina, we teased out the effects of quality score base filtering or trimming on de novo transcriptome reconstruction. We showed that assemblies produced from reads subjected to different quality score thresholds contain truncated and missing transfrags when compared to those from untrimmed reads. Our data supports the fact that de novo assembling of untrimmed data is challenging for de Bruijn graph assemblers. However, our results indicates that comparing the assemblies from untrimmed and trimmed read subsets can suggest appropriate filtering parameters and enable selection of the optimum de novo transcriptome assembly in non-model organisms.

  14. Evaluation of effect of Ophiostoma novo-ulmi on four major wood ...

    African Journals Online (AJOL)

    Evaluation of effect of Ophiostoma novo-ulmi on four major wood species of the elm family in Rasht (North West of Iran) ... the diameter size of vessels and the number of xylary rays in four species: Ulmus carpinifolia, Ulmus glabra, Zelkova carpinifolia and Celtis australis as important factors in host resistance to elm disease.

  15. De novo formation of centrosomes in vertebrate cells arrested during S phase

    NARCIS (Netherlands)

    Khodjakov, A; Rieder, CL; Sluder, G; Cassels, G; Sibon, O; Wang, CL

    2002-01-01

    The centrosome usually replicates in a semiconservative fashion, i.e., new centrioles form in association with preexisting "maternal" centrioles. De novo formation of centrioles has been reported for a few highly specialized cell types but it has not been seen in vertebrate somatic cells. We find

  16. Robust de novo pathway enrichment with KeyPathwayMiner 5

    DEFF Research Database (Denmark)

    Alcaraz, Nicolas; List, Markus; Dissing-Hansen, Martin

    2016-01-01

    Identifying functional modules or novel active pathways, recently termed de novo pathway enrichment, is a computational systems biology challenge that has gained much attention during the last decade. Given a large biological interaction network, KeyPathwayMiner extracts connected subnetworks tha...

  17. De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder

    Science.gov (United States)

    Dong, Shan; Walker, Michael F.; Carriero, Nicholas J.; DiCola, Michael; Willsey, A. Jeremy; Ye, Adam Y.; Waqar, Zainulabedin; Gonzalez, Luis E.; Overton, John D.; Frahm, Stephanie; Keaney, John F.; Teran, Nicole A.; Dea, Jeanselle; Mandell, Jeffrey D.; Bal, Vanessa Hus; Sullivan, Catherine A.; DiLullo, Nicholas M.; Khalil, Rehab O.; Gockley, Jake; Yuksel, Zafer; Sertel, Sinem M.; Ercan-Sencicek, A. Gulhan; Gupta, Abha R.; Mane, Shrikant M.; Sheldon, Michael; Brooks, Andrew I.; Roeder, Kathryn; Devlin, Bernie; State, Matthew W.; Wei, Liping; Sanders, Stephan J.

    2014-01-01

    SUMMARY Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single nucleotide variants to autism spectrum disorders (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. Through the application of a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR=1.6; 95%CI=1.0-2.7; p=0.03), are more common in female probands (p=0.02), are enriched among genes encoding FMRP targets (p=6×10−9), and arise predominantly on the paternal chromosome (p<0.001). Based on mutation rates in probands versus unaffected siblings, de novo frameshift indels contribute to risk in approximately 3.0% of individuals with ASD. Finally, through observing clustering of mutations in unrelated probands, we report two novel ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release. PMID:25284784

  18. Novo Jornalismo: fronteiras litero-factuais em A sangue Frio e em Radical Chique

    Directory of Open Access Journals (Sweden)

    Francisco Aquinei Timóteo Queirós

    2012-12-01

    Full Text Available A pesquisa busca analisar de que forma fato e ficção se entrecruzam no “movimento” do Novo Jornalismo, a partir das obras A sangue Frio e Radical Chique e o Novo Jornalismo, de Truman Capote e Tom Wolfe, respectivamente. Pretende-se, a partir da investigação do corpus em estudo, revelar os aspectos que aproximam o fato jornalístico, a notícia e a reportagem às técnicas literárias do romance, do conto e da crônica. O estudo investiga o Novo Jornalismo sob o viés de textos centrais das áreas de teoria literária e estudos jornalísticos utilizando autores como Mikhail Bakhtin, Hayden White, Paul Ricoeur, Muniz Sodré; além de referenciar outros escritores que, como Tom Wolfe e Truman Capote, fizeram parte de um grande movimento renovador do jornalismo literário nos anos 1950, 1960 e 1970 chamado, genericamente, de Novo Jornalismo.

  19. CycloBranch: De Novo Sequencing of Nonribosomal Peptides from Accurate Product Ion Mass Spectra

    Czech Academy of Sciences Publication Activity Database

    Novák, Jiří; Lemr, Karel; Schug, K. A.; Havlíček, Vladimír

    2015-01-01

    Roč. 26, č. 10 (2015), s. 1780-1786 ISSN 1044-0305 R&D Projects: GA ČR(CZ) GAP206/12/1150 Grant - others:OPPC(XE) CZ.2.16/3.1.00/24023 Institutional support: RVO:61388971 Keywords : De novo sequencing * Nonribosomal peptides * Linear Subject RIV: CE - Biochemistry Impact factor: 3.031, year: 2015

  20. Novo Jornalismo: fronteiras litero-factuais em A sangue Frio e em Radical Chique

    Directory of Open Access Journals (Sweden)

    Francisco Aquinei Timóteo Queirós

    2012-03-01

    Full Text Available http://dx.doi.org/10.5007/1984-784X.2012v12n18p130 A pesquisa busca analisar de que forma fato e ficção se entrecruzam no “movimento” do Novo Jornalismo, a partir das obras A sangue Frio e Radical Chique e o Novo Jornalismo, de Truman Capote e Tom Wolfe, respectivamente. Pretende-se, a partir da investigação do corpus em estudo, revelar os aspectos que aproximam o fato jornalístico, a notícia e a reportagem às técnicas literárias do romance, do conto e da crônica. O estudo investiga o Novo Jornalismo sob o viés de textos centrais das áreas de teoria literária e estudos jornalísticos utilizando autores como Mikhail Bakhtin, Hayden White, Paul Ricoeur, Muniz Sodré; além de referenciar outros escritores que, como Tom Wolfe e Truman Capote, fizeram parte de um grande movimento renovador do jornalismo literário nos anos 1950, 1960 e 1970 chamado, genericamente, de Novo Jornalismo.

  1. Predicting survival of de novo metastatic breast cancer in Asian women: systematic review and validation study.

    Science.gov (United States)

    Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G M; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M

    2014-01-01

    In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48-0.53) to 0.63 (95% CI, 0.60-0.66). The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making.

  2. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

    NARCIS (Netherlands)

    Hoischen, Alexander; van Bon, Bregje W. M.; Rodríguez-Santiago, Benjamín; Gilissen, Christian; Vissers, Lisenka E. L. M.; de Vries, Petra; Janssen, Irene; van Lier, Bart; Hastings, Rob; Smithson, Sarah F.; Newbury-Ecob, Ruth; Kjaergaard, Susanne; Goodship, Judith; McGowan, Ruth; Bartholdi, Deborah; Rauch, Anita; Peippo, Maarit; Cobben, Jan M.; Wieczorek, Dagmar; Gillessen-Kaesbach, Gabriele; Veltman, Joris A.; Brunner, Han G.; de Vries, Bert B. B. A.

    2011-01-01

    Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is

  3. De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy

    DEFF Research Database (Denmark)

    de Lange, Iris M; Helbig, Katherine L; Weckhuysen, Sarah

    2016-01-01

    BACKGROUND: Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellect...

  4. Wound complications and surgical events in de novo heart transplant patients treated with everolimus

    DEFF Research Database (Denmark)

    Rashidi, Mitra; Esmaily, Sorosh; Fiane, Arnt E

    2016-01-01

    OBJECTIVES: The use of mammalian target of rapamycin (mTOR) inhibitors have been limited by adverse events (AE), including delayed wound healing. We retrospectively reviewed all AE and serious AE (SAE) in The Scandinavian heart transplant (HTx) everolimus (EVE) de novo trial with early calcineurin...

  5. Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism

    Directory of Open Access Journals (Sweden)

    Kyleen Luhrs

    2017-01-01

    Full Text Available The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n=62, de novo deletion copy number variations (DEL, n=74, de novo likely gene-disrupting mutations (LGDM, n=267, and children without a known genetic etiology (NON, n=2111. Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships.

  6. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

    DEFF Research Database (Denmark)

    Muona, M.; Berkovic, S. F.; Dibbens, L. M.

    2015-01-01

    Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonicclonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo...

  7. The impact of employee satisfaction on productivity in Tiskarna Novo mesto, Ltd.

    Directory of Open Access Journals (Sweden)

    Simona Cimperman

    2016-06-01

    Full Text Available Research Question: Does employee satisfaction, impact on productivity? How are these two variables associated? What is the job satisfaction in Tiskarna Novo mesto, Ltd. What needs to be done to make employees more satisfied at work and, consequently, more productive? Purpose: The purpose of the study is to determine what are the factors that influence employee satisfaction Tiskarna Novo mesto, Ltd. and check the connection between work satisfaction and employee productivity. The aim of the research is to examine what is the level of job satisfaction of employees in Tiskarna Novo mesto, Ltd. And find our reasons and factors that prevent employees were satisfied in the workplace. Method: In this study we used a descriptive method and the method of combining the study of domestic and foreign literature. Pending the results we have come to interview employees in the Tiskarna Novo mesto, Ltd. Results: We conducted a survey among employees in Tiskarna Novo mesto, Ltd and we came to the conclusion that the employees are medium satisfied – the average grade point job satisfaction of employees was 3.1 (evaluated on a 5-point Likert scale. The worst assessed was factor in job satisfaction opportunity for advancement and educational opportunities. We have found out that factors like receiving praise and awards as well as good interpersonal relations are those that affect good on job satisfaction, on the other hand conflict is the one that reduces job satisfaction. The existence of links between work satisfaction and productivity were not found (r = -0.061. Organization: The organization and managers, it is important to know which are the factors by which employees are satisfied or dissatisfied. Results of the research will give managers a clear picture of the factors of satisfaction / dissatisfaction and opinion on productivity. Society: The employees it means a lot to have your job satisfaction and consequently they are more productive. Originality: The

  8. TRANSPORT OF PATIENTS FOR PRIMARY PTCA FROM GENERAL HOSPITAL NOVO MESTO TO LJUBLJANA IN 2002

    Directory of Open Access Journals (Sweden)

    Renata Okrajšek

    2004-12-01

    Full Text Available Background. The treatment of acute coronary syndrome (ACS with ST-segment elevation with primary percutaneous transluminal coronary angioplasty (PTCA is the best way to treat these patients. Primary PTCA is also practicable with patients who are admitted into institution without catheter laboratory. The transport of patients into the tertiary institution is safe, but it is important to keep the time of ischemia as short as possible and to reach the time interval of door-balloon as recommended by the guidelines. The ACS patients with ST-segment elevation that were directed into General Hospital Novo mesto after examination at the internistic emergency department have been redirected to KC Ljubljana for realization of PTCA since October 2001.Methods. A prospective analysis of patients with ACS with STsegment elevation, who had been transferred from General Hospital Novo mesto to KC Ljubljana in the period from January 1, 2002 to December 31, 2002 to have a primary PTCA, was performed. The analysis comprised the following: the time interval of handling the patients at Internistic department of General Hospital Novo mesto, the time of transport of patients to Ljubljana and total time interval from the arrival of patients to General Hospital Novo mesto to the first inflation of balloon in Ljubljana. We monitored the complications that occurred during the treatment of the patients.Results. In the above mentioned period 29 patients (24 males and 5 females were transported from the General Hospital Novo mesto to the KC Ljubljana to have a primary PTCA performed. The total time interval measured between the patients’ arrival to General Hospital Novo mesto to the first inflation of balloon in Ljubljana in the year 2002 was 145 minutes, which is 17 minutes better than in the previous period. The time interval recommended by the guidelines was achieved with four patients.Conclusions. By recognizing the problems that had encountered with directing the

  9. A prognostic scoring model for survival after locoregional therapy in de novo stage IV breast cancer.

    Science.gov (United States)

    Kommalapati, Anuhya; Tella, Sri Harsha; Goyal, Gaurav; Ganti, Apar Kishor; Krishnamurthy, Jairam; Tandra, Pavan Kumar

    2018-05-02

    The role of locoregional treatment (LRT) remains controversial in de novo stage IV breast cancer (BC). We sought to analyze the role of LRT and prognostic factors of overall survival (OS) in de novo stage IV BC patients treated with LRT utilizing the National Cancer Data Base (NCDB). The objective of the current study is to create and internally validate a prognostic scoring model to predict the long-term OS for de novo stage IV BC patients treated with LRT. We included de novo stage IV BC patients reported to NCDB between 2004 and 2015. Patients were divided into LRT and no-LRT subsets. We randomized LRT subset to training and validation cohorts. In the training cohort, a seventeen-point prognostic scoring system was developed based on the hazard ratios calculated using Cox-proportional method. We stratified both training and validation cohorts into two "groups" [group 1 (0-7 points) and group 2 (7-17 points)]. Kaplan-Meier method and log-rank test were used to compare OS between the two groups. Our prognostic score was validated internally by comparing the OS between the respective groups in both the training and validation cohorts. Among 67,978 patients, LRT subset (21,200) had better median OS as compared to that of no-LRT (45 vs. 24 months; p < 0.0001). The group 1 and group 2 in the training cohort showed a significant difference in the 3-year OS (p < 0.0001) (68 vs. 26%). On internal validation, comparable OS was seen between the respective groups in each cohort (p = 0.77). Our prognostic scoring system will help oncologists to predict the prognosis in de novo stage IV BC patients treated with LRT. Although firm treatment-related conclusions cannot be made due to the retrospective nature of the study, LRT appears to be associated with a better OS in specific subgroups.

  10. De Novo Heart Failure After Kidney Transplantation: Trends in Incidence and Outcomes.

    Science.gov (United States)

    Lenihan, Colin R; Liu, Sai; Deswal, Anita; Montez-Rath, Maria E; Winkelmayer, Wolfgang C

    2018-03-29

    Heart failure is an important cause of morbidity and mortality following kidney transplantation. Some studies in the general population have shown that the incidence of heart failure has decreased during the past 20 years. However, it is not currently known whether such a trend exists in the kidney transplantation population. Retrospective observational cohort study. Adult patients included in the US Renal Data System who underwent their first kidney transplantation in the United States between 1998 and 2010 with at least 6 months of continuous Medicare parts A and B coverage before transplantation and no prior evidence for a diagnosis of heart failure before kidney transplantation. Calendar year of transplantation and calendar year of posttransplantation heart failure diagnosis. De novo posttransplantation heart failure defined using International Classification of Diseases, Ninth Revision diagnosis codes and mortality following de novo posttransplantation heart failure diagnosis. Secular trends in de novo post-kidney transplantation heart failure were examined using Cox proportional hazards analysis. Within a study cohort of 48,771 patients, 7,269 developed de novo heart failure within 3 years of kidney transplantation, with a median time to heart failure of 0.76 years. The adjusted HR for heart failure with death as competing risk comparing patients who underwent transplantation in 2010 with those who underwent transplantation in 1998 was 0.69 (95% CI, 0.60-0.79). No temporal trend in mortality following a diagnosis of post-kidney transplantation heart failure was observed. Potential residual confounding from either incorrectly ascertained or unavailable confounders. The cohort was limited to Medicare beneficiaries. Adjusted for demographic and clinical characteristics, the risk for developing de novo post-kidney transplantation heart failure has declined significantly between 1998 and 2010, with no apparent change in subsequent mortality. Copyright © 2018

  11. Hominoid-specific de novo protein-coding genes originating from long non-coding RNAs.

    Directory of Open Access Journals (Sweden)

    Chen Xie

    2012-09-01

    Full Text Available Tinkering with pre-existing genes has long been known as a major way to create new genes. Recently, however, motherless protein-coding genes have been found to have emerged de novo from ancestral non-coding DNAs. How these genes originated is not well addressed to date. Here we identified 24 hominoid-specific de novo protein-coding genes with precise origination timing in vertebrate phylogeny. Strand-specific RNA-Seq analyses were performed in five rhesus macaque tissues (liver, prefrontal cortex, skeletal muscle, adipose, and testis, which were then integrated with public transcriptome data from human, chimpanzee, and rhesus macaque. On the basis of comparing the RNA expression profiles in the three species, we found that most of the hominoid-specific de novo protein-coding genes encoded polyadenylated non-coding RNAs in rhesus macaque or chimpanzee with a similar transcript structure and correlated tissue expression profile. According to the rule of parsimony, the majority of these hominoid-specific de novo protein-coding genes appear to have acquired a regulated transcript structure and expression profile before acquiring coding potential. Interestingly, although the expression profile was largely correlated, the coding genes in human often showed higher transcriptional abundance than their non-coding counterparts in rhesus macaque. The major findings we report in this manuscript are robust and insensitive to the parameters used in the identification and analysis of de novo genes. Our results suggest that at least a portion of long non-coding RNAs, especially those with active and regulated transcription, may serve as a birth pool for protein-coding genes, which are then further optimized at the transcriptional level.

  12. De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

    Directory of Open Access Journals (Sweden)

    Shan Dong

    2014-10-01

    Full Text Available Summary: Whole-exome sequencing (WES studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs to autism spectrum disorder (ASD. However, challenges in the reliable detection of de novo insertions and deletions (indels have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals, we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0–2.7; p = 0.03, are more common in female probands (p = 0.02, are enriched among genes encoding FMRP targets (p = 6 × 10−9, and arise predominantly on the paternal chromosome (p < 0.001. On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5, a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release. : Insertions and deletions (indels have proven especially difficult to detect in exome sequencing data. Dong et al. now identify indels in exome data for 787 autism spectrum disorder (ASD families. They demonstrate association between de novo indels that alter the reading frame and ASD. Furthermore, by observing clustering of indels in unrelated probands, they uncover two additional ASD-associated genes: KMT2E (MLL5, a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

  13. De novo synthesis of adenine nucleotides in different skeletal muscle fiber types

    International Nuclear Information System (INIS)

    Tullson, P.C.; John-Alder, H.B.; Hood, D.A.; Terjung, R.L.

    1988-01-01

    Management of adenine nucleotide catabolism differs among skeletal muscle fiber types. This study evaluated whether there are corresponding differences in the rates of de novo synthesis of adenine nucleotide among fiber type sections of skeletal muscle using an isolated perfused rat hindquarter preparation. Label incorporation into adenine nucleotides from the [1-14C]glycine precursor was determined and used to calculate synthesis rates based on the intracellular glycine specific radioactivity. Results show that intracellular glycine is closely related to the direct precursor pool. Rates of de novo synthesis were highest in fast-twitch red muscle (57.0 +/- 4.0, 58.2 +/- 4.4 nmol.h-1.g-1; deep red gastrocnemius and vastus lateralis), relatively high in slow-twitch red muscle (47.0 +/- 3.1; soleus), and low in fast-twitch white muscle (26.1 +/- 2.0 and 21.6 +/- 2.3; superficial white gastrocnemius and vastus lateralis). Rates for four mixed muscles were intermediate, ranging between 32.3 and 37.3. Specific de novo synthesis rates exhibited a strong correlation (r = 0.986) with muscle section citrate synthase activity. Turnover rates (de novo synthesis rate/adenine nucleotide pool size) were highest in high oxidative muscle (0.82-1.06%/h), lowest in low oxidative muscle (0.30-0.35%/h), and intermediate in mixed muscle (0.44-0.55%/h). Our results demonstrate that differences in adenine nucleotide management among fiber types extends to the process of de novo adenine nucleotide synthesis

  14. De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone.

    Science.gov (United States)

    Citterio, Cintia E; Veluswamy, Balaji; Morgan, Sarah J; Galton, Valerie A; Banga, J Paul; Atkins, Stephen; Morishita, Yoshiaki; Neumann, Susanne; Latif, Rauf; Gershengorn, Marvin C; Smith, Terry J; Arvan, Peter

    2017-09-15

    The thyroid gland secretes primarily tetraiodothyronine (T 4 ), and some triiodothyronine (T 3 ). Under normal physiological circumstances, only one-fifth of circulating T 3 is directly released by the thyroid, but in states of hyperactivation of thyroid-stimulating hormone receptors (TSHRs), patients develop a syndrome of relative T 3 toxicosis. Thyroidal T 4 production results from iodination of thyroglobulin (TG) at residues Tyr 5 and Tyr 130 , whereas thyroidal T 3 production may originate in several different ways. In this study, the data demonstrate that within the carboxyl-terminal portion of mouse TG, T 3 is formed de novo independently of deiodination from T 4 We found that upon iodination in vitro , de novo T 3 formation in TG was decreased in mice lacking TSHRs. Conversely, de novo T 3 that can be formed upon iodination of TG secreted from PCCL3 (rat thyrocyte) cells was augmented from cells previously exposed to increased TSH, a TSHR agonist, a cAMP analog, or a TSHR-stimulating antibody. We present data suggesting that TSH-stimulated TG phosphorylation contributes to enhanced de novo T 3 formation. These effects were reversed within a few days after removal of the hyperstimulating conditions. Indeed, direct exposure of PCCL3 cells to human serum from two patients with Graves' disease, but not control sera, led to secretion of TG with an increased intrinsic ability to form T 3 upon in vitro iodination. Furthermore, TG secreted from human thyrocyte cultures hyperstimulated with TSH also showed an increased intrinsic ability to form T 3 Our data support the hypothesis that TG processing in the secretory pathway of TSHR-hyperstimulated thyrocytes alters the structure of the iodination substrate in a way that enhances de novo T 3 formation, contributing to the relative T 3 toxicosis of Graves' disease.

  15. Genome sequencing of bacteria: sequencing, de novo assembly and rapid analysis using open source tools.

    Science.gov (United States)

    Kisand, Veljo; Lettieri, Teresa

    2013-04-01

    De novo genome sequencing of previously uncharacterized microorganisms has the potential to open up new frontiers in microbial genomics by providing insight into both functional capabilities and biodiversity. Until recently, Roche 454 pyrosequencing was the NGS method of choice for de novo assembly because it generates hundreds of thousands of long reads (tools for processing NGS data are increasingly free and open source and are often adopted for both their high quality and role in promoting academic freedom. The error rate of pyrosequencing the Alcanivorax borkumensis genome was such that thousands of insertions and deletions were artificially introduced into the finished genome. Despite a high coverage (~30 fold), it did not allow the reference genome to be fully mapped. Reads from regions with errors had low quality, low coverage, or were missing. The main defect of the reference mapping was the introduction of artificial indels into contigs through lower than 100% consensus and distracting gene calling due to artificial stop codons. No assembler was able to perform de novo assembly comparable to reference mapping. Automated annotation tools performed similarly on reference mapped and de novo draft genomes, and annotated most CDSs in the de novo assembled draft genomes. Free and open source software (FOSS) tools for assembly and annotation of NGS data are being developed rapidly to provide accurate results with less computational effort. Usability is not high priority and these tools currently do not allow the data to be processed without manual intervention. Despite this, genome assemblers now readily assemble medium short reads into long contigs (>97-98% genome coverage). A notable gap in pyrosequencing technology is the quality of base pair calling and conflicting base pairs between single reads at the same nucleotide position. Regardless, using draft whole genomes that are not finished and remain fragmented into tens of contigs allows one to characterize

  16. De Novo Assembly of Highly Substituted Morpholines and Piperazines

    NARCIS (Netherlands)

    Patil, Pravin; Madhavachary, Rudrakshula; Kurpiewska, Katarzyna; Kalinowska-Tłuścik, Justyna; Dömling, Alexander

    2017-01-01

    The morpholine and piperazine with their remarkable physical and biochemical properties are popular heterocycles in organic and medicinal chemistry used in rational property design. However, in the majority of cases these rings are added to an existing molecule in a building block approach thus

  17. De novo transcriptome assembly facilitates characterisation of fast-evolving gene families, MHC class I in the bank vole (Myodes glareolus).

    Science.gov (United States)

    Migalska, M; Sebastian, A; Konczal, M; Kotlík, P; Radwan, J

    2017-04-01

    The major histocompatibility complex (MHC) plays a central role in the adaptive immune response and is the most polymorphic gene family in vertebrates. Although high-throughput sequencing has increasingly been used for genotyping families of co-amplifying MHC genes, its potential to facilitate early steps in the characterisation of MHC variation in nonmodel organism has not been fully explored. In this study we evaluated the usefulness of de novo transcriptome assembly in characterisation of MHC sequence diversity. We found that although de novo transcriptome assembly of MHC I genes does not reconstruct sequences of individual alleles, it does allow the identification of conserved regions for PCR primer design. Using the newly designed primers, we characterised MHC I sequences in the bank vole. Phylogenetic analysis of the partial MHC I coding sequence (2-4 exons) of the bank vole revealed a lack of orthology to MHC I of other Cricetidae, consistent with the high gene turnover of this region. The diversity of expressed alleles was characterised using ultra-deep sequencing of the third exon that codes for the peptide-binding region of the MHC molecule. High allelic diversity was demonstrated, with 72 alleles found in 29 individuals. Interindividual variation in the number of expressed loci was found, with the number of alleles per individual ranging from 5 to 14. Strong signatures of positive selection were found for 8 amino acid sites, most of which are inferred to bind antigens in human MHC, indicating conservation of structure despite rapid sequence evolution.

  18. Rapid de novo shape encoding: a challenge to connectionist modeling

    OpenAIRE

    Greene, Ernest

    2018-01-01

    Neural network (connectionist) models are designed to encode image features and provide the building blocks for object and shape recognition. These models generally call for: a) initial diffuse connections from one neuron population to another, and b) training to bring about a functional change in those connections so that one or more high-tier neurons will selectively respond to a specific shape stimulus. Advanced models provide for translation, size, and rotation invariance. The present dis...

  19. Transferência do fator caturra para o cultivar Mundo Novo de Coffea arabica Transfer of the CT gene to Mundo Novo cultivar

    Directory of Open Access Journals (Sweden)

    A. Carvalho

    1972-01-01

    Full Text Available No presente trabalho são relatados os estudos realizados visando à introdução do gene Ct (caturra que contribui para reduzir a altura da planta, no cultivar Mundo" Novo de Coffea arabica.Estudaram-se, em ensaios de produtividade, as populações Fv F.,, F3 e F4. Nessas populações e principalmente entre os descendentes dos "caféeiros H 2077-2-5 e H 2077-2-12, foram selecionadas plantas homozigotas para os alelos Ct e também para os alelos responsáveis pela cor do fruto xc ou Xc. Essas combinações foram denominadas 'Catuaí Amarelo' e 'Catuaí Vermelho', respectivamente, e suas características são apresentadas. Os novos cultivares vêm-se mostrando de interesse econômico para as regiões cafeeiras não somente pelo porte pequeno, mas também pela produtividade, pelo vigor vegetativo e pela precocidade.The successful transfer of the Ct gene for short internode to the tall cultivar of Coffea arábica'Mundo Novo' is reported. Individual selections were carried out in the F1, F2, F3 and F4 generations. It was found that early selection in the F2 generation was quite effective. A remarkably good correlation was found between productitivity of F2 plants and the yield of the F3 and F4 generations. Plants of the F4 generation have shown reasonable uniformity and high yield in several trials. The new selections showed to be early producers. Two new cultivars were released namely 'Catuaí Amarelo' and 'Catuaí Vermelho'. The former has yellow fruits whereas the latter has red fruits. The plants are much shorter that the ones of Mundo Novo. The new cultivars have a very strong secondary and tertiary branching. Because of these characteristics Catuaí Amarelo and Catuaí Vermelho are being planted in large scale replacing the tall cultivars.

  20. De Novo Ultrascale Atomistic Simulations On High-End Parallel Supercomputers

    Energy Technology Data Exchange (ETDEWEB)

    Nakano, A; Kalia, R K; Nomura, K; Sharma, A; Vashishta, P; Shimojo, F; van Duin, A; Goddard, III, W A; Biswas, R; Srivastava, D; Yang, L H

    2006-09-04

    We present a de novo hierarchical simulation framework for first-principles based predictive simulations of materials and their validation on high-end parallel supercomputers and geographically distributed clusters. In this framework, high-end chemically reactive and non-reactive molecular dynamics (MD) simulations explore a wide solution space to discover microscopic mechanisms that govern macroscopic material properties, into which highly accurate quantum mechanical (QM) simulations are embedded to validate the discovered mechanisms and quantify the uncertainty of the solution. The framework includes an embedded divide-and-conquer (EDC) algorithmic framework for the design of linear-scaling simulation algorithms with minimal bandwidth complexity and tight error control. The EDC framework also enables adaptive hierarchical simulation with automated model transitioning assisted by graph-based event tracking. A tunable hierarchical cellular decomposition parallelization framework then maps the O(N) EDC algorithms onto Petaflops computers, while achieving performance tunability through a hierarchy of parameterized cell data/computation structures, as well as its implementation using hybrid Grid remote procedure call + message passing + threads programming. High-end computing platforms such as IBM BlueGene/L, SGI Altix 3000 and the NSF TeraGrid provide an excellent test grounds for the framework. On these platforms, we have achieved unprecedented scales of quantum-mechanically accurate and well validated, chemically reactive atomistic simulations--1.06 billion-atom fast reactive force-field MD and 11.8 million-atom (1.04 trillion grid points) quantum-mechanical MD in the framework of the EDC density functional theory on adaptive multigrids--in addition to 134 billion-atom non-reactive space-time multiresolution MD, with the parallel efficiency as high as 0.998 on 65,536 dual-processor BlueGene/L nodes. We have also achieved an automated execution of hierarchical QM

  1. APRIMORAMENTO HUMANO: UM NOVO TEMA DA AGENDA FILOSÓFICA

    Directory of Open Access Journals (Sweden)

    Marco Antonio Azevedo

    2015-07-01

    human capacities, preserving and restoring health or promoting human well-being. It also enables us to overcome human limitations and reach way beyond our "natural design". That being said, what could possibly justify the fear for these new directions of biotechnology? Should medicine and health care change their traditional goals and begin searching for artificial improvements to wellness in human nature? In this paper, I will hereby present and briefly discuss the main topics of the contemporary issue of human enhancement: the therapy-enhancement distinction, the possibility of cognitive enhancements and better physical performances, the fight against senescence, the arguments for and against human eugenics, the search for perfection, the quest of moral enhancement, the problem of public priorities, and some questions on medical ethics. Then, finally, I will want to present some realist perspectives on the subject.

  2. De novo mutations in the genome organizer CTCF cause intellectual disability

    DEFF Research Database (Denmark)

    Gregor, Anne; Oti, Martin; Kouwenhoven, Evelyn N

    2013-01-01

    An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift...... mutations and one de novo missense mutation in CTCF in individuals with intellectual disability, microcephaly, and growth retardation. Furthermore, an individual with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates...... and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three individuals with point mutations revealed deregulation of genes involved in signal transduction...

  3. Whole-Genome de novo Sequencing Of Quail And Grey Partridge

    DEFF Research Database (Denmark)

    Holm, Lars-Erik; Panitz, Frank; Burt, Dave

    2011-01-01

    The development in sequencing methods has made it possible to perform whole genome de novo sequencing of species without large commercial interests. Within the EU-financed QUANTOMICS project (KBBE-2A-222664), we have performed de novo sequencing of quail (Coturnix coturnix) and grey partridge...... (Perdix perdix) on a Genome Analyzer GAII (Illumina) using paired-end sequencing. The amount of generated sequences amounts to 8 to 9 Gb for each species. The analysis and assembly of the generated sequences is ongoing. Access to the whole genome sequence from these two species will enable enhanced...... comparative studies towards the chicken genome and will aid in identifying evolutionarily conserved sequences within the Galliformes. The obtained sequences from quail and partridge represent a beginning of generating the whole genome sequence for these species. The continuation of establishing the genome...

  4. NxRepair: error correction in de novo sequence assembly using Nextera mate pairs

    Directory of Open Access Journals (Sweden)

    Rebecca R. Murphy

    2015-06-01

    Full Text Available Scaffolding errors and incorrect repeat disambiguation during de novo assembly can result in large scale misassemblies in draft genomes. Nextera mate pair sequencing data provide additional information to resolve assembly ambiguities during scaffolding. Here, we introduce NxRepair, an open source toolkit for error correction in de novo assemblies that uses Nextera mate pair libraries to identify and correct large-scale errors. We show that NxRepair can identify and correct large scaffolding errors, without use of a reference sequence, resulting in quantitative improvements in the assembly quality. NxRepair can be downloaded from GitHub or PyPI, the Python Package Index; a tutorial and user documentation are also available.

  5. Trans-10, cis-12 conjugated linoleic acid decreases de novo lipid synthesis in human adipocytes

    DEFF Research Database (Denmark)

    Obsen, Thomas; Faergeman, Nils J; Chung, Soonkyu

    2012-01-01

    7-12 h, respectively. The mRNA levels of liver X receptor (LXR)α and sterol regulatory element binding protein (SREBP)-1c, transcription factors that regulate SCD-1, were decreased by 10,12 CLA within 5 h. These data suggest that the isomer-specific decrease in de novo lipid synthesis by 10,12 CLA......]-oleic or [(14)C]-linoleic acids. When using [(14)C]-acetic acid and [(14)C]-pyruvic acid as substrates, 30 μM 10,12 CLA, but not 9,11 CLA, decreased de novo synthesis of triglyceride, free FA, diacylglycerol, cholesterol esters, cardiolipin, phospholipids and ceramides within 3-24 h. Treatment with 30 μM 10...... is due, in part, to the rapid repression of lipogenic transcription factors that regulate MUFA synthesis, suggesting an anti-obesity mechanism unique to this trans FA....

  6. Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

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    Atsushi Takata

    2018-01-01

    Full Text Available Recent studies have established important roles of de novo mutations (DNMs in autism spectrum disorders (ASDs. Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the “de novo paradigm” of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244 and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.

  7. Alternative normalization methods demonstrate widespread cortical hypometabolism in untreated de novo Parkinson's disease

    DEFF Research Database (Denmark)

    Berti, Valentina; Polito, C; Borghammer, Per

    2012-01-01

    , recent studies suggested that conventional data normalization procedures may not always be valid, and demonstrated that alternative normalization strategies better allow detection of low magnitude changes. We hypothesized that these alternative normalization procedures would disclose more widespread...... metabolic alterations in de novo PD. METHODS: [18F]FDG PET scans of 26 untreated de novo PD patients (Hoehn & Yahr stage I-II) and 21 age-matched controls were compared using voxel-based analysis. Normalization was performed using gray matter (GM), white matter (WM) reference regions and Yakushev...... normalization. RESULTS: Compared to GM normalization, WM and Yakushev normalization procedures disclosed much larger cortical regions of relative hypometabolism in the PD group with extensive involvement of frontal and parieto-temporal-occipital cortices, and several subcortical structures. Furthermore...

  8. A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle

    DEFF Research Database (Denmark)

    Agerholm, Jørgen Steen; McEvoy, Fintan; Heegaard, Steffen

    2017-01-01

    was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause. Results Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial...... chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member...... of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events...

  9. A rare case of de novo gigantic ovarian abscess within an endometrioma.

    Science.gov (United States)

    Hameed, Aisha; Mehta, Vaishali; Sinha, Prabha

    2010-06-01

    We are reporting a rare case of de novo ovarian abscess in an endometrioma. Ovarian abscess within an endometrioma is a rare gynecological problem, but de novo abscess in the endometrioma is even rarer. Most of the ovarian abscesses develop in the endometriomas following interventions, e.g., aspiration, pelvic surgery, and oocyte retrieval. We are presenting a case of a spontaneous giant abscess in a large ovarian cyst in a nulliparous woman who presented with acute abdomen. Patient was treated in a district general hospital with multidisciplinary approach. Thirteen liters of the pus were drained. She has had a sub total (supra cervical) hysterectomy and bilateral salpingo-oophorectomy (BSO) performed. Histology of the abscess wall confirmed endometriotic nature of the cyst. Patient made an uneventful recovery and was discharged home on the 14th postoperative day. This case highlights that endometrioma and its complication can present as a surgical emergency and should be dealt as one.

  10. The significance of trilineage myelodysplasia in de novo acute myeloblastic leukemia: Clinical and laboratory features

    OpenAIRE

    Lima, CSP; Vassalo, J; LorandMetze, I; Bechelli, APP; Souza, CA

    1997-01-01

    A prospective study was undertaken to elucidate the clinical and laboratory differences between tie novo acute myeloid leukemia (AML) and AML with trilineage myelodysplasia (AML-TMDS). One hundred and seven patients with AML were diagnosed at the University Hospital between January 1987 and July 1992, and were followed until July 1995. TMDS was identified in 17 of them (16%). With regard to age and sex distribution no difference was found between AML patients with and without TMDS (p = 0.43, ...

  11. Perinatal Autopsy Findings in a Case of De Novo Hypohidrotic Ectodermal Dysplasia.

    Science.gov (United States)

    Chikkannaiah, Panduranga; Nagaraju, Smitha; Kangle, Rajit; Gosavi, Mansi

    2015-01-01

    Ectodermal dysplasia are group of inherited disorders involving the developmental defects of ectodermal structures like hair, teeth, nails, sweat glands, and others. X-linked recessive inheritance is most common. Here we describe perinatal autopsy findings in a case of de novo ectodermal dysplasia in a female fetus. To the best of our knowledge, this is the first fetal autopsy description in a case of ectodermal dysplasia.

  12. Demonstration of de novo synthesis of enzymes by density labelling with stable isotopes

    International Nuclear Information System (INIS)

    Huebner, G.; Hirschberg, K.

    1977-01-01

    The technique of in vivo density labelling of proteins with H 2 18 O and 2 H 2 O has been used to investigate hormonal regulation and developmental expression of enzymes in plant cells. Buoyant density data obtained from isopycnic equilibrium centrifugation demonstrated that the cytokinine-induced nitrate reductase activity and the gibberellic acid-induced phosphatase activity in isolated embryos of Agrostemma githago are activities of enzymes synthesized de novo. The increase in alanine-specific aminopeptidase in germinating A. githago seeds is not due to de novo synthesis but to the release of preformed enzyme. On the basis of this result it is possible to apply the enzyme aminopeptidase as an internal density standard in equilibrium centrifugation. Density labelling experiments on proteins in pea cotyledons have been used to study the change in the activity of acid phosphatase, alanine-specific aminopeptidase, and peroxidase during germination. The activities of these enzymes increase in cotyledons of Pisum sativum. Density labelling by 18 O and 2 H demonstrates de novo synthesis of these three enzymes. The differential time course of enzyme induction shows the advantage of using H 2 18 O as labelling substance in cases when the enzyme was synthesized immediately at the beginning of germination. At this stage of development the amino-acid pool available for synthesis is formed principally by means of hydrolysis of storage proteins. The incorporation of 2 H into the new proteins takes place in a measurable amount at a stage of growth in which the amino acids are also synthesized de novo. The enzyme acid phosphatase of pea cotyledons was chosen to demonstrate the possibility of using the density labelling technique to detect protein turnover. (author)

  13. Optimizing de novo common wheat transcriptome assembly using short-read RNA-Seq data

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    Duan Jialei

    2012-08-01

    Full Text Available Abstract Background Rapid advances in next-generation sequencing methods have provided new opportunities for transcriptome sequencing (RNA-Seq. The unprecedented sequencing depth provided by RNA-Seq makes it a powerful and cost-efficient method for transcriptome study, and it has been widely used in model organisms and non-model organisms to identify and quantify RNA. For non-model organisms lacking well-defined genomes, de novo assembly is typically required for downstream RNA-Seq analyses, including SNP discovery and identification of genes differentially expressed by phenotypes. Although RNA-Seq has been successfully used to sequence many non-model organisms, the results of de novo assembly from short reads can still be improved by using recent bioinformatic developments. Results In this study, we used 212.6 million pair-end reads, which accounted for 16.2 Gb, to assemble the hexaploid wheat transcriptome. Two state-of-the-art assemblers, Trinity and Trans-ABySS, which use the single and multiple k-mer methods, respectively, were used, and the whole de novo assembly process was divided into the following four steps: pre-assembly, merging different samples, removal of redundancy and scaffolding. We documented every detail of these steps and how these steps influenced assembly performance to gain insight into transcriptome assembly from short reads. After optimization, the assembled transcripts were comparable to Sanger-derived ESTs in terms of both continuity and accuracy. We also provided considerable new wheat transcript data to the community. Conclusions It is feasible to assemble the hexaploid wheat transcriptome from short reads. Special attention should be paid to dealing with multiple samples to balance the spectrum of expression levels and redundancy. To obtain an accurate overview of RNA profiling, removal of redundancy may be crucial in de novo assembly.

  14. Primary intraosseous squamous cell carcinoma of the mandible arising de novo.

    Science.gov (United States)

    Shamim, Thorakkal

    2009-07-01

    Primary intraosseous squamous cell carcinoma is an odontogenic tumour with aggressive behaviour usually noticed in 6th to 7th decades of life. The tumour is characterized by progressive swelling of the jaw, pain and loosening of teeth. Microscopically, the lesion is showing foci of keratinising cells separated by collagenous connective tissue stroma. A case of primary intraosseous squamous cell carcinoma of mandible arising de novo in a 40-year-old man is reported.

  15. De novo and salvage pathway precursor incorporation during DNA replication at the nuclear matrix

    International Nuclear Information System (INIS)

    Panzeter, P.L.

    1988-01-01

    Total nuclear DNA can be empirically subdivided into low salt-soluble (LS) DNA (75-80%), high salt-soluble (HS) DNA (18-23%), and nuclear matrix-associated (NM) DNA which remains tightly bound to the nuclear matrix (∼2%). The most-newly replicated DNA is that associated with the nuclear matrix in regenerating rat liver. Analyses of the DNA fractions after various pulse times revealed that the salvage and de novo pathway DNA precursors investigated were incorporated preferentially into NM-DNA at early pulse times, after which the radioactivity became progressively incorporated into HS- and LS-DNA, respectively. These results support two models of nuclear matrix-associated DNA replication, proposed previously, and a third model presented in this dissertation. In addition, the incorporation of de novo pathway precursors lagged significantly (> 10 minutes) behind the incorporation of precursors entering through the salvage pathway. Channeling of salvage pathway precursors to DNA replication sites would explain the more rapid uptake of salvage precursors into NM-DNA than de novo precursors. To investigate the possibility of this heretofore in vitro phenomenon, the incorporation of the salvage precursor, ( 3 H)deoxythymidine, and the de novo precursor, ( 14 C)orotic acid, into NM-DNA and dTTP was examined in regenerating rat liver. There was no significant difference between the incorporation pattern of ( 14 C)orotic acid into NM-DNA thymine and that of ( 14 C)orotic acid into soluble dTTP. Contrastingly, the salvage pathway precursor, ( 3 H)deoxythymidine, labeled NM-DNA before labeling the dTTP pool

  16. De novo complex intra chromosomal rearrangement after ICSI: characterisation by BACs micro array-CGH

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    Quimsiyeh Mazin

    2008-12-01

    Full Text Available Abstract Background In routine Assisted Reproductive Technology (ART men with severe oligozoospermia or azoospermia should be informed about the risk of de novo congenital or chromosomal abnormalities in ICSI program. Also the benefits of preimplantation or prenatal genetic diagnosis practice need to be explained to the couple. Methods From a routine ICSI attempt, using ejaculated sperm from male with severe oligozoospermia and having normal karyotype, a 30 years old pregnant woman was referred to prenatal diagnosis in the 17th week for bichorionic biamniotic twin gestation. Amniocentesis was performed because of the detection of an increased foetal nuchal translucency for one of the fetus by the sonographic examination during the 12th week of gestation (WG. Chromosome and DNA studies of the fetus were realized on cultured amniocytes Results Conventional, molecular cytogenetic and microarray CGH experiments allowed us to conclude that the fetus had a de novo pericentromeric inversion associated with a duplication of the 9p22.1-p24 chromosomal region, 46,XY,invdup(9(p22.1p24 [arrCGH 9p22.1p24 (RP11-130C19 → RP11-87O1x3]. As containing the critical 9p22 region, our case is in coincidence with the general phenotype features of the partial trisomy 9p syndrome with major growth retardation, microcephaly and microretrognathia. Conclusion This de novo complex chromosome rearrangement illustrates the possible risk of chromosome or gene defects in ICSI program and the contribution of array-CGH for mapping rapidly de novo chromosomal imbalance.

  17. Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid.

    Science.gov (United States)

    McReynolds, Melanie R; Wang, Wenqing; Holleran, Lauren M; Hanna-Rose, Wendy

    2017-07-07

    NAD + biosynthesis is an attractive and promising therapeutic target for influencing health span and obesity-related phenotypes as well as tumor growth. Full and effective use of this target for therapeutic benefit requires a complete understanding of NAD + biosynthetic pathways. Here, we report a previously unrecognized role for a conserved phosphoribosyltransferase in NAD + biosynthesis. Because a required quinolinic acid phosphoribosyltransferase (QPRTase) is not encoded in its genome, Caenorhabditis elegans are reported to lack a de novo NAD + biosynthetic pathway. However, all the genes of the kynurenine pathway required for quinolinic acid (QA) production from tryptophan are present. Thus, we investigated the presence of de novo NAD + biosynthesis in this organism. By combining isotope-tracing and genetic experiments, we have demonstrated the presence of an intact de novo biosynthesis pathway for NAD + from tryptophan via QA, highlighting the functional conservation of this important biosynthetic activity. Supplementation with kynurenine pathway intermediates also boosted NAD + levels and partially reversed NAD + -dependent phenotypes caused by mutation of pnc-1 , which encodes a nicotinamidase required for NAD + salvage biosynthesis, demonstrating contribution of de novo synthesis to NAD + homeostasis. By investigating candidate phosphoribosyltransferase genes in the genome, we determined that the conserved uridine monophosphate phosphoribosyltransferase (UMPS), which acts in pyrimidine biosynthesis, is required for NAD + biosynthesis in place of the missing QPRTase. We suggest that similar underground metabolic activity of UMPS may function in other organisms. This mechanism for NAD + biosynthesis creates novel possibilities for manipulating NAD + biosynthetic pathways, which is key for the future of therapeutics. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Predicting survival of de novo metastatic breast cancer in Asian women: systematic review and validation study.

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    Hui Miao

    Full Text Available BACKGROUND: In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. MATERIALS AND METHODS: We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic. RESULTS: We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48-0.53 to 0.63 (95% CI, 0.60-0.66. CONCLUSION: The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making.

  19. De novo assembly of human genomes with massively parallel short read sequencing

    DEFF Research Database (Denmark)

    Li, Ruiqiang; Zhu, Hongmei; Ruan, Jue

    2010-01-01

    genomes from short read sequences. We successfully assembled both the Asian and African human genome sequences, achieving an N50 contig size of 7.4 and 5.9 kilobases (kb) and scaffold of 446.3 and 61.9 kb, respectively. The development of this de novo short read assembly method creates new opportunities...... for building reference sequences and carrying out accurate analyses of unexplored genomes in a cost-effective way....

  20. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

    Directory of Open Access Journals (Sweden)

    Chihiro Okuma

    2015-07-01

    Conclusion: In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

  1. Axonal regeneration and development of de novo axons from distal dendrites of adult feline commissural interneurons after a proximal axotomy

    DEFF Research Database (Denmark)

    Fenrich, Keith K; Skelton, Nicole; MacDermid, Victoria E

    2007-01-01

    Following proximal axotomy, several types of neurons sprout de novo axons from distal dendrites. These processes may represent a means of forming new circuits following spinal cord injury. However, it is not know whether mammalian spinal interneurons, axotomized as a result of a spinal cord injury......, develop de novo axons. Our goal was to determine whether spinal commissural interneurons (CINs), axotomized by 3-4-mm midsagittal transection at C3, form de novo axons from distal dendrites. All experiments were performed on adult cats. CINs in C3 were stained with extracellular injections of Neurobiotin...... at 4-5 weeks post injury. The somata of axotomized CINs were identified by the presence of immunoreactivity for the axonal growth-associated protein-43 (GAP-43). Nearly half of the CINs had de novo axons that emerged from distal dendrites. These axons lacked immunoreactivity for the dendritic protein...

  2. De Novo Metabolic Engineering and the Promise of Synthetic DNA

    Science.gov (United States)

    Klein-Marcuschamer, Daniel; Yadav, Vikramaditya G.; Ghaderi, Adel; Stephanopoulos, Gregory N.

    The uncertain price and tight supply of crude oil and the ever-increasing demand for clean energy have prompted heightened attention to the development of sustainable fuel technologies that ensure continued economic development while maintaining stewardship of the environment. In the face of these enormous challenges, biomass has emerged as a viable alternative to petroleum for the production of energy, chemicals, and materials owing to its abundance, inexpensiveness, and carbon-neutrality. Moreover, the immense ease and efficiency of biological systems at converting biomass-derived feedstocks into fuels, chemicals, and materials has generated renewed interest in biotechnology as a replacement for traditional chemical processes. Aided by the ever-expanding repertoire of microbial genetics and plant biotechnology, improved understanding of gene regulation and cellular metabolism, and incessantly accumulating gene and protein data, scientists are now contemplating engineering microbial cell factories to produce fuels, chemical feedstocks, polymers and pharmaceuticals in an economically and environmentally sustainable way. This goal resonates with that of metabolic engineering - the improvement of cellular properties through the intelligent design, rational modification, or directed evolution of biochemical pathways, and arguably, metabolic engineering seems best positioned to achieve the concomittant goals of environmental stewardship and economic prolificity.

  3. Building a Better Fragment Library for De Novo Protein Structure Prediction

    Science.gov (United States)

    de Oliveira, Saulo H. P.; Shi, Jiye; Deane, Charlotte M.

    2015-01-01

    Fragment-based approaches are the current standard for de novo protein structure prediction. These approaches rely on accurate and reliable fragment libraries to generate good structural models. In this work, we describe a novel method for structure fragment library generation and its application in fragment-based de novo protein structure prediction. The importance of correct testing procedures in assessing the quality of fragment libraries is demonstrated. In particular, the exclusion of homologs to the target from the libraries to correctly simulate a de novo protein structure prediction scenario, something which surprisingly is not always done. We demonstrate that fragments presenting different predominant predicted secondary structures should be treated differently during the fragment library generation step and that exhaustive and random search strategies should both be used. This information was used to develop a novel method, Flib. On a validation set of 41 structurally diverse proteins, Flib libraries presents both a higher precision and coverage than two of the state-of-the-art methods, NNMake and HHFrag. Flib also achieves better precision and coverage on the set of 275 protein domains used in the two previous experiments of the the Critical Assessment of Structure Prediction (CASP9 and CASP10). We compared Flib libraries against NNMake libraries in a structure prediction context. Of the 13 cases in which a correct answer was generated, Flib models were more accurate than NNMake models for 10. “Flib is available for download at: http://www.stats.ox.ac.uk/research/proteins/resources”. PMID:25901595

  4. De novo assembly of plant body plan: a step ahead of Deadpool.

    Science.gov (United States)

    Kareem, Abdul; Radhakrishnan, Dhanya; Sondhi, Yash; Aiyaz, Mohammed; Roy, Merin V; Sugimoto, Kaoru; Prasad, Kalika

    2016-08-01

    While in the movie Deadpool it is possible for a human to recreate an arm from scratch, in reality plants can even surpass that. Not only can they regenerate lost parts, but also the whole plant body can be reborn from a few existing cells. Despite the decades old realization that plant cells possess the ability to regenerate a complete shoot and root system, it is only now that the underlying mechanisms are being unraveled. De novo plant regeneration involves the initiation of regenerative mass, acquisition of the pluripotent state, reconstitution of stem cells and assembly of regulatory interactions. Recent studies have furthered our understanding on the making of a complete plant system in the absence of embryonic positional cues. We review the recent studies probing the molecular mechanisms of de novo plant regeneration in response to external inductive cues and our current knowledge of direct reprogramming of root to shoot and vice versa. We further discuss how de novo regeneration can be exploited to meet the demands of green culture industries and to serve as a general model to address the fundamental questions of regeneration across the plant kingdom.

  5. A rice gene of de novo origin negatively regulates pathogen-induced defense response.

    Directory of Open Access Journals (Sweden)

    Wenfei Xiao

    Full Text Available How defense genes originated with the evolution of their specific pathogen-responsive traits remains an important problem. It is generally known that a form of duplication can generate new genes, suggesting that a new gene usually evolves from an ancestral gene. However, we show that a new defense gene in plants may evolve by de novo origination, resulting in sophisticated disease-resistant functions in rice. Analyses of gene evolution showed that this new gene, OsDR10, had homologs only in the closest relative, Leersia genus, but not other subfamilies of the grass family; therefore, it is a rice tribe-specific gene that may have originated de novo in the tribe. We further show that this gene may evolve a highly conservative rice-specific function that contributes to the regulation difference between rice and other plant species in response to pathogen infections. Biologic analyses including gene silencing, pathologic analysis, and mutant characterization by transformation showed that the OsDR10-suppressed plants enhanced resistance to a broad spectrum of Xanthomonas oryzae pv. oryzae strains, which cause bacterial blight disease. This enhanced disease resistance was accompanied by increased accumulation of endogenous salicylic acid (SA and suppressed accumulation of endogenous jasmonic acid (JA as well as modified expression of a subset of defense-responsive genes functioning both upstream and downstream of SA and JA. These data and analyses provide fresh insights into the new biologic and evolutionary processes of a de novo gene recruited rapidly.

  6. De novo point mutations in patients diagnosed with ataxic cerebral palsy.

    Science.gov (United States)

    Parolin Schnekenberg, Ricardo; Perkins, Emma M; Miller, Jack W; Davies, Wayne I L; D'Adamo, Maria Cristina; Pessia, Mauro; Fawcett, Katherine A; Sims, David; Gillard, Elodie; Hudspith, Karl; Skehel, Paul; Williams, Jonathan; O'Regan, Mary; Jayawant, Sandeep; Jefferson, Rosalind; Hughes, Sarah; Lustenberger, Andrea; Ragoussis, Jiannis; Jackson, Mandy; Tucker, Stephen J; Németh, Andrea H

    2015-07-01

    Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

  7. Norgal: extraction and de novo assembly of mitochondrial DNA from whole-genome sequencing data.

    Science.gov (United States)

    Al-Nakeeb, Kosai; Petersen, Thomas Nordahl; Sicheritz-Pontén, Thomas

    2017-11-21

    Whole-genome sequencing (WGS) projects provide short read nucleotide sequences from nuclear and possibly organelle DNA depending on the source of origin. Mitochondrial DNA is present in animals and fungi, while plants contain DNA from both mitochondria and chloroplasts. Current techniques for separating organelle reads from nuclear reads in WGS data require full reference or partial seed sequences for assembling. Norgal (de Novo ORGAneLle extractor) avoids this requirement by identifying a high frequency subset of k-mers that are predominantly of mitochondrial origin and performing a de novo assembly on a subset of reads that contains these k-mers. The method was applied to WGS data from a panda, brown algae seaweed, butterfly and filamentous fungus. We were able to extract full circular mitochondrial genomes and obtained sequence identities to the reference sequences in the range from 98.5 to 99.5%. We also assembled the chloroplasts of grape vines and cucumbers using Norgal together with seed-based de novo assemblers. Norgal is a pipeline that can extract and assemble full or partial mitochondrial and chloroplast genomes from WGS short reads without prior knowledge. The program is available at: https://bitbucket.org/kosaidtu/norgal .

  8. Autism Spectrum Disorder in a Girl with a De Novo X;19 Balanced Translocation

    Science.gov (United States)

    Baruffi, Marcelo Razera; de Souza, Deise Helena; Bicudo da Silva, Rosana Aparecida; Ramos, Ester Silveira; Moretti-Ferreira, Danilo

    2012-01-01

    Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process. PMID:23074688

  9. Autism Spectrum Disorder in a Girl with a De Novo X;19 Balanced Translocation

    Directory of Open Access Journals (Sweden)

    Marcelo Razera Baruffi

    2012-01-01

    Full Text Available Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19(p21.2;q13.4. Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY. Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

  10. Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling.

    Science.gov (United States)

    Scarlatti, Francesca; Sala, Giusy; Somenzi, Giulia; Signorelli, Paola; Sacchi, Nicoletta; Ghidoni, Riccardo

    2003-12-01

    Resveratrol (3,4',5-trans-trihydroxystilbene), a phytoalexin present in grapes and red wine, is emerging as a natural compound with potential anticancer properties. Here we show that resveratrol can induce growth inhibition and apoptosis in MDA-MB-231, a highly invasive and metastatic breast cancer cell line, in concomitance with a dramatic endogenous increase of growth inhibitory/proapoptotic ceramide. We found that accumulation of ceramide derives from both de novo ceramide synthesis and sphingomyelin hydrolysis. More specifically we demonstrated that ceramide accumulation induced by resveratrol can be traced to the activation of serine palmitoyltransferase (SPT), the key enzyme of de novo ceramide biosynthetic pathway, and neutral sphingomyelinase (nSMase), a main enzyme involved in the sphingomyelin/ceramide pathway. However, by using specific inhibitors of SPT, myriocin and L-cycloserine, and nSMase, gluthatione and manumycin, we found that only the SPT inhibitors could counteract the biological effects induced by resveratrol. Thus, resveratrol seems to exert its growth inhibitory/apoptotic effect on the metastatic breast cancer cell line MDA-MB-231 by activating the de novo ceramide synthesis pathway.

  11. Building a better fragment library for de novo protein structure prediction.

    Directory of Open Access Journals (Sweden)

    Saulo H P de Oliveira

    Full Text Available Fragment-based approaches are the current standard for de novo protein structure prediction. These approaches rely on accurate and reliable fragment libraries to generate good structural models. In this work, we describe a novel method for structure fragment library generation and its application in fragment-based de novo protein structure prediction. The importance of correct testing procedures in assessing the quality of fragment libraries is demonstrated. In particular, the exclusion of homologs to the target from the libraries to correctly simulate a de novo protein structure prediction scenario, something which surprisingly is not always done. We demonstrate that fragments presenting different predominant predicted secondary structures should be treated differently during the fragment library generation step and that exhaustive and random search strategies should both be used. This information was used to develop a novel method, Flib. On a validation set of 41 structurally diverse proteins, Flib libraries presents both a higher precision and coverage than two of the state-of-the-art methods, NNMake and HHFrag. Flib also achieves better precision and coverage on the set of 275 protein domains used in the two previous experiments of the the Critical Assessment of Structure Prediction (CASP9 and CASP10. We compared Flib libraries against NNMake libraries in a structure prediction context. Of the 13 cases in which a correct answer was generated, Flib models were more accurate than NNMake models for 10. "Flib is available for download at: http://www.stats.ox.ac.uk/research/proteins/resources".

  12. De novo and inherited private variants in MAP1B in periventricular nodular heterotopia.

    Science.gov (United States)

    Heinzen, Erin L; O'Neill, Adam C; Zhu, Xiaolin; Allen, Andrew S; Bahlo, Melanie; Chelly, Jamel; Dobyns, William B; Freytag, Saskia; Guerrini, Renzo; Leventer, Richard J; Poduri, Annapurna; Robertson, Stephen P; Walsh, Christopher A; Zhang, Mengqi

    2018-05-08

    Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.

  13. De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy

    Science.gov (United States)

    Guella, Ilaria; Huh, Linda; McKenzie, Marna B.; Toyota, Eric B.; Bebin, E. Martina; Thompson, Michelle L.; Cooper, Gregory M.; Evans, Daniel M.; Buerki, Sarah E.; Adam, Shelin; Van Allen, Margot I.; Nelson, Tanya N.; Connolly, Mary B.; Farrer, Matthew J.

    2016-01-01

    Objective: We describe 2 additional patients with early-onset epilepsy with a de novo FGF12 mutation. Methods: Whole-exome sequencing was performed in 2 unrelated patients with early-onset epilepsy and their unaffected parents. Genetic variants were assessed by comparative trio analysis. Clinical evolution, EEG, and neuroimaging are described. The phenotype and response to treatment was reviewed and compared to affected siblings in the original report. Results: We identified the same FGF12 de novo mutation reported previously (c.G155A, p.R52H) in 2 additional patients with early-onset epilepsy. Similar to the original brothers described, both presented with tonic seizures in the first month of life. In the first patient, seizures responded to sodium channel blockers and her development was normal at 11 months. Patient 2 is a 15-year-old girl with treatment-resistant focal epilepsy, moderate intellectual disability, and autism. Carbamazepine (sodium channel blocker) was tried later in her course but not continued due to an allergic reaction. Conclusions: The identification of a recurrent de novo mutation in 2 additional unrelated probands with early-onset epilepsy supports the role of FGF12 p.R52H in disease pathogenesis. Affected carriers presented with similar early clinical phenotypes; however, this report expands the phenotype associated with this mutation which contrasts with the progressive course and early mortality of the siblings in the original report. PMID:27872899

  14. Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification

    Directory of Open Access Journals (Sweden)

    Richard J Allen

    2017-03-01

    Full Text Available Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes. To accomplish this we developed a novel simplification technique which uses the available information about the properties of the individual enzymes to bound the parameters of a single governing ‘transfer function’. This method should be applicable to any model with linear chains of enzymes that are well stimulated. We validated this approach with computational simulations and analytical justification in a limiting case. Using this technique we generated a simple model of hepatic de-novo lipogenesis in these experimental conditions that matched prior data. This model can be used to assess pharmacological intervention at specific points on this pathway. We have demonstrated this with prospective simulation of acetyl-CoA carboxylase inhibition. This simplification technique suggests how the constituent properties of an enzymatic chain of reactions gives rise to the sensitivity (to substrate of the pathway as a whole.

  15. Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification.

    Science.gov (United States)

    Allen, Richard J; Musante, Cynthia J

    2017-01-01

    Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes. To accomplish this we developed a novel simplification technique which uses the available information about the properties of the individual enzymes to bound the parameters of a single governing 'transfer function'. This method should be applicable to any model with linear chains of enzymes that are well stimulated. We validated this approach with computational simulations and analytical justification in a limiting case. Using this technique we generated a simple model of hepatic de-novo lipogenesis in these experimental conditions that matched prior data. This model can be used to assess pharmacological intervention at specific points on this pathway. We have demonstrated this with prospective simulation of acetyl-CoA carboxylase inhibition. This simplification technique suggests how the constituent properties of an enzymatic chain of reactions gives rise to the sensitivity (to substrate) of the pathway as a whole.

  16. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.

    Science.gov (United States)

    Hamilton, P J; Campbell, N G; Sharma, S; Erreger, K; Herborg Hansen, F; Saunders, C; Belovich, A N; Sahai, M A; Cook, E H; Gether, U; McHaourab, H S; Matthies, H J G; Sutcliffe, J S; Galli, A

    2013-12-01

    De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions.

  17. De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy.

    Science.gov (United States)

    Zarrei, Mehdi; Fehlings, Darcy L; Mawjee, Karizma; Switzer, Lauren; Thiruvahindrapuram, Bhooma; Walker, Susan; Merico, Daniele; Casallo, Guillermo; Uddin, Mohammed; MacDonald, Jeffrey R; Gazzellone, Matthew J; Higginbotham, Edward J; Campbell, Craig; deVeber, Gabrielle; Frid, Pam; Gorter, Jan Willem; Hunt, Carolyn; Kawamura, Anne; Kim, Marie; McCormick, Anna; Mesterman, Ronit; Samdup, Dawa; Marshall, Christian R; Stavropoulos, Dimitri J; Wintle, Richard F; Scherer, Stephen W

    2018-02-01

    PurposeHemiplegia is a subtype of cerebral palsy (CP) in which one side of the body is affected. Our earlier study of unselected children with CP demonstrated de novo and clinically relevant rare inherited genomic copy-number variations (CNVs) in 9.6% of participants. Here, we examined the prevalence and types of CNVs specifically in hemiplegic CP.MethodsWe genotyped 97 unrelated probands with hemiplegic CP and their parents. We compared their CNVs to those of 10,851 population controls, in order to identify rare CNVs (<0.1% frequency) that might be relevant to CP. We also sequenced exomes of "CNV-positive" trios.ResultsWe detected de novo CNVs and/or sex chromosome abnormalities in 7/97 (7.2%) of probands, impacting important developmental genes such as GRIK2, LAMA1, DMD, PTPRM, and DIP2C. In 18/97 individuals (18.6%), rare inherited CNVs were found, affecting loci associated with known genomic disorders (17p12, 22q11.21) or involving genes linked to neurodevelopmental disorders.ConclusionWe found an increased rate of de novo CNVs in the hemiplegic CP subtype (7.2%) compared to controls (1%). This result is similar to that for an unselected CP group. Combined with rare inherited CNVs, the genomic data impacts the understanding of the potential etiology of hemiplegic CP in 23/97 (23.7%) of participants.

  18. Use of transient elastography to predict de novo recurrence after radiofrequency ablation for hepatocellular carcinoma.

    Science.gov (United States)

    Lee, Sang Hoon; Kim, Seung Up; Jang, Jeong Won; Bae, Si Hyun; Lee, Sanghun; Kim, Beom Kyung; Park, Jun Yong; Kim, Do Young; Ahn, Sang Hoon; Han, Kwang-Hyub

    2015-01-01

    Liver stiffness (LS) measurement using transient elastography can accurately assess the degree of liver fibrosis, which is associated with the risk of the development of hepatocellular carcinoma (HCC). We investigated whether LS values could predict HCC de novo recurrence after radiofrequency ablation (RFA). This retrospective, multicenter study analyzed 111 patients with HCC who underwent RFA and LS measurement using transient elastography between May 2005 and April 2011. All patients were followed until March 2013 to monitor for HCC recurrence. This study included 76 men and 35 women with a mean age of 62.4 years, and the mean LS value was 21.2 kPa. During the follow-up period (median 22.4 months), 47 (42.3%) patients experienced HCC de novo recurrence, and 18 (16.2%) died. Patients with recurrence had significantly more frequent liver cirrhosis, more frequent history of previous treatment for HCC, higher total bilirubin, larger spleen size, larger total tumor size, higher tumor number, higher LS values, and lower platelet counts than those without recurrence (all P13.0 kPa were at significantly greater risk for recurrence after RFA, with a hazard ratio (HR) of 3.115 (95% confidence interval [CI], 1.238-7.842, Pmeasurement is a useful predictor of HCC de novo recurrence and overall survival after RFA.

  19. Cognitive impairment is associated with Hoehn and Yahr stages in early, de novo Parkinson disease patients.

    Science.gov (United States)

    Siciliano, Mattia; De Micco, Rosa; Trojano, Luigi; De Stefano, Manuela; Baiano, Chiara; Passaniti, Carla; De Mase, Antonio; Russo, Antonio; Tedeschi, Gioacchino; Tessitore, Alessandro

    2017-08-01

    The relationship between motor impairment and cognitive deterioration has long been described in Parkinson's disease (PD). The aim of the study was to compare cognitive performance of de novo PD patients in relation to the motor impairment severity according to Hoehn and Yahr (HY) stages. Forty de novo PD patients at HY stage I and 40 patients at HY stage II completed a standardized neuropsychological battery. A multivariate analysis of covariance was used to compare cognitive performance between HY groups. Odds ratios (ORs) were employed to explore the risk of cognitive impairment between HY stages. Finally, the prevalence of mild cognitive impairment (MCI) was estimated for patients in HY stage I and II. Patients at HY stage I obtained better scores on neuropsychological tests than patients at HY stage II (p = 0.001). Univariate analysis of covariance revealed significant differences between HY stages on Rey's auditory verbal learning test -immediate recall (p cognitive impairment were greater for HY stage II than stage I group. MCI occurred in 7.5% of patients in HY stage I, and in 42.5% of patients in HY stage II. In de novo PD patients, the severity of motor impairment at the diagnosis is associated to cognitive deficits and higher risk of MCI. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. De novo-based transcriptome profiling of male-sterile and fertile watermelon lines.

    Science.gov (United States)

    Rhee, Sun-Ju; Kwon, Taehyung; Seo, Minseok; Jang, Yoon Jeong; Sim, Tae Yong; Cho, Seoae; Han, Sang-Wook; Lee, Gung Pyo

    2017-01-01

    The whole-genome sequence of watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai), a valuable horticultural crop worldwide, was released in 2013. Here, we compared a de novo-based approach (DBA) to a reference-based approach (RBA) using RNA-seq data, to aid in efforts to improve the annotation of the watermelon reference genome and to obtain biological insight into male-sterility in watermelon. We applied these techniques to available data from two watermelon lines: the male-sterile line DAH3615-MS and the male-fertile line DAH3615. Using DBA, we newly annotated 855 watermelon transcripts, and found gene functional clusters predicted to be related to stimulus responses, nucleic acid binding, transmembrane transport, homeostasis, and Golgi/vesicles. Among the DBA-annotated transcripts, 138 de novo-exclusive differentially-expressed genes (DEDEGs) related to male sterility were detected. Out of 33 randomly selected newly annotated transcripts and DEDEGs, 32 were validated by RT-qPCR. This study demonstrates the usefulness and reliability of the de novo transcriptome assembly in watermelon, and provides new insights for researchers exploring transcriptional blueprints with regard to the male sterility.

  1. Photoreactivation of conversion and de novo suppressor mutation in Escherichia coli

    Energy Technology Data Exchange (ETDEWEB)

    Bockrath, R C; Plamer, J E [Indiana Univ., Indianapolis (USA). Dept. of Microbiology

    1977-04-01

    Studies of mutagenesis and photoreactivation in various E.coli strains have shown that conversion mutation of a mutant containing an amber suppressor to one containing an ochre suppressor is sensitive to photoreactivation. Direct photoreactivation by photoreactivating light (PRL) after uv mutagenesis reduced mutation frequencies by a factor of about 2 for each minute of exposure during the first 5 to 8 min of exposure for cells with normal repair capacity. Conversion and potential de novo suppressor mutations were about equally sensitive. For conversion, the sensitivities to PRL were identical in the repair-normal and excisions-repair-deficient strains. For de novo suppressor mutation, the rate of mutation frequency reduction by PRL in the repair-deficient strain was about one-half that in the other strains. The results suggest that ultraviolet radiation produces both de novo suppressor mutation and conversion at the sup(E,B) locus by photoreversible pyrimidine dimers in the DNA. The causative dimers could be Thy()Cyt dimers in the transcribed strand or the non-transcribed strand, respectively.

  2. Predicting biological system objectives de novo from internal state measurements

    Directory of Open Access Journals (Sweden)

    Maranas Costas D

    2008-01-01

    , facilitating the interrogation of cellular design principles and development of cellular engineering applications. Furthermore, we describe how growth is the best-fit objective function for the yeast metabolic network given experimentally-measured fluxes.

  3. Similar prognosis of transformed and de novo diffuse large B-cell lymphomas in patients treated with immunochemotherapy.

    Science.gov (United States)

    Sorigue, Marc; Garcia, Olga; Baptista, Maria Joao; Sancho, Juan-Manuel; Tapia, Gustavo; Mate, José Luis; Feliu, Evarist; Navarro, José-Tomás; Ribera, Josep-Maria

    2017-03-22

    The prognosis of diffuse large B-cell lymphomas (DLBCL) transformed from indolent lymphoma (TL) has been considered poorer than that of de novo DLBCL. However, it seems to have improved since the introduction of rituximab. We compared the characteristics (including the cell-of-origin), and the prognosis of 29 patients with TL and 101 with de novo DLBCL treated with immunochemotherapy. Patients with TL and de novo DLBCL had similar characteristics. All TL cases evolving from follicular lymphoma were germinal-center B-cell-like, while those TL from marginal zone lymphoma or chronic lymphocytic leukemia were non-germinal-center B-cell-like. The complete response rate was similar in TL and de novo DLBCL (62 vs. 66%, P=.825). The 5-year overall and progression-free survival probabilities (95% CI) were 59% (40-78) and 41% (22-60) for TL and 63% (53-73) and 60% (50-70) for de novo DLBCL, respectively (P=.732 for overall survival and P=.169 for progression-free survival). In this study, the prognosis of TL and de novo DLBCL treated with immunochemotherapy was similar. The role of intensification with stem cell transplantation in the management of TL may be questionable in the rituximab era. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  4. An 11bp region with stem formation potential is essential for de novo DNA methylation of the RPS element.

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    Matthew Gentry

    Full Text Available The initiation of DNA methylation in Arabidopsis is controlled by the RNA-directed DNA methylation (RdDM pathway that uses 24nt siRNAs to recruit de novo methyltransferase DRM2 to the target site. We previously described the REPETITIVE PETUNIA SEQUENCE (RPS fragment that acts as a hot spot for de novo methylation, for which it requires the cooperative activity of all three methyltransferases MET1, CMT3 and DRM2, but not the RdDM pathway. RPS contains two identical 11nt elements in inverted orientation, interrupted by a 18nt spacer, which resembles the features of a stemloop structure. The analysis of deletion/substitution derivatives of this region showed that deletion of one 11nt element RPS is sufficient to eliminate de novo methylation of RPS. In addition, deletion of a 10nt region directly adjacent to one of the 11nt elements, significantly reduced de novo methylation. When both 11nt regions were replaced by two 11nt elements with altered DNA sequence but unchanged inverted repeat homology, DNA methylation was not affected, indicating that de novo methylation was not targeted to a specific DNA sequence element. These data suggest that de novo DNA methylation is attracted by a secondary structure to which the two 11nt elements contribute, and that the adjacent 10nt region influences the stability of this structure. This resembles the recognition of structural features by DNA methyltransferases in animals and suggests that similar mechanisms exist in plants.

  5. Assessing the Impact of De Novo Social Ties within Health Intervention Settings: New Questions for Health Behavior Intervention Research.

    Science.gov (United States)

    Tesdahl, Eric; Gesell, Sabina B

    2015-12-01

    Recent developments in the study of health and social networks have focused on linkages between health outcomes and naturally occurring social relations, such as friendship or kinship. Based on findings in this area, a new generation of health behavior intervention programs have been implemented that rely on the formation of new social relations among program participants. However, little is known about the qualities of these de novo social relations. We examined the social networks of 59 participants within a randomized controlled trial of an intervention designed to prevent excessive gestational weight gain. We employed exponential random graph modeling techniques to analyze supportive relationships formed between participants in the intervention arm, to detect unique effects of program participation on the likelihood of forming ties. Program participation had a positive effect on the likelihood of forming supportive social relations, however, in this particular timeframe we did not detect any additional effect of such relations on the health behaviors or outcomes of interest. Our findings raise two critical questions: do short-term group-level programs reliably lead to the formation of new social relations among participants; and do these relations have a unique effect on health outcomes relative to standard methods of health behavior intervention? © 2015 Wiley Periodicals, Inc.

  6. Heterologous aggregates promote de novo prion appearance via more than one mechanism.

    Directory of Open Access Journals (Sweden)

    Fatih Arslan

    2015-01-01

    Full Text Available Prions are self-perpetuating conformational variants of particular proteins. In yeast, prions cause heritable phenotypic traits. Most known yeast prions contain a glutamine (Q/asparagine (N-rich region in their prion domains. [PSI+], the prion form of Sup35, appears de novo at dramatically enhanced rates following transient overproduction of Sup35 in the presence of [PIN+], the prion form of Rnq1. Here, we establish the temporal de novo appearance of Sup35 aggregates during such overexpression in relation to other cellular proteins. Fluorescently-labeled Sup35 initially forms one or a few dots when overexpressed in [PIN+] cells. One of the dots is perivacuolar, colocalizes with the aggregated Rnq1 dot and grows into peripheral rings/lines, some of which also colocalize with Rnq1. Sup35 dots that are not near the vacuole do not always colocalize with Rnq1 and disappear by the time rings start to grow. Bimolecular fluorescence complementation failed to detect any interaction between Sup35-VN and Rnq1-VC in [PSI+][PIN+] cells. In contrast, all Sup35 aggregates, whether newly induced or in established [PSI+], completely colocalize with the molecular chaperones Hsp104, Sis1, Ssa1 and eukaryotic release factor Sup45. In the absence of [PIN+], overexpressed aggregating proteins such as the Q/N-rich Pin4C or the non-Q/N-rich Mod5 can also promote the de novo appearance of [PSI+]. Similar to Rnq1, overexpressed Pin4C transiently colocalizes with newly appearing Sup35 aggregates. However, no interaction was detected between Mod5 and Sup35 during [PSI+] induction in the absence of [PIN+]. While the colocalization of Sup35 and aggregates of Rnq1 or Pin4C are consistent with the model that the heterologous aggregates cross-seed the de novo appearance of [PSI+], the lack of interaction between Mod5 and Sup35 leaves open the possibility of other mechanisms. We also show that Hsp104 is required in the de novo appearance of [PSI+] aggregates in a [PIN

  7. NOVO SISTEMA DE SEMEADURA CONSERVACIONISTA MULTIFUNCIONAL PARA A AGRICULTURA FAMILIAR: NOVO DRAGÃO/ NEW CONSERVATIONIST SYSTEM SEEDING FOR SMALL FARMS WITH MULTIFUNCTIONAL NEW DRAGON

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    Daniel ALBIERO

    2010-11-01

    Full Text Available A agricultura familiar exerce papel importante na agricultura brasileira, sendo responsável por grande parcela da produção nacional de alimentos. No entanto não possui muitos equipamentos específicos para a semeadura. O objetivo principal deste trabalho foi o desenvolvimento e testes de um novo sistema de semeadura conservacionista para a agricultura familiar através de uma máquina multifuncional. Uma nova semeadora construída na filosofia de plantio em faixas com “Paraplow” Rotativo foi testada em campo em experimentos sob condições reais. Como resultado obteve-se um protótipo com bom desempenho na semeadura de soja, de fácil operação e manutenção, e principalmente adaptado às necessidades operacionais da agricultura familiar.Palavras-chaves: Sistema de semeadura, agricultura familiar, semedora multifuncional.

  8. Da família patriarcal à contemporânea. Entre o vellho e o novo: o surgimento dos novos arranjos familiares

    OpenAIRE

    Móas, Luciane da Costa

    2012-01-01

    O presente artigo propõe uma dupla abordagem da família levando em consideração o caráter socioantropológico e também histórico-evolutivo da legislação brasileira. Tem como objetivo interrogar a ideia de crise na ou da família em razão das mudanças verificadas em sua constituição: abandonou-se o modelo patriarcal, único existente no passado, que cedeu o passo aos modelos diversos, dos quais se originaram os novos arranjos familiares. O texto cuida da família como o fenômeno social que nos é m...

  9. "A poesia dos simples": arte popular e nação no Estado Novo "The poetry of the simple": popular art and nation in the Estado Novo

    Directory of Open Access Journals (Sweden)

    Vera Marques Alves

    2007-05-01

    Full Text Available Nos anos 30 e 40 do século XX, o Secretariado da Propaganda Nacional - órgão máximo da propaganda do regime de Salazar - desenvolveu um largo conjunto de iniciativas folcloristas que marcaram a memória crítica do Estado Novo. Este artigo sonda os limites de uma interpretação que reduz tal política a um instrumento de domesticação do povo, mostrando que é nos mecanismos de afirmação da nação, dentro e fora das fronteiras portuguesas, que podemos encontrar a explicação mais pertinente para a campanha etnográfica então empreendida. E é em função de tal proposta que abordaremos ainda os processos de manipulação e selecção dos materiais da cultura popular aí implicados, mostrando como, através dos mesmos, o SPN;/;SNI veiculou um retrato do país baseado na imagem do povo português enquanto camponês-esteta.In the 1930’ and 1940’ the Secretariado da Propaganda Nacional - the propaganda head office of Salazar’s dictatorship - promoted several folkloristic events, which became a core element of the Estado Novo current memory. This paper shows how the Secretariado‘s ethnographic campaign relates mostly with the politics of national identity building developed inside the Portuguese borders and in the international arena. In this context, I examine the selective approach to the folk culture materials evolved in those pratics. I also try to illuminate the ways by witch such materials were used to create a representation of the Portuguese folk as a people of artist-peasants, and of Portugal as a pacific and lovable country.

  10. Contrôle genético dos "frutos chochos" no Café "Mundo Novo" Manofactorial inheritance of "empty-locule" in the Mundo Novo coffee

    Directory of Open Access Journals (Sweden)

    A. J. T. Mendes

    1955-01-01

    Full Text Available 1. Decorre do presente trabalho que no Café Mundo Novo há dois grupos distintos de plantas : a de baixa ocorrência de frutos chochos; b de alta ocorrência de frutos chochos. 2. Há evidências de que a existência de 2 grupos distintos de plantas é devida a um par de fatores genéticos Dd. As plantas onde é baixa a ocorrência de frutos chochos são de constituição genética DD. As demais são Dd. Não há o grupo dd, pois que a combinação endosperma ddd e embrião dd é letal. 3. Segundo a hipótese, a letalidade dos fatores dd se manifesta quando o endosperma tem 2 a 3 mm de diâmetro; nesse ponto estaciona o crescimento e êle se transforma num disco (donde o símbolo d para o gen em questão. Raras vêzes a ação letal se manifesta antes dêsse estado e então nada ou quase nada resta do endosperma. Outras vezes a ação letal é tardia: o endosperma se desenvolve em semente mas esta não germina. 4. As populações de café Mundo Novo que estão se formando no Estado de São Paulo terão diferentes proporções de plantas com e sem o defeito das lojas vazias, dependendo isso da fonte onde se procurarem as sementes. 5. Limitando-se a selecionar as plantas Mundo Novo dentro do grupo de baixa ocorrência de chochos o melhorista encontra base científica para ehminar um notório defeito da variedade.It was shown in a recent paper that the occurrence of empty locules in coffee fruits of the variety Mundo Novo (Coffea arabica L. is due to an arrest in the endosperm development that takes place at a definite stage, leading to the formation of a small disc ; this rudimentary type of endosperm has been called "discoid endosperm". A suggestion was then made that this process might be controlled by genetic factors. Under this assumption, normal plants were DD; plants in which the defect occurred, Dd, and the homozygous, recessive form was lethal. The high correlation between discoid endosperm and empty locules permitted a clear

  11. CIPESC® Curitiba: o trabalho da enfermagem no Distrito Bairro Novo CIPESC® Curitiba: el trabajo de enfermería en el Districto Bairro Novo CIPESC® Curitiba: the work of nursing at Bairro Novo District

    Directory of Open Access Journals (Sweden)

    Denise Maria Altino

    2006-08-01

    Full Text Available Curitiba implantou em rede o sistema Classificação Internacional das Práticas de Enfermagem em Saúde Coletiva - CIPESC®. O presente estudo objetivou identificar as atividades exercidas pelos profissionais de enfermagem nas unidades de saúde do distrito Bairro Novo de Curitiba. Trata-se de uma pesquisa descritiva em que foram entrevistados auxiliares e enfermeiras utilizando-se de um check-list. Os resultados mostram que: o acolhimento é realizado por todos; as auxiliares se ocupam mais das atividades assistencial-procedimentais; a totalidade das enfermeiras realiza consulta de enfermagem diariamente, recorrendo ao prontuário eletrônico de base CIPESC®. Conclui-se que, excetuando-se as atividades de pesquisa, houve intensificação e ampliação das atividades assistenciais sistematizadas e embasadas no trabalho cotidiano da enfermagem, intra e extramuros.Curitiba implantó el sistema Clasificación Internacional de las Prácticas de Enfermería en Salud Colectiva - CIPESC®. El presente estudio objetivó identificar las actividades ejercidas por personal de enfermería en la red de atención básica de la salud del distrito Bairro Novo, Curitiba. Ha hecho una investigación junto a los trabajadores de enfermería, recorriendo-se a check-list. Los resultados mostrarán: todos realizan el acogimiento; las auxiliares de enfermería se ocupan más de las actividades asistencial-procedimentales; todas las enfermeras realizan consulta de enfermería diariamente, utilizando-se del prontuario electrónico bases CIPESC®. En conclusión, excepto las actividades del investigación, hube intensificación y ampliación de las actividades asistenciales, que se ubican sistematizadas e embasadas en el trabajo cotidiano de la enfermería, así como la educación y planeamiento.Curitiba has been utilized system CIPESC® - International Nursing Practice Classification in Collective Health. This study goal identifies the activities of nursing staff in

  12. Protocell design through modular compartmentalization.

    Science.gov (United States)

    Miller, David; Booth, Paula J; Seddon, John M; Templer, Richard H; Law, Robert V; Woscholski, Rudiger; Ces, Oscar; Barter, Laura M C

    2013-10-06

    De novo synthetic biological design has the potential to significantly impact upon applications such as energy generation and nanofabrication. Current designs for constructing organisms from component parts are typically limited in scope, as they utilize a cut-and-paste ideology to create simple stepwise engineered protein-signalling pathways. We propose the addition of a new design element that segregates components into lipid-bound 'proto-organelles', which are interfaced with response elements and housed within a synthetic protocell. This design is inspired by living cells, which utilize multiple types of signalling molecules to facilitate communication between isolated compartments. This paper presents our design and validation of the components required for a simple multi-compartment protocell machine, for coupling a light transducer to a gene expression system. This represents a general design concept for the compartmentalization of different types of artificial cellular machinery and the utilization of non-protein signal molecules for signal transduction.

  13. Identification of a novel Plasmopara halstedii elicitor protein combining de novo peptide sequencing algorithms and RACE-PCR

    Directory of Open Access Journals (Sweden)

    Madlung Johannes

    2010-05-01

    Full Text Available Abstract Background Often high-quality MS/MS spectra of tryptic peptides do not match to any database entry because of only partially sequenced genomes and therefore, protein identification requires de novo peptide sequencing. To achieve protein identification of the economically important but still unsequenced plant pathogenic oomycete Plasmopara halstedii, we first evaluated the performance of three different de novo peptide sequencing algorithms applied to a protein digests of standard proteins using a quadrupole TOF (QStar Pulsar i. Results The performance order of the algorithms was PEAKS online > PepNovo > CompNovo. In summary, PEAKS online correctly predicted 45% of measured peptides for a protein test data set. All three de novo peptide sequencing algorithms were used to identify MS/MS spectra of tryptic peptides of an unknown 57 kDa protein of P. halstedii. We found ten de novo sequenced peptides that showed homology to a Phytophthora infestans protein, a closely related organism of P. halstedii. Employing a second complementary approach, verification of peptide prediction and protein identification was performed by creation of degenerate primers for RACE-PCR and led to an ORF of 1,589 bp for a hypothetical phosphoenolpyruvate carboxykinase. Conclusions Our study demonstrated that identification of proteins within minute amounts of sample material improved significantly by combining sensitive LC-MS methods with different de novo peptide sequencing algorithms. In addition, this is the first study that verified protein prediction from MS data by also employing a second complementary approach, in which RACE-PCR led to identification of a novel elicitor protein in P. halstedii.

  14. Sequence protein identification by randomized sequence database and transcriptome mass spectrometry (SPIDER-TMS): from manual to automatic application of a 'de novo sequencing' approach.

    Science.gov (United States)

    Pascale, Raffaella; Grossi, Gerarda; Cruciani, Gabriele; Mecca, Giansalvatore; Santoro, Donatello; Sarli Calace, Renzo; Falabella, Patrizia; Bianco, Giuliana

    Sequence protein identification by a randomized sequence database and transcriptome mass spectrometry software package has been developed at the University of Basilicata in Potenza (Italy) and designed to facilitate the determination of the amino acid sequence of a peptide as well as an unequivocal identification of proteins in a high-throughput manner with enormous advantages of time, economical resource and expertise. The software package is a valid tool for the automation of a de novo sequencing approach, overcoming the main limits and a versatile platform useful in the proteomic field for an unequivocal identification of proteins, starting from tandem mass spectrometry data. The strength of this software is that it is a user-friendly and non-statistical approach, so protein identification can be considered unambiguous.

  15. De Novo Assembly and Characterization of the Transcriptome of Grasshopper Shirakiacris shirakii

    Directory of Open Access Journals (Sweden)

    Zhongying Qiu

    2016-07-01

    Full Text Available Background: The grasshopper Shirakiacris shirakii is an important agricultural pest and feeds mainly on gramineous plants, thereby causing economic damage to a wide range of crops. However, genomic information on this species is extremely limited thus far, and transcriptome data relevant to insecticide resistance and pest control are also not available. Methods: The transcriptome of S. shirakii was sequenced using the Illumina HiSeq platform, and we de novo assembled the transcriptome. Results: Its sequencing produced a total of 105,408,878 clean reads, and the de novo assembly revealed 74,657 unigenes with an average length of 680 bp and N50 of 1057 bp. A total of 28,173 unigenes were annotated for the NCBI non-redundant protein sequences (Nr, NCBI non-redundant nucleotide sequences (Nt, a manually-annotated and reviewed protein sequence database (Swiss-Prot, Gene Ontology (GO and Kyoto Encyclopedia of Genes and Genomes (KEGG databases. Based on the Nr annotation results, we manually identified 79 unigenes encoding cytochrome P450 monooxygenases (P450s, 36 unigenes encoding carboxylesterases (CarEs and 36 unigenes encoding glutathione S-transferases (GSTs in S. shirakii. Core RNAi components relevant to miroRNA, siRNA and piRNA pathways, including Pasha, Loquacious, Argonaute-1, Argonaute-2, Argonaute-3, Zucchini, Aubergine, enhanced RNAi-1 and Piwi, were expressed in S. shirakii. We also identified five unigenes that were homologous to the Sid-1 gene. In addition, the analysis of differential gene expressions revealed that a total of 19,764 unigenes were up-regulated and 4185 unigenes were down-regulated in larvae. In total, we predicted 7504 simple sequence repeats (SSRs from 74,657 unigenes. Conclusions: The comprehensive de novo transcriptomic data of S. shirakii will offer a series of valuable molecular resources for better studying insecticide resistance, RNAi and molecular marker discovery in the transcriptome.

  16. BayesMotif: de novo protein sorting motif discovery from impure datasets.

    Science.gov (United States)

    Hu, Jianjun; Zhang, Fan

    2010-01-18

    Protein sorting is the process that newly synthesized proteins are transported to their target locations within or outside of the cell. This process is precisely regulated by protein sorting signals in different forms. A major category of sorting signals are amino acid sub-sequences usually located at the N-terminals or C-terminals of protein sequences. Genome-wide experimental identification of protein sorting signals is extremely time-consuming and costly. Effective computational algorithms for de novo discovery of protein sorting signals is needed to improve the understanding of protein sorting mechanisms. We formulated the protein sorting motif discovery problem as a classification problem and proposed a Bayesian classifier based algorithm (BayesMotif) for de novo identification of a common type of protein sorting motifs in which a highly conserved anchor is present along with a less conserved motif regions. A false positive removal procedure is developed to iteratively remove sequences that are unlikely to contain true motifs so that the algorithm can identify motifs from impure input sequences. Experiments on both implanted motif datasets and real-world datasets showed that the enhanced BayesMotif algorithm can identify anchored sorting motifs from pure or impure protein sequence dataset. It also shows that the false positive removal procedure can help to identify true motifs even when there is only 20% of the input sequences containing true motif instances. We proposed BayesMotif, a novel Bayesian classification based algorithm for de novo discovery of a special category of anchored protein sorting motifs from impure datasets. Compared to conventional motif discovery algorithms such as MEME, our algorithm can find less-conserved motifs with short highly conserved anchors. Our algorithm also has the advantage of easy incorporation of additional meta-sequence features such as hydrophobicity or charge of the motifs which may help to overcome the limitations of

  17. New experimental model for training in videosurgery Novo modelo experimental para treinamento em videocirurgia

    Directory of Open Access Journals (Sweden)

    Danilo Malta Batista

    2012-10-01

    Full Text Available PURPOSE: To develop a new experimental model of lower cost for training in videosurgery. METHODS: This project was performed at the Nucleus of Experimental Surgery of the Bahiana School of Medicine and Public Health, based on previous models described in the literature and under the supervision of the full professor of Operative Technique and Experimental Surgery II. It was made a model cube-shaped, made of wood, with holes distributed in various locations, rubber stoppers for the holes and lined externally with carpet, and internally with laminate. RESULTS: The new experimental model is of low cost and reproduces quite faithfully several videosurgical procedures. CONCLUSION: Medical schools interested in the subject may adopt the new model for training in videosurgery without the need of high costs for making and using these models.OBJETIVO: Desenvolver um novo modelo experimental de baixo custo para treinamento em videocirurgia MÉTODOS: Este projeto foi conduzido no Núcleo de Cirurgia Experimental da Escola Bahiana de Medicina e Saúde Pública, baseado em modelos prévios descritos na literatura e sob a supervisão do professor titular de Técnica Operatória e Cirurgia Experimental II. Foi feito um modelo em formato de cubo, de madeira, com furos distribuídos em vários locais, tampas de borracha para os orifícios e forrado externamente com carpete e internamente com laminado. RESULTADOS: O novo modelo experimental desenvolvido é de baixo custo e reproduz de forma bastante fiel diversos procedimentos videocirúrgicos. CONCLUSÃO: Faculdades médicas interessadas no tema poderão adotar o novo modelo para o treinamento em videocirurgia sem que sejam necessários gastos elevados para a confecção e o uso desses modelos.

  18. Locoregional symptoms in patients with de novo metastatic prostate cancer: Morbidity, management, and disease outcome.

    Science.gov (United States)

    Patrikidou, Anna; Brureau, Laurent; Casenave, Julien; Albiges, Laurence; Di Palma, Mario; Patard, Jean-Jacques; Baumert, Hervé; Blanchard, Pierre; Bossi, Alberto; Kitikidou, Kyriaki; Massard, Christophe; Fizazi, Karim; Blanchet, Pascal; Loriot, Yohann

    2015-05-01

    The paradigm change observed over the last few years in several solid tumors emphasizes the value of locoregional treatment in the presence of metastatic disease, currently ignored in de novo prostate cancer (CaP). We investigated the effect of the primary tumor that is left untreated on prostate cancer-specific morbidity and mortality, time to castration resistance, and overall survival (OS). We performed a bicentric cohort study. The overall population included de novo metastatic CaP managed at the Genito-Urinary Oncology Unit of the Gustave Roussy Institute and the Urology Clinic of the University Hospital of Pointe-à-Pitre, France. Descriptive statistical and outcome analyses were performed in the overall cohort and also separately in the N+M0 and M+subgroups. The overall cohort included 263 patients. Approximately two-thirds of patients (64%) presented with locoregional symptoms at diagnosis, and 78% throughout the disease. Of the symptomatic patients, 59% required a locoregional procedure. Median OS of patients with locoregional symptoms at diagnosis was shorter than in those who were asymptomatic (47 vs. 86 mo, P = 0.0007); this difference was maintained in the N+M0 and M+subgroups. Median OS and time to castration resistance showed a nonsignificant trend in favor of patients undergoing a locoregional treatment at diagnosis. The presence of symptoms due to locoregional disease in de novo metastatic CaP entails significant morbidity and even mortality and requires active management. Randomized prospective trials are needed to evaluate the role of initial definite locoregional treatment in these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Developing de novo human artificial chromosomes in embryonic stem cells using HSV-1 amplicon technology.

    Science.gov (United States)

    Moralli, Daniela; Monaco, Zoia L

    2015-02-01

    De novo artificial chromosomes expressing genes have been generated in human embryonic stem cells (hESc) and are maintained following differentiation into other cell types. Human artificial chromosomes (HAC) are small, functional, extrachromosomal elements, which behave as normal chromosomes in human cells. De novo HAC are generated following delivery of alpha satellite DNA into target cells. HAC are characterized by high levels of mitotic stability and are used as models to study centromere formation and chromosome organisation. They are successful and effective as gene expression vectors since they remain autonomous and can accommodate larger genes and regulatory regions for long-term expression studies in cells unlike other viral gene delivery vectors currently used. Transferring the essential DNA sequences for HAC formation intact across the cell membrane has been challenging for a number of years. A highly efficient delivery system based on HSV-1 amplicons has been used to target DNA directly to the ES cell nucleus and HAC stably generated in human embryonic stem cells (hESc) at high frequency. HAC were detected using an improved protocol for hESc chromosome harvesting, which consistently produced high-quality metaphase spreads that could routinely detect HAC in hESc. In tumour cells, the input DNA often integrated in the host chromosomes, but in the host ES genome, it remained intact. The hESc containing the HAC formed embryoid bodies, generated teratoma in mice, and differentiated into neuronal cells where the HAC were maintained. The HAC structure and chromatin composition was similar to the endogenous hESc chromosomes. This review will discuss the technological advances in HAC vector delivery using HSV-1 amplicons and the improvements in the identification of de novo HAC in hESc.

  20. Facebook - Um novo espaço autobiográfico?

    Directory of Open Access Journals (Sweden)

    Maria Tereza Lima

    2015-07-01

    Full Text Available O arigo "Facebook - Um novo espaço autobiográfico?" tem como objetivo central investigar como a perspectiva autobiográfica e biográfica se configura em uma rede social. Levando em consideração esse novo espaço de exteriorização da memória, analisamos as escolhas de uma pessoa ao postar os mais diversos gêneros textuais no Facebook e verificamos até que ponto tais fragmentos textuais narram a história de um indivíduo. Quais textos são postados? O que foi escolhido e o que foi excluído desse perfil? O autor trava um pacto de leitura com o leitor? Se levarmos em consideração que os textos postados nessa rede social são textos produzidos pelo próprio autor do perfil e de autores diversos, como configuraremos esses espaços virtuais? Autobiográficos e biográficos? Quem escreve a página virtual é o próprio autor do perfil ou múltiplos autores? Com as redes sociais, surge um novo modelo de autobiografia e de biógrafo? Esses e tantos outros questionamentos nortearam nossas investigações e permitiram-nos conhecer um pouco mais sobre as estratégias autobiográficas dos autores virtuais contemporâneos.

  1. ESTADO E NOVOS AGENTES SOCIAIS NA RECONSTRUÇÃO DO ESPAÇO

    Directory of Open Access Journals (Sweden)

    Cláudio Barbosa da Costa

    2006-07-01

    Full Text Available Este estudo tem como objetivo principal sistematizar novas questões referentes à complexidade das ações dos agentes sociais na construção do espaço contemporâneo, e que vem interferindo, de maneira significativa, na forma como o Estado vem realizando o processo de intervenção no território. Os eixos analíticos do estudo serão constituídos pelo novo patamar de acumulação que constitui a globalização, os grandes agentes econômicos internacionais e as novas referências da chamada lógica civilizatória, na qual emergem sujeitos sociais que ao buscarem romper com idéia dominante de desenvolvimento e de crescimento, vêm construindo novas formas de lidar com a natureza, com o território e com o trabalho, estabelecendo a alteridade, a partir da luta pela sua legitimidade. A compreensão teórica dos novos movimentos sociais possibilitou um melhor entendimento do papel histórico destes agentes na construção contemporânea do espaço e das suas relações com o vetor ecológico e o desenvolvimento sustentável. Para finalizar, realizamos uma análise histórica das intervenções do Estado brasileiro na construção do território nacional, buscando identificar a complexidade dos agentes da sociedade civil, e as possibilidades e os limites da constituição de um projeto geopolítico através de um novo pacto social, que resguardando as diferenças, consideram-se as territorialidades dos setores sociais historicamente excluídos do processo de

  2. De novo analysis of transcriptome dynamics in the migratory locust during the development of phase traits.

    Directory of Open Access Journals (Sweden)

    Shuang Chen

    Full Text Available Locusts exhibit remarkable density-dependent phenotype (phase changes from the solitary to the gregarious, making them one of the most destructive agricultural pests. This phenotype polyphenism arises from a single genome and diverse transcriptomes in different conditions. Here we report a de novo transcriptome for the migratory locust and a comprehensive, representative core gene set. We carried out assembly of 21.5 Gb Illumina reads, generated 72,977 transcripts with N50 2,275 bp and identified 11,490 locust protein-coding genes. Comparative genomics analysis with eight other sequenced insects was carried out to identify the genomic divergence between hemimetabolous and holometabolous insects for the first time and 18 genes relevant to development was found. We further utilized the quantitative feature of RNA-seq to measure and compare gene expression among libraries. We first discovered how divergence in gene expression between two phases progresses as locusts develop and identified 242 transcripts as candidates for phase marker genes. Together with the detailed analysis of deep sequencing data of the 4(th instar, we discovered a phase-dependent divergence of biological investment in the molecular level. Solitary locusts have higher activity in biosynthetic pathways while gregarious locusts show higher activity in environmental interaction, in which genes and pathways associated with regulation of neurotransmitter activities, such as neurotransmitter receptors, synthetase, transporters, and GPCR signaling pathways, are strongly involved. Our study, as the largest de novo transcriptome to date, with optimization of sequencing and assembly strategy, can further facilitate the application of de novo transcriptome. The locust transcriptome enriches genetic resources for hemimetabolous insects and our understanding of the origin of insect metamorphosis. Most importantly, we identified genes and pathways that might be involved in locust development

  3. Sequential search leads to faster, more efficient fragment-based de novo protein structure prediction.

    Science.gov (United States)

    de Oliveira, Saulo H P; Law, Eleanor C; Shi, Jiye; Deane, Charlotte M

    2018-04-01

    Most current de novo structure prediction methods randomly sample protein conformations and thus require large amounts of computational resource. Here, we consider a sequential sampling strategy, building on ideas from recent experimental work which shows that many proteins fold cotranslationally. We have investigated whether a pseudo-greedy search approach, which begins sequentially from one of the termini, can improve the performance and accuracy of de novo protein structure prediction. We observed that our sequential approach converges when fewer than 20 000 decoys have been produced, fewer than commonly expected. Using our software, SAINT2, we also compared the run time and quality of models produced in a sequential fashion against a standard, non-sequential approach. Sequential prediction produces an individual decoy 1.5-2.5 times faster than non-sequential prediction. When considering the quality of the best model, sequential prediction led to a better model being produced for 31 out of 41 soluble protein validation cases and for 18 out of 24 transmembrane protein cases. Correct models (TM-Score > 0.5) were produced for 29 of these cases by the sequential mode and for only 22 by the non-sequential mode. Our comparison reveals that a sequential search strategy can be used to drastically reduce computational time of de novo protein structure prediction and improve accuracy. Data are available for download from: http://opig.stats.ox.ac.uk/resources. SAINT2 is available for download from: https://github.com/sauloho/SAINT2. saulo.deoliveira@dtc.ox.ac.uk. Supplementary data are available at Bioinformatics online.

  4. Optimizing and benchmarking de novo transcriptome sequencing: from library preparation to assembly evaluation.

    Science.gov (United States)

    Hara, Yuichiro; Tatsumi, Kaori; Yoshida, Michio; Kajikawa, Eriko; Kiyonari, Hiroshi; Kuraku, Shigehiro

    2015-11-18

    RNA-seq enables gene expression profiling in selected spatiotemporal windows and yields massive sequence information with relatively low cost and time investment, even for non-model species. However, there remains a large room for optimizing its workflow, in order to take full advantage of continuously developing sequencing capacity. Transcriptome sequencing for three embryonic stages of Madagascar ground gecko (Paroedura picta) was performed with the Illumina platform. The output reads were assembled de novo for reconstructing transcript sequences. In order to evaluate the completeness of transcriptome assemblies, we prepared a reference gene set consisting of vertebrate one-to-one orthologs. To take advantage of increased read length of >150 nt, we demonstrated shortened RNA fragmentation time, which resulted in a dramatic shift of insert size distribution. To evaluate products of multiple de novo assembly runs incorporating reads with different RNA sources, read lengths, and insert sizes, we introduce a new reference gene set, core vertebrate genes (CVG), consisting of 233 genes that are shared as one-to-one orthologs by all vertebrate genomes examined (29 species)., The completeness assessment performed by the computational pipelines CEGMA and BUSCO referring to CVG, demonstrated higher accuracy and resolution than with the gene set previously established for this purpose. As a result of the assessment with CVG, we have derived the most comprehensive transcript sequence set of the Madagascar ground gecko by means of assembling individual libraries followed by clustering the assembled sequences based on their overall similarities. Our results provide several insights into optimizing de novo RNA-seq workflow, including the coordination between library insert size and read length, which manifested in improved connectivity of assemblies. The approach and assembly assessment with CVG demonstrated here would be applicable to transcriptome analysis of other species as

  5. A «educação nova» e o estado novo

    OpenAIRE

    Alho, Albérico Afonso Costa

    2008-01-01

    A reforma do ensino técnico foi filha das mudanças que espreitavam no Portugal do pós-guerra. Apesar do espartilho imposto à liberdade de expressão, quase todos os sectores sociais vão tomar posição sobre os novos caminhos enunciados para o ensino profissional. Das associações patronais aos sectores oposicionistas, ninguém ficou indiferente às novas propostas que emergiam da reforma.

  6. Anterior abdominal wall leiomyoma arising de novo in a fertile women: A case report

    International Nuclear Information System (INIS)

    Cho, Je Young; Woo, Ji Young; Hong, Hye Suk; Yang, Ik; Lee, Yul; Hwang, Ji Young; Kim, Han Myun; Shin, Mi Kyung

    2016-01-01

    Abdominal wall leiomyoma arising de novo is very rare, hence the reported imaging findings of this disease are also rare. We reported the case of a 33-year-old woman who presented with an abdominal wall mass without antecedent gynecological surgeries. The initial abdominal computed tomography (CT) showed thickening of the left rectus abdominis and the loss of intervening fat between the rectus abdominis and the lateral abdominal muscles. After 8 months, the follow-up contrast-enhanced CT and ultrasonography (US) showed a lentiform-shaped mass with isodensity to the adjacent muscles. The US-guided biopsy was consistent with leiomyoma

  7. Anterior abdominal wall leiomyoma arising de novo in a fertile women: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Je Young; Woo, Ji Young; Hong, Hye Suk; Yang, Ik; Lee, Yul; Hwang, Ji Young; Kim, Han Myun; Shin, Mi Kyung [Hallym University College of Medicine, Kangnam Sacred Heart Hospital, Seoul (Korea, Republic of)

    2016-01-15

    Abdominal wall leiomyoma arising de novo is very rare, hence the reported imaging findings of this disease are also rare. We reported the case of a 33-year-old woman who presented with an abdominal wall mass without antecedent gynecological surgeries. The initial abdominal computed tomography (CT) showed thickening of the left rectus abdominis and the loss of intervening fat between the rectus abdominis and the lateral abdominal muscles. After 8 months, the follow-up contrast-enhanced CT and ultrasonography (US) showed a lentiform-shaped mass with isodensity to the adjacent muscles. The US-guided biopsy was consistent with leiomyoma.

  8. Chromosome aberrations and oncogene alterations in atomic bomb related leukemias - different mechanisms from de novo leukemias

    International Nuclear Information System (INIS)

    Tanaka, K.; Tanaka, H.; Kamada, N.

    2003-01-01

    It is well known that leukemia occurred more frequently among atomic bomb survivors. In 132 atomic bomb related ( AB- related) leukemia patients during 1978-1999, 33 acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients had their exposure doses of more than 1Gy (DS86). Chromosome aberrations of the 33 patients were compared with those from 588 de novo AML/MDS patients who had been bone before August 1945 as control. No FAB M3 patient was observed in the exposed group. Most AB-related AML preceded a long term of MDS stage. Twenty seven of the 33 patients showed complex types of chromosome aberrations with more than three chromosomes involving chromosomes 5,7 and 11. The number of chromosomes abnormality per cell in the AB-related leukemia was 3.78 while 0.92 in de novo leukemia. Only one of the 33 patients had normal karyotype, while 44.1% in de novo leukemia patients. Translocations of chromosome 11 at 11q13 to 11q23 and deletion/ loss of chromosome 20 were frequently observed in AB-related leukemia. No leukemia-type specific translocations such as t(8;21),t(15;17) and 11q23 were found in the 33 AB-related leukemia patients. Furthermore, molecular analyses using FISH and PCR-SSCP revealed the presence of breakpoint located outside of MLL gene in the patients with translocations at 11q22-23 and DNA base derangements of RUNT domain of AML1(CBF β 2)gene with AML/MDS patients without t(8;21) and with a high dose of exposure. These results suggest that AB-related leukemia derives from an exposed pluripotent hematopoietic stem cell which has been preserved for a long time in the bone marrow, expressing high genetic instability such as microsatellite instability. On the other hand, de novo leukemia develops from a committed hematopoietic stem cell and shows simple and leukemia-type specific chromosome aberrations. These findings are important for understanding mechanisms for radiation-induced leukemia

  9. Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients

    DEFF Research Database (Denmark)

    Andreassen, A K; Andersson, B; Gustafsson, F

    2016-01-01

    In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal...... events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow...

  10. A Psicologia no novo contexto mundial Psychology in the new world context

    Directory of Open Access Journals (Sweden)

    Carla Faria Leitão

    2003-12-01

    Full Text Available Profundas alterações no mundo contemporâneo criaram um novo contexto de produção científica, caracterizado pela desconstrução de antigas teorias e pela construção de uma nova rede de conhecimentos. Neste artigo, analisamos algumas teorias recentemente desenvolvidas nas ciências sociais e na filosofia que compõem esta rede: as teorias pós-modernas, as teorias da modernização reflexiva e a teoria da Revolução da Tecnologia da Informação. Visamos com isto munir os psicólogos de conhecimentos advindos de outros campos disciplinares que sirvam como ponto de partida para a análise das mudanças subjetivas introduzidas pelo novo cenário mundial. Argumentamos que a psicologia ainda observa o homem contemporâneo a partir de categorias tradicionais, desconsiderando que transformações sociais profundas geram impactos psicológicos não menos profundos e dificilmente captáveis a partir de antigos referenciais. Concluímos que um conhecimento mais aprofundado das transformações radicais em curso no mundo atual pode ajudar os psicólogos a rever suas antigas certezas a respeito do homem e a aventurar novos olhares sobre os também novos fenômenos humanos.Profound changes in the contemporary world have created a new context for scientific work, characterised by the deconstruction of old theories and the construction of a new network of knowledge. In this article, we analyse a few theories recently developed in the social sciences and in philosophy that make up this network: post-modernist theories, reflexive modernisation theories and Information Technology Revolution theory. In this way, we aim to provide psychologists with insights produced in other fields of knowledge that can serve as a starting point for the analysis of the subjective changes introduced by the new global scenario. We argue that psychology still observes contemporary man on the basis of traditional categories, ignoring the fact that profound social changes

  11. Novos táxons de Lamiinae (Coleoptera, Cerambycidae da América do Sul

    Directory of Open Access Journals (Sweden)

    Maria Helena M. Galileo

    2012-06-01

    Full Text Available Novos táxons descritos: Acanthoderini, Nesozineus osorioensis sp. nov., do Brasil (Rio Grande do Sul; Calliini, Drycothaea clara sp. nov., do Brasil (Rondônia e Drycothaea hovorei sp. nov., do Equador (Napo; Forsteriini, Itacolomi gen. nov., espécie-tipo I. letiziae sp. nov., do Brasil (Minas Gerais; Yapyguara gen. nov., espécie-tipo Y. fusca sp. nov., da Bolívia (Santa Cruz; Xenofreini, Xenofrea zischkai sp. nov., do Equador (Napo e da Bolívia (Santa Cruz.

  12. Identification of de Novo Fanconi Anemia in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

    Science.gov (United States)

    2016-05-13

    Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Fanconi Anemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  13. De novo assembly of plant body plan: a step ahead of Deadpool

    OpenAIRE

    Kareem, Abdul; Radhakrishnan, Dhanya; Sondhi, Yash; Aiyaz, Mohammed; Roy, Merin V.; Sugimoto, Kaoru; Prasad, Kalika

    2016-01-01

    Abstract While in the movie Deadpool it is possible for a human to recreate an arm from scratch, in reality plants can even surpass that. Not only can they regenerate lost parts, but also the whole plant body can be reborn from a few existing cells. Despite the decades old realization that plant cells possess the ability to regenerate a complete?shoot and root system, it is only now that the underlying mechanisms are being unraveled. De novo plant regeneration involves the initiation of regen...

  14. O Estado Novo, o rádio e seus órgãos reguladores

    Directory of Open Access Journals (Sweden)

    Othon Jambeiro

    2003-01-01

    Full Text Available This paper analyses the Brazilian broadcasting regulation in the 1935-1945 period, including the Estado Novo coup d'etat preparation, its implementation, consolidation and fall. It is taken into account the historical context and the national and international changes which occured in that period. It also analyses the rules for broadcasting and mass communication media, particularly on control issues. Functions, structure and acting of the Departmento de Imprensa e Propaganda - DIP area studied, in the perspective of understanding the role of the most important intelligence agency of the Vargas government.

  15. De novo development of eosinophilic myocarditis with left ventricular assist device support as bridge to transplant.

    Science.gov (United States)

    Pereira, Naveen L; Park, Soon J; Daly, Richard C; Kushwaha, Sudhir S; Edwards, William D

    2010-10-01

    The de novo development of myocarditis during left ventricular assist device support for dilated cardiomyopathy has not been previously described. We report a case of severe eosinophilic myocarditis associated with the use of leukotriene-receptor antagonist montelukast that developed during left ventricular assist device support accompanied by intra-device thrombus formation that was hemodynamically tolerated and subsequently discovered in the explanted heart. There may be no visible change in cardiac function as assessed by echocardiography, but the diagnosis should be entertained with the development of peripheral eosinophilia. Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  16. Analysis of the NovoTwist pen needle in comparison with conventional screw-thread needles.

    Science.gov (United States)

    Aye, Tandy

    2011-11-01

    Administration of insulin via a pen device may be advantageous over a vial and syringe system. Hofman and colleagues introduce a new insulin pen needle, the NovoTwist, to simplify injections to a small group of children and adolescents. Their overall preferences and evaluation of the handling of the needle are reported in the study. This new needle has the potential to ease administration of insulin via a pen device that may increase both the use of a pen device and adherence to insulin therapy. © 2011 Diabetes Technology Society.

  17. De-novo discovery of differentially abundant transcription factor binding sites including their positional preference.

    Science.gov (United States)

    Keilwagen, Jens; Grau, Jan; Paponov, Ivan A; Posch, Stefan; Strickert, Marc; Grosse, Ivo

    2011-02-10

    Transcription factors are a main component of gene regulation as they activate or repress gene expression by binding to specific binding sites in promoters. The de-novo discovery of transcription factor binding sites in target regions obtained by wet-lab experiments is a challenging problem in computational biology, which has not been fully solved yet. Here, we present a de-novo motif discovery tool called Dispom for finding differentially abundant transcription factor binding sites that models existing positional preferences of binding sites and adjusts the length of the motif in the learning process. Evaluating Dispom, we find that its prediction performance is superior to existing tools for de-novo motif discovery for 18 benchmark data sets with planted binding sites, and for a metazoan compendium based on experimental data from micro-array, ChIP-chip, ChIP-DSL, and DamID as well as Gene Ontology data. Finally, we apply Dispom to find binding sites differentially abundant in promoters of auxin-responsive genes extracted from Arabidopsis thaliana microarray data, and we find a motif that can be interpreted as a refined auxin responsive element predominately positioned in the 250-bp region upstream of the transcription start site. Using an independent data set of auxin-responsive genes, we find in genome-wide predictions that the refined motif is more specific for auxin-responsive genes than the canonical auxin-responsive element. In general, Dispom can be used to find differentially abundant motifs in sequences of any origin. However, the positional distribution learned by Dispom is especially beneficial if all sequences are aligned to some anchor point like the transcription start site in case of promoter sequences. We demonstrate that the combination of searching for differentially abundant motifs and inferring a position distribution from the data is beneficial for de-novo motif discovery. Hence, we make the tool freely available as a component of the open

  18. S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

    Science.gov (United States)

    Cantalupo, Anna

    2016-01-01

    Initially discovered as abundant components of eukaryotic cell membranes, sphingolipids are now recognized as important bioactive signaling molecules that modulate a variety of cellular functions, including those relevant to cancer and immunologic, inflammatory, and cardiovascular disorders. In this review, we discuss recent advances in our understanding of the role of sphingosine-1-phosphate (S1P) receptors in the regulation of vascular function, and focus on how de novo biosynthesized sphingolipids play a role in blood pressure homeostasis. The therapeutic potential of new drugs that target S1P signaling is also discussed. PMID:27317800

  19. Visões do Novo Mundo na pintura religiosa da Renascença

    Directory of Open Access Journals (Sweden)

    Yobenj Aucardo Chicangana-Bayona

    2013-06-01

    Full Text Available Este artigo aborda o estudo dos elementos familiares aos exploradores europeus que estabeleceram suas primeiras coordenadas a partir de analogias com o Paraíso e com Cocanha para assimilar e interpretar pictoricamente o Novo Mundo, uma realidade antes desconhecida, e integrá-la à cultura ocidental. Assim, o Cristianismo é muito importante, porque vai oferecer o referencial - em um primeiro momento - para estabelecer a imagem do índio em episódios religiosos da cultura ocidental europeia. Uma imagem que ora será positiva, vinculada ao paraíso, e ora negativa, sendo vinculada ao inferno.

  20. A inclusão na perspectiva do novo paradigma da ciência

    Directory of Open Access Journals (Sweden)

    Reinoldo Marqueza

    2011-12-01

    Full Text Available O estudo aborda o processo de transição paradigmática da ciência moderna para a ciência pós-moderna. Salienta as características do paradigma atual, a crise desse paradigma e aponta os contornos do paradigma emergente na perspectiva do sociólogo Boaventura Sousa Santos. Refere a Educação Inclusiva como um novo processo de produção e de apropriação do conhecimento e como uma nova forma de estar na relação.Palavras-chave: Paradigma. Conhecimento. Educação Inclusiva.

  1. Novos biomateriais poliméricos para implantes ósseos

    OpenAIRE

    Ferreira, Sara Cristina Silva

    2016-01-01

    Os danos dos tecidos ósseos representam um problema importante de saúde em todo o mundo. Um dos componentes principais utilizados em engenharia de tecidos são os materiais de suporte, estruturas 3D formadas por matrizes porosas, que visam proporcionar o desenvolvimento do novo tecido. Muitas das matrizes poliméricas porosas (espumas) utilizadas em aplicações médicas são constituídas por poliuretanos, sendo estes produzidos a partir de isocianatos (produtos tóxicos) e polióis. Assim, surge a n...

  2. SV2: accurate structural variation genotyping and de novo mutation detection from whole genomes.

    Science.gov (United States)

    Antaki, Danny; Brandler, William M; Sebat, Jonathan

    2018-05-15

    Structural variation (SV) detection from short-read whole genome sequencing is error prone, presenting significant challenges for population or family-based studies of disease. Here, we describe SV2, a machine-learning algorithm for genotyping deletions and duplications from paired-end sequencing data. SV2 can rapidly integrate variant calls from multiple structural variant discovery algorithms into a unified call set with high genotyping accuracy and capability to detect de novo mutations. SV2 is freely available on GitHub (https://github.com/dantaki/SV2). jsebat@ucsd.edu. Supplementary data are available at Bioinformatics online.

  3. A comprehensive cytogenetic classification of 1466 Chinese patients with de novo acute lymphoblastic leukemia.

    Science.gov (United States)

    Li, Xin; Li, Juan; Hu, Yanjie; Xie, Wei; Du, Wen; Liu, Wei; Li, Xiaoqing; Chen, Xiangjun; Li, Hongrui; Wang, Junfeng; Zhang, Lannan; Huang, Shiang

    2012-06-01

    Cytogenetics and molecular cytogenetics of 1466 Chinese patients with de novo acute lymphoblastic leukemia (ALL) were studied. Cytogenetic results were available in 1175 patients. Cross-correlations of 23 subclasses of cytogenetic abnormalities were described. Childhood cases had higher incidences of normal karyotype, t(1;19), +8, 12q-, +21, +22 and high hyperdiploidy with 51-65 chromosomes, and lower incidences of t(9;22) and -5/5q- than adult ones (all pcytogenetic subclasses with immunophenotyping subgroups of ALL were studied. Our study presents the cytogenetic characteristics of a large series of Chinese ALL patients. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. A Presença da Gastronomia Alemã na Hotelaria de Novo Hamburgo, RS

    OpenAIRE

    mary sandra ashton; Ana Cristina Müller

    2013-01-01

    Esse estudo tem por objetivo investigar os elementos e características da gastronomia alemã presentes nos serviços hoteleiros de Novo Hamburgo. Tem ênfase na gastronomia, evidenciando e (re) conhecendo os hábitos e costumes alimentares trazidos pela imigração germânica e sua relação com a oferta de alimentos nos hotéis da cidade, como diferencial no quesito turismo cultural. Para tanto, foram utilizados autores reconhe...

  5. Emergence, Retention and Selection: A Trilogy of Origination for Functional De Novo Proteins from Ancestral LncRNAs in Primates.

    Directory of Open Access Journals (Sweden)

    Jia-Yu Chen

    2015-07-01

    Full Text Available While some human-specific protein-coding genes have been proposed to originate from ancestral lncRNAs, the transition process remains poorly understood. Here we identified 64 hominoid-specific de novo genes and report a mechanism for the origination of functional de novo proteins from ancestral lncRNAs with precise splicing structures and specific tissue expression profiles. Whole-genome sequencing of dozens of rhesus macaque animals revealed that these lncRNAs are generally not more selectively constrained than other lncRNA loci. The existence of these newly-originated de novo proteins is also not beyond anticipation under neutral expectation, as they generally have longer theoretical lifespan than their current age, due to their GC-rich sequence property enabling stable ORFs with lower chance of non-sense mutations. Interestingly, although the emergence and retention of these de novo genes are likely driven by neutral forces, population genetics study in 67 human individuals and 82 macaque animals revealed signatures of purifying selection on these genes specifically in human population, indicating a proportion of these newly-originated proteins are already functional in human. We thus propose a mechanism for creation of functional de novo proteins from ancestral lncRNAs during the primate evolution, which may contribute to human-specific genetic novelties by taking advantage of existed genomic contexts.

  6. Critical importance of the de novo pyrimidine biosynthesis pathway for Trypanosoma cruzi growth in the mammalian host cell cytoplasm

    International Nuclear Information System (INIS)

    Hashimoto, Muneaki; Morales, Jorge; Fukai, Yoshihisa; Suzuki, Shigeo; Takamiya, Shinzaburo; Tsubouchi, Akiko; Inoue, Syou; Inoue, Masayuki; Kita, Kiyoshi; Harada, Shigeharu; Tanaka, Akiko; Aoki, Takashi; Nara, Takeshi

    2012-01-01

    Highlights: ► We established Trypanosoma cruzi lacking the gene for carbamoyl phosphate synthetase II. ► Disruption of the cpsII gene significantly reduced the growth of epimastigotes. ► In particular, the CPSII-null mutant severely retarded intracellular growth. ► The de novo pyrimidine pathway is critical for the parasite growth in the host cell. -- Abstract: The intracellular parasitic protist Trypanosoma cruzi is the causative agent of Chagas disease in Latin America. In general, pyrimidine nucleotides are supplied by both de novo biosynthesis and salvage pathways. While epimastigotes—an insect form—possess both activities, amastigotes—an intracellular replicating form of T. cruzi—are unable to mediate the uptake of pyrimidine. However, the requirement of de novo pyrimidine biosynthesis for parasite growth and survival has not yet been elucidated. Carbamoyl-phosphate synthetase II (CPSII) is the first and rate-limiting enzyme of the de novo biosynthetic pathway, and increased CPSII activity is associated with the rapid proliferation of tumor cells. In the present study, we showed that disruption of the T. cruzicpsII gene significantly reduced parasite growth. In particular, the growth of amastigotes lacking the cpsII gene was severely suppressed. Thus, the de novo pyrimidine pathway is important for proliferation of T. cruzi in the host cell cytoplasm and represents a promising target for chemotherapy against Chagas disease.

  7. Whole Exome Sequencing for a Patient with Rubinstein-Taybi Syndrome Reveals de Novo Variants besides an Overt CREBBP Mutation

    Directory of Open Access Journals (Sweden)

    Hee Jeong Yoo

    2015-03-01

    Full Text Available Rubinstein-Taybi syndrome (RSTS is a rare condition with a prevalence of 1 in 125,000–720,000 births and characterized by clinical features that include facial, dental, and limb dysmorphology and growth retardation. Most cases of RSTS occur sporadically and are caused by de novo mutations. Cytogenetic or molecular abnormalities are detected in only 55% of RSTS cases. Previous genetic studies have yielded inconsistent results due to the variety of methods used for genetic analysis. The purpose of this study was to use whole exome sequencing (WES to evaluate the genetic causes of RSTS in a young girl presenting with an Autism phenotype. We used the Autism diagnostic observation schedule (ADOS and Autism diagnostic interview revised (ADI-R to confirm her diagnosis of Autism. In addition, various questionnaires were used to evaluate other psychiatric features. We used WES to analyze the DNA sequences of the patient and her parents and to search for de novo variants. The patient showed all the typical features of Autism, WES revealed a de novo frameshift mutation in CREBBP and de novo sequence variants in TNC and IGFALS genes. Mutations in the CREBBP gene have been extensively reported in RSTS patients, while potential missense mutations in TNC and IGFALS genes have not previously been associated with RSTS. The TNC and IGFALS genes are involved in central nervous system development and growth. It is possible for patients with RSTS to have additional de novo variants that could account for previously unexplained phenotypes.

  8. A case of de novo duplication of 15q24-q26.3

    Directory of Open Access Journals (Sweden)

    Hye Ran Kim

    2011-06-01

    Full Text Available Distal duplication, or trisomy 15q, is an extremely rare chromosomal disorder characterized by prenatal and postnatal overgrowth, mental retardation, and craniofacial malformations. Additional abnormalities typically include an unusually short neck, malformations of the fingers and toes, scoliosis and skeletal malformations, genital abnormalities, particularly in affected males, and, in some cases, cardiac defects. The range and severity of symptoms and physical findings may vary from case to case, depending upon the length and location of the duplicated portion of chromosome 15q. Most reported cases of duplication of the long arm of chromosome 15 frequently have more than one segmental imbalance resulting from unbalanced translocations involving chromosome 15 and deletions in another chromosome, as well as other structural chromosomal abnormalities. We report a female newborn with a de novo duplication, 15q24- q26.3, showing intrauterine overgrowth, a narrow asymmetric face with down-slanting palpebral fissures, a large, prominent nose, and micrognathia, arachnodactyly, camptodactyly, congenital heart disease, hydronephrosis, and hydroureter. Chromosomal analysis showed a 46,XX,inv(9(p12q13,dup(15(q24q26.3. Array comparative genomic hybridization analysis revealed a gain of 42 clones on 15q24-q26.3. This case represents the only reported patient with a de novo 15q24-q26.3 duplication that did not result from an unbalanced translocation and did not have a concomitant monosomic component in Korea.

  9. De novo transcriptome assembly of drought tolerant CAM plants, Agave deserti and Agave tequilana.

    Science.gov (United States)

    Gross, Stephen M; Martin, Jeffrey A; Simpson, June; Abraham-Juarez, María Jazmín; Wang, Zhong; Visel, Axel

    2013-08-19

    Agaves are succulent monocotyledonous plants native to xeric environments of North America. Because of their adaptations to their environment, including crassulacean acid metabolism (CAM, a water-efficient form of photosynthesis), and existing technologies for ethanol production, agaves have gained attention both as potential lignocellulosic bioenergy feedstocks and models for exploring plant responses to abiotic stress. However, the lack of comprehensive Agave sequence datasets limits the scope of investigations into the molecular-genetic basis of Agave traits. Here, we present comprehensive, high quality de novo transcriptome assemblies of two Agave species, A. tequilana and A. deserti, built from short-read RNA-seq data. Our analyses support completeness and accuracy of the de novo transcriptome assemblies, with each species having a minimum of approximately 35,000 protein-coding genes. Comparison of agave proteomes to those of additional plant species identifies biological functions of gene families displaying sequence divergence in agave species. Additionally, a focus on the transcriptomics of the A. deserti juvenile leaf confirms evolutionary conservation of monocotyledonous leaf physiology and development along the proximal-distal axis. Our work presents a comprehensive transcriptome resource for two Agave species and provides insight into their biology and physiology. These resources are a foundation for further investigation of agave biology and their improvement for bioenergy development.

  10. Delayed manifestation and transmission bias of de novo chromosome mutations. Their relevance for radiation health effect

    International Nuclear Information System (INIS)

    Sasaki, Masao S.

    2006-01-01

    The origin and transmission of de novo chromosome mutations were reviewed on the basis of our chromosome studies in retinoblastoma patients and male infertility. In a series of 264 sporadic retinoblastoma families, gross chromosome rearrangements involving the RB1 locus were identified in 23 cases (8.7%), of which 16 were non-mosaic and 7 were mosaic mutations. The newly formed chromosome mutations, whether they were non-mosaic or mosaic, had a strong bias towards paternally derived chromosome, indicating that they shared a common mechanism where a pre-mutational event or instability is carried over to zygote by sperm and manifested as gross chromosome mutation at the early stages of development. The de novo chromosome mutations are preferentially transmitted through female carriers. This transmission bias is consistent with the finding of higher frequencies of translocation carriers in infertile men (7.69% versus 0.27% in general populations) in whom meiotic progression is severely suppressed, possibly through activation of meiotic checkpoints. Such a meiotic surveillance mechanism may minimize the spreading of newly-arisen chromosome mutations in populations. A quantitative model of meiotic surveillance mechanism is proposed and successfully applied to the published data on ''humped'' dose-response curves for radiation-induced spermatogonial reciprocal translocations in several mammalian species. (author)

  11. De novo biosynthesis of vanillin in fission yeast (Schizosaccharomyces pombe) and baker's yeast (Saccharomyces cerevisiae).

    Science.gov (United States)

    Hansen, Esben H; Møller, Birger Lindberg; Kock, Gertrud R; Bünner, Camilla M; Kristensen, Charlotte; Jensen, Ole R; Okkels, Finn T; Olsen, Carl E; Motawia, Mohammed S; Hansen, Jørgen

    2009-05-01

    Vanillin is one of the world's most important flavor compounds, with a global market of 180 million dollars. Natural vanillin is derived from the cured seed pods of the vanilla orchid (Vanilla planifolia), but most of the world's vanillin is synthesized from petrochemicals or wood pulp lignins. We have established a true de novo biosynthetic pathway for vanillin production from glucose in Schizosaccharomyces pombe, also known as fission yeast or African beer yeast, as well as in baker's yeast, Saccharomyces cerevisiae. Productivities were 65 and 45 mg/liter, after introduction of three and four heterologous genes, respectively. The engineered pathways involve incorporation of 3-dehydroshikimate dehydratase from the dung mold Podospora pauciseta, an aromatic carboxylic acid reductase (ACAR) from a bacterium of the Nocardia genus, and an O-methyltransferase from Homo sapiens. In S. cerevisiae, the ACAR enzyme required activation by phosphopantetheinylation, and this was achieved by coexpression of a Corynebacterium glutamicum phosphopantetheinyl transferase. Prevention of reduction of vanillin to vanillyl alcohol was achieved by knockout of the host alcohol dehydrogenase ADH6. In S. pombe, the biosynthesis was further improved by introduction of an Arabidopsis thaliana family 1 UDP-glycosyltransferase, converting vanillin into vanillin beta-D-glucoside, which is not toxic to the yeast cells and thus may be accumulated in larger amounts. These de novo pathways represent the first examples of one-cell microbial generation of these valuable compounds from glucose. S. pombe yeast has not previously been metabolically engineered to produce any valuable, industrially scalable, white biotech commodity.

  12. The significance of trilineage myelodysplasia in de novo acute myeloblastic leukemia: clinical and laboratory features.

    Science.gov (United States)

    Lima, C S; Vassalo, J; Lorand-Metze, I; Bechelli, A P; Souza, C A

    1997-01-01

    A prospective study was undertaken to elucidate the clinical and laboratory differences between de novo acute myeloid leukemia (AML) and AML with trilineage myelodysplasia (AML-TMDS). One hundred and seven patients with AML were diagnosed at the University Hospital between January 1987 and July 1992, and were followed until July 1995. TMDS was identified in 17 of them (16%). With regard to age and sex distribution no difference was found between AML patients with and without TMDS (p = 0.43, p = 0.54, respectively). The duration of symptoms at presentation in AML-TMDS was similar to those observed in de novo AML (p = 0.29). Hemoglobin values and platelet counts were similar in both groups of patients (p = 0.45, p = 0.44, respectively). However, peripheral white blood cell and neutrophil counts, as well as blast counts in AML-TMDS patients were lower than those observed in AML without TMDS patients (p leukemia transformation occurs in a more undifferentiated pluripotent stem cell, leading to a dysplastic residual hemopoiesis besides the blast proliferation; 2) the incidence of TMDS in our group of patients did not influence the clinical outcome after treatment of the disease.

  13. Therapeutic equivalence and pharmacokinetics of generic tacrolimus formulation in de novo kidney transplant patients.

    Science.gov (United States)

    Min, Sang-Il; Ha, Jongwon; Kim, Yon Su; Ahn, Sang Hyun; Park, Taejin; Park, Dae Do; Kim, Suh Min; Min, Seung-Kee; Hong, Hyejin; Ahn, Curie; Kim, Sang Joon

    2013-12-01

    There is a growing concern about the therapeutic equivalence of the generic tacrolimus formulation (GEN Tacrolimus) to the reference tacrolimus (REF Tacrolimus) in solid organ transplantation. A prospective, randomized study of 126 de novo renal transplant patients was conducted to compare the efficacy, safety and pharmacokinetic (PK) profiles between GEN tacrolimus (n = 63) and REF tacrolimus (n = 63). The PK of tacrolimus was evaluated on Day 10 and 6 months under steady-state condition. Crossover study was carried out in 66 patients at 6 months. On Day 10, 117 patients completed PK profiles (54 GEN tacrolimus and 63 REF tacrolimus) and GEN tacrolimus showed comparable C(0) (9.8 ± 2.5 versus 9.7 ± 3.0 ng/mL, P = 0.80) but significantly higher dose-normalized C(max) (309.1 ± 191.9 versus 192.5 ± 95.2 ng/mL/mg/kg, P PK profiles evaluated at 9 months showed that generic substitution also resulted in an 'early and high C(max)'. Efficacy and safety data were comparable over the 9-month study period. Therapeutic equivalence and the PK of GEN tacrolimus should be evaluated in patients undergoing de novo renal transplantation.

  14. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

    Science.gov (United States)

    Heinzen, Erin L.; Swoboda, Kathryn J.; Hitomi, Yuki; Gurrieri, Fiorella; Nicole, Sophie; de Vries, Boukje; Tiziano, F. Danilo; Fontaine, Bertrand; Walley, Nicole M.; Heavin, Sinéad; Panagiotakaki, Eleni; Fiori, Stefania; Abiusi, Emanuela; Di Pietro, Lorena; Sweney, Matthew T.; Newcomb, Tara M.; Viollet, Louis; Huff, Chad; Jorde, Lynn B.; Reyna, Sandra P.; Murphy, Kelley J.; Shianna, Kevin V.; Gumbs, Curtis E.; Little, Latasha; Silver, Kenneth; Ptác̆ek, Louis J.; Haan, Joost; Ferrari, Michel D.; Bye, Ann M.; Herkes, Geoffrey K.; Whitelaw, Charlotte M.; Webb, David; Lynch, Bryan J.; Uldall, Peter; King, Mary D.; Scheffer, Ingrid E.; Neri, Giovanni; Arzimanoglou, Alexis; van den Maagdenberg, Arn M.J.M.; Sisodiya, Sanjay M.; Mikati, Mohamad A.; Goldstein, David B.; Nicole, Sophie; Gurrieri, Fiorella; Neri, Giovanni; de Vries, Boukje; Koelewijn, Stephany; Kamphorst, Jessica; Geilenkirchen, Marije; Pelzer, Nadine; Laan, Laura; Haan, Joost; Ferrari, Michel; van den Maagdenberg, Arn; Zucca, Claudio; Bassi, Maria Teresa; Franchini, Filippo; Vavassori, Rosaria; Giannotta, Melania; Gobbi, Giuseppe; Granata, Tiziana; Nardocci, Nardo; De Grandis, Elisa; Veneselli, Edvige; Stagnaro, Michela; Gurrieri, Fiorella; Neri, Giovanni; Vigevano, Federico; Panagiotakaki, Eleni; Oechsler, Claudia; Arzimanoglou, Alexis; Nicole, Sophie; Giannotta, Melania; Gobbi, Giuseppe; Ninan, Miriam; Neville, Brian; Ebinger, Friedrich; Fons, Carmen; Campistol, Jaume; Kemlink, David; Nevsimalova, Sona; Laan, Laura; Peeters-Scholte, Cacha; van den Maagdenberg, Arn; Casaer, Paul; Casari, Giorgio; Sange, Guenter; Spiel, Georg; Boneschi, Filippo Martinelli; Zucca, Claudio; Bassi, Maria Teresa; Schyns, Tsveta; Crawley, Francis; Poncelin, Dominique; Vavassori, Rosaria

    2012-01-01

    Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. AHC is usually a sporadic disorder with unknown etiology. Using exome sequencing of seven patients with AHC, and their unaffected parents, we identified de novo nonsynonymous mutations in ATP1A3 in all seven AHC patients. Subsequent sequence analysis of ATP1A3 in 98 additional patients revealed that 78% of AHC cases have a likely causal ATP1A3 mutation, including one inherited mutation in a familial case of AHC. Remarkably, six ATP1A3 mutations explain the majority of patients, including one observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset-dystonia-parkinsonism, AHC-causing mutations revealed consistent reductions in ATPase activity without effects on protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC, and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in this gene. PMID:22842232

  15. Colorimetry provides a rapid objective measurement of de novo hair growth rate in mice.

    Science.gov (United States)

    Tzung, Tien-Yi; Yang, Chia-Yi; Huang, Yung-Chang; Kao, Fu-Jen

    2009-11-01

    Depilated mice have been used as a test platform for hair growth-regulating agents. However, currently available assessment tools for hair growth in mice are less than ideal. Tristimulus colorimetry of the fur color of depilated agouti, albino, and black mice with L*, a*, and b* values were performed daily until the full growth of pelage. Using light-emitting diode (LED) irradiation (650 and 890 nm) with a daily dose of 3.5 J/cm(2) as hair growth regulators, the hair growth rates observed by the global assessment were compared with those derived from colorimetry. In contrast to a* and b* values, L* values changed more drastically over time in the anagen phase regardless of fur color. Unlike the inhibitory effect of 650 nm irradiation, LED of 890 nm promoted de novo hair regrowth in mice. The difference in hair growth rates detected by colorimetry paralleled the observation made by the global assessment. The L* value of fur color obtained by tristimulus colorimetry was a sensitive yet quantitative indicator of de novo hair growth, and could be used to project the hair growth rate in mice.

  16. De novo transcriptome assembly of two different peach cultivars grown in Korea

    Directory of Open Access Journals (Sweden)

    Yeonhwa Jo

    2015-12-01

    Full Text Available Peach (Prunus persica is one of the most popular stone fruits worldwide. Next generation sequencing (NGS has facilitated genome and transcriptome analyses of several stone fruit trees. In this study, we conducted de novo transcriptome analyses of two peach cultivars grown in Korea. Leaves of two cultivars, referred to as Jangtaek and Mibaek, were harvested and used for library preparation. The two prepared libraries were paired-end sequenced by the HiSeq2000 system. We obtained 8.14 GB and 9.62 GB sequence data from Jangtaek and Mibaek (NCBI accession numbers: SRS1056585 and SRS1056587, respectively. The Trinity program was used to assemble two transcriptomes de novo, resulting in 110,477 (Jangtaek and 136,196 (Mibaek transcripts. TransDecoder identified possible coding regions in assembled transcripts. The identified proteins were subjected to BLASTP search against NCBI's non-redundant database for functional annotation. This study provides transcriptome data for two peach cultivars, which might be useful for genetic marker development and comparative transcriptome analyses.

  17. De novo generation of infectious prions with bacterially expressed recombinant prion protein.

    Science.gov (United States)

    Zhang, Zhihong; Zhang, Yi; Wang, Fei; Wang, Xinhe; Xu, Yuanyuan; Yang, Huaiyi; Yu, Guohua; Yuan, Chonggang; Ma, Jiyan

    2013-12-01

    The prion hypothesis is strongly supported by the fact that prion infectivity and the pathogenic conformer of prion protein (PrP) are simultaneously propagated in vitro by the serial protein misfolding cyclic amplification (sPMCA). However, due to sPMCA's enormous amplification power, whether an infectious prion can be formed de novo with bacterially expressed recombinant PrP (rPrP) remains to be satisfactorily resolved. To address this question, we performed unseeded sPMCA with rPrP in a laboratory that has never been exposed to any native prions. Two types of proteinase K (PK)-resistant and self-perpetuating recombinant PrP conformers (rPrP-res) with PK-resistant cores of 17 or 14 kDa were generated. A bioassay revealed that rPrP-res(17kDa) was highly infectious, causing prion disease in wild-type mice with an average survival time of about 172 d. In contrast, rPrP-res(14kDa) completely failed to induce any disease. Our findings reveal that sPMCA is sufficient to initiate various self-perpetuating PK-resistant rPrP conformers, but not all of them possess in vivo infectivity. Moreover, generating an infectious prion in a prion-free environment establishes that an infectious prion can be formed de novo with bacterially expressed rPrP.

  18. De novo formation of nucleoli in developing mouse embryos originating from enucleolated zygotes.

    Science.gov (United States)

    Kyogoku, Hirohisa; Fulka, Josef; Wakayama, Teruhiko; Miyano, Takashi

    2014-06-01

    The large, compact oocyte nucleoli, sometimes referred to as nucleolus precursor bodies (NPBs), are essential for embryonic development in mammals; in their absence, the oocytes complete maturation and can be fertilized, but no nucleoli are formed in the zygote or embryo, leading to developmental failure. It has been convincingly documented that zygotes inherit the oocyte nucleolar material and form NPBs again in pronuclei. It is commonly accepted that during early embryonic development, the original compact zygote NPBs gradually transform into reticulated nucleoli of somatic cells. Here, we show that zygote NPBs are not required for embryonic and full-term development in the mouse. When NPBs were removed from late-stage zygotes by micromanipulation, the enucleolated zygotes developed to the blastocyst stage and, after transfer to recipients, live pups were obtained. We also describe de novo formation of nucleoli in developing embryos. After removal of NPBs from zygotes, they formed new nucleoli after several divisions. These results indicate that the zygote NPBs are not used in embryonic development and that the nucleoli in developing embryos originate from de novo synthesized materials. © 2014. Published by The Company of Biologists Ltd.

  19. Brain metabolic correlates of dopaminergic degeneration in de novo idiopathic Parkinson's disease

    International Nuclear Information System (INIS)

    Berti, Valentina; Polito, Cristina; Vanzi, Eleonora; Cristofaro, Maria Teresa de; Pellicano, Giannantonio; Mungai, Francesco; Formiconi, Andreas Robert; Pupi, Alberto; Ramat, Silvia; Marini, Paolo; Sorbi, Sandro

    2010-01-01

    The aim of the present study was to evaluate the reciprocal relationships between motor impairment, dopaminergic dysfunction, and cerebral metabolism (rCMRglc) in de novo Parkinson's disease (PD) patients. Twenty-six de novo untreated PD patients were scanned with 123 I-FP-CIT SPECT and 18 F-FDG PET. The dopaminergic impairment was measured with putaminal 123 I-FP-CIT binding potential (BP), estimated with two different techniques: an iterative reconstruction algorithm (BP OSEM ) and the least-squares (LS) method (BP LS ). Statistical parametric mapping (SPM) multiple regression analyses were performed to determine the specific brain regions in which UPDRS III scores and putaminal BP values correlated with rCMRglc. The SPM results showed a negative correlation between UPDRS III and rCMRglc in premotor cortex, and a positive correlation between BP OSEM and rCMRglc in premotor and dorsolateral prefrontal cortex, not surviving at multiple comparison correction. Instead, there was a positive significant correlation between putaminal BP LS and rCMRglc in premotor, dorsolateral prefrontal, anterior prefrontal, and orbitofrontal cortex (p LS is an efficient parameter for exploring the correlations between PD severity and rCMRglc cortical changes. The correlation between dopaminergic degeneration and rCMRglc in several prefrontal regions likely represents the cortical functional correlate of the dysfunction in the motor basal ganglia-cortical circuit in PD. This finding suggests focusing on the metabolic course of these areas to follow PD progression and to analyze treatment effects. (orig.)

  20. A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia.

    Science.gov (United States)

    Nicolas, Gaël; Jacquin, Agnès; Thauvin-Robinet, Christel; Rovelet-Lecrux, Anne; Rouaud, Olivier; Pottier, Cyril; Aubriot-Lorton, Marie-Hélène; Rousseau, Stéphane; Wallon, David; Duvillard, Christian; Béjot, Yannick; Frébourg, Thierry; Giroud, Maurice; Campion, Dominique; Hannequin, Didier

    2014-10-01

    Idiopathic basal ganglia calcification (IBGC) is characterized by brain calcification and a wide variety of neurologic and psychiatric symptoms. In families with autosomal dominant inheritance, three causative genes have been identified: SLC20A2, PDGFRB, and, very recently, PDGFB. Whereas in clinical practice sporadic presentation of IBGC is frequent, well-documented reports of true sporadic occurrence are rare. We report the case of a 20-year-old woman who presented laryngeal dystonia revealing IBGC. Her healthy parents' CT scans were both normal. We identified in the proband a new nonsense mutation in exon 4 of PDGFB, c.439C>T (p.Gln147*), which was absent from the parents' DNA. This mutation may result in a loss-of-function of PDGF-B, which has been shown to cause IBGC in humans and to disrupt the blood-brain barrier in mice, resulting in brain calcification. The c.439C>T mutation is located between two previously reported nonsense mutations, c.433C>T (p.Gln145*) and c.445C>T (p.Arg149*), on a region that could be a hot spot for de novo mutations. We present the first full demonstration of the de novo occurrence of an IBGC-causative mutation in a sporadic case.

  1. De novo biosynthesis of volatiles induced by insect herbivory in cotton plants

    International Nuclear Information System (INIS)

    Pare, P.W.; Tumlinson, J.H.

    1997-01-01

    In response to insect feeding on the leaves, cotton (Gossypium hirsutum L.) plants release elevated levels of volatiles, which can serve as a chemical signal that attracts natural enemies of the herbivore to the damaged plant. Pulse-labeling experiments with [13C]CO2 demonstrated that many of the volatiles released, including the acyclic terpenes (E,E)-alpha-farnesene, (E)-beta-farnesene, (E)-beta-ocimene, linalool,(E)-4,8-dimethyl-1,3,7-nonatriene, and (E,E)-4,8,12-trimethyl-1,3,7,11-tridecatetrane, as well as the shikimate pathway product indole, are biosynthesized de novo following insect damage. However, other volatile constituents, including several cyclic terpenes, butyrates, and green leaf volatiles of the lipoxygenase pathway are released from storage or synthesized from stored intermediates. Analysis of volatiles from artificially damaged plants, with and without beet armyworm (Spodoptera exigua Hubner) oral secretions exogenously applied to the leaves, as well as volatiles from beet armyworm-damaged and -undamaged control plants, demonstrated that the application of caterpillar oral secretions increased both the production and release of several volatiles that are synthesized de novo in response to insect feeding. These results establish that the plant plays an active and dynamic role in mediating the interaction between herbivores and natural enemies of herbivores

  2. Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes.

    Science.gov (United States)

    Maher, Geoffrey J; McGowan, Simon J; Giannoulatou, Eleni; Verrill, Clare; Goriely, Anne; Wilkie, Andrew O M

    2016-03-01

    De novo point mutations arise predominantly in the male germline and increase in frequency with age, but it has not previously been possible to locate specific, identifiable mutations directly within the seminiferous tubules of human testes. Using microdissection of tubules exhibiting altered expression of the spermatogonial markers MAGEA4, FGFR3, and phospho-AKT, whole genome amplification, and DNA sequencing, we establish an in situ strategy for discovery and analysis of pathogenic de novo mutations. In 14 testes from men aged 39-90 y, we identified 11 distinct gain-of-function mutations in five genes (fibroblast growth factor receptors FGFR2 and FGFR3, tyrosine phosphatase PTPN11, and RAS oncogene homologs HRAS and KRAS) from 16 of 22 tubules analyzed; all mutations have known associations with severe diseases, ranging from congenital or perinatal lethal disorders to somatically acquired cancers. These results support proposed selfish selection of spermatogonial mutations affecting growth factor receptor-RAS signaling, highlight its prevalence in older men, and enable direct visualization of the microscopic anatomy of elongated mutant clones.

  3. A multi-method approach toward de novo glycan characterization: a Man-5 case study.

    Science.gov (United States)

    Prien, Justin M; Prater, Bradley D; Cockrill, Steven L

    2010-05-01

    Regulatory agencies' expectations for biotherapeutic approval are becoming more stringent with regard to product characterization, where minor species as low as 0.1% of a given profile are typically identified. The mission of this manuscript is to demonstrate a multi-method approach toward de novo glycan characterization and quantitation, including minor species at or approaching the 0.1% benchmark. Recently, unexpected isomers of the Man(5)GlcNAc(2) (M(5)) were reported (Prien JM, Ashline DJ, Lapadula AJ, Zhang H, Reinhold VN. 2009. The high mannose glycans from bovine ribonuclease B isomer characterization by ion trap mass spectrometry (MS). J Am Soc Mass Spectrom. 20:539-556). In the current study, quantitative analysis of these isomers found in commercial M(5) standard demonstrated that they are in low abundance (2-aminobenzoic acid to detect and chromatographically resolve multiple M(5) isomers in bovine ribonuclease B. With this multi-method approach, we have the capabilities to comprehensively characterize a biotherapeutic's glycan array in a de novo manner, including structural isomers at >/=0.1% of the total chromatographic peak area.

  4. Damaging de novo mutations diminish motor skills in children on the autism spectrum.

    Science.gov (United States)

    Buja, Andreas; Volfovsky, Natalia; Krieger, Abba M; Lord, Catherine; Lash, Alex E; Wigler, Michael; Iossifov, Ivan

    2018-02-20

    In individuals with autism spectrum disorder (ASD), de novo mutations have previously been shown to be significantly correlated with lower IQ but not with the core characteristics of ASD: deficits in social communication and interaction and restricted interests and repetitive patterns of behavior. We extend these findings by demonstrating in the Simons Simplex Collection that damaging de novo mutations in ASD individuals are also significantly and convincingly correlated with measures of impaired motor skills. This correlation is not explained by a correlation between IQ and motor skills. We find that IQ and motor skills are distinctly associated with damaging mutations and, in particular, that motor skills are a more sensitive indicator of mutational severity than is IQ, as judged by mutational type and target gene. We use this finding to propose a combined classification of phenotypic severity: mild (little impairment of either), moderate (impairment mainly to motor skills), and severe (impairment of both IQ and motor skills). Copyright © 2018 the Author(s). Published by PNAS.

  5. REQUALIFICAÇÃO URBANA E DESPEJOS EM CENTROS NOVO E ANTIGO DE SALVADOR

    Directory of Open Access Journals (Sweden)

    John Gledhill

    Full Text Available A cidade de Salvador replica o processo de “acumulação por espoliação”, característico de um urbanismo neoliberal em todo o mundo. Neste artigo, comparamos como atua a lógica da requalificação urbana em duas zonas da cidade. A primeira é uma grande e historicamente combativa favela localizada na região que tem se tornado o mais moderno “novo centro” da cidade. Nela, a chave dos problemas são os novos projetos de mobilidade urbana e a construção de condomínios para outras classes sociais. A segunda zona é o centro colonial da cidade, que experimenta uma nova fase de gentrificação. Ali, as políticas de patrimônio histórico se encontram com outras políticas, transformando os remanescentes espaços públicos da cidade neoliberal securitizada em zonas mais seguras para turistas e residentes mais ricos. Enfatizamos o valor de um entendimento etnograficamente fundamentado para compreender o que essas mudanças significam para moradores pobres da cidade, assim como a complexidade, a heterogeneidade e a ambiguidade de suas diferentes reações.

  6. De novo mutations in HCN1 cause early infantile epileptic encephalopathy.

    Science.gov (United States)

    Nava, Caroline; Dalle, Carine; Rastetter, Agnès; Striano, Pasquale; de Kovel, Carolien G F; Nabbout, Rima; Cancès, Claude; Ville, Dorothée; Brilstra, Eva H; Gobbi, Giuseppe; Raffo, Emmanuel; Bouteiller, Delphine; Marie, Yannick; Trouillard, Oriane; Robbiano, Angela; Keren, Boris; Agher, Dahbia; Roze, Emmanuel; Lesage, Suzanne; Nicolas, Aude; Brice, Alexis; Baulac, Michel; Vogt, Cornelia; El Hajj, Nady; Schneider, Eberhard; Suls, Arvid; Weckhuysen, Sarah; Gormley, Padhraig; Lehesjoki, Anna-Elina; De Jonghe, Peter; Helbig, Ingo; Baulac, Stéphanie; Zara, Federico; Koeleman, Bobby P C; Haaf, Thomas; LeGuern, Eric; Depienne, Christel

    2014-06-01

    Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.

  7. De Novo Advanced Adult-Onset Offending: New Evidence from a Population of Federal Correctional Clients.

    Science.gov (United States)

    DeLisi, Matt; Tahja, Katherine N; Drury, Alan J; Elbert, Michael J; Caropreso, Daniel E; Heinrichs, Timothy

    2018-01-01

    Adult antisocial behavior is almost always predated by delinquency during childhood or adolescence; however, there is also evidence of adult-onset criminal offending. This study examined this controversial subgroup of offenders using self-reported and official data from a total population of federal correctional clients selected from the Midwestern United States. Difference of means t-tests, chi-square tests, and logistic regression models found that 11.7% of clients had an adult onset of offending and 2.7% of clients (n = 23) had an onset occurring at age 60 years or older. This group-introduced as de novo advanced adult-onset offenders-had high socioeconomic status, mixed evidence of adverse childhood experiences, and virtually no usage of drugs with the exception of alcohol. These offenders were primarily convicted of social security and white-collar crimes and evinced remarkably low psychopathology and criminal risk. More research is needed to replicate the phenomenon of de novo advanced adult-onset offending. © 2017 American Academy of Forensic Sciences.

  8. Developmental and adult-specific processes contribute to de novo neuromuscular regeneration in the lizard tail.

    Science.gov (United States)

    Tokuyama, Minami A; Xu, Cindy; Fisher, Rebecca E; Wilson-Rawls, Jeanne; Kusumi, Kenro; Newbern, Jason M

    2018-01-15

    Peripheral nerves exhibit robust regenerative capabilities in response to selective injury among amniotes, but the regeneration of entire muscle groups following volumetric muscle loss is limited in birds and mammals. In contrast, lizards possess the remarkable ability to regenerate extensive de novo muscle after tail loss. However, the mechanisms underlying reformation of the entire neuromuscular system in the regenerating lizard tail are not completely understood. We have tested whether the regeneration of the peripheral nerve and neuromuscular junctions (NMJs) recapitulate processes observed during normal neuromuscular development in the green anole, Anolis carolinensis. Our data confirm robust axonal outgrowth during early stages of tail regeneration and subsequent NMJ formation within weeks of autotomy. Interestingly, NMJs are overproduced as evidenced by a persistent increase in NMJ density 120 and 250 days post autotomy (DPA). Substantial Myelin Basic Protein (MBP) expression could also be detected along regenerating nerves indicating that the ability of Schwann cells to myelinate newly formed axons remained intact. Overall, our data suggest that the mechanism of de novo nerve and NMJ reformation parallel, in part, those observed during neuromuscular development. However, the prolonged increase in NMJ number and aberrant muscle differentiation hint at processes specific to the adult response. An examination of the coordinated exchange between peripheral nerves, Schwann cells, and newly synthesized muscle of the regenerating neuromuscular system may assist in the identification of candidate molecules that promote neuromuscular recovery in organisms incapable of a robust regenerative response. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Evaluation of the impact of RNA preservation methods of spiders for de novo transcriptome assembly.

    Science.gov (United States)

    Kono, Nobuaki; Nakamura, Hiroyuki; Ito, Yusuke; Tomita, Masaru; Arakawa, Kazuharu

    2016-05-01

    With advances in high-throughput sequencing technologies, de novo transcriptome sequencing and assembly has become a cost-effective method to obtain comprehensive genetic information of a species of interest, especially in nonmodel species with large genomes such as spiders. However, high-quality RNA is essential for successful sequencing, and sample preservation conditions require careful consideration for the effective storage of field-collected samples. To this end, we report a streamlined feasibility study of various storage conditions and their effects on de novo transcriptome assembly results. The storage parameters considered include temperatures ranging from room temperature to -80°C; preservatives, including ethanol, RNAlater, TRIzol and RNAlater-ICE; and sample submersion states. As a result, intact RNA was extracted and assembly was successful when samples were preserved at low temperatures regardless of the type of preservative used. The assemblies as well as the gene expression profiles were shown to be robust to RNA degradation, when 30 million 150-bp paired-end reads are obtained. The parameters for sample storage, RNA extraction, library preparation, sequencing and in silico assembly considered in this work provide a guideline for the study of field-collected samples of spiders. © 2015 John Wiley & Sons Ltd.

  10. De novo centriole formation in human cells is error-prone and does not require SAS-6 self-assembly.

    Science.gov (United States)

    Wang, Won-Jing; Acehan, Devrim; Kao, Chien-Han; Jane, Wann-Neng; Uryu, Kunihiro; Tsou, Meng-Fu Bryan

    2015-11-26

    Vertebrate centrioles normally propagate through duplication, but in the absence of preexisting centrioles, de novo synthesis can occur. Consistently, centriole formation is thought to strictly rely on self-assembly, involving self-oligomerization of the centriolar protein SAS-6. Here, through reconstitution of de novo synthesis in human cells, we surprisingly found that normal looking centrioles capable of duplication and ciliation can arise in the absence of SAS-6 self-oligomerization. Moreover, whereas canonically duplicated centrioles always form correctly, de novo centrioles are prone to structural errors, even in the presence of SAS-6 self-oligomerization. These results indicate that centriole biogenesis does not strictly depend on SAS-6 self-assembly, and may require preexisting centrioles to ensure structural accuracy, fundamentally deviating from the current paradigm.

  11. Lethal Ultra-Early Subarachnoid Hemorrhage Due to Rupture of De Novo Aneurysm 5 Months After Primary Aneurysmatic Subarachnoid Hemorrhage.

    Science.gov (United States)

    Walter, Johannes; Unterberg, Andreas W; Zweckberger, Klaus

    2018-05-01

    Approximately 1% of all patients surviving rupture of a cerebral aneurysm suffer from a second aneurysmatic subarachnoid hemorrhage later in their lives, 61% of which are caused by rupture of a de novo aneurysm. Latency between bleedings is usually many years, and younger patients tend to achieve better outcomes from a second subarachnoid hemorrhage. We report an unusual case of lethal ultra-early rupture of a de novo aneurysm of the anterior communicating artery only 5 months after the initial subarachnoid hemorrhage and complete coiling in a young, healthy male patient. Despite complete aneurysm obliteration, young age, and good recovery, patients may be subjected to secondary subarachnoid hemorrhages from de novo aneurysms after only a few months of the initial bleeding. Early-control magnetic resonance angiography might hence be advisable. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells

    KAUST Repository

    Takahashi, Yuta

    2017-05-05

    CpG islands (CGIs) are primarily promoter-associated genomic regions and are mostly unmethylated within highly methylated mammalian genomes. The mechanisms by which CGIs are protected from de novo methylation remain elusive. Here we show that insertion of CpG-free DNA into targeted CGIs induces de novo methylation of the entire CGI in human pluripotent stem cells (PSCs). The methylation status is stably maintained even after CpG-free DNA removal, extensive passaging, and differentiation. By targeting the DNA mismatch repair gene MLH1 CGI, we could generate a PSC model of a cancer-related epimutation. Furthermore, we successfully corrected aberrant imprinting in induced PSCs derived from an Angelman syndrome patient. Our results provide insights into how CpG-free DNA induces de novo CGI methylation and broaden the application of targeted epigenome editing for a better understanding of human development and disease.

  13. Autosomal dominant cutis laxa with progeroid features due to a novel, de novo mutation in ALDH18A1.

    Science.gov (United States)

    Bhola, Priya T; Hartley, Taila; Bareke, Eric; Boycott, Kym M; Nikkel, Sarah M; Dyment, David A

    2017-06-01

    De novo dominant mutations in the aldehyde dehydrogenase 18 family member A1 (ALDH18A1) gene have recently been shown to cause autosomal dominant cutis laxa with progeroid features (MIM 616603). To date, all de novo dominant mutations have been found in a single highly conserved amino acid residue at position p.Arg138. We report an 8-year-old male with a clinical diagnosis of autosomal dominant cutis laxa (ADCL) with progeroid features and a novel de novo missense mutation in ALDH18A1 (NM_002860.3: c.377G>A (p.Arg126His)). This is the first report of an individual with ALDH18A1-ADCL due to a substitution at a residue other than p.Arg138. Knowledge of the complete spectrum of dominant-acting mutations that cause this rare syndrome will have implications for molecular diagnosis and genetic counselling of these families.

  14. Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages.

    Science.gov (United States)

    Rangel-Salazar, Rubén; Wickström-Lindholm, Marie; Aguilar-Salinas, Carlos A; Alvarado-Caudillo, Yolanda; Døssing, Kristina B V; Esteller, Manel; Labourier, Emmanuel; Lund, Gertrud; Nielsen, Finn C; Rodríguez-Ríos, Dalia; Solís-Martínez, Martha O; Wrobel, Katarzyna; Wrobel, Kazimierz; Zaina, Silvio

    2011-11-25

    We previously showed that a VLDL- and LDL-rich mix of human native lipoproteins induces a set of repressive epigenetic marks, i.e. de novo DNA methylation, histone 4 hypoacetylation and histone 4 lysine 20 (H4K20) hypermethylation in THP-1 macrophages. Here, we: 1) ask what gene expression changes accompany these epigenetic responses; 2) test the involvement of candidate factors mediating the latter. We exploited genome expression arrays to identify target genes for lipoprotein-induced silencing, in addition to RNAi and expression studies to test the involvement of candidate mediating factors. The study was conducted in human THP-1 macrophages. Native lipoprotein-induced de novo DNA methylation was associated with a general repression of various critical genes for macrophage function, including pro-inflammatory genes. Lipoproteins showed differential effects on epigenetic marks, as de novo DNA methylation was induced by VLDL and to a lesser extent by LDL, but not by HDL, and VLDL induced H4K20 hypermethylation, while HDL caused H4 deacetylation. The analysis of candidate factors mediating VLDL-induced DNA hypermethylation revealed that this response was: 1) surprisingly, mediated exclusively by the canonical maintenance DNA methyltransferase DNMT1, and 2) independent of the Dicer/micro-RNA pathway. Our work provides novel insights into epigenetic gene regulation by native lipoproteins. Furthermore, we provide an example of DNMT1 acting as a de novo DNA methyltransferase independently of canonical de novo enzymes, and show proof of principle that de novo DNA methylation can occur independently of a functional Dicer/micro-RNA pathway in mammals.

  15. Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages

    Directory of Open Access Journals (Sweden)

    Rangel-Salazar Rubén

    2011-11-01

    Full Text Available Abstract Background We previously showed that a VLDL- and LDL-rich mix of human native lipoproteins induces a set of repressive epigenetic marks, i.e. de novo DNA methylation, histone 4 hypoacetylation and histone 4 lysine 20 (H4K20 hypermethylation in THP-1 macrophages. Here, we: 1 ask what gene expression changes accompany these epigenetic responses; 2 test the involvement of candidate factors mediating the latter. We exploited genome expression arrays to identify target genes for lipoprotein-induced silencing, in addition to RNAi and expression studies to test the involvement of candidate mediating factors. The study was conducted in human THP-1 macrophages. Results Native lipoprotein-induced de novo DNA methylation was associated with a general repression of various critical genes for macrophage function, including pro-inflammatory genes. Lipoproteins showed differential effects on epigenetic marks, as de novo DNA methylation was induced by VLDL and to a lesser extent by LDL, but not by HDL, and VLDL induced H4K20 hypermethylation, while HDL caused H4 deacetylation. The analysis of candidate factors mediating VLDL-induced DNA hypermethylation revealed that this response was: 1 surprisingly, mediated exclusively by the canonical maintenance DNA methyltransferase DNMT1, and 2 independent of the Dicer/micro-RNA pathway. Conclusions Our work provides novel insights into epigenetic gene regulation by native lipoproteins. Furthermore, we provide an example of DNMT1 acting as a de novo DNA methyltransferase independently of canonical de novo enzymes, and show proof of principle that de novo DNA methylation can occur independently of a functional Dicer/micro-RNA pathway in mammals.

  16. De novo status epilepticus is associated with adverse outcome: An 11-year retrospective study in Hong Kong.

    Science.gov (United States)

    Lui, Hoi Ki Kate; Hui, Kwok Fai; Fong, Wing Chi; Ip, Chun Tak; Lui, Hiu Tung Colin

    2016-08-01

    To identify predictors of poor clinical outcome in patients presenting to the intensive care units with status epilepticus (SE), in particular for patients presenting with de novo status epileptics. A retrospective review was performed on patients admitted to the intensive care units with status epilepticus in two hospitals in Hong Kong over an 11-year period from 2003 to 2013. A total of 87 SE cases were analyzed. The mean age of patients was 49.3 years (SD 14.9 years). Eighteen subjects (20.7%) had breakthrough seizure, which was the most common etiology for the status epilepticus episodes. Seventy-eight subjects (89.7%) had convulsive status epilepticus (CSE) and 9 subjects (10.3%) had non-convulsive status epilepticus (NCSE) on presentation. The 30-day mortality rate of all subjects was 18.4%. Non-convulsive status epilepticus was more common in patients with de novo status epilepticus when compared to those with existing history of epilepsy (15.5% Vs. 0%, p=0.03). Patients with de novo status epilepticus were older (52 Vs 43, p=0.009). De novo status epilepticus was associated with longer status duration (median 2.5 days, IQR 5 days), longer ICU stay (median 7.5 days, IQR 9 days) and poorer outcome (OR 4.15, 95% CI 1.53-11.2). For patients presenting to intensive care units with status epilepticus, those with de novo status epileptics were older and were more likely to develop non-convulsive status epilepticus. De novo status epilepticus was associated with poorer outcome. Continuous EEG monitoring would help identifying NCSE and potentially help improving clinical outcomes. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  17. De novo assembly and characterization of the transcriptome, and development of SSR markers in wax gourd (Benicasa hispida.

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    Biao Jiang

    Full Text Available BACKGROUND: Wax gourd is a widely used vegetable of Cucuribtaceae, and also has important medicinal and health values. However, the genomic resources of wax gourd were scarcity, and only a few nucleotide sequences could be obtained in public databases. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we examined transcriptome in wax gourd. More than 44 million of high quality reads were generated from five different tissues of wax gourd using Illumina paired-end sequencing technology. Approximately 4 Gbp data were generated, and de novo assembled into 65,059 unigenes, with an N50 of 1,132 bp. Based on sequence similarity search with known protein database, 36,070 (55.4% showed significant similarity to known proteins in Nr database, and 24,969 (38.4% had BLAST hits in Swiss-Prot database. Among the annotated unigenes, 14,994 of wax gourd unigenes were assigned to GO term annotation, and 23,977 were found to have COG classifications. In addition, a total of 18,713 unigenes were assigned to 281 KEGG pathways. Furthermore, 6,242 microsatellites (simple sequence repeats were detected as potential molecular markers in wax gourd. Two hundred primer pairs for SSRs were designed for validation of the amplification and polymorphism. The result showed that 170 of the 200 primer pairs were successfully amplified and 49 (28.8% of them exhibited polymorphisms. CONCLUSION/SIGNIFICANCE: Our study enriches the genomic resources of wax gourd and provides powerful information for future studies. The availability of this ample amount of information about the transcriptome and SSRs in wax gourd could serve as valuable basis for studies on the physiology, biochemistry, molecular genetics and molecular breeding of this important vegetable crop.

  18. De novo assembly, gene annotation, and marker discovery in stored-product pest Liposcelis entomophila (Enderlein using transcriptome sequences.

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    Dan-Dan Wei

    Full Text Available BACKGROUND: As a major stored-product pest insect, Liposcelis entomophila has developed high levels of resistance to various insecticides in grain storage systems. However, the molecular mechanisms underlying resistance and environmental stress have not been characterized. To date, there is a lack of genomic information for this species. Therefore, studies aimed at profiling the L. entomophila transcriptome would provide a better understanding of the biological functions at the molecular levels. METHODOLOGY/PRINCIPAL FINDINGS: We applied Illumina sequencing technology to sequence the transcriptome of L. entomophila. A total of 54,406,328 clean reads were obtained and that de novo assembled into 54,220 unigenes, with an average length of 571 bp. Through a similarity search, 33,404 (61.61% unigenes were matched to known proteins in the NCBI non-redundant (Nr protein database. These unigenes were further functionally annotated with gene ontology (GO, cluster of orthologous groups of proteins (COG, and Kyoto Encyclopedia of Genes and Genomes (KEGG databases. A large number of genes potentially involved in insecticide resistance were manually curated, including 68 putative cytochrome P450 genes, 37 putative glutathione S-transferase (GST genes, 19 putative carboxyl/cholinesterase (CCE genes, and other 126 transcripts to contain target site sequences or encoding detoxification genes representing eight types of resistance enzymes. Furthermore, to gain insight into the molecular basis of the L. entomophila toward thermal stresses, 25 heat shock protein (Hsp genes were identified. In addition, 1,100 SSRs and 57,757 SNPs were detected and 231 pairs of SSR primes were designed for investigating the genetic diversity in future. CONCLUSIONS/SIGNIFICANCE: We developed a comprehensive transcriptomic database for L. entomophila. These sequences and putative molecular markers would further promote our understanding of the molecular mechanisms underlying

  19. Utilization of marble from Bejui mine - Currais Novos/RN in ceramic mass; Analise da incorporacao de marmore da mina Brejui - Currais Novos/RN na massa ceramica

    Energy Technology Data Exchange (ETDEWEB)

    Farias, D.S.U. de; Souza, M.M. de; Almeida, A.B.D. de; Lima, T.C. de; Nobrega, L.F.P. de M. [Instituto Federal de Ciencia e Tecnologia do Rio Grande do Norte (IFRN), Natal, RN (Brazil); Mendes, L.B., E-mail: debora_suf_00@hotmail.com [Fundacao de Apoio a Pesquisa do Rio Grande do Norte (FAPERN), Natal RN (Brazil)

    2016-07-01

    Mining in Mine Brejui, in Currais Novos - RN, is related to the extraction of scheelite, however the marble of the region is not fully tapped. Aiming to provide a utility to this carbonate rock very abundant in the Serido region, this work is to evaluate, from its chemical and other tests, the addition of marble in the ceramic mass. For the analysis, the samples were collected, then comminuted and sieved to #200 and, right after, characterized by fluorescence X-ray method (FRX). The results indicate a high concentration of CaO (95%), a flux element, and very low content of Fe{sub 2}O{sub 3} and SO{sub 3} (less than 0.6%). After produced the samples, there were performed the water absorption tests and linear shrinkage, which has indicate satisfactory results and classifying them as porcelain. Therefore, with the significant potential of the marble, other laboratory tests may be performed to analyze its incorporation in the formulation of ceramic bodies, being economically viable and adding proper use and commercial value to the rock. (author)

  20. Produtividade e rendimento das duas classes de plantas existentes no Café "Mundo Novo" Fruit and seed yields of two classes of Mundo Novo coffee plants

    Directory of Open Access Journals (Sweden)

    A. J. T. Mendes

    1955-01-01

    Full Text Available Dados já publicados sobre produção de frutos e rendimento em sementes, de progênies do café Mundo Novo, foram reclassificados com base na existência de duas classes distintas de plantas : a aquelas heterozigotas (Dd, em que há ocorrência de endosperma discóide e conseqüente formação de maior quantidade de frutos chochos ; e b aquelas homozigotas (DD em que o endosperma é normal e por conseguinte os frutos são normais. Verificou-se que o peso da produção em frutos das plantas Dd é, em média, maior que o das plantas DD. A ocorrência do endosperma discóide, no entanto, acarreta um rendimento menor em sementes, para igual peso de frutos. O resultado final em peso de sementes chega a pender em favor das plantas DD, sem, no entanto, haver uma diferença estatisticamente significativa. A existência de plantas Dd nos cafezais é, portanto, prejudicial, uma vez que, para produzir mais frutos elas retiram maior quantidade de elementos minerais do solo ; a maior produção exige maior mão de obra na colheita ; e o pêso do produto final, café beneficiado, não é compensador, pois não é superior ao das plantas DD. As fontes de sementes são várias, atualmente ; se o fornecedor não faz qualquer seleção, as plantas com o defeito tendem a diminuir ; se o fornecedor, imaginando que faz seleção, escolhe as plantas aparentemente mais produtivas, o defeito aumentará na nova plantação ; se o fornecedor das sementes leva em consideração a produtividade e ao mesmo tempo a não ocorrência de frutos chochos, a nova plantação estará pràticamente isenta do defeito. Sómente as sementes certificadas pelo Instituto Agronômico apresentam a garantia de produzir exclusivamente plantas DD.Evidence presented in previous papers indicated that two classes of plants are present in ordinary populations of Mundo Novo coffee (Coffea arabica L. : a heterozygotes (Dd in which the occurrence of "discoid endosperm" is responsible for the

  1. A SA8000 e a responsabilidade social das empresas: a emergência de um novo paradigma?

    OpenAIRE

    Lopes, Ana Catarina Marques Figueiredo Caetano

    2004-01-01

    Mestrado em Desenvolvimento e Cooperação Internacional A Responsabilidade Social das Empresas, não é um tema novo. Durante muito tempo foi discutido e interpretado no âmbito do debate sobre as responsabilidades que uma empresa deve assumir para além daquelas que tem perante os seus accionistas, e das impostas por lei. Hoje, observamos a emergência de um novo paradigma assente no reconhecimento que o sector privado não só pode, mas deve, fazer mais para combater a pobreza, preservar o meio ...

  2. NOVOS PRODUTOS SOB O ENFOQUE DO SISTEMA DE CONSUMO E A ORIENTAÇÃO PARA O MERCADO

    OpenAIRE

    Mauro Calixta Tavares; Valéria Braga Pinto

    2009-01-01

    A orientação para o mercado tem sido abordada com suas possíveis implicações na estrutura, processos, pessoas, desenvolvimento de novos produtos, inovação e flexibilidade estratégica, entre outras possibilidades. O foco do presente capítulo é sobre sua relação com novos produtos sob a perspectiva de sistema de consumo. A partir de um estudo exploratório, os alunos de um programa de MBA, divididos em grupos, realizaram um trabalho envolvendo o consumo de vários produtos e serviços sob a perspe...

  3. Para além do lumpen-indigenismo: novos aspectos informacionais da política indigenista brasileira

    Directory of Open Access Journals (Sweden)

    Rodrigo Piquet Saboia de Mello

    2017-06-01

    Full Text Available O artigo em tela propõe uma releitura do artigo intitulado “O lumpen-indigenismo do estado brasileiro” do antropólogo Jorge Pozzobon tendo por objetivo reelaborar alguns conceitos e propostas do autor em tempo outrora, assim como estabelecer uma ponte para os novos fenômenos informacionais que advém do conjunto político-jurídico hodierno, assim como no fortalecimento do protagonismo indígena na construção de novos modelos de participação e gerenciamento da informação indígena.

  4. Estudo do mecanismo de ação de novos compostos de ruténio com atividade antitumoral

    OpenAIRE

    Carvalho, Andreia Catarina Guerreiro Morais de

    2017-01-01

    Tese de mestrado, Bioquímica (Bioquímica Médica), Universidade de Lisboa, Faculdade de Ciências, 2017 A quimioterapia é um tratamento tradicional do cancro. Sua alta toxicidade, afetando tecidos saudáveis, e a resistência intrínseca a fármacos são obstáculos que precisam de ser superados. Desta forma, a identificação de novos agentes quimioterapêuticos é fundamental para novos progressos no tratamento do cancro. Uma abordagem inclui complexos de ruténio, que foram reconhecidos como uma alt...

  5. Desenvolvimento de um novo produto cerâmico para pavimentação de passeios e áreas públicas

    Directory of Open Access Journals (Sweden)

    Lilian Lima Dias

    Full Text Available Resumo Mobilidade e segurança são temas cada vez mais discutidos nos grandes centros urbanos, e as iniciativas nesse universo devem prever soluções práticas e econômicas, que gerem benefícios para os cidadãos. O pavimento, um dos fatores para a qualidade urbana, é a via de acesso indispensável para garantir o direito de ir e vir. Entre as soluções, o pavimento intertravado se destaca como um dos produtos mais recomendados na pavimentação das calçadas e áreas públicas. Em países da Europa e da América Latina a pavimentação com sistemas intertravados de cerâmicas é amplamente utilizada, porém essa prática ainda é pouco observada no Brasil, pela inexistência desse produto no mercado local. Desse modo, o objetivo deste projeto foi o desenvolvimento de pavimentos intertravados de cerâmica visando ao uso em passeios e áreas públicas. Também foram adicionados ao novo produto desenvolvido resíduos queimados oriundos do próprio processo de fabricação, os quais são chamados de cacos ou chamote, para diminuir a quantidade de material a ser descartado no meio ambiente. Após os resultados positivos na caracterização dos produtos, foram criados novos designs para essa tipologia de produtos, os quais foram produzidos em escala laboratorial.

  6. Analysis of pyrimidine synthesis "de novo" intermediates in urine and dried urine filter- paper strips with HPLC-electrospray tandem mass spectrometry

    NARCIS (Netherlands)

    van Kuilenburg, André B. P.; van Lenthe, Henk; Löffler, Monika; van Gennip, Albert H.

    2004-01-01

    BACKGROUND: The concentrations of the pyrimidine "de novo" metabolites and their degradation products in urine are useful indicators for the diagnosis of an inborn error of the pyrimidine de novo pathway or a urea-cycle defect. Until now, no procedure was available that allowed the analysis of all

  7. De novo origin of VCY2 from autosome to Y-transposed amplicon.

    Directory of Open Access Journals (Sweden)

    Peng-Rong Cao

    Full Text Available The formation of new genes is a primary driving force of evolution in all organisms. The de novo evolution of new genes from non-protein-coding genomic regions is emerging as an important additional mechanism for novel gene creation. Y chromosomes underlie sex determination in mammals and contain genes that are required for male-specific functions. In this study, a search was undertaken for Y chromosome de novo genes derived from non-protein-coding sequences. The Y chromosome orphan gene variable charge, Y-linked (VCY2, is an autosome-derived gene that has sequence similarity to large autosomal fragments but lacks an autosomal protein-coding homolog. VCY2 locates in the amplicon containing long DNA fragments that were transposed from autosomes to the Y chromosome before the ape-monkey split. We confirmed that VCY2 cannot be encoded by autosomes due to the presence of multiple disablers that disrupt the open reading frame, such as the absence of start or stop codons and the presence of premature stop codons. Similar observations have been made for homologs in the autosomes of the chimpanzee, gorilla, rhesus macaque, baboon and out-group marmoset, which suggests that there was a non-protein-coding ancestral VCY2 that was common to apes and monkeys that predated the transposition event. Furthermore, while protein-coding orthologs are absent, a putative non-protein-coding VCY2 with conserved disablers was identified in the rhesus macaque Y chromosome male-specific region. This finding implies that VCY2 might have not acquired its protein-coding ability before the ape-monkey split. VCY2 encodes a testis-specific expressed protein and is involved in the pathologic process of male infertility, and the acquisition of this gene might improve male fertility. This is the first evidence that de novo genes can be generated from transposed autosomal non-protein-coding segments, and this evidence provides novel insights into the evolutionary history of the Y

  8. De novo hepatic steatosis drives atherogenic risk in liver transplantation recipients.

    Science.gov (United States)

    Idowu, Michael O; Chhatrala, Ravi; Siddiqui, M Bilal; Driscoll, Carolyn; Stravitz, R Todd; Sanyal, Arun J; Bhati, Chandra; Sargeant, Carol; Luketic, Velimir A; Sterling, Richard K; Contos, Melissa; Matherly, Scott; Puri, Puneet; Siddiqui, M Shadab

    2015-11-01

    Nonalcoholic fatty liver disease is associated with cardiovascular disease (CVD) in the general population. Despite a high prevalence of de novo hepatic steatosis after liver transplantation (LT), there are no data exploring the association between hepatic steatosis after LT and atherogenic risk. The aim of the study was to explore the impact of hepatic steatosis on serum atherogenic markers in liver transplantation recipients (LTRs). Biomarkers of CVD risk were compared in 89 LTRs with no known history of dyslipidemia, ischemic heart disease, or graft cirrhosis. To avoid potential confounders, LTRs on oral hypoglycemic agents, exogenous insulin, corticosteroids, or lipid-lowering therapy were excluded. Only patients for whom histological assessment was available after LT were included in the study. Thirty-five LTRs had de novo hepatic steatosis after LT, whereas 54 did not. Both cohorts were similar with regards to age, sex, ethnicity, and follow-up from LT. Additionally, the traditional lipid profile was similar between the 2 cohorts. LTRs with hepatic steatosis had higher serum concentrations of small-dense low-density lipoprotein cholesterol (sdLDL-C; 34.8 ± 16.9 versus 22.7 ± 11.2 mg/dL; P hepatic steatosis had higher serum insulin concentrations (27.8 ± 41.8 versus 11.7 ± 7.8 uU/mL; P Steatosis grade was directly related to sdLDL-C, sdLDL-P, insulin, VLDL-P, and VLDL-size. In multivariate analysis, the association between steatosis grade and sdLDL-C (β = 0.03; P = 0.029), VLDL-size (β = 0.316; P = 0.04), and low-density lipoprotein particle size (β = -0.27; P = 0.05) was independent of sex, body mass index, age, diabetes mellitus, time from transplant, and indication for LT. In conclusion, de novo hepatic steatosis after LT is associated with atherogenic lipoproteins and independent of traditional CVD risk factors. © 2015 American Association for the Study of Liver Diseases.

  9. De Novo Nodal Diffuse Large B-Cell Lymphoma: Identification of Biologic Prognostic Factors

    International Nuclear Information System (INIS)

    Abd El-Hameed, A.

    2005-01-01

    Diffuse large B-cell Lymphoma (DLBCL) represents the most frequent type of non-Hodgkin lymphoma (NHL). Although combination chemotherapy has improved the outcome, long-term cure is now possible for approximately 50% of all patients. making the search for parameters identifying patients at high risk particularly needed. The presence of bcl-2 gene rearrangement in de novo DLBCL suggests a possible follicle center cell origin and perhaps a distinct clinical behavior. This study investigated the frequency and prognostic significance of t( 14; 18) translocation and bcl-2 protein overexpression in a cohort of patients with de novo nodal DLBCL who where uniformly evaluated and treated. Material and Methods: A total of 40 patients with de novo nodal DLBCL treated at National Cancer Institute (NCI), Cairo University were investigated. Formal infixed, paraffin-embedded sections were analyzed for: I) bcl-2 gene rearrangement including major break point region (mbr) and minor cluster region (mcr) by polymerase chain reaction (PCR). and 2) bcl-2 protein expression by immunohistochemistry using Dako 124 clone. Results were correlated with the clinical features and subsequent clinical course. Bcl-2 gene rearrangement was detected in 8 cases (20%). 2 cases at mbr, and 6 cases at mcr. Bcl-2 protein (> I 0%) was expressed in 24 cases (60%), irrespective of the presence of t( 14; 18) translocation. The t( 14; 18), and bcl-2 protein overexpression were more frequently associated with failure to achieve a complete response to therapy (ρ=0.008. and 0.04. respectively). DLBCL patients with t(14;18), and bcl-2 protein expression had a significantly reduced 5-year disease free survival (ρ=0.04, and 0.01, respectively). The t( 14; 18) translocation, and bcl-2 protein expression define a group of DLBCL patients with a poor prognosis, and could be used to tailor treatment, and to identify candidates for therapeutic approaches. Geographic differences in t(14;18) may be related to the

  10. De novo formation of left-right asymmetry by posterior tilt of nodal cilia.

    Directory of Open Access Journals (Sweden)

    Shigenori Nonaka

    2005-08-01

    Full Text Available In the developing mouse embryo, leftward fluid flow on the ventral side of the node determines left-right (L-R asymmetry. However, the mechanism by which the rotational movement of node cilia can generate a unidirectional flow remains hypothetical. Here we have addressed this question by motion and morphological analyses of the node cilia and by fluid dynamic model experiments. We found that the cilia stand, not perpendicular to the node surface, but tilted posteriorly. We further confirmed that such posterior tilt can produce leftward flow in model experiments. These results strongly suggest that L-R asymmetry is not the descendant of pre-existing L-R asymmetry within each cell but is generated de novo by combining three sources of spatial information: antero-posterior and dorso-ventral axes, and the chirality of ciliary movement.

  11. A Tissue-Mapped Axolotl De Novo Transcriptome Enables Identification of Limb Regeneration Factors

    Directory of Open Access Journals (Sweden)

    Donald M. Bryant

    2017-01-01

    Full Text Available Mammals have extremely limited regenerative capabilities; however, axolotls are profoundly regenerative and can replace entire limbs. The mechanisms underlying limb regeneration remain poorly understood, partly because the enormous and incompletely sequenced genomes of axolotls have hindered the study of genes facilitating regeneration. We assembled and annotated a de novo transcriptome using RNA-sequencing profiles for a broad spectrum of tissues that is estimated to have near-complete sequence information for 88% of axolotl genes. We devised expression analyses that identified the axolotl orthologs of cirbp and kazald1 as highly expressed and enriched in blastemas. Using morpholino anti-sense oligonucleotides, we find evidence that cirbp plays a cytoprotective role during limb regeneration whereas manipulation of kazald1 expression disrupts regeneration. Our transcriptome and annotation resources greatly complement previous transcriptomic studies and will be a valuable resource for future research in regenerative biology.

  12. De Novo transcriptome assembly of Zingiber officinale cv. Suruchi of Odisha.

    Science.gov (United States)

    Gaur, Mahendra; Das, Aradhana; Sahoo, Rajesh Kumar; Kar, Basudeba; Nayak, Sanghamitra; Subudhi, Enketeswara

    2016-09-01

    Zingiber officinale Rosc., known as ginger, is an Asian crop, popularly used in every household kitchen and commercially used in bakery, beverage, food and pharmaceutical industries. The present study deals with de novo transcriptome assembly of an elite ginger cultivar Suruchi by next generation sequencing methodology. From the analysis 10.9 GB raw data was obtained which can be available in NCBI accession number SAMN03761185. We identified 41,969 transcripts using Trinity RNA-Seq from ginger rhizome of Suruchi variety from Odisha. The transcript length varied from 300 bp to 8404 bp with a total length of 3,96,40,526 bp and N50 of 1251 bp. To the best of our knowledge, this is the first transcriptome data of an elite ginger cultivar Suruchi released for Odisha state of India which will help molecular biologists to develop genetic markers for identification of cultivars.

  13. The sequence and de novo assembly of the giant panda genome

    Science.gov (United States)

    Li, Ruiqiang; Fan, Wei; Tian, Geng; Zhu, Hongmei; He, Lin; Cai, Jing; Huang, Quanfei; Cai, Qingle; Li, Bo; Bai, Yinqi; Zhang, Zhihe; Zhang, Yaping; Wang, Wen; Li, Jun; Wei, Fuwen; Li, Heng; Jian, Min; Li, Jianwen; Zhang, Zhaolei; Nielsen, Rasmus; Li, Dawei; Gu, Wanjun; Yang, Zhentao; Xuan, Zhaoling; Ryder, Oliver A.; Leung, Frederick Chi-Ching; Zhou, Yan; Cao, Jianjun; Sun, Xiao; Fu, Yonggui; Fang, Xiaodong; Guo, Xiaosen; Wang, Bo; Hou, Rong; Shen, Fujun; Mu, Bo; Ni, Peixiang; Lin, Runmao; Qian, Wubin; Wang, Guodong; Yu, Chang; Nie, Wenhui; Wang, Jinhuan; Wu, Zhigang; Liang, Huiqing; Min, Jiumeng; Wu, Qi; Cheng, Shifeng; Ruan, Jue; Wang, Mingwei; Shi, Zhongbin; Wen, Ming; Liu, Binghang; Ren, Xiaoli; Zheng, Huisong; Dong, Dong; Cook, Kathleen; Shan, Gao; Zhang, Hao; Kosiol, Carolin; Xie, Xueying; Lu, Zuhong; Zheng, Hancheng; Li, Yingrui; Steiner, Cynthia C.; Lam, Tommy Tsan-Yuk; Lin, Siyuan; Zhang, Qinghui; Li, Guoqing; Tian, Jing; Gong, Timing; Liu, Hongde; Zhang, Dejin; Fang, Lin; Ye, Chen; Zhang, Juanbin; Hu, Wenbo; Xu, Anlong; Ren, Yuanyuan; Zhang, Guojie; Bruford, Michael W.; Li, Qibin; Ma, Lijia; Guo, Yiran; An, Na; Hu, Yujie; Zheng, Yang; Shi, Yongyong; Li, Zhiqiang; Liu, Qing; Chen, Yanling; Zhao, Jing; Qu, Ning; Zhao, Shancen; Tian, Feng; Wang, Xiaoling; Wang, Haiyin; Xu, Lizhi; Liu, Xiao; Vinar, Tomas; Wang, Yajun; Lam, Tak-Wah; Yiu, Siu-Ming; Liu, Shiping; Zhang, Hemin; Li, Desheng; Huang, Yan; Wang, Xia; Yang, Guohua; Jiang, Zhi; Wang, Junyi; Qin, Nan; Li, Li; Li, Jingxiang; Bolund, Lars; Kristiansen, Karsten; Wong, Gane Ka-Shu; Olson, Maynard; Zhang, Xiuqing; Li, Songgang; Yang, Huanming; Wang, Jian; Wang, Jun

    2013-01-01

    Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes. PMID:20010809

  14. The NOVO Network: the original scientific basis for its establishment and our R&D vision

    DEFF Research Database (Denmark)

    Winkel, Jørgen; Edwards, Kasper; Dellve, L.

    2017-01-01

    Systems” in the healthcare sector. It was founded in 2006 in Copenhagen and was financially supported by the Nordic Council of Ministers from 2007 to 2015. The motivation to establish the NOVO Network arose when reviewing the literature regarding opportunities to create sustainable production systems....... This work was initiated year 2002 and resultet in a systematic review published 2011 (Westgaard and Winkel 2011). Already in 2006 it was concluded that ergonomic interventions have limited musculoskeletal and mental health effects in a long-range perspective while rationalization has predominant negative...... be challenged due to the frequent negative impact of rationalization on ergonomics and vice versa. This call for dialogue processes between the stakeholders taking more holistic systems perspectives. Dialogue-based change processes may be more common in the Nordic countries compared to other parts of the world...

  15. O novo paradigma da violência The new paradigm of violence

    Directory of Open Access Journals (Sweden)

    Michel Wieviorka

    1997-05-01

    Full Text Available O autor procura redimensionar o conceito de violência dentro do atual estado de globalização mundial. Crise internacional, narcotráfico, derrocada do bloco socialista no leste europeu, políticas assistenciais de organismos internacionais, conceitos de desenvolvimento e de subdesenvolvimento, terrorismo, sectarismo político e religioso, novas conceituações culturais e sociais são temas trabalhados pelo autor com vistas ao estabelecimento de um novo paradigma da violência.The author tries to requalify the concept of violence under the influences of a context of world globalization. International crisis, drug traffic, collapse of the socialist governments, concepts of development and under-development, terrorism, political and religious sectarisms, new culture and social conceptualizations, these are some of the themes which are discussed by the author with the objective to propose a new pardigm for violence.

  16. Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient.

    Science.gov (United States)

    Kajtár, Béla; Rajnics, Péter; Egyed, Miklós; Alizadeh, Hussain

    2015-01-01

    The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature. © 2015 by the Association of Clinical Scientists, Inc.

  17. Paternal Age Explains a Major Portion of De Novo Germline Mutation Rate Variability in Healthy Individuals.

    Directory of Open Access Journals (Sweden)

    Simon L Girard

    Full Text Available De novo mutations (DNM are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots.

  18. De novo activating epidermal growth factor mutations (EGFR) in small-cell lung cancer.

    Science.gov (United States)

    Thai, Alesha; Chia, Puey L; Russell, Prudence A; Do, Hongdo; Dobrovic, Alex; Mitchell, Paul; John, Thomas

    2017-09-01

    In Australia, mutations in epidermal growth factor mutations (EGFR) occur in 15% of patients diagnosed with non-small-cell lung cancer and are found with higher frequency in female, non-smokers of Asian ethnicity. Activating mutations in the EGFR gene are rarely described in SCLC. We present two cases of de novo EGFR mutations in patients with SCLC detected in tissue and in plasma cell free DNA, both of whom were of Asian ethnicity and never-smokers. These two cases add to the growing body of evidence suggesting that screening for EGFR mutations in SCLC should be considered in patients with specific clinical features. © 2017 Royal Australasian College of Physicians.

  19. Novos realismos e o risco da ficção

    Directory of Open Access Journals (Sweden)

    Vera Lúcia Follain de Figueiredo

    2010-01-01

    Full Text Available Entre as correntes teóricas contemporâneas, há uma tendência em considerar que a função da imagem midiática já não é imitar, nem sequer fazer-se passar pela realidade, mas substituir o próprio mundo real. Tal pensamento tem aberto caminho para a valorização de narrativas que parecem retratar, espontaneamente, cenas de um “real autêntico”. Partindo desse ponto, o texto discute a crise da ficção e os novos realismos, indagando quais os parâmetros utilizados, em nossos dias, quando se classifica um texto como realista.

  20. A chloroplast pathway for the de novo biosynthesis of triacylglycerol in Chlamydomonas reinhardtii

    Energy Technology Data Exchange (ETDEWEB)

    Fan, J.; Xu, C.; Andre, C.

    2011-06-23

    Neutral lipid metabolism has been extensively studied in yeast, plants and mammals. In contrast, little information is available regarding the biochemical pathway, enzymes and regulatory factors involved in the biosynthesis of triacylglycerol (TAG) in microalgae. In the conventional TAG biosynthetic pathway widely accepted for yeast, plants and mammals, TAG is assembled in the endoplasmic reticulum (ER) from its immediate precursor diacylglycerol (DAG) made by ER-specific acyltransferases, and is deposited exclusively in lipid droplets in the cytosol. Here, we demonstrated that the unicellular microalga Chlamydomonas reinhardtii employs a distinct pathway that uses DAG derived almost exclusively from the chloroplast to produce TAG. This unique TAG biosynthesis pathway is largely dependent on de novo fatty acid synthesis, and the TAG formed in this pathway is stored in lipid droplets in both the chloroplast and the cytosol. These findings have wide implications for understanding TAG biosynthesis and storage and other areas of lipid metabolism in microalgae and other organisms.

  1. De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive.

    Science.gov (United States)

    Tokita, Mari J; Braxton, Alicia A; Shao, Yunru; Lewis, Andrea M; Vincent, Marie; Küry, Sébastien; Besnard, Thomas; Isidor, Bertrand; Latypova, Xénia; Bézieau, Stéphane; Liu, Pengfei; Motter, Connie S; Melver, Catherine Ward; Robin, Nathaniel H; Infante, Elena M; McGuire, Marianne; El-Gharbawy, Areeg; Littlejohn, Rebecca O; McLean, Scott D; Bi, Weimin; Bacino, Carlos A; Lalani, Seema R; Scott, Daryl A; Eng, Christine M; Yang, Yaping; Schaaf, Christian P; Walkiewicz, Magdalena A

    2016-09-01

    SON is a key component of the spliceosomal complex and a critical mediator of constitutive and alternative splicing. Additionally, SON has been shown to influence cell-cycle progression, genomic integrity, and maintenance of pluripotency in stem cell populations. The clear functional relevance of SON in coordinating essential cellular processes and its presence in diverse human tissues suggests that intact SON might be crucial for normal growth and development. However, the phenotypic effects of deleterious germline variants in SON have not been clearly defined. Herein, we describe seven unrelated individuals with de novo variants in SON and propose that deleterious variants in SON are associated with a severe multisystem disorder characterized by developmental delay, persistent feeding difficulties, and congenital malformations, including brain anomalies. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy.

    Science.gov (United States)

    Vari, Maria Stella; Traverso, Monica; Bellini, Tommaso; Madia, Francesca; Pinto, Francesca; Minetti, Carlo; Striano, Pasquale; Zara, Federico

    2017-08-01

    Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and may be associated with acquired central nervous system lesions or could be genetic. Various susceptibility genes and environmental factors are believed to be involved in the aetiology of TLE, which is considered to be a heterogeneous, polygenic, and complex disorder. Rare point mutations in LGI1, DEPDC5, and RELN as well as some copy number variations (CNVs) have been reported in families with TLE patients. We perform a genetic analysis by Array-CGH in a patient with dysmorphic features and temporal lobe epilepsy. We report a de novo duplication of the long arm of chromosome 12. We confirm that 12q22-q23.3 is a candidate locus for familial temporal lobe epilepsy with febrile seizures and highlight the role of chromosomal rearrangements in patients with epilepsy and intellectual disability. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  3. Transcriptional regulator-mediated activation of adaptation genes triggers CRISPR de novo spacer acquisition

    DEFF Research Database (Denmark)

    Liu, Tao; Li, Yingjun; Wang, Xiaodi

    2015-01-01

    Acquisition of de novo spacer sequences confers CRISPR-Cas with a memory to defend against invading genetic elements. However, the mechanism of regulation of CRISPR spacer acquisition remains unknown. Here we examine the transcriptional regulation of the conserved spacer acquisition genes in Type I......, it was demonstrated that the transcription level of csa1, cas1, cas2 and cas4 was significantly enhanced in a csa3a-overexpression strain and, moreover, the Csa1 and Cas1 protein levels were increased in this strain. Furthermore, we demonstrated the hyperactive uptake of unique spacers within both CRISPR loci...... in the presence of the csa3a overexpression vector. The spacer acquisition process is dependent on the CCN PAM sequence and protospacer selection is random and non-directional. These results suggested a regulation mechanism of CRISPR spacer acquisition where a single transcriptional regulator senses the presence...

  4. Robust de novo pathway enrichment with KeyPathwayMiner 5 [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Nicolas Alcaraz

    2016-06-01

    Full Text Available Identifying functional modules or novel active pathways, recently termed de novo pathway enrichment, is a computational systems biology challenge that has gained much attention during the last decade. Given a large biological interaction network, KeyPathwayMiner extracts connected subnetworks that are enriched for differentially active entities from a series of molecular profiles encoded as binary indicator matrices. Since interaction networks constantly evolve, an important question is how robust the extracted results are when the network is modified. We enable users to study this effect through several network perturbation techniques and over a range of perturbation degrees. In addition, users may now provide a gold-standard set to determine how enriched extracted pathways are with relevant genes compared to randomized versions of the original network.

  5. Um novo modelo de previsão de demanda para inovações radicais

    Directory of Open Access Journals (Sweden)

    Donald Neumann

    2014-09-01

    Full Text Available Este trabalho apresenta um novo modelo para a previsão de demanda de inovações radicais baseada em simulação de Dinâmica de Sistemas que combina conceitos do modelo de difusão de Bass e do modelo de escolha discreta. Diferentemente de outras abordagens existentes, esta proposta permite estimar não somente a fatia de mercado do produto, mas também seu comportamento no tempo (timing, a partir das preferências individuais do consumidor e das forças que as influenciam. O modelo proposto pode ser facilmente parametrizado através da Conjoint Analysis e foi testado em escala real no mercado alemão de carros elétricos. Os resultados obtidos colocam em evidência o potencial da abordagem proposta, auxiliando na compreensão dos principais fatores na escolha desse produto.

  6. Marketing de Novos Produtos: Lançamento e Inovação

    Directory of Open Access Journals (Sweden)

    Adriana Conceicao Dutra

    2014-12-01

    Full Text Available Atualmente as empresas lançam um produto com o objetivo de permanecerem por mais tempo no mercado. Embora muitas empresas fracassassem ao lançarem um produto, seria um mito dizer que as maiorias dos novos produtos fracassam ou que seu sucesso vai de acordo com sua atratividade. A modernização traz consigo as premissas, a eficiência, a qualidade e a produtividade, que de certa forma impõem uma carga à sociedade como um todo. Superar as expectativas dos consumidores, por meio de produtos e serviços inovadores, assegura vantagens competitivas e permite às empresas a ocupação de posições de liderança, em mercados altamente competitivos.

  7. Pegylated interferon de novo-induce autoimmune haemolytic anaemia in chronic hepatitis C patient.

    Science.gov (United States)

    Said, Ashraf; Elbahrawy, Ashraf; Alfiomy, Mohamed; Abdellah, Mohamed; Shahat, Khaled; Salah, Mohamed; Mostafa, Sadek; Elwassief, Ahmed; Aboelfotoh, Attef; Abdelhafeez, Hafez; El-Sherif, Assem

    2011-08-11

    A 55-year-old Egyptian woman with chronic hepatitis C undergoing treatment with pegylated interferon (Peg-IFN) alfa-2a plus ribavirin was referred to our hospital on November 2010 with prolonged easy fatigability and an attack of syncope; she had no prior history of autoimmune disorders or allergy. Laboratory investigations documented the presence of Peg-IFN induced autoimmune haemolytic anaemia and autoimmune thyroiditis. Intravenous γ globulin (IVGG) failed to correct the autoimmune process; on the other hand steroid therapy dramatically corrected both haematological and thyroid values, and step down the immune process. Our report indicated that Peg-IFN de novo-induce autoimmune haemolysis, documenting a previous report. IVGG failed to step down the immune process in our case.

  8. De novo assembly and annotation of the Antarctic copepod (Tigriopus kingsejongensis) transcriptome.

    Science.gov (United States)

    Kim, Hui-Su; Lee, Bo-Young; Han, Jeonghoon; Lee, Young Hwan; Min, Gi-Sik; Kim, Sanghee; Lee, Jae-Seong

    2016-08-01

    The whole transcriptome of the Antarctic copepod (Tigriopus kingsejongensis) was sequenced using Illumina RNA-seq. De novo assembly was performed with 64,785,098 raw reads using Trinity, which assembled into 81,653 contigs. TransDecoder found 38,250 candidate coding contigs which showed homology to other species by BLAST analysis. Functional gene annotation was performed by Gene Ontology (GO), InterProScan, and KEGG pathway analyses. Finally, we identified a number of expressed gene catalog for T. kingsejongensis that is a useful model animal for gene information-based polar research to uncover molecular mechanisms of environmental adaptation on harsh environments. In particular, we observed highly developing lipid metabolism in T. kingsejongensis directly compared to those of the Far East Pacific coast copepod Tigriopus japonicus at the transcriptome level. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Anterior Abdominal Wall Leiomyoma Arising De Novo in a Perimenopausal Woman

    Directory of Open Access Journals (Sweden)

    Hamed A. Al-Wadaani

    2012-07-01

    Full Text Available Extrauterine or extraintestinal leiomyomas are extremely uncommon especially in the pre-peritoneal area or within the anterior abdominal wall muscles. These tumors have been ascribed to intraoperative seeding during resection of a fibroid or a leiomyoma of gut, to exogenous hormone replacement therapy or a major derangement of glucose and/or lipid metabolism. So far, there is no published report of de novo origin of anterior abdominal wall pure leiomyoma in the literature. The author herein reports a case of perimenopausal multiparous woman without any listing of previous gynecological surgery or hormone therapy who presented with a large pre-peritoneal intramuscular leiomyoma of the anterior abdominal wall. The patient underwent complete primary resection with amelioration of her symptoms.

  10. Prognostic factors in de novo myelodysplastic syndrome in young and middle-aged people

    Directory of Open Access Journals (Sweden)

    Наталья Николаевна Климкович

    2015-01-01

    Full Text Available We spent multivariate analysis of clinical and laboratory parameters for the prediction of de-novo myelodysplastic syndromes (MDS patients aged 18-60 years. The results of clinical application of prognostic systems in MDS show that there is a large variability within individual risk groups, especially at low-risk MDS. So now hematologists conduct research aimed at identifying additional adverse risk MDS. This is done so that patients with low-risk MDS embodiments and unfavorable prognosis could benefit from early therapeutic intervention, and not only be clinician monitored until disease progression. We found that additional adverse risk factors for the development of MDS are the expression of CD95 in bone marrow ≤40 % and FLT3≥60 %. The expression level of CD95 in bone marrow cells≤40 % and FLT3≥60 % can be considered as a prognostic marker progression of MDS and time start specific therapy

  11. De novo acute leukemia with a sole 5q-: morphological, immunological, and clinical correlations.

    Science.gov (United States)

    Duchayne, E; Dastugue, N; Kuhlein, E; Huguet, F; Pris, J

    1993-11-01

    The 5 q deletion is frequently found in myelodysplastic syndromes and acute non lymphoid leukemia, but this anomaly is usually found in secondary diseases and associated with many other chromosomal aberrations. This report describes four cases of "de novo" acute leukemia with a sole 5q- anomaly. They had no cytological, genetic or clinical characteristics of secondary disorders. It is important to note that of the four patients studied, three had proliferation of immature blast cells. One case was classified as a MO AML and two as "undifferentiated" acute leukemia. Furthermore, these four cases of acute leukemia showed a deletion of the same portion of the long arm of chromosome 5: q22q33. On the same part of this chromosome many hematopoietic growth factor genes have been located, like IL3 and GM-CSF which have early undifferentiated hematopoietic stem cells as a their target.

  12. Growth in rice cells requires de novo purine biosynthesis by the blast fungus Magnaporthe oryzae

    Science.gov (United States)

    Fernandez, Jessie; Yang, Kuan Ting; Cornwell, Kathryn M.; Wright, Janet D.; Wilson, Richard A.

    2013-01-01

    Increasing incidences of human disease, crop destruction and ecosystem perturbations are attributable to fungi and threaten socioeconomic progress and food security on a global scale. The blast fungus Magnaporthe oryzae is the most devastating pathogen of cultivated rice, but its metabolic requirements in the host are unclear. Here we report that a purine-requiring mutant of M. oryzae could develop functional appressoria, penetrate host cells and undergo the morphogenetic transition to elaborate bulbous invasive hyphae from primary hyphae, but further in planta growth was aborted. Invasive hyphal growth following rice cell ingress is thus dependent on de novo purine biosynthesis by the pathogen and, moreover, plant sources of purines are neither available to the mutant nor required by the wild type during the early biotrophic phase of infection. This work provides new knowledge about the metabolic interface between fungus and host that might be applicable to other important intracellular fungal pathogens. PMID:23928947

  13. GEODIVERSIDADE, GEOPATRIMÔNIO E GEOTURISMO EM CURRAIS NOVOS, NE DO BRASIL

    Directory of Open Access Journals (Sweden)

    Wendson Dantas de Araújo Medeiros

    2011-01-01

    Full Text Available En este artículo se aborda el asunto de la geodiversidad, geoconservación, geopatrimonio y geoturismo, estudiando el caso de un municipio en el interior del Nordeste brasilero. Se trata de una contribución al debate geográfi co sobre el uso racional y planifi cado de la geodiversidad por el turismo, especialmente el geoturismo. Por lo tanto, se discuten los conceptos de la geodiversidad y geoturismo, tomando como referencia espacial el municipio de Currais Novos/RN, en particular, algunos elementos que se consideran de valor. Por último, se sugieren medidas para uso sostenible de esta geodiversidad, con fi nalidad de obtener una mejor planifi cación e gestión de estas áreas.

  14. Effluents and releases of tritium from Novo-Voronezh-5 reactor

    International Nuclear Information System (INIS)

    Babenko, A.G.; Mekhedov, B.N.; Podporinova, L.E.; Popov, S.V.; Shalin, A.N.

    1990-01-01

    Results of systematic measurements of tritium concentration within technological systems of reactor of Novo-Voronezh NPP conducted to evaluate tritium effluents and releases and radiation doses to population from these effluents and releases are given. It is shown that 68% concerning tritium total amount were disposed into sewerage while 17% - through vent tube and 15% - with water and steam from secondary circuit systems. Standartized tritium effluents from WWER-1000 reactor for 5 year run constitute 15±1.9 GBq/MWxyear and it corresponds to mean value of effluents for foreign NPPs. Tritium concentration in the atmosphere constituted according to calculations (4.1-20)x10 -5 Bq/l. Conclusion is made about insignificant dose to population from tritium gaseous effluents. Detail study is necessary for dose connected with tritium contained in water effluents

  15. Outcomes of de novo and acute decompensated heart failure patients according to ejection fraction.

    Science.gov (United States)

    Choi, Ki Hong; Lee, Ga Yeon; Choi, Jin-Oh; Jeon, Eun-Seok; Lee, Hae-Young; Cho, Hyun-Jai; Lee, Sang Eun; Kim, Min-Seok; Kim, Jae-Joong; Hwang, Kyung-Kuk; Chae, Shung Chull; Baek, Sang Hong; Kang, Seok-Min; Choi, Dong-Ju; Yoo, Byung-Su; Kim, Kye Hun; Park, Hyun-Young; Cho, Myeong-Chan; Oh, Byung-Hee

    2018-03-01

    There are conflicting results among previous studies regarding the prognosis of heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF). This study aimed to compare the outcomes of patients with de novo acute heart failure (AHF) or acute decompensated HF (ADHF) according to HFpEF (EF≥50%), or HFrEF (EF<40%) and to define the prognosis of patients with HF with mid-range EF (HFmrEF, 40≤EF<50%). Between March 2011 and February 2014, 5625 consecutive patients with AHF were recruited from 10 university hospitals. A total of 5414 (96.2%) patients with EF data were enrolled, which consisted of 2867 (53.0%) patients with de novo and 2547 (47.0%) with ADHF. Each of the enrolled group was stratified by EF. In de novo, all-cause death rates were not significantly different between HFpEF and HFrEF (HFpEF vs HFrEF, 206/744 (27.7%) vs 438/1631 (26.9%), HR adj 1.15, 95% CI 0.96 to 1.38, p=0.14). However, among patients with ADHF, HFrEF had a significantly higher mortality rate compared with HFpEF (HFpEF vs HFrEF, 245/613 (40.0%) vs 694/1551 (44.7%), HR adj 1.25, 95% CI 1.06 to 1.47, p=0.007). Also, in ADHF, HFmrEF was associated with a significantly lower mortality rate within 1 year compared with HFrEF (HFmrEF vs HFrEF, 88/383 (23.0%) vs 430/1551 (27.7%), HR adj 1.31, 95% CI 1.03 to 1.65, p=0.03), but a significantly higher mortality rate after 1 year compared with HFpEF (HFmrEF vs HFpEF, 83/295 (28.1%) vs 101/469 (21.5%), HR adj 0.70, 95% CI 0.52 to 0.96, p=0.02). HFpEF may indicate a better prognosis compared with HFrEF in ADHF, but not in de novo AHF. For patients with ADHF, the prognosis associated with HFmrEF was similar to that of HFpEF within the first year following hospitalisation and similar to HFrEF 1  year after hospitalisation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted

  16. De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux.

    Science.gov (United States)

    Fujita, Atsushi; Isidor, Bertrand; Piloquet, Hugues; Corre, Pierre; Okamoto, Nobuhiko; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Saitsu, Hirotomo; Miyake, Noriko; Matsumoto, Naomichi

    2016-09-01

    MEIS2 aberrations are considered to be the cause of intellectual disability, cleft palate and cardiac septal defect, as MEIS2 copy number variation is often observed with these phenotypes. To our knowledge, only one nucleotide-level change-specifically, an in-frame MEIS2 deletion-has so far been reported. Here, we report a female patient with a de novo nonsense mutation (c.611C>G, p.Ser204*) in MEIS2. She showed severe intellectual disability, moderate motor/verbal developmental delay, cleft palate, cardiac septal defect, hypermetropia, severe feeding difficulties with gastro-esophageal reflux and constipation. By reviewing this patient and previous patients with MEIS2 point mutations, we found that feeding difficulty with gastro-esophageal reflux appears to be one of the core clinical features of MEIS2 haploinsufficiency, in addition to intellectual disability, cleft palate and cardiac septal defect.

  17. A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.

    Science.gov (United States)

    Sznajer, Yves; Coldéa, Cristina; Meire, Françoise; Delpierre, Isabelle; Sekhara, Tayeb; Touraine, Renaud L

    2008-04-15

    Type 4 Waardenburg syndrome represents a well define entity caused by neural crest derivatives anomalies (melanocytes, intrinsic ganglion cells, central, autonomous and peripheral nervous systems) leading, with variable expressivity, to pigmentary anomalies, deafness, mental retardation, peripheral neuropathy, and Hirschsprung disease. Autosomal dominant mode of inheritance is prevalent when Sox10 gene mutation is identified. We report the natural history of a child who presented with synophrys, vivid blue eye, deafness, bilateral complete semicircular canals agenesis with mental retardation, subtle signs for peripheral neuropathy and lack of Hirschsprung disease. SOX10 gene sequencing identified "de novo" splice site mutation (c.698-2A > C). The present phenotype and the genotype findings underline the wide spectrum of SOX10 gene implication in unusual type 4 Waardenburg syndrome patient. Copyright 2008 Wiley-Liss, Inc.

  18. Globalização: novo paradigma das ciências sociais

    OpenAIRE

    Ianni,Octavio

    1994-01-01

    As ciências sociais estão sendo desafiadas a pensar a globalização do mundo. No fim do século XX, quando se anuncia o XXI, elas se defrontam com os dilemas que se abrem com a globalização das coisas, gentes e idéias. Há processos e estruturas sociais, econômicos, políticos, culturais e outros que apenas começam a ser estudados. Além do que é local, nacional e regional, colocam-se problemas novos e fundamentais com a emergência da sociedade global. As fronteiras geográficas e históricas, cultu...

  19. KeyPathwayMiner - De-novo network enrichment by combining multiple OMICS data and biological networks

    DEFF Research Database (Denmark)

    Baumbach, Jan; Alcaraz, Nicolas; Pauling, Josch K.

    We tackle the problem of de-novo pathway extraction. Given a biological network and a set of case-control studies, KeyPathwayMiner efficiently extracts and visualizes all maximal connected sub-networks that contain mainly genes that are dysregulated, e.g., differentially expressed, in most cases ...

  20. Interstitial deletion 1p as a result of a de novo reciprocal 1p;2p translocation

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Jensen, P H

    1985-01-01

    A 5-month-old female patient with psychomotor retardation and minor dysmorphisms is described. Cytogenetic analysis using high-resolution banding technique revealed an interstitial deletion of the short arm of one chromosome 1 (p21----p22.2) resulting from a de novo translocation t(1;2)(p22;p25)....

  1. Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation

    OpenAIRE

    Bourne, Stephanie C.; Townsend, Katelin N.; Shyr, Casper; Matthews, Allison; Lear, Scott A.; Attariwala, Raj; Lehman, Anna; Wasserman, Wyeth W.; van Karnebeek, Clara; Sinclair, Graham; Vallance, Hilary; Gibson, William T.

    2017-01-01

    We describe a woman who presented with cataracts, optic atrophy, lipodystrophy/lipoatrophy, and peripheral neuropathy. Exome sequencing identified a c.235C > G p.(Leu79Val) variant in the optic atrophy 3 (OPA3) gene that was confirmed to be de novo. This report expands the severity of the phenotypic spectrum of autosomal dominant OPA3 mutations.

  2. Immobilization of cadmium in soils by UV-mutated Bacillus subtilis 38 bioaugmentation and NovoGro amendment

    International Nuclear Information System (INIS)

    Jiang Chunxiao; Sun Hongwen; Sun Tieheng; Zhang Qingmin; Zhang Yanfeng

    2009-01-01

    Immobilization of cadmium (10 mg Cd per kilogram soil) in soil by bioaugmentation of a UV-mutated microorganism, Bacillus subtilis 38 accompanied with amendment of a bio-fertilizer, NovoGro was investigated using extractable cadmium (E-Cd) by DTPA. B. subtilis 38, the mutant with the strongest resistance against Cd, could bioaccumulate Cd four times greater than the original wild type. Single bioaugmentation of B. subtilis 38 (SB treatment) to soil however did not reduce E-Cd significantly, while the amendment of NovoGro (SN treatment) reduced E-Cd remarkably. Simultaneous application of B. subtilis 38 and NovoGro (SNB treatment) exhibited a synergetic effect compared to the single SB and SN treatment. The immobilization effect was significantly affected by temperature, soil moisture, and pH. It seems that the immobilization on Cd reached the maximum when environmental conditions favored the activity of microorganisms. Under the optimum conditions, after 90 days incubation, E-Cd was 3.34, 3.39, 2.25 and 0.87 mg kg -1 in the control soil, SB, SN and SNB soils, respectively. NovoGro not only showed a great capacity for Cd adsorption, but also promoted the growth of B. subtilis 38. This study provides a potential cost-effective technique for in situ remediation of Cd contaminated soils with bioaugmentation.

  3. Characterization of a de novo duplication of 11p14----p13, using fluorescent in situ hybridization and southern hybridization

    NARCIS (Netherlands)

    Speleman, F.; Mannens, M.; Redeker, B.; Vercruyssen, M.; van Oostveldt, P.; Leroy, J.; Slater, R.

    1991-01-01

    A de novo 11p+ chromosome was found in a child with mild mental retardation but no other remarkable dysmorphic characteristics. Banding studies suggested a duplication of regions 11p13 and 11p14 or regions 11p14 and 11p15. Using fluorescent in situ hybridization and digital imaging microscopy, we

  4. Beroepsdifferentiatie in de tandheelkunde 19 : Het effect van parodontale behandeling op de mate van de novo plaquevorming

    NARCIS (Netherlands)

    Dahan, M; Timmerman, M F; van Winkelhoff, A J; van der Velden, U

    In order to determine whether the quantity of bacteria in saliva and the degree of periodontal infection influence the speed of de novo plaque formation in periodontitis patients, 23 patients rinsed with 10 ml sterile saline. All teeth were then supragingivally and professionally cleaned, after

  5. Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells

    KAUST Repository

    Takahashi, Yuta; Wu, Jun; Suzuki, Keiichiro; Martinez-Redondo, Paloma; Li, Mo; Liao, Hsin-Kai; Wu, Min-Zu; Herná ndez-Bení tez, Reyna; Hishida, Tomoaki; Shokhirev, Maxim Nikolaievich; Esteban, Concepcion Rodriguez; Sancho-Martinez, Ignacio; Belmonte, Juan Carlos Izpisua

    2017-01-01

    that insertion of CpG-free DNA into targeted CGIs induces de novo methylation of the entire CGI in human pluripotent stem cells (PSCs). The methylation status is stably maintained even after CpG-free DNA removal, extensive passaging, and differentiation

  6. Radiotherapy, especially at young age, increases the risk for de novo brain tumors in patients treated for pituitary tumors

    NARCIS (Netherlands)

    Burman, Pia; Van Beek, André P.; Biller, Beverly M.K.; Camacho-Hubner, Cecilia; Mattsson, Anders F.

    Background: Excess mortality due to de novo malignant brain tumors was recently found in a national study of patients with hypopituitarism following treatment of pituitary tumors. Here, we examined a larger multi-national cohort to corroborate and extend this observation. Objective: To investigate

  7. Dysplastic vs. Common Naevus-associated vs. De novo Melanomas: An Observational Retrospective Study of 1,021 Patients

    Directory of Open Access Journals (Sweden)

    Alejandro Martin-Gorgojo

    2018-03-01

    Full Text Available The aim of this case-case study was to determine the differences between dysplastic and common naevus-associated melanomas (NAM and de novo melanomas. A total of 1,021 prospectively collected patients with invasive cutaneous melanoma from an oncology referral centre were included in the study. Of these, 75.51% had de novo melanomas, 12.93% dysplastic NAM, and 11.56% common NAM. Dysplastic NAM, compared with de novo melanomas, were associated with intermittently photo-exposed sites, atypical melanocytic naevi, decreased tumour thickness, and presence of MC1R non-synonymous variants. Common NAM were more frequent on the trunk and of superficial spreading type. Comparison of dysplastic with common NAM showed significant difference only with regard to mitoses. Both subtypes of NAM shared less aggressive traits than de novo melanomas, albeit with no significant differences in survival after multivariate adjustment. In conclusion, NAM present with less aggressive traits, mostly due to a greater awareness among patients of changing moles than due to their intrinsic biological characteristics.

  8. De Novo whole genome sequence of Xylella fastidiosa subsp. multiplex strain BB01 from blueberry in Georgia, USA

    Science.gov (United States)

    This study reports a de novo assembled draft genome sequence of Xylella fastidiosa subsp. multiplex strain BB01 causing blueberry bacterial leaf scorch in Georgia, USA. The BB01 genome is 2,517,579 bp with a G+C content of 51.8% and 2,943 open reading frames (ORFs) and 48 RNA genes....

  9. Effect of Reaction Time on PCDD and PCDF Formation by De novo Synthetic Reactions under Oxygen Deficient and Rich Atmosphere

    Czech Academy of Sciences Publication Activity Database

    Grabic, R.; Pekárek, Vladimír; Ullrich, Jan; Punčochář, Miroslav; Fišerová, Eva; Karban, Jindřich; Šebestová, M.

    2002-01-01

    Roč. 49, č. 7 (2002), s. 691-696 ISSN 0045-6535 R&D Projects: GA ČR GA104/97/S002; GA AV ČR IAA4072901 Keywords : activated carbon * Copper chloride * de novo synthesis Subject RIV: CC - Organic Chemistry Impact factor: 1.461, year: 2002

  10. Trends in presentation, management and survival of patients with de novo metastatic breast cancer in a Southeast Asian setting

    NARCIS (Netherlands)

    Bhoo Pathy, Nirmala; Verkooijen, Helena Marieke; Tan, Ern-Yu; Miao, Hui; Taib, Nur Aishah Mohd; Brand, Judith S.; Dent, Rebecca A.; See, Mee-Hoong; Subramaniam, ShriDevi; Chan, Patrick; Lee, Soo-Chin; Hartman, Mikael; Yip, Cheng-Har

    2015-01-01

    Up to 25% of breast cancer patients in Asia present with de novo metastatic disease. We examined the survival trends of Asian patients with metastatic breast cancer over fifteen years. The impact of changes in patient's demography, tumor characteristics, tumor burden, and treatment on survival trend

  11. Effects of Stress, Reactive Oxygen Species, and the SOS Response on De Novo Acquisition of Antibiotic Resistance in Escherichia coli

    NARCIS (Netherlands)

    Händel, N.; Hoeksema, M.; Freijo Mata, M.; Brul, S.; ter Kuile, B.H.

    2015-01-01

    Strategies to prevent the development of antibiotic resistance in bacteria are needed to reduce the threat of infectious diseases to human health. The de novo acquisition of resistance due to mutations and/or phenotypic adaptation occurs rapidly as a result of interactions of gene expression and

  12. Structural variation in two human genomes mapped at single-nucleotide resolution by whole genome de novo assembly

    DEFF Research Database (Denmark)

    Li, Yingrui; Zheng, Hancheng; Luo, Ruibang

    2011-01-01

    Here we use whole-genome de novo assembly of second-generation sequencing reads to map structural variation (SV) in an Asian genome and an African genome. Our approach identifies small- and intermediate-size homozygous variants (1-50 kb) including insertions, deletions, inversions and their precise...

  13. Batch-processing of imaging or liquid-chromatography mass spectrometry datasets and De Novo sequencing of polyketide siderophores

    Czech Academy of Sciences Publication Activity Database

    Novák, Jiří; Sokolová, Lucie; Lemr, Karel; Pluháček, Tomáš; Palyzová, Andrea; Havlíček, Vladimír

    2017-01-01

    Roč. 1865, č. 7 (2017), s. 768-775 ISSN 1570-9639 R&D Projects: GA ČR(CZ) GA16-20229S; GA MŠk(CZ) LO1509 Institutional support: RVO:61388971 Keywords : Mass spectrometry imaging * De novo sequencing * Siderophores Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 2.773, year: 2016

  14. Novo tipo de evaporímetro terrestre A new type of evaporimeter

    Directory of Open Access Journals (Sweden)

    Rino N. Tosello

    1960-01-01

    Full Text Available No presente trabalho descreve-se um novo tipo de evaporímetro, cujo princípio de funcionamento está baseado em leis físicas que regem o fenômeno de tensão superficial. Neste tipo de evaporímetro a medida da evaporação é feita por processo volumétrieo, dispensando o emprego de mecanismos de precisão e dispendiosos. Foi feita uma análise matemática do princípio de funcionamento do novo evaporímetro, demonstrando-se oferecer exatidão plenamente satisfatória para propósitos práticos. São dados suficientes detalhes construtivos, de instalação e operação, a fim de permitir que pessoas e entidades interessadas possam reproduzi-lo e comprovar as vantagens de seu emprêgo.In this paper is described a new type of evaporimeter, the principle of operation of which is based on physical laws governing the surface tension phenomenon. The measurement of evaporation in, the new evaporimeter, described as Evaporimeter IA-58, is made by simple volumetric procedure, thus avoiding the use of precise and expensive mechanisms. A mathematical analysis of the principle of operation is made, and proves that the new evaporimeter can offer satisfactory xeaults for practical use. The operation of the new evaporimeter is very simple, since only volumetric measurements are made, with a graduated cylinder of 1000 ml, both of the added water to restore the water level to the same initial level and the outflown or excess water. It is believed that enough details are given to allow the understanding of the construction, installation and operation of the new evaporimeter, bo that interested persons or organizations could have the model reproduced and verify the advantage of its use.

  15. Categorização de questões de Física do novo ENEM

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    Jesusney Silva Hernandes

    2013-04-01

    Full Text Available http://dx.doi.org/10.5007/2175-7941.2013v30n1p58 Este artigo estuda questões que envolvem Física nas provas de Ciências da Natureza e suas Tecnologias do novo ENEM. Selecionamos itens que evidenciam alguma Física nestas provas. Classificamos as questões por Competência e Habilidade segundo a matriz de referência do Exame e, através da análise de conteúdo de Bardin (2010, propusemos, para cada grupo de itens inseridos em uma dada competência, um agrupamento em categorias. A partir da observação e reflexão das categorias emergentes apresentamos ao longo do texto orientações sobre características das situações-problema que abordam alguma Física no novo ENEM. Além disso, através da análise das categorias emergentes, procuramos avaliar a aproximação das questões selecionadas com as orientações presentes nos Parâmetros Curriculares Nacionais para o Ensino Médio (PCNEM, nas Orientações Complementares aos Parâmetros Curriculares Nacionais (PCN+ e nas Orientações Curriculares para o Ensino Médio (OCEM. Percebemos que muitas orientações que surgiram das categorias emergentes atendem às orientações dos PCN, PCN+ e OCEM. Esperamos que nossa pesquisa possa contribuir para o alinhamento da prática docente com um ensino de Física inovador pautado no desenvolvimento de competências e habilidades, viabilizando melhoria de aprendizado e, consequentemente, de desempenho em Exames como o ENEM.

  16. Algorithm for selection of optimized EPR distance restraints for de novo protein structure determination

    Science.gov (United States)

    Kazmier, Kelli; Alexander, Nathan S.; Meiler, Jens; Mchaourab, Hassane S.

    2010-01-01

    A hybrid protein structure determination approach combining sparse Electron Paramagnetic Resonance (EPR) distance restraints and Rosetta de novo protein folding has been previously demonstrated to yield high quality models (Alexander et al., 2008). However, widespread application of this methodology to proteins of unknown structures is hindered by the lack of a general strategy to place spin label pairs in the primary sequence. In this work, we report the development of an algorithm that optimally selects spin labeling positions for the purpose of distance measurements by EPR. For the α-helical subdomain of T4 lysozyme (T4L), simulated restraints that maximize sequence separation between the two spin labels while simultaneously ensuring pairwise connectivity of secondary structure elements yielded vastly improved models by Rosetta folding. 50% of all these models have the correct fold compared to only 21% and 8% correctly folded models when randomly placed restraints or no restraints are used, respectively. Moreover, the improvements in model quality require a limited number of optimized restraints, the number of which is determined by the pairwise connectivities of T4L α-helices. The predicted improvement in Rosetta model quality was verified by experimental determination of distances between spin labels pairs selected by the algorithm. Overall, our results reinforce the rationale for the combined use of sparse EPR distance restraints and de novo folding. By alleviating the experimental bottleneck associated with restraint selection, this algorithm sets the stage for extending computational structure determination to larger, traditionally elusive protein topologies of critical structural and biochemical importance. PMID:21074624

  17. De Novo Biosynthesis of Vanillin in Fission Yeast (Schizosaccharomyces pombe) and Baker's Yeast (Saccharomyces cerevisiae) ▿

    Science.gov (United States)

    Hansen, Esben H.; Møller, Birger Lindberg; Kock, Gertrud R.; Bünner, Camilla M.; Kristensen, Charlotte; Jensen, Ole R.; Okkels, Finn T.; Olsen, Carl E.; Motawia, Mohammed S.; Hansen, Jørgen

    2009-01-01

    Vanillin is one of the world's most important flavor compounds, with a global market of 180 million dollars. Natural vanillin is derived from the cured seed pods of the vanilla orchid (Vanilla planifolia), but most of the world's vanillin is synthesized from petrochemicals or wood pulp lignins. We have established a true de novo biosynthetic pathway for vanillin production from glucose in Schizosaccharomyces pombe, also known as fission yeast or African beer yeast, as well as in baker's yeast, Saccharomyces cerevisiae. Productivities were 65 and 45 mg/liter, after introduction of three and four heterologous genes, respectively. The engineered pathways involve incorporation of 3-dehydroshikimate dehydratase from the dung mold Podospora pauciseta, an aromatic carboxylic acid reductase (ACAR) from a bacterium of the Nocardia genus, and an O-methyltransferase from Homo sapiens. In S. cerevisiae, the ACAR enzyme required activation by phosphopantetheinylation, and this was achieved by coexpression of a Corynebacterium glutamicum phosphopantetheinyl transferase. Prevention of reduction of vanillin to vanillyl alcohol was achieved by knockout of the host alcohol dehydrogenase ADH6. In S. pombe, the biosynthesis was further improved by introduction of an Arabidopsis thaliana family 1 UDP-glycosyltransferase, converting vanillin into vanillin β-d-glucoside, which is not toxic to the yeast cells and thus may be accumulated in larger amounts. These de novo pathways represent the first examples of one-cell microbial generation of these valuable compounds from glucose. S. pombe yeast has not previously been metabolically engineered to produce any valuable, industrially scalable, white biotech commodity. PMID:19286778

  18. The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study.

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    Richard Hansen

    Full Text Available Children presenting for the first time with inflammatory bowel disease (IBD offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.100 children undergoing colonoscopy were recruited including 44 treatment naïve de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates. Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae. No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312.This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.This study is publically registered on the United Kingdom Clinical Research Network Portfolio (9633.

  19. A de novo variant in the ASPRV1 gene in a dog with ichthyosis.

    Science.gov (United States)

    Bauer, Anina; Waluk, Dominik P; Galichet, Arnaud; Timm, Katrin; Jagannathan, Vidhya; Sayar, Beyza S; Wiener, Dominique J; Dietschi, Elisabeth; Müller, Eliane J; Roosje, Petra; Welle, Monika M; Leeb, Tosso

    2017-03-01

    Ichthyoses are a heterogeneous group of inherited cornification disorders characterized by generalized dry skin, scaling and/or hyperkeratosis. Ichthyosis vulgaris is the most common form of ichthyosis in humans and caused by genetic variants in the FLG gene encoding filaggrin. Filaggrin is a key player in the formation of the stratum corneum, the uppermost layer of the epidermis and therefore crucial for barrier function. During terminal differentiation of keratinocytes, the precursor profilaggrin is cleaved by several proteases into filaggrin monomers and eventually processed into free amino acids contributing to the hydration of the cornified layer. We studied a German Shepherd dog with a novel form of ichthyosis. Comparing the genome sequence of the affected dog with 288 genomes from genetically diverse non-affected dogs we identified a private heterozygous variant in the ASPRV1 gene encoding "aspartic peptidase, retroviral-like 1", which is also known as skin aspartic protease (SASPase). The variant was absent in both parents and therefore due to a de novo mutation event. It was a missense variant, c.1052T>C, affecting a conserved residue close to an autoprocessing cleavage site, p.(Leu351Pro). ASPRV1 encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. By immunofluorescence staining we showed that the filaggrin expression pattern was altered in the affected dog. Thus, our findings provide strong evidence that the identified de novo variant is causative for the ichthyosis in the affected dog and that ASPRV1 plays an essential role in skin barrier formation. ASPRV1 is thus a novel candidate gene for unexplained human forms of ichthyoses.

  20. A de novo variant in the ASPRV1 gene in a dog with ichthyosis.

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    Anina Bauer

    2017-03-01

    Full Text Available Ichthyoses are a heterogeneous group of inherited cornification disorders characterized by generalized dry skin, scaling and/or hyperkeratosis. Ichthyosis vulgaris is the most common form of ichthyosis in humans and caused by genetic variants in the FLG gene encoding filaggrin. Filaggrin is a key player in the formation of the stratum corneum, the uppermost layer of the epidermis and therefore crucial for barrier function. During terminal differentiation of keratinocytes, the precursor profilaggrin is cleaved by several proteases into filaggrin monomers and eventually processed into free amino acids contributing to the hydration of the cornified layer. We studied a German Shepherd dog with a novel form of ichthyosis. Comparing the genome sequence of the affected dog with 288 genomes from genetically diverse non-affected dogs we identified a private heterozygous variant in the ASPRV1 gene encoding "aspartic peptidase, retroviral-like 1", which is also known as skin aspartic protease (SASPase. The variant was absent in both parents and therefore due to a de novo mutation event. It was a missense variant, c.1052T>C, affecting a conserved residue close to an autoprocessing cleavage site, p.(Leu351Pro. ASPRV1 encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. By immunofluorescence staining we showed that the filaggrin expression pattern was altered in the affected dog. Thus, our findings provide strong evidence that the identified de novo variant is causative for the ichthyosis in the affected dog and that ASPRV1 plays an essential role in skin barrier formation. ASPRV1 is thus a novel candidate gene for unexplained human forms of ichthyoses.

  1. The genome of flax (Linum usitatissimum) assembled de novo from short shotgun sequence reads.

    Science.gov (United States)

    Wang, Zhiwen; Hobson, Neil; Galindo, Leonardo; Zhu, Shilin; Shi, Daihu; McDill, Joshua; Yang, Linfeng; Hawkins, Simon; Neutelings, Godfrey; Datla, Raju; Lambert, Georgina; Galbraith, David W; Grassa, Christopher J; Geraldes, Armando; Cronk, Quentin C; Cullis, Christopher; Dash, Prasanta K; Kumar, Polumetla A; Cloutier, Sylvie; Sharpe, Andrew G; Wong, Gane K-S; Wang, Jun; Deyholos, Michael K

    2012-11-01

    Flax (Linum usitatissimum) is an ancient crop that is widely cultivated as a source of fiber, oil and medicinally relevant compounds. To accelerate crop improvement, we performed whole-genome shotgun sequencing of the nuclear genome of flax. Seven paired-end libraries ranging in size from 300 bp to 10 kb were sequenced using an Illumina genome analyzer. A de novo assembly, comprised exclusively of deep-coverage (approximately 94× raw, approximately 69× filtered) short-sequence reads (44-100 bp), produced a set of scaffolds with N(50) =694 kb, including contigs with N(50)=20.1 kb. The contig assembly contained 302 Mb of non-redundant sequence representing an estimated 81% genome coverage. Up to 96% of published flax ESTs aligned to the whole-genome shotgun scaffolds. However, comparisons with independently sequenced BACs and fosmids showed some mis-assembly of regions at the genome scale. A total of 43384 protein-coding genes were predicted in the whole-genome shotgun assembly, and up to 93% of published flax ESTs, and 86% of A. thaliana genes aligned to these predicted genes, indicating excellent coverage and accuracy at the gene level. Analysis of the synonymous substitution rates (K(s) ) observed within duplicate gene pairs was consistent with a recent (5-9 MYA) whole-genome duplication in flax. Within the predicted proteome, we observed enrichment of many conserved domains (Pfam-A) that may contribute to the unique properties of this crop, including agglutinin proteins. Together these results show that de novo assembly, based solely on whole-genome shotgun short-sequence reads, is an efficient means of obtaining nearly complete genome sequence information for some plant species. © 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.

  2. Characterization and analysis of a de novo transcriptome from the pygmy grasshopper Tetrix japonica.

    Science.gov (United States)

    Qiu, Zhongying; Liu, Fei; Lu, Huimeng; Huang, Yuan

    2017-05-01

    The pygmy grasshopper Tetrix japonica is a common insect distributed throughout the world, and it has the potential for use in studies of body colour polymorphism, genomics and the biology of Tetrigoidea (Insecta: Orthoptera). However, limited biological information is available for this insect. Here, we conducted a de novo transcriptome study of adult and larval T. japonica to provide a better understanding of its gene expression and develop genomic resources for future work. We sequenced and explored the characteristics of the de novo transcriptome of T. japonica using Illumina HiSeq 2000 platform. A total of 107 608 206 paired-end clean reads were assembled into 61 141 unigenes using the trinity software; the mean unigene size was 771 bp, and the N50 length was 1238 bp. A total of 29 225 unigenes were functionally annotated to the NCBI nonredundant protein sequences (Nr), NCBI nonredundant nucleotide sequences (Nt), a manually annotated and reviewed protein sequence database (Swiss-Prot), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. A large number of putative genes that are potentially involved in pigment pathways, juvenile hormone (JH) metabolism and signalling pathways were identified in the T. japonica transcriptome. Additionally, 165 769 and 156 796 putative single nucleotide polymorphisms occurred in the adult and larvae transcriptomes, respectively, and a total of 3162 simple sequence repeats were detected in this assembly. This comprehensive transcriptomic data for T. japonica will provide a usable resource for gene predictions, signalling pathway investigations and molecular marker development for this species and other pygmy grasshoppers. © 2016 John Wiley & Sons Ltd.

  3. Outcomes of kidney transplant tourism and risk factors for de novo urothelial carcinoma.

    Science.gov (United States)

    Tsai, Hsin-Lin; Chang, Jei-Wen; Wu, Tsai-Hun; King, Kuang-Liang; Yang, Ling-Yu; Chan, Yu-Jiun; Yang, An-Hang; Chang, Fu-Pang; Pan, Chin-Chen; Yang, Wu-Chang; Loong, Che-Chuan

    2014-07-15

    To date, the outcomes of transplant tourism have not been reported extensively. In addition, data about the accuracy of urine cytology for the detection and the role of the BK virus (BKV) in the carcinogenesis of urothelial carcinoma (UC) after renal transplantation are lacking. Three hundred seven patients who received deceased donor kidney transplants between January 2003 and December 2009 were retrospectively studied. The clinical parameters and outcomes between the domestic and tourist groups were compared. We also investigated the risk factors and role of BKV in the carcinogenesis of de novo UC by quantitative real-time polymerase chain reaction. The subjects in the tourist group were older at transplantation and had a shorter dialysis time before transplantation. There were significantly higher incidence rates of BKV viruria, Pneumocystis jiroveci pneumonia, and malignancy in the tourist group. Graft and patient survival were superior in the domestic group. A total of 43 cancers were identified, and the most common type of malignancy was UC (23 patients, 53.5%). The tourist group had a significantly higher incidence of tumors. The sensitivity and specificity of urine cytology for detecting UC were 73.9% and 94.7%, respectively. Independent predictors of UC included female sex, use of Chinese herbal medicine, and transplant tourism. Only two patients (8.7%) with UC had detectable BKV. Transplant tourism was a risk factor for infection and de novo malignancy. Urothelial carcinoma was the most common malignancy after kidney transplantation. Regular screening for the early detection of UC by urine cytology or periodic sonographic surveys is mandatory, especially for those at high risk.

  4. De novo assembly of the perennial ryegrass transcriptome using an RNA-Seq strategy.

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    Jacqueline D Farrell

    Full Text Available Perennial ryegrass is a highly heterozygous outbreeding grass species used for turf and forage production. Heterozygosity can affect de-Bruijn graph assembly making de novo transcriptome assembly of species such as perennial ryegrass challenging. Creating a reference transcriptome from a homozygous perennial ryegrass genotype can circumvent the challenge of heterozygosity. The goals of this study were to perform RNA-sequencing on multiple tissues from a highly inbred genotype to develop a reference transcriptome. This was complemented with RNA-sequencing of a highly heterozygous genotype for SNP calling.De novo transcriptome assembly of the inbred genotype created 185,833 transcripts with an average length of 830 base pairs. Within the inbred reference transcriptome 78,560 predicted open reading frames were found of which 24,434 were predicted as complete. Functional annotation found 50,890 transcripts with a BLASTp hit from the Swiss-Prot non-redundant database, 58,941 transcripts with a Pfam protein domain and 1,151 transcripts encoding putative secreted peptides. To evaluate the reference transcriptome we targeted the high-affinity K+ transporter gene family and found multiple orthologs. Using the longest unique open reading frames as the reference sequence, 64,242 single nucleotide polymorphisms were found. One thousand sixty one open reading frames from the inbred genotype contained heterozygous sites, confirming the high degree of homozygosity.Our study has developed an annotated, comprehensive transcriptome reference for perennial ryegrass that can aid in determining genetic variation, expression analysis, genome annotation, and gene mapping.

  5. De novo transcriptome sequencing of axolotl blastema for identification of differentially expressed genes during limb regeneration

    Science.gov (United States)

    2013-01-01

    Background Salamanders are unique among vertebrates in their ability to completely regenerate amputated limbs through the mediation of blastema cells located at the stump ends. This regeneration is nerve-dependent because blastema formation and regeneration does not occur after limb denervation. To obtain the genomic information of blastema tissues, de novo transcriptomes from both blastema tissues and denervated stump ends of Ambystoma mexicanum (axolotls) 14 days post-amputation were sequenced and compared using Solexa DNA sequencing. Results The sequencing done for this study produced 40,688,892 reads that were assembled into 307,345 transcribed sequences. The N50 of transcribed sequence length was 562 bases. A similarity search with known proteins identified 39,200 different genes to be expressed during limb regeneration with a cut-off E-value exceeding 10-5. We annotated assembled sequences by using gene descriptions, gene ontology, and clusters of orthologous group terms. Targeted searches using these annotations showed that the majority of the genes were in the categories of essential metabolic pathways, transcription factors and conserved signaling pathways, and novel candidate genes for regenerative processes. We discovered and confirmed numerous sequences of the candidate genes by using quantitative polymerase chain reaction and in situ hybridization. Conclusion The results of this study demonstrate that de novo transcriptome sequencing allows gene expression analysis in a species lacking genome information and provides the most comprehensive mRNA sequence resources for axolotls. The characterization of the axolotl transcriptome can help elucidate the molecular mechanisms underlying blastema formation during limb regeneration. PMID:23815514

  6. De Novo Centromere Formation and Centromeric Sequence Expansion in Wheat and its Wide Hybrids.

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    Xiang Guo

    2016-04-01

    Full Text Available Centromeres typically contain tandem repeat sequences, but centromere function does not necessarily depend on these sequences. We identified functional centromeres with significant quantitative changes in the centromeric retrotransposons of wheat (CRW contents in wheat aneuploids (Triticum aestivum and the offspring of wheat wide hybrids. The CRW signals were strongly reduced or essentially lost in some wheat ditelosomic lines and in the addition lines from the wide hybrids. The total loss of the CRW sequences but the presence of CENH3 in these lines suggests that the centromeres were formed de novo. In wheat and its wide hybrids, which carry large complex genomes or no sequenced genome, we performed CENH3-ChIP-dot-blot methods alone or in combination with CENH3-ChIP-seq and identified the ectopic genomic sequences present at the new centromeres. In adcdition, the transcription of the identified DNA sequences was remarkably increased at the new centromere, suggesting that the transcription of the corresponding sequences may be associated with de novo centromere formation. Stable alien chromosomes with two and three regions containing CRW sequences induced by centromere breakage were observed in the wheat-Th. elongatum hybrid derivatives, but only one was a functional centromere. In wheat-rye (Secale cereale hybrids, the rye centromere-specific sequences spread along the chromosome arms and may have caused centromere expansion. Frequent and significant quantitative alterations in the centromere sequence via chromosomal rearrangement have been systematically described in wheat wide hybridizations, which may affect the retention or loss of the alien chromosomes in the hybrids. Thus, the centromere behavior in wide crosses likely has an important impact on the generation of biodiversity, which ultimately has implications for speciation.

  7. De novo prediction of human chromosome structures: Epigenetic marking patterns encode genome architecture.

    Science.gov (United States)

    Di Pierro, Michele; Cheng, Ryan R; Lieberman Aiden, Erez; Wolynes, Peter G; Onuchic, José N

    2017-11-14

    Inside the cell nucleus, genomes fold into organized structures that are characteristic of cell type. Here, we show that this chromatin architecture can be predicted de novo using epigenetic data derived from chromatin immunoprecipitation-sequencing (ChIP-Seq). We exploit the idea that chromosomes encode a 1D sequence of chromatin structural types. Interactions between these chromatin types determine the 3D structural ensemble of chromosomes through a process similar to phase separation. First, a neural network is used to infer the relation between the epigenetic marks present at a locus, as assayed by ChIP-Seq, and the genomic compartment in which those loci reside, as measured by DNA-DNA proximity ligation (Hi-C). Next, types inferred from this neural network are used as an input to an energy landscape model for chromatin organization [Minimal Chromatin Model (MiChroM)] to generate an ensemble of 3D chromosome conformations at a resolution of 50 kilobases (kb). After training the model, dubbed Maximum Entropy Genomic Annotation from Biomarkers Associated to Structural Ensembles (MEGABASE), on odd-numbered chromosomes, we predict the sequences of chromatin types and the subsequent 3D conformational ensembles for the even chromosomes. We validate these structural ensembles by using ChIP-Seq tracks alone to predict Hi-C maps, as well as distances measured using 3D fluorescence in situ hybridization (FISH) experiments. Both sets of experiments support the hypothesis of phase separation being the driving process behind compartmentalization. These findings strongly suggest that epigenetic marking patterns encode sufficient information to determine the global architecture of chromosomes and that de novo structure prediction for whole genomes may be increasingly possible. Copyright © 2017 the Author(s). Published by PNAS.

  8. The Rickettsia Endosymbiont of Ixodes pacificus Contains All the Genes of De Novo Folate Biosynthesis

    Science.gov (United States)

    Bodnar, James; Mortazavi, Bobak; Laurent, Timothy; Deason, Jeff; Thephavongsa, Khanhkeo; Zhong, Jianmin

    2015-01-01

    Ticks and other arthropods often are hosts to nutrient providing bacterial endosymbionts, which contribute to their host’s fitness by supplying nutrients such as vitamins and amino acids. It has been detected, in our lab, that Ixodes pacificus is host to Rickettsia species phylotype G021. This endosymbiont is predominantly present, and 100% maternally transmitted in I. pacificus. To study roles of phylotype G021 in I. pacificus, bioinformatic and molecular approaches were carried out. MUMmer genome alignments of whole genome sequence of I. scapularis, a close relative to I. pacificus, against completely sequenced genomes of R. bellii OSU85-389, R. conorii, and R. felis, identified 8,190 unique sequences that are homologous to Rickettsia sequences in the NCBI Trace Archive. MetaCyc metabolic reconstructions revealed that all folate gene orthologues (folA, folC, folE, folKP, ptpS) required for de novo folate biosynthesis are present in the genome of Rickettsia buchneri in I. scapularis. To examine the metabolic capability of phylotype G021 in I. pacificus, genes of the folate biosynthesis pathway of the bacterium were PCR amplified using degenerate primers. BLAST searches identified that nucleotide sequences of the folA, folC, folE, folKP, and ptpS genes possess 98.6%, 98.8%, 98.9%, 98.5% and 99.0% identity respectively to the corresponding genes of Rickettsia buchneri. Phylogenetic tree constructions show that the folate genes of phylotype G021 and homologous genes from various Rickettsia species are monophyletic. This study has shown that all folate genes exist in the genome of Rickettsia species phylotype G021 and that this bacterium has the genetic capability for de novo folate synthesis. PMID:26650541

  9. Characterization of Liaoning cashmere goat transcriptome: sequencing, de novo assembly, functional annotation and comparative analysis.

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    Hongliang Liu

    Full Text Available Liaoning cashmere goat is a famous goat breed for cashmere wool. In order to increase the transcriptome data and accelerate genetic improvement for this breed, we performed de novo transcriptome sequencing to generate the first expressed sequence tag dataset for the Liaoning cashmere goat, using next-generation sequencing technology.Transcriptome sequencing of Liaoning cashmere goat on a Roche 454 platform yielded 804,601 high-quality reads. Clustering and assembly of these reads produced a non-redundant set of 117,854 unigenes, comprising 13,194 isotigs and 104,660 singletons. Based on similarity searches with known proteins, 17,356 unigenes were assigned to 6,700 GO categories, and the terms were summarized into three main GO categories and 59 sub-categories. 3,548 and 46,778 unigenes had significant similarity to existing sequences in the KEGG and COG databases, respectively. Comparative analysis revealed that 42,254 unigenes were aligned to 17,532 different sequences in NCBI non-redundant nucleotide databases. 97,236 (82.51% unigenes were mapped to the 30 goat chromosomes. 35,551 (30.17% unigenes were matched to 11,438 reported goat protein-coding genes. The remaining non-matched unigenes were further compared with cattle and human reference genes, 67 putative new goat genes were discovered. Additionally, 2,781 potential simple sequence repeats were initially identified from all unigenes.The transcriptome of Liaoning cashmere goat was deep sequenced, de novo assembled, and annotated, providing abundant data to better understand the Liaoning cashmere goat transcriptome. The potential simple sequence repeats provide a material basis for future genetic linkage and quantitative trait loci analyses.

  10. High rates of de novo 15q11q13 inversions in human spermatozoa

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    Molina Òscar

    2012-02-01

    Full Text Available Abstract Low-Copy Repeats predispose the 15q11-q13 region to non-allelic homologous recombination. We have already demonstrated that a significant percentage of Prader-Willi syndrome (PWS fathers have an increased susceptibility to generate 15q11q13 deletions in spermatozoa, suggesting the participation of intrachromatid exchanges. This work has been focused on assessing the incidence of de novo 15q11q13 inversions in spermatozoa of control donors and PWS fathers in order to determine the basal rates of inversions and to confirm the intrachromatid mechanism as the main cause of 15q11q13 anomalies. Semen samples from 10 control donors and 16 PWS fathers were processed and analyzed by triple-color FISH. Three differentially labeled BAC-clones were used: one proximal and two distal of the 15q11-q13 region. Signal associations allowed the discrimination between normal and inverted haplotypes, which were confirmed by laser-scanning confocal microscopy. Two types of inversions were detected which correspond to the segments involved in Class I and II PWS deletions. No significant differences were observed in the mean frequencies of inversions between controls and PWS fathers (3.59% ± 0.46 and 9.51% ± 0.87 vs 3.06% ± 0.33 and 10.07% ± 0.74. Individual comparisons showed significant increases of inversions in four PWS fathers (P Results suggest that the incidence of heterozygous inversion carriers in the general population could reach significant values. This situation could have important implications, as they have been described as predisposing haplotypes for genomic disorders. As a whole, results confirm the high instability of the 15q11-q13 region, which is prone to different types of de novo reorganizations by intrachromatid NAHR.

  11. Indirect coupling of phosphate release to de novo tension generation during muscle contraction.

    Science.gov (United States)

    Davis, J S; Rodgers, M E

    1995-01-01

    A key question in muscle contraction is how tension generation is coupled to the chemistry of the actomyosin ATPase. Biochemical and mechanochemical experiments link tension generation to a change in structure associated with phosphate release. Length-jump and temperature-jump experiments, on the other hand, implicate phase 2slow, a significantly faster, markedly strain-sensitive kinetic process in tension generation. We use a laser temperature jump to probe the kinetics and mechanism of tension generation in skinned rabbit psoas fibers--an appropriate method since both phosphate release and phase 2slow are readily perturbed by temperature. Kinetics characteristic of the structural change associated with phosphate release are observed only when phosphate is added to fibers. When present, it causes a reduction in fiber tension; otherwise, no force is generated when it is perturbed. We therefore exclude this step from tension generation. The kinetics of de novo tension generation by the temperature-jump equivalent of phase 2slow appear unaffected by phosphate binding. We therefore propose that phosphate release is indirectly coupled to de novo tension generation via a steady-state flux through an irreversible step. We conclude that tension generation occurs in the absence of chemical change as the result of an entropy-driven transition between strongly bound crossbridges in the actomyosin-ADP state. The mechanism resembles the operation of a clock, with phosphate release providing the energy to tension the spring, and the irreversible step functions as the escapement mechanism, which is followed in turn by tension generation as the movement of the hands. Images Fig. 6 PMID:7479824

  12. Brain metabolic correlates of dopaminergic degeneration in de novo idiopathic Parkinson's disease

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    Berti, Valentina; Polito, Cristina; Vanzi, Eleonora; Cristofaro, Maria Teresa de; Pellicano, Giannantonio; Mungai, Francesco; Formiconi, Andreas Robert; Pupi, Alberto [University of Florence, Department of Clinical Pathophysiology, Florence (Italy); Ramat, Silvia; Marini, Paolo; Sorbi, Sandro [University of Florence, Department of Psychiatric and Neurological Sciences, Florence (Italy)

    2010-03-15

    The aim of the present study was to evaluate the reciprocal relationships between motor impairment, dopaminergic dysfunction, and cerebral metabolism (rCMRglc) in de novo Parkinson's disease (PD) patients. Twenty-six de novo untreated PD patients were scanned with {sup 123}I-FP-CIT SPECT and {sup 18}F-FDG PET. The dopaminergic impairment was measured with putaminal {sup 123}I-FP-CIT binding potential (BP), estimated with two different techniques: an iterative reconstruction algorithm (BP{sub OSEM}) and the least-squares (LS) method (BP{sub LS}). Statistical parametric mapping (SPM) multiple regression analyses were performed to determine the specific brain regions in which UPDRS III scores and putaminal BP values correlated with rCMRglc. The SPM results showed a negative correlation between UPDRS III and rCMRglc in premotor cortex, and a positive correlation between BP{sub OSEM} and rCMRglc in premotor and dorsolateral prefrontal cortex, not surviving at multiple comparison correction. Instead, there was a positive significant correlation between putaminal BP{sub LS} and rCMRglc in premotor, dorsolateral prefrontal, anterior prefrontal, and orbitofrontal cortex (p < 0.05, corrected for multiple comparison). Putaminal BP{sub LS} is an efficient parameter for exploring the correlations between PD severity and rCMRglc cortical changes. The correlation between dopaminergic degeneration and rCMRglc in several prefrontal regions likely represents the cortical functional correlate of the dysfunction in the motor basal ganglia-cortical circuit in PD. This finding suggests focusing on the metabolic course of these areas to follow PD progression and to analyze treatment effects. (orig.)

  13. High Incidence of De Novo and Subclinical Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy and Cardiac Rhythm Management Device.

    Science.gov (United States)

    Wilke, Iris; Witzel, Katrin; Münch, Julia; Pecha, Simon; Blankenberg, Stephan; Reichenspurner, Hermann; Willems, Stephan; Patten, Monica; Aydin, Ali

    2016-07-01

    Atrial fibrillation (AF) is an important prognostic parameter in patients with hypertrophic cardiomyopathy (HCM). Though cardiac rhythm management (CRM) devices (e.g., ICD, pacemaker or implantable loop recorder) can detect subclinical AF, data describing the incidence of AF are rare. We therefore investigated the incidence and clinical impact of de novo and subclinical AF detected by CRM devices in patients with HCM. In our retrospective single-center study, we included patients with HCM and need for CRM devices. The primary endpoint of the study was the incidence of clinical and subclinical de novo AF. During follow-up, patients were screened for adverse events like stroke, ventricular arrhythmia, heart failure, or death. From 192 HCM patients, 44 patients received a CRM device (38 ICDs, 5 pacemakers, 1 implantable loop recorder). In 14 of these patients (32%), AF had been documented before device implantation. Thirty (68%) patients were free from AF at the time of implantation. During a median follow-up of 595 days (interquartile range, 367-890 days), de novo AF was recorded in 16 of these 30 patients (53%). Fourteen (88%) of the 16 patients with de novo AF were free from any clinical symptoms, so these patients were classified to have subclinical AF. In logistic regression analysis, age was the only significant predictor for an increased risk of AF. AF is common in patients with HCM who need a CRM device. More than 50% of these patients develop de novo AF that was predominantly subclinical in our cohort. © 2016 Wiley Periodicals, Inc.

  14. Organ-Specific Alterations in Fatty Acid De Novo Synthesis and Desaturation in a Rat Model of Programmed Obesity

    Directory of Open Access Journals (Sweden)

    Desai Mina

    2011-05-01

    Full Text Available Abstract Background Small for gestational age (SGA leads to increased risk of adult obesity and metabolic syndrome. Offspring exposed to 50% maternal food restriction in utero are born smaller than Controls (FR, catch-up in growth by the end of the nursing period, and become obese adults. The objective of the study was to determine stearoyl-CoA desaturase activity (SCD1 and rates of de novo fatty acid synthesis in young FR and Control offspring tissues at the end of the nursing period, as possible contributors to catch-up growth. Methods From gestational day 10 to term, dams fed ad libitum (Control or were 50% food-restricted to produce small FR pups. Control dams nursed all pups. At postnatal day 1 (p1 and p21, offspring body tissues were analyzed by GC/MS, and desaturation indices of palmitoleate/palmitate and oleate/stearate were calculated. SCD1 gene expression was determined by real-time PCR on adipose and liver. Offspring were enriched with deuterium that was given to dams in drinking water during lactation and de novo synthesis of offspring body tissues was determined at p21. Primary adipocyte cell cultures were established at p21 and exposed to U13C-glucose. Results FR offspring exhibited higher desaturation index in p1 and p21 adipose tissue, but decreased desaturation index in liver at p21. SCD1 gene expression at p21 was correspondingly increased in adipose and decreased in liver. FR subcutaneous fat demonstrated increased de novo synthesis at p21. Primary cell cultures exhibited increased de novo synthesis in FR. Conclusions Adipose tissue is the first site to exhibit increased de novo synthesis and desaturase activity in FR. Therefore, abnormal lipogenesis is already present prior to onset of obesity during the period of catch-up growth. These abnormalities may contribute to future obesity development.

  15. Melhoramento do cafeeiro: XLII. Produtividade de progênies derivadas de hibridação dos cultivares Laurina e Mundo Novo Coffee breeding: XLII. Yield of progenies from crosses of Laurina and Mundo Novo cultivars of Coffea arabica L.

    Directory of Open Access Journals (Sweden)

    Alcides Carvalho

    1988-01-01

    Full Text Available O cultivar Laurina de Coffea arabica L. caracteriza-se pelo pequeno porte, folhas de dimensões reduzidas, frutos afilados na base, sementes pequenas e afiladas, pequeno rendimento e reduzida produção. Apresenta, no entanto, bebida de boa qualidade e baixo teor de cafeína nas sementes. Suas principais características são controladas pela ação de um par de alelos recessivos lrlr, de acentuado efeito pleiotrópico. Devido ao atual interesse do comércio por produto de baixo teor de cafeína, iniciaram-se pesquisas tendo em vista principalmente aumentar a produtividade do 'Laurina'. Para esse fim, realizaram-se numerosas hibridações de cafeeiros do 'Laurina' com os do 'Mundo Novo' (Coffea arabica e, posteriormente, retrocruzamentos com o 'Mundo Novo'. Estudaram-se as progênies F2 e retrocruzamentos com o 'Mundo Novo' (RC em Campinas, em um experimento, anotando-se as produções por oito anos consecutivos. Separaram-se algumas progênies F2 em dois grupos, antes do plantio: normais (LrLr,Lrlr e laurina (Irlr. Como testemunhas, usaram-se progênies do 'Mundo Novo' e 'Catuaí Amarelo' de C. arabica. O conjunto de plantas F2 do grupo laurina e os retrocruzamentos tiveram produção média maior do que as plantas F2 normais, porém menor do que as testemunhas. Alguns retrocruzamentos e progênies F2 apresentaram plantas com razoável produtividade, indicando que, através de retrocruzamentos com o 'Mundo Novo', podem-se obter novos tipos comerciais com as características morfológicas do 'Laurina'. Fizeram-se considerações sobre a melhor capacidade de combinação do 'Laurina' com algumas seleções do 'Mundo Novo'.The Laurina cultivars of Coffea arabica L. has a reduced plant size, small leaves, small and pointed seeds and low yield capacity. However the seeds have a good cup quality and the desirable characteristic of low caffeine content The Laurina phenotype is supposed to be controlled by a pair of recessive alleles lrlr, with

  16. De novo DESIGN AND SYNTHESIS OF AN ICE-BINDING, DENDRIMERIC, POLYPEPTIDE BASED ON INSECT ANTIFREEZE PROTEINS

    Directory of Open Access Journals (Sweden)

    Ricardo Vera Bravo

    2011-12-01

    Full Text Available A new strategy is presented for the designand synthesis of peptides that exhibitice-binding and antifreeze activity. Apennant-type dendrimer polypeptidescaffold combining an α-helical backbonewith four short β-strand branches wassynthesized in solid phase using Fmocchemistry in a divergent approach. The51-residue dendrimer was characterizedby reverse phase high performance liquidchromatography, mass spectrometry andcircular dichroism. Each β-strand branchcontained three overlapping TXT aminoacid repeats, an ice-binding motif foundin the ice-binding face of the sprucebudworm (Choristoneura fumiferanaand beetle (Tenebrio molitor antifreezeproteins. Ice crystals in the presence ofthe polypeptide monomer displayed flat,hexagonal plate morphology, similar tothat produced by weakly active antifreezeproteins. An oxidized dimeric form of thedendrimer polypeptide also produced flathexagonal ice crystals and was capableof inhibiting ice crystal growth upontemperature reduction, a phenomenontermed thermal hysteresis, a definingproperty of antifreeze proteins. Linkageof the pennant-type dendrimer to a trifunctionalcascade-type polypeptideproduced a trimeric macromolecule thatgave flat hexagonal ice crystals withhigher thermal hysteresis activity thanthe dimer or monomer and an ice crystal burst pattern similar to that producedby samples containing insect antifreezeproteins. This macromolecule was alsocapable of inhibiting ice recrystallization.

  17. De novo fragment-based design of inhibitors of DXS guided by spin-diffusion-based NMR spectroscopy

    NARCIS (Netherlands)

    Masini, T.; Pilger, J.; Kroezen, B. S.; Illarionov, B.; Lottmann, P.; Fischer, M.; Griesinger, C.; Hirsch, A. K. H.

    We applied for the first time an innovative ligand-based NMR methodology (STI) to a medicinal-chemistry project aimed at the development of inhibitors for the enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXS). DXS is the first enzyme of the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway,

  18. Crystal engineering using a "turtlebug" algorithm: A de novo approach to the design of binodal metal-organic frameworks

    KAUST Repository

    McColm, Gregory L.

    2011-09-07

    A new series of computer programs that enumerate three-dimensional periodic embedded nets (i.e., representing crystals) is based on an algorithm that can theoretically enumerate all possible structures for all possible periodic topologies. Unlike extant programs, this algorithm employs algebraic and combinatorial machinery developed during the 1980s in combinatorial and geometric group theory and ancillary fields. This algorithm was validated by a demonstration program that found all strictly binodal periodic edge-transitive 3,4-, 3,6-, 4,4-, and 4,6-coordinated nets listed in the RCSR database. These programs could be used in two ways: to suggest new ways for targeting known nets, and to provide blueprints for new chemically feasible nets. They rely on a discrete version of "turtle geometry" adapted for these nets. © 2011 American Chemical Society.

  19. Tryptophan tags and de novo designed complementary affinity ligands for the expression and purification of recombinant proteins.

    Science.gov (United States)

    Pina, Ana Sofia; Carvalho, Sara; Dias, Ana Margarida G C; Guilherme, Márcia; Pereira, Alice S; Caraça, Luciana T; Coroadinha, Ana Sofia; Lowe, Christopher R; Roque, A Cecília A

    2016-11-11

    A common strategy for the production and purification of recombinant proteins is to fuse a tag to the protein terminal residues and employ a "tag-specific" ligand for fusion protein capture and purification. In this work, we explored the effect of two tryptophan-based tags, NWNWNW and WFWFWF, on the expression and purification of Green Fluorescence Protein (GFP) used as a model fusion protein. The titers obtained with the expression of these fusion proteins in soluble form were 0.11mgml -1 and 0.48mgml -1 for WFWFWF and NWNWNW, respectively. A combinatorial library comprising 64 ligands based on the Ugi reaction was prepared and screened for binding GFP-tagged and non-tagged proteins. Complementary ligands A2C2 and A3C1 were selected for the effective capture of NWNWNW and WFWFWF tagged proteins, respectively, in soluble forms. These affinity pairs displayed 10 6 M -1 affinity constants and Qmax values of 19.11±2.60ugg -1 and 79.39ugg -1 for the systems WFWFWF AND NWNWNW, respectively. GFP fused to the WFWFWF affinity tag was also produced as inclusion bodies, and a refolding-on column strategy was explored using the ligand A4C8, selected from the combinatorial library of ligands but in presence of denaturant agents. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Crystal engineering using a "turtlebug" algorithm: A de novo approach to the design of binodal metal-organic frameworks

    KAUST Repository

    McColm, Gregory L.; Clark, W. Edwin; Eddaoudi, Mohamed; Wojtas, Łukasz; Zaworotko, Michael J.

    2011-01-01

    A new series of computer programs that enumerate three-dimensional periodic embedded nets (i.e., representing crystals) is based on an algorithm that can theoretically enumerate all possible structures for all possible periodic topologies. Unlike extant programs, this algorithm employs algebraic and combinatorial machinery developed during the 1980s in combinatorial and geometric group theory and ancillary fields. This algorithm was validated by a demonstration program that found all strictly binodal periodic edge-transitive 3,4-, 3,6-, 4,4-, and 4,6-coordinated nets listed in the RCSR database. These programs could be used in two ways: to suggest new ways for targeting known nets, and to provide blueprints for new chemically feasible nets. They rely on a discrete version of "turtle geometry" adapted for these nets. © 2011 American Chemical Society.

  1. Membrane interaction and secondary structure of de novo designed arginine-and tryptophan peptides with dual function

    KAUST Repository

    Rydberg, Hanna A.; Carlsson, Nils; Nordé n, Bengt

    2012-01-01

    of arg/trp peptides and investigated how the position and number of tryptophans affect cellular uptake. Here we explore the antimicrobial properties and the interaction with lipid model membranes of these peptides, using minimal inhibitory concentrations

  2. De novo design of ligands for metal separation. Annual progress report, September 15, 1996 - September 14, 1997

    International Nuclear Information System (INIS)

    1997-01-01

    'The specific aim of this report is to parameterize force field to reproduce geometries and relative energetics of metal-ligand complexes for cesium, strontium, plutonium, uranium, americium and other relevent alkali, transition, lanthanide and actinide metals. As an initial attempt to examine parametrization, Dr. Yasuo Takeuchi has examined parameters for iron in combination with the molecular mechanics force field. The authors realize that most of the current ad hoc methodologies used to model metal interactions in the past do not have a firm theoretical foundation for modeling the d and f orbitals. They have, therefore, started a collaboration with Prof. Anders Carlsson of the Department of Physics to provide a theoretically correct functional form for the metal force field. Prof. Carlsson has an extensive track record in the derivation of the form of angular force fields from analysis of the quantum-mechanical electronic structure. His most important related works have treated the angular forces around transition-metal (TM) atoms in an aluminum host, the angular forces in elemental bcc transition metals, and the origins of angular and torsional forces in well-bonded s-p systems. They propose to apply the basic ideas of these calculations to developing force laws for transition metal ions in biomolecules. Of particular relevance to the proposed work is his study analyzing angular forces around transition metal (TM) atoms embedded in an aluminum host. Such TM atoms have a profound effect on the host structure, often entirely reassembling the host structure in order to satisfy the angular bonding constraints around the TM atoms. For example, at a concentration of only 1 ∼ TM to 12 ∼ Al, the transition metals Mn, Mo, Tc, W, and Re form the Al 12 W structure, in which the underlying fcc aluminum lattice is disassembled and reassembled into icosahedra which surround the transition-metal atoms. The Al 12 W structure is a body-centered cubic arrangement of such icosahedra. This behavior is analogous to that of several transition metals in proteins and other potential hosts, for example the formation of square-planar or Jahn-teller distorted octahedral structure by Cu 2+ ions in many proteins. In both cases, the transition metal atom or ion has strong preferences regarding its angular environment. Of course, other effects, such as steric constraints on the ligands, are also important and dominate in some cases.'

  3. High prevalence of morphological subtype FAB M1 in adults with de novo acute myeloid leukemia in São José dos Campos, São Paulo

    Directory of Open Access Journals (Sweden)

    Fernando Callera

    Full Text Available CONTEXT AND OBJECTIVE: Geographical variations have been described in acute myelogenous leukemia (AML. In Brazil, few studies have been published on this. The aim of this study was to demonstrate the high prevalence of French-American-British (FAB M1 subtype in adults with de novo AML in São José dos Campos, State of São Paulo, Brazil. DESIGN AND SETTING: Retrospective analysis, at Hospital Pio XII in São José dos Campos, a public non-teaching institution. METHODS: Records from 39 consecutive adult patients with de novo AML referred to Hospital Pio XII between January 2002 and September 2004 were reviewed. Peripheral blood and blood marrow smears were reviewed blindly by five hematologists and classified according to FAB criteria. The rates of remission, relapse, mortality according treatment phase, survival and leukemia-free survival were calculated. RESULTS: The prevalence of each category as determined via a consensus among five observers was M0: 0%; M1: 43.6%; M2: 30.7%; M3: 12.8%; M4: 5.1%; M5: 2.6%: M6: 2.6%; and M7: 2.6%. The remission and the relapse rates were 82% and 41% respectively. The mortality rate was 69% (induction of remission: 7/39, 17.9%; post induction: 10/32, 31.2%; and relapse: 10/16, 62.5%. The survival rate was 30% and leukemia-free survival was 33%. CONCLUSIONS: The study demonstrated a high prevalence of FAB M1 subtype in adults with de novo AML in São José dos Campos. Our data suggest the occurrence of different regional prevalences of FAB AML categories in Brazil.

  4. Protein Design Using Unnatural Amino Acids

    Science.gov (United States)

    Bilgiçer, Basar; Kumar, Krishna

    2003-11-01

    With the increasing availability of whole organism genome sequences, understanding protein structure and function is of capital importance. Recent developments in the methodology of incorporation of unnatural amino acids into proteins allow the exploration of proteins at a very detailed level. Furthermore, de novo design of novel protein structures and function is feasible with unprecedented sophistication. Using examples from the literature, this article describes the available methods for unnatural amino acid incorporation and highlights some recent applications including the design of hyperstable protein folds.

  5. La nación pluricontinental: La entelequia colonial del Estado Novo (1930-1974

    Directory of Open Access Journals (Sweden)

    Adolfo Cueto Rodríguez

    2013-12-01

    Full Text Available Entre la aprobación del Acto Colonial el 8 julio de 1930 y la caída de la Dictadura en Portugal el 25 de abril de 1974 mediaron casi cuarenta y cuatro años. Durante ese tiempo el imperio luso maduró y vivió diferentes coyunturas internacionales, siempre bajo la tutela de un único régimen político en la Metrópoli. La longevidad del Estado Novo se ha querido explicar por su capacidad de adaptación y resistencia. Sin embargo, fue precisamente en el plano colonial donde ese ejercicio de acomodación mostró con mayor virulencia sus limitaciones. Como antes habían hecho la Monarquía constitucional y la Iª República, el «salazarismo» también aplicó su doctrina política a la administración del ultramar. Pero en su caso, la defensa férrea de la unidad imperial a través de los principios y canales antidemocráticos que le eran propios, y el hecho de hacerlo en un tiempo radicalmente diferente al de los regímenes que lo precedieron, condujo a su colapso y a la emancipación abrupta del Imperio, como es sabido. No obstante, hasta la llegada a ese desenlace, el Régimen no permaneció inmóvil frente a la Descolonización. Al seguimiento de la reflexión en torno a lo que debían y podían ser las relaciones Metrópoli-Ultramar, y al esbozo de lo que fueron las «correcciones» políticoadministrativas consubstanciales, será a lo que dedicaremos el texto que sigue.Nearly forty four years have passed between the approval of the Colonial Act, on the 8th July 1930, and the fall of the Dictatorship in Portugal, on the 25th April 1974. During that time, the Portuguese Empire has matured and lived through different international contexts, always under the rule of a unique regime of the Metrópole. The duration of the Estado Novo is partly explained by its capacity to adjust and endure. However, it was precisely in the colonial context that this «exercise of adjustment» most experienced its limits

  6. Functional characterization of a rice de novo DNA methyltransferase, OsDRM2, expressed in Escherichia coli and yeast

    Energy Technology Data Exchange (ETDEWEB)

    Pang, Jinsong, E-mail: pangjs542@nenu.edu.cn [Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin 130024 (China); Dong, Mingyue; Li, Ning; Zhao, Yanli [Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin 130024 (China); Liu, Bao, E-mail: baoliu@nenu.edu.cn [Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin 130024 (China)

    2013-03-01

    Highlights: ► A rice de novo DNA methyltransferase OsDRM2 was cloned. ► In vitro methylation activity of OsDRM2 was characterized with Escherichia coli. ► Assays of OsDRM2 in vivo methylation were done with Saccharomyces cerevisiae. ► OsDRM2 methylation activity is not preferential to any type of cytosine context. ► The activity of OsDRM2 is independent of RdDM pathway. - Abstract: DNA methylation of cytosine nucleotides is an important epigenetic modification that occurs in most eukaryotic organisms and is established and maintained by various DNA methyltransferases together with their co-factors. There are two major categories of DNA methyltransferases: de novo and maintenance. Here, we report the isolation and functional characterization of a de novo methyltransferase, named OsDRM2, from rice (Oryza sativa L.). The full-length coding region of OsDRM2 was cloned and transformed into Escherichia coli and Saccharomyces cerevisiae. Both of these organisms expressed the OsDRM2 protein, which exhibited stochastic de novo methylation activity in vitro at CG, CHG, and CHH di- and tri-nucleotide patterns. Two lines of evidence demonstrated the de novo activity of OsDRM2: (1) a 5′-CCGG-3′ containing DNA fragment that had been pre-treated with OsDRM2 protein expressed in E. coli was protected from digestion by the CG-methylation-sensitive isoschizomer HpaII; (2) methylation-sensitive amplified polymorphism (MSAP) analysis of S. cerevisiae genomic DNA from transformants that had been introduced with OsDRM2 revealed CG and CHG methylation levels of 3.92–9.12%, and 2.88–6.93%, respectively, whereas the mock control S. cerevisiae DNA did not exhibit cytosine methylation. These results were further supported by bisulfite sequencing of the 18S rRNA and EAF5 genes of the transformed S. cerevisiae, which exhibited different DNA methylation patterns, which were observed in the genomic DNA. Our findings establish that OsDRM2 is an active de novo DNA

  7. Functional characterization of a rice de novo DNA methyltransferase, OsDRM2, expressed in Escherichia coli and yeast

    International Nuclear Information System (INIS)

    Pang, Jinsong; Dong, Mingyue; Li, Ning; Zhao, Yanli; Liu, Bao

    2013-01-01

    Highlights: ► A rice de novo DNA methyltransferase OsDRM2 was cloned. ► In vitro methylation activity of OsDRM2 was characterized with Escherichia coli. ► Assays of OsDRM2 in vivo methylation were done with Saccharomyces cerevisiae. ► OsDRM2 methylation activity is not preferential to any type of cytosine context. ► The activity of OsDRM2 is independent of RdDM pathway. - Abstract: DNA methylation of cytosine nucleotides is an important epigenetic modification that occurs in most eukaryotic organisms and is established and maintained by various DNA methyltransferases together with their co-factors. There are two major categories of DNA methyltransferases: de novo and maintenance. Here, we report the isolation and functional characterization of a de novo methyltransferase, named OsDRM2, from rice (Oryza sativa L.). The full-length coding region of OsDRM2 was cloned and transformed into Escherichia coli and Saccharomyces cerevisiae. Both of these organisms expressed the OsDRM2 protein, which exhibited stochastic de novo methylation activity in vitro at CG, CHG, and CHH di- and tri-nucleotide patterns. Two lines of evidence demonstrated the de novo activity of OsDRM2: (1) a 5′-CCGG-3′ containing DNA fragment that had been pre-treated with OsDRM2 protein expressed in E. coli was protected from digestion by the CG-methylation-sensitive isoschizomer HpaII; (2) methylation-sensitive amplified polymorphism (MSAP) analysis of S. cerevisiae genomic DNA from transformants that had been introduced with OsDRM2 revealed CG and CHG methylation levels of 3.92–9.12%, and 2.88–6.93%, respectively, whereas the mock control S. cerevisiae DNA did not exhibit cytosine methylation. These results were further supported by bisulfite sequencing of the 18S rRNA and EAF5 genes of the transformed S. cerevisiae, which exhibited different DNA methylation patterns, which were observed in the genomic DNA. Our findings establish that OsDRM2 is an active de novo DNA

  8. Differences in Recurrence Rate and De Novo Incontinence after Endoscopic Treatment of Vesicourethral Stenosis and Bladder Neck Stenosis

    Directory of Open Access Journals (Sweden)

    Jennifer Kranz

    2017-08-01

    Full Text Available ObjectivesThe objective of this study was to compare the recurrence rate and de novo incontinence after endoscopic treatment of vesicourethral stenosis (VUS after radical prostatectomy (RP and for bladder neck stenosis (BNS after transurethral resection of the prostate (TURP.MethodsRetrospective analysis of patients treated endoscopically for VUS after RP or for BNS after TURP at three German tertiary care centers between March 2009 and June 2016. Investigated endpoints were recurrence rate and de novo incontinence. Chi-squared tests and t-tests were used to model the differences between groups.ResultsA total of 147 patients underwent endoscopic therapy for VUS (59.2% or BNS (40.8%. Mean age was 68.3 years (range 44–86, mean follow-up 27.1 months (1–98. Mean time to recurrence after initial therapy was 23.9 months (1–156, mean time to recurrence after prior endoscopic therapy for VUS or BNS was 12.0 months (1–159. Patients treated for VUS underwent significantly more often radiotherapy prior to endoscopic treatment (33.3 vs. 13.3%; p = 0.006 and the recurrence rate was significantly higher (59.8 vs. 41.7%; p = 0.031. The overall success rate of TUR for VUS was 40.2%, success rate of TUR for BNS was 58.3%. TUR for BNS is significantly more successful (p = 0.031. The mean number of TUR for BNS vs. TUR for VUS in successful cases was 1.5 vs. 1.8, which was not significantly different. The rate of de novo incontinence was significantly higher in patients treated for VUS (13.8 vs. 1.7%; p = 0.011. After excluding those patients with radiotherapy prior to endoscopic treatment, the recurrence rate did not differ significantly between both groups (60.3% for VUS vs. 44.2% for BNS; p = 0.091, whereas the rate of de novo incontinence (13.8 for VUS vs. 0% for BNS; p = 0.005 stayed significantly higher in patients treated for VUS.ConclusionMost patients with BNS are successfully treated endoscopically. In patients with

  9. Design Methodology - Design Synthesis

    DEFF Research Database (Denmark)

    Andreasen, Mogens Myrup

    2003-01-01

    Design Methodology is part of our practice and our knowledge about designing, and it has been strongly supported by the establishing and work of a design research community. The aim of this article is to broaden the reader¿s view of designing and Design Methodology. This is done by sketching...... the development of Design Methodology through time and sketching some important approaches and methods. The development is mainly forced by changing industrial condition, by the growth of IT support for designing, but also by the growth of insight into designing created by design researchers.......ABSTRACT Design Methodology shall be seen as our understanding of how to design; it is an early (emerging late 60ies) and original articulation of teachable and learnable methodics. The insight is based upon two sources: the nature of the designed artefacts and the nature of human designing. Today...

  10. Novos sedativos hipnóticos The newer sedative-hypnotics

    Directory of Open Access Journals (Sweden)

    Lucia Sukys-Claudino

    2010-09-01

    Full Text Available Nas últimas décadas houve um esforço para o desenvolvimento de hipnóticos mais seguros e eficazes. Zolpidem, zaleplona, zopiclona, eszopiclona (drogas-z e indiplona são moduladores do receptor GABA-A, os quais agem de forma seletiva na subunidade α1, exibindo, desta forma, mecanismos similares de ação, embora evidências recentes sugiram que a eszopiclona não seja tão seletiva para a subunidade α1 quanto o zolpidem. Ramelteon e tasimelteon são novos agentes crono-hipnóticos seletivos para os receptores de melatonina MT1 e MT2. Por outro lado, nos últimos anos, o consumo de drogas antidepressivas sedativas tem aumentado significativamente no tratamento da insônia. Como droga experimental, a eplivanserina tem sido testada como um potente agonista inverso do subtipo 5-HT2A da serotonina, com um uso potencial na dificuldade da manutenção do sono. Outro agente farmacológico para o tratamento da insônia é o almorexant, o qual apresenta um novo mecanismo de ação envolvendo antagonismo do sistema hipocretinérgico, desta forma levando à indução do sono. Finalmente, também discutiremos o potencial papel de outras drogas gabaérgicas no tratamento da insônia.There has been a search for more effective and safe hypnotic drugs in the last decades. Zolpidem, zaleplon, zopiclone, eszopiclone (the z-drugs and indiplon are GABA-A modulators which bind selectively α1 subunits, thus, exhibiting similar mechanisms of action, although recent evidence suggests that eszopiclone is not as selective for α1 subunit as zolpidem is. Ramelteon and tasimelteon are new chrono-hypnotic agents, selective for melatonin MT1 and MT2 receptors. On the other hand, the consumption of sedative antidepressant drugs is significantly increasing for the treatment of insomnia, in the last years. As an experimental drug, eplivanserin is being tested as a potent antagonist of serotonin 2-A receptors (ASTAR with a potential use in sleep maintenance difficulty

  11. De novo assembly of Phlomis purpurea after challenging with Phytophthora cinnamomi.

    Science.gov (United States)

    Baldé, Aladje; Neves, Dina; García-Breijo, Francisco J; Pais, Maria Salomé; Cravador, Alfredo

    2017-09-06

    Phlomis plants are a source of biological active substances with potential applications in the control of phytopathogens. Phlomis purpurea (Lamiaceae) is autochthonous of southern Iberian Peninsula and Morocco and was found to be resistant to Phytophthora cinnamomi. Phlomis purpurea has revealed antagonistic effect in the rhizosphere of Quercus suber and Q. ilex against P. cinnamomi. Phlomis purpurea roots produce bioactive compounds exhibiting antitumor and anti-Phytophthora activities with potential to protect susceptible plants. Although these important capacities of P. purpurea have been demonstrated, there is no transcriptomic or genomic information available in public databases that could bring insights on the genes underlying this anti-oomycete activity. Using Illumina technology we obtained a de novo assembly of P. purpurea transcriptome and differential transcript abundance to identify putative defence related genes in challenged versus non-challenged plants. A total of 1,272,600,000 reads from 18 cDNA libraries were merged and assembled into 215,739 transcript contigs. BLASTX alignment to Nr NCBI database identified 124,386 unique annotated transcripts (57.7%) with significant hits. Functional annotation identified 83,550 out of 124,386 unique transcripts, which were mapped to 141 pathways. 39% of unigenes were assigned GO terms. Their functions cover biological processes, cellular component and molecular functions. Genes associated with response to stimuli, cellular and primary metabolic processes, catalytic and transporter functions were among those identified. Differential transcript abundance analysis using DESeq revealed significant differences among libraries depending on post-challenge times. Comparative cyto-histological studies of P. purpurea roots challenged with P. cinnamomi zoospores and controls revealed specific morphological features (exodermal strips and epi-cuticular layer), that may provide a constitutive efficient barrier against

  12. A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle.

    Science.gov (United States)

    Agerholm, Jørgen S; McEvoy, Fintan J; Heegaard, Steffen; Charlier, Carole; Jagannathan, Vidhya; Drögemüller, Cord

    2017-08-02

    Surveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause. Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire. FDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given

  13. Failure of Noninvasive Ventilation for De Novo Acute Hypoxemic Respiratory Failure: Role of Tidal Volume.

    Science.gov (United States)

    Carteaux, Guillaume; Millán-Guilarte, Teresa; De Prost, Nicolas; Razazi, Keyvan; Abid, Shariq; Thille, Arnaud W; Schortgen, Frédérique; Brochard, Laurent; Brun-Buisson, Christian; Mekontso Dessap, Armand

    2016-02-01

    A low or moderate expired tidal volume can be difficult to achieve during noninvasive ventilation for de novo acute hypoxemic respiratory failure (i.e., not due to exacerbation of chronic lung disease or cardiac failure). We assessed expired tidal volume and its association with noninvasive ventilation outcome. Prospective observational study. Twenty-four bed university medical ICU. Consecutive patients receiving noninvasive ventilation for acute hypoxemic respiratory failure between August 2010 and February 2013. Noninvasive ventilation was uniformly delivered using a simple algorithm targeting the expired tidal volume between 6 and 8 mL/kg of predicted body weight. Expired tidal volume was averaged and respiratory and hemodynamic variables were systematically recorded at each noninvasive ventilation session. Sixty-two patients were enrolled, including 47 meeting criteria for acute respiratory distress syndrome, and 32 failed noninvasive ventilation (51%). Pneumonia (n = 51, 82%) was the main etiology of acute hypoxemic respiratory failure. The median (interquartile range) expired tidal volume averaged over all noninvasive ventilation sessions (mean expired tidal volume) was 9.8 mL/kg predicted body weight (8.1-11.1 mL/kg predicted body weight). The mean expired tidal volume was significantly higher in patients who failed noninvasive ventilation as compared with those who succeeded (10.6 mL/kg predicted body weight [9.6-12.0] vs 8.5 mL/kg predicted body weight [7.6-10.2]; p = 0.001), and expired tidal volume was independently associated with noninvasive ventilation failure in multivariate analysis. This effect was mainly driven by patients with PaO2/FIO2 up to 200 mm Hg. In these patients, the expired tidal volume above 9.5 mL/kg predicted body weight predicted noninvasive ventilation failure with a sensitivity of 82% and a specificity of 87%. A low expired tidal volume is almost impossible to achieve in the majority of patients receiving noninvasive ventilation

  14. Globalização: novo paradigma das ciências sociais

    Directory of Open Access Journals (Sweden)

    Octavio Ianni

    1994-08-01

    Full Text Available As ciências sociais estão sendo desafiadas a pensar a globalização do mundo. No fim do século XX, quando se anuncia o XXI, elas se defrontam com os dilemas que se abrem com a globalização das coisas, gentes e idéias. Há processos e estruturas sociais, econômicos, políticos, culturais e outros que apenas começam a ser estudados. Além do que é local, nacional e regional, colocam-se problemas novos e fundamentais com a emergência da sociedade global. As fronteiras geográficas e históricas, culturais e civilizatórias parecem modificar-se em direções e formas surpreendentes. Indivíduo, grupo, classe, coletividade e povo são colocados diante de outros horizontes. O próprio pensamento científico é desafiado a elaborar conceitos e interpretações para dar conta de realidades pouco conhecidas. As teorias da globalização, que começam a ser esboçadas, revelam o empenho das ciências sociais em explicar o que há de novo no que vai pelo mundo.Social sciences are now being challenged to think on the world's globalization. At the end of the twentieth century and dawn of the twenty first, they are faced with the dilemas that open up with the globalization of things, people and ideas: There are social, economical, political, cultural and other processes and structures that are just begining to be studied. Besides what is local, national and regional, new and fundamental problems appear with the rising global society. The geographic, historical, cultural and civilizatorian limits seem to change in surprising ways and directions. The individual, group, class, colectivity and people are put before other horizons. The scientific thinking itself is called upon to elaborate concepts and interpretations to account for little known realities. The globalization theories that are just being sketched show the efforts of Social Sciences to explain what is new going on in the world.

  15. Transcription and chromatin determinants of de novo DNA methylation timing in oocytes.

    Science.gov (United States)

    Gahurova, Lenka; Tomizawa, Shin-Ichi; Smallwood, Sébastien A; Stewart-Morgan, Kathleen R; Saadeh, Heba; Kim, Jeesun; Andrews, Simon R; Chen, Taiping; Kelsey, Gavin

    2017-01-01

    Gametogenesis in mammals entails profound re-patterning of the epigenome. In the female germline, DNA methylation is acquired late in oogenesis from an essentially unmethylated baseline and is established largely as a consequence of transcription events. Molecular and functional studies have shown that imprinted genes become methylated at different times during oocyte growth; however, little is known about the kinetics of methylation gain genome wide and the reasons for asynchrony in methylation at imprinted loci. Given the predominant role of transcription, we sought to investigate whether transcription timing is rate limiting for de novo methylation and determines the asynchrony of methylation events. Therefore, we generated genome-wide methylation and transcriptome maps of size-selected, growing oocytes to capture the onset and progression of methylation. We find that most sequence elements, including most classes of transposable elements, acquire methylation at similar rates overall. However, methylation of CpG islands (CGIs) is delayed compared with the genome average and there are reproducible differences amongst CGIs in onset of methylation. Although more highly transcribed genes acquire methylation earlier, the major transitions in the oocyte transcriptome occur well before the de novo methylation phase, indicating that transcription is generally not rate limiting in conferring permissiveness to DNA methylation. Instead, CGI methylation timing negatively correlates with enrichment for histone 3 lysine 4 (H3K4) methylation and dependence on the H3K4 demethylases KDM1A and KDM1B, implicating chromatin remodelling as a major determinant of methylation timing. We also identified differential enrichment of transcription factor binding motifs in CGIs acquiring methylation early or late in oocyte growth. By combining these parameters into multiple regression models, we were able to account for about a fifth of the variation in methylation timing of CGIs. Finally

  16. Risk Factors for De Novo Malignancies in Women After Kidney Transplantation: A Multicenter Transversal Study.

    Science.gov (United States)

    Helmy, Samir; Marschalek, Julian; Bader, Yvonne; Koch, Marianne; Schmidt, Alice; Kanzler, Marina; Gyoeri, Georg; Polterauer, Stephan; Reinthaller, Alexander; Grimm, Christoph

    2016-06-01

    Transplantation results in a 5-time elevated risk for a variety of malignancies (Kaposi sarcoma, skin, liver, lung, gastrointestinal cancer). A patient's risk for malignancies could be of particular interest for the follow-up programs of patients and risk adaption after kidney transplantation. The aim of this study was to identify independent risk factors for de novo malignancies in women after renal transplantation. This is a multicenter transversal study, conducted at the Medical University of Vienna and Hospital Rudolfstiftung, Vienna, Austria. We included female kidney graft recipients who were transplanted between 1980 and 2012 and followed-up at our institutions (N = 280). Clinical data of patients were extracted from hospital charts and electronic patient files. Patients were interviewed using a standardized questionnaire regarding their medical history, history of transplantation, and malignant diseases. Detailed information about present and past immunosuppressive regimens, rejection episodes and therapies, renal graft function, and information about primary disease was obtained. Diagnostic work-up and/or surgical exploration was performed if any presence of malignancy was suspected during routine follow-up. Histological specimens were obtained from all patients. the presence of de novo malignancy after kidney transplantation. Two hundred sixty-two women were included for statistical analysis. Median (interquartile range) follow-up period after transplantation was 101.1 (27.3-190.7) months. Thirty-two patients (12.2%) developed a malignancy: dermatologic malignancies (5.7%), breast cancer (3.4%), cervical cancer (0.8%), lung cancer (0.4%), gastrointestinal malignancies (1.5%), vulvar cancer (0.4%), and unclassified malignancies (1.9%). Median (interquartile range) time to malignancy after transplantation was 185.9 (92.0-257.6) months. Cumulative cancer rates were 4.9% (1 year), 14.4% (3 years), 16.4% (5 years), and 21.8% (10 years). Second transplantations

  17. Os novos paradigmas do direito e o poder transformador da jurisdição

    Directory of Open Access Journals (Sweden)

    Emília Simeão Albino Sako

    2002-12-01

    Full Text Available The domain of information and technology implied social transformations and caused one of the major crisis of Law's regulating capacity. In cross-modernity, Positive Law faces a social context marked by misery, dissatisfaction, insecurity, and exclusion, problems caused mostly by inhumane economic practices, centered in the idea of profit and, by means of research, carried out in vulnerable human beings, animals, and vegetables. The new courses of economy, politics, science, and technology demand a new way of thinking and of applying Law. The judge has to fill the gaps and imperfections of Positive Law and, in the solution of troublesome cases, often times he/she will have to go beyond its traditional genetics, that is, beyond the right traditionally created by the State. When Positive Law does not present at least one answer to the problem, the judge will have to make use of the legal system, to mould the facts to the Law or the Law to the facts so that a solution is provided.O domínio da informação e os avanços da ciência e da tecnologia implicaram transformações sociais e ensejaram uma das maiores crises da capacidade reguladora do direito. Na pós-modernidade, o direito positivo depara-se com um contexto social marcado pela miséria, insatisfação, insegurança e exclusão, mazelas causadas principalmente pelas práticas econômicas desumanas, centradas na idéia de lucro, e pelas pesquisas, realizadas em seres humanos vulneráveis, em animais e vegetais. Os novos rumos da economia, política, ciência e tecnologia exigem do intérprete, principalmente do juiz, um novo modo de pensar e aplicar o direito. O juiz tem de suprir as faltas e imperfeições do direito positivo e, na solução dos casos problemáticos, muitas vezes, tem de ir além de sua genética tradicional, ou seja, além do direito tradicionalmente criado pelo Estado. Quando o direito positivo não apresentar pelo menos uma resposta ao problema, o juiz terá de

  18. Combining independent de novo assemblies optimizes the coding transcriptome for nonconventional model eukaryotic organisms.

    Science.gov (United States)

    Cerveau, Nicolas; Jackson, Daniel J

    2016-12-09

    Next-generation sequencing (NGS) technologies are arguably the most revolutionary technical development to join the list of tools available to molecular biologists since PCR. For researchers working with nonconventional model organisms one major problem with the currently dominant NGS platform (Illumina) stems from the obligatory fragmentation of nucleic acid material that occurs prior to sequencing during library preparation. This step creates a significant bioinformatic challenge for accurate de novo assembly of novel transcriptome data. This challenge becomes apparent when a variety of modern assembly tools (of which there is no shortage) are applied to the same raw NGS dataset. With the same assembly parameters these tools can generate markedly different assembly outputs. In this study we present an approach that generates an optimized consensus de novo assembly of eukaryotic coding transcriptomes. This approach does not represent a new assembler, rather it combines the outputs of a variety of established assembly packages, and removes redundancy via a series of clustering steps. We test and validate our approach using Illumina datasets from six phylogenetically diverse eukaryotes (three metazoans, two plants and a yeast) and two simulated datasets derived from metazoan reference genome annotations. All of these datasets were assembled using three currently popular assembly packages (CLC, Trinity and IDBA-tran). In addition, we experimentally demonstrate that transcripts unique to one particular assembly package are likely to be bioinformatic artefacts. For all eight datasets our pipeline generates more concise transcriptomes that in fact possess more unique annotatable protein domains than any of the three individual assemblers we employed. Another measure of assembly completeness (using the purpose built BUSCO databases) also confirmed that our approach yields more information. Our approach yields coding transcriptome assemblies that are more likely to be

  19. A randomized, double-blind, cross-over, phase IV trial of oros-methylphenidate (CONCERTA(®)) and generic novo-methylphenidate ER-C (NOVO-generic).

    Science.gov (United States)

    Fallu, Angelo; Dabouz, Farida; Furtado, Melissa; Anand, Leena; Katzman, Martin A

    2016-08-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with onset during childhood. Multiple aspects of a child's development are hindered, in both home and school settings, with negative impacts on social, emotional, and cognitive functioning. If left untreated, ADHD is commonly associated with poor academic achievement and low occupational status, as well as increased risk of substance abuse and delinquency. The objective of this study was to evaluate adult ADHD subject reported outcomes when switched from a stable dose of CONCERTA(®) to the same dose of generic Novo-methylphenidate ER-C(®). Randomized, double-blind, cross-over, phase IV trial consisted of two phases in which participants with a primary diagnosis of ADHD were randomized in a 1:1 ratio to 3 weeks of treatment with CONCERTA or generic Novo-Methylphenidate ER-C. Following 3 weeks of treatment, participants were crossed-over to receive the other treatment for an additional 3 weeks. Primary efficacy was assessed through the use of the Treatment Satisfaction Questionnaire for Medication, Version II (TSQM-II). Participants with ADHD treated with CONCERTA were more satisfied in terms of efficacy and side effects compared to those receiving an equivalent dose of generic Novo-Methylphenidate ER-C. All participants chose to continue with CONCERTA treatment at the conclusion of the study. Although CONCERTA and generic Novo-Methylphenidate ER-C have been deemed bioequivalent, however the present findings demonstrate clinically and statistically significant differences between generic and branded CONCERTA. Further investigation of these differences is warranted.

  20. Designing Material Materialising Design

    DEFF Research Database (Denmark)

    Nicholas, Paul

    2013-01-01

    Designing Material Materialising Design documents five projects developed at the Centre for Information Technology and Architecture (CITA) at the Royal Danish Academy of Fine Arts, School of Architecture. These projects explore the idea that new designed materials might require new design methods....... Focusing on fibre reinforced composites, this book sustains an exploration into the design and making of elastically tailored architectural structures that rely on the use of computational design to predict sensitive interdependencies between geometry and behaviour. Developing novel concepts...