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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 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.

  4. Pathway design using de novo steps through uncharted biochemical spaces.

    Science.gov (United States)

    Kumar, Akhil; Wang, Lin; Ng, Chiam Yu; Maranas, Costas D

    2018-01-12

    Existing retrosynthesis tools generally traverse production routes from a source to a sink metabolite using known enzymes or de novo steps. Generally, important considerations such as blending known transformations with putative steps, complexity of pathway topology, mass conservation, cofactor balance, thermodynamic feasibility, microbial chassis selection, and cost are largely dealt with in a posteriori fashion. The computational procedure we present here designs bioconversion routes while simultaneously considering any combination of the aforementioned design criteria. First, we track and codify as rules all reaction centers using a prime factorization-based encoding technique (rePrime). Reaction rules and known biotransformations are then simultaneously used by the pathway design algorithm (novoStoic) to trace both metabolites and molecular moieties through balanced bio-conversion strategies. We demonstrate the use of novoStoic in bypassing steps in existing pathways through putative transformations, assembling complex pathways blending both known and putative steps toward pharmaceuticals, and postulating ways to biodegrade xenobiotics.

  5. 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.

  6. NovoFLAP: A ligand-based de novo design approach for the generation of medicinally relevant ideas.

    Science.gov (United States)

    Damewood, James R; Lerman, Charles L; Masek, Brian B

    2010-07-26

    NovoFLAP is a computer-aided de novo design tool that generates medicinally relevant ideas for ligand-based projects. The approach combines an evolutionary algorithm (EA-Inventor) with a powerful ligand-based scoring function that uses both molecular shape and pharmacophore features in a multiconformational context (FLAP). We demonstrate that NovoFLAP can generate novel ideas that are not only appealing to design scientists but are also validated by comparison to compounds known to demonstrate activity at the desired biological target. NovoFLAP provides a novel computer-aided design technique that can be used to generate ideas that maintain desirable molecular attributes, such as activity at the primary biological target, while offering opportunities to surmount additional design challenges. Application to the design of the first nonbasic 5HT(1B) antagonist is presented.

  7. Perspectivas aos "novos designers de moda" no mercado de trabalho

    OpenAIRE

    Venturelli, Valéria Gomes Denelle

    2010-01-01

    Este trabalho tem como objetivo investigar os jovens que escolhem o curso de Negócios da Moda (com o foco em criação) na Universidade Anhembi Morumbi que conseguem trabalhar nessa área quando se formam e como é este processo. Sabemos que isto engloba entender de que forma a produção criativa desse novo designer de moda é assimilada pelo mercado de trabalho. Uma primeira entrevista foi realizada com o intuito de identificar o grupo de 33 alunos que optaram pelo curso de Negócios da Moda na Uni...

  8. Accurate de novo design of hyperstable constrained peptides

    Energy Technology Data Exchange (ETDEWEB)

    Bhardwaj, Gaurav; Mulligan, Vikram Khipple; Bahl, Christopher D.; Gilmore, Jason M.; Harvey, Peta J.; Cheneval, Olivier; Buchko, Garry W.; Pulavarti, Surya V. S. R. K.; Kaas, Quentin; Eletsky, Alexander; Huang, Po-Ssu; Johnsen, William A.; Greisen, Per Jr; Rocklin, Gabriel J.; Song, Yifan; Linsky, Thomas W.; Watkins, Andrew; Rettie, Stephen A.; Xu, Xianzhong; Carter, Lauren P.; Bonneau, Richard; Olson, James M.; Coutsias, Evangelos; Correnti, Colin E.; Szyperski, Thomas; Craik, David J.; Baker, David

    2016-09-14

    Covalently-crosslinked peptides present attractive opportunities for developing new therapeutics. Lying between small molecule and protein therapeutics in size, natural crosslinked peptides play critical roles in signaling, virulence and immunity. Engineering novel peptides with precise control over their three-dimensional structures is a significant challenge. Here we describe the development of computational methods for de novo design of conformationally-restricted peptides, and the use of these methods to design hyperstable disulfide-stabilized miniproteins, heterochiral peptides, and N-C cyclic peptides. Experimentally-determined X-ray and NMR structures for 12 of the designs are nearly identical to the computational models. The computational design methods and stable scaffolds provide the basis for a new generation of peptide-based drugs.

  9. The quest for novel chemical matter and the contribution of computer-aided de novo design.

    Science.gov (United States)

    Pirard, Bernard

    2011-03-01

    Identifying novel chemical matter is the focus of many drug discovery efforts. Through these efforts, computer-based de novo design of drug-like molecules, which aim to build an entire molecule 'from scratch', has emerged as a valuable approach to identify novel chemical matter. In this paper, the author discusses the recent research efforts that aim to build, in silico, more chemically accessible molecules, sample more efficiently the chemical space and rank the proposed molecules. The author reviews de novo design algorithms developed between 2008 and 2010 and the issue of validation, and highlights some recent successful applications of de novo design to drug discovery projects. Although research has addressed the lack of synthetic accessibility of the molecules proposed by the first generation of de novo design tools, the lack of accurate scoring function remains a major limitation of structure-based de novo design. However, de novo design is a valuable approach to generate either chemical starting points or ideas.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. Molecular de-novo design through deep reinforcement learning.

    Science.gov (United States)

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

    2017-09-04

    This work introduces a method to tune a sequence-based generative model for molecular de novo design that through augmented episodic likelihood can learn to generate structures with certain specified desirable properties. We demonstrate how this model can execute a range of tasks such as generating analogues to a query structure and generating compounds predicted to be active against a biological target. As a proof of principle, the model is first trained to generate molecules that do not contain sulphur. As a second example, the model is trained to generate analogues to the drug Celecoxib, a technique that could be used for scaffold hopping or library expansion starting from a single molecule. Finally, when tuning the model towards generating compounds predicted to be active against the dopamine receptor type 2, the model generates structures of which more than 95% are predicted to be active, including experimentally confirmed actives that have not been included in either the generative model nor the activity prediction model. Graphical abstract .

  15. Adversarial Threshold Neural Computer for Molecular de Novo Design.

    Science.gov (United States)

    Putin, Evgeny; Asadulaev, Arip; Vanhaelen, Quentin; Ivanenkov, Yan; Aladinskaya, Anastasia V; Aliper, Alex; Zhavoronkov, Alex

    2018-03-30

    In this article, we propose the deep neural network Adversarial Threshold Neural Computer (ATNC). The ATNC model is intended for the de novo design of novel small-molecule organic structures. The model is based on generative adversarial network architecture and reinforcement learning. ATNC uses a Differentiable Neural Computer as a generator and has a new specific block, called adversarial threshold (AT). AT acts as a filter between the agent (generator) and the environment (discriminator + objective reward functions). Furthermore, to generate more diverse molecules we introduce a new objective reward function named Internal Diversity Clustering (IDC). In this work, ATNC is tested and compared with the ORGANIC model. Both models were trained on the SMILES string representation of the molecules, using four objective functions (internal similarity, Muegge druglikeness filter, presence or absence of sp 3 -rich fragments, and IDC). The SMILES representations of 15K druglike molecules from the ChemDiv collection were used as a training data set. For the different functions, ATNC outperforms ORGANIC. Combined with the IDC, ATNC generates 72% of valid and 77% of unique SMILES strings, while ORGANIC generates only 7% of valid and 86% of unique SMILES strings. For each set of molecules generated by ATNC and ORGANIC, we analyzed distributions of four molecular descriptors (number of atoms, molecular weight, logP, and tpsa) and calculated five chemical statistical features (internal diversity, number of unique heterocycles, number of clusters, number of singletons, and number of compounds that have not been passed through medicinal chemistry filters). Analysis of key molecular descriptors and chemical statistical features demonstrated that the molecules generated by ATNC elicited better druglikeness properties. We also performed in vitro validation of the molecules generated by ATNC; results indicated that ATNC is an effective method for producing hit compounds.

  16. 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.

  17. Reaction-driven de novo design, synthesis and testing of potential type II kinase inhibitors.

    Science.gov (United States)

    Schneider, Gisbert; Geppert, Tim; Hartenfeller, Markus; Reisen, Felix; Klenner, Alexander; Reutlinger, Michael; Hähnke, Volker; Hiss, Jan A; Zettl, Heiko; Keppner, Sarah; Spänkuch, Birgit; Schneider, Petra

    2011-03-01

    De novo design of drug-like compounds with a desired pharmacological activity profile has become feasible through innovative computer algorithms. Fragment-based design and simulated chemical reactions allow for the rapid generation of candidate compounds as blueprints for organic synthesis. We used a combination of complementary virtual-screening tools for the analysis of de novo designed compounds that were generated with the aim to inhibit inactive polo-like kinase 1 (Plk1), a target for the development of cancer therapeutics. A homology model of the inactive state of Plk1 was constructed and the nucleotide binding pocket conformations in the DFG-in and DFG-out state were compared. The de novo-designed compounds were analyzed using pharmacophore matching, structure-activity landscape analysis, and automated ligand docking. One compound was synthesized and tested in vitro. The majority of the designed compounds possess a generic architecture present in known kinase inhibitors. Predictions favor kinases as targets of these compounds but also suggest potential off-target effects. Several bioisosteric replacements were suggested, and de novo designed compounds were assessed by automated docking for potential binding preference toward the inactive (type II inhibitors) over the active conformation (type I inhibitors) of the kinase ATP binding site. One selected compound was successfully synthesized as suggested by the software. The de novo-designed compound exhibited inhibitory activity against inactive Plk1 in vitro, but did not show significant inhibition of active Plk1 and 38 other kinases tested. Computer-based de novo design of screening candidates in combination with ligand- and receptor-based virtual screening generates motivated suggestions for focused library design in hit and lead discovery. Attractive, synthetically accessible compounds can be obtained together with predicted on- and off-target profiles and desired activities.

  18. 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.

  19. Advanced approaches for the characterization of a de novo designed antiparallel coiled coil peptide

    NARCIS (Netherlands)

    Pagel, K; Seeger, K; Seiwert, B; Villa, Alessandra; Mark, AE; Berger, S; Koksch, B

    2005-01-01

    We report here an advanced approach for the characterization of the folding pattern of a de novo designed antiparallel coiled coil peptide by high-resolution methods. Incorporation of two fluorescence labels at the C- and N-terminus of the peptide chain as well as modi. cation of two hydrophobic

  20. De Novo Design of Iron-Sulfur Proteins.

    Science.gov (United States)

    Dizicheh, Zahra B; Halloran, Nicholas; Asma, William; Ghirlanda, Giovanna

    2017-01-01

    Iron-sulfur proteins are one of the most abundant and functionally pliable redox proteins found in all living organisms. Because of their crucial role in mediating electron transfer processes, minimalist model systems have been developed as a proxy to study natural Fe-S redox proteins and to dissect rules to enable tuning of their redox and electron transfer activities. This goal has been pursued through computational design, mutagenesis in the first and second coordination sphere, metal substitution, cofactor replacement, and the use of unnatural amino acids to stabilize a given cluster. In this chapter, we discuss the most recent design strategies to introduce various Fe-S clusters into natural and artificial protein scaffolds. Practical approaches for the cluster reconstitution, hydrogen production, and electrochemical characterization are mentioned. © 2017 Elsevier Inc. All rights reserved.

  1. 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

    2017-01-01

    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 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. PMID:26225466

  2. De Novo Design of a Tumor-Penetrating Peptide

    Science.gov (United States)

    Alberici, Luca; Roth, Lise; Sugahara, Kazuki N.; Agemy, Lilach; Kotamraju, Venkata R.; Teesalu, Tambet; Bordignon, Claudio; Traversari, Catia; Rizzardi, Gian-Paolo; Ruoslahti, Erkki

    2012-01-01

    Poor penetration of anti-tumor drugs into the extravascular tumor tissue isoften a major factor limiting the efficacy of cancer treatments. Our group has recently described a strategy to enhance tumor penetration of chemotherapeutic drugs through use of iRGD peptide (CRGDK/RGPDC). This peptide comprises two sequence motifs: RGD, which binds to αvβ3/5 integrins on tumor endothelia and tumor cells and a cryptic CendR motif (R/KXXR/K-OH). Once integrin binding has brought iRGD to the tumor, the peptide is proteolytically cleaved to expose the cryptic CendR motif. The truncated peptide loses affinity for its primary receptor and binds to neuropilin-1, activating a tissue-penetration pathway that delivers the peptide along with attached or co-administered payload into the tumor mass. Here we describe the design of a new tumor-penetrating peptide based on the current knowledge of homing sequences and internalizing receptors. The tumor-homing motif in the new peptide is the NGR sequence, which binds to endothelial CD13. The NGR sequence was placed in the context of a CendR motif (RNGR), and this sequence was embedded in the iRGD framework. The resulting peptide (CRNGRGPDC, iNGR) homed to tumor vessels and penetrated into tumor tissue more effectively than the standard NGR peptide. iNGR induced greater tumor penetration of coupled nanoparticles and co-administered compounds than NGR. Doxorubicin given together with iNGR was significantly more efficacious than the drug alone. These results show that a tumor-specific, tissue-penetrating peptide can be constructed from known sequence elements. This principle may be useful in designing tissue-penetrating peptides for other diseases. PMID:23151901

  3. Designing active template molecules by combining computational de novo design and human chemist's expertise.

    Science.gov (United States)

    Lameijer, Eric-Wubbo; Tromp, Reynier A; Spanjersberg, Ronald F; Brussee, Johannes; Ijzerman, Adriaan P

    2007-04-19

    We used a new software tool for de novo design, the "Molecule Evoluator", to generate a number of small molecules. Explicit constraints were a relatively low molecular weight and otherwise limited functionality, for example, low numbers of hydrogen bond donors and acceptors, one or two aromatic rings, and a small number of rotatable bonds. In this way, we obtained a collection of scaffold- or templatelike molecules rather than fully "decorated" ones. We asked medicinal chemists to evaluate the suggested molecules for ease of synthesis and overall appeal, allowing them to make structural changes to the molecules for these reasons. On the basis of their recommendations, we synthesized eight molecules with an unprecedented (not patented) yet simple structure, which were subsequently tested in a screen of 83 drug targets, mostly G protein-coupled receptors. Four compounds showed affinity for biogenic amine targets (receptor, ion channel, and transport protein), reflecting the training of the medicinal chemists involved. Apparently the generation of leadlike solutions helped the medicinal chemists to select good starting points for future lead optimization, away from existing compound libraries.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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

    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 ...

  9. Cryo-transmission electron microscopy structure of a gigadalton peptide fiber of de novo design.

    Science.gov (United States)

    Sharp, Thomas H; Bruning, Marc; Mantell, Judith; Sessions, Richard B; Thomson, Andrew R; Zaccai, Nathan R; Brady, R Leo; Verkade, Paul; Woolfson, Derek N

    2012-08-14

    Nature presents various protein fibers that bridge the nanometer to micrometer regimes. These structures provide inspiration for the de novo design of biomimetic assemblies, both to address difficulties in studying and understanding natural systems, and to provide routes to new biomaterials with potential applications in nanotechnology and medicine. We have designed a self-assembling fiber system, the SAFs, in which two small α-helical peptides are programmed to form a dimeric coiled coil and assemble in a controlled manner. The resulting fibers are tens of nm wide and tens of μm long, and, therefore, comprise millions of peptides to give gigadalton supramolecular structures. Here, we describe the structure of the SAFs determined to approximately 8 Å resolution using cryotransmission electron microscopy. Individual micrographs show clear ultrastructure that allowed direct interpretation of the packing of individual α-helices within the fibers, and the construction of a 3D electron density map. Furthermore, a model was derived using the cryotransmission electron microscopy data and side chains taken from a 2.3 Å X-ray crystal structure of a peptide building block incapable of forming fibers. This was validated using single-particle analysis techniques, and was stable in prolonged molecular-dynamics simulation, confirming its structural viability. The level of self-assembly and self-organization in the SAFs is unprecedented for a designed peptide-based material, particularly for a system of considerably reduced complexity compared with natural proteins. This structural insight is a unique high-resolution description of how α-helical fibrils pack into larger protein fibers, and provides a basis for the design and engineering of future biomaterials.

  10. O design de notícias para tablet e o novo papel do designer

    OpenAIRE

    Raquel Corrêa Cordeiro

    2014-01-01

    Esta pesquisa traz um panorama do mercado jornalístico para tablet. Classifica as variações de publicações digitais. Mostra os hábitos de leitura em dispositivos móveis e as formas de negócios. Apresenta como o designer se posiciona nesse fluxo de trabalho. Analisa o caso do jornal O Globo, que, com produtos impressos e digitais, proporcionou entrevistas com designers de diversas mídias. Ainda há a análise de O Globo a Mais, revista exclusivamente digital.

  11. 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.

  12. 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.

  13. Electron transfer activity of a de novo designed copper center in a three-helix bundle fold.

    Science.gov (United States)

    Plegaria, Jefferson S; Herrero, Christian; Quaranta, Annamaria; Pecoraro, Vincent L

    2016-05-01

    In this work, we characterized the intermolecular electron transfer (ET) properties of a de novo designed metallopeptide using laser-flash photolysis. α3D-CH3 is three helix bundle peptide that was designed to contain a copper ET site that is found in the β-barrel fold of native cupredoxins. The ET activity of Cuα3D-CH3 was determined using five different photosensitizers. By exhibiting a complete depletion of the photo-oxidant and the successive formation of a Cu(II) species at 400 nm, the transient and generated spectra demonstrated an ET transfer reaction between the photo-oxidant and Cu(I)α3D-CH3. This observation illustrated our success in integrating an ET center within a de novo designed scaffold. From the kinetic traces at 400 nm, first-order and bimolecular rate constants of 10(5) s(-1) and 10(8) M(-1) s(-1) were derived. Moreover, a Marcus equation analysis on the rate versus driving force study produced a reorganization energy of 1.1 eV, demonstrating that the helical fold of α3D requires further structural optimization to efficiently perform ET. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. De novo designed proteins from a library of artificial sequences function in Escherichia coli and enable cell growth.

    Directory of Open Access Journals (Sweden)

    Michael A Fisher

    Full Text Available A central challenge of synthetic biology is to enable the growth of living systems using parts that are not derived from nature, but designed and synthesized in the laboratory. As an initial step toward achieving this goal, we probed the ability of a collection of >10(6 de novo designed proteins to provide biological functions necessary to sustain cell growth. Our collection of proteins was drawn from a combinatorial library of 102-residue sequences, designed by binary patterning of polar and nonpolar residues to fold into stable 4-helix bundles. We probed the capacity of proteins from this library to function in vivo by testing their abilities to rescue 27 different knockout strains of Escherichia coli, each deleted for a conditionally essential gene. Four different strains--ΔserB, ΔgltA, ΔilvA, and Δfes--were rescued by specific sequences from our library. Further experiments demonstrated that a strain simultaneously deleted for all four genes was rescued by co-expression of four novel sequences. Thus, cells deleted for ∼0.1% of the E. coli genome (and ∼1% of the genes required for growth under nutrient-poor conditions can be sustained by sequences designed de novo.

  15. 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.

  16. 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

  17. 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.

  18. Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10 Receptor-1 Mimetics.

    Directory of Open Access Journals (Sweden)

    Gloria Ruiz-Gómez

    Full Text Available Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1, which are relevant for its interaction with interleukin-10 (IL-10 has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands.

  19. Structural principles for computational and de novo design of 4Fe-4S metalloproteins.

    Science.gov (United States)

    Nanda, Vikas; Senn, Stefan; Pike, Douglas H; Rodriguez-Granillo, Agustina; Hansen, Will A; Khare, Sagar D; Noy, Dror

    2016-05-01

    Iron-sulfur centers in metalloproteins can access multiple oxidation states over a broad range of potentials, allowing them to participate in a variety of electron transfer reactions and serving as catalysts for high-energy redox processes. The nitrogenase FeMoCO cluster converts di-nitrogen to ammonia in an eight-electron transfer step. The 2(Fe4S4) containing bacterial ferredoxin is an evolutionarily ancient metalloprotein fold and is thought to be a primordial progenitor of extant oxidoreductases. Controlling chemical transformations mediated by iron-sulfur centers such as nitrogen fixation, hydrogen production as well as electron transfer reactions involved in photosynthesis are of tremendous importance for sustainable chemistry and energy production initiatives. As such, there is significant interest in the design of iron-sulfur proteins as minimal models to gain fundamental understanding of complex natural systems and as lead-molecules for industrial and energy applications. Herein, we discuss salient structural characteristics of natural iron-sulfur proteins and how they guide principles for design. Model structures of past designs are analyzed in the context of these principles and potential directions for enhanced designs are presented, and new areas of iron-sulfur protein design are proposed. This article is part of a Special issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, protein networks, edited by Ronald L. Koder and J.L Ross Anderson. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. De Novo Design of Supercharged, Unfolded Protein Polymers, and Their Assembly into Supramolecular Aggregates

    NARCIS (Netherlands)

    Kolbe, Anke; Mercato, Loretta L. del; Abbasi, Azhar Z.; Rivera Gil, Pilar; Gorzini, Sekineh J.; Huibers, Willem; Poolman, Bert; Parak, Wolfgang J.; Herrmann, Andreas

    2011-01-01

    Here we report for the first time the design and expression of highly charged, unfolded protein polymers based on elastin-like peptides (ELPs). Positively and negatively charged variants were achieved by introducing lysine and glutamic acid residues, respectively, within the repetitive pentapeptide

  1. Grid-based molecular footprint comparison method for docking and de novo design: application to HIVgp41.

    Science.gov (United States)

    Balius, Trent E; Allen, William J; Mukherjee, Sudipto; Rizzo, Robert C

    2013-05-30

    Scoring functions are a critically important component of computer-aided screening methods for the identification of lead compounds during early stages of drug discovery. Here, we present a new multigrid implementation of the footprint similarity (FPS) scoring function that was recently developed in our laboratory which has proven useful for identification of compounds which bind to a protein on a per-residue basis in a way that resembles a known reference. The grid-based FPS method is much faster than its Cartesian-space counterpart, which makes it computationally tractable for on-the-fly docking, virtual screening, or de novo design. In this work, we establish that: (i) relatively few grids can be used to accurately approximate Cartesian space footprint similarity, (ii) the method yields improved success over the standard DOCK energy function for pose identification across a large test set of experimental co-crystal structures, for crossdocking, and for database enrichment, and (iii) grid-based FPS scoring can be used to tailor construction of new molecules to have specific properties, as demonstrated in a series of test cases targeting the viral protein HIVgp41. The method is available in the program DOCK6. Copyright © 2013 Wiley Periodicals, Inc.

  2. 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.

  3. 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...... methods. For all proteins, immobilization causes a decrease in protein stability and a loosening of the helix packing, as reflected by a partial dissociation of a histidine ligand in the ferrous state and very low redox potentials. For the covalently attached MOP-C, the overall interfacial redox process...

  4. 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...... 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...

  5. 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/.

  6. 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

  7. Fast, cheap and out of control--Insights into thermodynamic and informatic constraints on natural protein sequences from de novo protein design.

    Science.gov (United States)

    Brisendine, Joseph M; Koder, Ronald L

    2016-05-01

    The accumulated results of thirty years of rational and computational de novo protein design have taught us important lessons about the stability, information content, and evolution of natural proteins. First, de novo protein design has complicated the assertion that biological function is equivalent to biological structure - demonstrating the capacity to abstract active sites from natural contexts and paste them into non-native topologies without loss of function. The structure-function relationship has thus been revealed to be either a generality or strictly true only in a local sense. Second, the simplification to "maquette" topologies carried out by rational protein design also has demonstrated that even sophisticated functions such as conformational switching, cooperative ligand binding, and light-activated electron transfer can be achieved with low-information design approaches. This is because for simple topologies the functional footprint in sequence space is enormous and easily exceeds the number of structures which could have possibly existed in the history of life on Earth. Finally, the pervasiveness of extraordinary stability in designed proteins challenges accepted models for the "marginal stability" of natural proteins, suggesting that there must be a selection pressure against highly stable proteins. This can be explained using recent theories which relate non-equilibrium thermodynamics and self-replication. This article is part of a Special Issue entitled Biodesign for Bioenergetics--The design and engineering of electronc transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Structural Characterization of de Novo Designed L5K5W Model Peptide Isomers with Potent Antimicrobial and Varied Hemolytic Activities

    Directory of Open Access Journals (Sweden)

    Sung-Jean Park

    2013-01-01

    Full Text Available In an effort to develop short antimicrobial peptides with simple amino acid compositions, we generated a series of undecapeptide isomers having the L5K5W formula. Amino acid sequences were designed to be perfectly amphipathic when folded into a helical conformation by converging leucines onto one side and lysines onto the other side of the helical axis. The single tryptophans, whose positions were varied in the primary structures, were located commonly at the critical amphipathic interface in the helical wheel projection. Helical conformations and the tryptophanyl environments of the 11 L5K5W peptides were confirmed and characterized by circular dichroism, fluorescence and nuclear magnetic resonance spectroscopy. All of the isomers exhibited a potent, broad-spectrum of antibacterial activity with just a slight variance in individual potency, whereas their hemolytic activities against human erythrocytes were significantly diversified. Interestingly, helical dispositions and fluorescence blue shifts of the peptides in aqueous trifluoroethanol solutions, rather than in detergent micelles, showed a marked linear correlation with their hemolytic potency. These results demonstrate that our de novo design strategy for amphipathic helical model peptides is effective for developing novel antimicrobial peptides and their hemolytic activities can be estimated in correlation with structural parameters.

  9. Structural characterization of de novo designed L5K5W model peptide isomers with potent antimicrobial and varied hemolytic activities.

    Science.gov (United States)

    Kim, Seo-Jin; Kim, Jae-Seok; Lee, Yoo-Sup; Sim, Dae-Won; Lee, Sung-Hee; Bahk, Young-Yil; Lee, Kwang-Ho; Kim, Eun-Hee; Park, Sung-Jean; Lee, Bong-Jin; Won, Hyung-Sik

    2013-01-11

    In an effort to develop short antimicrobial peptides with simple amino acid compositions, we generated a series of undecapeptide isomers having the L(5)K(5)W formula. Amino acid sequences were designed to be perfectly amphipathic when folded into a helical conformation by converging leucines onto one side and lysines onto the other side of the helical axis. The single tryptophans, whose positions were varied in the primary structures, were located commonly at the critical amphipathic interface in the helical wheel projection. Helical conformations and the tryptophanyl environments of the 11 L(5)K(5)W peptides were confirmed and characterized by circular dichroism, fluorescence and nuclear magnetic resonance spectroscopy. All of the isomers exhibited a potent, broad-spectrum of antibacterial activity with just a slight variance in individual potency, whereas their hemolytic activities against human erythrocytes were significantly diversified. Interestingly, helical dispositions and fluorescence blue shifts of the peptides in aqueous trifluoroethanol solutions, rather than in detergent micelles, showed a marked linear correlation with their hemolytic potency. These results demonstrate that our de novo design strategy for amphipathic helical model peptides is effective for developing novel antimicrobial peptides and their hemolytic activities can be estimated in correlation with structural parameters.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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...

  15. 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.

  16. A De Novo programming approach for a robust closed-loop supply chain network design under uncertainty: An M/M/1 queueing model

    Directory of Open Access Journals (Sweden)

    Sarow Saeedi

    2015-04-01

    Full Text Available This paper considers the capacity determination in a closed-loop supply chain network when a queueing system is established in the reverse flow. Since the queueing system imposes costs on the model, the decision maker faces the challenge of determining the capacity of facilities in such a way that a compromise between the queueing costs and the fixed costs of opening new facilities could be obtained. We develop a De Novo programming approach to determine the capacity of recovery facilities in the reverse flow. To this aim, a mixed integer nonlinear programming (MINLP model is integrated with the De Novo programming and the robust counterpart of this model is proposed to cope with the uncertainty of the parameters. To solve the model, an interactive fuzzy programming approach is combined with the hard worst case robust programming. Numerical results show the performance of the developed model in determining the capacity of facilities.

  17. 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...

  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. 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

  20. 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.

  1. 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)

  2. Entretenimento hospitalar: um novo conceito de melhoria na qualidade de vida baseada no Design de Interfaces e ambiente computacional hipermídia

    Directory of Open Access Journals (Sweden)

    Vera Maria Jubram Kalache

    2014-07-01

    Full Text Available Este projeto propõe o uso de uma ferramenta digital para pacientes internados, com o objetivo de amenizar a ansiedade e favorecer a sua recuperação. Para tanto, baseia-se no uso do Entretenimento, por meio de aplicativos fundamentados, escolhidos a partir de uma pesquisa e da análise de profissionais das áreas envolvidas. Os aplicativos são ferramentas de lazer e não devem ser confundidos com práticas terapêuticas. O presente trabalho visa à importância do bem-estar e à qualidade de vida no ambiente hospitalar. Elaborou-se uma proposta de arquitetura de dados para os aplicativos e as interfaces gráficas para cada módulo do dispositivo. As informações foram levantadas durante a observação informal em atividade de voluntariado. A partir delas, foi possível desenvolver e descrever os aspectos de design e as principais vantagens da utilização da tecnologia Tablet, além da sua funcionalidade para o Entretenimento Hospitalar. Implementou-se um módulo conceitual de aplicativo, utilizando informações do módulo de nutrição. Assim, foi possível explorar as relações entre as necessidades emocionais identificadas e as necessidades de entretenimento, lazer e socialização.

  3. 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.

  4. 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

  5. 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 ...

  6. RAMPART: a workflow management system for de novo genome assembly.

    Science.gov (United States)

    Mapleson, Daniel; Drou, Nizar; Swarbreck, David

    2015-06-01

    The de novo assembly of genomes from whole- genome shotgun sequence data is a computationally intensive, multi-stage task and it is not known a priori which methods and parameter settings will produce optimal results. In current de novo assembly projects, a popular strategy involves trying many approaches, using different tools and settings, and then comparing and contrasting the results in order to select a final assembly for publication. Herein, we present RAMPART, a configurable workflow management system for de novo genome assembly, which helps the user identify combinations of third-party tools and settings that provide good results for their particular genome and sequenced reads. RAMPART is designed to exploit High performance computing environments, such as clusters and shared memory systems, where available. RAMPART is available under the GPLv3 license at: https://github.com/TGAC/RAMPART. © The Author 2015. Published by Oxford University Press.

  7. ONU: velhos problemas novos desafios

    Directory of Open Access Journals (Sweden)

    KARIN COSTA VASQUEZ

    2010-12-01

    Full Text Available A grande quantidade de crises enfrenta pela Organização das Nações Unidas recentemente contribuiu enormente para o aumento da desilusão com relação à essa instituição. Nesse sentido o presente artigo busca oferecer um panorama da ONU,tendo como focos os antigos problemas a serem enfrentados e os novos constrangimentos que ela deverá enfrentar.

  8. 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......” 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...

  9. De novo Transcriptome Analysis in Perennial Ryegrass

    DEFF Research Database (Denmark)

    Farrell, Jacqueline Danielle; Byrne, Stephen; Asp, Torben

    Perennial ryegrass (Lolium perenne L.) is an important grass species for both forage and amenity purposes for temperate regions worldwide. It is envisaged that breeding efforts may be enhanced with the assistance of new breeding technologies such as genomic selection. A major step towards genomic...... of functional markers for improved ryegrass breeding. Therefore, the goal of this study is to analyze a de novo assembly of the perennial ryegrass transcriptome from the same inbred genotype being used for de novo genome assembly. Furthermore, we also conducted de novo transcriptome assembly with other...

  10. De novo Families: Lesbian Motherhood.

    Science.gov (United States)

    Hayman, Brenda; Wilkes, Lesley

    2017-01-01

    The aim of this recent Australian study was to explore the experiences of lesbian women choosing motherhood. Participants included 30 self-identifying lesbian mothers. Data were collected via interviews, data collection sheets, and online journaling. The interview and journaling data were analyzed using constant comparative analysis and subsequently illuminated three main themes: becoming mothers, constructing motherhood, and legitimizing our family. These papers described the journey to motherhood and specifically explored the various methods of conception and other decisions that participants made when planning their family, the challenge of heteronormativity in health care, and legitimizing the role of the non-birth mother in de novo families. This article aims to present the participants' experiences of motherhood that was a constant topic found woven throughout all three of the identified themes. Participants identified that they had a unique opportunity to create their own mothering roles in the absence of significant "lesbian mother" role models and that they were able to adjust and to adapt their roles depending on fluctuating circumstances.

  11. De Novo Arteriovenous Malformation after Aneurysm Clipping.

    Science.gov (United States)

    Shidoh, Satoka; Kobayashi, Masahito; Akaji, Kazunori; Kano, Tadashige; Tanizaki, Yoshio; Mihara, Ban

    2017-07-01

    We report a 73-year-old woman with de novo arteriovenous malformations (AVMs) that developed in the ipsilateral parietal lobe after craniotomy and aneurysm clipping. While intracerebral AVMs are considered to be congenital lesions, there have been several reported cases of acquired AVM arising after ischemic or traumatic episodes. We summarize previously reported cases of such acquired 'de novo' AVMs with a discussion of some pathophysiological responses or factors suggested to promote their development.

  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. A suite of de novo c-type cytochromes for functional oxidoreductase engineering.

    Science.gov (United States)

    Watkins, Daniel W; Armstrong, Craig T; Beesley, Joseph L; Marsh, Jane E; Jenkins, Jonathan M X; Sessions, Richard B; Mann, Stephen; Ross Anderson, J L

    2016-05-01

    Central to the design of an efficient de novo enzyme is a robust yet mutable protein scaffold. The maquette approach to protein design offers precisely this, employing simple four-α-helix bundle scaffolds devoid of evolutionary complexity and with proven tolerance towards iterative protein engineering. We recently described the design of C2, a de novo designed c-type cytochrome maquette that undergoes post-translational modification in E. coli to covalently graft heme onto the protein backbone in vivo. This de novo cytochrome is capable of reversible oxygen binding, an obligate step in the catalytic cycle of many oxygen-activating oxidoreductases. Here we demonstrate the flexibility of both the maquette platform and the post-translational machinery of E. coli by creating a suite of functional de novo designed c-type cytochromes. We explore the engineering tolerances of the maquette by selecting alternative binding sites for heme C attachment and creating di-heme maquettes either by appending an additional heme C binding motif to the maquette scaffold or by binding heme B through simple bis-histidine ligation to a second binding site. The new designs retain the essential properties of the parent design but with significant improvements in structural stability. Molecular dynamics simulations aid the rationalization of these functional improvements while providing insight into the rules for engineering heme C binding sites in future iterations. This versatile, functional suite of de novo c-type cytochromes shows significant promise in providing robust platforms for the future engineering of de novo oxygen-activating oxidoreductases. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electron transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. 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®

    Directory of Open Access Journals (Sweden)

    Höybye C

    2013-04-01

    Full Text Available Charlotte Höybye,1 Lars Sävendahl,2 Henrik Thybo Christesen,3 Peter Lee,4 Birgitte Tønnes Pedersen,5 Michael Schlumpf,6 John Germak,7 Judith Ross8 1Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Endocrinology, Metabolism and Diabetes, 2Department of Women’s and Children’s Health, Karolinska Institute and Division of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; 3Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; 4Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA; 5Global Development, Novo Nordisk A/S, Søborg, Denmark; 6Global Medical Affairs Biopharm, Novo Nordisk Health Care AG, Zurich, Switzerland; 7Clinical Development and Medical Affairs, Novo Nordisk Inc, Princeton, NJ, USA; 8Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA Objective: 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. Design: The NordiNet® International Outcome Study (IOS and the American Norditropin® Studies: Web Enabled Research (ANSWER Program® are two complementary, non-interventional, observational studies that adhere to current guidelines for pharmacoepidemiological data. Patients: The studies include pediatric and adult patients receiving Norditropin®, as prescribed by their physicians. Measurements: The studies gather long-term data on the safety and effectiveness of real-life treatment with the recombinant human GH, Norditropin®. We describe the origins, aims, objectives, and design methodology of

  15. Abordagem racional no planejamento de novos tuberculostáticos: inibidores da InhA, enoil-ACP redutase do M. tuberculosis Rational approach in the new antituberculosis agent design: inhibitors of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Carolina Horta Andrade

    2008-06-01

    Full Text Available Associada à disseminação da infecção causada pelo HIV, a tuberculose (TB é considerada, atualmente, problema mundial de saúde pública devido às proporções que vem assumindo. A resistência micobacteriana aos fármacos utilizados na terapêutica é a principal causa da reincidência da TB. Diante deste quadro alarmante, o desenvolvimento de novos e seletivos fármacos anti-TB se faz urgente e necessário. A biossíntese de ácidos graxos é um processo bioquímico realizado por procariotos e eucariotos, o qual fornece precursores essenciais à montagem de componentes celulares importantes, tais como fosfolipídeos, lipoproteínas, lipopolissacarídeos, ácidos micólicos e envelope celular. As diferenças bioquímicas e funcionais entre o mecanismo biossintético de ácidos graxos em bactérias e mamíferos tornam-no alvo relevante ao planejamento de novos antibacterianos, mais seletivos e menos tóxicos. As enoil-ACP redutases são enzimas cruciais à etapa de alongamento de ácidos graxos, considerados produtos intermediários na biossíntese de ácidos micólicos - os principais componentes da parede celular micobacteriana. Portanto, tais enzimas são tidas como alvos moleculares no planejamento racional de novos tuberculostáticos. Avanços recentes no processo de descoberta de novos agentes anti-TB, particularmente os inibidores da enoil-ACP redutase, serão discutidos nesta revisão.In conjunction with the spread of HIV infection, tuberculosis (TB has been among the worldwide health threats. Mycobacteria resistance to the drugs currently used in the therapeutics is the main cause of TB resurgence. In view of this severe situation, the new and selective anti-TB design is of utmost importance. Fatty acid biosynthesis is a prokariontes and eucariontes biochemical process that supplies essential precursors for the assembly of important cellular components, such as phospholipids, lipoproteins, lipopolysaccharides, mycolic acids and

  16. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

    Science.gov (United States)

    Golmard, L; Delnatte, C; Laugé, A; Moncoutier, V; Lefol, C; Abidallah, K; Tenreiro, H; Copigny, F; Giraudeau, M; Guy, C; Barbaroux, C; Amorim, G; Briaux, A; Guibert, V; Tarabeux, J; Caputo, S; Collet, A; Gesta, P; Ingster, O; Stern, M-H; Rouleau, E; de Pauw, A; Gauthier-Villars, M; Buecher, B; Bézieau, S; Stoppa-Lyonnet, D; Houdayer, C

    2016-03-10

    BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

  17. 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

  18. 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.

  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. Materiais avançados: novos produtos e novos processos na indústria automobilística

    Directory of Open Access Journals (Sweden)

    Heloisa V. de Medina

    1998-06-01

    Full Text Available Esse artigo mostra o desenvolvimento recente dos materiais novos e avançados e seus impactos na organização insustrial exigindo flexibilidade em todas as fases: P&D, projeto e produção. Essas mudanças estão gerando produtos novos e melhorados e atendendo também aos requisitos ambientais. Discute-se o conceito de materiais avançados e apresenta-se os desenvolvimentos recentes nesse campo. O desenvolvimento de materiais especiais para o setor automobilístico é também enfatizado como exemplo significativo da revolução dos materiais e seus impactos inovadores na estrutura industrial deste setor vital.This article shows the recent development of new and advanced materials and its impatcs on the industrial organization, asking for flexiblility from the R&D through the design fase until the production level. These changes are enabling new and better products and also meeting environmental requirements. The concept of advanced material is discussed and the recent progresses on materials field are presented.. The development of special materials and its new applications in the automotive industry is also stressed as a significant exemple of the materials revolution and its innovative impacts on the industrial structure of this core sector.

  1. 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.

  2. Viral proteins originated de novo by overprinting can be identified by codon usage: application to the "gene nursery" of Deltaretroviruses.

    Directory of Open Access Journals (Sweden)

    Angelo Pavesi

    Full Text Available A well-known mechanism through which new protein-coding genes originate is by modification of pre-existing genes, e.g. by duplication or horizontal transfer. In contrast, many viruses generate protein-coding genes de novo, via the overprinting of a new reading frame onto an existing ("ancestral" frame. This mechanism is thought to play an important role in viral pathogenicity, but has been poorly explored, perhaps because identifying the de novo frames is very challenging. Therefore, a new approach to detect them was needed. We assembled a reference set of overlapping genes for which we could reliably determine the ancestral frames, and found that their codon usage was significantly closer to that of the rest of the viral genome than the codon usage of de novo frames. Based on this observation, we designed a method that allowed the identification of de novo frames based on their codon usage with a very good specificity, but intermediate sensitivity. Using our method, we predicted that the Rex gene of deltaretroviruses has originated de novo by overprinting the Tax gene. Intriguingly, several genes in the same genomic region have also originated de novo and encode proteins that regulate the functions of Tax. Such "gene nurseries" may be common in viral genomes. Finally, our results confirm that the genomic GC content is not the only determinant of codon usage in viruses and suggest that a constraint linked to translation must influence codon usage.

  3. Katome: de novo DNA assembler implemented in rust

    Science.gov (United States)

    Neumann, Łukasz; Nowak, Robert M.; Kuśmirek, Wiktor

    2017-08-01

    Katome is a new de novo sequence assembler written in the Rust programming language, designed with respect to future parallelization of the algorithms, run time and memory usage optimization. The application uses new algorithms for the correct assembly of repetitive sequences. Performance and quality tests were performed on various data, comparing the new application to `dnaasm', `ABySS' and `Velvet' genome assemblers. Quality tests indicate that the new assembler creates more contigs than well-established solutions, but the contigs have better quality with regard to mismatches per 100kbp and indels per 100kbp. Additionally, benchmarks indicate that the Rust-based implementation outperforms `dnaasm', `ABySS' and `Velvet' assemblers, written in C++, in terms of assembly time. Lower memory usage in comparison to `dnaasm' is observed.

  4. 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.

  5. Modeling de novo granulation of anaerobic sludge.

    Science.gov (United States)

    Doloman, Anna; Varghese, Honey; Miller, Charles D; Flann, Nicholas S

    2017-07-17

    A unique combination of mechanical, physiochemical and biological forces influences granulation during processes of anaerobic digestion. Understanding this process requires a systems biology approach due to the need to consider not just single-cell metabolic processes, but also the multicellular organization and development of the granule. In this computational experiment, we address the role that physiochemical and biological processes play in granulation and provide a literature-validated working model of anaerobic granule de novo formation. The agent-based model developed in a cDynoMiCs simulation environment successfully demonstrated a de novo granulation in a glucose fed system, with the average specific methanogenic activity of 1.11 ml C H 4 /g biomass and formation of a 0.5 mm mature granule in 33 days. The simulated granules exhibit experimental observations of radial stratification: a central dead core surrounded by methanogens then encased in acidogens. Practical application of the granulation model was assessed on the anaerobic digestion of low-strength wastewater by measuring the changes in methane yield as experimental configuration parameters were systematically searched. In the model, the emergence of multicellular organization of anaerobic granules from randomly mixed population of methanogens and acidogens was observed and validated. The model of anaerobic de novo granulation can be used to predict the morphology of the anaerobic granules in a alternative substrates of interest and to estimate methane potential of the resulting microbial consortia. The study demonstrates a successful integration of a systems biology approach to model multicellular systems with the engineering of an efficient anaerobic digestion system.

  6. De novo psychogenic seizures after epilepsy surgery: case report

    Directory of Open Access Journals (Sweden)

    MONTENEGRO MARIA AUGUSTA

    2000-01-01

    Full Text Available The occurrence of de novo psychogenic seizures after epilepsy surgery is rare, and is estimated in 1.8% to 3.6%. Seizures after epilepsy surgery should be carefully evaluated, and de novo psychogenic seizures should be considered especially when there is a change in the ictal semiology. We report a patient with de novo psychogenic seizures after anterior temporal lobe removal for refractory temporal lobe epilepsy. Once psychogenic seizures were diagnosed and psychiatric treatment was started, seizures stopped.

  7. De novo pathway-based biomarker identification

    DEFF Research Database (Denmark)

    Alcaraz, Nicolas; List, Markus; Batra, Richa

    2017-01-01

    datasets. Attempts to mitigate these drawbacks have led to the development of network-based approaches that integrate pathway information to produce meta-gene (MG) features. Also, MG approaches have only dealt with the two-class problem of good versus poor outcome prediction. Stratifying patients based...... 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. Cuidadores de idosos: um novo / velho trabalho

    OpenAIRE

    Resende,Márcia Colamarco Ferreira; Dias,Elizabeth Costa

    2008-01-01

    O texto tem como objetivo discutir as repercussões do novo/velho trabalho dos cuidadores de idosos na sua saúde e o suporte que existe atualmente para eles. O estudo se fundamenta na referência do campo temático da Saúde do Trabalhador. Segundo a literatura, a ocupação de cuidador de idosos parece ser uma atividade exercida predominantemente dentro do setor informal de trabalho, por alguém da família e do sexo feminino, e tem trazido conseqüências na qualidade do cuidado ao idoso e na saúde d...

  9. Novos valores ou nova hierarquia de valores?

    Directory of Open Access Journals (Sweden)

    Vera Rudge Werneck

    2010-04-01

    Full Text Available O artigo tem por objetivo mostrar que não existem novos valores mas sim novas hierarquias de valores. Cada geração em cada tempo e lugar vai hierarquizar os valores diferentemente. Tece uma análise das várias modalidades de valores considerando a sensibilidade como o processo cognitivo próprio para o seu conhecimento. Fundamentando-se teoricamente em Max Scheler, passando para Yvan Gobry, até concluir com um exemplo de hierarquização de valores.

  10. Desenvolvimento de um novo conceito de refrigerante

    OpenAIRE

    Ribeiro, Tânia Isabel Bragança

    2011-01-01

    Dissertação para obtenção de grau de mestre em Tecnologia e Segurança Alimentar – Qualidade Alimentar A indústria de refrigerantes e sumos é um subsector da indústria de bebidas não-alcoólicas, de grande impacte na economia e elevada competitividade. O desenvolvimento de novos produtos e a garantia de qualidade dos produtos são de extrema importância nesta indústria. Actualmente, o consumidor é bastante preocupado com a saúde, procurando produtos que possam não comprometer e/ou impulsionar...

  11. 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.

  12. 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

  13. 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.

  14. Um novo gerador de topologias da Internet.

    OpenAIRE

    Maciel, Joylan Nunes

    2016-01-01

    Dissertação apresentada como requisito parcial para a obtenção do grau de Mestre em Informática no Programa de Pós-Graduação em Informática, Setor de Ciências Exatas, Universidade Federal do Paraná. Orientadora: Profa. Dra. Cristina Duarte Murta. 2008 A geração de topologias sintéticas da Internet tem aplicação fundamental em experimentos com novos protocolos e serviços, propostos com freqüência pela comunidade de pesquisa na área de redes de computadores e sistemas distribuídos. As novas ...

  15. Marcelo Caetano : últimas razones del Estado Novo

    Directory of Open Access Journals (Sweden)

    Hipólito de la Torre Gómez

    2007-01-01

    Full Text Available El reformismo de Marcelo Caetano, ensayado durante sus años de gobierno, resultó insuficiente para responder a los desafíos de la sociedad portuguesa, que acabaron por desembocar en la ruptura del 25 de Abril. Las razones del fracaso de la reforma marcelista se han atribuido a menudo a las dificultades del Presidente del Consejo para maniobrar, prácticamente sin margen y sin tiempo, entre poderosas presiones políticas contrapuestas. Sin embargo, el análisis de su pensamiento político, expreso en las manifestaciones realizadas durante los años de su Gobierno, revelan que en lo sustancial su ideario nunca se salió de los parámetros ideológicos y políticos del Estado Novo. Su reformismo no iba más allá de un intento honesto de relegitimar el régimen mediante un proceso de efectiva institucionalización de la actividad política, de dinamización representativa, de modernización socioeconómica y de aperturismo liberalizador.The reformist policy of Marcelo Caetano was incapable of overcoming the challenges of Portuguese society that eventually led to the outbreak of 25th April. The reasons for this failure have been often linked to the President’s difficulties to implement changes in the midst of powerful and opposed political pressures. Nevertheless, the analysis of his political thought expressed in the speeches and statements produced during his government period, shows that essentially marcelist’s ideas never exceeded the «Estado Novo» ideological framework. So, his reforming policy never went beyond an honest attempt to renew the regime throughout a more institutionalised and representative political practice, a deeper tolerance of public liberties and an economic and social modernization. All that could at the ouset raise popular hopes, but it could never flow into democracy.

  16. 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

  17. [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.

  18. 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.

  19. 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

    damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1...... trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably...... (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT....

  20. 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

  1. REVIEW ARTICLE Case report of newborn with de novo partial ...

    Indian Academy of Sciences (India)

    Navya

    2017-03-24

    2 2q37.3 and a de novo monosomy 9p24.3. The clinical findings of this patient include congenital heart defects, dysmorphic facial features, hypotonia, feeding difficulties and microcephaly. Ultrasonographic prenatal findings ...

  2. 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?

  3. 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....

  4. Clinical characteristics of de novo nonalcoholic fatty liver disease following pancreaticoduodenectomy

    International Nuclear Information System (INIS)

    Tanaka, Naoki; Horiuchi, Akira; Yokoyama, Takahide

    2011-01-01

    Hepatic steatosis may develop after pancreatic resection, but its clinicopathological features remain unclear. We explored the clinical characteristics of newly appearing nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), designated as de novo NAFLD after PD. Of 83 patients who underwent PD between 2001 and 2006, the patients with regular alcohol consumption after PD (n=3), those who were unavailable for regular abdominal computed tomography follow-up (n=12), and those who died within 6 months of PD (n=8) were excluded from the study. In the remaining 60 patients, the prevalence and clinical features of de novo NAFLD after PD were examined. NAFLD developed after PD in 14 (23%) patients in our cohort. Liver biopsy was performed in 8 patients and all showed typical steatohepatitis. Compared with the patients who had conventional nonalcoholic steatohepatitis (NASH), patients with post-PD de novo NASH demonstrated significant decreases in body mass index and lower levels of serum albumin, cholesterol, apolipoprotein B, and homeostasis model assessment for insulin resistance. Multivariate logistic regression analysis revealed that pancreatic head cancer was associated with an increased risk of developing NAFLD after PD (odds ratio 12.0, 95% confidence interval 2.0-71.4, P=0.006). Increased dosage of oral pancreatic enzymes significantly ameliorated the steatosis, as well as leading to the recovery of body weight loss and resolution of the biochemical abnormalities. De novo NAFLD/NASH after PD is characterized by non-obesity and lack of hyperlipidemia and insulin resistance and is associated with pancreatic exocrine insufficiency. In such patients, intensifying pancreatic enzyme supplementation may be useful. (author)

  5. 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.

  6. 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

  7. Constrained De Novo Sequencing of Peptides with Application to Conotoxins

    Science.gov (United States)

    Bhatia, Swapnil; Kil, Yong J.; Ueberheide, Beatrix; Chait, Brian; Tayo, Lemmuel L.; Cruz, Lourdes J.; Lu, Bingwen; Yates, John R.; Bern, Marshall

    We describe algorithms for incorporating prior sequence knowledge into the candidate generation stage of de novo peptide sequencing by tandem mass spectrometry. We focus on two types of prior knowledge: homology to known sequences encoded by a regular expression or position-specific score matrix, and amino acid content encoded by a multiset of required residues. We show an application to de novo sequencing of cone snail toxins, which are molecules of special interest as pharmaceutical leads and as probes to study ion channels. Cone snail toxins usually contain 2, 4, 6, or 8 cysteine residues, and the number of residues can be determined by a relatively simple mass spectrometry experiment. We show here that the prior knowledge of the number of cysteines in a precursor ion is highly advantageous for de novo sequencing.

  8. Canvas SPW: calling de novo copy number variants in pedigrees.

    Science.gov (United States)

    Ivakhno, Sergii; Roller, Eric; Colombo, Camilla; Tedder, Philip; Cox, Anthony J

    2018-02-01

    Whole genome sequencing is becoming a diagnostics of choice for the identification of rare inherited and de novo copy number variants in families with various pediatric and late-onset genetic diseases. However, joint variant calling in pedigrees is hampered by the complexity of consensus breakpoint alignment across samples within an arbitrary pedigree structure. We have developed a new tool, Canvas SPW, for the identification of inherited and de novo copy number variants from pedigree sequencing data. Canvas SPW supports a number of family structures and provides a wide range of scoring and filtering options to automate and streamline identification of de novo variants. Canvas SPW is available for download from https://github.com/Illumina/canvas. sivakhno@illumina.com. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  9. 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

  10. 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

  11. Design

    DEFF Research Database (Denmark)

    Jensen, Ole B.; Pettiway, Keon

    2017-01-01

    by designers, planners, etc. (staging from above) and mobile subjects (staging from below). A research agenda for studying situated practices of mobility and mobilities design is outlined in three directions: foci of studies, methods and approaches, and epistemologies and frames of thinking. Jensen begins......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...... 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...

  12. 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....

  13. 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…

  14. 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......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 designers, planners, etc. (staging from above) and mobile subjects (staging from below). A research agenda for studying situated practices of mobility and mobilities design is outlined in three directions: foci of studies, methods and approaches, and epistemologies and frames of thinking. Jensen begins...... 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...

  15. Risk factors for de novo hepatitis B infection in pediatric living donor liver transplantation

    OpenAIRE

    Rao, Wei; Xie, Man; Yang, Tao; Zhang, Jian-Jun; Gao, Wei; Deng, Yong-Lin; Zheng, Hong; Pan, Cheng; Liu, Yi-He; Shen, Zhong-Yang

    2014-01-01

    AIM: To investigate the incidence of de novo hepatitis B virus (HBV) infection after pediatric living donor liver transplantation (LDLT) and to analyze the risk factors associated with this de novo HBV infection.

  16. Characteristics of de novo structural changes in the human genome

    NARCIS (Netherlands)

    Kloosterman, Wigard P.; Francioli, Laurent C.; Hormozdiari, Fereydoun; Marschall, Tobias; Hehir-Kwa, Jayne Y.; Abdellaoui, Abdel; Lameijer, Eric-Wubbo; Moed, Matthijs H.; Koval, Vyacheslav; Renkens, Ivo; van Roosmalen, Markus J.; Arp, Pascal; Karssen, Lennart C.; Coe, Bradley P.; Handsaker, Robert E.; Suchiman, Eka D.; Cuppen, Edwin; Thung, Djie Tjwan; McVey, Mitch; Wendl, Michael C.; Uitterlinden, Andre; van Duijn, Cornelia M.; Swertz, Morris A.; Wijmenga, Cisca; van Ommen, GertJan B.; Slagboom, P. Eline; Boomsma, Dorret I.; Schoenhuth, Alexander; Eichler, Evan E.; de Bakker, Paul I. W.; Ye, Kai; Guryev, Victor

    Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de

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

    African Journals Online (AJOL)

    Jane

    2011-07-25

    Jul 25, 2011 ... Our study was aimed towards computational proteomic analysis and 3D structural modeling of this novel bacteriocin protein encoded by the earlier aforementioned gene. Different bioinformatics tools and machine learning techniques were used for protein structural classification. De novo protein modeling ...

  18. De novo autoimmune hepatitis following liver transplantation for ...

    African Journals Online (AJOL)

    De novo autoimmune hepatitis (AIH) is a rare disorder first described in 1998. It occurs in patients who underwent liver transplantation for a different etiology. We present the case of a 56-year-old woman who was diagnosed with primary biliary cirrhosis and had liver transplantation for refractory pruritis. Seven years after ...

  19. 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.

  20. 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...

  1. 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 ...

  2. 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

    The impact of mixture spectra deconvolution on the performance of four popular de novo sequencing programs was tested using artificially constructed mixture spectra as well as experimental proteomics data. Mixture fragmentation spectra are recognized as a limitation in proteomics because they dec...

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

    NARCIS (Netherlands)

    Willsey, A. Jeremy; Fernandez, Thomas V.; Yu, Dongmei; King, Robert A.; Dietrich, Andrea; Xing, Jinchuan; Sanders, Stephan J.; Mandell, Jeffrey D.; Huang, Alden Y.; Richer, Petra; Smith, Louw; Dong, Shan; Samocha, Kaitlin E.; Neale, Benjamin M.; Coppola, Giovanni; Mathews, Carol A.; Tischfield, Jay A.; Scharf, Jeremiah M.; State, Matthew W.; Heiman, Gary A.; Abdulkadir, Mohamed; Bohnenpoll, Julia; Bromberg, Yana; Brown, Lawrence W.; Cheon, Keun-Ah; Coffey, Barbara J.; Deng, Li; Elzerman, Lonneke; Fründt, Odette; Garcia-Delgar, Blanca; Gedvilaite, Erika; Gilbert, Donald L.; Grice, Dorothy E.; Hagstrøm, Julie; Hedderly, Tammy; Heyman, Isobel; Hoekstra, Pieter J.; Hong, Hyun Ju; Huyser, Chaim; Ibanez-Gomez, Laura; Kim, Young Key; Kim, Young-Shin; Koh, Yun-Joo; Kook, Sodahm; Kuperman, Samuel; Lamerz, Andreas; Leventhal, Bennett; Ludolph, Andrea G.; Lühr da Silva, Claudia; Madruga-Garrido, Marcos; Maras, Athanasios; Mir, Pablo; Morer, Astrid; Münchau, Alexander; Murphy, Tara L.; Nasello, Cara; Openneer, Thaïra J. C.; Plessen, Kerstin J.; Roessner, Veit; Sanders, Stephan; Shin, Eun-Young; Sival, Deborah A.; Song, Dong-Ho; Song, Jungeun; Stolte, Anne Marie; Sun, Nawei; Tübing, Jennifer; Visscher, Frank; Walker, Michael F.; Wanderer, Sina; Wang, Shuoguo; Woods, Martin; Zhang, Yeting; Zhou, Anbo; Zinner, Samuel H.; Barr, Cathy L.; Batterson, James R.; Berlin, Cheston; Bruun, Ruth D.; Budman, Cathy L.; Cath, Danielle C.; Chouinard, Sylvain; Cox, Nancy J.; Darrow, Sabrina; Davis, Lea K.; Dion, Yves; Freimer, Nelson B.; Grados, Marco A.; Hirschtritt, Matthew E.; Illmann, Cornelia; Kurlan, Roger; Leckman, James F.; Lyon, Gholson J.; Malaty, Irene A.; MaMahon, William M.; Okun, Michael S.; Osiecki, Lisa; Pauls, David L.; Posthuma, Danielle; Ramensky, Vasily; Robertson, Mary M.; Rouleau, Guy A.; Sandor, Paul; Singer, Harvey S.; Smit, Jan; Sul, Jae-Hoon

    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

  4. Illumina-based de novo transcriptome sequencing and analysis of ...

    Indian Academy of Sciences (India)

    2017-12-18

    Dec 18, 2017 ... 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 ...

  5. Automated de novo metabolite identification with mass spectrometry and cheminformatics

    NARCIS (Netherlands)

    Peironcely Miguel, Julio Eduardo

    2014-01-01

    In this thesis new algorithms and methods that enable the de novo identification of metabolites have been developed. The aim was to find methods to propose candidate structures for unknown metabolites using MSn data as starting point. These methods have been integrated into a semi-automated pipeline

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

    Indian Academy of Sciences (India)

    2016-08-05

    Aug 5, 2016 ... With the advent of short-reads-based genome sequencing approaches, large number of organisms are being sequenced all over the world. Most of these assemblies are done using some de novo short read assemblers and other related approaches. However, the contigs produced this way are prone to ...

  7. De novo peroxisome biogenesis: Evolving concepts and conundrums.

    Science.gov (United States)

    Agrawal, Gaurav; Subramani, Suresh

    2016-05-01

    Peroxisomes proliferate by growth and division of pre-existing peroxisomes or could arise de novo. Though the de novo pathway of peroxisome biogenesis is a more recent discovery, several studies have highlighted key mechanistic details of the pathway. The endoplasmic reticulum (ER) is the primary source of lipids and proteins for the newly-formed peroxisomes. More recently, an intricate sorting process functioning at the ER has been proposed, that segregates specific PMPs first to peroxisome-specific ER domains (pER) and then assembles PMPs selectively into distinct pre-peroxisomal vesicles (ppVs) that later fuse to form import-competent peroxisomes. In addition, plausible roles of the three key peroxins Pex3, Pex16 and Pex19, which are also central to the growth and division pathway, have been suggested in the de novo process. In this review, we discuss key developments and highlight the unexplored avenues in de novo peroxisome biogenesis. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Control of Cell Fate Reprogramming Towards De Novo Shoot Organogenesis.

    Science.gov (United States)

    Tian, Xin; Zhang, Chen; Xu, Jian

    2017-12-23

    Many plants have a high regenerative capacity, which can be used to induce de novo organogenesis and produce various valuable plant species and products. In the classic 2-step protocol for de novo shoot organogenesis, small pieces of plant parts or tissues known as explants are initially cultured on an auxin-rich medium to produce a cell mass called callus. Upon transfer to a cytokinin-rich medium, a subpopulation of cells within the callus acquire shoot cell fate and subsequently develop into a fertile shoot. Cell fate reprogramming during de novo organogenesis is thus recognized as the decisive step to progressively acquire new cell types, in response to a change in the levels of plant hormones auxin and cytokinin. Currently, the molecular mechanisms underlying the onset and completion of cell fate reprogramming remains partly understood. In this review, we sought to summarize the most recent progress made in the study of cell fate reprogramming during de novo shoot organogenesis, and highlight the critical roles of epigenetic and transcription factors in the developmental timing of cell fate reprogramming. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. 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 ...

  10. TUBB4A de novo mutations cause isolated hypomyelination

    NARCIS (Netherlands)

    Pizzino, Amy; Pierson, Tyler Mark; Guo, Yiran; Helman, Guy; Fortini, Sebastian; Guerrero, Kether; Saitta, Sulagna; Murphy, Jennifer Louise Patrick; Padiath, Quasar; Xie, Yi; Hakonarson, Hakon; Xu, Xun; Funari, Tara; Fox, Michelle; Taft, Ryan J.; van der Knaap, Marjo S.; Bernard, Geneviève; Schiffmann, Raphael; Simons, Cas; Vanderver, Adeline

    2014-01-01

    We present a series of unrelated patients with isolated hypomyelination, with or without mild cerebellar atrophy, and de novo TUBB4A mutations. Patients in 2 large institutional review board-approved leukodystrophy bioregistries at Children's National Medical Center and Montreal Children's Hospital

  11. Cardiovascular dysautonomia in de novo Parkinson's disease without orthostatic hypotension.

    Science.gov (United States)

    Oka, H; Toyoda, C; Yogo, M; Mochio, S

    2011-02-01

    Clinical symptoms of Parkinson's disease (PD) include not only motor distress, but also autonomic dysfunction. To study the characteristics of subclinical autonomic nervous dysfunction in de novo PD without orthostatic hypotension (OH). Autonomic nervous function including cardiac sympathetic gain was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure in 20 patients with de novo PD without OH. Decreased cardiac MIBG uptake was found even in patients with PD without OH. Hemodynamic studies using the Valsalva maneuver revealed that patients with PD without OH had preserved baroreceptor reflex sensitivity in phase II and phase IV. Blood pressures normally responded in early and late phase II, but not in phase IV. Blood pressure recovery time was slightly reduced in patients with PD without OH when compared with the value in controls. The low frequency component of the RR interval and systolic blood pressure and the ratio of RR-LF to RR-HF in de novo PD without OH were significantly reduced when compared with the control values, whereas the high frequency component of the RR interval did not differ significantly. These results show that latent cardiac and vasomotor sympathetic dysfunction but not parasympathetic dysfunction is already present in early stage de novo PD, even without orthostatic hypotension. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.

  12. Whole exome sequencing reveals a MLL de novo mutation ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 94; Issue 4. Whole exome sequencing reveals a de novo mutation associated with mild developmental delay ... Keywords. Wiedemann–Steiner syndrome; whole exome sequencing; hairy elbows; hypertrichosis cubiti; gene; KMT2A; developmental delay; children.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. The Strategic Design Perspective

    DEFF Research Database (Denmark)

    Rasmussen, Jørgen

    2006-01-01

    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...... changed its focus from drugs and doctors, to the well-being of patients, and thereby created a completely new product, the NovoPen. This product has benefited the company immensely, and even more so, benefited the quality of life for the patients. I will argue that designers must take their share...

  18. Exploring alternate states and oligomerization preferences of coiled-coils by de novo structure modeling.

    Science.gov (United States)

    Rämisch, Sebastian; Lizatović, Robert; André, Ingemar

    2015-02-01

    Homomeric coiled-coils can self-assemble into a wide range of structural states with different helix topologies and oligomeric states. In this study, we have combined de novo structure modeling with stability calculations to simultaneously predict structure and oligomeric states of homomeric coiled-coils. For dimers an asymmetric modeling protocol was developed. Modeling without symmetry constraints showed that backbone asymmetry is important for the formation of parallel dimeric coiled-coils. Collectively, our results demonstrate that high-resolution structure of coiled-coils, as well as parallel and antiparallel orientations of dimers and tetramers, can be accurately predicted from sequence. De novo modeling was also used to generate models of competing oligomeric states, which were used to compare stabilities and thus predict the native stoichiometry from sequence. In a benchmark set of 33 coiled-coil sequences, forming dimers to pentamers, up to 70% of the oligomeric states could be correctly predicted. The calculations demonstrated that the free energy of helix folding could be an important factor for determining stability and oligomeric state of homomeric coiled-coils. The computational methods developed here should be broadly applicable to studies of sequence-structure relationships in coiled-coils and the design of higher order assemblies with improved oligomerization specificity. © 2014 Wiley Periodicals, Inc.

  19. Novo desenvolvimentismo e liberalismo enraizado New developmentalism and embedded liberalism

    Directory of Open Access Journals (Sweden)

    Reinaldo Gonçalves

    2012-12-01

    Full Text Available O objetivo geral deste artigo é discutir a evolução da formulação político‑ideológica de desenvolvimento econômico conhecida como novo desenvolvimentismo. O objetivo específico é demonstrar a hipótese de que o novo desenvolvimentismo é mais uma versão do liberalismo enraizado, que exprime o compromisso entre as diretrizes estratégicas do liberalismo e a intervenção estatal orientada para a estabilização macroeconômica.The general objective of this article is to discuss the evolution of the political and ideological formulation of the economic development known as new developmentalism. The specific objective is to demonstrate the hypothesis that the new developmentalism is a version of the embedded liberalism, that expresses the compromise between the strategic guidelines of the liberalism and the state interventionism focused on macroeconomic stabilization.

  20. 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

  1. 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.

  2. 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.

  3. O paradigma do desenvolvimento: do mito fundador ao novo desenvolvimento

    Directory of Open Access Journals (Sweden)

    Anete B.L. Ivo

    Full Text Available Este artigo busca historicizar contextos que reorientaram a noção de desenvolvimento, no Brasil, desde os anos 30-80, passando pelo ajuste neoliberal dos anos 90, até inflexões atuais que indagam se o novo intervencionismo massivo e estratégico do Estado em políticas sociais para os mais pobres aponta para um novo modelo de desenvolvimento. A análise apresenta inflexões do modelo cepalino de 50-60 e tenta priorizar dimensões sociais na mediação das contradições entre a economia, a política e o institucional. O fio condutor toma dois vetores analíticos: o tema do conflito (redistributivo e o da integração. O primeiro é assentado nas coalizões das classes e confronto entre atores nacionais e agências multilaterais; e o da integração, na contraface do conflito, considera a abertura das políticas públicas e, também, a inovação de atores sociais e políticos em novos arranjos voltados para os objetivos do bem-estar social e da cidadania, de uma perspectiva mais sustentada.

  4. Tinindo Trincando: Contracultura e rock no samba dos Novos Baianos

    Directory of Open Access Journals (Sweden)

    VARGAS, Herom

    2011-12-01

    Full Text Available The aim of this article is to discuss aspects linked to counterculture and rock in musical production of the Brazilian band Novos Baianos in the 70’s. Having the context of Brazilian popular music from that decade as a background, two points will be discussed: 1 the particular understanding of counterculture made by the band, and 2 the experimental mix between rock and Brazilian popular musical genres. The counterculture aspects – according to Roszak (1972, Muggiatti (1981, Goffman e Joy (2007, Risério (2005, Dunn (2001; 2002 – will be observed from memories of one of the band’s leaders, the lyricist Luiz Galvão, in his book Anos 70: novos e baianos (1997, and from the scenes of the movie Novos Baianos F.C., directed by Solano Ribeiro (1973. On musical experimentation, some of their songs recorded in the 70’s point the ways of use of rock’s aesthetic elements, especially in guitar arrangements of the musician Pepeu Gomes

  5. 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

  6. The Strategic Design Perspective

    DEFF Research Database (Denmark)

    Rasmussen, Jørgen

    2006-01-01

    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...... changed its focus from drugs and doctors, to the well-being of patients, and thereby created a completely new product, the NovoPen. This product has benefited the company immensely, and even more so, benefited the quality of life for the patients. I will argue that designers must take their share......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...

  7. De novo copy number variations in cloned dogs from the same nuclear donor.

    Science.gov (United States)

    Jung, Seung-Hyun; Yim, Seon-Hee; Oh, Hyun Ju; Park, Jung Eun; Kim, Min Jung; Kim, Geon A; Kim, Tae-Min; Kim, Jin-Soo; Lee, Byeong Chun; Chung, Yeun-Jun

    2013-12-09

    Somatic mosaicism of copy number variants (CNVs) in human body organs and de novo CNV event in monozygotic twins suggest that de novo CNVs can occur during mitotic recombination. These de novo CNV events are important for understanding genetic background of evolution and diverse phenotypes. In this study, we explored de novo CNV event in cloned dogs with identical genetic background. We analyzed CNVs in seven cloned dogs using the nuclear donor genome as reference by array-CGH, and identified five de novo CNVs in two of the seven clones. Genomic qPCR, dye-swap array-CGH analysis and B-allele profile analysis were used for their validation. Two larger de novo CNVs (5.2 Mb and 338 Kb) on chromosomes X and 19 in clone-3 were consistently validated by all three experiments. The other three smaller CNVs (sized from 36.1 to 76.4 Kb) on chromosomes 2, 15 and 32 in clone-3 and clone-6 were verified by at least one of the three validations. In addition to the de novo CNVs, we identified a 37 Mb-sized copy neutral de novo loss of heterozygosity event on chromosome 2 in clone-6. To our knowledge, this is the first report of de novo CNVs in the cloned dogs which were generated by somatic cell nuclear transfer technology. To study de novo genetic events in cloned animals can help understand formation mechanisms of genetic variants and their biological implications.

  8. Clinical Implications of Phosphorylated STAT3 Expression in de novo Diffuse Large B-cell Lymphoma

    DEFF Research Database (Denmark)

    Ok, Chi Y; Chen, Jiayu; Xu-Monette, Ziju

    2014-01-01

    PURPOSE: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact...... of phosphorylated STAT3 (pSTAT3) on prognosis are limited. EXPERIMENTAL DESIGN: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma...... biomarkers, and genetic translocations. RESULTS: pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall...

  9. 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.

  10. 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.

  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...... of the art and present the first framework for assessing the performance of existing methods. We identified 19 tools and selected seven representative candidates for a comparative analysis with more than 12,000 runs, spanning different biological networks, molecular profiles, and parameters. Our results show...

  12. Ecodesign: um novo paradigma moderno inscrito entre moda e consumo?

    OpenAIRE

    Andréia Mesacasa; Hieda Maria Pagliosa Corona; Nilvânia Aparecida Mello

    2010-01-01

    Este artigo pretende analisar as relações existentes entre a modernidade, a moda que rege as formas do vestir, o consumo evidenciado pela sociedade capitalista e suas implicações na prática do ecodesign que integra um novo paradigma no contexto vivenciado pelos indivíduos e a natureza. A modernidade possui como principais características a separação entre tempo-espaço, o desenvolvimento dos mecanismos de desencaixe e a apropriação reflexiva do conhecimento que desloca a vida social da fixidez...

  13. Ileus as first sign of de novo neuroendocrine prostate cancer

    DEFF Research Database (Denmark)

    Jochumsen, Mads Ryø; Sahlholdt, Bjørn Agerbo; Jensen, Jørgen Bjerggaard

    2017-01-01

    A 73-year-old man with almost no previous medical history was admitted acute with stomach pain, distended abdomen, stop of defecation and feculent vomiting. The patient had been constipated for three months and about a month before admission, a coloscopy was performed presenting no findings...... is more often seen as a result of treatment with hormone therapy. This case presents a rare debut symptom of a rare form of de novo cancer, illustrating the importance of a proper digital rectal examination when diagnosing constipation and acute abdomen....

  14. 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.

  15. De novo assembly and transcriptome analysis of contrasting sugarcane varieties.

    Directory of Open Access Journals (Sweden)

    Claudio Benicio Cardoso-Silva

    Full Text Available Sugarcane is an important crop and a major source of sugar and alcohol. In this study, we performed de novo assembly and transcriptome annotation for six sugarcane genotypes involved in bi-parental crosses. The de novo assembly of the sugarcane transcriptome was performed using short reads generated using the Illumina RNA-Seq platform. We produced more than 400 million reads, which were assembled into 72,269 unigenes. Based on a similarity search, the unigenes showed significant similarity to more than 28,788 sorghum proteins, including a set of 5,272 unigenes that are not present in the public sugarcane EST databases; many of these unigenes are likely putative undescribed sugarcane genes. From this collection of unigenes, a large number of molecular markers were identified, including 5,106 simple sequence repeats (SSRs and 708,125 single-nucleotide polymorphisms (SNPs. This new dataset will be a useful resource for future genetic and genomic studies in this species.

  16. 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

  17. Multi-nucleotide de novo Mutations in Humans.

    Directory of Open Access Journals (Sweden)

    Søren Besenbacher

    2016-11-01

    Full Text Available Mutation of the DNA molecule is one of the most fundamental processes in biology. In this study, we use 283 parent-offspring trios to estimate the rate of mutation for both single nucleotide variants (SNVs and short length variants (indels in humans and examine the mutation process. We found 17812 SNVs, corresponding to a mutation rate of 1.29 × 10-8 per position per generation (PPPG and 1282 indels corresponding to a rate of 9.29 × 10-10 PPPG. We estimate that around 3% of human de novo SNVs are part of a multi-nucleotide mutation (MNM, with 558 (3.1% of mutations positioned less than 20kb from another mutation in the same individual (median distance of 525bp. The rate of de novo mutations is greater in late replicating regions (p = 8.29 × 10-19 and nearer recombination events (p = 0.0038 than elsewhere in the genome.

  18. 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.

  19. Molecular characterization of de novo secondary trisomy 13

    Energy Technology Data Exchange (ETDEWEB)

    Shaffer, L.G.; McCaskill, C.; Han, Jin-Yeong [Baylor College of Medicine, Houston, TX (United States); Choo, K.H.A. [Murdoch Institute, Melbourne (Australia); Cutillo, D.M.; Donnenfeld, A.E. [Pennyslvania Hospital, PA (United States); Weiss, L.; Van Dyke, D.L. [Henry Ford Hospital, Detroit, MI (United States)

    1994-11-01

    Unbalanced Robertsonian translocations are a significant cause of mental retardation and fetal wastage. The majority of homologous rearrangements of chromosome 21 in Down syndrome have been shown to be isochromosomes. Aside from chromosome 21, very little is known about other acrocentric homologous rearrangements. In this study, four cases of de novo secondary trisomy 13 are presented. FISH using alpha-satellite sequences, rDNA, and a pTRI-6 satellite I sequence specific to the short arm of chromosome 13 showed all four rearrangements to be dicentric an apparently devoid of ribosomal genes. Three of four rearrangements retained the pTRI-6 satellite I sequence. Case 1 was the exception, showing a deletion of this sequence in the rearrangement, although both parental chromosomes 13 had strong positive hybridization signals. Eleven microsatellite markers from chromosome 13 were also used to characterize the rearrangements. Of the four possible outcomes, one maternal Robertsonian translocation, two paternal isochromosomes, and one maternal isochromosomes were observed. A double recombination was observed in the maternally derived rob(13q13q). No recombination events were detected in any isochromosome. The parental origins and molecular chromosomal structure of these cases are compared with previous studies of de novo acrocentric rearrangements. 20 refs., 3 figs., 2 tabs.

  20. 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.

  1. De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome.

    Science.gov (United States)

    Sleven, Hannah; Welsh, Seth J; Yu, Jing; Churchill, Mair E A; Wright, Caroline F; Henderson, Alex; Horvath, Rita; Rankin, Julia; Vogt, Julie; Magee, Alex; McConnell, Vivienne; Green, Andrew; King, Mary D; Cox, Helen; Armstrong, Linlea; Lehman, Anna; Nelson, Tanya N; Williams, Jonathan; Clouston, Penny; Hagman, James; Németh, Andrea H

    2017-01-05

    Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study. The core phenotype includes moderate to severe intellectual disability, and many individuals exhibit cerebellar ataxia, subtle facial dysmorphism, strabismus, and vesicoureteric reflux, suggesting that EBF3 has a widespread developmental role. Pathogenic de novo variants identified in EBF3 include multiple loss-of-function and missense mutations. Structural modeling suggested that the missense mutations affect DNA binding. Functional analysis of mutant proteins with missense substitutions revealed reduced transcriptional activities and abilities to form heterodimers with wild-type EBF3. We conclude that EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. De Novo Synthesis of Steroids and Oxysterols in Adipocytes*

    Science.gov (United States)

    Li, Jiehan; Daly, Edward; Campioli, Enrico; Wabitsch, Martin; Papadopoulos, Vassilios

    2014-01-01

    Local production and action of cholesterol metabolites such as steroids or oxysterols within endocrine tissues are currently recognized as an important principle in the cell type- and tissue-specific regulation of hormone effects. In adipocytes, one of the most abundant endocrine cells in the human body, the de novo production of steroids or oxysterols from cholesterol has not been examined. Here, we demonstrate that essential components of cholesterol transport and metabolism machinery in the initial steps of steroid and/or oxysterol biosynthesis pathways are present and active in adipocytes. The ability of adipocyte CYP11A1 in producing pregnenolone is demonstrated for the first time, rendering adipocyte a steroidogenic cell. The oxysterol 27-hydroxycholesterol (27HC), synthesized by the mitochondrial enzyme CYP27A1, was identified as one of the major de novo adipocyte products from cholesterol and its precursor mevalonate. Inhibition of CYP27A1 activity or knockdown and deletion of the Cyp27a1 gene induced adipocyte differentiation, suggesting a paracrine or autocrine biological significance for the adipocyte-derived 27HC. These findings suggest that the presence of the 27HC biosynthesis pathway in adipocytes may represent a defense mechanism to prevent the formation of new fat cells upon overfeeding with dietary cholesterol. PMID:24280213

  3. De novo synthesis of steroids and oxysterols in adipocytes.

    Science.gov (United States)

    Li, Jiehan; Daly, Edward; Campioli, Enrico; Wabitsch, Martin; Papadopoulos, Vassilios

    2014-01-10

    Local production and action of cholesterol metabolites such as steroids or oxysterols within endocrine tissues are currently recognized as an important principle in the cell type- and tissue-specific regulation of hormone effects. In adipocytes, one of the most abundant endocrine cells in the human body, the de novo production of steroids or oxysterols from cholesterol has not been examined. Here, we demonstrate that essential components of cholesterol transport and metabolism machinery in the initial steps of steroid and/or oxysterol biosynthesis pathways are present and active in adipocytes. The ability of adipocyte CYP11A1 in producing pregnenolone is demonstrated for the first time, rendering adipocyte a steroidogenic cell. The oxysterol 27-hydroxycholesterol (27HC), synthesized by the mitochondrial enzyme CYP27A1, was identified as one of the major de novo adipocyte products from cholesterol and its precursor mevalonate. Inhibition of CYP27A1 activity or knockdown and deletion of the Cyp27a1 gene induced adipocyte differentiation, suggesting a paracrine or autocrine biological significance for the adipocyte-derived 27HC. These findings suggest that the presence of the 27HC biosynthesis pathway in adipocytes may represent a defense mechanism to prevent the formation of new fat cells upon overfeeding with dietary cholesterol.

  4. Design, Synthesis and Biological Activity of Novel Reversible Peptidyl FVIIa Inhibitors Rh-Catalyzed Enantioselective Synthesis of Diaryl Amines

    DEFF Research Database (Denmark)

    Storgaard, Morten

    This thesis describes two different projects. The first project deals with the design, synthesis and biological activity of novel reversible peptidyl FVIIa inhibitors (Chapter 1–3). FVIIa was launced as NovoSeven R over a decade ago by Novo Nordisk for the treatment of hemophilia A and B complica......This thesis describes two different projects. The first project deals with the design, synthesis and biological activity of novel reversible peptidyl FVIIa inhibitors (Chapter 1–3). FVIIa was launced as NovoSeven R over a decade ago by Novo Nordisk for the treatment of hemophilia A and B...

  5. 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.

  6. 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...

  7. 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...

  8. 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

    Next-generation massively parallel DNA sequencing technologies provide ultrahigh throughput at a substantially lower unit data cost; however, the data are very short read length sequences, making de novo assembly extremely challenging. Here, we describe a novel method for de novo assembly of larg...

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

    DEFF Research Database (Denmark)

    2014-01-01

    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...

  10. 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.

  11. De Novo duplication in Charcot-Marie-Tooth Type 1A

    Energy Technology Data Exchange (ETDEWEB)

    Mandich, P.; Bellone, E.; Ajmar, F. [and others

    1996-09-01

    We read with interest the paper on {open_quotes}Prevalence and Origin of De Novo Duplications in Charcot-Marie-Tooth Disease Type 1A: First Report of a De Novo Duplication with a Maternal Origin,{close_quotes}. They reported their experience with 10 sporadic cases of Charcot-Marie-Tooth type 1A (CMT1A) in which it was demonstrated that the disease had arisen as the result of a de novo duplication. They analyzed the de novo-duplication families by using microsatellite markers and identified the parental origin of the duplication in eight cases. In one family the duplication was of maternal origin, whereas in the remaining seven cases it was of paternal origin. The authors concluded that their report was the first evidence of a de novo duplication of maternal origin, suggesting that this is not a phenomenon associated solely with male meiosis. 7 refs.

  12. FSG: Fast String Graph Construction for De Novo Assembly.

    Science.gov (United States)

    Bonizzoni, Paola; Vedova, Gianluca Della; Pirola, Yuri; Previtali, Marco; Rizzi, Raffaella

    2017-10-01

    The string graph for a collection of next-generation reads is a lossless data representation that is fundamental for de novo assemblers based on the overlap-layout-consensus paradigm. In this article, we explore a novel approach to compute the string graph, based on the FM-index and Burrows and Wheeler Transform. We describe a simple algorithm that uses only the FM-index representation of the collection of reads to construct the string graph, without accessing the input reads. Our algorithm has been integrated into the string graph assembler (SGA) as a standalone module to construct the string graph. The new integrated assembler has been assessed on a standard benchmark, showing that fast string graph (FSG) is significantly faster than SGA while maintaining a moderate use of main memory, and showing practical advantages in running FSG on multiple threads. Moreover, we have studied the effect of coverage rates on the running times.

  13. De novo artistic activity following insular-SII ischemia.

    Science.gov (United States)

    Thomas-Anterion, Catherine; Creac'h, Christelle; Dionet, Elsa; Borg, Céline; Extier, Chantal; Faillenot, Isabelle; Peyron, Roland

    2010-07-01

    We report here the case of a female patient who developed the following behavioural changes after a brain lesion involving the left posterior insula and SII cortices. She discovered de novo artistic capabilities for painting, with an episodic and compulsive need to paint ("hyperpainting"), but also exhibited changes in her ability to feel emotions. In addition, she had a typical neuropathic pain syndrome, including provoked pain and spontaneous pain, whose intensity was worsened when she painted with cold colours. This case-report suggests some kind of synaesthesiae, which has previously been reported for other sensory modalities. These findings suggest that a cross-talk between emotional, thermosensory, pain, and motivational functions may take place during recovery, at the level of the left insular-SII cortices. Copyright 2010. Published by Elsevier B.V.

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

    Science.gov (United States)

    Chakravarty, Ambar

    2011-01-01

    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. PMID:22346020

  15. 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.

  16. 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.

  17. De novo synthesis of a sunscreen compound in vertebrates.

    Science.gov (United States)

    Osborn, Andrew R; Almabruk, Khaled H; Holzwarth, Garrett; Asamizu, Shumpei; LaDu, Jane; Kean, Kelsey M; Karplus, P Andrew; Tanguay, Robert L; Bakalinsky, Alan T; Mahmud, Taifo

    2015-05-12

    Ultraviolet-protective compounds, such as mycosporine-like amino acids (MAAs) and related gadusols produced by some bacteria, fungi, algae, and marine invertebrates, are critical for the survival of reef-building corals and other marine organisms exposed to high-solar irradiance. These compounds have also been found in marine fish, where their accumulation is thought to be of dietary or symbiont origin. In this study, we report the unexpected discovery that fish can synthesize gadusol de novo and that the analogous pathways are also present in amphibians, reptiles, and birds. Furthermore, we demonstrate that engineered yeast containing the fish genes can produce and secrete gadusol. The discovery of the gadusol pathway in vertebrates provides a platform for understanding its role in these animals, and the possibility of engineering yeast to efficiently produce a natural sunscreen and antioxidant presents an avenue for its large-scale production for possible use in pharmaceuticals and cosmetics.

  18. 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.

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

    DEFF Research Database (Denmark)

    Cao, Hongzhi; Wu, Honglong; Luo, Ruibang

    2015-01-01

    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...... 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...... 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...

  20. 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.

  1. 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.

  2. Physicochemical investigation of medieval ceramics from excavation site Novo Brdo

    Directory of Open Access Journals (Sweden)

    Čugalj Snežana S.

    2008-01-01

    Full Text Available Artefacts produced or treated at high temperatures provide information about manufacturing techniques. Well preserved ceramic objects are therefore excellent chronological markers as well as general markers of society development. In order to determine provenance of pottery fragments, archaeologists classify samples according to their physical characteristics, decoration and aesthetic style. However, a more objective multidisciplinary approach, based on undoubted results, is necessary to complete this study. In this work we have investigated 27 samples of medieval ceramics from excavation site Novo Brdo, using X-ray fluorescence (XRF, FTIR spectroscopy and X-ray powder diffraction (XRPD. Novo Brdo was large and rich mining and trading center of Serbia in XIV and XV century. A large number of ceramic samples found during the systematic excavation of this archaeological site allow good choice of samples for both destructive and nondestructive analysis. Combining results obtained by different experimental techniques, i.e. by FT-IR spectroscopy, after deconvolution of the spectra, and XRPD analysis, we have determined mineralogical composition and technology of production of investigated pottery. Estimated temperature of firing ranged from 800 to 900 °C, which is in agreement with the presence of high-temperature minerals like gehlenite and anorthite. Firing was preformed in the oxidation atmosphere since hematite, which is formed only in oxidation atmosphere, is detected in all investigated samples. Cross sections showed presence of defects and inhomogeneity of investigated ceramic, which indicates fast and incomplete firing procedure. All these findings indicate that investigated pottery was produced in the domestic workshops. The obtained results will be used to build up the National database for medieval ceramics as well as the database for the Balkan region.

  3. 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

  4. Congenital cataracts: de novo gene conversion event in CRYBB2.

    Science.gov (United States)

    Garnai, Sarah J; Huyghe, Jeroen R; Reed, David M; Scott, Kathleen M; Liebmann, Jeffrey M; Boehnke, Michael; Richards, Julia E; Ritch, Robert; Pawar, Hemant

    2014-01-01

    To identify the cause of congenital cataracts in a consanguineous family of Ashkenazi Jewish ancestry. We performed genome-wide linkage analysis and whole-exome sequencing for the initial discovery of variants, and we confirmed the variants using gene-specific primers and Sanger sequencing. We found significant evidence of linkage to chromosome 22, under an autosomal dominant inheritance model, with a maximum logarithm of the odds (LOD) score of 3.91 (16.918 to 25.641 Mb). Exome sequencing identified three nonsynonymous changes in the CRYBB2 exon 5 coding sequence that are consistent with the sequence of the corresponding region of the pseudogene CRYBB2P1. The identification of these changes was complicated by possible mismapping of some mutated CRYBB2 sequences to CRYBB2P1. Sequencing with gene-specific primers confirmed that the changes--rs2330991, c.433 C>T (p.R145W); rs2330992, c.440A>G (p.Q147R); and rs4049504, c.449C>T (p.T150M)--present in all ten affected family members are located in CRYBB2 and are not artifacts of cross-reaction with CRYBB2P1. We did not find these changes in six unaffected family members, including the unaffected grandfather who contributed the affected haplotype, nor did we find them in the 100 Ashkenazi Jewish controls. Our data are consistent with a de novo gene conversion event, transferring 270 base pairs at most from CRYBB2P1 to exon 5 of CRYBB2. This study highlights how linkage mapping can be complicated by de novo mutation events, as well as how sequence-analysis pipeline mapping of short reads from next-generation sequencing can be complicated by the existence of pseudogenes or other highly homologous sequences.

  5. De novo GABRG2 mutations associated with epileptic encephalopathies

    Science.gov (United States)

    Shen, Dingding; Hernandez, Ciria C; Shen, Wangzhen; Hu, Ningning; Poduri, Annapurna; Shiedley, Beth; Rotenberg, Alex; Datta, Alexandre N; Leiz, Steffen; Patzer, Steffi; Boor, Rainer; Ramsey, Kerri; Goldberg, Ethan; Helbig, Ingo; Ortiz-Gonzalez, Xilma R; Lemke, Johannes R; Marsh, Eric D; Macdonald, Robert L

    2017-01-01

    Abstract Epileptic encephalopathies are a devastating group of severe childhood onset epilepsies with medication-resistant seizures and poor developmental outcomes. Many epileptic encephalopathies have a genetic aetiology and are often associated with de novo mutations in genes mediating synaptic transmission, including GABAA receptor subunit genes. Recently, we performed next generation sequencing on patients with a spectrum of epileptic encephalopathy phenotypes, and we identified five novel (A106T, I107T, P282S, R323W and F343L) and one known (R323Q) de novo GABRG2 pathogenic variants (mutations) in eight patients. To gain insight into the molecular basis for how these mutations contribute to epileptic encephalopathies, we compared the effects of the mutations on the properties of recombinant α1β2γ2L GABAA receptors transiently expressed in HEK293T cells. Using a combination of patch clamp recording, immunoblotting, confocal imaging and structural modelling, we characterized the effects of these GABRG2 mutations on GABAA receptor biogenesis and channel function. Compared with wild-type α1β2γ2L receptors, GABAA receptors containing a mutant γ2 subunit had reduced cell surface expression with altered subunit stoichiometry or decreased GABA-evoked whole-cell current amplitudes, but with different levels of reduction. While a causal role of these mutations cannot be established directly from these results, the functional analysis together with the genetic information suggests that these GABRG2 variants may be major contributors to the epileptic encephalopathy phenotypes. Our study further expands the GABRG2 phenotypic spectrum and supports growing evidence that defects in GABAergic neurotransmission participate in the pathogenesis of genetic epilepsies including epileptic encephalopathies. PMID:27864268

  6. Factors Associated With Ambulatory Activity in De Novo Parkinson Disease.

    Science.gov (United States)

    Christiansen, Cory; Moore, Charity; Schenkman, Margaret; Kluger, Benzi; Kohrt, Wendy; Delitto, Anthony; Berman, Brian; Hall, Deborah; Josbeno, Deborah; Poon, Cynthia; Robichaud, Julie; Wellington, Toby; Jain, Samay; Comella, Cynthia; Corcos, Daniel; Melanson, Ed

    2017-04-01

    Objective ambulatory activity during daily living has not been characterized for people with Parkinson disease prior to initiation of dopaminergic medication. Our goal was to characterize ambulatory activity based on average daily step count and examine determinants of step count in nonexercising people with de novo Parkinson disease. We analyzed baseline data from a randomized controlled trial, which excluded people performing regular endurance exercise. Of 128 eligible participants (mean ± SD = 64.3 ± 8.6 years), 113 had complete accelerometer data, which were used to determine daily step count. Multiple linear regression was used to identify factors associated with average daily step count over 10 days. Candidate explanatory variable categories were (1) demographics/anthropometrics, (2) Parkinson disease characteristics, (3) motor symptom severity, (4) nonmotor and behavioral characteristics, (5) comorbidities, and (6) cardiorespiratory fitness. Average daily step count was 5362 ± 2890 steps per day. Five factors explained 24% of daily step count variability, with higher step count associated with higher cardiorespiratory fitness (10%), no fear/worry of falling (5%), lower motor severity examination score (4%), more recent time since Parkinson disease diagnosis (3%), and the presence of a cardiovascular condition (2%). Daily step count in nonexercising people recruited for this intervention trial with de novo Parkinson disease approached sedentary lifestyle levels. Further study is warranted for elucidating factors explaining ambulatory activity, particularly cardiorespiratory fitness, and fear/worry of falling. Clinicians should consider the costs and benefits of exercise and activity behavior interventions immediately after diagnosis of Parkinson disease to attenuate the health consequences of low daily step count.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A170).

  7. BioMog: A Computational Framework for the De Novo Generation or Modification of Essential Biomass Components

    Science.gov (United States)

    Tervo, Christopher J.; Reed, Jennifer L.

    2013-01-01

    The success of genome-scale metabolic modeling is contingent on a model's ability to accurately predict growth and metabolic behaviors. To date, little focus has been directed towards developing systematic methods of proposing, modifying and interrogating an organism's biomass requirements that are used in constraint-based models. To address this gap, the biomass modification and generation (BioMog) framework was created and used to generate lists of biomass components de novo, as well as to modify predefined biomass component lists, for models of Escherichia coli (iJO1366) and of Shewanella oneidensis (iSO783) from high-throughput growth phenotype and fitness datasets. BioMog's de novo biomass component lists included, either implicitly or explicitly, up to seventy percent of the components included in the predefined biomass equations, and the resulting de novo biomass equations outperformed the predefined biomass equations at qualitatively predicting mutant growth phenotypes by up to five percent. Additionally, the BioMog procedure can quantify how many experiments support or refute a particular metabolite's essentiality to a cell, and it facilitates the determination of inconsistent experiments and inaccurate reaction and/or gene to reaction associations. To further interrogate metabolite essentiality, the BioMog framework includes an experiment generation algorithm that allows for the design of experiments to test whether a metabolite is essential. Using BioMog, we correct experimental results relating to the essentiality of thyA gene in E. coli, as well as perform knockout experiments supporting the essentiality of protoheme. With these capabilities, BioMog can be a valuable resource for analyzing growth phenotyping data and component of a model developer's toolbox. PMID:24339916

  8. 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 ...

  9. Structural and functional properties of designed globins

    Indian Academy of Sciences (India)

    Administrator

    Abstract. 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 ...

  10. 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.

  11. 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

  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. 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...

  14. 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

    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......, in the WM and Yakushev normalized analyses, stage II patients displayed more prominent cortical hypometabolism than did stage I patients. CONCLUSION: The use of alternative normalization procedures, other than GM, suggests that much more extensive cortical hypometabolism is present in untreated de novo PD...

  15. Immunotherapy for De Novo renal transplantation: what's in the pipeline?

    Science.gov (United States)

    Tedesco Silva, Helio; Pinheiro Machado, Paula; Rosso Felipe, Claudia; Medina Pestana, Jose Osmar

    2006-01-01

    Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes. There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence. Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials. It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation. Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways. In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids. Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors. Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models. The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases. CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials. FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy. Fingolimod (FTY720), a synthetic sphingosine phosphate receptor

  16. 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

  17. 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

  18. 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

    2016-04-01

    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.

  19. 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.

  20. Complicated diverticulitis in a de novo kidney transplanted patient.

    Science.gov (United States)

    TuŢă, Liliana Ana; Boşoteanu, Mădălina; Dumitru, Eugen; Deacu, Mariana

    2017-01-01

    Diverticular disease is frequent amongst the elderly and immunosuppressed patients. It mainly presents as sigmoid diverticulitis, but severe complications, like bleedings, infections and colon perforation may occur, frequently due to immunosuppressive therapy. Moreover, antibiotherapy and hemostatics may not efficiently control evolution in such cases. Early diagnose and adequate treatment of colonic diverticulosis complicated with lower gastrointestinal bleeding and diverticulitis in immunocompromised patients. We report a 55-year-old patient who underwent de novo renal transplantation one year ago and recently developed a severe diverticular bleeding complicated by hemorrhagic shock. Colonoscopic examination revealed diverticular disease with diverticulitis and severe, diffuse bleeding, mainly in the descending colon. Due to his immunocompromised status and unfavorable evolution under hemostatics, recombinant coagulation factor VIIa (rFVIIa) was given to avoid surgery. The bleeding stopped after two doses of rFVIIa. Unfortunately, after three weeks, lower quadrant pain, tenderness, abdominal distention, and fever occurred, in spite of immunosuppressive drug changing and adequate conservative therapy. Abdominal computed tomography (CT) scan revealed complicated diverticulitis, so patient underwent surgery, with partial colectomy, followed by total recovery. In conclusion, diverticulosis coli complicated with lower gastrointestinal bleeding and diverticulitis in immunocompromised patients was for us a challenging diagnosis, as well as a therapeutic issue. Treatment options, usually based on our local resources and expertise, considered conservatory therapy as the first choice, keeping surgical maneuvers just as a rescue solution.

  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. Simple Approach for De Novo Structural Identification of Mannose Trisaccharides

    Science.gov (United States)

    Hsu, Hsu Chen; Liew, Chia Yen; Huang, Shih-Pei; Tsai, Shang-Ting; Ni, Chi-Kung

    2017-12-01

    Oligosaccharides have diverse functions in biological systems. However, the structural determination of oligosaccharides remains difficult and has created a bottleneck in carbohydrate research. In this study, a new approach for the de novo structural determination of underivatized oligosaccharides is demonstrated. A low-energy collision-induced dissociation (CID) of sodium ion adducts was used to facilitate the cleavage of desired chemical bonds during the dissociation. The selection of fragments for the subsequent CID was guided using a procedure that we built from the understanding of the saccharide dissociation mechanism. The linkages, anomeric configurations, and branch locations of oligosaccharides were determined by comparing the CID spectra of oligosaccharide with the fragmentation patterns based on the dissociation mechanism and our specially prepared disaccharide CID spectrum database. The usefulness of this method was demonstrated to determine the structures of several mannose trisaccharides. This method can also be applied in the structural determination of oligosaccharides larger than trisaccharides and containing hexose other than mannose if authentic standards are available. [Figure not available: see fulltext.

  3. 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.

  4. Simple Approach for De Novo Structural Identification of Mannose Trisaccharides

    Science.gov (United States)

    Hsu, Hsu Chen; Liew, Chia Yen; Huang, Shih-Pei; Tsai, Shang-Ting; Ni, Chi-Kung

    2018-03-01

    Oligosaccharides have diverse functions in biological systems. However, the structural determination of oligosaccharides remains difficult and has created a bottleneck in carbohydrate research. In this study, a new approach for the de novo structural determination of underivatized oligosaccharides is demonstrated. A low-energy collision-induced dissociation (CID) of sodium ion adducts was used to facilitate the cleavage of desired chemical bonds during the dissociation. The selection of fragments for the subsequent CID was guided using a procedure that we built from the understanding of the saccharide dissociation mechanism. The linkages, anomeric configurations, and branch locations of oligosaccharides were determined by comparing the CID spectra of oligosaccharide with the fragmentation patterns based on the dissociation mechanism and our specially prepared disaccharide CID spectrum database. The usefulness of this method was demonstrated to determine the structures of several mannose trisaccharides. This method can also be applied in the structural determination of oligosaccharides larger than trisaccharides and containing hexose other than mannose if authentic standards are available.

  5. De novo transcriptome of the Hemimetabolous German cockroach (Blattella germanica.

    Directory of Open Access Journals (Sweden)

    Xiaojie Zhou

    Full Text Available BACKGROUND: The German cockroach, Blattella germanica, is an important insect pest that transmits various pathogens mechanically and causes severe allergic diseases. This insect has long served as a model system for studies of insect biology, physiology and ecology. However, the lack of genome or transcriptome information heavily hinder our further understanding about the German cockroach in every aspect at a molecular level and on a genome-wide scale. To explore the transcriptome and identify unique sequences of interest, we subjected the B. germanica transcriptome to massively parallel pyrosequencing and generated the first reference transcriptome for B. germanica. METHODOLOGY/PRINCIPAL FINDINGS: A total of 1,365,609 raw reads with an average length of 529 bp were generated via pyrosequencing the mixed cDNA library from different life stages of German cockroach including maturing oothecae, nymphs, adult females and males. The raw reads were de novo assembled to 48,800 contigs and 3,961 singletons with high-quality unique sequences. These sequences were annotated and classified functionally in terms of BLAST, GO and KEGG, and the genes putatively coding detoxification enzyme systems, insecticide targets, key components in systematic RNA interference, immunity and chemoreception pathways were identified. A total of 3,601 SSRs (Simple Sequence Repeats loci were also predicted. CONCLUSIONS/SIGNIFICANCE: The whole transcriptome pyrosequencing data from this study provides a usable genetic resource for future identification of potential functional genes involved in various biological processes.

  6. 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.

  7. Considerações sobre novos rumos para o Direito

    Directory of Open Access Journals (Sweden)

    Aristides Cimadon

    2010-07-01

    Full Text Available Neste artigo polemiza-se a prática judiciária e jurídica fundamentada no positivismo. Aborda-se uma crítica sobre as ações dos operadores jurídicos que se fundamentam na razão ornamental e no jeito. Reclama-se por uma produção jurídica ligada ao Direito Justo a serviço da cidadania e da sociedade. Mostra-se que a uma crise sintomática na produção das leis que, em geral, não tem preocupação com o bem-estar coletivo. Identifica-se a globalização de valores e relações econômicas que definem um conjunto de princípios reguladores da produção normativa. Por outro lado, questiona-se a ética e a moral como inspiração da operação jurídica e a necessidade de que a formação jurídica se paute por novos rumos que vislumbrem a Justiça como objetivo essencial do Direito. Palavras-chave: Direito. Justiça. Ética. Moral. Cidadania.

  8. De novo pericentric inversion of chromosome 9 in congenital anomaly.

    Science.gov (United States)

    Jeong, Seon-Yong; Kim, Bo-Young; Yu, Jae Eun

    2010-09-01

    The pericentric inversion of chromosome 9 is one of the most common structural balanced chromosomal variations and has been found in both normal populations and patients with various abnormal phenotypes and diseases. The aim of this study was to re-evaluate the clinical impact of inv(9)(p11q13). We studied the karyotypes of 431 neonates with congenital anomalies at the Pediatric Clinic in Ajou University Hospital between 2004 and 2008 and retrospectively reviewed their clinical data. Chromosomal aberrations were detected in 60 patients (13.9%). The most common type of structural abnormality was inv(9)(p11q13), found in eight patients. Clinical investigation revealed that all eight cases with inv(9)(p11q13) had various congenital anomalies including: polydactyly, club foot, microtia, deafness, asymmetric face, giant Meckel's diverticulum, duodenal diaphragm, small bowel malrotation, pulmonary stenosis, cardiomyopathy, arrhythmia, and intrauterine growth restriction. The cytogenetic analysis of parents showed that all of the cases were de novo heterozygous inv(9)(p11q13). Since our results indicate that the incidence of inv(9)(p11q13) in patients with congenital anomalies was not significantly different from the normal population, inv(9)(p11q13) does not appear to be pathogenic with regard to the congenital anomalies. Some other, to date unknown, causes of the anomalies remain to be identified.

  9. De Novo Assembly and Characterization of the Xenocatantops brachycerus Transcriptome

    Science.gov (United States)

    Zhang, Xinmei; Qiu, Zhongying; Huang, Yuan

    2018-01-01

    Grasshoppers are common pests but also have high nutritional and commercial potential. Xenocatantops brachycerus Willemse (Orthoptera: Acrididae) is an economically important grasshopper species that is reared in China. Using the IlluminaHiSeqTM 4000 platform, three transcriptomes of the adult male, adult female, and nymph of X. brachycerus were sequenced. A total of 133,194,848 clean reads were obtained and de novo assembled into 43,187 unigenes with an average length of 964 bp (N50 of 1799 bp); of these, 24,717 (57.23%) unigenes matched known proteins. Based on these annotations, many putative transcripts related to X. brachycerus growth, development, environmental adaptability, and metabolism of nutritional components and bioactive components were identified. In addition, the expression profiles of all three transcriptome datasets were analyzed, and many differentially expressed genes were detected using RSEM and PossionDis. Unigenes. Unigenes with functions associated with growth and development exhibited higher transcript levels at the nymph stage, and unigenes associated with environmental adaptability showed increased transcription in the adults. These comprehensive X. brachycerus transcriptomic data will provide a useful molecular resource for gene prediction, molecular marker development, and studies on signaling pathways in this species and will serve as a reference for the efficient use of other grasshoppers. PMID:29419810

  10. 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.

  11. 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

  12. 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.

  13. Automated Antibody De Novo Sequencing and Its Utility in Biopharmaceutical Discovery

    Science.gov (United States)

    Sen, K. Ilker; Tang, Wilfred H.; Nayak, Shruti; Kil, Yong J.; Bern, Marshall; Ozoglu, Berk; Ueberheide, Beatrix; Davis, Darryl; Becker, Christopher

    2017-05-01

    Applications of antibody de novo sequencing in the biopharmaceutical industry range from the discovery of new antibody drug candidates to identifying reagents for research and determining the primary structure of innovator products for biosimilar development. When murine, phage display, or patient-derived monoclonal antibodies against a target of interest are available, but the cDNA or the original cell line is not, de novo protein sequencing is required to humanize and recombinantly express these antibodies, followed by in vitro and in vivo testing for functional validation. Availability of fully automated software tools for monoclonal antibody de novo sequencing enables efficient and routine analysis. Here, we present a novel method to automatically de novo sequence antibodies using mass spectrometry and the Supernovo software. The robustness of the algorithm is demonstrated through a series of stress tests.

  14. A ORIGEM DOS PRESBÍTEROS-EPÍSCOPOS NA IGREJA DO NOVO TESTAMENTO (I

    Directory of Open Access Journals (Sweden)

    Antonio José de Almeida

    2000-01-01

    Full Text Available O presente estudo propõe-se a investigar a origem do ministério episcopal, na medida em que é observável nos escritos do Novo Testamento. Depois de uma breve introdução metodológica, recolhem-se sinteticamente as principais informações do Novo Testamento sobre os ministérios eclesiais, em sua totalidade, diversidade e unidade.

  15. 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....

  16. 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.

  17. Comparing the effect of different mouthrinses on de novo plaque formation.

    Science.gov (United States)

    Narayan, Arun; Mendon, Chaya

    2012-07-01

    Several antiplaque agents are being available in the market in spite of vast development of modern medical science, satisfactory treatment of 'oral diseases' by newer drugs is not fully achieved, rather the chemical compounds has exposed the patients to it is different ill effects, therefore, there is interest to find out effective remedy of any disease by harmless herbal drugs thus the aim of this study was to compare plaque formation at 24 hours after the use of Triphala, Hi ora, Chlorhexidine and Colgate Plax mouth washes. A controlled, randomized, double-blind, crossover clinical trial was designed. Thirty subjects underwent four consecutive experimental phases with four treatments: Triphala, Hi Ora, Chlorhexidine and Colgate Plax. On the day of study, the subjects discontinued all other oral hygiene habits and were randomly assigned for treatment with the experimental mouthwash. Each experimental phase was preceded by a 28-day washout period. Plaque formation was recorded after one undisturbed day. Triphala, Hi Ora and Chlorhexidine reduced de novo plaque formation to a greater extent than the colgate plax mouthwash (p plaque efficacy similar to that of chlorhexdine, and was more effective at inhibiting plaque formation than the Colgate Plax mouth wash.

  18. 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.

  19. SOAPdenovo2: an empirically improved memory-efficient short-read de novo assembler

    Directory of Open Access Journals (Sweden)

    Luo Ruibang

    2012-12-01

    Full Text Available Abstract Background There is a rapidly increasing amount of de novo genome assembly using next-generation sequencing (NGS short reads; however, several big challenges remain to be overcome in order for this to be efficient and accurate. SOAPdenovo has been successfully applied to assemble many published genomes, but it still needs improvement in continuity, accuracy and coverage, especially in repeat regions. Findings To overcome these challenges, we have developed its successor, SOAPdenovo2, which has the advantage of a new algorithm design that reduces memory consumption in graph construction, resolves more repeat regions in contig assembly, increases coverage and length in scaffold construction, improves gap closing, and optimizes for large genome. Conclusions Benchmark using the Assemblathon1 and GAGE datasets showed that SOAPdenovo2 greatly surpasses its predecessor SOAPdenovo and is competitive to other assemblers on both assembly length and accuracy. We also provide an updated assembly version of the 2008 Asian (YH genome using SOAPdenovo2. Here, the contig and scaffold N50 of the YH genome were ~20.9 kbp and ~22 Mbp, respectively, which is 3-fold and 50-fold longer than the first published version. The genome coverage increased from 81.16% to 93.91%, and memory consumption was ~2/3 lower during the point of largest memory consumption.

  20. A review of ensemble methods for de novo motif discovery in ChIP-Seq data.

    Science.gov (United States)

    Lihu, Andrei; Holban, Ştefan

    2015-11-01

    De novo motif discovery is a difficult computational task. Historically, dedicated algorithms always reported a high percentage of false positives. Their performance did not improve considerably even after they adapted to handle large amounts of chromatin immunoprecipitation sequencing (ChIP-Seq) data. Several studies have advocated aggregating complementary algorithms, combining their predictions to increase the accuracy of the results. This led to the development of ensemble methods. To form a better view on modern ensembles, we review all compound tools designed for ChIP-Seq. After a brief introduction to basic algorithms and early ensembles, we describe the most recent tools. We highlight their limitations and strengths by presenting their architecture, the input options and their output. To provide guidance for next-generation sequencing practitioners, we observe the differences and similarities between them. Last but not least, we identify and recommend several features to be implemented by any novel ensemble algorithm. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  1. Computational Protein Design

    DEFF Research Database (Denmark)

    Johansson, Kristoffer Enøe

    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......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...

  2. 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...

  3. 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.

  4. Novos conceitos em cuidados paliativos na unidade de terapia intensiva

    Directory of Open Access Journals (Sweden)

    Cristina Bueno Terzi Coelho

    Full Text Available RESUMO Alguns dos pacientes admitidos em uma unidade de terapia intensiva podem enfrentar condições de doença terminal, que geralmente levam à morte. O conhecimento sobre cuidados paliativos é recomendado para os profissionais de saúde encarregados do cuidado destes pacientes. Em muitas situações, os pacientes devem ser avaliados diariamente, já que a introdução de novos tratamentos pode ou não ser benéfica para eles. As discussões entre os membros da equipe de saúde, relacionadas ao prognóstico e aos objetivos do tratamento, devem ser avaliadas cuidadosamente em cooperação com os pacientes e seus familiares. A adoção na unidade de terapia intensiva de protocolos relacionados a pacientes em final da vida é fundamental. É importante ter uma equipe multidisciplinar para determinar se é necessário deixar de iniciar ou mesmo retirar tratamentos avançados. Além disto, pacientes e familiares devem ser informados de que os cuidados paliativos envolvem o melhor tratamento possível para aquela situação específica, assim como respeitar suas vontades e considerar as bases sociais e espirituais dos mesmos. Assim, o objetivo desta revisão foi apresentar os cuidados paliativos como uma opção razoável para dar suporte à equipe da unidade de terapia intensiva na assistência a pacientes com doença terminal. São apresentadas atualizações com relação a dieta, ventilação mecânica e diálise nestes pacientes. Ainda, discutiremos o programa, comum nos Estados Unidos, conhecido como filosofia hospice, como alternativa ao ambiente da unidade de terapia intensiva/hospital.

  5. Prevalence and origin of De Novo duplications in Charcot-Marie-Tooth disease type 1A: First report of a De Novo duplication with a maternal origin

    Energy Technology Data Exchange (ETDEWEB)

    Blair, I.P.; Nash, J.; Gordon, M.J.; Nicholson, G.A. [Univ. of Sydney, New South Wales (United Kingdom)

    1996-03-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Sporadic cases of CMT have been described since the earliest reports of the disease. The most frequent form of the disorder, CMT1A, is associated with a 1.5-Mb DNA duplication on chromosome 17p11.2, which segregates with the disease. In order to investigate the prevalence of de novo CMT1A duplications, this study examined 118 duplication-positive CMT1A families. In 10 of these families it was demonstrated that the disease had arisen as the result of a de novo mutation. By taking into account the ascertainment of families, it can be estimated that {>=}10% of autosomal dominant CMT1 families are due to de novo duplications. The CMT1A duplication is thought to be the product of unequal crossing over between parental chromosome 17 homologues during meiosis. Polymorphic markers from within the duplicated region were used to determine the parental origin of these de novo duplications in eight informative families. Seven were of paternal and one of maternal origin. This study represents the first report of a de novo duplication with a maternal origin and indicates that it is not a phenomenon associated solely with male meioses. Recombination fractions for the region duplicated in CMT1A are larger in females than in males. That suggests that oogenesis may be afforded greater protection from misalignment during synapsis, and/or that there may be lower activity of those factors or mechanisms that lead to unequal crossing over at the CMT1A locus. 41 refs., 2 figs.

  6. 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

  7. Stabilization of dengue virus polymerase in de novo initiation assay provides advantages for compound screening.

    Science.gov (United States)

    Niyomrattanakit, Pornwaratt; Wan, Kah Fei; Chung, Ka Yan; Abas, Siti Nurdiana; Seh, Cheah Chen; Dong, Hongping; Lim, Chin Chin; Chao, Alexander Theodore; Lee, Chang Bok; Nilar, Shahul; Lescar, Julien; Shi, Pei-Yong; Beer, David; Lim, Siew Pheng

    2015-07-01

    Dengue virus (DENV) NS5 protein comprises an N-terminal methyltransferase domain and a C-terminal RNA-dependent RNA polymerase domain (RdRp). DENV RdRp is responsible for viral RNA synthesis via a de novo initiation mechanism and represents an attractive target for anti-viral therapy. Herein we describe the characterization of its de novo initiation activities by PAGE analyses and the knowledge gained was used to develop a fluorescent-based assay. A highly processive and robust assay was achieved by addition of cysteine in the assay buffer. This stabilized the apo-enzyme, and rendered optimal de novo initiation activity while balancing its intrinsic terminal transferase activity. Steady-state kinetic parameters of the NTP and RNA substrates under these optimal conditions were determined for DENV1-4 FL NS5. Heavy metal ions such as Zn(++) and Co(++) as well as high levels of monovalent salts, suppressed DENV polymerase de novo initiation activities. This assay was validated with nucleotide chain terminators and used to screen two diverse small library sets. The screen data obtained was further compared with concurrent screens performed with a DENV polymerase elongation fluorescent assay utilizing pre-complexed enzyme-RNA. A higher hit-rate was obtained for the de novo initiation assay compared to the elongation assay (∼2% versus ∼0.1%). All the hits from the latter assay are also identified in the de novo initiation assay, indicating that the de novo initiation assay performed with the stabilized apo-enzyme has the advantage of providing additional chemical starting entities for inhibiting this enzyme. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. 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...

  9. 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.

  10. 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

  11. Structural and functional properties of designed globins

    Indian Academy of Sciences (India)

    Administrator

    De novo protein design is now thought to be an essential approach to elucidate the principles of protein ... We have proposed a new computational method to find the amino acid sequence that fits to a given protein .... Furthermore, the extinction coefficients of these peaks are also similar to those of natural globins and are ...

  12. 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.

  13. Suppression of polygalacturonase gene expression in the phytopathogenic fungus Ophiostoma novo-ulmi by RNA interference.

    Science.gov (United States)

    Carneiro, Joyce S; de la Bastide, Paul Y; Chabot, Meghan; Lerch, Lindsey; Hintz, William E

    2010-05-01

    The fungal pathogen, Ophiostomo novo-ulmi, has been responsible for the rapid decline of American elm (Ulmus americana) across North America and remains a serious threat to surviving elm populations. The production of pectinolytic polygalacturonase enzymes has been implicated as a virulence factor for many fungal pathogens, including O. novo-ulmi. Previous work has shown that the targeted disruption of the endopolygalacturonase gene locus epg1 of O. novo-ulmi reduced, but did not eliminate pectinase activity. In the present study, we evaluated the use of RNA interference (RNAi) as a method of suppressing expression of the epg1 locus in O. novo-ulmi and compared its efficiency to the gene disruption method. While there was a reduction in epg1-specific mRNA transcripts and in the amount of polygalacturonase enzyme secreted for both methods of gene regulation, neither method completely suppressed the expression of pectinase activity. There was, however, a significantly greater reduction in both transcript levels and secreted enzyme observed for some of the RNAi transformants. As the first demonstration of RNAi in O. novo-ulmi, this method of gene regulation shows promise in future studies of gene expression and pathogenicity. Copyright 2010 Elsevier Inc. All rights reserved.

  14. 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.

  15. Plasma levels of immunoinflammatory markers in De Novo coronary atherosclerosis and coronary restenosis postangioplasty

    Directory of Open Access Journals (Sweden)

    Alexandre Schaan de Quadros

    2001-05-01

    Full Text Available OBJECTIVE: To compare circulating plasma levels of immunoinflammatory markers in patients with known de novo coronary artery disease and patients with postangioplasty restenosis. METHODS: Using enzymatic immunoabsorbent assay, we measured plasma levels of soluble interleukin-2 receptosr, tumor necrosis factor alpha, and soluble tumor necrosis alpha receptors I and II in 11 patients with restenosis postcoronary angioplasty (restenosis group, in 10 patients with primary atherosclerosis (de novo group who were referred for coronary angiography because of stable or unstable angina, and in 9 healthy volunteers (control group. Levels of soluble interleukin-2 receptors were significantly higher in the de novo group compared with that in the restenosis and control groups. Levels were also higher in the restenosis group compared with that in the control group. Plasma levels of tumor necrosis alpha and receptor levels were significantly higher in the de novo group compared to with that in the restenosis and control groups, but levels in the restenosis group were not different from that in the controls. CONCLUSION: Coronary artery disease, either primary or secondary to restenosis, is associated with significant immunoinflammatory activity, which can be assessed by examining the extent of circulating plasma levels of inflammatory markers. Moreover, patients with de novo lesions appear to have increased inflammatory activity compared with patients with restenosis.

  16. Polyunsaturated Fatty Acids StimulateDe novoLipogenesis and Improve Glucose Homeostasis during Refeeding with High Fat Diet.

    Science.gov (United States)

    Crescenzo, Raffaella; Mazzoli, Arianna; Cancelliere, Rosa; Bianco, Francesca; Giacco, Antonia; Liverini, Giovanna; Dulloo, Abdul G; Iossa, Susanna

    2017-01-01

    Aims: The recovery of body weight after a period of caloric restriction is accompanied by an enhanced efficiency of fat deposition and hyperinsulinemia-which are exacerbated by isocaloric refeeding on a high fat diet rich in saturated and monounsaturated fatty acids (SFA-MUFA), and poor in polyunsaturated fatty acids (PUFA), and associated with a blunting of de novo lipogenesis in adipose tissue and liver. As high fat diets rich in PUFA have been shown to limit the excess fat deposition and improve glucose homeostasis, we investigated here the extent to which de novo lipogenesis in liver and adipose tissues (white and brown), as well as hepatic oxidative stress, are influenced by refeeding on diets rich in PUFA. Design: In rats calorically restricted for 14 days and refed for 14 days on isocaloric amounts of a high fat diet rich in lard (i.e., high SFA-MUFA) or in safflower and linseed oils (rich in PUFA), we investigated energy balance, body composition, glycemic profile, and the regulation of fatty acid synthase (rate-limiting enzyme of de novo lipogenesis) in liver, white and brown adipose tissue. We also evaluated oxidative stress in liver and skeletal muscle and markers of hepatic inflammation. Results: Rats refed the PUFA diet gained less lipids and more proteins compared to rats refed SFA-MUFA diet and showed lower amount of visceral and epididymal white adipose tissue, but increased depots of interscapular brown adipose tissue, with higher expression of the uncoupling protein 1. A significant increase in non-protein respiratory quotient and carbohydrate utilization was found in rats refed PUFA diet. Rats refed PUFA diet showed improved glucose homeostasis, as well as lower triglycerides and cholesterol levels. Fatty acid synthase activity was significantly higher in liver, white and brown adipose tissue, while lipid peroxidation and the degree of inflammation in the liver were significantly lower, in rats refed PUFA diet. Conclusions: When considering the

  17. Citologia do desenvolvimento dos frutos sem sementes no café "mundo novo" Cytology of the development of empty fruits in the mundo novo coffee

    Directory of Open Access Journals (Sweden)

    A. J. T. Mendes

    1954-01-01

    Full Text Available Uma pequena porcentagem de frutos sem sementes é comum às plantas de tôdas as variedades de Coffea arabica, parecendo tratar-se de um fenômeno puramente fisiológico. No café Mundo Novo porém, além dêste tipo de plantas, há outras com elevada porcentagem de lojas vazias ("chochos". Constituindo isto um grave defeito para uma variedade comercial, procurou-se estudar a sua causa. As observações feitas no processo da microsporogênese mostraram irregularidades na distribuição dos cromossômios. Sendo encontradas tanto nas plantas de alta porcentagem como nas de baixa porcentagem de chochos, não deve residir nessas anomalias a causa procurada. Em estudos comparativos dos dois tipos de plantas do Mundo Novo e da variedade bourbon, pôde-se verificar : a que, em linhas gerais, o processo da formação do saco embrionário e o desenvolvimento do endosperma e do embrião são idênticos, havendo um ligeiro atrazo para as plantas Mundo Novo ; b que nestas últimas existem anormalidades diversas no saco embrionário, em proporção muito mais elevada do que no bourbon. Ocorrendo com igual freqüência nos dois tipos de plantas do café Mundo Novo, estas anormalidades também não devem se relacionar com a formação de chochos. Estudos realizados em frutos de diversas idades, permitiram relacionar a alta freqüência de lojas vazias com o aparecimento de uma estrutura anormal, em forma de disco, encontrada no interior dos restos de perisperma. Êste "disco" (com cêrca de 3 mm de diâmetro só apareceu na planta de alta freqüência de chochos, não tendo sido constatado na planta Mundo Novo de baixa freqüência de chochos, nem na planta bourbon. O exame citológico revelou que essa estrutura é constituida de endosperma, contendo um embrião anormal ; de côr clara a princípio, torna-se pardacenta à medida que degenera ; recebeu a denominação de "endosperma discóide". De oito plantas examinadas a seguir, encontrou-se endosperma disc

  18. [A de novo mutation of P gene causes oculocutaneous albinism type 2 with prenatal diagnosis].

    Science.gov (United States)

    Zhang, Liyun; Xu, Bei; Zhong, Yanfang; Chen, Xiaofei; Zheng, Hui; Jiang, Weiying; Li, Hongyi

    2013-06-01

    To determine the genotype of a family affected with oculocutaneous albinism (OCA) and to provide genetic counseling and prenatal diagnosis. To determine the genotypes and mutational sites through PCR and sequencing for all exons and exon-intron junctions of 4 OCA genes in the proband and the P gene of her parents. Prenatal genotyping of the fetus was carried out using amniocentesis sample. The patient was diagnosed with OCA2 based on a genotype of c.1327G>A/c.2360C>T. Her father was heterozygous for c.2360C> T, whilst her mother has none of the two mutations. c.1327G>A is therefore a maternal de novo mutation. Neither of the mutations was found in the fetus. A maternally inherited de novo mutation c.1327G>A has been identified in the patient. In order to detect de novo mutations, full sequence analysis is necessary.

  19. 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...

  20. 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

    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...... health effects – particularly within healthcare. This was the basis for creating the NOVO triangle emphasizing that intervention research for improved work environment in healthcare also needs to consider efficiency and quality aspects to increase organizational sustainability; i.e. the joint...... for development of more sustainable production systems in healthcare”. Future R&D performed within the framework of our NOVO network should substantiate this hypothesis. In practical terms, this necessitates expanded research protocols....

  1. Redefining the role of de novo fatty acid synthesis in Plasmodium parasites.

    Science.gov (United States)

    Tarun, Alice S; Vaughan, Ashley M; Kappe, Stefan H I

    2009-12-01

    Fatty acids are essential components of membranes, and are also involved in cell signalling. Plasmodium, the parasite that causes malaria, scavenges fatty acids from its hosts. However, Plasmodium also possesses enzymes for a prokaryotic-like de novo fatty acid synthesis pathway, which resides in the apicoplast. Recent research has demonstrated that Plasmodium parasites depend on de novo fatty acid synthesis only for liver-stage development. This finding demonstrates that basic anabolic functions of Plasmodium parasites are not necessary for the growth and replication of every life cycle stage. We discuss the role of fatty acid metabolism in Plasmodium and why we believe that de novo fatty acid synthesis is only required for parasite late liver-stage development.

  2. 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.

  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

    2011-06-02

    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.

  4. De novo transcriptome characterization of Lilium 'Sorbonne' and key enzymes related to the flavonoid biosynthesis.

    Science.gov (United States)

    Zhang, Ming-fang; Jiang, Ling-min; Zhang, Dong-mei; Jia, Gui-xia

    2015-02-01

    Lily is an important cut-flower and bulb crop in the commercial market. Here, transcriptome profiling of Lilium 'Sorbonne' was conducted through de novo sequencing based on Illumina platform. This research aims at revealing basic information and data that can be used for applied purposes especially the molecular regulatory information on flower color formation in lily. In total, 36,920,680 short reads which corresponded to 3.32 GB of total nucleotides, were produced through transcriptome sequencing. These reads were assembled into 39,636 Unigenes, of which 30,986 were annotated in Nr, Nt, Swiss-Prot, KEGG, COG, GO databases. Based on the three public protein databases, a total of 32,601 coding sequences were obtained. Meanwhile, 19,242 Unigenes were assigned to 128 KEGG pathways. Those with the greatest representation by unique sequences were for ''metabolic pathways'' (5,406 counts, 28.09 %). Our transcriptome revealed 156 Unigenes that encode key enzymes in the flavonoid biosynthesis pathway including CHS, CHI, F3H, FLS, DFR, etc. MISA software identified 2,762 simple sequence repeats, from which 1,975 primers pairs were designed. Over 2,762 motifs were identified, of which the most frequent was AG/CT (659, 23.86 %), followed by A/T (615, 22.27 %) and CCG/CGG (416, 15.06 %). Based on the results, we believe that the color formation of the Lilium 'Sorbonne' flower was mainly controlled by the flavonoid biosynthesis pathway. Additionally, this research provides initial genetic resources that will be valuable to the lily community for other molecular biology research, and the SSRs will facilitate marker-assisted selection in lily breeding.

  5. 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.

  6. Evaluation of hybrid and non-hybrid methods for de novo assembly of nanopore reads.

    Science.gov (United States)

    Sović, Ivan; Križanović, Krešimir; Skala, Karolj; Šikić, Mile

    2016-09-01

    Recent emergence of nanopore sequencing technology set a challenge for established assembly methods. In this work, we assessed how existing hybrid and non-hybrid de novo assembly methods perform on long and error prone nanopore reads. We benchmarked five non-hybrid (in terms of both error correction and scaffolding) assembly pipelines as well as two hybrid assemblers which use third generation sequencing data to scaffold Illumina assemblies. Tests were performed on several publicly available MinION and Illumina datasets of Escherichia coli K-12, using several sequencing coverages of nanopore data (20×, 30×, 40× and 50×). We attempted to assess the assembly quality at each of these coverages, in order to estimate the requirements for closed bacterial genome assembly. For the purpose of the benchmark, an extensible genome assembly benchmarking framework was developed. Results show that hybrid methods are highly dependent on the quality of NGS data, but much less on the quality and coverage of nanopore data and perform relatively well on lower nanopore coverages. All non-hybrid methods correctly assemble the E. coli genome when coverage is above 40×, even the non-hybrid method tailored for Pacific Biosciences reads. While it requires higher coverage compared to a method designed particularly for nanopore reads, its running time is significantly lower. https://github.com/kkrizanovic/NanoMark mile.sikic@fer.hr 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.

  7. 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.

  8. De novo cancers following liver transplantation: a single center experience in China.

    Directory of Open Access Journals (Sweden)

    Songfeng Yu

    Full Text Available BACKGROUND: De novo cancers are a growing problem that has become one of the leading causes of late mortality after liver transplantation. The incidences and risk factors varied among literatures and fewer concerned the Eastern population. AIMS: The aim of this study was to examine the incidence and clinical features of de novo cancers after liver transplantation in a single Chinese center. METHODS: 569 patients who received liver transplantation and survived for more than 3 months in a single Chinese center were retrospectively reviewed. RESULTS: A total of 18 de novo cancers were diagnosed in 17 recipients (13 male and 4 female after a mean of 41 ± 26 months, with an overall incidence of 3.2%, which was lower than that in Western people. Of these, 8 (3.32% cases were from 241 recipients with malignant liver diseases before transplant, while 10 (3.05% cases were from 328 recipients with benign diseases. The incidence rates were comparable, p = 0.86. Furthermore, 2 cases developed in 1 year, 5 cases in 3 years and 11 cases over 3 years. The most frequent cancers developed after liver transplantation were similar to those in the general Chinese population but had much higher incidence rates. CONCLUSIONS: Liver transplant recipients were at increased risk for developing de novo cancers. The incidence rates and pattern of de novo cancers in Chinese population are different from Western people due to racial and social factors. Pre-transplant malignant condition had no relationship to de novo cancer. Exact risk factors need further studies.

  9. Risk factors for de novo hepatitis B infection in pediatric living donor liver transplantation.

    Science.gov (United States)

    Rao, Wei; Xie, Man; Yang, Tao; Zhang, Jian-Jun; Gao, Wei; Deng, Yong-Lin; Zheng, Hong; Pan, Cheng; Liu, Yi-He; Shen, Zhong-Yang

    2014-09-28

    To investigate the incidence of de novo hepatitis B virus (HBV) infection after pediatric living donor liver transplantation (LDLT) and to analyze the risk factors associated with this de novo HBV infection. The clinical and laboratory data of children who underwent LDLT from June 2010 to September 2012 in First Center Hospital in Tianjin, China, were retrospectively included in the study. Intrahepatic HBV DNA in donors and recipients was quantified by real-time polymerase chain reaction using DNA extracted from formalin-fixed, paraffin-embedded tissues. Between June 2010 to September 2012, 32 consecutive pediatric patients underwent LDLT in our institute. Thirty LDLT patients (13 girls and 17 boys) were followed up for a median of 15 mo, of whom 53.3% (16/30) were hepatitis B core antibody (HBcAb) positive and 36.7% (11/30) were hepatitis B surface antibody (HBsAb)/HBcAb positive before transplantation. Sixteen of the children received HBcAb-positive allografts, and 43.7% (7/16) of the grafts were found to be intrahepatic HBV DNA positive. De novo HBV infection developed in 16.1% (5/30) of the children within a median of 11 mo after transplantation. All five of the HBV-infected children had received HBcAb-positive allografts, four of which were intrahepatic HBV DNA positive. Two of the children developed de novo HBV infection despite the preoperative presence of both HBsAb and HBcAb In pediatric recipients, positive intrahepatic HBV DNA in allografts could be a risk factor for de novo HBV infection from HBcAb-positive allografts. HBsAb/HBcAb positivity in pediatric LDLT patients before transplantation exhibited only weak effectiveness in protecting them against de novo HBV infection from HBcAb-positive allografts.

  10. Detection of de novo synthesized form of microsomal cytochrome P-448 by autofluorography

    Energy Technology Data Exchange (ETDEWEB)

    Chasonikova, O.B.; Lab. of Xenobiochemistry, Inst. of Clinical and Experimental Medicine, Siberian Branch, Academy of Medical Sciences of the USSR, Novosibirsk; Tsyrlov, I.B.

    1986-06-01

    This paper suggests a simple and informative method of detection of de novo synthesized forms of microsomal cytochrome P-450. The method is based on autofluorography of the gel after electrophoretic fractionation of liver microsomal proteins of rats previously injected with inducers of components of the monooxygenase system, followed by C 14-leucine. From the results obtained by autofluorography it is shown that during induction of the monooxygenase system of rat liver with MCh and TCDD at least two forms of cytochromes of the P-448 type with mol. wt. of 53 and 56 kd were synthesized de novo.

  11. Mechanism of increased rate of de novo purine biosynthesis in rat liver after bilateral adrenalectomy

    International Nuclear Information System (INIS)

    Itakura, M.; Maeda, N.; Yamashita, K.

    1986-01-01

    The incorporation of C-14-glycine to hepatic purines increased proving the increased rate of de novo purine biosynthesis in rat liver after bilateral adrenalectomy in comparison to sham-operated controls It is shown that the increased rate of de novo purine biosynthesis in adrenalectomized rat liver is compensatory against the increased catabolism of purine ribonucleotides as a result of the increased AMP concentration and that it is mediated by the increased concentration of PRPP. The study demonstrates the importance of the physiological amount of adrenocortical hormone to sustain the normal concentrations nad the metabolism of purine ribonucleotides in liver

  12. AS CARTAS CATÓLICAS NO CÂNON DO NOVO TESTAMENTO

    OpenAIRE

    Waldecir Gonzaga

    2017-01-01

    RESUMO: Nossa intenção, neste artigo, é oferecer um estudo acerca deste conjunto das cartas do Novo Testamento intituladas Cartas Católicas, que desde a antiguidade têm enfrentado não poucos ou indiferentes problemas, seja na aceitação seja no estudo de seu corpus, como o grupo de cartas do Novo Testamento menos estudado ou explorado, mesmo em nossos seminários, faculdades e universidades religiosas em geral, sejam eles católicos ou protestantes; também cremos não ser exagero afirmar que os t...

  13. 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...... 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...

  14. De novo Diagnosis of Fabry Disease among Italian Adults with Acute Ischemic Stroke or Transient Ischemic Attack.

    Science.gov (United States)

    Romani, Ilaria; Borsini, Walter; Nencini, Patrizia; Morrone, Amelia; Ferri, Lorenzo; Frusconi, Sabrina; Donadio, Vincenzo Angelo; Liguori, Rocco; Donati, Maria Alice; Falconi, Serena; Pracucci, Giovanni; Inzitari, Domenico

    2015-11-01

    Cerebrovascular complications are often the first cause of hospitalization in patients with Fabry disease (FD). Screenings for FD among stroke patients have yielded discrepant results, likely as a result of heterogeneous or incomplete assessment. We designed a study to identify FD among adults 60 years of age or younger who were consecutively admitted for acute ischemic stroke or transient ischemic attack (TIA) to a stroke neurology service in Italy. Patients with first-ever or recurrent events were included, irrespective of gender, risk factors, or stroke type. We screened male patients using α-galactosidase A enzyme assay, and female patients using DNA sequencing. FD was eventually established after a broad multidisciplinary discussion. We screened 108 patients (61% males, median age: 48 years); 84% of these patients had stroke. De novo FD diagnosis was established in 3 patients (2.8%; 95% confidence interval, .57-8.18): a 59-year-old man with recurrent lacunar-like strokes and multiple risk factors; a 42-year-old woman with recurrent cryptogenic minor strokes; and a 32-year-old woman with recurrent strokes previously attributed to Behçet's disease. Screened patients were systematically asked for typical FD symptoms; each of the de novo patients reported one or more of the following: episodes of hand/foot pain during fever, angiokeratoma, and family history of heart disease. In all of the patients events were recurrent, and lacunar-like infarcts characterized their brain imaging. Prevalence of FD among nonselected adults 60 years of age or younger with acute ischemic stroke or TIA is not negligible. A systematic search for FD in a stroke setting, using a comprehensive clinical, biochemical, and genetic screening protocol, may be worthwhile. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. 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.

  16. 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

  17. A mulher trabalhadora em Santa Maria durante o Estado Novo (1937-1945 = The woman worker in Santa Maria during the Estado Novo (1937-1945

    Directory of Open Access Journals (Sweden)

    Fausto, Letícia da Silva

    2014-01-01

    Full Text Available Este trabalho apresenta um estudo sobre a história das mulheres santamarienses no período da Ditadura do Estado Novo, que está sendo desenvolvido no Mestrado em História da Universidade Federal de Santa Maria (UFSM. O tema da pesquisa é a inserção da mulher no mundo do trabalho e sua atuação para a garantia e conquista de direitos sociais e trabalhistas durante o período do Estado Novo (1937-1945, no município de Santa Maria, RS. A escolha do Estado Novo no Brasil se deu em virtude deste ser um período onde muitas conquistas dos trabalhadores estavam sendo objeto de legislação específica e ao mesmo tempo um momento de repressão política, de forte aparato policial e repressivo e do fortalecimento dos sindicatos, sob a tutela do Estado e da luta dos trabalhadores para a garantia destes direitos, historicamente conquistados. As mulheres por séculos passaram despercebidas pela história, reprimidas em uma sociedade machista e autoritária, onde grande parte dos autores insere o homem no palco das lutas por reinvindicações e direitos trabalhistas

  18. O novo papel do designer instrucional e designer gráfico na era dos tablets educativos

    OpenAIRE

    Tessaro, Annye Cristiny; Bunn, Denise Aparecida; Costa, Alexandre Marino; Costa, Patricia Regina; Moritz, Gilberto Oliveira

    2013-01-01

    A utilização dos tablets como instrumento pedagógico é uma realidade que está aos poucos surgindo no contexto escolar. Os dispositivos móveis já fazem parte da rotina dos estudantes. Na era digital, estar conectado é fazer parte do mundo, é ter uma posição privilegiada da informação e da comunicação. Considerar esses dispositivos como instrumentos pedagógicos emerge da necessidade de se agregar a realidade dos estudantes ao contexto educacional. A inserção dos tablets já está o...

  19. Failure of stop and go in de novo Parkinson's disease-a functional magnetic resonance imaging study

    NARCIS (Netherlands)

    Vriend, C.; Gerrits, N.J.H.M.; Berendse, H.W.; Veltman, D.J.; van den Heuvel, O.A.; van der Werf, Y.D.

    2015-01-01

    Behavioral impairments in response inhibition and initiation are common in Parkinson's disease (PD) and are associated with reduced impulse control. No prior study, however, has investigated the functional correlates of response inhibition in de novo PD. Twenty-one de novo PD patients and 37 matched

  20. Failure of stop and go in de novo Parkinson's disease-a functional magnetic resonance imaging study

    NARCIS (Netherlands)

    Vriend, Chris; Gerrits, Niels J H M; Berendse, Henk W; Veltman, Dick J; van den Heuvel, Odile A; van der Werf, Ysbrand D

    Behavioral impairments in response inhibition and initiation are common in Parkinson's disease (PD) and are associated with reduced impulse control. No prior study, however, has investigated the functional correlates of response inhibition in de novo PD. Twenty-one de novo PD patients and 37 matched

  1. Em busca da caixa mágica: o Estado Novo e a televisão Searching for the magic box: the Estado Novo and the television

    Directory of Open Access Journals (Sweden)

    Áureo Busetto

    2007-12-01

    Full Text Available A análise histórica sobre a Exposição de Televisão (Rio de Janeiro, 1939, evento promovido pelo Estado Novo em parceria com o Terceiro Reich alemão, permite trazer, além de dados sobre a história da TV no Brasil, elementos de compreensão sobre as primeiras relações entre poder político e esse meio de comunicação no país. Pois, a demonstração pública da TV aos brasileiros foi utilizada como peça de propaganda do Estado Novo, servindo-lhe para reforçar a sua propalada superioridade sobre outras formas de governo, legitimar o regime entre os vários segmentos sociais e compor o rol de argumentações favoráveis ao alinhamento Brasil-Alemanha. Ademais, o artigo pretende jogar novas luzes sobre as pretensões da ditadura varguista com relaç��o à propaganda política e sobre a ação da imprensa frente ao controle estadonovista no período anterior ao funcionamento do DIP.The historical analysis of the Television Exhibition (Rio de Janeiro, 1939, an event promoted by the Estado Novo in partnership with the Third German Reich, lets us examine, in addition to data on the history of TV in Brazil, some elements in the understanding of the first relationships between political power and this means of communication in the country. The public demonstration of television to the Brazilians was used as part of the propaganda of the Estado Novo, serving to underscore its alleged superiority over other forms of government, legitimize the régime among various social segments and make up the list of arguments favorable to a Brazil-Germany alignment. In addition, the article aims at throwing new light on the pretensions of the Getulio Vargas dictatorship in relation to political propaganda and on the activities of the press in relation to the control of the Estado Novo in the period prior to the functioning of the DIP.

  2. 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.

  3. 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.

  4. 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.

  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. De Novo Chromosome Copy Number Variation in Fanconi Anemia-Associated Hematopoietic Defects

    Science.gov (United States)

    2014-08-01

    the endogenous and exogenous agents that promote de novo CNV formation, remain largely unknown. We hypothesize that the FA-BRCA pathway, through its...Adam, Z., Rani, R., Zhang, X. and Pang, Q. (2008) Oxidative stress in Fanconi anemia hematopoiesis and disease progression. Antioxid Redox Signal, 10

  7. 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.

  8. 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...

  9. Phenotype and clinical course in a family with a new de novo Twinkle gene mutation

    DEFF Research Database (Denmark)

    Jeppesen, Tina Dysgaard; Schwartz, M.; Colding-Jorgensen, E.

    2008-01-01

    The Twinkle gene product is important for mtDNA replication. Only a few reports have investigated the clinically effect of mutations in this gene. We describe a new de novo mutation (1110C > A) in the PEO1 gene in a mother and her two sons. The mother had progressive ophthalmoplegia, limb weakness...

  10. Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: a stable isotope study

    NARCIS (Netherlands)

    Buijs, Nikki; Brinkmann, Saskia J. H.; Oosterink, J. Efraim; Luttikhold, Joanna; Schierbeek, Henk; Wisselink, Willem; Beishuizen, Albertus; van Goudoever, Johannes B.; Houdijk, Alexander P. J.; van Leeuwen, Paul A. M.; Vermeulen, Mechteld A. R.

    2014-01-01

    Arginine plays a role in many different pathways in multiple cell types. Consequently, a shortage of arginine, caused by pathologic conditions such as cancer or injury, has the potential to disturb many cellular and organ functions. Glutamine is the ultimate source for de novo synthesis of arginine

  11. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

    NARCIS (Netherlands)

    Lessel, D.; Schob, C.; Kury, S.; Reinders, M.R.F.; Harel, T.; Eldomery, M.K.; Coban-Akdemir, Z.; Denecke, J.; Edvardson, S.; Colin, E.; Stegmann, A.P.; Gerkes, E.H.; Tessarech, M.; Bonneau, D.; Barth, M.; Besnard, T.; Cogne, B.; Revah-Politi, A.; Strom, T.M.; Rosenfeld, J.A.; Yang, Y; Posey, J.E.; Immken, L.; Oundjian, N.; Helbig, K.L.; Meeks, N.; Zegar, K.; Morton, J.; Schieving, J.H.; Claasen, A.; Huentelman, M.; Narayanan, V.; Ramsey, K.; Brunner, H.G.; Elpeleg, O.; Mercier, S.; Bezieau, S.; Kubisch, C.; Kleefstra, T.; Kindler, S.; Lupski, J.R.; Kreienkamp, H.J.

    2017-01-01

    DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe

  12. Impact of modern chemotherapy on the survival of women presenting with de novo metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Pal Sumanta K

    2012-09-01

    Full Text Available Abstract Background Data that directly associate utilization of novel systemic therapies with survival trends in metastatic breast cancer (MBC are limited. In the setting of de novo MBC, large registry analyses cite positive temporal trends in survival, but the extent to which advances in systemic therapy have contributed to these gains is not clear. Methods The City of Hope Cancer Registry was used to identify a consecutive series of patients with de novo MBC who received their first line of therapy between 1985 and 2004. Comprehensive clinicopathologic and treatment-related data were collected for each patient. Univariate analyses were conducted via Cox regression to identify factors associated with improved survival. Multivariate analysis was also conducted via Cox regression and the stepwise procedure was used to identify independent predictors of survival. Results A total of 324 patients with de novo MBC were identified. After application of exclusion criteria, including the sole presence of supraclavicular node metastasis, 274 patients were retained in the analysis. The treatment-related characteristics associated with improved survival included: use of endocrine therapy (hazard ratio [HR] 0.60, 95%CI 0.47-0.77; P Conclusions The overall survival of women with de novo metastatic breast cancer has improved over the past 20 years. However, the contribution of conventional cytotoxic agents to this improvement is minimal.

  13. 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

  14. 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...

  15. De novo Xp terminal deletion in a triple X female with recurrent ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 93; Issue 3. De novo Xp terminal deletion in a triple X female with recurrent spontaneous abortions: a case report. Tahir M. Malla Arshad A. Pandith Fayaz A. Dar Mahrukh H. Zargar Zafar A. Shah. Research Note Volume 93 Issue 3 December 2014 pp 819-822 ...

  16. 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

  17. 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...

  18. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

    NARCIS (Netherlands)

    Riviere, Jean-Baptiste; van Bon, Bregje W. M.; Hoischen, Alexander; Kholmanskikh, Stanislav S.; O'Roak, Brian J.; Gilissen, Christian; Gijsen, Sabine; Sullivan, Christopher T.; Christian, Susan L.; Abdul-Rahman, Omar A.; Atkin, Joan F.; Chassaing, Nicolas; Drouin-Garraud, Valerie; Fry, Andrew E.; Fryns, Jean-Pierre; Gripp, Karen W.; Kempers, Marlies; Kleefstra, Tjitske; Mancini, Grazia M. S.; Nowaczyk, Malgorzata J. M.; van Ravenswaaij-Arts, Conny M. A.; Roscioli, Tony; Marble, Michael; Rosenfeld, Jill A.; Siu, Victoria M.; de Vries, Bert B. A.; Shendure, Jay; Verloes, Alain; Veltman, Joris A.; Brunner, Han G.; Ross, M. Elizabeth; Pilz, Daniela T.; Dobyns, William B.

    Brain malformations are individually rare but collectively common causes of developmental disabilities(1-3). Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations(4,5). Here, we report a study of

  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. Changes in 5-HT2A receptor expression in untreated, de novo patients with Parkinson's disease.

    Science.gov (United States)

    Melse, Maartje; Tan, Sonny K H; Temel, Yasin; van Kroonenburgh, Marinus J P G; Leentjens, Albert F G

    2014-01-01

    Serotonin (5-HT) has long been implied in the pathophysiology of Parkinson's disease (PD). In addition, the 5-HT2A receptor is associated with the regulation of motor function and mood. To assess regional 5-HT2A receptor expression in unmedicated patients with de novo PD. Eight de novo, drug naïve patients with PD and eight healthy control subjects underwent a single photon emission computed tomography (SPECT) scan with the highly selective 5-HT2A radioligand 123I-5-I-R91150. In de novo PD patients 5-HT2A receptor binding was significantly reduced in the anterior striatum and the premotor cortex in PD patients compared to controls. In addition, occipital binding was elevated in PD patients. No changes in 5-HT2A receptor binding were found in the prefrontal and parietal cortex. In de novo PD patients, 5-HT2A receptor expression is changed in key areas of the basal ganglia-thalamocortical motor circuit and occipital cortex. This suggests altered 5-HT neurotransmission to contribute to development of PD motor and non-motor symptoms.

  1. 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

    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...

  2. Co-occurrence of a de novo Williams and 22q11.2 microdeletion syndromes.

    Science.gov (United States)

    Shukla, Anju; Mandal, Kausik; Patil, Siddaramappa J; Kishore, Yougal; Phadke, Shubha R; Girisha, Katta M

    2015-08-01

    We report on a child with de novo deletions involving the 7q11.23 (Williams syndrome) and 22q11.2 (Velocardiofacial/DiGeorge syndrome) regions. We describe the clinical features of this rare double microdeletion syndrome reported here for the first time. © 2015 Wiley Periodicals, Inc.

  3. Characteristics of extension and de novo recurrent spontaneous coronary artery dissection.

    Science.gov (United States)

    Main, Anthony; Prakash, Roshan; Starovoytov, Andrew; Sabbaghan, Amir; Aymong, Eve; Mancini, G B John; Saw, Jacqueline

    2017-12-08

    Spontaneous coronary artery dissection (SCAD) is an under-recognised and important cause of myocardial infarction in young women. Recurrent SCAD is frequent but poorly understood. We aimed to explore the clinical and angiographic characteristics, and outcomes of recurrent SCAD. Patients with SCAD extension or recurrence prospectively followed at Vancouver General Hospital were included in this retrospective study. SCAD diagnosis was confirmed by two experienced cardiologists. Detailed medical history, baseline demographics, angiographic results, and clinical details of index SCAD and recurrent events were recorded. SCAD extension was defined as angiographic extension of a previously dissected coronary segment, and de novo recurrent SCAD was defined as new spontaneous dissection. We identified 43 patients with SCAD recurrence with mean age 48.9±8.4 years; 38/43 were women, and 32/43 had fibromuscular dysplasia. Nine patients had SCAD extension at median time of five (1-19) days, while 34 patients had de novo recurrent SCAD at median time of 1,487 (107- 6,461) days after the index SCAD event. All SCAD extension patients had worsening of the index dissected segment, with 5/9 involving extension to adjacent segments, while all de novo recurrent SCAD patients had new dissections affecting coronary segments distinct from the index dissection. De novo recurrent SCAD invariably affected new segments distinct from previously dissected segments.

  4. 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

  5. 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...

  6. A framework for the detection of de novo mutations in family-based sequencing data

    NARCIS (Netherlands)

    L.C. Francioli (Laurent); M. Cretu-Stancu (Mircea); K.V. Garimella (Kiran); M. Fromer (Menachem); W.P. Kloosterman (Wigard); Genome of the Netherlands Consortium; K. Samocha (Kaitlin); B. Neale (Benjamin); M.J. Daly (Mark); E. Banks (Eric); M.A. DePristo (Mark); P.I.W. de Bakker (Paul)

    2017-01-01

    textabstractGermline mutation detection from human DNA sequence data is challenging due to the rarity of such events relative to the intrinsic error rates of sequencing technologies and the uneven coverage across the genome. We developed PhaseByTransmission (PBT) to identify de novo single

  7. A framework for the detection of de novo mutations in family-based sequencing data

    NARCIS (Netherlands)

    Francioli, Laurent C.; Cretu-Stancu, Mircea; Garimella, Kiran V.; Fromer, Menachem; Kloosterman, Wigard P.; Samocha, Kaitlin E.; Neale, Benjamin M.; Daly, Mark J.; Banks, Eric; DePristo, Mark A.; de Bakker, Paul IW

    2016-01-01

    Germline mutation detection from human DNA sequence data is challenging due to the rarity of such events relative to the intrinsic error rates of sequencing technologies and the uneven coverage across the genome. We developed PhaseByTransmission (PBT) to identify de novo single nucleotide variants

  8. Degradation and de novo synthesis of D1 protein and psbA ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Biosciences; Volume 25; Issue 1. Degradation and de novo synthesis of D1 protein and psbA transcript in reinhardtii during UV-B inactivation of photosynthesis. Ratnesh Haturvedi Adhey Hyam. Articles Volume 25 Issue 1 March 2000 pp 65-71 ...

  9. As Notas explicativas do Antigo e Novo Testamento de John Wesley

    OpenAIRE

    Daniel Lago

    2009-01-01

    Uma análise das Notas Explicativas de John Wesley nos oferece uma nova perspectiva sobre o trabalho deste multifacetado reformador. Suas Notas, junto com sua tradução do Novo Testamento, surpreendem pela clareza intelectual e profundidade teológica.

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

    DEFF Research Database (Denmark)

    Fürstenberg-Hägg, Joel

    . Adult females are shown to transfer CNglcs to the eggs following emergence from the pupa, providing protection against predation at this vulnerable developmental stage. It is finally speculated that de novo biosynthesis of CNglcs enabled colonization of and subsequently sequestration from the food plant...

  11. De novo reconstruction of plant RNA and DNA virus genomes from viral siRNAs

    Science.gov (United States)

    In antiviral defense, plants produce massive quantities of 21-24 nucleotide siRNAs. Here we demonstrate that the complete genomes of DNA and RNA viruses and viroids can be reconstructed by deep sequencing and de novo assembly of viral/viroid siRNAs from experimentally- and naturally-infected plants....

  12. 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

  13. 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...

  14. Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene

    NARCIS (Netherlands)

    Meggouh, F.; Bienfait, H. M. E.; Weterman, M. A. J.; de Visser, M.; Baas, F.

    2006-01-01

    We report a 32-year-old patient with Charcot-Marie-Tooth (CMT2B) including foot ulcerations. Genetic analysis identified a de novo mutation in the small GTP-ase late endosomal RAB7 gene, consisting of a c.471G>C, p.Lys157Asn missense mutation. This observation strongly supports the hypothesis that

  15. 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

  16. 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.

  17. Diagnosis and Subtyping of De Novo and Relapsed Mediastinal Lymphomas by Endobronchial Ultrasound Needle Aspiration

    Science.gov (United States)

    Moonim, Mufaddal T.; Breen, Ronan; Fields, Paul A.

    2013-01-01

    Rationale: The current management of lymphoma requires accurate diagnosis and subtyping of de novo lymphoma and of relapsed or refractory lymphoma in known cases. The role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the clinical management of lymphomas is unclear. Objectives: To investigate the use of EBUS-TBNA in the diagnosis of de novo and relapsed mediastinal lymphomas. Methods: A total of 2,256 consecutive patients who underwent EBUS-TBNA in a tertiary center between February 2008 and April 2013 were prospectively evaluated. The diagnostic accuracy and clinical use of EBUS-TBNA in 100 cases of de novo or suspected relapsed mediastinal lymphoma was investigated by comparing EBUS-TBNA diagnosis with the final diagnosis. Measurements and Main Results: De novo mediastinal lymphoma was correctly diagnosed by EBUS-TBNA in 45 (88%) of 51 and relapsed lymphoma in 15 (100%) of 15 lymphoma cases. EBUS-TBNA accurately established a diagnosis other than lymphoma in 32 (97%) of 33 patients with suspected lymphoma relapse. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in the diagnosis of mediastinal lymphoma were 89%, 97%, 98%, 83%, and 91%, respectively. Sensitivity of EBUS-TBNA in subtyping lymphomas into high-grade non-Hodgkin lymphoma, low-grade non-Hodgkin lymphoma, and Hodgkin lymphoma was 90%, 100%, and 79%, respectively. EBUS-TBNA diagnosis was adequate for clinical management in 84 (84%) of 100 cases. Conclusions: Multimodality evaluation of EBUS-TBNA can be successful in the diagnosis of de novo mediastinal lymphomas and is ideally suited in distinguishing lymphoma relapse from alternative pathologies; it is least sensitive in subtyping Hodgkin lymphoma. PMID:24047336

  18. 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

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

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    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.

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

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    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.

  1. Chemical defense balanced by sequestration and de novo biosynthesis in a lepidopteran specialist.

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    Joel Fürstenberg-Hägg

    Full Text Available The evolution of sequestration (uptake and accumulation relative to de novo biosynthesis of chemical defense compounds is poorly understood, as is the interplay between these two strategies. The Burnet moth Zygaena filipendulae (Lepidoptera and its food-plant Lotus corniculatus (Fabaceae poses an exemplary case study of these questions, as Z. filipendulae belongs to the only insect family known to both de novo biosynthesize and sequester the same defense compounds directly from its food-plant. Z. filipendulae and L. corniculatus both contain the two cyanogenic glucosides linamarin and lotaustralin, which are defense compounds that can be hydrolyzed to liberate toxic hydrogen cyanide. The overall amounts and ratios of linamarin and lotaustralin in Z. filipendulae are tightly regulated, and only to a low extent reflect the ratio in the ingested food-plant. We demonstrate that Z. filipendulae adjusts the de novo biosynthesis of CNglcs by regulation at both the transcriptional and protein level depending on food plant composition. Ultimately this ensures that the larva saves energy and nitrogen while maintaining an effective defense system to fend off predators. By using in situ PCR and immunolocalization, the biosynthetic pathway was resolved to the larval fat body and integument, which infers rapid replenishment of defense compounds following an encounter with a predator. Our study supports the hypothesis that de novo biosynthesis of CNglcs in Z. filipendulae preceded the ability to sequester, and facilitated a food-plant switch to cyanogenic plants, after which sequestration could evolve. Preservation of de novo biosynthesis allows fine-tuning of the amount and composition of CNglcs in Z. filipendulae.

  2. Designing misfolded proteins by energy landscaping.

    Science.gov (United States)

    Bhattacherjee, Arnab; Biswas, Parbati

    2011-01-13

    Conformational fluctuations in the native state ensemble enhance the complexity in designing de novo protein sequences that may fold correctly into a desired target structure. In this work, the results of a self-consistent mean field theory are applied to a cubic lattice model of proteins and real nonhomologous proteins to assess the designability of folded, misfolded, and unfolded conformations. This theory, for the first time, accounts for the properties of misfolded sequences in terms of a generalized foldability criterion and characterizes the topography of the sequence energy landscape in terms of folded, misfolded, and unfolded ensemble of conformations. For a given foldability criterion, the folded, misfolded, and unfolded conformations may be distinctly classified by tuning the energy variance of the native state ensemble. This implies a promising route to de novo protein design and provides useful insights into understanding the impact of conformational similarity/diversity on the folding-misfolding-unfolding transition.

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

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    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.

  4. Genetic and metabolomic analysis of AdeD and AdeI mutants of de novo purine biosynthesis: cellular models of de novo purine biosynthesis deficiency disorders.

    Science.gov (United States)

    Duval, Nathan; Luhrs, Kyleen; Wilkinson, Terry G; Baresova, Veronika; Skopova, Vaclava; Kmoch, Stanislav; Vacano, Guido N; Zikanova, Marie; Patterson, David

    2013-03-01

    Purines are molecules essential for many cell processes, including RNA and DNA synthesis, regulation of enzyme activity, protein synthesis and function, energy metabolism and transfer, essential coenzyme function, and cell signaling. Purines are produced via the de novo purine biosynthesis pathway. Mutations in purine biosynthetic genes, for example phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS, E.C. 6.3.2.6/E.C. 4.1.1.21), can lead to developmental anomalies in lower vertebrates. Alterations in PAICS expression in humans have been associated with various types of cancer. Mutations in adenylosuccinate lyase (ADSL, E.C. 4.3.2.2) or 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC, E.C. 2.1.2.3/E.C. 3.5.4.10) lead to inborn errors of metabolism with a range of clinical symptoms, including developmental delay, severe neurological symptoms, and autistic features. The pathogenetic mechanism is unknown for these conditions, and no effective treatments exist. The study of cells carrying mutations in the various de novo purine biosynthesis pathway genes provides one approach to analysis of purine disorders. Here we report the characterization of AdeD Chinese hamster ovary (CHO) cells, which carry genetic mutations encoding p.E177K and p.W363* variants of PAICS. Both mutations impact PAICS structure and completely abolish its biosynthesis. Additionally, we describe a sensitive and rapid analytical method for detection of purine de novo biosynthesis intermediates based on high performance liquid chromatography with electrochemical detection. Using this technique we detected accumulation of AIR in AdeD cells. In AdeI cells, mutant for the ADSL gene, we detected accumulation of SAICAR and SAMP and, somewhat unexpectedly, accumulation of AIR. This method has great potential for metabolite profiling of de novo purine biosynthesis pathway mutants, identification of novel genetic

  5. Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios

    DEFF Research Database (Denmark)

    Besenbacher, Søren; Liu, Siyang; Gonzalez-Izarzugaza, Jose Maria

    2015-01-01

    Building a population-specific catalogue of single nucleotide variants (SNVs), indels andstructural variants (SVs) with frequencies, termed a national pan-genome, is critical forfurther advancing clinical and public health genetics in large cohorts. Here we report a Danishpan-genome obtained from...... sequencing 10 trios to high depth (50). We report 536k novelSNVs and 283k novel short indels from mapping approaches and develop a population-widede novo assembly approach to identify 132k novel indels larger than 10 nucleotides with lowfalse discovery rates. We identify a higher proportion of indels and SVs...

  6. COMPUTATIONAL APPROACHES FOR RATIONAL DESIGN OF PROTEINS WITH NOVEL FUNCTIONALITIES

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    Manish Kumar Tiwari

    2012-09-01

    Full Text Available Proteins are the most multifaceted macromolecules in living systems and have various important functions, including structural, catalytic, sensory, and regulatory functions. Rational design of enzymes is a great challenge to our understanding of protein structure and physical chemistry and has numerous potential applications. Protein design algorithms have been applied to design or engineer proteins that fold, fold faster, catalyze, catalyze faster, signal, and adopt preferred conformational states. The field of de novo protein design, although only a few decades old, is beginning to produce exciting results. Developments in this field are already having a significant impact on biotechnology and chemical biology. The application of powerful computational methods for functional protein designing has recently succeeded at engineering target activities. Here, we review recently reported de novo functional proteins that were developed using various protein design approaches, including rational design, computational optimization, and selection from combinatorial libraries, highlighting recent advances and successes.

  7. The effect of a chlorhexidine regimen on de novo plaque formation.

    Science.gov (United States)

    Sekino, Satoshi; Ramberg, Per; Uzel, Naciye Guzin; Socransky, Sigmund; Lindhe, Jan

    2004-08-01

    To evaluate the effect of a pretreatment regimen that combined meticulous mechanical tooth cleaning with the daily use of chlorhexidine (rinse, gargle and tongue application) on de novo plaque formation and on the recolonization of various microbiological species in plaque and saliva during a 4-day period of no oral hygiene. Ten subjects aged 24-36 years with gingivitis were recruited. The study was designed as a double blind cross-over clinical trial including two phases. Each experimental phase comprised one preparatory period of 7 days and one plaque accumulation period of 4 days. During the preparatory period, the volunteers (i) performed meticulous mechanical tooth cleaning using toothbrush and dentifrice and (ii) were, in addition, given two sessions of professional tooth cleaning (PTC) The final PTC was delivered after bacterial sampling had been made on Day 0. In the Control group, no additional plaque control measures were included. In the Test group, the participants in addition to the mechanical measures (i) rinsed twice daily, for 60 s each time with a 0.2% chlorhexidine solution, (ii) gargled twice daily for 10 s with the chlorhexidine preparation, and finally (iii) brushed the dorsum of the tongue for 60 s, twice daily, with a 1.0% chlorhexidine gel. During the 4-day plaque accumulation period, the participants abstained from all mechanical and chemical plaque control measures. On Days 0, 1, 2 and 4 the quantity and quality of plaque formed was assessed by clinical means and by DNA probe techniques. The microbiota of the saliva was studied in samples obtained on Days 0 and 4. It was demonstrated that chlorhexidine used as a mouthrinse combined with gargling and tongue application during the preparatory period significantly retarded the amount of plaque that formed on tooth surfaces during the following 4 days of no oral hygiene. Further, the number of microorganisms present in the biofilm representing Days 0, 1 and 2 of the "plaque accumulation period

  8. Characterization of common carp transcriptome: sequencing, de novo assembly, annotation and comparative genomics.

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    Peifeng Ji

    Full Text Available BACKGROUND: Common carp (Cyprinus carpio is one of the most important aquaculture species of Cyprinidae with an annual global production of 3.4 million tons, accounting for nearly 14% of the freshwater aquaculture production in the world. Due to the economical and ecological importance of common carp, genomic data are eagerly needed for genetic improvement purpose. However, there is still no sufficient transcriptome data available. The objective of the project is to sequence transcriptome deeply and provide well-assembled transcriptome sequences to common carp research community. RESULT: Transcriptome sequencing of common carp was performed using Roche 454 platform. A total of 1,418,591 clean ESTs were collected and assembled into 36,811 cDNA contigs, with average length of 888 bp and N50 length of 1,002 bp. Annotation was performed and a total of 19,165 unique proteins were identified from assembled contigs. Gene ontology and KEGG analysis were performed and classified all contigs into functional categories for understanding gene functions and regulation pathways. Open Reading Frames (ORFs were detected from 29,869 (81.1% contigs with an average ORF length of 763 bp. From these contigs, 9,625 full-length cDNAs were identified with sequence length from 201 bp to 9,956 bp. Comparative analysis revealed that 27,693(75.2% contigs have significant similarity to zebrafish Refseq proteins, and 24,371(66.2%, 24,501(66.5% and 25,025(70.0% to teraodon, medaka and three-spined stickleback refseq proteins. A total of 2,064 microsatellites were initially identified from 1,730 contigs, and 1,639 unique sequences had sufficient flanking sequences on both sides for primer design. CONCLUSION: The transcriptome of common carp had been deep sequenced, de novo assembled and characterized, providing the valuable resource for better understanding of common carp genome. The transcriptome data will facilitate future functional studies on common carp genome, and

  9. APRIMORAMENTO HUMANO: UM NOVO TEMA DA AGENDA FILOSÓFICA

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    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.

  10. Genome editing as a tool to achieve the crop ideotype and de novo domestication of wild relatives: Case study in tomato.

    Science.gov (United States)

    Zsögön, Agustin; Cermak, Tomas; Voytas, Dan; Peres, Lázaro Eustáquio Pereira

    2017-03-01

    The ideotype is a theoretical model of an archetypal cultivated plant. Recent progress in genome editing is aiding the pursuit of this ideal in crop breeding. Breeding is relatively straightforward when the traits in question are monogenic in nature and show Mendelian inheritance. Conversely, traits with a diffuse, polygenic basis such as abiotic stress resistance are more difficult to harness. In recent years, many genes have been identified that are important for plant domestication and act by increasing yield, grain or fruit size or altering plant architecture. Here, we propose that (a) key monogenic traits whose physiology has been unveiled can be molecularly tailored to achieve the ideotype; and (b) wild relatives of crops harboring polygenic stress resistance genes or other traits of interest could be de novo domesticated by manipulating monogenic yield-related traits through state-of-the-art gene editing techniques. An overview of the genomic and physiological challenges in the world's main staple crops is provided. We focus on tomato and its wild Solanum (section Lycopersicon) relatives as a suitable model for molecular design in the pursuit of the ideotype for elite cultivars and to test de novo domestication of wild relatives. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Patients with Fanconi anemia and AML have different cytogenetic clones than de novo cases of AML.

    Science.gov (United States)

    Rochowski, Andrzej; Olson, Susan B; Alonzo, Todd A; Gerbing, Robert B; Lange, Beverly J; Alter, Blanche P

    2012-11-01

    Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9), and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management. Copyright © 2012 Wiley Periodicals, Inc. This article is a U.S. Government work and is in the public domain in the USA.

  12. Neurosecretory protein GL stimulates food intake, de novo lipogenesis, and onset of obesity.

    Science.gov (United States)

    Iwakoshi-Ukena, Eiko; Shikano, Kenshiro; Kondo, Kunihiro; Taniuchi, Shusuke; Furumitsu, Megumi; Ochi, Yuta; Sasaki, Tsutomu; Okamoto, Shiki; Bentley, George E; Kriegsfeld, Lance J; Minokoshi, Yasuhiko; Ukena, Kazuyoshi

    2017-08-11

    Mechanisms underlying the central regulation of food intake and fat accumulation are not fully understood. We found that neurosecretory protein GL (NPGL), a newly-identified neuropeptide, increased food intake and white adipose tissue (WAT) in rats. NPGL-precursor gene overexpression in the hypothalamus caused increases in food intake, WAT, body mass, and circulating insulin when fed a high calorie diet. Intracerebroventricular administration of NPGL induced de novo lipogenesis in WAT, increased insulin, and it selectively induced carbohydrate intake. Neutralizing antibody administration decreased the size of lipid droplets in WAT. Npgl mRNA expression was upregulated by fasting and low insulin levels. Additionally, NPGL-producing cells were responsive to insulin. These results point to NPGL as a novel neuronal regulator that drives food intake and fat deposition through de novo lipogenesis and acts to maintain steady-state fat level in concert with insulin. Dysregulation of NPGL may be a root cause of obesity.

  13. Novos marcadores biológicos na pneumonia comunitária grave

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    Lígia Sarmet Cunha Farah Rabello

    2011-12-01

    Full Text Available A pneumonia adquirida na comunidade é a doença infecciosa que mais comumente exige internação em unidades de terapia intensiva e o diagnóstico precoce e preciso da pneumonia adquirida na comunidade ainda é um desafio. Os biomarcadores desempenham um importante papel auxiliando no julgamento clínico no Serviço de Emergência e são adjuvantes na avaliação da resposta terapêutica. Novos biomarcadores como cortisol, proadrenomedulina e endotelina-1 demonstraram estar associados a gravidade da doença e a evolução em curto prazo. Este artigo de revisão irá se basear no uso clínico de novos biomarcadores, na sua capacidade de predizer gravidade e de monitorar a resposta ao tratamento empregado.

  14. De novo ABCD1 gene mutation in an Indian patient with adrenoleukodystrophy.

    Science.gov (United States)

    Kumar, Neeraj; Shukla, Pallavi; Taneja, Krishna K; Kalra, Veena; Bansal, Surendra K

    2008-10-01

    A large number of ABCD1 gene mutations have been reported all over the world, but not previously in India. We report on the first known patient with childhood cerebral adrenoleukodystrophy and a de novo 3' splice-site mutation in this gene. Magnetic resonance imaging of the brain revealed large, confluent, hyperintense areas in the bilateral cerebral white matter, predominantly parieto-occipital, with extensions into posterior regions that led to breakdown of the blood-brain barrier. An increased level of very long chain fatty acids was also consistent with the biochemical defect for adrenoleukodystrophy. Sequencing of the ABCD1 gene of this patient identified a 3' splice-site mutation in the intervening sequence 4 (-2a > g). We did not find any mutation in the gene of the proband's mother, which confirms its de novo occurrence.

  15. Nucleolar development and allocation of key nucleolar proteins require de novo transcription in bovine embryos

    DEFF Research Database (Denmark)

    Svarcova, Olga; Laurincik, Jozef; Avery, Birthe

    2007-01-01

    The goal of the present study was to investigate whether key nucleolar proteins involved in ribosomal RNA (rRNA) transcription and processing are transcribed de novo or from maternally inherited messenger RNAs (mRNA) in bovine embryos, and to which extent de novo transcription of these proteins m......RNA is required for the development of functional nucleoli during the major activation of the embryonic genome. Immunofluorescence for localization of key nucleolar proteins, autoradiography for detection of transcriptional activity, and transmission electron microscopy were applied to in vitro produc ed bovine...... embryos cultured from the 2-cell stage with or without (control groups) a-amanitin, which blocks the RNA plymerases II and III transcription and, thus the synthesis of mRNA. In the control groups, weak autoradiographic labelling was initially observed in the periphery of few nuclei at the 4-cell...

  16. A ORIGEM DOS PRESBÍTEROS-EPÍSCOPOS NA IGREJA DO NOVO TESTAMENTO (II

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    Antonio José de Almeida

    2001-01-01

    Full Text Available Evidentemente, não é fácil, a partir dos dados até aqui levantados, reconstruir a trajetória da origem dos presbíteros-epíscopos no Novo Testamento. Sem esses dados, porém, esta tarefa seria impossível ou, facilmente cairia em simplificações ou distorções. Nossa hipótese de reconstituição dessa trajetória percorrerá as quatro etapas da reconstituição histórica do conjunto dos ministérios atestados pelo Novo Testamento, proposta na seção anterior, destacando o que interessa, neste amplo e complexo universo, ao ministério dos presbíteros-epíscopos.

  17. Molecular analysis of "de novo" purine biosynthesis in solanaceous species and in Arabidopsis thaliana

    DEFF Research Database (Denmark)

    van der Graaff, Eric; Hooykaas, Paul; Lein, Wolfgang

    2004-01-01

    Purine nucleotides are essential components to sustain plant growth and development. In plants they are either synthesized "de novo" during the process of purine biosynthesis or are recycled from purine bases and purine nucleosides throughout the salvage pathway. Comparison between animals......, microorganisms and Arabidopsis, the first plant species with a completely sequenced genome, shows that plants principally use the same biochemical steps to synthesize purine nucleotides and possess all the essential genes and enzymes. Here we report on the cloning and molecular analysis of the complete purine...... biosynthesis pathway in plants, and the in planta functional analysis of PRPP (5-phosphoribosyl-1-pyrophoshate) amidotransferase (ATase), catalyzing the first committed step of the "de novo" purine biosynthesis. The cloning of the genes involved in the purine biosynthesis pathway was attained by a screening...

  18. Depiction of the martyrdom of Saint Ignatius Theophorus in the prothesis of Novo Hopovo

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    Popović Milica

    2015-01-01

    Full Text Available In the art of the Christian East, the depictions of the martyrdom of Saint Ignatius Theophorus, bishop of Antioch, can usually be found among the illustrations of the Menologion. The scene from the monastery of Novo Hopovo, dated to the 1600s, is one of the rare independent depictions of Saint Ignatius’s martyrdom. The paper discusses the iconography of this scene and possible reasons for placing it in the prothesis of the katholikon of Novo Hopovo. The inclusion of a scene showing the martyrdom of the bishop of Antioch into the thematic repertoire of this compartment is a solitary example in Serbian medieval and Byzantine monumental painting. [Projekat Ministarstva nauke Republike Srbije, br. 177036: Srpska srednjovekovna umetnost i njen evropski kontekst

  19. Um desafio novo: o biodiesel Biodiesel: a new challenge

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    Guilherme Leite da Silva Dias

    2007-04-01

    Full Text Available Esta nota procura mostrar a natureza da regulação de combustíveis no Brasil dentro de um monopólio de fato, com preços casados para os biocombustíveis em relação a seus substitutos fósseis mais próximos. Isso cria um ambiente de remuneração para o biodiesel muito baixo, além de subordiná-lo à logística de distribuição do monopólio. Um ambiente fora do monopólio, isento de carga fiscal e de comercialização a curtas distâncias, seria mais adequado para o ambiente requerido de incentivos para a inovação tecnológica.The regulatory framework for fuels in Brazil is an effective monopoly, with matching prices for close substitutes. Biodiesel prices are unattractive because domestic diesel prices are below international relative oil prices, transportation logistics burden furthermore with unnecessary routes designed for fossil fuels, beyond heavy indirect taxation. An alternative framework, without taxation, for short distance supply, with a large variety of raw materials is better suited for technological innovation.

  20. 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.

  1. APRIMORAMENTO HUMANO: UM NOVO TEMA DA AGENDA FILOSÓFICA

    Directory of Open Access Journals (Sweden)

    Marco Antonio Azevedo

    2015-07-01

    Full Text Available Since before we can remember, humanity aims toovercome its biological limitations; such a goal has certainly playeda key role in the advent of technique. However, despite the benefitsthat technique may bring, the people who make use of it willinevitably be under risk of harm. Even though human technicalwisdom consists in attaining the best result without compromisinganybody’s safety, misuses are always a possibility in the horizon.Nowadays, technology can be used for more than just improvinghuman 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 complex intra chromosomal rearrangement after ICSI: characterisation by BACs micro array-CGH

    Directory of Open Access Journals (Sweden)

    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.

  3. Cinema, Fascism and Propaganda. A historical approximation to the Portuguese Estado Novo

    Directory of Open Access Journals (Sweden)

    Alberto Pena-Rodríguez

    2012-01-01

    Full Text Available The Portuguese dictatorship of António de Oliveira Salazar used the cinema as an efficient propaganda instrument to consolidate the Estado Novo regime in the 1930s. Portugal’s National Propaganda Secretariat and other structures controlling public communication played an important role in persuading the Portuguese society and promoting a positive image of the Salazarist abroad. During the Spanish Civil War, the Portuguese cinematic propaganda intensified its campaign against communism and in favour of the Iberian fascism.

  4. Totalitarismo e a “fabricação de um novo homem”

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    José João Neves Barbosa Vicente

    2016-11-01

    Full Text Available O objetivo deste texto é discutir e apresentar, de uma forma introdutória, os esforços dos regimes totalitários do século XX no sentido de “fabricar um novo homem” capaz de obediência total ao Estado, a partir dos estudos desenvolvidos por Hannah Arendt, em sua obra Origens do totalitarismo.

  5. 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

  6. APONTAMENTOS SOBRE O USO DA FOTOGRAFIA PELA POLÍCIA POLÍTICA NO ESTADO NOVO

    OpenAIRE

    Carvalho, Thiago Fabres de; Bisi, Adriana de Oliveira Gonzaga

    2016-01-01

    Academic studies demonstrate the wide use of photography by the Police Policy (DEOPS) in the Estado Novo regime. This article seeks to assert that the photographic image acquires such centrality in police institutional practice. The 'declared ' explanation is that the technical use of photography, given the objectivity and realism to it intrinsic, is a legitimate tool to record and demonstrate the political crime. In addition, the study aims to reveal the functions ' undeclared ' the implemen...

  7. [Abnormality of blood coagulation indexes in patients with de novo acute leukemia and its clinical significance].

    Science.gov (United States)

    Xiao, Fang-Fang; Hu, Kai-Xun; Guo, Mei; Qiao, Jian-Hui; Sun, Qi-Yun; Ai, Hui-Sheng; Yu, Chang-Lin

    2013-04-01

    To explore hemorrhage risk and the clinical significance of abnormal change of prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen (FIB), plasma thrombin time (TT) and d-dimer (D-D) in de novo acute leukemia (except for APL), the different bleeding manifestations of 114 cases of de novo acute leukemia with different coagulation indexes were analyzed retrospectively. The correlation between these blood coagulation indexes and the possible correlative clinical characteristics were analysed, including age, sex, type of acute leukemia, initial white blood cell(WBC) and platelet(Plt) count, the proportion of blast cells in bone marrow and cytogenetic abnormality of patients at diagnosis. The results indicated that the incidence of abnormal blood coagulation was as high as 78.1% for de novo AL patients. These patients with 5 normal blood coagulation indexes may have mild bleeding manifestation, but the more abnormal indexes, the more severe bleeding. Both PT and D-D were sensitive indexes for diagnosis of level II bleeding. Incidence of abnormal blood coagulation significantly correlates with the proportion of blast cells in bone marrow (χ(2) = 4.184, OR = 1.021, P coagulation. It is concluded that the coagulation and fibrinolysis are abnormal in most patients with de novo acute leukemia. More abnormal indexes indicate more severe bleeding, and both PT and D-D are sensitive indexes for diagnosis of level II bleeding. Higher proportion of blast cells in bone marrow predicts higher incidence of abnormal blood clotting. Acute leukemia with elderly age, high white blood cell count and adverse cytogenetics do not predict severer abnormal blood clotting. Detection of PT, APTT, TT, FIB, and D-D may help to judge whether the patients are in a state of hypercoagulability or disseminated intravenous coagulation, which will provide experiment evidences for early intervention and medication.

  8. Identification of mutations including de novo mutations in Korean patients with hypokalaemic periodic paralysis.

    Science.gov (United States)

    Kim, S H; Kim, U K; Chae, J J; Kim, D J; Oh, H Y; Kim, B J; Lee, C C

    2001-05-01

    Hypokalaemic periodic paralysis (hypoPP) is an autosomal dominant disorder involving the abnormal function of ion channels and it is characterized by paralysis attacks of varying severity, accompanied by a fall in blood potassium levels. Linkage analysis showed that the candidate locus responsible for hypoPP was localized to chromosome 1q31-32, and this locus encoded the muscle dihydropyridine-sensitive calcium channel alpha(1)-subunit (CACNA1S). So far, three different mutations in CACNA1S gene have been identified in patients with hypoPP: Arg528His, Arg1239His and Arg1239Gly in Caucasian patients. However, there are few reports about the mutations of CACNA1S gene in other races. In this study, four Korean families with five hypoPP patients were screened for mutations of CACNA1S gene with polymerase chain reaction-based restriction analysis and single-strand conformation polymorphism analysis. To determine the mode of inheritance, haplotype analysis was done with three microsatellite markers (D1S1726, CACNL1A3, and D1S1723). Arg528His mutation was detected in three families, and one family had no known mutations. Moreover, for the first time, we detected de novo Arg528His mutations in two out of three families with hypoPP. Haplotype analysis using three microsatellite markers (D1S1726, CACNL1A3, and D1S1723) suggested the occurrence of de novo Arg528His mutations in two of the three families with Arg528His mutation. Arg528His mutations of CACNA1S, including de novo Arg528His mutations, were found in Korean patients with hypoPP. These results imply that de novo mutation, in addition to non-penetrance, is one of the genetic mechanisms that can explain the previous clinical observation that hypoPP occurs sporadically without family history.

  9. Purine de novo synthesis and salvage during testicular development in the rat

    International Nuclear Information System (INIS)

    Allsop, J.; Watts, R.W.E.

    1986-01-01

    The authors determine if there is a critical stage intesticular development in the Sprague-Dawley rat as judged to be specifically susceptible to HPRT deficiency. Purine de novo synthesis activity was measured by the incorporation of C 14-formate into the testicular tissue total purines. Observations show that the metabolic fundtion of the tubule epithelium and the HPRT-deficiency acting there is sufficient to explain the lack of structural development in the Lesch-Nyhan syndrome

  10. 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.

  11. Compacting and correcting Trinity and Oases RNA-Seq de novo assemblies

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    Cédric Cabau

    2017-02-01

    Full Text Available Background De novo transcriptome assembly of short reads is now a common step in expression analysis of organisms lacking a reference genome sequence. Several software packages are available to perform this task. Even if their results are of good quality it is still possible to improve them in several ways including redundancy reduction or error correction. Trinity and Oases are two commonly used de novo transcriptome assemblers. The contig sets they produce are of good quality. Still, their compaction (number of contigs needed to represent the transcriptome and their quality (chimera and nucleotide error rates can be improved. Results We built a de novo RNA-Seq Assembly Pipeline (DRAP which wraps these two assemblers (Trinity and Oases in order to improve their results regarding the above-mentioned criteria. DRAP reduces from 1.3 to 15 fold the number of resulting contigs of the assemblies depending on the read set and the assembler used. This article presents seven assembly comparisons showing in some cases drastic improvements when using DRAP. DRAP does not significantly impair assembly quality metrics such are read realignment rate or protein reconstruction counts. Conclusion Transcriptome assembly is a challenging computational task even if good solutions are already available to end-users, these solutions can still be improved while conserving the overall representation and quality of the assembly. The de novo RNA-Seq Assembly Pipeline (DRAP is an easy to use software package to produce compact and corrected transcript set. DRAP is free, open-source and available under GPL V3 license at http://www.sigenae.org/drap.

  12. Examination of Triacylglycerol Biosynthetic Pathways via De Novo Transcriptomic and Proteomic Analyses in an Unsequenced Microalga

    Science.gov (United States)

    2011-10-17

    using a variety of water sources, including fresh, brackish, saline, and waste water [1,4,5]. At current production levels, oleaginous microalgae also...underpinnings of microalgal biology than any other microalga to date. However, this species lacks the intrinsic high-lipid productivity of many oleaginous...Examination of Triacylglycerol Biosynthetic Pathways via De Novo Transcriptomic and Proteomic Analyses in an Unsequenced Microalga Michael T

  13. Inhibition of Ceramide De Novo Synthesis Ameliorates Diet Induced Skeletal Muscles Insulin Resistance

    OpenAIRE

    Kurek, Krzysztof; Mikłosz, Agnieszka; Łukaszuk, Bartłomiej; Chabowski, Adrian; Górski, Jan; Żendzian-Piotrowska, Małgorzata

    2015-01-01

    Nowadays wrong nutritional habits and lack of physical activity give a rich soil for the development of insulin resistance and obesity. Many researches indicate lipids, especially the one from the sphingolipids class, as the group of molecules heavily implicated in the progress of insulin resistance in skeletal muscle. Recently, scientists have focused their scrutiny on myriocin, a potent chemical compound that inhibits ceramide (i.e., central hub of sphingolipids signaling pathway) de novo s...

  14. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.

    Science.gov (United States)

    Hamdan, Fadi F; Myers, Candace T; Cossette, Patrick; Lemay, Philippe; Spiegelman, Dan; Laporte, Alexandre Dionne; Nassif, Christina; Diallo, Ousmane; Monlong, Jean; Cadieux-Dion, Maxime; Dobrzeniecka, Sylvia; Meloche, Caroline; Retterer, Kyle; Cho, Megan T; Rosenfeld, Jill A; Bi, Weimin; Massicotte, Christine; Miguet, Marguerite; Brunga, Ledia; Regan, Brigid M; Mo, Kelly; Tam, Cory; Schneider, Amy; Hollingsworth, Georgie; FitzPatrick, David R; Donaldson, Alan; Canham, Natalie; Blair, Edward; Kerr, Bronwyn; Fry, Andrew E; Thomas, Rhys H; Shelagh, Joss; Hurst, Jane A; Brittain, Helen; Blyth, Moira; Lebel, Robert Roger; Gerkes, Erica H; Davis-Keppen, Laura; Stein, Quinn; Chung, Wendy K; Dorison, Sara J; Benke, Paul J; Fassi, Emily; Corsten-Janssen, Nicole; Kamsteeg, Erik-Jan; Mau-Them, Frederic T; Bruel, Ange-Line; Verloes, Alain; Õunap, Katrin; Wojcik, Monica H; Albert, Dara V F; Venkateswaran, Sunita; Ware, Tyson; Jones, Dean; Liu, Yu-Chi; Mohammad, Shekeeb S; Bizargity, Peyman; Bacino, Carlos A; Leuzzi, Vincenzo; Martinelli, Simone; Dallapiccola, Bruno; Tartaglia, Marco; Blumkin, Lubov; Wierenga, Klaas J; Purcarin, Gabriela; O'Byrne, James J; Stockler, Sylvia; Lehman, Anna; Keren, Boris; Nougues, Marie-Christine; Mignot, Cyril; Auvin, Stéphane; Nava, Caroline; Hiatt, Susan M; Bebin, Martina; Shao, Yunru; Scaglia, Fernando; Lalani, Seema R; Frye, Richard E; Jarjour, Imad T; Jacques, Stéphanie; Boucher, Renee-Myriam; Riou, Emilie; Srour, Myriam; Carmant, Lionel; Lortie, Anne; Major, Philippe; Diadori, Paola; Dubeau, François; D'Anjou, Guy; Bourque, Guillaume; Berkovic, Samuel F; Sadleir, Lynette G; Campeau, Philippe M; Kibar, Zoha; Lafrenière, Ronald G; Girard, Simon L; Mercimek-Mahmutoglu, Saadet; Boelman, Cyrus; Rouleau, Guy A; Scheffer, Ingrid E; Mefford, Heather C; Andrade, Danielle M; Rossignol, Elsa; Minassian, Berge A; Michaud, Jacques L

    2017-11-02

    Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  15. Maternal and fetal outcome in de novo preeclampsia in comparison to superimposed preeclampsia: a two-year observational study.

    Science.gov (United States)

    Rezk, Mohamed; Gamal, Awni; Emara, Mahmoud

    2015-05-01

    To assess the maternal and fetal outcome in women with de novo preeclampsia (PE) in comparison to superimposed PE. This was a prospective 2-year observational study carried out at Menoufia University Hospital, Egypt, in which 164 patients out of 6472 pregnant women were diagnosed with PE (78 with de novo PE and 86 with superimposed PE). Enrolled patients were followed to assess the maternal and fetal outcome. There was a significant higher women with liver impairment and delivery by caesarean section in the de novo PE group (p 0.05). There was a significantly higher small for gestational age, prematurity, NICU admission and perinatal mortality in the superimposed PE group (p 0.05). Women with de novo PE have higher risks of liver impairment and delivery by cesarean section. On the other hand, women with superimposed PE have higher risks of poorer fetal outcome.

  16. 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.

  17. CHH islands: de novo DNA methylation in near-gene chromatin regulation in maize.

    Science.gov (United States)

    Gent, Jonathan I; Ellis, Nathanael A; Guo, Lin; Harkess, Alex E; Yao, Yingyin; Zhang, Xiaoyu; Dawe, R Kelly

    2013-04-01

    Small RNA-mediated regulation of chromatin structure is an important means of suppressing unwanted genetic activity in diverse plants, fungi, and animals. In plants specifically, 24-nt siRNAs direct de novo methylation to repetitive DNA, both foreign and endogenous, in a process known as RNA-directed DNA methylation (RdDM). Many components of the de novo methylation machinery have been identified recently, including multiple RNA polymerases, but specific genetic features that trigger methylation remain poorly understood. By applying whole-genome bisulfite sequencing to maize, we found that transposons close to cellular genes (particularly within 1 kb of either a gene start or end) are strongly associated with de novo methylation, as evidenced both by 24-nt siRNAs and by methylation specifically in the CHH sequence context. In addition, we found that the major classes of transposons exhibited a gradient of CHH methylation determined by proximity to genes. Our results further indicate that intergenic chromatin in maize exists in two major forms that are distinguished based on proximity to genes-one form marked by dense CG and CHG methylation and lack of transcription, and one marked by CHH methylation and activity of multiple forms of RNA polymerase. The existence of the latter, which we call CHH islands, may have implications for how cellular gene expression could be coordinated with immediately adjacent transposon repression in a large genome with a complex organization of genes interspersed in a landscape of transposons.

  18. 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 .

  19. Monosomal karyotype is not a predictor of dismal outcome in childhood de novo acute myeloid leukemia.

    Science.gov (United States)

    Lee, Na Hee; Choi, Young Bae; Yi, Eun-Sang; Lee, Soo Hyun; Kim, Hee-Jin; Lee, Ji Won; Sung, Ki Woong; Koo, Hong Hoe; Yoo, Keon Hee

    2016-11-01

    Monosomal karyotype (MK) is known as a far end of the unfavorable cytogenetics in adult acute myeloid leukemia (AML), while available data in childhood AML is scarce. In this study, we investigated the prevalence and prognostic value of MK with retrospectively analyzed 119 patients newly diagnosed with childhood de novo AML. Ten patients (8.4%) revealed to have MK. All MK-positive (MK(+)) AML were associated with complex cytogenetic abnormalities and belonged to the cytogenetic adverse-risk group. Nine of MK(+) patients (90%) achieved complete remission. The event-free survival (EFS) and overall survival (OS) of MK(+) adverse group were comparable to the ESF and OS of MK-negative non-adverse group (EFS 60.0±15.5% vs 59.0±5.1%, P=0.925; OS 70.0±14.5% vs 58.1±5.3%, P=0.696). In multivariate analysis, MK was not an independent adverse prognostic factor for EFS (hazard ratio 0.45, 95% C.I. 0.13-1.50, P=0.194). In addition, 7 of 9 MK(+) patients who received allogeneic hematopoietic stem cell transplantation (HSCT) survived event-free, with a median follow-up of 64 months. In conclusion, MK did not act as an adverse prognostic factor in childhood de novo AML. Allogeneic HSCT might have contributed to the excellent outcome of MK(+) childhood de novo AML. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Engineering Methylobacterium extorquens for de novo synthesis of the sesquiterpenoid α-humulene from methanol.

    Science.gov (United States)

    Sonntag, Frank; Kroner, Cora; Lubuta, Patrice; Peyraud, Rémi; Horst, Angelika; Buchhaupt, Markus; Schrader, Jens

    2015-11-01

    Over the last 10 to 15 years, metabolic engineering of microbes has become a versatile tool for high-level de novo synthesis of terpenoids, with the sesquiterpenoids armopha-1,4-diene, farnesene and artemisinic acid as prime examples. However, almost all cell factory approaches towards terpenoids to date have been based on sugar as the raw material, which is mainly used as a food resource and subject to high price volatilities. In this study we present de novo synthesis of the sesquiterpenoid α-humulene from the abundantly available non-food carbon source methanol by metabolically engineered Methylobacterium extorquens AM1. Expression of α-humulene synthase from Zingiber zerumbet in combination with farnesyl pyrophosphate (FPP) synthase from Saccharomyces cerevisiae led to concentrations of up to 18 mg/L α-humulene. Introduction of a prokaryotic mevalonate pathway from Myxococcus xanthus in combination with ribosome binding site optimization of α-humulene and FPP synthases increased product concentration 3-fold. This value was additionally raised by 30% using a carotenoid synthesis deficient mutant strain. Final product concentrations of up to 1.65 g/L were obtained in methanol limited fed-batch cultivations, which is the highest titer of de novo synthesized α-humulene reported to date. This study demonstrates the potential of M. extorquens as a future platform strain for the production of high-value terpenoids from the alternative carbon source methanol. Copyright © 2015 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  1. 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".

  2. De novo inflammatory bowel disease after pediatric kidney or liver transplant.

    Science.gov (United States)

    Fernandes, Melissa A; Braun, Hillary J; Evason, Kim; Rhee, Sue; Perito, Emily R

    2017-02-01

    A subset of children who receive a liver and/or kidney transplant develop de novo inflammatory bowel disease-like chronic intestinal inflammation, not explained by infection or medications, following transplant. We have conducted a single-center, retrospective case series describing the unique clinical and histologic features of this IBD-like chronic intestinal inflammation following solid organ transplant. At our center, nine of 327 kidney or liver recipients developed de novo IBD following transplant (six liver, two kidney, one liver-kidney). Most children presented with prolonged hematochezia and diarrhea and were treated with aminosalicylates. At time of diagnosis, five were not currently using mycophenolate mofetil for transplant immunosuppression. Histologic and endoscopic findings at IBD diagnosis included inflammation, ulcerations, granulomas, and chronic colitis. Since diagnosis, no patients have required surgical intervention, or escalation to biologic therapy, nor developed stricturing or perianal disease. In this case series, de novo post-transplant IBD developed in 4% of pediatric liver and/or kidney recipients; however, it often does not fit the classic patterns of Crohn's disease or ulcerative colitis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Alternative normalization methods demonstrate widespread cortical hypometabolism in untreated de novo Parkinson’s disease

    Science.gov (United States)

    BERTI, V.; POLITO, C.; BORGHAMMER, P.; RAMAT, S.; MOSCONI, L.; VANZI, E.; DE CRISTOFARO, M. T.; DE LEON, M.; SORBI, S.; PUPI, A.

    2013-01-01

    Aim Previous positron emission tomography (PET) [18F]fluorodeoxyglucose ([18F]FDG) studies in Parkinson’s disease (PD) demonstrated that moderate to late stage patients display widespread cortical hypometabolism, whereas early stage PD patients exhibit little or no cortical changes. However, 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, in the WM and Yakushev normalized analyses, stage II patients displayed more prominent cortical hypometabolism than did stage I patients. Conclusion The use of alternative normalization procedures, other than GM, suggests that much more extensive cortical hypometabolism is present in untreated de novo PD patients than hitherto reported. The finding may have implications for our understanding of the basic pathophysiology of early-stage PD. PMID:22695340

  4. 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.

  5. 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.

  6. First de novo whole genome sequencing and assembly of the pink-footed goose.

    Science.gov (United States)

    Pujolar, J M; Dalén, L; Olsen, R A; Hansen, M M; Madsen, J

    2018-03-01

    Annotated genomes can provide new perspectives on the biology of species. We present the first de novo whole genome sequencing for the pink-footed goose. In order to obtain a high-quality de novo assembly the strategy used was to combine one short insert paired-end library with two mate-pair libraries. The pink-footed goose genome was assembled de novo using three different assemblers and an assembly evaluation was subsequently performed in order to choose the best assembler. For our data, ALLPATHS-LG performed the best, since the assembly produced covers most of the genome, while introducing the fewest errors. A total of 26,134 genes were annotated, with bird species accounting for virtually all BLAST hits. We also estimated the substitution rate in the pink-footed goose, which can be of use in future demographic studies, by using a comparative approach with the genome of the chicken, the mallard and the swan goose. A substitution rate of 1.38×10 -7 per nucleotide per generation was obtained when comparing the genomes of the two closely-related goose species (the pink-footed and the swan goose). Altogether, we provide a valuable tool for future genomic studies aiming at particular genes and regions of the pink-footed goose genome as well as other bird species. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. 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

    2010-01-01

    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.Improving a host organism's cellular traits and the potential design of new phenotypes is strongly dependent on the ability to effectively control the organism's genetic machinery. In fact, finely-tuned gene expression is imperative for achieving an optimal balance between pathway expression and cell viability, while avoiding cytotoxicity due to accumulation of certain gene products or metabolites. Early attempts to engineer a cell's metabolism almost exclusively relied on merely deleting or over

  8. 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.

  9. Proteomics of Soil and Sediment: Protein Identification by De Novo Sequencing of Mass Spectra Complements Traditional Database Searching

    Science.gov (United States)

    Miller, S.; Rizzo, A. I.; Waldbauer, J.

    2015-12-01

    Proteomics has the potential to elucidate the metabolic pathways and taxa responsible for in situ biogeochemical transformations. However, low rates of protein identification from high resolution mass spectra have been a barrier to the development of proteomics in complex environmental samples. Much of the difficulty lies in the computational challenge of linking mass spectra to their corresponding proteins. Traditional database search methods for matching peptide sequences to mass spectra are often inadequate due to the complexity of environmental proteomes and the large database search space, as we demonstrate with soil and sediment proteomes generated via a range of extraction methods. One alternative to traditional database searching is de novo sequencing, which identifies peptide sequences without the need for a database. BLAST can then be used to match de novo sequences to similar genetic sequences. Assigning confidence to putative identifications has been one hurdle for the implementation of de novo sequencing. We found that accurate de novo sequences can be screened by quality score and length. Screening criteria are verified by comparing the results of de novo sequencing and traditional database searching for well-characterized proteomes from simple biological systems. The BLAST hits of screened sequences are interrogated for taxonomic and functional information. We applied de novo sequencing to organic topsoil and marine sediment proteomes. Peak-rich proteomes, which can result from various extraction techniques, yield thousands of high-confidence protein identifications, an improvement over previous proteomic studies of soil and sediment. User-friendly software tools for de novo metaproteomics analysis have been developed. This "De Novo Analysis" Pipeline is also a faster method of data analysis than constructing a tailored sequence database for traditional database searching.

  10. Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis.

    Directory of Open Access Journals (Sweden)

    Timothy A Graubert

    Full Text Available Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS. Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow and germline (skin DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion and performed total exonic gene resequencing (479 amplicons and array comparative genomic hybridization (CGH. We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50% in CD34+ cells from del(5q MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion.

  11. 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.

  12. Assembly and annotation of a non-model gastropod (Nerita melanotragus) transcriptome: a comparison of de novo assemblers.

    Science.gov (United States)

    Amin, Shorash; Prentis, Peter J; Gilding, Edward K; Pavasovic, Ana

    2014-08-01

    The sequencing, de novo assembly and annotation of transcriptome datasets generated with next generation sequencing (NGS) has enabled biologists to answer genomic questions in non-model species with unprecedented ease. Reliable and accurate de novo assembly and annotation of transcriptomes, however, is a critically important step for transcriptome assemblies generated from short read sequences. Typical benchmarks for assembly and annotation reliability have been performed with model species. To address the reliability and accuracy of de novo transcriptome assembly in non-model species, we generated an RNAseq dataset for an intertidal gastropod mollusc species, Nerita melanotragus, and compared the assembly produced by four different de novo transcriptome assemblers; Velvet, Oases, Geneious and Trinity, for a number of quality metrics and redundancy. Transcriptome sequencing on the Ion Torrent PGM™ produced 1,883,624 raw reads with a mean length of 133 base pairs (bp). Both the Trinity and Oases de novo assemblers produced the best assemblies based on all quality metrics including fewer contigs, increased N50 and average contig length and contigs of greater length. Overall the BLAST and annotation success of our assemblies was not high with only 15-19% of contigs assigned a putative function. We believe that any improvement in annotation success of gastropod species will require more gastropod genome sequences, but in particular an increase in mollusc protein sequences in public databases. Overall, this paper demonstrates that reliable and accurate de novo transcriptome assemblies can be generated from short read sequencers with the right assembly algorithms.

  13. 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.

  14. 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

  15. 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...

  16. Computer-aided design of small molecules for chemical genomics.

    Science.gov (United States)

    Dean, Philip M

    2005-01-01

    De novo design provides an in silico toolkit for the design of novel molecular structures to a set of specified structural constraints, and is thus ideally suited for creating molecules for chemical genomics. The design process involves manipulation of the input, modification of structural constraints, and further processing of the de novo-generated molecules using various modular toolkits. The development of a theoretical framework for each of these stages will provide novel practical solutions to the problem of creating compounds with maximal chemical diversity. This chapter describes the fundamental problems encountered in the application of novel chemical design technologies to chemical genomics by means of a formal representation. Formal representations help to outline and clarify ideas and hypotheses that can then be explored using mathematical algorithms. It is only by developing this rigorous foundation, that in silico design can progress in a rational way.

  17. "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.

  18. 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

  19. 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

  20. 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.

  1. Effect of various chlorhexidine regimens on salivary bacteria and de novo plaque formation.

    Science.gov (United States)

    Sekino, Satoshi; Ramberg, Per; Uzel, Naciye Guzin; Socransky, Sigmund; Lindhe, Jan

    2003-10-01

    The aim of the present experiment was to study the effect of different chlorhexidine regimens on the number of bacteria in saliva, and on de novo plaque formation. Ten subjects with gingivitis, but no signs of destructive periodontitis, were recruited. Following a screening examination, the volunteers were given oral hygiene instruction, meticulous scaling and professional mechanical tooth cleaning (PTC). The PTC was repeated once every 3 days during a 2-week period to establish healthy gingival conditions. The study was designed as a double-blind cross-over clinical trial including three phases. Each experimental phase comprised one preparatory period of 7 days and one plaque accumulation period (no oral hygiene measures) of 4 days. During all preparatory periods, the volunteers (i) performed mechanical tooth cleaning using a toothbrush and dentifrice and (ii) were, in addition, given two sessions of PTC. The final PTC was delivered after bacterial sampling had been made on Day 0. Preparatory period A: the participants continued the self-performed plaque control regimen that employed only mechanical means. Preparatory period B: the participants were in addition instructed to rinse and gargle, twice daily, with a 0.2% chlorhexidine mouthrinse. Preparatory period C: in addition to the above, the participants were instructed to brush the dorsum of the tongue for 60 s, twice daily, with a 1.0% chlorhexidine gel. Following each plaque accumulation period, there was a 10-day washout interval. The presence and amount of dental plaque (QHI) was scored after 1, 2 and 4 days of no oral hygiene. Samples of saliva were obtained on Day 0 and after 1 and 2 days. The samples were placed on Brucella agar plates and incubated (anaerobically) for 5 days. The total number of colony-forming units was determined and used to estimate the density of bacteria in saliva. In period A, the mean QHI increased from 1.0 (Day 1) to 1.4 (Day 2) and 2.1 (Day 4). The corresponding scores for

  2. Da disciplina ao controle: novos processos de subjetivação no mundo do trabalho

    Directory of Open Access Journals (Sweden)

    Attila Magno e Silva Barbosa

    2012-12-01

    Full Text Available http://dx.doi.org/10.5007/2175-7984.2012v11n22p75 Partindo do pressuposto de que as relações de poder são contextuais, históricas e em constante transformação, este artigo tem como objetivo refletir sobre a passagem da chamada sociedade disciplinar para a sociedade de controle. Tomaremos como referência o “mundo do trabalho” por entendermos que nele testemunhamos a constituição de um novo processo de subjetivação em que a disciplina, antes circunscrita em um sistema fechado – no caso em questão, a fábrica –, deu lugar a formas de controle que se estendem por todas as esferas da vida social. Para nós, o suporte discursivo desse novo dispositivo de poder seria o discurso do trabalhador como  empreendedor de si mesmo”. Iniciaremos nossa discussão versando sobre a analítica do poder de Foucault, mais precisamente sobre a noção de sociedade disciplinar que teria tido seu apogeu no início do século XX e desde então teria perdido força e cedido lugar à sociedade de controle, esta noção melhor desenvolvida por Deleuze. Nesse sentido, refletiremos sobre a ocorrência de um novo processo de subjetivação e como novas formas de controle passam a ser exercidas no mundo do trabalho.

  3. De novo gene evolution of antifreeze glycoproteins in codfishes revealed by whole genome sequence data.

    Science.gov (United States)

    Baalsrud, Helle Tessand; Tørresen, Ole Kristian; Hongrø Solbakken, Monica; Salzburger, Walter; Hanel, Reinhold; Jakobsen, Kjetill S; Jentoft, Sissel

    2017-12-05

    New genes can arise through duplication of a pre-existing gene or de novo from non-coding DNA, providing raw material for evolution of new functions in response to a changing environment. A prime example is the independent evolution of antifreeze glycoprotein genes (afgps) in the Arctic codfishes and Antarctic notothenioids to prevent freezing. However, the highly repetitive nature of these genes complicates studies of their organization. In notothenioids, afgps evolved from an extant gene, yet the evolutionary origin of afgps in codfishes is unknown. Here, we demonstrate that afgps in codfishes have evolved de novo from non-coding DNA 13-18 Ma, coinciding with the cooling of the Northern Hemisphere. Using whole-genome sequence data from several codfishes and notothenioids, we find higher copy number of afgp in species exposed to more severe freezing suggesting a gene dosage effect. Notably, antifreeze function is lost in one lineage of codfishes analogous to the afgp losses in non-Antarctic notothenioids. This indicates that selection can eliminate the antifreeze function when freezing is no longer imminent. Additionally, we show that evolution of afgp-assisting antifreeze potentiating protein genes (afpps) in notothenioids coincides with origin and lineage-specific losses of afgp. The origin of afgps in codfishes is one of the first examples of an essential gene born from non-coding DNA in a non-model species. Our study underlines the power of comparative genomics to uncover past molecular signatures of genome evolution, and further highlights the impact of de novo gene origin in response to a changing selection regime. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  4. X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism.

    Science.gov (United States)

    Wang, Ying; Busin, Rachel; Reeves, Catherine; Bezman, Lena; Raymond, Gerald; Toomer, Cicely J; Watkins, Paul A; Snowden, Ann; Moser, Ann; Naidu, Sakkubai; Bibat, Genila; Hewson, Stacy; Tam, Karen; Clarke, Joe T R; Charnas, Lawrence; Stetten, Gail; Karczeski, Barbara; Cutting, Garry; Steinberg, Steven

    2011-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection. Amongst 489 X-ALD families tested at Kennedy Krieger Institute, we identified 20 cases in which the ABCD1 mutation was de novo in the index case, indicating that the mutation arose in the maternal germ line and supporting a new mutation rate of at least 4.1% for this group. In addition, we identified 10 cases in which a de novo mutation arose in the mother or the grandmother of the index case. In two of these cases studies indicated that the mothers were low level gonosomal mosaics. In a third case biochemical, molecular and pedigree analysis indicated the mother was a gonadal mosaic. To the best of our knowledge mosaicism has not been previously reported in X-ALD. In addition, we identified one pedigree in which the maternal grandfather was mosaic for the familial ABCD1 mutation. Less than 1% of our patient population had evidence of gonadal or gonosomal mosaicism, suggesting it is a rare occurrence for this gene and its associated disorders. However, the residual maternal risk for having additional ovum carrying the mutant allele identified in an index case that appears to have a de novo mutation is at least 13%. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. 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.

  6. 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.

  7. Rare de novo copy number variants in patients with congenital pulmonary atresia.

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    Li Xie

    Full Text Available BACKGROUND: Ongoing studies using genomic microarrays and next-generation sequencing have demonstrated that the genetic contributions to cardiovascular diseases have been significantly ignored in the past. The aim of this study was to identify rare copy number variants in individuals with congenital pulmonary atresia (PA. METHODS AND RESULTS: Based on the hypothesis that rare structural variants encompassing key genes play an important role in heart development in PA patients, we performed high-resolution genome-wide microarrays for copy number variations (CNVs in 82 PA patient-parent trios and 189 controls with an Illumina SNP array platform. CNVs were identified in 17/82 patients (20.7%, and eight of these CNVs (9.8% are considered potentially pathogenic. Five de novo CNVs occurred at two known congenital heart disease (CHD loci (16p13.1 and 22q11.2. Two de novo CNVs that may affect folate and vitamin B12 metabolism were identified for the first time. A de novo 1-Mb deletion at 17p13.2 may represent a rare genomic disorder that involves mild intellectual disability and associated facial features. CONCLUSIONS: Rare CNVs contribute to the pathogenesis of PA (9.8%, suggesting that the causes of PA are heterogeneous and pleiotropic. Together with previous data from animal models, our results might help identify a link between CHD and folate-mediated one-carbon metabolism (FOCM. With the accumulation of high-resolution SNP array data, these previously undescribed rare CNVs may help reveal critical gene(s in CHD and may provide novel insights about CHD pathogenesis.

  8. ESTADO E NOVOS AGENTES SOCIAIS NA RECONSTRUÇÃO DO ESPAÇO

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    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

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

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    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

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

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    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.

  11. Mapping of the bovine genes of the de novo AMP synthesis pathway.

    Science.gov (United States)

    Bønsdorff, T; Gautier, M; Farstad, W; Rønningen, K; Lingaas, F; Olsaker, I

    2004-12-01

    Summary The purine nucleotides adenosine monophosphate (AMP) and guanosine monophosphate (GMP) are critical for energy metabolism, cell signalling and cell reproduction. Despite their essential function, little is known about the regulation and in vivo expression pattern of the genes involved in the de novo purine synthesis pathway. The complete coding region of the bovine phosphoribosylaminoimidazole carboxylase gene (PAICS), which catalyses steps 6 and 7 of the de novo purine biosynthesis pathway, as well as bovine genomic sequences of the six other genes in the pathway producing inosine monophosphate (IMP) and AMP [phosphoribosyl pyrophosphate amidotransferase (PPAT), phosphoribosylglycinamide formyltransferase (GART), phosphoribosylformylglycinamidine synthase (PFAS), adenylosuccinate lyase (ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) and adenylosuccinate synthase (ADSS)], were identified. The genes were mapped to segments of six different bovine chromosomes using a radiation hybrid (RH) cell panel. The gene PPAT, coding for the presumed rate-limiting enzyme of the purine de novo pathway was closely linked to PAICS on BTA6. These, and the other bovine locations i.e. GART at BTA1, PFAS at BTA19, ADSL at BTA5, ATIC at BTA2 and ADSS at BTA16, are in agreement with published comparative maps of cattle and man. PAICS and PPAT genes are known to be closely linked in human, rat and chicken. Previously, an expressed sequence fragment of PAICS (Bos taurus corpus luteum, BTCL9) was mapped to BTA13. By isolation and characterization of a BAC clone, we have now identified a PAICS processed pseudogene sequence (psiPAICS) on BTA13. Processed pseudogene sequences of PAICS and other genes of the purine biosynthesis pathway were identified in several mammalian species, indicating that the genes of this pathway have been susceptible to retrotransposition. The seven bovine genes are expressed at a higher level in testicular and

  12. 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.

  13. Discovery and characterization of de novo sialic acid biosynthesis in the phylum Fusobacterium

    Science.gov (United States)

    Lewis, Amanda L; Robinson, Lloyd S; Agarwal, Kavita; Lewis, Warren G

    2016-01-01

    Sialic acids are nine-carbon backbone carbohydrates found in prominent outermost positions of glycosylated molecules in mammals. Mimicry of sialic acid (N-acetylneuraminic acid, Neu5Ac) enables some pathogenic bacteria to evade host defenses. Fusobacterium nucleatum is a ubiquitous oral bacterium also linked with invasive infections throughout the body. We employed multidisciplinary approaches to test predictions that F. nucleatum engages in de novo synthesis of sialic acids. Here we show that F. nucleatum sbsp. polymorphum ATCC10953 NeuB (putative Neu5Ac synthase) restores Neu5Ac synthesis to an Escherichia coli neuB mutant. Moreover, purified F. nucleatum NeuB participated in synthesis of Neu5Ac from N-acetylmannosamine and phosphoenolpyruvate in vitro. Further studies support the interpretation that F. nucleatum ATCC10953 NeuA encodes a functional CMP-sialic acid synthetase and suggest that it may also contain a C-terminal sialic acid O-acetylesterase. We also performed BLAST queries of F. nucleatum genomes, revealing that only 4/31 strains encode a complete pathway for de novo Neu5Ac synthesis. Biochemical studies including mass spectrometry were consistent with the bioinformatic predictions, showing that F. nucleatum ATCC10953 synthesizes high levels of Neu5Ac, whereas ATCC23726 and ATCC25586 do not express detectable levels above background. While there are a number of examples of sialic acid mimicry in other phyla, these experiments provide the first biochemical and genetic evidence that a member of the phylum Fusobacterium can engage in de novo Neu5Ac synthesis. PMID:27613803

  14. Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy.

    Science.gov (United States)

    de Kovel, Carolien G F; Meisler, Miriam H; Brilstra, Eva H; van Berkestijn, Frederique M C; van 't Slot, Ruben; van Lieshout, Stef; Nijman, Isaac J; O'Brien, Janelle E; Hammer, Michael F; Estacion, Mark; Waxman, Stephen G; Dib-Hajj, Sulayman D; Koeleman, Bobby P C

    2014-11-01

    Recently, de novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathies (EIEE13). Functional studies on the first described case demonstrated gain-of-function effects of the mutation. We describe a novel de novo mutation of SCN8A in a patient with epileptic encephalopathy, and functional characterization of the mutant protein. Whole exome sequencing was used to discover the variant. We generated a mutant cDNA, transfected HEK293 cells, and performed Western blotting to assess protein stability. To study channel functional properties, patch-clamp experiments were carried out in transfected neuronal ND7/23 cells. The proband exhibited seizure onset at 6 months of age, diffuse brain atrophy, and more profound developmental impairment than the original case. The mutation p.Arg233Gly in the voltage sensing transmembrane segment D1S4 was present in the proband and absent in both parents. This mutation results in a temperature-sensitive reduction in protein expression as well as reduced sodium current amplitude and density and a relative increased response to a slow ramp stimulus, though this did not result in an absolute increased current at physiological temperatures. The new de novo SCN8A mutation is clearly deleterious, resulting in an unstable protein with reduced channel activity. This differs from the gain-of-function attributes of the first SCN8A mutation in epileptic encephalopathy, pointing to heterogeneity of mechanisms. Since Nav1.6 is expressed in both excitatory and inhibitory neurons, a differential effect of a loss-of-function of Nav1.6 Arg223Gly on inhibitory interneurons may underlie the epilepsy phenotype in this patient. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. 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

  16. SMRT sequencing only de novo assembly of the sugar beet (Beta vulgaris) chloroplast genome.

    Science.gov (United States)

    Stadermann, Kai Bernd; Weisshaar, Bernd; Holtgräwe, Daniela

    2015-09-16

    Third generation sequencing methods, like SMRT (Single Molecule, Real-Time) sequencing developed by Pacific Biosciences, offer much longer read length in comparison to Next Generation Sequencing (NGS) methods. Hence, they are well suited for de novo- or re-sequencing projects. Sequences generated for these purposes will not only contain reads originating from the nuclear genome, but also a significant amount of reads originating from the organelles of the target organism. These reads are usually discarded but they can also be used for an assembly of organellar replicons. The long read length supports resolution of repetitive regions and repeats within the organelles genome which might be problematic when just using short read data. Additionally, SMRT sequencing is less influenced by GC rich areas and by long stretches of the same base. We describe a workflow for a de novo assembly of the sugar beet (Beta vulgaris ssp. vulgaris) chloroplast genome sequence only based on data originating from a SMRT sequencing dataset targeted on its nuclear genome. We show that the data obtained from such an experiment are sufficient to create a high quality assembly with a higher reliability than assemblies derived from e.g. Illumina reads only. The chloroplast genome is especially challenging for de novo assembling as it contains two large inverted repeat (IR) regions. We also describe some limitations that still apply even though long reads are used for the assembly. SMRT sequencing reads extracted from a dataset created for nuclear genome (re)sequencing can be used to obtain a high quality de novo assembly of the chloroplast of the sequenced organism. Even with a relatively small overall coverage for the nuclear genome it is possible to collect more than enough reads to generate a high quality assembly that outperforms short read based assemblies. However, even with long reads it is not always possible to clarify the order of elements of a chloroplast genome sequence reliantly

  17. Movimento estudantil brasileiro: Práticas militantes na ótica dos Novos Movimentos Sociais

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    Marcos Ribeiro Mesquita

    2012-10-01

    Full Text Available Este artigo visa identificar na estrutura e organização do movimento estudantil conteúdos e formas organizativas que nos indiquem o surgimento de uma nova sociabilidade militante. Para tanto, foi necessário analisar as relações entre os diversos grupos organizados do movimento estudantil, desde os mais institucionalizados, àqueles que empreendem outras formas de fazer política. A pluralidade de expressões estudantis, de novos formatos, metodologias e pautas parecem apontar para esta sociabilidade, apesar do forte caráter tradicional que a política estudantil institucional ainda possui.

  18. O Estado Novo, o rádio e seus órgãos reguladores

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    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.

  19. 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...... of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing data sets. Our...

  20. A Psicologia no novo contexto mundial Psychology in the new world context

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    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

  1. Direito Fraterno: em busca de um novo paradigma jurídico

    OpenAIRE

    Marieta Izabel Martins Maia

    2011-01-01

    Neste trabalho procuramos estudar o surgimento de um novo paradigma: o Direito Fraterno. Sob a ótica da dimensão constitucional, onde se busca analisar, concomitantemente, o conceitomais amplificado de cidadania e soberania estatal, no contexto global da pós-modernidade, utilizando-se como material de pesquisa a escassa bibliografia existente sobre o tema. Procuramos,também, estudar as mudanças paradigmáticas que sofreram os Direitos Humanos na evolução da humanidade. Vislumbrando-se como pan...

  2. Recent Advances Towards The Discovery Of Drug-Like Peptides De Novo

    Directory of Open Access Journals (Sweden)

    Michael eGoldflam

    2015-12-01

    Full Text Available Peptides are important natural molecules that possess functions as diverse as antibiotics, toxins, venoms and hormones, for example. However, whilst these peptides have useful properties, there are many targets and pathways that are not addressed through the activities of natural peptidic compounds. In these circumstances, directed evolution techniques, such as phage display, have been developed to sample the diverse chemical and structural repertoire of small peptides for useful means. In this review, we consider recent concepts that relate peptide structure to drug-like attributes and how these are incorporated within display technologies to deliver peptides de novo with valuable pharmaceutical properties.

  3. 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.

  4. NOVO GÊNERO E ESPÉCIE DE LAGARTO DO ESTADO DO CEARÁ (LACERTILIA: TEIIDAE)

    OpenAIRE

    Cunha, Osvaldo Rodrigues da; Lima-Verde, José Santiago; Lima, Almira Claudia Marinho

    1991-01-01

    Um novo gênero e espécie de lacertílio (Colobosauroides cearensis sp. n.) ocorre em enclave florestal do maciço de Baturité e na periferia da cidade de Fortaleza, Ceará. A Serra de Baturité localiza-se aproximadamente entre 4. a 4. 30'S e 38. 40' a 39. 1O'W, de direção NNE - SSW Faz-se uma análise dos locais de coleta da nova espécie, e análises comparativas com os gêneros afins Anotosaura, Colobodactylus e Colobo­saura.

  5. Merremoside D: de novo synthesis of the purported structure, NMR analysis, and comparison of spectral data.

    Science.gov (United States)

    Sharif, Ehesan U; Wang, Hua-Yu Leo; Akhmedov, Novruz G; O'Doherty, George A

    2014-01-17

    The first synthesis of the purported structure of Merremoside D has been achieved in 22 longest linear steps. The de novo asymmetric synthesis relied on the use of asymmetric catalysis to selectively install all 21 stereocenters in the final compounds from commercially available achiral starting materials. Adiabatic gradient 2D NMR techniques (gHSQCAD, gHMBCAD, gH2BCAD, gHSQCTOXYAD, ROESYAD) were used to completely assign the structure of synthetic Merremoside D. Comparison of our assignments with the limited NMR data reported for natural Merremoside D allows for the tentative confirmation of its structure.

  6. Reflexos Contábeis no Novo Código Civil de 2002

    Directory of Open Access Journals (Sweden)

    Ildefonso Assing

    2003-07-01

    Full Text Available Através do presente trabalho, visa-se apresentar aos contabilistas e demais interessados na área contábil, as principais alterações, práticas e teóricas, a respeito do exercício das funções contábeis no novo código civil de 2002. Para facilitar o entendimento dos artigos inerentes à função, menciona-se o artigo e comenta-se o mesmo, a fim de posicionar o interessado no contexto atual.

  7. 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...

  8. Comparison of De Novo Transcriptome Assemblers and k-mer Strategies Using the Killifish, Fundulus heteroclitus.

    Science.gov (United States)

    Rana, Satshil B; Zadlock, Frank J; Zhang, Ziping; Murphy, Wyatt R; Bentivegna, Carolyn S

    2016-01-01

    De novo assembly of non-model organism's transcriptomes has recently been on the rise in concert with the number of de novo transcriptome assembly software programs. There is a knowledge gap as to what assembler software or k-mer strategy is best for construction of an optimal de novo assembly. Additionally, there is a lack of consensus on which evaluation metrics should be used to assess the quality of de novo transcriptome assemblies. Six different assembly strategies were evaluated from four different assemblers. The Trinity assembly was used in its default 25 single k-mer value while Bridger, Oases, and SOAPdenovo-Trans were performed with multiple k-mer strategies. Bridger, Oases, and SOAPdenovo-Trans used a small multiple k-mer (SMK) strategy consisting of the k-mer lengths of 21, 25, 27, 29, 31, and 33. Additionally, Oases and SOAPdenovo-Trans were performed using a large multiple k-mer (LMK) strategy consisting of k-mer lengths of 25, 35, 45, 55, 65, 75, and 85. Eleven metrics were used to evaluate each assembly strategy including three genome related evaluation metrics (contig number, N50 length, Contigs >1 kb, reads) and eight transcriptome evaluation metrics (mapped back to transcripts (RMBT), number of full length transcripts, number of open reading frames, Detonate RSEM-EVAL score, and percent alignment to the southern platyfish, Amazon molly, BUSCO and CEGMA databases). The assembly strategy that performed the best, that is it was within the top three of each evaluation metric, was the Bridger assembly (10 of 11) followed by the Oases SMK assembly (8 of 11), the Oases LMK assembly (6 of 11), the Trinity assembly (4 of 11), the SOAP LMK assembly (4 of 11), and the SOAP SMK assembly (3 of 11). This study provides an in-depth multi k-mer strategy investigation concluding that the assembler itself had a greater impact than k-mer size regardless of the strategy employed. Additionally, the comprehensive performance transcriptome evaluation metrics utilized

  9. 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.

  10. 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

  11. Um novo olhar sobre o aprendizado: incursões ao Imaginário

    OpenAIRE

    Marreiros, Paula Regina Lima

    2000-01-01

    Na presente dissertação propomos um novo olhar acerca da aprendizagem de língua inglesa que considera o Imaginário como elemento que ultrapassa as questões metodológicas, pedagógicas e psicológicas. Baseado no pensamento de Cornelius Castoriadis, este referencial, visto socialmente e historicamente, é de fundamental importância para que se entendam as dimensões significativas que a aprendizagem de uma língua estrangeira - no caso em questão, o inglês – vem adquirindo. Partindo da motivação de...

  12. De novo production of the monoterpenoid geranic acid by metabolically engineered Pseudomonas putida.

    Science.gov (United States)

    Mi, Jia; Becher, Daniela; Lubuta, Patrice; Dany, Sarah; Tusch, Kerstin; Schewe, Hendrik; Buchhaupt, Markus; Schrader, Jens

    2014-12-04

    Production of monoterpenoids as valuable chemicals using recombinant microbes is a growing field of interest. Unfortunately, antimicrobial activity of most monoterpenoids hampers a wide application of microorganisms for their production. Strains of Pseudomonas putida, a fast growing and metabolically versatile bacterium, often show an outstanding high tolerance towards organic solvents and other toxic compounds. Therefore, Pseudomonas putida constitutes an attractive alternative host in comparison to conventionally used microorganisms. Here, metabolic engineering of solvent tolerant Pseudomonas putida as a novel microbial cell factory for de novo production of monoterpenoids is reported for the first time, exemplified by geranic acid production from glycerol as carbon source. The monoterpenoic acid is an attractive compound for application in the flavor, fragrance, cosmetics and agro industries. A comparison between Escherichia coli, Saccharomyces cerevisiae and Pseudomonas putida concerning the ability to grow in the presence of geranic acid revealed that the pseudomonad bears a superior resilience compared to the conventionally used microbes. Moreover, Pseudomonas putida DSM 12264 wildtype strain efficiently oxidized externally added geraniol to geranic acid with no further degradation. Omitting external dosage of geraniol but functionally expressing geraniol synthase (GES) from Ocimum basilicum, a first proof-of-concept for de novo biosynthesis of 1.35 mg/L geranic acid in P. putida DSM 12264 was achieved. Doubling the amount of glycerol resulted in twice the amount of product. Co-expression of the six genes of the mevalonate pathway from Myxococcus xanthus to establish flux from acetyl-CoA to the universal terpenoid precursor isopentenylpyrophosphate yielded 36 mg/L geranic acid in shake flask experiments. In the bioreactor, the recombinant strain produced 193 mg/L of geranic acid under fed-batch conditions within 48 h. Metabolic engineering turned Pseudomonas

  13. 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.

  14. Efeito das lojas vazias, sôbre o rendimento do café mundo novo Influence of the empty seeds on the outturn of mundo novo coffee

    Directory of Open Access Journals (Sweden)

    L. C. Mônaco

    1960-01-01

    Full Text Available O rendimento do café, isto é, a relação entre o pêso de café maduro para o de beneficiado, é influenciado, entre outros fatôres, pela ocorrência de frutos com lojas sem sementes, os quais flutuam quando colocados no água. Procurando avaliar o efeito de quantidades variáveis dêste tipo de frutos sôbre o rendimento do café Mundo Novo, foram preparados quatro grupos de cinco amostras, contendo 0, 25, 50, 75 e 100 por cento de frutos dessa natureza. Nestas amostras realizaram-se observações sôbre as quantidades de sementes moca, concha e chato, tamanho, densidade e pêso dos sementes. Os dados obtidos mostraram que o abôrto do endosperma em uma das lojas do fruto não afetou as características de pêso, densidade e tamanho das sementes desenvolvidas no outra loja do fruto. Verificou-se, também, que as sementes moca diminuíram à medida que aumentaram nas amostras as quantidades de frutos com lojas sem sementes, sendo êste fato atribuído ao número reduzido de frutos moca que flutuam no água. As sementes concha, ao contrário, aumentaram com as crescentes porções de frutos que boiam nas amostras preparadas, o que talvez possa ser atribuível a um efeito pleiotrópico do fator genético responsável pelo abôrto do endosperma. O rendimento apresentou uma forte tendência de piorar com o aumento do quantidade de lojas sem sementes nas amostras e a análise estatística levou à conclusão de que se trata de um efeito linear. Os resultados dêste ensaio vieram mostrar que o processo de seleção que vem sendo adotado para o café Nundo Novo, eliminando a maioria das plantas com alta quantidade de lojas vazias, é eficiente e assim dsve ser prosseguido.The major factor that has notable influence on the outturn of the coffee (the berry to clean coffee weight relation is the occurrence of fruits with empty seed, which float when put in water. In order to have information on the effect of this kind of fruits on the outturn of the

  15. Critical importance of the de novo pyrimidine biosynthesis pathway for Trypanosoma cruzi growth in the mammalian host cell cytoplasm

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Muneaki, E-mail: muneaki@juntendo.ac.jp [Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Morales, Jorge; Fukai, Yoshihisa; Suzuki, Shigeo; Takamiya, Shinzaburo; Tsubouchi, Akiko; Inoue, Syou [Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Inoue, Masayuki [Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Kita, Kiyoshi [Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Harada, Shigeharu [Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Tanaka, Akiko [Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama 230-0045 (Japan); Aoki, Takashi [Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Nara, Takeshi, E-mail: tnara@juntendo.ac.jp [Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan)

    2012-01-20

    Highlights: Black-Right-Pointing-Pointer We established Trypanosoma cruzi lacking the gene for carbamoyl phosphate synthetase II. Black-Right-Pointing-Pointer Disruption of the cpsII gene significantly reduced the growth of epimastigotes. Black-Right-Pointing-Pointer In particular, the CPSII-null mutant severely retarded intracellular growth. Black-Right-Pointing-Pointer 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.

  16. 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.

  17. 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.

  18. Design Methodology - Design Synthesis

    DEFF Research Database (Denmark)

    Andreasen, Mogens Myrup

    2003-01-01

    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...... 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....

  19. 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.

  20. Survival of de novo stage IV breast cancer patients over three decades.

    Science.gov (United States)

    Hölzel, Dieter; Eckel, Renate; Bauerfeind, Ingo; Baier, Bernd; Beck, Thomas; Braun, Michael; Ettl, Johannes; Hamann, Ulrich; Harbeck, Nadia; Kiechle, Marion; Mahner, Sven; Schindlbeck, Christian; de Waal, Johann; Engel, Jutta

    2017-03-01

    De novo stage IV breast cancer patients (BC IV ) depict a clinical picture not influenced by adjuvant therapy. Therefore, the time-dependent impact of changes in diagnostics and treatments on progression and survival can best be evaluated in this subgroup. BC IV patients from 1978 to 2013 registered in the Munich Cancer Registry were divided into four periods, and the trends were analysed. Survival was estimated by Kaplan-Meier methods, and prognostic factors were fitted with Cox proportional hazard models. Between 1978 and 2013, 88,759 patients were diagnosed with 92,807 cases of invasive and non-invasive BC. Of these patients, 4756 patients had distant metastases (MET) at diagnosis. The 5-year survival rate improved from 17.4 to 24.7%, while the pattern of metastases did not change. Improved staging diagnostics, a screening programme and primary systemic therapy changed the composition of prognostic strata. Patients with a similar composition as the 1978-1987 cohort exhibited a median survival difference of 13 months; however, neither univariate nor multivariate analysis showed a survival effect for the four periods as a surrogate indicator for changing treatments. HER2+ patients have with 27.6 months a slightly longer survival than all other BC IV patients. Survival of de novo BC IV has only modestly improved since the late 1970s, partially masked by changing distributions of prognostic factors due to changes in diagnostics.

  1. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.

    Science.gov (United States)

    Küry, Sébastien; Besnard, Thomas; Ebstein, Frédéric; Khan, Tahir N; Gambin, Tomasz; Douglas, Jessica; Bacino, Carlos A; Craigen, William J; Sanders, Stephan J; Lehmann, Andrea; Latypova, Xénia; Khan, Kamal; Pacault, Mathilde; Sacharow, Stephanie; Glaser, Kimberly; Bieth, Eric; Perrin-Sabourin, Laurence; Jacquemont, Marie-Line; Cho, Megan T; Roeder, Elizabeth; Denommé-Pichon, Anne-Sophie; Monaghan, Kristin G; Yuan, Bo; Xia, Fan; Simon, Sylvain; Bonneau, Dominique; Parent, Philippe; Gilbert-Dussardier, Brigitte; Odent, Sylvie; Toutain, Annick; Pasquier, Laurent; Barbouth, Deborah; Shaw, Chad A; Patel, Ankita; Smith, Janice L; Bi, Weimin; Schmitt, Sébastien; Deb, Wallid; Nizon, Mathilde; Mercier, Sandra; Vincent, Marie; Rooryck, Caroline; Malan, Valérie; Briceño, Ignacio; Gómez, Alberto; Nugent, Kimberly M; Gibson, James B; Cogné, Benjamin; Lupski, James R; Stessman, Holly A F; Eichler, Evan E; Retterer, Kyle; Yang, Yaping; Redon, Richard; Katsanis, Nicholas; Rosenfeld, Jill A; Kloetzel, Peter-Michael; Golzio, Christelle; Bézieau, Stéphane; Stankiewicz, Paweł; Isidor, Bertrand

    2017-02-02

    Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. 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.

  3. De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination.

    Science.gov (United States)

    Montani, Laura; Pereira, Jorge A; Norrmén, Camilla; Pohl, Hartmut B F; Tinelli, Elisa; Trötzmüller, Martin; Figlia, Gianluca; Dimas, Penelope; von Niederhäusern, Belinda; Schwager, Rachel; Jessberger, Sebastian; Semenkovich, Clay F; Köfeler, Harald C; Suter, Ueli

    2018-02-06

    Myelination calls for a remarkable surge in cell metabolism to facilitate lipid and membrane production. Endogenous fatty acid (FA) synthesis represents a potentially critical process in myelinating glia. Using genetically modified mice, we show that Schwann cell (SC) intrinsic activity of the enzyme essential for de novo FA synthesis, fatty acid synthase (FASN), is crucial for precise lipid composition of peripheral nerves and fundamental for the correct onset of myelination and proper myelin growth. Upon FASN depletion in SCs, epineurial adipocytes undergo lipolysis, suggestive of a compensatory role. Mechanistically, we found that a lack of FASN in SCs leads to an impairment of the peroxisome proliferator-activated receptor (PPAR) γ-regulated transcriptional program. In agreement, defects in myelination of FASN-deficient SCs could be ameliorated by treatment with the PPARγ agonist rosiglitazone ex vivo and in vivo . Our results reveal that FASN-driven de novo FA synthesis in SCs is mandatory for myelination and identify lipogenic activation of the PPARγ transcriptional network as a putative downstream functional mediator. © 2018 Montani et al.

  4. 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.)

  5. 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.

  6. Um fungo novo do caeté Bilboque, a new genus of hyphomycetes on calathea

    Directory of Open Access Journals (Sweden)

    A. P. Viégas

    1960-01-01

    Full Text Available Um fungo hifomicete, ocasionando lesões em folhas de Calathea sp., da família Marantaceae, vulgarmente chamada caeté e tido como novo à micologia brasileira é agora descrito pela primeira vez. Êsse organismo foi constatado também em fôlhas de Canna sp., da família Cannaceae, no Estado do Rio de Janeiro. Ao gênero novo deu-se o nome de Bilboque. À espécie, magnificum. A etimologia do gênero é apresentada e discutida, assim como a posição taxonômica do hifomicete, amparando-as na morfologia. Vai ilustrada com séries de figuras a bico de pena pelo próprio autor.A new genus of the Hyphomycetes is described on living leaves of Calathea sp., caeté in Tupi and Portuguese, a plant belonging to the family Marantaceae. The new erected genus has been called Bilboque, and the specific name magnificum: The implications which this genus have when compared to other well known genera, like Polythrincium, Cordana and Piricularia are focussed, and in order to clear problems dealing with morphological features of the new genus its characteristics have been shown in four serial sequences of figures by Indian ink, all them by the hand of the writer.

  7. Identification of phosphopeptides with unknown cleavage specificity by a de novo sequencing assisted database search strategy.

    Science.gov (United States)

    Dong, Mingming; Ye, Mingliang; Cheng, Kai; Dong, Jing; Zhu, Jun; Qin, Hongqiang; Bian, Yangyang; Zou, Hanfa

    2014-11-01

    In theory, proteases with broad cleavage specificity could be applied to digest protein samples to improve the phosphoproteomic analysis coverage. However, in practice this approach is seldom employed. This is because the identification of phosphopeptides without enzyme specificity by conventional database search strategy is extremely difficult due to the huge search space. In this study, we investigated the performance of a de novo sequencing assisted database search strategy for the identification of such phosphopeptides. Firstly, we compared the performance of conventional database search strategy and the de novo sequencing assisted database search strategy for the identification of peptides and phosphopeptides without stetting enzyme specificity. It was found that the identification sensitivity dropped significantly for the conventional one while it was only slightly decreased for the new approach. Then, this new search strategy was applied to identify phosphopeptides generated by Proteinase K digestion, which resulted in the identification of 717 phosphopeptides. Finally, this strategy was utilized for the identification of serum endogenous phosphopeptides, which were generated in vivo by different kinds of proteases and kinases, and the identification of 68 unique serum endogenous phosphopepitdes was successfully achieved. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Metabolic distinction of Ulmus minor xylem tissues after inoculation with Ophiostoma novo-ulmi.

    Science.gov (United States)

    Martín, Juan A; Solla, Alejandro; Coimbra, Manuel A; Gil, Luis

    2005-10-01

    Dutch elm disease (DED) is the most devastating and widespread disease of elms. The pathogen, Ophiostoma novo-ulmi, spreads systemically causing xylem vessels blocking and cavitation, and ultimately resulting in the development of a wilt syndrome. Twig samples from susceptible and resistant Ulmus minor trees were harvested at 0, 5, 15, 30, 60, and 120 days post-inoculation (dpi) with O. novo-ulmi. Fourier transform-infrared (FT-IR) spectroscopy, in tandem with chemometrics, was used to monitor changes in wood chemistry as consequence of infection. Principal component analysis distinguished between spectra from inoculated and control elms, and from susceptible- and resistant-inoculated elms. By 30 dpi, infected xylem showed reduced relative levels of carbohydrates and enhanced relative levels of phenolic compounds, probably due to the degradation of cell wall polysaccharides by fungal enzymes and the synthesis of host defence compounds. On 15 dpi, samples from resistant-inoculated elms showed higher levels of starch than samples from susceptible-inoculated elms, suggesting that availability of starch reserves could affect the tree's capacity for defensive responses. The results showed the power of FT-IR spectroscopy for analysing changes in the major components of elm xylem as consequence of infection by DED, and its potential for detecting metabolic profiles related to host resistance.

  9. Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth.

    Science.gov (United States)

    Liu, Liu; Zhao, Xiaoping; Zhao, Li; Li, Jiajin; Yang, Hao; Zhu, Zongping; Liu, Jianjun; Huang, Gang

    2016-03-01

    Dysregulation of the sterol regulatory element-binding transcription factors sterol regulatory element-binding protein (SREBP) and SREBF activates de novo lipogenesis to high levels in cancer cells, a critical event in driving malignant growth. In this study, we identified an important posttranslational mechanism by which SREBP1a is regulated during metabolic reprogramming in cancer cells. Mass spectrometry revealed protein arginine methyltransferase 5 (PRMT5) as a binding partner of SREBP1a that symmetrically dimethylated it on R321, thereby promoting transcriptional activity. Furthermore, PRMT5-induced methylation prevented phosphorylation of SREBP1a on S430 by GSK3β, leading to its disassociation from Fbw7 (FBXW7) and its evasion from degradation through the ubiquitin-proteasome pathway. Consequently, methylation-stabilized SREBP1a increased de novo lipogenesis and accelerated the growth of cancer cells in vivo and in vitro. Clinically, R321 symmetric dimethylation status was associated with malignant progression of human hepatocellular carcinoma, where it served as an independent risk factor of poor prognosis. By showing how PRMT5-induced methylation of SREBP1a triggers hyperactivation of lipid biosynthesis, a key event in tumorigenesis, our findings suggest a new generalized strategy to selectively attack tumor metabolism. ©2016 American Association for Cancer Research.

  10. 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.

  11. 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.

  12. Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance.

    Science.gov (United States)

    Horn, Morten A; Retterstøl, Lars; Abdelnoor, Michael; Skjeldal, Ola H; Tallaksen, Chantal M E

    2013-03-01

    To investigate X-linked adrenoleukodystrophy in an unselected population, we performed a population based, cross-sectional prevalence study, supplemented by a retrospective study of deceased subjects. Sixty-three subjects (34 males, 29 females) belonging to 22 kindreds were included. Thirty-nine subjects (13 males, 26 females) were alive, and 24 (21 males, 3 females) were deceased on the prevalence day. The point prevalence of X-linked adrenoleukodystrophy in Norway on July 1, 2011, was 0.8 per 100,000 inhabitants. The incidence at birth in the period 1956-1995 was 1.6 per 100,000 inhabitants. An age-dependent penetrance was observed among males and females, with more severe phenotypes appearing with rising age. Only 5% of deceased males had not developed cerebral leukodystrophy. No female older than 50 years was neurologically intact. Sixteen mutations in the ABCD1 gene were identified. De novo mutations were found in 19% of probands. The frequency of X-linked adrenoleukodystrophy was lower in Norway than reported in the literature. A more severe natural course than previously reported was observed, indicating a need for better follow-up of both male and female patients. Given the high rate of de novo mutations, identification programs such as newborn screening may be required to offer timely treatment to all patients. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. 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.

  14. De novo transcriptome characterization of Vitis vinifera cv. Corvina unveils varietal diversity

    Directory of Open Access Journals (Sweden)

    Venturini Luca

    2013-01-01

    Full Text Available Abstract Background Plants such as grapevine (Vitis spp. display significant inter-cultivar genetic and phenotypic variation. The genetic components underlying phenotypic diversity in grapevine must be understood in order to disentangle genetic and environmental factors. Results We have shown that cDNA sequencing by RNA-seq is a robust approach for the characterization of varietal diversity between a local grapevine cultivar (Corvina and the PN40024 reference genome. We detected 15,161 known genes including 9463 with novel splice isoforms, and identified 2321 potentially novel protein-coding genes in non-annotated or unassembled regions of the reference genome. We also discovered 180 apparent private genes in the Corvina genome which were missing from the reference genome. Conclusions The de novo assembly approach allowed a substantial amount of the Corvina transcriptome to be reconstructed, improving known gene annotations by robustly defining gene structures, annotating splice isoforms and detecting genes without annotations. The private genes we discovered are likely to be nonessential but could influence certain cultivar-specific characteristics. Therefore, the application of de novo transcriptome assembly should not be restricted to species lacking a reference genome because it can also improve existing reference genome annotations and identify novel, cultivar-specific genes.

  15. 'Novos produtos' como competência do advogado 'New products' as a lawyer's competence

    Directory of Open Access Journals (Sweden)

    Gilberto de Abreu Sodré Carvalho

    2008-06-01

    Full Text Available A participação profissional do advogado em projetos de "novos produtos" tem sido comum há muito tempo no brasil. Entretanto, não se sabe da formulação de qualquer técnica de aceitação geral para a contribuição do advogado. Este artigo, dentro da temática 'direito & gestão', visa oferecer uma possível metodologia para projetos de novos produtos em que o advogado tenha papel protagonista. Nessa metodologia, o termo proposto "pré-produto" comporta a idéia de um objeto sendo modelado de acordo com sua adaptação a sistemas ambientais sob estruturantes jurídicas até que se torne um produto a ser lançado.Counsel's professional participation in 'new products' projects has been seen for a long time, in Brazil. However, to our knowledge, no generally accepted technique for counsel's contribution thereto has been developed yet. This article in the field of 'law & management' aims at providing a possible new products project methodology in which counsel is assigned a protagonist role. In such methodology the coined term 'pre-product' shows the idea of an object being modeled in accordance with its adaptation to several legal structured environment systems until it becomes a product to be launched.

  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...... 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.......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...

  17. Measures of de novo synthesis of milk components from propionate in lactating goats

    International Nuclear Information System (INIS)

    Emmanuel, B.; Kennelly, J.J.

    1985-01-01

    Possible direct contributions of propionate to de novo synthesis of milk components by the mammary gland of lactating goats fed a concentrate-roughage diet have been studied in vivo by primed constant infusion of [1-carbon-14]propionate into the right mammary artery. Specific radioactivities of milk galactose, fatty acids, and protein were higher in the infused than in the uninfused half of the mammary gland, suggesting de novo synthesis of these compounds in the udder. Specific radioactivities of milk glucose in both udder halves were identical, ruling out any possibility of mammary gland-derived glucose from propionate of blood plasma under the experimental conditions. Of milk galactose, .8% was derived from propionate of blood plasma, and of milk glucose, 98% was derived from glucose of blood plasma. After intraruminal infusion of unlabeled propionic acid at 11 g/h, concentration of propionate in blood plasma was doubled, its contribution to milk galactose was increased to 1.5%, and proportions of milk odd-numbered fatty acids were increased. Propionate was incorporated largely into milk odd-numbered fatty acids. The authors conclude that small amounts of propionate can be incorporated into principal components of milk in the mammary gland of lactating goats

  18. 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

  19. 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.

  20. 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.

  1. De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment

    Science.gov (United States)

    Hempel, Maja; Cremer, Kirsten; Ockeloen, Charlotte W.; Lichtenbelt, Klaske D.; Herkert, Johanna C.; Denecke, Jonas; Haack, Tobias B.; Zink, Alexander M.; Becker, Jessica; Wohlleber, Eva; Johannsen, Jessika; Alhaddad, Bader; Pfundt, Rolph; Fuchs, Sigrid; Wieczorek, Dagmar; Strom, Tim M.; van Gassen, Koen L.I.; Kleefstra, Tjitske; Kubisch, Christian; Engels, Hartmut; Lessel, Davor

    2015-01-01

    CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398∗), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability. PMID:26340335

  2. De novo transcriptome assembly for the lung of the ornamented pygmy frog (Microhyla fissipes

    Directory of Open Access Journals (Sweden)

    Lusha Liu

    2017-09-01

    Full Text Available Microhyla fissipes, belonging to Neobatrachia, is a new model organism to study developmental biology, adaptive mechanisms from aquatic to terrestrial life, environmental toxicology, and human disease. M. fissipes use of lungs soon after hatching makes it extremely valuable for the study of lung function and development mechanisms. However, our knowledge of genes and pathways associated with lung development in M. fissipes is very limited. In this study, we conducted de novo transcriptome assembly for the lung of M. fissipes using the Illumina HiSeq4000 platform. We obtained approximately 9.0 GB clean data from the lung of the stage 28 tadpole with lung inflation (NCBI accession numbers: SRP107055. De novo transcriptome assembly identified 209,358 transcripts and 93,813 unigenes. In addition, BLASTX against NR, NT, KO, SwissProt, PFAM, GO and KOG databases were used to annotate all the 93,813 unigenes. This study provides the transcriptome and functional annotation of genes in M. fissipes lung development, which will be useful for comparative transcriptome analyses and promote research into mechanism of lung development in anuran.

  3. De-novo transcriptome sequencing of a normalized cDNA pool from influenza infected ferrets.

    Directory of Open Access Journals (Sweden)

    Jeremy V Camp

    Full Text Available The ferret is commonly used as a model for studies of infectious diseases. The genomic sequence of this animal model is not yet characterized, and only a limited number of fully annotated cDNAs are currently available in GenBank. The majority of genes involved in innate or adaptive immune response are still lacking, restricting molecular genetic analysis of host response in the ferret model. To enable de novo identification of transcriptionally active ferret genes in response to infection, we performed de-novo transcriptome sequencing of animals infected with H1N1 A/California/07/2009. We also included splenocytes induced with bacterial lipopolysaccharide to allow for identification of transcripts specifically induced by gram-negative bacteria. We pooled and normalized the cDNA library in order to delimit the risk of sequencing only highly expressed genes. While normalization of the cDNA library removes the possibility of assessing expression changes between individual animals, it has been shown to increase identification of low abundant transcripts. In this study, we identified more than 19,000 partial ferret transcripts, including more than 1000 gene orthologs known to be involved in the innate and the adaptive immune response.

  4. De novo fear conditioning across diagnostic groups in the affective disorders: evidence for learning impairments.

    Science.gov (United States)

    Otto, Michael W; Moshier, Samantha J; Kinner, Dina G; Simon, Naomi M; Pollack, Mark H; Orr, Scott P

    2014-09-01

    De novo fear conditioning paradigms have served as a model for how clinical anxiety may be acquired and maintained. To further examine variable findings in the acquisition and extinction of fear responses between clinical and nonclinical samples, we assessed de novo fear conditioning outcomes in outpatients with either anxiety disorders or depression and healthy subjects recruited from the community. Overall, we found evidence for attenuated fear conditioning, as measured by skin conductance, among the patient sample, with significantly lower fear acquisition among patients with depression and posttraumatic stress disorder. These acquisition deficits were evident in both the simple (considering the CS+only) and differential (evaluating the CS+in relation to the CS-) paradigms. Examination of extinction outcomes were hampered by the low numbers of patients who achieved adequate conditioning, but the available data indicated slower extinction among the patient, primarily panic disorder, sample. Results are interpreted in the context of the cognitive deficits that are common to the anxiety and mood disorders, with attention to a range of potential factors, including mood comorbidity, higher-and lower-order cognitive processes and deficits, and medication use, that may modulate outcomes in fear conditioning studies, and, potentially, in exposure-based cognitive behavioral therapy. Copyright © 2014. Published by Elsevier Ltd.

  5. 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.

  6. Identification of the First De Novo UBIAD1 Gene Mutation Associated with Schnyder Corneal Dystrophy

    Directory of Open Access Journals (Sweden)

    Benjamin R. Lin

    2016-01-01

    Full Text Available Purpose. To report the identification of the first de novo UBIAD1 missense mutation in an individual with Schnyder corneal dystrophy (SCD. Methods. A slit lamp examination was performed on a 47-year-old woman without a family history of corneal disorders. The proband’s parents, two sisters, and son were also examined and genomic DNA from all six individuals was collected. The exons and exon-intron boundaries of UBIAD1 were screened using Sanger sequencing. Identified mutations were screened for in 200 control chromosomes. In silico analysis predicted the impact of identified mutations on protein function and structure. Results. Slit lamp examination of the proband revealed findings consistent with SCD. Corneas of the family members appeared unaffected. Screening of UBIAD1 in the proband identified a novel heterozygous c.308C>T mutation, predicted to encode the missense amino acid substitution p.(Thr103Ile. This mutation was not identified in any of the family members or in 200 control chromosomes and was predicted to be damaging to normal protein function and structure. Conclusions. We present a novel heterozygous de novo missense mutation in UBIAD1, p.(Thr103Ile, identified in a patient with classic clinical features of SCD. This highlights the value of genetic testing in clinical diagnostic settings, even in the absence of a positive family history.

  7. The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia.

    Science.gov (United States)

    Eisfeld, A-K; Mrózek, K; Kohlschmidt, J; Nicolet, D; Orwick, S; Walker, C J; Kroll, K W; Blachly, J S; Carroll, A J; Kolitz, J E; Powell, B L; Wang, E S; Stone, R M; de la Chapelle, A; Byrd, J C; Bloomfield, C D

    2017-10-01

    Recurrent chromosomal abnormalities and gene mutations detected at the time of diagnosis of acute myeloid leukemia (AML) are associated with particular disease features, treatment response and survival of AML patients, and are used to denote specific disease entities in the World Health Organization classification of myeloid neoplasms and acute leukemia. However, large studies that integrate cytogenetic and comprehensive mutational information are scarce. We created a comprehensive oncoprint of mutations associated with recurrent cytogenetic findings by combining the information on mutational patterns of 80 cancer- and leukemia-associated genes with cytogenetic findings in 1603 adult patients with de novo AML. We show unique differences in the mutational profiles among major cytogenetic subsets, identify novel associations between recurrent cytogenetic abnormalities and both specific gene mutations and gene functional groups, and reveal differences in cytogenetic and mutational features between patients younger than 60 years and those aged 60 years or older. The identified associations between cytogenetic and molecular genetic data may help guide mutation testing in AML, and result in more focused application of targeted therapy in patients with de novo AML.

  8. Exome analysis of Smith-Magenis-like syndrome cohort identifies de novo likely pathogenic variants.

    Science.gov (United States)

    Berger, Seth I; Ciccone, Carla; Simon, Karen L; Malicdan, May Christine; Vilboux, Thierry; Billington, Charles; Fischer, Roxanne; Introne, Wendy J; Gropman, Andrea; Blancato, Jan K; Mullikin, James C; Gahl, William A; Huizing, Marjan; Smith, Ann C M

    2017-04-01

    Smith-Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader-Willi Syndrome (PWS) region. This can help clarify NDN's role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders. Identification and characterization of ID-related genes that assist in development of common developmental pathways and/or gene-networks, may inform disease mechanism and treatment strategies.

  9. 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

  10. Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells.

    Science.gov (United States)

    Takahashi, Yuta; Wu, Jun; Suzuki, Keiichiro; Martinez-Redondo, Paloma; Li, Mo; Liao, Hsin-Kai; Wu, Min-Zu; Hernández-Benítez, Reyna; Hishida, Tomoaki; Shokhirev, Maxim Nikolaievich; Esteban, Concepcion Rodriguez; Sancho-Martinez, Ignacio; Belmonte, Juan Carlos Izpisua

    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. Copyright © 2017, American Association for the Advancement of Science.

  11. Curva de Phillips novo keynesiana, custo marginal e expectativas de inflação no Brasil

    OpenAIRE

    Carvalho, Bruno Silva

    2009-01-01

    A importância deste trabalho será analisar a dinâmica inflacionária brasileira de acordo com um modelo híbrido de curva de Phillips baseado nos estudos sobre a curva de Phillips “Novo-Keynesiana”. Através deste estudo será possível avaliar a inflação passada e as expectativas de inflação como determinantes à inflação corrente e a aplicabilidade da curva de Phillips “Novo-Keynesiana” para o caso brasileiro. As conclusões do estudo darão uma indicação mais concreta do novo dinami...

  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. A GNR e o novo regime jurídico das armas e suas munições

    OpenAIRE

    Fernandes, Márcio

    2011-01-01

    O novo Regime Jurídico das Armas e suas Munições, aprovado pela Lei n.º5/2006, de 23 de Fevereiro, veio harmonizar todo o sistema jurídico relativo às armas de fogo, no intuito de reforçar o combate aos elevados índices de criminalidade que se vinham a registar em Portugal. Este novo regime permitiu controlar, de uma forma mais eficaz, a detenção, uso e porte de arma por parte dos cidadãos, combatendo a proliferação de armas ilegais e definiu um novo tipo de operaç...

  14. 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.

  15. A USABILIDADE DE UM AMBIENTE VIRTUAL DE APRENDIZAGEM: UM ESTUDO SOBRE O MOODLE NO IFRN – CAMPUS CURRAIS NOVOS

    Directory of Open Access Journals (Sweden)

    Giovana Silva Santos

    2015-12-01

    Full Text Available O Moodle, ambiente virtual de aprendizagem derivado do conceito de e-Learning, foi implantado em diversas instituições de ensino, aumentando assim a oferta de cursos de ensino a distância consideravelmente na última década, bem como as instituições que atuam com essa metodologia. Destaca-se na modalidade de educação a distância, a importância da estrutura fornecida pela instituição aos alunos que deve permear por características baseadas numa usabilidade adequada, pois é através da interface que o usuário/aluno percebe, vê e busca as informações. Nessa perspectiva, o presente estudo buscou identificar as características referentes à usabilidade do moodle no IFRN – Campus Currais Novos. A pesquisa, feita no período de dezembro de 2014 a janeiro de 2015, de caráter descritivo e de campo foi realizada com 153 alunos (com 86 respostas válidas do curso técnico em Segurança do Trabalho através da aplicação de questionário em que os dados foram coletados e em seguida analisados. Os resultados revelaram que a maior parte dos alunos pesquisados está satisfeita com o moodle, porém, uma parcela considerável dos alunos se mostraram descontentes com o mesmo, explicitando, em sua maioria, que o design precisa ser melhorado. Por fim, os resultados apresentados se limitam a uma realidade específica de um ambiente virtual, de um curso e uma instituição, não podendo ser generalizado para outras instituições, cursos ou ambientes virtuais.

  16. De novo assembly and characterization of the transcriptome, and development of SSR markers in wax gourd (Benicasa hispida.

    Directory of Open Access Journals (Sweden)

    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.

  17. De novo assembly, gene annotation, and marker discovery in stored-product pest Liposcelis entomophila (Enderlein using transcriptome sequences.

    Directory of Open Access Journals (Sweden)

    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

  18. De novo assembly and characterization of the global transcriptome for Rhyacionia leptotubula using Illumina paired-end sequencing.

    Directory of Open Access Journals (Sweden)

    Jia-Ying Zhu

    Full Text Available BACKGROUND: The pine tip moth, Rhyacionia leptotubula (Lepidoptera: Tortricidae is one of the most destructive forestry pests in Yunnan Province, China. Despite its importance, less is known regarding all aspects of this pest. Understanding the genetic information of it is essential for exploring the specific traits at the molecular level. Thus, we here sequenced the transcriptome of R. leptotubula with high-throughput Illumina sequencing. METHODOLOGY/PRINCIPAL FINDINGS: In a single run, more than 60 million sequencing reads were generated. De novo assembling was performed to generate a collection of 46,910 unigenes with mean length of 642 bp. Based on Blastx search with an E-value cut-off of 10(-5, 22,581 unigenes showed significant similarities to known proteins from National Center for Biotechnology Information (NCBI non-redundant (Nr protein database. Of these annotated unigenes, 10,360, 6,937 and 13,894 were assigned to Gene Ontology (GO, Clusters of Orthologous Group (COG, and Kyoto Encyclopedia of Genes and Genomes (KEGG databases, respectively. A total of 5,926 unigenes were annotated with domain similarity derived functional information, of which 55 and 39 unigenes respectively encoding the insecticide resistance related enzymes, cytochrome P450 and carboxylesterase. Using the transcriptome data, 47 unigenes belonging to the typical "stress" genes of heat shock protein (Hsp family were retrieved. Furthermore, 1,450 simple sequence repeats (SSRs were detected; 3.09% of the unigenes contained SSRs. Large numbers of SSR primer pairs were designed and out of randomly verified primer pairs 80% were successfully yielded amplicons. CONCLUSIONS/SIGNIFICANCE: A large of putative R. leptotubula transcript sequences has been obtained from the deep sequencing, which extensively increases the comprehensive and integrated genomic resources of this pest. This large-scale transcriptome dataset will be an important information platform for promoting our

  19. Prevention of de novo hepatitis B infection from HbcAb-positive donors in living donor liver transplantation.

    Science.gov (United States)

    Lee, K W; Lee, D S; Lee, H H; Kim, S J; Joh, J W; Seo, J M; Choe, Y H; Lee, S K

    2004-10-01

    Hepatitis B virus (HBV) prophylaxis is necessary to prevent de novo hepatitis B infection from HbcAb-positive donors. However, which protocol is more effective is somewhat controversial. Also, it is uncertain whether it is necessary to administer HBV prophylaxis for HbsAb-positive recipients. This study attempted to determine whether it is necessary to administer HBV prophylaxis for HbsAb-positive patients and to evaluate the efficacy of an HBIG monotherapy protocol. From May 1996 to July 2001, among 128 donors examined for HbcAb, 58 donors (45.3%) were HbcAb-positive. Eighteen HbcAb-positive grafts were transplanted to HbsAg-negative recipients. The 4 patients who died of unrelated causes were excluded from this study. Of 14 study cases, 12 recipients were HbsAb-positive, and 2 were HbsAb-naive. Prior to late 1998, we used HBV vaccination only for de novo infection prophylaxis. However, starting from December 1998, HBIG was administered from the time of the liver transplantation regardless of HBsAb positivity. The overall rate of de novo HBV infections from HbcAb-positive donors was 21.4% (3 of 14). All 3 recipients without HBIG prophylaxis presented with de novo HBV infections. Two were HbsAb-positive preoperatively. No de novo HBV infections occurred among recipients with HBIG prophylaxis. Therefore, it is essential to administer HBV prophylaxis even for vaccinated HbsAb-positive patients. HBIG monotherapy is effective to prevent de novo hepatitis B infections from HbcAb-positive donors in living donor liver transplantation.

  20. The Goddard and Saturn Genes Are Essential for Drosophila Male Fertility and May Have Arisen De Novo.

    Science.gov (United States)

    Gubala, Anna M; Schmitz, Jonathan F; Kearns, Michael J; Vinh, Tery T; Bornberg-Bauer, Erich; Wolfner, Mariana F; Findlay, Geoffrey D

    2017-05-01

    New genes arise through a variety of mechanisms, including the duplication of existing genes and the de novo birth of genes from noncoding DNA sequences. While there are numerous examples of duplicated genes with important functional roles, the functions of de novo genes remain largely unexplored. Many newly evolved genes are expressed in the male reproductive tract, suggesting that these evolutionary innovations may provide advantages to males experiencing sexual selection. Using testis-specific RNA interference, we screened 11 putative de novo genes in Drosophila melanogaster for effects on male fertility and identified two, goddard and saturn, that are essential for spermatogenesis and sperm function. Goddard knockdown (KD) males fail to produce mature sperm, while saturn KD males produce few sperm, and these function inefficiently once transferred to females. Consistent with a de novo origin, both genes are identifiable only in Drosophila and are predicted to encode proteins with no sequence similarity to any annotated protein. However, since high levels of divergence prevented the unambiguous identification of the noncoding sequences from which each gene arose, we consider goddard and saturn to be putative de novo genes. Within Drosophila, both genes have been lost in certain lineages, but show conserved, male-specific patterns of expression in the species in which they are found. Goddard is consistently found in single-copy and evolves under purifying selection. In contrast, saturn has diversified through gene duplication and positive selection. These data suggest that de novo genes can acquire essential roles in male reproduction. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. 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

  2. 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)

  3. 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...

  4. A Swedish family with de novo alpha-synuclein A53T mutation: evidence for early cortical dysfunction

    DEFF Research Database (Denmark)

    Puschmann, Andreas; Ross, Owen A; Vilariño-Güell, Carles

    2009-01-01

    A de novo alpha-synuclein A53T (p.Ala53 Th; c.209G > A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria, and cog......A de novo alpha-synuclein A53T (p.Ala53 Th; c.209G > A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria...

  5. De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities

    DEFF Research Database (Denmark)

    Martin, Sonja; Chamberlin, Adam; Shinde, Deepali N

    2017-01-01

    Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses...... information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior...

  6. 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...

  7. 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

    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...... and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706). We identified monogenic variants in single case reports and smaller studies (≤200 subjects) and variants considered to increase susceptibility of disease in 3 larger...

  8. 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.

  9. Detrimental roles of TNF-alpha in the antiphospholipid syndrome and de novo synthesis of antiphospholipid antibodies induced by biopharmaceuticals against TNF-alpha.

    Science.gov (United States)

    Bećarević, Mirjana

    2017-11-01

    Antiphospholipid syndrome (APS) is an autoimmune disease that is characterized by arterial and/or venous thrombosis and/or recurrent pregnancy losses. Obstetric APS (OAPS) is considered as a distinct entity from vascular APS (VAPS). In the absence of any additional disease, APS is designated as primary (PAPS), while the term secondary APS (SAPS) is used when other diseases are associated. Catastrophic APS (CAPS) is characterized by the rapid development of multiple thrombosis in various vital organs. The presence of antiphospholipid antibodies (aPL Abs) is considered as a laboratory criterion for APS diagnosis. aPL Abs cause an increase in systemic and decidual TNF-alpha levels in experimental model of APS (eAPS), while paradoxically, administration of TNF-alpha blockers has been associated with de novo synthesis of aPL Abs in patients with various autoimmune diseases. While eAPS provides evidence for the fact that application of TNF-alpha blockers has beneficial effects, lack of randomized prospective studies is the main obstacle for consideration of TNF-alpha blockers administration as a therapeutic option not for all, but at least for selected cases of APS patients despite compelling evidence for detrimental roles of TNF-alpha for both VASP and OAPS. This article represents a review of previously published reports on detrimental roles of TNF-alpha in APS, reports on the application of anti-TNF-alpha agents in eAPS and articles that reported de novo synthesis of aPL Abs induced by biopharmaceuticals against TNF-alpha.

  10. 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...

  11. Anchored design of protein-protein interfaces.

    Directory of Open Access Journals (Sweden)

    Steven M Lewis

    Full Text Available Few existing protein-protein interface design methods allow for extensive backbone rearrangements during the design process. There is also a dichotomy between redesign methods, which take advantage of the native interface, and de novo methods, which produce novel binders.Here, we propose a new method for designing novel protein reagents that combines advantages of redesign and de novo methods and allows for extensive backbone motion. This method requires a bound structure of a target and one of its natural binding partners. A key interaction in this interface, the anchor, is computationally grafted out of the partner and into a surface loop on the design scaffold. The design scaffold's surface is then redesigned with backbone flexibility to create a new binding partner for the target. Careful choice of a scaffold will bring experimentally desirable characteristics into the new complex. The use of an anchor both expedites the design process and ensures that binding proceeds against a known location on the target. The use of surface loops on the scaffold allows for flexible-backbone redesign to properly search conformational space.This protocol was implemented within the Rosetta3 software suite. To demonstrate and evaluate this protocol, we have developed a benchmarking set of structures from the PDB with loop-mediated interfaces. This protocol can recover the correct loop-mediated interface in 15 out of 16 tested structures, using only a single residue as an anchor.

  12. Fact or fiction: updates on how protein-coding genes might emerge de novo from previously non-coding DNA [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Jonathan F Schmitz

    2017-01-01

    Full Text Available Over the last few years, there has been an increasing amount of evidence for the de novo emergence of protein-coding genes, i.e. out of non-coding DNA. Here, we review the current literature and summarize the state of the field. We focus specifically on open questions and challenges in the study of de novo protein-coding genes such as the identification and verification of de novo-emerged genes. The greatest obstacle to date is the lack of high-quality genomic data with very short divergence times which could help precisely pin down the location of origin of a de novo gene. We conclude that, while there is plenty of evidence from a genetics perspective, there is a lack of functional studies of bona fide de novo genes and almost no knowledge about protein structures and how they come about during the emergence of de novo protein-coding genes. We suggest that future studies should concentrate on the functional and structural characterization of de novo protein-coding genes as well as the detailed study of the emergence of functional de novo protein-coding genes.

  13. 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

  14. 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

  15. De novo transcriptome sequencing in Anopheles funestus using Illumina RNA-seq technology.

    Directory of Open Access Journals (Sweden)

    Jacob E Crawford

    Full Text Available BACKGROUND: Anopheles funestus is one of the primary vectors of human malaria, which causes a million deaths each year in sub-Saharan Africa. Few scientific resources are available to facilitate studies of this mosquito species and relatively little is known about its basic biology and evolution, making development and implementation of novel disease control efforts more difficult. The An. funestus genome has not been sequenced, so in order to facilitate genome-scale experimental biology, we have sequenced the adult female transcriptome of An. funestus from a newly founded colony in Burkina Faso, West Africa, using the Illumina GAIIx next generation sequencing platform. METHODOLOGY/PRINCIPAL FINDINGS: We assembled short Illumina reads de novo using a novel approach involving iterative de novo assemblies and "target-based" contig clustering. We then selected a conservative set of 15,527 contigs through comparisons to four Dipteran transcriptomes as well as multiple functional and conserved protein domain databases. Comparison to the Anopheles gambiae immune system identified 339 contigs as putative immune genes, thus identifying a large portion of the immune system that can form the basis for subsequent studies of this important malaria vector. We identified 5,434 1:1 orthologues between An. funestus and An. gambiae and found that among these 1:1 orthologues, the protein sequence of those with putative immune function were significantly more diverged than the transcriptome as a whole. Short read alignments to the contig set revealed almost 367,000 genetic polymorphisms segregating in the An. funestus colony and demonstrated the utility of the assembled transcriptome for use in RNA-seq based measurements of gene expression. CONCLUSIONS/SIGNIFICANCE: We developed a pipeline that makes de novo transcriptome sequencing possible in virtually any organism at a very reasonable cost ($6,300 in sequencing costs in our case. We anticipate that our approach

  16. Método de decisão dos processos de prototipagem rápida na concepção de novos produtos

    Directory of Open Access Journals (Sweden)

    Osiris Canciglieri Junior

    2015-06-01

    Full Text Available A tecnologia de prototipagem de produtos por adição de material (Rapid Prototyping e por remoção de material (Subtractive Rapid Prototyping pode variar em: qualidade, tempo e custos, dependendo das características do produto. A escolha da tecnologia muitas vezes está condicionada à decisão empírica do designer/engenheiro ou operador, devido ao tipo de material, dimensão e precisão. Este artigo apresenta um método para tomada de decisão que auxilia a escolha da tecnologia de prototipagem rápida mais adequada na concepção de novos produtos. Foram utilizados os conceitos de DFM (Design for Manufacturing, CAD (Computer Aided Design, RPD (Rapid Product Development e MAUT (Multiattribute Utility em dois produtos de diferente estrutura e material (composto leve e simples maciço para avaliar e validar o método proposto. Os resultados apresentam comparações entre as tecnologias de prototipagem rápida a partir de critérios para tomada de decisão, aperfeiçoando a concepção de protótipos mais eficientes.

  17. Designing Communication Design

    DEFF Research Database (Denmark)

    Løvlie, Anders Sundnes

    2016-01-01

    Innovating in the field of new media genres requires methods for producing designs that can succeed in being disseminated and used outside of design research labs. This article uses the author's experiences with the development of university courses in communication design to address the research...... question: How can we design courses to give students the competencies they need to work as designers of new media? Based on existing approaches from UX design and other fields, I present a model that has demonstrated its usefulness in the development of commercial products and services. The model...

  18. 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.

  19. Converting cell fates: generating hematopoietic stem cells de novo via transcription factor reprogramming.

    Science.gov (United States)

    Daniel, Michael G; Lemischka, Ihor R; Moore, Kateri

    2016-04-01

    Even though all paradigms of stem cell therapy and regenerative medicine emerged from the study of hematopoietic stem cells (HSCs), the inability to generate these cells de novo or expand them in vitro persists. Initial efforts to obtain these cells began with the use of embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technologies, but these strategies have yet to yield fully functional cells. Subsequently, more recent approaches involve transcription factor (TF) overexpression to reprogram PSCs and various somatic cells. The induction of pluripotency with just four TFs by Yamanaka informs our ability to convert cell fates and demonstrates the feasibility of utilizing terminally differentiated cells to generate cells with multilineage potential. In this review, we discuss the recent efforts undertaken using TF-based reprogramming strategies to convert several cell types into HSCs. © 2016 New York Academy of Sciences.

  20. 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.

  1. Novos anti-histamínicos: uma visão crítica

    OpenAIRE

    Camelo-Nunes,Inês Cristina

    2006-01-01

    OBJETIVO: Avaliar criticamente os mais novos anti-histamínicos anti-H1 e os diferentes termos utilizados para denominá-los, com base na revisão de evidências sobre o papel dos anti-H1 no tratamento das doenças alérgicas. FONTES DOS DADOS: Artigos originais, revisões e consensos indexados nos bancos de dados MEDLINE e PUBMED de 1998 a 2006. Palavra chave: anti-histamínicos. SÍNTESE DOS DADOS: Os anti-histamínicos de segunda geração diferenciam-se dos de primeira geração por sua elevada especif...

  2. Histamina, receptores de histamina e anti-histamínicos: novos conceitos

    OpenAIRE

    Criado,Paulo Ricardo; Criado,Roberta Fachini Jardim; Maruta,Celina W.; Machado Filho,Carlos d'Apparecida

    2010-01-01

    As drogas com ação anti-histamínica estão entre as medicações mais comumente prescritas na prática dermatológica diária, tanto em adultos como em crianças. Este artigo aborda os novos conceitos da função dos receptores de histamina (receptores H1) e discute os efeitos anti-inflamatórios dessas drogas. A segunda geração de anti-histamínicos difere da primeira geração devido a sua elevada especificidade e afinidade pelos receptores H1 periféricos e devido a seu menor efeito no sistema nervoso c...

  3. 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.

  4. 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

    2010-01-21

    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.

  5. 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

    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...... exhibiting a ductal carcinoma at the age of 40. METHODS: Variations were identified by denaturing high performance liquid chromatography (dHPLC) and sequencing of the BRCA1 and BRCA2 genes. The effect of the mutation on splicing was examined by exon trapping in COS-7 cells and by RT-PCR on RNA isolated from...... leucocytes and carcinoma tissue. RESULTS: A novel BRCA2 variant in the splice donor site of exon 21 (nucleotide 8982+1 G-->A/c.8754+1 G-->A) was identified. Exon trapping showed that the mutation activates a cryptic splice site 46 base pairs 3' of exon 21, resulting in the inclusion of a premature stop codon...

  6. A dynamic programming approach to de novo peptide sequencing via tandem mass spectrometry.

    Science.gov (United States)

    Chen, T; Kao, M Y; Tepel, M; Rush, J; Church, G M

    2001-01-01

    Tandem mass spectrometry fragments a large number of molecules of the same peptide sequence into charged molecules of prefix and suffix peptide subsequences and then measures mass/charge ratios of these ions. The de novo peptide sequencing problem is to reconstruct the peptide sequence from a given tandem mass spectral data of k ions. By implicitly transforming the spectral data into an NC-spectrum graph G (V, E) where /V/ = 2k + 2, we can solve this problem in O(/V//E/) time and O(/V/2) space using dynamic programming. For an ideal noise-free spectrum with only b- and y-ions, we improve the algorithm to O(/V/ + /E/) time and O(/V/) space. Our approach can be further used to discover a modified amino acid in O(/V//E/) time. The algorithms have been implemented and tested on experimental data.

  7. Biodisponibilidade e atividade antineoplasica de um novo modificador da resposta biologica

    OpenAIRE

    Giselle Zenker Justo

    1996-01-01

    Resumo:Os efeitos do composto MAPA, um agregado protêico de fosfolinoleato-palmitoleato de amônio e magnésio foram estudados, in vivo, com o objetivo de investigar parte do seu mecanismo de ação. O estudo foi dividido em duas etapas, ambas consideradas pré-clínicas como convém à descrição de novos fármacos sob investigação. Numa primeira etapa foi estudada a biodisponibilidade do composto em ratos Wistar tratados com dose única de 750 mg/Kg de MAPA intraperitoneal (IP), através da variação do...

  8. De Novo transcriptome assembly of Zingiber officinale cv. Suruchi of Odisha

    Directory of Open Access Journals (Sweden)

    Mahendra Gaur

    2016-09-01

    Full Text Available 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.

  9. De Novo Mutation in ABCC9 Causes Hypertrichosis Acromegaloid Facial Features Disorder.

    Science.gov (United States)

    Afifi, Hanan H; Abdel-Hamid, Mohamed S; Eid, Maha M; Mostafa, Inas S; Abdel-Salam, Ghada M H

    2016-01-01

    A 13-year-old Egyptian girl with generalized hypertrichosis, gingival hyperplasia, coarse facial appearance, no cardiovascular or skeletal anomalies, keloid formation, and multiple labial frenula was referred to our clinic for counseling. Molecular analysis of the ABCC9 gene showed a de novo missense mutation located in exon 27, which has been described previously with Cantu syndrome. An overlap between Cantu syndrome, acromegaloid facial syndrome, and hypertrichosis acromegaloid facial features disorder is apparent at the phenotypic and molecular levels. The patient reported here gives further evidence that these syndromes are an expression of the ABCC9-related disorders, ranging from hypertrichosis and acromegaloid facies to the severe end of Cantu syndrome. © 2016 Wiley Periodicals, Inc.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

    associated with failure of tissue healing. Secondary endpoint was total number of events involving surgical intervention. RESULTS: There were no significant differences between the groups with regards to wound complications (EVE=20, CyA=12)(p=0.08) or total surgical events (EVE=38, CyA=34) (p=0.44). Age>54......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...... (CNI) avoidance (SCHEDULE). The aim of the study was to compare wound complications between EVE and CNI based regimen. MATERIALS AND METHODS: A total of 115 patients (mean age 51 ± 13 years, 73% men) were randomized within five days post-HTx to low dose EVE and reduced dose Cyclosporine (CyA) followed...

  16. Phenotype and clinical course in a family with a new de novo Twinkle gene mutation

    DEFF Research Database (Denmark)

    Jeppesen, Tina Dysgaard; Schwartz, M.; Colding-Jorgensen, E.

    2008-01-01

    The Twinkle gene product is important for mtDNA replication. Only a few reports have investigated the clinically effect of mutations in this gene. We describe a new de novo mutation (1110C > A) in the PEO1 gene in a mother and her two sons. The mother had progressive ophthalmoplegia, limb weakness......, sensory neuropathy, elevated resting plasma lactate, glucose intolerance and impaired VO2max while her sons only had mild ptosis. In accordance with the clinical presentation, abnormal morphological findings in muscle and multiple deletions and depletion of mtDNA in muscle were more pronounced...... in the proband than in her sons. (C) 2007 Elsevier B.V. All rights reserved Udgivelsesdato: 2008/4...

  17. Transformações no mundo laboral e novos desafios do sindicalismo português

    Directory of Open Access Journals (Sweden)

    Elísio Estanque

    2012-10-01

    Full Text Available O problema da transformação das relações laborais tem necessariamente de ser discutido à luz do actual contexto de globalização económica para que se compreendam as consequências deste processo para o movimento sindical e os novos desafios que este tem hoje pela frente. Como se sabe, a economia mundial assentou desde sempre em múltiplos desequilíbrios entre centros e periferias. Mas, hoje, os contrastes entre pólos de desenvolvimento e zonas de exclusão e de miséria não só assumem contornos ...

  18. 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.

  19. Annotation and Re-Sequencing of Genes from De Novo Transcriptome Assembly of Abies alba (Pinaceae

    Directory of Open Access Journals (Sweden)

    Anna M. Roschanski

    2013-01-01

    Full Text Available Premise of the study: We present a protocol for the annotation of transcriptome sequence data and the identification of candidate genes therein using the example of the nonmodel conifer Abies alba. Methods and Results: A normalized cDNA library was built from an A. alba seedling. The sequencing on a 454 platform yielded more than 1.5 million reads that were de novo assembled into 25 149 contigs. Two complementary approaches were applied to annotate gene fragments that code for (1 well-known proteins and (2 proteins that are potentially adaptively relevant. Primer development and testing yielded 88 amplicons that could successfully be resequenced from genomic DNA. Conclusions: The annotation workflow offers an efficient way to identify potential adaptively relevant genes from the large quantity of transcriptome sequence data. The primer set presented should be prioritized for single-nucleotide polymorphism detection in adaptively relevant genes in A. alba.

  20. Annotation and re-sequencing of genes from de novo transcriptome assembly of Abies alba (Pinaceae).

    Science.gov (United States)

    Roschanski, Anna M; Fady, Bruno; Ziegenhagen, Birgit; Liepelt, Sascha

    2013-01-01

    We present a protocol for the annotation of transcriptome sequence data and the identification of candidate genes therein using the example of the nonmodel conifer Abies alba. • A normalized cDNA library was built from an A. alba seedling. The sequencing on a 454 platform yielded more than 1.5 million reads that were de novo assembled into 25149 contigs. Two complementary approaches were applied to annotate gene fragments that code for (1) well-known proteins and (2) proteins that are potentially adaptively relevant. Primer development and testing yielded 88 amplicons that could successfully be resequenced from genomic DNA. • The annotation workflow offers an efficient way to identify potential adaptively relevant genes from the large quantity of transcriptome sequence data. The primer set presented should be prioritized for single-nucleotide polymorphism detection in adaptively relevant genes in A. alba.

  1. 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.

  2. Effects of dietary nutrient composition on de novo lipogenesis in gilthead sea bream (Sparus aurata)

    DEFF Research Database (Denmark)

    Ekmann, Kim Schøn

    rate of 18.7 to 123.7 mg/kg biomass/day, when feeding iso-DP and iso-DE diets ranging between 6 and 24% dietary starch, respectively. Additionally, up to 68.8% of the hepatic glycogen pool could be attributed to dietary starch, while the same was true for up to 38.8% of the whole body glycogen pool...... (using diets otherwise iso-DP and iso-DE). The apparent retention of saturated fatty acids (SAFA) and mono unsaturated fatty acids (MUFA) were positively related to dietary starch level (and negatively related to dietary lipid level), exceeding 100% in fish fed high starch diets. These findings...... substantiate that considerable de novo lipogenesis was taking place and apparently subject to nutritional control, while apparent retention of poly unsaturated fatty acids (PUFA) appeared to be un-affected by dietary treatment. Combined, this caused the SAFA and MUFA content of the fish to increase...

  3. 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

  4. 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.

  5. Recommendations for the use of everolimus in de novo kidney transplantation: False beliefs, myths and realities.

    Science.gov (United States)

    Pascual, Julio; Diekmann, Fritz; Fernández-Rivera, Constantino; Gómez-Marqués, Gonzalo; Gutiérrez-Dalmau, Alex; Pérez-Sáez, María José; Sancho-Calabuig, Asunción; Oppenheimer, Federico

    The immunosuppressive combination most commonly used in de novo kidney transplantation comprises a calcineurin inhibitor (CI), tacrolimus, a mycophenolic acid derivative and steroids. The evidence which underlies this practice is based in the Symphony trial with controlled follow-up of one year, in which no comparator group included the combination CI-mTOR inhibitor. Different high-quality clinical trials support the use of everolimus as a standard immunosuppressive drug associated with reduced exposure of a CI in kidney transplantation. This combination could improve health related outcomes in kidney transplantation recipients. The present recommendations constitute an attempt to summarise the scientific evidence supporting this practice, discuss false beliefs, myths and facts, and offer specific guidelines for safe use, avoiding complications. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  6. 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...

  7. 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.

  8. 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.

  9. [Men of the sugarcane fields and their hospitals: the architecture of health under the Estado Novo].

    Science.gov (United States)

    Monteiro, Marcia Rocha

    2011-12-01

    The article explores the emergence of an architectural heritage in the realm of healthcare assistance for workers in the sugarcane agroindustry in Brazil following enactment of the law known as the Estatuto da Lavoura Canavieira (1941), under the auspices of the Instituto do Açúcar e do Álcool and as part of Estado Novo policies (1937-1945). The institute proposed solutions based on surveys conducted at sugarcane mills in cane-producing states and on the medical and hospital system adopted by the institute's enlightened bureaucracy in the 1940s, which took the U.S. system as its model. Special focus is given to the central hospitals in Pernambuco and especially in Alagoas, which opposed institute guidelines.

  10. 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.

  11. 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

  12. 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...

  13. De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Motley, William W; Palaima, Paulius; Yum, Sabrina W; Gonzalez, Michael A; Tao, Feifei; Wanschitz, Julia V; Strickland, Alleene V; Löscher, Wolfgang N; De Vriendt, Els; Koppi, Stefan; Medne, Livija; Janecke, Andreas R; Jordanova, Albena; Zuchner, Stephan; Scherer, Steven S

    2016-06-01

    We performed whole exome sequencing on a patient with Charcot-Marie-Tooth disease type 1 and identified a de novo mutation in PMP2, the gene that encodes the myelin P2 protein. This mutation (p.Ile52Thr) was passed from the proband to his one affected son, and segregates with clinical and electrophysiological evidence of demyelinating neuropathy. We then screened a cohort of 136 European probands with uncharacterized genetic cause of Charcot-Marie-Tooth disease and identified another family with Charcot-Marie-Tooth disease type 1 that has a mutation affecting an adjacent amino acid (p.Thr51Pro), which segregates with disease. Our genetic and clinical findings in these kindred demonstrate that dominant PMP2 mutations cause Charcot-Marie-Tooth disease type 1. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. 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.

  15. 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.

  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. Symmetry-Directed Self-Assembly of a Tetrahedral Protein Cage Mediated by de Novo-Designed Coiled Coils.

    Science.gov (United States)

    Badieyan, Somayesadat; Sciore, Aaron; Eschweiler, Joseph D; Koldewey, Philipp; Cristie-David, Ajitha S; Ruotolo, Brandon T; Bardwell, James C A; Su, Min; Marsh, E Neil G

    2017-10-05

    The organization of proteins into new hierarchical forms is an important challenge in synthetic biology. However, engineering new interactions between protein subunits is technically challenging and typically requires extensive redesign of protein-protein interfaces. We have developed a conceptually simple approach, based on symmetry principles, that uses short coiled-coil domains to assemble proteins into higher-order structures. Here, we demonstrate the assembly of a trimeric enzyme into a well-defined tetrahedral cage. This was achieved by genetically fusing a trimeric coiled-coil domain to its C terminus through a flexible polyglycine linker sequence. The linker length and coiled-coil strength were the only parameters that needed to be optimized to obtain a high yield of correctly assembled protein cages. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. A novel de novo 2.5 Mb microdeletion of 7q22.1 harbours candidate ...

    Indian Academy of Sciences (India)

    on a de novo 7q22.1 hemizygous microdeletion, 2.5 Mb in size, detected in our patient. Clinical report. An 8 year-old girl was referred for neurobehavioural dis- orders, moderate dysmorphic features, obesity and develop- mental delay evident since birth. She was the third child born to healthy nonconsanguineous parents.

  19. De novo assembly and characterization of the carrot transcriptome reveals novel genes, new markers, and genetic diversity

    Science.gov (United States)

    Among next generation sequence technologies, platforms such as Illumina and SOLiD produce short reads but with higher coverage and lower cost per sequenced nucleotide than 454 or Sanger. A challenge now is to develop efficient strategies to use short-read length platforms for de novo assembly and ma...

  20. 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