WorldWideScience

Sample records for serial protein misfolding

  1. Protein Misfolding and Human Disease

    DEFF Research Database (Denmark)

    Gregersen, Niels; Bross, Peter Gerd; Vang, Søren

    2006-01-01

    phenylketonuria, Parkinson's disease, α-1-antitrypsin deficiency, familial neurohypophyseal diabetes insipidus, and short-chain acyl-CoA dehydrogenase deficiency. Despite the differences, an emerging paradigm suggests that the cellular effects of protein misfolding provide a common framework that may contribute...

  2. Mechanisms of protein misfolding: Novel therapeutic approaches to protein-misfolding diseases

    Science.gov (United States)

    Salahuddin, Parveen; Siddiqi, Mohammad Khursheed; Khan, Sanaullah; Abdelhameed, Ali Saber; Khan, Rizwan Hasan

    2016-11-01

    In protein misfolding, protein molecule acquires wrong tertiary structure, thereby induces protein misfolding diseases. Protein misfolding can occur through various mechanisms. For instance, changes in environmental conditions, oxidative stress, dominant negative mutations, error in post-translational modifications, increase in degradation rate and trafficking error. All of these factors cause protein misfolding thereby leading to diseases conditions. Both in vitro and in vivo observations suggest that partially unfolded or misfolded intermediates are particularly prone to aggregation. These partially misfolded intermediates aggregate via the interaction with the complementary intermediates and consequently enhance oligomers formation that grows into fibrils and proto-fibrils. The amyloid fibrils for example, accumulate in the brain and central nervous system (CNS) as amyloid deposits in the Parkinson's disease (PD), Alzheimer's disease (AD), Prion disease and Amylo lateral Sclerosis (ALS). Furthermore, tau protein shows intrinsically disorder conformation; therefore its interaction with microtubule is impaired and this protein undergoes aggregation. This is also underlying cause of Alzheimers and other neurodegenerative diseases. Treatment of such misfolding maladies is considered as one of the most important challenges of the 21st century. Currently, several treatments strategies have been and are being discovered. These therapeutic interventions partly reversed or prevented the pathological state. More recently, a new approach was discovered, which employs nanobodies that targets multisteps in fibril formation pathway that may possibly completely cure these misfolding diseases. Keeping the above views in mind in the current review, we have comprehensively discussed the different mechanisms underlying protein misfolding thereby leading to diseases conditions and their therapeutic interventions.

  3. Mechanisms of protein misfolding: Novel therapeutic approaches to protein-misfolding diseases

    DEFF Research Database (Denmark)

    Salahuddin, Parveen; Siddiqi, Mohammad Khursheed; Khan, Sanaullah

    2016-01-01

    ’s disease (PD), Alzheimer’s disease (AD), Prion disease and Amylo lateral Sclerosis (ALS). Furthermore, tau protein shows intrinsically disorder conformation; therefore its interaction with microtubule is impaired and this protein undergoes aggregation. This is also underlying cause of Alzheimers and other......In protein misfolding, protein molecule acquires wrong tertiary structure, thereby induces protein misfolding diseases. Protein misfolding can occur through various mechanisms. For instance, changes in environmental conditions, oxidative stress, dominant negative mutations, error in post......-translational modifications, increase in degradation rate and trafficking error. All of these factors cause protein misfolding thereby leading to diseases conditions. Both in vitro and in vivo observations suggest that partially unfolded or misfolded intermediates are particularly prone to aggregation. These partially...

  4. Markov state models of protein misfolding

    Science.gov (United States)

    Sirur, Anshul; De Sancho, David; Best, Robert B.

    2016-02-01

    Markov state models (MSMs) are an extremely useful tool for understanding the conformational dynamics of macromolecules and for analyzing MD simulations in a quantitative fashion. They have been extensively used for peptide and protein folding, for small molecule binding, and for the study of native ensemble dynamics. Here, we adapt the MSM methodology to gain insight into the dynamics of misfolded states. To overcome possible flaws in root-mean-square deviation (RMSD)-based metrics, we introduce a novel discretization approach, based on coarse-grained contact maps. In addition, we extend the MSM methodology to include "sink" states in order to account for the irreversibility (on simulation time scales) of processes like protein misfolding. We apply this method to analyze the mechanism of misfolding of tandem repeats of titin domains, and how it is influenced by confinement in a chaperonin-like cavity.

  5. Protein misfolding disorders: pathogenesis and intervention

    DEFF Research Database (Denmark)

    Gregersen, Niels

    2006-01-01

    of the functional structure of cellular proteins. Aberrant proteins, the result of production errors, inherited or acquired amino acid substitutions or damage, especially oxidative modifications, can in many cases not fold correctly and will be trapped in misfolded conformations. To rid the cell of misfolded...... be accompanied by a gain-of-function pathogenesis, which in many cases determines the pathological and clinical features. Examples are Parkinson and Huntington diseases. Although a number of strategies have been tried to decrease the amounts of accumulated and aggregated proteins, a likely future strategy seems......Newly synthesized proteins in the living cell must go through a folding process to attain their functional structure. To achieve this in an efficient fashion, all organisms, including humans, have evolved a large set of molecular chaperones that assist the folding as well as the maintenance...

  6. Protein Misfolding Cyclic Amplification of Infectious Prions.

    Science.gov (United States)

    Moda, Fabio

    2017-01-01

    Transmissible spongiform encephalopathies, or prion diseases, are a group of incurable disorders caused by the accumulation of an abnormally folded prion protein (PrP Sc ) in the brain. According to the "protein-only" hypothesis, PrP Sc is the infectious agent able to propagate the disease by acting as a template for the conversion of the correctly folded prion protein (PrP C ) into the pathological isoform. Recently, the mechanism of PrP C conversion has been mimicked in vitro using an innovative technique named protein misfolding cyclic amplification (PMCA). This technology represents a great tool for studying diverse aspects of prion biology in the field of basic research and diagnosis. Moreover, PMCA can be expanded for the study of the misfolding process associated to other neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and frontotemporal lobar degeneration. © 2017 Elsevier Inc. All rights reserved.

  7. Protein misfolding and obstructive lung disease.

    LENUS (Irish Health Repository)

    Greene, Catherine M

    2010-11-01

    The endoplasmic reticulum has evolved a number of mechanisms to manage the accumulation of incorrectly folded proteins. This results in loss of function of these proteins, but occasionally, in conditions such as α-1 antitrpysin (A1AT) deficiency, the misfolded protein can acquire a toxic gain of function promoting exaggerated ER stress responses and inflammation. Mutations leading to deficiency in a second serine proteinase inhibitor, α-1 antichymotrpysin (ACT), can induce potentially similar consequences. A1AT and ACT deficiencies are associated with chronic obstructive lung disease. Until recently, it was thought that the lung diseases associated with these conditions were entirely due to loss of antiprotease protection in the lung (i.e., loss of function), whereas gain of function was the major cause of the liver disease associated with A1AT deficiency. This paradigm is being increasingly challenged because ER stress is being recognized in bronchial epithelial cells and inflammatory cells normally resident in the lung, giving rise to an inflammatory phenotype that adds to the proteolytic burden associated with these conditions. In this article, we describe the cellular mechanisms that are activated to cope with an increasing burden of misfolded proteins within the ER in A1AT and ACT deficiency, show how these events are linked to inflammation, and outline the therapeutic strategies that can potentially interfere with production of misfolded proteins.

  8. Experimental investigation of protein folding and misfolding.

    Science.gov (United States)

    Dobson, Christopher M

    2004-09-01

    Newly synthesised proteins need to fold, often to intricate and close-packed structures, in order to function. The underlying mechanism by which this complex process takes place both in vitro and in vivo is now becoming understood, at least in general terms, as a result of the application of a wide range of biophysical and computational methods used in combination with the techniques of biochemistry and protein engineering. It is increasingly apparent, however, that folding is not only crucial for generating biological activity, but that it is also coupled to a wide range of processes within the cell, ranging from the trafficking of proteins to specific organelles to the regulation of cell growth and differentiation. Not surprisingly, therefore, the failure of proteins to fold appropriately, or to remain correctly folded, is associated with a large number of cellular malfunctions that give rise to disease. Misfolding, and its consequences such as aggregation, can be investigated by extending the types of techniques used to study the normal folding process. Application of these techniques is enabling the development of a unified description of the interconversion and regulation of the different conformational states available to proteins in living systems. Such a description proves a generic basis for understanding the fundamental links between protein misfolding and its associated clinical disorders, such as Alzheimer's disease and Type II diabetes, and for exploring novel therapeutic strategies directed at their prevention and treatment on a rational basis.

  9. Protein aggregation and misfolding: good or evil?

    Science.gov (United States)

    Pastore, Annalisa; Temussi, Pierandrea

    2012-06-01

    Protein aggregation and misfolding have important implications in an increasing number of fields ranging from medicine to biology to nanotechnology and material science. The interest in understanding this field has accordingly increased steadily over the last two decades. During this time the number of publications that have been dedicated to protein aggregation has increased exponentially, tackling the problem from several different and sometime contradictory perspectives. This review is meant to summarize some of the highlights that come from these studies and introduce this topical issue on the subject. The factors that make a protein aggregate and the cellular strategies that defend from aggregation are discussed together with the perspectives that the accumulated knowledge may open.

  10. Protein aggregation and misfolding: good or evil?

    International Nuclear Information System (INIS)

    Pastore, Annalisa; Temussi, Pierandrea

    2012-01-01

    Protein aggregation and misfolding have important implications in an increasing number of fields ranging from medicine to biology to nanotechnology and material science. The interest in understanding this field has accordingly increased steadily over the last two decades. During this time the number of publications that have been dedicated to protein aggregation has increased exponentially, tackling the problem from several different and sometime contradictory perspectives. This review is meant to summarize some of the highlights that come from these studies and introduce this topical issue on the subject. The factors that make a protein aggregate and the cellular strategies that defend from aggregation are discussed together with the perspectives that the accumulated knowledge may open. (topical review)

  11. Protein degradation and protection against misfolded or damaged proteins

    Science.gov (United States)

    Goldberg, Alfred L.

    2003-12-01

    The ultimate mechanism that cells use to ensure the quality of intracellular proteins is the selective destruction of misfolded or damaged polypeptides. In eukaryotic cells, the large ATP-dependent proteolytic machine, the 26S proteasome, prevents the accumulation of non-functional, potentially toxic proteins. This process is of particular importance in protecting cells against harsh conditions (for example, heat shock or oxidative stress) and in a variety of diseases (for example, cystic fibrosis and the major neurodegenerative diseases). A full understanding of the pathogenesis of the protein-folding diseases will require greater knowledge of how misfolded proteins are recognized and selectively degraded.

  12. Cellular proteostasis: degradation of misfolded proteins by lysosomes

    Science.gov (United States)

    Jackson, Matthew P.

    2016-01-01

    Proteostasis refers to the regulation of the cellular concentration, folding, interactions and localization of each of the proteins that comprise the proteome. One essential element of proteostasis is the disposal of misfolded proteins by the cellular pathways of protein degradation. Lysosomes are an important site for the degradation of misfolded proteins, which are trafficked to this organelle by the pathways of macroautophagy, chaperone-mediated autophagy and endocytosis. Conversely, amyloid diseases represent a failure in proteostasis, in which proteins misfold, forming amyloid deposits that are not degraded effectively by cells. Amyloid may then exacerbate this failure by disrupting autophagy and lysosomal proteolysis. However, targeting the pathways that regulate autophagy and the biogenesis of lysosomes may present approaches that can rescue cells from the deleterious effects of amyloidogenic proteins. PMID:27744333

  13. Mechanisms of protein misfolding in conformational lung diseases.

    LENUS (Irish Health Repository)

    McElvaney, N G

    2012-08-01

    Genetic or environmentally-induced alterations in protein structure interfere with the correct folding, assembly and trafficking of proteins. In the lung the expression of misfolded proteins can induce a variety of pathogenetic effects. Cystic fibrosis (CF) and alpha-1 antitrypsin (AAT) deficiency are two major clinically relevant pulmonary disorders associated with protein misfolding. Both are genetic diseases the primary causes of which are expression of mutant alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) and SERPINA1, respectively. The most common and best studied mutant forms of CFTR and AAT are ΔF508 CFTR and the Glu342Lys mutant of AAT called ZAAT, respectively. Non-genetic mechanisms can also damage protein structure and induce protein misfolding in the lung. Cigarette-smoke contains oxidants and other factors that can modify a protein\\'s structure, and is one of the most significant environmental causes of protein damage within the lung. Herein we describe the mechanisms controlling the folding of wild type and mutant versions of CFTR and AAT proteins, and explore the consequences of cigarette-smoke-induced effects on the protein folding machinery in the lung.

  14. Semiotic Selection of Mutated or Misfolded Receptor Proteins

    DEFF Research Database (Denmark)

    Giorgi, Franco; Bruni, Luis Emilio; Maggio, Roberto

    2013-01-01

    contention that the plasma membrane acts as the locus where several contextual cues may be integrated. As such it allows the semiotic selection of those receptor configurations that provide cells with the minimum essential requirements for agency. The occurrence of protein misfolding makes it impossible...... focused on the significance and semiotic nature of the interplay between membrane receptors and the epigenetic control of gene expression, as mediated by the control of mismatched repairing and protein folding mechanisms....

  15. Hemin as a generic and potent protein misfolding inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yanqin [School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005 (Australia); Carver, John A. [Discipline of Pharmacology, The University of Adelaide, Adelaide, SA 5005 (Australia); Ho, Lam H.; Elias, Abigail K. [School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005 (Australia); Musgrave, Ian F. [Research School of Chemistry, The Australian National University, Canberra, ACT 0200 (Australia); Pukala, Tara L., E-mail: tara.pukala@adelaide.edu.au [School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005 (Australia)

    2014-11-14

    Highlights: • Hemin prevents Aβ42, α-synuclein and RCM-κ-casein forming amyloid fibrils. • Hemin inhibits the β-sheet structure formation of Aβ42. • Hemin reduces the cell toxicity caused by fibrillar Aβ42. • Hemin dissociates partially formed Aβ42 fibrils. • Hemin prevents amorphous aggregation by ADH, catalase and γs-crystallin. - Abstract: Protein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer’s disease, Parkinson’s disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases.

  16. Frustration in the energy landscapes of multidomain protein misfolding.

    Science.gov (United States)

    Zheng, Weihua; Schafer, Nicholas P; Wolynes, Peter G

    2013-01-29

    Frustration from strong interdomain interactions can make misfolding a more severe problem in multidomain proteins than in single-domain proteins. On the basis of bioinformatic surveys, it has been suggested that lowering the sequence identity between neighboring domains is one of nature's solutions to the multidomain misfolding problem. We investigate folding of multidomain proteins using the associative-memory, water-mediated, structure and energy model (AWSEM), a predictive coarse-grained protein force field. We find that reducing sequence identity not only decreases the formation of domain-swapped contacts but also decreases the formation of strong self-recognition contacts between β-strands with high hydrophobic content. The ensembles of misfolded structures that result from forming these amyloid-like interactions are energetically disfavored compared with the native state, but entropically favored. Therefore, these ensembles are more stable than the native ensemble under denaturing conditions, such as high temperature. Domain-swapped contacts compete with self-recognition contacts in forming various trapped states, and point mutations can shift the balance between the two types of interaction. We predict that multidomain proteins that lack these specific strong interdomain interactions should fold reliably.

  17. Protein folding and misfolding shining light by infrared spectroscopy

    CERN Document Server

    Fabian, Heinz

    2012-01-01

    Infrared spectroscopy is a new and innovative technology to study protein folding/misfolding events in the broad arsenal of techniques conventionally used in this field. The progress in understanding protein folding and misfolding is primarily due to the development of biophysical methods which permit to probe conformational changes with high kinetic and structural resolution. The most commonly used approaches rely on rapid mixing methods to initiate the folding event via a sudden change in solvent conditions. Traditionally, techniques such as fluorescence, circular dichroism or visible absorption are applied to probe the process. In contrast to these techniques, infrared spectroscopy came into play only very recently, and the progress made in this field up to date which now permits to probe folding events over the time scale from picoseconds to minutes has not yet been discussed in a book. The aim of this book is to provide an overview of the developments as seen by some of the main contributors to the field...

  18. Molecular chaperones in targeting misfolded proteins for ubiquitin-dependent degradation

    DEFF Research Database (Denmark)

    Kriegenburg, Franziska; Ellgaard, Lars; Hartmann-Petersen, Rasmus

    2012-01-01

    The accumulation of misfolded proteins presents a considerable threat to the health of individual cells and has been linked to severe diseases, including neurodegenerative disorders. Considering that, in nature, cells often are exposed to stress conditions that may lead to aberrant protein...... conformational changes, it becomes clear that they must have an efficient quality control apparatus to refold or destroy misfolded proteins. In general, cells rely on molecular chaperones to seize and refold misfolded proteins. If the native state is unattainable, misfolded proteins are targeted for degradation...... via the ubiquitin-proteasome system. The specificity of this proteolysis is generally provided by E3 ubiquitin-protein ligases, hundreds of which are encoded in the human genome. However, rather than binding the misfolded proteins directly, most E3s depend on molecular chaperones to recognize...

  19. Protein misfolding specifies recruitment to cytoplasmic inclusion bodies.

    Science.gov (United States)

    Bersuker, Kirill; Brandeis, Michael; Kopito, Ron R

    2016-04-25

    Inclusion bodies (IBs) containing aggregated disease-associated proteins and polyubiquitin (poly-Ub) conjugates are universal histopathological features of neurodegenerative diseases. Ub has been proposed to target proteins to IBs for degradation via autophagy, but the mechanisms that govern recruitment of ubiquitylated proteins to IBs are not well understood. In this paper, we use conditionally destabilized reporters that undergo misfolding and ubiquitylation upon removal of a stabilizing ligand to examine the role of Ub conjugation in targeting proteins to IBs that are composed of an N-terminal fragment of mutant huntingtin, the causative protein of Huntington's disease. We show that reporters are excluded from IBs in the presence of the stabilizing ligand but are recruited to IBs after ligand washout. However, we find that Ub conjugation is not necessary to target reporters to IBs. We also report that forced Ub conjugation by the Ub fusion degradation pathway is not sufficient for recruitment to IBs. Finally, we find that reporters and Ub conjugates are stable at IBs. These data indicate that compromised folding states, rather than conjugation to Ub, can specify recruitment to IBs. © 2016 Bersuker et al.

  20. Strain-dependent profile of misfolded prion protein aggregates.

    Science.gov (United States)

    Morales, Rodrigo; Hu, Ping Ping; Duran-Aniotz, Claudia; Moda, Fabio; Diaz-Espinoza, Rodrigo; Chen, Baian; Bravo-Alegria, Javiera; Makarava, Natallia; Baskakov, Ilia V; Soto, Claudio

    2016-02-15

    Prions are composed of the misfolded prion protein (PrP(Sc)) organized in a variety of aggregates. An important question in the prion field has been to determine the identity of functional PrP(Sc) aggregates. In this study, we used equilibrium sedimentation in sucrose density gradients to separate PrP(Sc) aggregates from three hamster prion strains (Hyper, Drowsy, SSLOW) subjected to minimal manipulations. We show that PrP(Sc) aggregates distribute in a wide range of arrangements and the relative proportion of each species depends on the prion strain. We observed a direct correlation between the density of the predominant PrP(Sc) aggregates and the incubation periods for the strains studied. The relative presence of PrP(Sc) in fractions of different sucrose densities was indicative of the protein deposits present in the brain as analyzed by histology. Interestingly, no association was found between sensitivity to proteolytic degradation and aggregation profiles. Therefore, the organization of PrP molecules in terms of the density of aggregates generated may determine some of the particular strain properties, whereas others are independent from it. Our findings may contribute to understand the mechanisms of strain variation and the role of PrP(Sc) aggregates in prion-induced neurodegeneration.

  1. Physico-Pathologic Mechanisms Involved in Neurodegeneration: Misfolded Protein-Plasma Membrane Interactions.

    Science.gov (United States)

    Shrivastava, Amulya Nidhi; Aperia, Anita; Melki, Ronald; Triller, Antoine

    2017-07-05

    Several neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are characterized by prominent loss of synapses and neurons associated with the presence of abnormally structured or misfolded protein assemblies. Cell-to-cell transfer of misfolded proteins has been proposed for the intra-cerebral propagation of these diseases. When released, misfolded proteins diffuse in the 3D extracellular space before binding to the plasma membrane of neighboring cells, where they diffuse on a 2D plane. This reduction in diffusion dimension and the cell surface molecular crowding promote deleterious interactions with native membrane proteins, favoring clustering and further aggregation of misfolded protein assemblies. These processes open up new avenues for therapeutics development targeting the initial interactions of deleterious proteins with the plasma membrane or the subsequent pathological signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Highly efficient amplification of chronic wasting disease agent by protein misfolding cyclical amplification with beads (PMCAb)

    Science.gov (United States)

    Johnson, Chad J.; Aiken, Judd M.; McKenzie, Debbie; Samuel, Michael D.; Pedersen, Joel A.

    2012-01-01

    Protein misfolding cyclic amplification (PMCA) has emerged as an important technique for detecting low levels of pathogenic prion protein in biological samples. The method exploits the ability of the pathogenic prion protein to convert the normal prion protein to a proteinase K-resistant conformation. Inclusion of Teflon® beads in the PMCA reaction (PMCAb) has been previously shown to increase the sensitivity and robustness of detection for the 263 K and SSLOW strains of hamster-adapted prions. Here, we demonstrate that PMCAb with saponin dramatically increases the sensitivity of detection for chronic wasting disease (CWD) agent without compromising the specificity of the assay (i.e., no false positive results). Addition of Teflon® beads increased the robustness of the PMCA reaction, resulting in a decrease in the variability of PMCA results. Three rounds of serial PMCAb allowed detection of CWD agent from a 6.7×10−13 dilution of 10% brain homogenate (1.3 fg of source brain). Titration of the same brain homogenate in transgenic mice expressing cervid prion protein (Tg(CerPrP)1536+/−mice) allowed detection of CWD agent from the 10−6 dilution of 10% brain homogenate. PMCAb is, thus, more sensitive than bioassay in transgenic mice by a factor exceeding 105. Additionally, we are able to amplify CWD agent from brain tissue and lymph nodes of CWD-positive white-tailed deer having Prnp alleles associated with reduced disease susceptibility.

  3. Highly efficient amplification of chronic wasting disease agent by protein misfolding cyclic amplification with beads (PMCAb.

    Directory of Open Access Journals (Sweden)

    Chad J Johnson

    Full Text Available Protein misfolding cyclic amplification (PMCA has emerged as an important technique for detecting low levels of pathogenic prion protein in biological samples. The method exploits the ability of the pathogenic prion protein to convert the normal prion protein to a proteinase K-resistant conformation. Inclusion of Teflon® beads in the PMCA reaction (PMCAb has been previously shown to increase the sensitivity and robustness of detection for the 263 K and SSLOW strains of hamster-adapted prions. Here, we demonstrate that PMCAb with saponin dramatically increases the sensitivity of detection for chronic wasting disease (CWD agent without compromising the specificity of the assay (i.e., no false positive results. Addition of Teflon® beads increased the robustness of the PMCA reaction, resulting in a decrease in the variability of PMCA results. Three rounds of serial PMCAb allowed detection of CWD agent from a 6.7 × 10(-13 dilution of 10% brain homogenate (1.3 fg of source brain. Titration of the same brain homogenate in transgenic mice expressing cervid prion protein (Tg(CerPrP1536(+/- mice allowed detection of CWD agent from the 10(-6 dilution of 10% brain homogenate. PMCAb is, thus, more sensitive than bioassay in transgenic mice by a factor exceeding 10(5. Additionally, we are able to amplify CWD agent from brain tissue and lymph nodes of CWD-positive white-tailed deer having Prnp alleles associated with reduced disease susceptibility.

  4. Chaperonins fight aminoglycoside-induced protein misfolding and promote short-term tolerance in Escherichia coli

    DEFF Research Database (Denmark)

    Goltermann, Lise; Good, Liam; Bentin, Thomas

    2013-01-01

    For almost half of a century, we have known that aminoglycoside antibiotics corrupt ribosomes, causing translational misreading, yet it remains unclear whether or not misreading triggers protein misfolding, and possible effects of chaperone action on drug susceptibilities are poorly understood...

  5. Dual Functional Small Molecule Probes as Fluorophore and Ligand for Misfolding Proteins

    OpenAIRE

    Zhang, Xueli; Ran, Chongzhao

    2013-01-01

    Misfolding of a protein is a destructive process for variety of diseases that include neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington disease, mad cow disease, amyotrophic lateral sclerosis (ALS), and frontal temporal dementia (FTD), and other non-CNS diseases such as diabetes, cystic fibrosis, and lysosomal storage diseases. Formation of various misfunctional large assembles of the misfolded protein is the primary consequence. To detect the formation of ...

  6. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.

    Science.gov (United States)

    Ciechanover, Aaron; Kwon, Yong Tae

    2015-03-13

    Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

  7. Protein misfolding and cellular stress in disease and ageing - Concepts and protocols

    Directory of Open Access Journals (Sweden)

    Carlo Alberto Redi

    2011-09-01

    Full Text Available To those readers that already got the Protein misfolding and disease volume, this new title can sound as an update or a second edition of the previous volume: well, this is not the case. To those colleagues that would like to enter the fascinating field of protein’s misfolding this new volume constitutes an excellent opportunity to be driven on the causes and mechanisms that are actually know to produce the misfolding. For both types of scientists this volume is a must: the subtitle already sounds as a warning since it reads concepts and protocols rather than methods and protocols. In other words, there is an entire section (part I, chapters 1-8 devoted to explain the concepts and the approaches we have gathered in these last years on the misfolding. These chapters are presented in the review style so that the relevant bibliographies are all there; in addition, this section is presenting the conceptual paradigma linking protein misfolding to ageing by conceiving the disease itself as premature ageing processes. Thus, the reader can take profit from this first part and become acquiented on the molecular effects brought about by protein misfolding at a cellular level and, generally speaking, on the pathogenetic mechanisms thereafter triggered by soluble prefibrillar aggregates...

  8. Why do alpha-beta parallel proteins, like flavodoxins, form misfolded off-pathway intermediates?

    NARCIS (Netherlands)

    Nabuurs, S.M.

    2009-01-01

    The question: “Why do α-β parallel proteins, like flavodoxins, form misfolded off-pathway
    intermediates?" is the main subject of this thesis. A. vinelandii apoflavodoxin is chosen as protein
    of interest as it is a representative of α-β parallel proteins, which are widely prevalent in

  9. Protein misfolding and disease: from the test tube to the organism.

    Science.gov (United States)

    Luheshi, Leila M; Crowther, Damian C; Dobson, Christopher M

    2008-02-01

    Protein misfolding is the underlying cause of many highly debilitating disorders ranging from Alzheimer's Disease to Cystic Fibrosis. Great strides have been made recently in understanding what causes proteins to misfold, primarily through the use of biophysical and computational techniques that enable systematic and quantitative analysis of the effects of a range of different perturbations in proteins. Correlation of the results of such analyses with observations made in animal models of disease has however been limited by their seemingly irreconcilable differences in methodology and scope. Several recent studies have however begun to overcome this limitation by combining the two approaches. This strategy has made it possible to investigate many of the consequences of protein misfolding in vivo, ranging from disease pathogenesis to epigenetic regulation, in the context of the fundamental physico-chemical principles derived from extensive and highly detailed studies undertaken in vitro.

  10. Distinct role of hydration water in protein misfolding and aggregation revealed by fluctuating thermodynamics analysis.

    Science.gov (United States)

    Chong, Song-Ho; Ham, Sihyun

    2015-04-21

    Protein aggregation in aqueous cellular environments is linked to diverse human diseases. Protein aggregation proceeds through a multistep process initiated by conformational transitions, called protein misfolding, of monomer species toward aggregation-prone structures. Various forms of aggregate species are generated through the association of misfolded monomers including soluble oligomers and amyloid fibrils. Elucidating the molecular mechanisms and driving forces involved in the misfolding and subsequent association has been a central issue for understanding and preventing protein aggregation diseases such as Alzheimer's, Parkinson's, and type II diabetes. In this Account, we provide a thermodynamic perspective of the misfolding and aggregation of the amyloid-beta (Aβ) protein implicated in Alzheimer's disease through the application of fluctuating thermodynamics. This approach "dissects" the conventional thermodynamic characterization of the end states into the one of the fluctuating processes connecting them, and enables one to analyze variations in the thermodynamic functions that occur during the course of protein conformational changes. The central quantity in this approach is the solvent-averaged effective energy, f = Eu + Gsolv, comprising the protein potential energy (Eu) and the solvation free energy (Gsolv), whose time variation reflects the protein dynamics on the free energy landscape. Protein configurational entropy is quantified by the magnitude of fluctuations in f. We find that misfolding of the Aβ monomer when released from a membrane environment to an aqueous phase is driven by favorable changes in protein potential energy and configurational entropy, but it is also accompanied by an unfavorable increase in solvation free energy. The subsequent dimerization of the misfolded Aβ monomers occurs in two steps. The first step, where two widely separated monomers come into contact distance, is driven by water-mediated attraction, that is, by a

  11. Histochemical approaches to assess cell-to-cell transmission of misfolded proteins in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    G. Natale

    2013-03-01

    Full Text Available Formation, aggregation and transmission of abnormal proteins are common features in neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. The mechanisms underlying protein alterations in neurodegenerative diseases remain controversial. Novel findings highlighted altered protein clearing systems as common biochemical pathways which generate protein misfolding, which in turn causes protein aggregation and protein spreading. In fact, proteinaceous aggregates are prone to cell-to-cell propagation. This is reminiscent of what happens in prion disorders, where the prion protein misfolds thus forming aggregates which spread to neighbouring cells. For this reason, the term prionoids is currently used to emphasize how several misfolded proteins are transmitted in neurodegenerative diseases following this prion-like pattern. Histochemical techniques including the use of specific antibodies covering both light and electron microscopy offer a powerful tool to describe these phenomena and investigate specific molecular steps. These include: prion like protein alterations; glycation of prion-like altered proteins to form advanced glycation end-products (AGEs; mechanisms of extracellular secretion; interaction of AGEs with specific receptors placed on neighbouring cells (RAGEs. The present manuscript comments on these phenomena aimed to provide a consistent scenario of the available histochemical approaches to dissect each specific step.

  12. Can misfolded proteins be beneficial? The HAMLET case.

    Science.gov (United States)

    Pettersson-Kastberg, Jenny; Aits, Sonja; Gustafsson, Lotta; Mossberg, Anki; Storm, Petter; Trulsson, Maria; Persson, Filip; Mok, K Hun; Svanborg, Catharina

    2009-01-01

    By changing the three-dimensional structure, a protein can attain new functions, distinct from those of the native protein. Amyloid-forming proteins are one example, in which conformational change may lead to fibril formation and, in many cases, neurodegenerative disease. We have proposed that partial unfolding provides a mechanism to generate new and useful functional variants from a given polypeptide chain. Here we present HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) as an example where partial unfolding and the incorporation of cofactor create a complex with new, beneficial properties. Native alpha-lactalbumin functions as a substrate specifier in lactose synthesis, but when partially unfolded the protein binds oleic acid and forms the tumoricidal HAMLET complex. When the properties of HAMLET were first described they were surprising, as protein folding intermediates and especially amyloid-forming protein intermediates had been regarded as toxic conformations, but since then structural studies have supported functional diversity arising from a change in fold. The properties of HAMLET suggest a mechanism of structure-function variation, which might help the limited number of human protein genes to generate sufficient structural diversity to meet the diverse functional demands of complex organisms.

  13. Kosmotropic anions promote conversion of recombinant prion protein into a PrPSc-like misfolded form.

    Directory of Open Access Journals (Sweden)

    Rodrigo Diaz-Espinoza

    Full Text Available Prions are self-propagating proteins involved in transmissible spongiform encephalopaties in mammals. An aberrant conformation with amyloid-like features of a cell surface protein, termed prion protein (PrP, is thought to be the essential component of the infectious particle, though accessory co-factor molecules such as lipids and nucleotides may be involved. The cellular co-factors and environmental conditions implicated in PrP misfolding are not completely understood. To address this issue, several studies have been done inducing misfolding of recombinant PrP (recPrP into classical amyloid structures using partially denaturing conditions. In this work, we report that misfolding of recPrP into PrP(Sc-like aggregates can be induced by simply incubating the protein in the presence of kosmotropic salts at concentrations that are known to retain or increase the stability of the protein. We used a simple experimental reaction (protein, buffer and salts submitted to agitation/incubation cycles at physiological temperature and pH. The formation of protease resistant-recPrP was time and salt-concentration dependent and required the presence of kosmotropic anions such as F(- or SO(4(-2. The molecular weights of the protease resistant recPrP fragments are reminiscent of those found in degradation assays of bona fide PrP(Sc. The aggregates also exhibited PrP(Sc-like ultrastructural features including rod-shape morphology under electron microscope, high beta-sheet content and thioflavin-T positive signal. The formation of recPrP aggregates with PrP(Sc biochemical features under conditions closer to physiological in the absence of organic co-factor molecules provides a simple setup that may prove helpful to understand the molecular mechanism of PrP misfolding.

  14. A Bystander Mechanism Explains the Specific Phenotype of a Broadly Expressed Misfolded Protein.

    Directory of Open Access Journals (Sweden)

    Lauren Klabonski

    2016-12-01

    Full Text Available Misfolded proteins in transgenic models of conformational diseases interfere with proteostasis machinery and compromise the function of many structurally and functionally unrelated metastable proteins. This collateral damage to cellular proteins has been termed 'bystander' mechanism. How a single misfolded protein overwhelms the proteostasis, and how broadly-expressed mutant proteins cause cell type-selective phenotypes in disease are open questions. We tested the gain-of-function mechanism of a R37C folding mutation in an endogenous IGF-like C.elegans protein DAF-28. DAF-28(R37C is broadly expressed, but only causes dysfunction in one specific neuron, ASI, leading to a distinct developmental phenotype. We find that this phenotype is caused by selective disruption of normal biogenesis of an unrelated endogenous protein, DAF-7/TGF-β. The combined deficiency of DAF-28 and DAF-7 biogenesis, but not of DAF-28 alone, explains the gain-of-function phenotype-deficient pro-growth signaling by the ASI neuron. Using functional, fluorescently-tagged protein, we find that, in animals with mutant DAF-28/IGF, the wild-type DAF-7/TGF-β is mislocalized to and accumulates in the proximal axon of the ASI neuron. Activation of two different branches of the unfolded protein response can modulate both the developmental phenotype and DAF-7 mislocalization in DAF-28(R37C animals, but appear to act through divergent mechanisms. Our finding that bystander targeting of TGF-β explains the phenotype caused by a folding mutation in an IGF-like protein suggests that, in conformational diseases, bystander misfolding may specify the distinct phenotypes caused by different folding mutations.

  15. The ER stress sensor PERK luminal domain functions as a molecular chaperone to interact with misfolded proteins

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Peng; Li, Jingzhi; Sha, Bingdong

    2016-11-29

    PERK is one of the major sensor proteins which can detect the protein-folding imbalance generated by endoplasmic reticulum (ER) stress. It remains unclear how the sensor protein PERK is activated by ER stress. It has been demonstrated that the PERK luminal domain can recognize and selectively interact with misfolded proteins but not native proteins. Moreover, the PERK luminal domain may function as a molecular chaperone to directly bind to and suppress the aggregation of a number of misfolded model proteins. The data strongly support the hypothesis that the PERK luminal domain can interact directly with misfolded proteins to induce ER stress signaling. To illustrate the mechanism by which the PERK luminal domain interacts with misfolded proteins, the crystal structure of the human PERK luminal domain was determined to 3.2 Å resolution. Two dimers of the PERK luminal domain constitute a tetramer in the asymmetric unit. Superimposition of the PERK luminal domain molecules indicated that the β-sandwich domain could adopt multiple conformations. It is hypothesized that the PERK luminal domain may utilize its flexible β-sandwich domain to recognize and interact with a broad range of misfolded proteins.

  16. Region-specific protein misfolding cyclic amplification reproduces brain tropism of prion strains.

    Science.gov (United States)

    Privat, Nicolas; Levavasseur, Etienne; Yildirim, Serfildan; Hannaoui, Samia; Brandel, Jean-Philippe; Laplanche, Jean-Louis; Béringue, Vincent; Seilhean, Danielle; Haïk, Stéphane

    2017-10-06

    Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrP Sc ). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrP Sc deposits within the brain and the spongiform lesions they induce. The mechanisms involved in this strain-specific targeting of distinct brain regions still are a fundamental, unresolved question in prion research. To address this question, we exploited a prion conversion in vitro assay, protein misfolding cyclic amplification (PMCA), by using experimental scrapie and human prion strains as seeds and specific brain regions from mice and humans as substrates. We show here that region-specific PMCA in part reproduces the specific brain targeting observed in experimental, acquired, and sporadic Creutzfeldt-Jakob diseases. Furthermore, we provide evidence that, in addition to cellular prion protein, other region- and species-specific molecular factors influence the strain-dependent prion conversion process. This important step toward understanding prion strain propagation in the human brain may impact research on the molecular factors involved in protein misfolding and the development of ultrasensitive methods for diagnosing prion disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Mathematical Modeling of Protein Misfolding Mechanisms in Neurological Diseases: A Historical Overview.

    Science.gov (United States)

    Carbonell, Felix; Iturria-Medina, Yasser; Evans, Alan C

    2018-01-01

    Protein misfolding refers to a process where proteins become structurally abnormal and lose their specific 3-dimensional spatial configuration. The histopathological presence of misfolded protein (MP) aggregates has been associated as the primary evidence of multiple neurological diseases, including Prion diseases, Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob disease. However, the exact mechanisms of MP aggregation and propagation, as well as their impact in the long-term patient's clinical condition are still not well understood. With this aim, a variety of mathematical models has been proposed for a better insight into the kinetic rate laws that govern the microscopic processes of protein aggregation. Complementary, another class of large-scale models rely on modern molecular imaging techniques for describing the phenomenological effects of MP propagation over the whole brain. Unfortunately, those neuroimaging-based studies do not take full advantage of the tremendous capabilities offered by the chemical kinetics modeling approach. Actually, it has been barely acknowledged that the vast majority of large-scale models have foundations on previous mathematical approaches that describe the chemical kinetics of protein replication and propagation. The purpose of the current manuscript is to present a historical review about the development of mathematical models for describing both microscopic processes that occur during the MP aggregation and large-scale events that characterize the progression of neurodegenerative MP-mediated diseases.

  18. Applying chaperones to protein-misfolding disorders: molecular chaperones against α-synuclein in Parkinson's disease.

    Science.gov (United States)

    Chaari, Ali; Hoarau-Véchot, Jessica; Ladjimi, Moncef

    2013-09-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called α-synuclein (α-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows α-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing α-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD. Published by Elsevier B.V.

  19. Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

    Science.gov (United States)

    Iturria-Medina, Yasser; Sotero, Roberto C; Toussaint, Paule J; Evans, Alan C

    2014-11-01

    Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

  20. Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Yasser Iturria-Medina

    2014-11-01

    Full Text Available Misfolded proteins (MP are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database. Furthermore, this model strongly supports a the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

  1. The Role of S-Nitrosylation and S-Glutathionylation of Protein Disulphide Isomerase in Protein Misfolding and Neurodegeneration

    Directory of Open Access Journals (Sweden)

    M. Halloran

    2013-01-01

    Full Text Available Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions. S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO- containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S-glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future.

  2. Effect of fullerenol surface chemistry on nanoparticle binding-induced protein misfolding

    Science.gov (United States)

    Radic, Slaven; Nedumpully-Govindan, Praveen; Chen, Ran; Salonen, Emppu; Brown, Jared M.; Ke, Pu Chun; Ding, Feng

    2014-06-01

    Fullerene and its derivatives with different surface chemistry have great potential in biomedical applications. Accordingly, it is important to delineate the impact of these carbon-based nanoparticles on protein structure, dynamics, and subsequently function. Here, we focused on the effect of hydroxylation -- a common strategy for solubilizing and functionalizing fullerene -- on protein-nanoparticle interactions using a model protein, ubiquitin. We applied a set of complementary computational modeling methods, including docking and molecular dynamics simulations with both explicit and implicit solvent, to illustrate the impact of hydroxylated fullerenes on the structure and dynamics of ubiquitin. We found that all derivatives bound to the model protein. Specifically, the more hydrophilic nanoparticles with a higher number of hydroxyl groups bound to the surface of the protein via hydrogen bonds, which stabilized the protein without inducing large conformational changes in the protein structure. In contrast, fullerene derivatives with a smaller number of hydroxyl groups buried their hydrophobic surface inside the protein, thereby causing protein denaturation. Overall, our results revealed a distinct role of surface chemistry on nanoparticle-protein binding and binding-induced protein misfolding.Fullerene and its derivatives with different surface chemistry have great potential in biomedical applications. Accordingly, it is important to delineate the impact of these carbon-based nanoparticles on protein structure, dynamics, and subsequently function. Here, we focused on the effect of hydroxylation -- a common strategy for solubilizing and functionalizing fullerene -- on protein-nanoparticle interactions using a model protein, ubiquitin. We applied a set of complementary computational modeling methods, including docking and molecular dynamics simulations with both explicit and implicit solvent, to illustrate the impact of hydroxylated fullerenes on the structure and

  3. GCK-MODY diabetes as a protein misfolding disease: the mutation R275C promotes protein misfolding, self-association and cellular degradation.

    Science.gov (United States)

    Negahdar, Maria; Aukrust, Ingvild; Molnes, Janne; Solheim, Marie H; Johansson, Bente B; Sagen, Jørn V; Dahl-Jørgensen, Knut; Kulkarni, Rohit N; Søvik, Oddmund; Flatmark, Torgeir; Njølstad, Pål R; Bjørkhaug, Lise

    2014-01-25

    GCK-MODY, dominantly inherited mild hyperglycemia, is associated with more than 600 mutations in the glucokinase gene. Different molecular mechanisms have been shown to explain GCK-MODY. Here, we report a Pakistani family harboring the glucokinase mutation c.823C>T (p.R275C). The recombinant and in cellulo expressed mutant pancreatic enzyme revealed slightly increased enzyme activity (kcat) and normal affinity for α-D-glucose, and resistance to limited proteolysis by trypsin comparable with wild-type. When stably expressed in HEK293 cells and MIN6 β-cells (at different levels), the mutant protein appeared misfolded and unstable with a propensity to form dimers and aggregates. Its degradation rate was increased, involving the lysosomal and proteasomal quality control systems. On mutation, a hydrogen bond between the R275 side-chain and the carbonyl oxygen of D267 is broken, destabilizing the F260-L271 loop structure and the protein. This promotes the formation of dimers/aggregates and suggests that an increased cellular degradation is the molecular mechanism by which R275C causes GCK-MODY. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Glycoform-independent prion conversion by highly efficient, cell-based, protein misfolding cyclic amplification.

    Science.gov (United States)

    Moudjou, Mohammed; Chapuis, Jérôme; Mekrouti, Mériem; Reine, Fabienne; Herzog, Laetitia; Sibille, Pierre; Laude, Hubert; Vilette, Didier; Andréoletti, Olivier; Rezaei, Human; Dron, Michel; Béringue, Vincent

    2016-07-07

    Prions are formed of misfolded assemblies (PrP(Sc)) of the variably N-glycosylated cellular prion protein (PrP(C)). In infected species, prions replicate by seeding the conversion and polymerization of host PrP(C). Distinct prion strains can be recognized, exhibiting defined PrP(Sc) biochemical properties such as the glycotype and specific biological traits. While strain information is encoded within the conformation of PrP(Sc) assemblies, the storage of the structural information and the molecular requirements for self-perpetuation remain uncertain. Here, we investigated the specific role of PrP(C) glycosylation status. First, we developed an efficient protein misfolding cyclic amplification method using cells expressing the PrP(C) species of interest as substrate. Applying the technique to PrP(C) glycosylation mutants expressing cells revealed that neither PrP(C) nor PrP(Sc) glycoform stoichiometry was instrumental to PrP(Sc) formation and strainness perpetuation. Our study supports the view that strain properties, including PrP(Sc) glycotype are enciphered within PrP(Sc) structural backbone, not in the attached glycans.

  5. Heavy metals and metalloids as a cause for protein misfolding and aggregation.

    Science.gov (United States)

    Tamás, Markus J; Sharma, Sandeep K; Ibstedt, Sebastian; Jacobson, Therese; Christen, Philipp

    2014-02-25

    While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly susceptible proteins, either by forming a complex with functional side chain groups or by displacing essential metal ions in metalloproteins. Recent studies have revealed an additional mode of metal action targeted at proteins in a non-native state; certain heavy metals and metalloids have been found to inhibit the in vitro refolding of chemically denatured proteins, to interfere with protein folding in vivo and to cause aggregation of nascent proteins in living cells. Apparently, unfolded proteins with motile backbone and side chains are considerably more prone to engage in stable, pluridentate metal complexes than native proteins with their well-defined 3D structure. By interfering with the folding process, heavy metal ions and metalloids profoundly affect protein homeostasis and cell viability. This review describes how heavy metals impede protein folding and promote protein aggregation, how cells regulate quality control systems to protect themselves from metal toxicity and how metals might contribute to protein misfolding disorders.

  6. GCK-MODY diabetes associated with protein misfolding, cellular self-association and degradation.

    Science.gov (United States)

    Negahdar, Maria; Aukrust, Ingvild; Johansson, Bente B; Molnes, Janne; Molven, Anders; Matschinsky, Franz M; Søvik, Oddmund; Kulkarni, Rohit N; Flatmark, Torgeir; Njølstad, Pål Rasmus; Bjørkhaug, Lise

    2012-11-01

    GCK-MODY, dominantly inherited mild fasting hyperglycemia, has been associated with >600 different mutations in the glucokinase (GK)-encoding gene (GCK). When expressed as recombinant pancreatic proteins, some mutations result in enzymes with normal/near-normal catalytic properties. The molecular mechanism(s) of GCK-MODY due to these mutations has remained elusive. Here, we aimed to explore the molecular mechanisms for two such catalytically 'normal' GCK mutations (S263P and G264S) in the F260-L270 loop of GK. When stably overexpressed in HEK293 cells and MIN6 β-cells, the S263P- and G264S-encoded mutations generated misfolded proteins with an increased rate of degradation (S263P>G264S) by the protein quality control machinery, and a propensity to self-associate (G264S>S263P) and form dimers (SDS resistant) and aggregates (partly Triton X-100 insoluble), as determined by pulse-chase experiments and subcellular fractionation. Thus, the GCK-MODY mutations S263P and G264S lead to protein misfolding causing destabilization, cellular dimerization/aggregation and enhanced rate of degradation. In silico predicted conformational changes of the F260-L270 loop structure are considered to mediate the dimerization of both mutant proteins by a domain swapping mechanism. Thus, similar properties may represent the molecular mechanisms for additional unexplained GCK-MODY mutations, and may also contribute to the disease mechanism in other previously characterized GCK-MODY inactivating mutations. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Interplay between Molecular Chaperones and the Ubiquitin-Proteasome System in Targeting of Misfolded Proteins for Degradation

    DEFF Research Database (Denmark)

    Poulsen, Esben Guldahl

    interacting with purified 26S proteasomes, and the subsequent characterization of two novel proteasome interacting proteins. The third study was aimed at analyzing the chaperone-assisted pathway leading to degradation of misfolded kinetochore proteins in S. pombe. In this study chaperones, E2s, E3s and DUBs...

  8. AAV exploits subcellular stress associated with inflammation, endoplasmic reticulum expansion, and misfolded proteins in models of cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    Jarrod S Johnson

    2011-05-01

    Full Text Available Barriers to infection act at multiple levels to prevent viruses, bacteria, and parasites from commandeering host cells for their own purposes. An intriguing hypothesis is that if a cell experiences stress, such as that elicited by inflammation, endoplasmic reticulum (ER expansion, or misfolded proteins, then subcellular barriers will be less effective at preventing viral infection. Here we have used models of cystic fibrosis (CF to test whether subcellular stress increases susceptibility to adeno-associated virus (AAV infection. In human airway epithelium cultured at an air/liquid interface, physiological conditions of subcellular stress and ER expansion were mimicked using supernatant from mucopurulent material derived from CF lungs. Using this inflammatory stimulus to recapitulate stress found in diseased airways, we demonstrated that AAV infection was significantly enhanced. Since over 90% of CF cases are associated with a misfolded variant of Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR, we then explored whether the presence of misfolded proteins could independently increase susceptibility to AAV infection. In these models, AAV was an order of magnitude more efficient at transducing cells expressing ΔF508-CFTR than in cells expressing wild-type CFTR. Rescue of misfolded ΔF508-CFTR under low temperature conditions restored viral transduction efficiency to that demonstrated in controls, suggesting effects related to protein misfolding were responsible for increasing susceptibility to infection. By testing other CFTR mutants, G551D, D572N, and 1410X, we have shown this phenomenon is common to other misfolded proteins and not related to loss of CFTR activity. The presence of misfolded proteins did not affect cell surface attachment of virus or influence expression levels from promoter transgene cassettes in plasmid transfection studies, indicating exploitation occurs at the level of virion trafficking or processing. Thus

  9. Cavitation during the protein misfolding cyclic amplification (PMCA) method – The trigger for de novo prion generation?

    International Nuclear Information System (INIS)

    Haigh, Cathryn L.; Drew, Simon C.

    2015-01-01

    The protein misfolding cyclic amplification (PMCA) technique has become a widely-adopted method for amplifying minute amounts of the infectious conformer of the prion protein (PrP). PMCA involves repeated cycles of 20 kHz sonication and incubation, during which the infectious conformer seeds the conversion of normally folded protein by a templating interaction. Recently, it has proved possible to create an infectious PrP conformer without the need for an infectious seed, by including RNA and the phospholipid POPG as essential cofactors during PMCA. The mechanism underpinning this de novo prion formation remains unknown. In this study, we first establish by spin trapping methods that cavitation bubbles formed during PMCA provide a radical-rich environment. Using a substrate preparation comparable to that employed in studies of de novo prion formation, we demonstrate by immuno-spin trapping that PrP- and RNA-centered radicals are generated during sonication, in addition to PrP-RNA cross-links. We further show that serial PMCA produces protease-resistant PrP that is oxidatively modified. We suggest a unique confluence of structural (membrane-mimetic hydrophobic/hydrophilic bubble interface) and chemical (ROS) effects underlie the phenomenon of de novo prion formation by PMCA, and that these effects have meaningful biological counterparts of possible relevance to spontaneous prion formation in vivo. - Highlights: • Sonication during PMCA generates free radicals at the surface of cavitation bubbles. • PrP-centered and RNA-centered radicals are formed in addition to PrP-RNA adducts. • De novo prions may result from ROS and structural constraints during cavitation

  10. Cavitation during the protein misfolding cyclic amplification (PMCA) method – The trigger for de novo prion generation?

    Energy Technology Data Exchange (ETDEWEB)

    Haigh, Cathryn L., E-mail: chaigh@unimelb.edu.au [Department of Pathology, The University of Melbourne, Victoria 3010 (Australia); Drew, Simon C., E-mail: sdrew@unimelb.edu.au [Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010 (Australia)

    2015-06-05

    The protein misfolding cyclic amplification (PMCA) technique has become a widely-adopted method for amplifying minute amounts of the infectious conformer of the prion protein (PrP). PMCA involves repeated cycles of 20 kHz sonication and incubation, during which the infectious conformer seeds the conversion of normally folded protein by a templating interaction. Recently, it has proved possible to create an infectious PrP conformer without the need for an infectious seed, by including RNA and the phospholipid POPG as essential cofactors during PMCA. The mechanism underpinning this de novo prion formation remains unknown. In this study, we first establish by spin trapping methods that cavitation bubbles formed during PMCA provide a radical-rich environment. Using a substrate preparation comparable to that employed in studies of de novo prion formation, we demonstrate by immuno-spin trapping that PrP- and RNA-centered radicals are generated during sonication, in addition to PrP-RNA cross-links. We further show that serial PMCA produces protease-resistant PrP that is oxidatively modified. We suggest a unique confluence of structural (membrane-mimetic hydrophobic/hydrophilic bubble interface) and chemical (ROS) effects underlie the phenomenon of de novo prion formation by PMCA, and that these effects have meaningful biological counterparts of possible relevance to spontaneous prion formation in vivo. - Highlights: • Sonication during PMCA generates free radicals at the surface of cavitation bubbles. • PrP-centered and RNA-centered radicals are formed in addition to PrP-RNA adducts. • De novo prions may result from ROS and structural constraints during cavitation.

  11. Serial Millisecond Crystallography of Membrane Proteins.

    Science.gov (United States)

    Jaeger, Kathrin; Dworkowski, Florian; Nogly, Przemyslaw; Milne, Christopher; Wang, Meitian; Standfuss, Joerg

    2016-01-01

    Serial femtosecond crystallography (SFX) at X-ray free-electron lasers (XFELs) is a powerful method to determine high-resolution structures of pharmaceutically relevant membrane proteins. Recently, the technology has been adapted to carry out serial millisecond crystallography (SMX) at synchrotron sources, where beamtime is more abundant. In an injector-based approach, crystals grown in lipidic cubic phase (LCP) or embedded in viscous medium are delivered directly into the unattenuated beam of a microfocus beamline. Pilot experiments show the application of microjet-based SMX for solving the structure of a membrane protein and compatibility of the method with de novo phasing. Planned synchrotron upgrades, faster detectors and software developments will go hand-in-hand with developments at free-electron lasers to provide a powerful methodology for solving structures from microcrystals at room temperature, ligand screening or crystal optimization for time-resolved studies with minimal or no radiation damage.

  12. H ferritin silencing induces protein misfolding in K562 cells: A Raman analysis

    KAUST Repository

    Zolea, Fabiana

    2015-10-09

    The redox state of the cell is involved in the regulation of many physiological functions as well as in the pathogenesis of several diseases, and is strictly dependent on the amount of iron in its catalytically active state. Alterations of iron homeostasis determine increased steady-state concentrations of Reactive Oxygen Species (ROS) that cause lipid peroxidation, DNA damage and altered protein folding. Ferritin keeps the intracellular iron in a non-toxic and readily available form and consequently plays a central role in iron and redox homeostasis. The protein is composed by 24 subunits of the H- and L-type, coded by two different genes, with structural and functional differences. The aim of this study was to shed light on the role of the single H ferritin subunit (FHC) in keeping the native correct protein three-dimensional structure. To this, we performed Raman spectroscopy on protein extracts from K562 cells subjected to FHC silencing. The results show a significant increase in the percentage of disordered structures content at a level comparable to that induced by H2O2 treatment in control cells. ROS inhibitor and iron chelator were able to revert protein misfolding. This integrated approach, involving Raman spectroscopy and targeted-gene silencing, indicates that an imbalance of the heavy-to-light chain ratio in the ferritin composition is able to induce severe but still reversible modifications in protein folding and uncovers new potential pathogenetic mechanisms associated to intracellular iron perturbation.

  13. H ferritin silencing induces protein misfolding in K562 cells: A Raman analysis

    KAUST Repository

    Zolea, Fabiana; Biamonte, Flavia; Candeloro, Patrizio; Di Sanzo, Maddalena; Cozzi, Anna; Di Vito, Anna; Quaresima, Barbara; Lobello, Nadia; Trecroci, Francesca; Di Fabrizio, Enzo M.; Levi, Sonia; Cuda, Giovanni; Costanzo, Francesco

    2015-01-01

    The redox state of the cell is involved in the regulation of many physiological functions as well as in the pathogenesis of several diseases, and is strictly dependent on the amount of iron in its catalytically active state. Alterations of iron homeostasis determine increased steady-state concentrations of Reactive Oxygen Species (ROS) that cause lipid peroxidation, DNA damage and altered protein folding. Ferritin keeps the intracellular iron in a non-toxic and readily available form and consequently plays a central role in iron and redox homeostasis. The protein is composed by 24 subunits of the H- and L-type, coded by two different genes, with structural and functional differences. The aim of this study was to shed light on the role of the single H ferritin subunit (FHC) in keeping the native correct protein three-dimensional structure. To this, we performed Raman spectroscopy on protein extracts from K562 cells subjected to FHC silencing. The results show a significant increase in the percentage of disordered structures content at a level comparable to that induced by H2O2 treatment in control cells. ROS inhibitor and iron chelator were able to revert protein misfolding. This integrated approach, involving Raman spectroscopy and targeted-gene silencing, indicates that an imbalance of the heavy-to-light chain ratio in the ferritin composition is able to induce severe but still reversible modifications in protein folding and uncovers new potential pathogenetic mechanisms associated to intracellular iron perturbation.

  14. Conformational Analysis of Misfolded Protein Aggregation by FRET and Live-Cell Imaging Techniques

    Directory of Open Access Journals (Sweden)

    Akira Kitamura

    2015-03-01

    Full Text Available Cellular homeostasis is maintained by several types of protein machinery, including molecular chaperones and proteolysis systems. Dysregulation of the proteome disrupts homeostasis in cells, tissues, and the organism as a whole, and has been hypothesized to cause neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS and Huntington’s disease (HD. A hallmark of neurodegenerative disorders is formation of ubiquitin-positive inclusion bodies in neurons, suggesting that the aggregation process of misfolded proteins changes during disease progression. Hence, high-throughput determination of soluble oligomers during the aggregation process, as well as the conformation of sequestered proteins in inclusion bodies, is essential for elucidation of physiological regulation mechanism and drug discovery in this field. To elucidate the interaction, accumulation, and conformation of aggregation-prone proteins, in situ spectroscopic imaging techniques, such as Förster/fluorescence resonance energy transfer (FRET, fluorescence correlation spectroscopy (FCS, and bimolecular fluorescence complementation (BiFC have been employed. Here, we summarize recent reports in which these techniques were applied to the analysis of aggregation-prone proteins (in particular their dimerization, interactions, and conformational changes, and describe several fluorescent indicators used for real-time observation of physiological states related to proteostasis.

  15. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-type bovine spongiform encephalopathy

    Science.gov (United States)

    Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from normal cellular prion protein to pathogenic misfolded conformation. This conversion has been used for in vitro assays including serial protein misfolding amplification...

  16. Protein misfolding cyclic amplification induces the conversion of recombinant prion protein to PrP oligomers causing neuronal apoptosis.

    Science.gov (United States)

    Yuan, Zhen; Yang, Lifeng; Chen, Baian; Zhu, Ting; Hassan, Mohammad Farooque; Yin, Xiaomin; Zhou, Xiangmei; Zhao, Deming

    2015-06-01

    The formation of neurotoxic prion protein (PrP) oligomers is thought to be a key step in the development of prion diseases. Recently, it was determined that the sonication and shaking of recombinant PrP can convert PrP monomers into β-state oligomers. Herein, we demonstrate that β-state oligomeric PrP can be generated through protein misfolding cyclic amplification from recombinant full-length hamster, human, rabbit, and mutated rabbit PrP, and that these oligomers can be used for subsequent research into the mechanisms of PrP-induced neurotoxicity. We have characterized protein misfolding cyclic amplification-induced monomer-to-oligomer conversion of PrP from three species using western blotting, circular dichroism, size-exclusion chromatography, and resistance to proteinase K (PK) digestion. We have further shown that all of the resulting β-oligomers are toxic to primary mouse cortical neurons independent of the presence of PrP(C) in the neurons, whereas the corresponding monomeric PrP were not toxic. In addition, we found that this toxicity is the result of oligomer-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3 in both wild-type and PrP(-/-) cortical neurons. It is our hope that these results may contribute to our understanding of prion transformation within the brain. We found that β-state oligomeric PrPs can be generated through protein misfolding cyclic amplification (PMCA) from recombinant full-length hamster, human, rabbit, and mutated rabbit PrP. β-oligomers are toxic to primary mouse cortical neurons independent of the presence of PrP(C) in the neurons, while the corresponding monomeric PrPs were not toxic. This toxicity is the result of oligomers-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3. These results may contribute to our understanding of prion transformation within the brain. © 2015 International Society for Neurochemistry.

  17. Inactivation of Template-Directed Misfolding of Infectious Prion Protein by Ozone

    Science.gov (United States)

    Ding, Ning; Price, Luke M.; Braithwaite, Shannon L.; Balachandran, Aru; Belosevic, Miodrag

    2012-01-01

    Misfolded prions (PrPSc) are well known for their resistance to conventional decontamination processes. The potential risk of contamination of the water environment, as a result of disposal of specified risk materials (SRM), has raised public concerns. Ozone is commonly utilized in the water industry for inactivation of microbial contaminants and was tested in this study for its ability to inactivate prions (263K hamster scrapie = PrPSc). Treatment variables included initial ozone dose (7.6 to 25.7 mg/liter), contact time (5 s and 5 min), temperature (4°C and 20°C), and pH (pH 4.4, 6.0, and 8.0). Exposure of dilute suspensions of the infected 263K hamster brain homogenates (IBH) (0.01%) to ozone resulted in the in vitro destruction of the templating properties of PrPSc, as measured by the protein misfolding cyclic amplification (PMCA) assay. The highest levels of prion inactivation (≥4 log10) were observed with ozone doses of 13.0 mg/liter, at pH 4.4 and 20°C, resulting in a CT (the product of residual ozone concentration and contact time) value as low as 0.59 mg · liter−1 min. A comparison of ozone CT requirements among various pathogens suggests that prions are more susceptible to ozone degradation than some model bacteria and protozoa and that ozone treatment may be an effective solution for inactivating prions in water and wastewater. PMID:22138993

  18. S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding.

    Science.gov (United States)

    Nakamura, T; Lipton, S A

    2007-07-01

    Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca(2+) influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones - such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins - can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

  19. Probing Early Misfolding Events in Prion Protein Mutants by NMR Spectroscopy

    Directory of Open Access Journals (Sweden)

    Gregor Ilc

    2013-08-01

    Full Text Available The post-translational conversion of the ubiquitously expressed cellular form of the prion protein, PrPC, into its misfolded and pathogenic isoform, known as prion or PrPSc, plays a key role in prion diseases. These maladies are denoted transmissible spongiform encephalopathies (TSEs and affect both humans and animals. A prerequisite for understanding TSEs is unraveling the molecular mechanism leading to the conversion process whereby most α-helical motifs are replaced by β-sheet secondary structures. Importantly, most point mutations linked to inherited prion diseases are clustered in the C-terminal domain region of PrPC and cause spontaneous conversion to PrPSc. Structural studies with PrP variants promise new clues regarding the proposed conversion mechanism and may help identify “hot spots” in PrPC involved in the pathogenic conversion. These investigations may also shed light on the early structural rearrangements occurring in some PrPC epitopes thought to be involved in modulating prion susceptibility. Here we present a detailed overview of our solution-state NMR studies on human prion protein carrying different pathological point mutations and the implications that such findings may have for the future of prion research.

  20. Larger aggregates of mutant seipin in Celia's Encephalopathy, a new protein misfolding neurodegenerative disease.

    Science.gov (United States)

    Ruiz-Riquelme, Alejandro; Sánchez-Iglesias, Sofía; Rábano, Alberto; Guillén-Navarro, Encarna; Domingo-Jiménez, Rosario; Ramos, Adriana; Rosa, Isaac; Senra, Ana; Nilsson, Peter; García, Ángel; Araújo-Vilar, David; Requena, Jesús R

    2015-11-01

    Celia's Encephalopathy (MIM #615924) is a recently discovered fatal neurodegenerative syndrome associated with a new BSCL2 mutation (c.985C>T) that results in an aberrant isoform of seipin (Celia seipin). This mutation is lethal in both homozygosity and compounded heterozygosity with a lipodystrophic BSCL2 mutation, resulting in a progressive encephalopathy with fatal outcomes at ages 6-8. Strikingly, heterozygous carriers are asymptomatic, conflicting with the gain of toxic function attributed to this mutation. Here we report new key insights about the molecular pathogenic mechanism of this new syndrome. Intranuclear inclusions containing mutant seipin were found in brain tissue from a homozygous patient suggesting a pathogenic mechanism similar to other neurodegenerative diseases featuring brain accumulation of aggregated, misfolded proteins. Sucrose gradient distribution showed that mutant seipin forms much larger aggregates as compared with wild type (wt) seipin, indicating an impaired oligomerization. On the other hand, the interaction between wt and Celia seipin confirmed by coimmunoprecipitation (CoIP) assays, together with the identification of mixed oligomers in sucrose gradient fractionation experiments can explain the lack of symptoms in heterozygous carriers. We propose that the increased aggregation and subsequent impaired oligomerization of Celia seipin leads to cell death. In heterozygous carriers, wt seipin might prevent the damage caused by mutant seipin through its sequestration into harmless mixed oligomers. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Hsp70-GlcNAc-binding activity is released by stress, proteasome inhibition, and protein misfolding

    International Nuclear Information System (INIS)

    Guinez, Celine; Mir, Anne-Marie; Leroy, Yves; Cacan, Rene; Michalski, Jean-Claude; Lefebvre, Tony

    2007-01-01

    Numerous recent works strengthen the idea that the nuclear and cytosolic-specific O-GlcNAc glycosylation protects cells against injuries. We have first investigated O-GlcNAc level and Hsp70-GlcNAc-binding activity (HGBA) behaviour after exposure of HeLa and HepG 2 cells to a wide variety of stresses. O-GlcNAc and HGBA responses were different according to the stress and according to the cell. HGBA was released for almost all stresses, while O-GlcNAc level was modified either upwards or downwards, depending to the stress. Against all expectations, we demonstrated that energy charge did not significantly vary with stress whereas UDP-GlcNAc pools were more dramatically affected even if differences in UDP-GlcNAc contents were not correlated with O-GlcNAc variations suggesting that O-GlcNAc transferase is itself finely regulated during cell injury. Finally, HGBA could be triggered by proteasome inhibition and by L-azetidine-2-carboxylic acid (a proline analogue) incorporation demonstrating that protein misfolding is one of the key-activator of this Hsp70 property

  2. A two-step protein quality control pathway for a misfolded DJ-1 variant in fission yeast

    DEFF Research Database (Denmark)

    Mathiassen, Søs Grønbæk; Larsen, Ida B.; Poulsen, Esben Guldahl

    2015-01-01

    A mutation, L166P, in the cytosolic protein, PARK7/DJ-1, causes protein misfolding and is linked to Parkinson disease. Here, we identify the fission yeast protein Sdj1 as the orthologue of DJ-1 and calculate by in silico saturation mutagenesis the effects of point mutants on its structural...... stability. We also map the degradation pathways for Sdj1-L169P, the fission yeast orthologue of the disease-causing DJ-1 L166P protein. Sdj1-L169P forms inclusions, which are enriched for the Hsp104 disaggregase. Hsp104 and Hsp70-type chaperones are required for efficient degradation of Sdj1-L169P...

  3. Prion protein misfolding affects calcium homeostasis and sensitizes cells to endoplasmic reticulum stress.

    Directory of Open Access Journals (Sweden)

    Mauricio Torres

    2010-12-01

    Full Text Available Prion-related disorders (PrDs are fatal neurodegenerative disorders characterized by progressive neuronal impairment as well as the accumulation of an abnormally folded and protease resistant form of the cellular prion protein, termed PrP(RES. Altered endoplasmic reticulum (ER homeostasis is associated with the occurrence of neurodegeneration in sporadic, infectious and familial forms of PrDs. The ER operates as a major intracellular calcium store, playing a crucial role in pathological events related to neuronal dysfunction and death. Here we investigated the possible impact of PrP misfolding on ER calcium homeostasis in infectious and familial models of PrDs. Neuro2A cells chronically infected with scrapie prions showed decreased ER-calcium content that correlated with a stronger upregulation of UPR-inducible chaperones, and a higher sensitivity to ER stress-induced cell death. Overexpression of the calcium pump SERCA stimulated calcium release and increased the neurotoxicity observed after exposure of cells to brain-derived infectious PrP(RES. Furthermore, expression of PrP mutants that cause hereditary Creutzfeldt-Jakob disease or fatal familial insomnia led to accumulation of PrP(RES and their partial retention at the ER, associated with a drastic decrease of ER calcium content and higher susceptibility to ER stress. Finally, similar results were observed when a transmembrane form of PrP was expressed, which is proposed as a neurotoxic intermediate. Our results suggest that alterations in calcium homeostasis and increased susceptibility to ER stress are common pathological features of both infectious and familial PrD models.

  4. Complex folding and misfolding effects of deer-specific amino acid substitutions in the β2-α2 loop of murine prion protein

    Science.gov (United States)

    Agarwal, Sonya; Döring, Kristina; Gierusz, Leszek A.; Iyer, Pooja; Lane, Fiona M.; Graham, James F.; Goldmann, Wilfred; Pinheiro, Teresa J. T.; Gill, Andrew C.

    2015-10-01

    The β2-α2 loop of PrPC is a key modulator of disease-associated prion protein misfolding. Amino acids that differentiate mouse (Ser169, Asn173) and deer (Asn169, Thr173) PrPC appear to confer dramatically different structural properties in this region and it has been suggested that amino acid sequences associated with structural rigidity of the loop also confer susceptibility to prion disease. Using mouse recombinant PrP, we show that mutating residue 173 from Asn to Thr alters protein stability and misfolding only subtly, whilst changing Ser to Asn at codon 169 causes instability in the protein, promotes oligomer formation and dramatically potentiates fibril formation. The doubly mutated protein exhibits more complex folding and misfolding behaviour than either single mutant, suggestive of differential effects of the β2-α2 loop sequence on both protein stability and on specific misfolding pathways. Molecular dynamics simulation of protein structure suggests a key role for the solvent accessibility of Tyr168 in promoting molecular interactions that may lead to prion protein misfolding. Thus, we conclude that ‘rigidity’ in the β2-α2 loop region of the normal conformer of PrP has less effect on misfolding than other sequence-related effects in this region.

  5. Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment

    Science.gov (United States)

    Zhou, Minghai; Ottenberg, Gregory; Sferrazza, Gian Franco; Hubbs, Christopher; Fallahi, Mohammad; Rumbaugh, Gavin; Brantley, Alicia F.

    2015-01-01

    The mechanisms of neuronal death in protein misfolding neurodegenerative diseases such as Alzheimer’s, Parkinson’s and prion diseases are poorly understood. We used a highly toxic misfolded prion protein (TPrP) model to understand neurotoxicity induced by prion protein misfolding. We show that abnormal autophagy activation and neuronal demise is due to severe, neuron-specific, nicotinamide adenine dinucleotide (NAD+) depletion. Toxic prion protein-exposed neuronal cells exhibit dramatic reductions of intracellular NAD+ followed by decreased ATP production, and are completely rescued by treatment with NAD+ or its precursor nicotinamide because of restoration of physiological NAD+ levels. Toxic prion protein-induced NAD+ depletion results from PARP1-independent excessive protein ADP-ribosylations. In vivo, toxic prion protein-induced degeneration of hippocampal neurons is prevented dose-dependently by intracerebral injection of NAD+. Intranasal NAD+ treatment of prion-infected sick mice significantly improves activity and delays motor impairment. Our study reveals NAD+ starvation as a novel mechanism of autophagy activation and neurodegeneration induced by a misfolded amyloidogenic protein. We propose the development of NAD+ replenishment strategies for neuroprotection in prion diseases and possibly other protein misfolding neurodegenerative diseases. PMID:25678560

  6. Caenorhabditis elegans as a model system for studying non-cell-autonomous mechanisms in protein-misfolding diseases

    Directory of Open Access Journals (Sweden)

    Carmen I. Nussbaum-Krammer

    2014-01-01

    Full Text Available Caenorhabditis elegans has a number of distinct advantages that are useful for understanding the basis for cellular and organismal dysfunction underlying age-associated diseases of protein misfolding. Although protein aggregation, a key feature of human neurodegenerative diseases, has been typically explored in vivo at the single-cell level using cells in culture, there is now increasing evidence that proteotoxicity has a non-cell-autonomous component and is communicated between cells and tissues in a multicellular organism. These discoveries have opened up new avenues for the use of C. elegans as an ideal animal model system to study non-cell-autonomous proteotoxicity, prion-like propagation of aggregation-prone proteins, and the organismal regulation of stress responses and proteostasis. This Review focuses on recent evidence that C. elegans has mechanisms to transmit certain classes of toxic proteins between tissues and a complex stress response that integrates and coordinates signals from single cells and tissues across the organism. These findings emphasize the potential of C. elegans to provide insights into non-cell-autonomous proteotoxic mechanisms underlying age-related protein-misfolding diseases.

  7. Why are proteins with glutamine- and asparagine-rich regions associated with protein misfolding diseases?

    Energy Technology Data Exchange (ETDEWEB)

    Cruzeiro, Leonor [CCMAR and FCT, University of Algarve, Campus de Gambelas, 8000 Faro (Portugal)

    2005-12-21

    The possibility that vibrational excited states (VESs) are the drivers of protein folding and function (the VES hypothesis) is explored to explain the reason why Gln- and Asn-rich proteins are associated with degenerative diseases. The Davydov/Scott model is extended to describe energy transfer from the water solution to the protein and vice versa. Computer simulations show that, on average, Gln and Asn residues lead to an initial larger absorption of energy from the environment to the protein, something that can explain the greater structural instability of prions. The sporadic, inherited and infectious character of prion diseases is discussed in the light of the VES hypothesis. An alternative treatment for prion diseases is suggested.

  8. Expansion of the octarepeat domain alters the misfolding pathway but not the folding pathway of the prion protein.

    Science.gov (United States)

    Leliveld, S Rutger; Stitz, Lothar; Korth, Carsten

    2008-06-10

    A misfolded conformation of the prion protein (PrP), PrP (Sc), is the essential component of prions, the infectious agents that cause transmissible neurodegenerative diseases. Insertional mutations that lead to an increase in the number of octarepeats (ORs) in PrP are linked to familial human prion disease. In this study, we investigated how expansion of the OR domain causes PrP to favor a prion-like conformation. Therefore, we compared the conformational and aggregation modulating properties of wild-type versus expanded OR domains, either as a fusion construct with the protein G B1 domain (GB1-OR) or as an integral part of full-length mouse PrP (MoPrP). Using circular dichroism spectroscopy, we first demonstrated that ORs are not unfolded but exist as an ensemble of three distinct conformers: polyproline helix-like, beta-turn, and "Trp-related". Domain expansion had little effect on the conformation of GB1-OR fusion proteins. When part of MoPrP however, OR domain expansion changed PrP's folding landscape, not by hampering the production of native alpha-helical monomers but by greatly reducing the propensity to form amyloid and by altering the assembly of misfolded, beta-rich aggregates. These features may relate to subtle pH-dependent conformational differences between wild-type and mutant monomers. In conclusion, we propose that PrP insertional mutations are pathogenic because they enhance specific misfolding pathways of PrP rather than by undermining native folding. This idea was supported by a trial bioassay in transgenic mice overexpressing wild-type MoPrP, where intracerebral injection of recombinant MoPrP with an expanded OR domain but not wild-type MoPrP caused prion disease.

  9. Disease Transmission by Misfolded Prion-Protein Isoforms, Prion-Like Amyloids, Functional Amyloids and the Central Dogma.

    Science.gov (United States)

    Daus, Martin L

    2016-01-04

    In 1982, the term "prions" (proteinaceous infectious particles) was coined to specify a new principle of infection. A misfolded isoform of a cellular protein has been described as the causative agent of a fatal neurodegenerative disease. At the beginning of prion research scientists assumed that the infectious agent causing transmissible spongiform encephalopathy (TSE) was a virus, but some unconventional properties of these pathogens were difficult to bring in line with the prevailing viral model. The discovery that prions (obviously devoid of any coding nucleic acid) can store and transmit information similarly to DNA was initially even denoted as being "heretical" but is nowadays mainly accepted by the scientific community. This review describes, from a historical point of view, how the "protein-only hypothesis" expands the Central Dogma. Definition of both, the prion principle and the Central Dogma, have been essential steps to understand information storage and transfer within and among cells and organisms. Furthermore, the current understanding of the infectivity of prion-proteins after misfolding is summarized succinctly. Finally, prion-like amyloids and functional amyloids, as found in yeast and bacteria, will be discussed.

  10. Disease Transmission by Misfolded Prion-Protein Isoforms, Prion-Like Amyloids, Functional Amyloids and the Central Dogma

    Directory of Open Access Journals (Sweden)

    Martin L. Daus

    2016-01-01

    Full Text Available In 1982, the term “prions” (proteinaceous infectious particles was coined to specify a new principle of infection. A misfolded isoform of a cellular protein has been described as the causative agent of a fatal neurodegenerative disease. At the beginning of prion research scientists assumed that the infectious agent causing transmissible spongiform encephalopathy (TSE was a virus, but some unconventional properties of these pathogens were difficult to bring in line with the prevailing viral model. The discovery that prions (obviously devoid of any coding nucleic acid can store and transmit information similarly to DNA was initially even denoted as being “heretical” but is nowadays mainly accepted by the scientific community. This review describes, from a historical point of view, how the “protein-only hypothesis” expands the Central Dogma. Definition of both, the prion principle and the Central Dogma, have been essential steps to understand information storage and transfer within and among cells and organisms. Furthermore, the current understanding of the infectivity of prion-proteins after misfolding is summarized succinctly. Finally, prion-like amyloids and functional amyloids, as found in yeast and bacteria, will be discussed.

  11. Chaperoning Proteins for Destruction: Diverse Roles of Hsp70 Chaperones and their Co-Chaperones in Targeting Misfolded Proteins to the Proteasome

    Directory of Open Access Journals (Sweden)

    Ayala Shiber

    2014-07-01

    Full Text Available Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are also necessary for the clearance of terminally misfolded proteins by the Ub-proteasome system. In this capacity, chaperones protect misfolded degradation substrates from spontaneous aggregation, facilitate their recognition by the Ub ligation machinery and finally shuttle the ubiquitylated substrates to the proteasome. The physiological importance of these functions is manifested by inefficient proteasomal degradation and the accumulation of protein aggregates during ageing or in certain neurodegenerative diseases, when chaperone levels decline. In this review, we focus on the diverse roles of stress-induced chaperones in targeting misfolded proteins to the proteasome and the consequences of their compromised activity. We further discuss the implications of these findings to the identification of new therapeutic targets for the treatment of amyloid diseases.

  12. Diminished self-chaperoning activity of the DeltaF508 mutant of CFTR results in protein misfolding.

    Directory of Open Access Journals (Sweden)

    Adrian W R Serohijos

    2008-02-01

    Full Text Available The absence of a functional ATP Binding Cassette (ABC protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR from apical membranes of epithelial cells is responsible for cystic fibrosis (CF. Over 90% of CF patients carry at least one mutant allele with deletion of phenylalanine at position 508 located in the N-terminal nucleotide binding domain (NBD1. Biochemical and cell biological studies show that the DeltaF508 mutant exhibits inefficient biosynthetic maturation and susceptibility to degradation probably due to misfolding of NBD1 and the resultant misassembly of other domains. However, little is known about the direct effect of the Phe508 deletion on the NBD1 folding, which is essential for rational design strategies of cystic fibrosis treatment. Here we show that the deletion of Phe508 alters the folding dynamics and kinetics of NBD1, thus possibly affecting the assembly of the complete CFTR. Using molecular dynamics simulations, we find that meta-stable intermediate states appearing on wild type and mutant folding pathways are populated differently and that their kinetic accessibilities are distinct. The structural basis of the increased misfolding propensity of the DeltaF508 NBD1 mutant is the perturbation of interactions in residue pairs Q493/P574 and F575/F578 found in loop S7-H6. As a proof-of-principle that the S7-H6 loop conformation can modulate the folding kinetics of NBD1, we virtually design rescue mutations in the identified critical interactions to force the S7-H6 loop into the wild type conformation. Two redesigned NBD1-DeltaF508 variants exhibited significantly higher folding probabilities than the original NBD1-DeltaF508, thereby partially rescuing folding ability of the NBD1-DeltaF508 mutant. We propose that these observed defects in folding kinetics of mutant NBD1 may also be modulated by structures separate from the 508 site. The identified structural determinants of increased misfolding propensity of

  13. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase

    NARCIS (Netherlands)

    Jank, Johanna M.; Maier, Esther M.; Reiβ, Dunja D.; Haslbeck, Martin; Kemter, Kristina F.; Truger, Marietta S.; Sommerhoff, Christian P.; Ferdinandusse, Sacha; Wanders, Ronald J.; Gersting, Søren W.; Muntau, Ania C.

    2014-01-01

    The implementation of expanded newborn screening programs reduced mortality and morbidity in medium-chain acyl-CoA dehydrogenase deficiency (MCADD) caused by mutations in the ACADM gene. However, the disease is still potentially fatal. Missense induced MCADD is a protein misfolding disease with a

  14. Temporal resolution of misfolded prion protein transport, accumulation, glial activation, and neuronal death in the retinas of mice inoculated with scrapie

    Science.gov (United States)

    Currently, there is a lack of pathologic landmarks to describe the progression of prion disease in vivo. The goal of this work was to determine the temporal relationship between the transport of misfolded prion protein from the brain to the retina, the accumulation of PrPSc in the retina, the respon...

  15. Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial).

    Science.gov (United States)

    Bella, Eleonora Dalla; Tramacere, Irene; Antonini, Giovanni; Borghero, Giuseppe; Capasso, Margherita; Caponnetto, Claudia; Chiò, Adriano; Corbo, Massimo; Eleopra, Roberto; Filosto, Massimiliano; Giannini, Fabio; Granieri, Enrico; Bella, Vincenzo La; Lunetta, Christian; Mandrioli, Jessica; Mazzini, Letizia; Messina, Sonia; Monsurrò, Maria Rosaria; Mora, Gabriele; Riva, Nilo; Rizzi, Romana; Siciliano, Gabriele; Silani, Vincenzo; Simone, Isabella; Sorarù, Gianni; Volanti, Paolo; Lauria, Giuseppe

    2017-08-11

    Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS. Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan

  16. Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases.

    Directory of Open Access Journals (Sweden)

    Humaira Adnan

    Full Text Available Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD, to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization. The A subunit has evolved to mimic a misfolded protein and hijack the ERAD membrane translocon (dislocon, to effect cytosolic access and cytopathology. We show such toxins compete for ERAD to rescue endogenous misfolded proteins. Cholera toxin or verotoxin (Shiga toxin containing genetically inactivated (± an N-terminal polyleucine tail A subunit can, within 2-4 hrs, temporarily increase F508delCFTR protein, the major cystic fibrosis (CF mutant (5-10x, F508delCFTR Golgi maturation (<10x, cell surface expression (20x and chloride transport (2x in F508del CFTR transfected cells and patient-derived F508delCFTR bronchiolar epithelia, without apparent cytopathology. These toxoids also increase glucocerobrosidase (GCC in N370SGCC Gaucher Disease fibroblasts (3x, another ERAD-exacerbated misfiling disease. We identify a new, potentially benign approach to the treatment of certain genetic protein misfolding diseases.

  17. Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases.

    Science.gov (United States)

    Adnan, Humaira; Zhang, Zhenbo; Park, Hyun-Joo; Tailor, Chetankumar; Che, Clare; Kamani, Mustafa; Spitalny, George; Binnington, Beth; Lingwood, Clifford

    2016-01-01

    Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER) 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD), to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant) subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization. The A subunit has evolved to mimic a misfolded protein and hijack the ERAD membrane translocon (dislocon), to effect cytosolic access and cytopathology. We show such toxins compete for ERAD to rescue endogenous misfolded proteins. Cholera toxin or verotoxin (Shiga toxin) containing genetically inactivated (± an N-terminal polyleucine tail) A subunit can, within 2-4 hrs, temporarily increase F508delCFTR protein, the major cystic fibrosis (CF) mutant (5-10x), F508delCFTR Golgi maturation (glucocerobrosidase (GCC) in N370SGCC Gaucher Disease fibroblasts (3x), another ERAD-exacerbated misfiling disease. We identify a new, potentially benign approach to the treatment of certain genetic protein misfolding diseases.

  18. The Type II Hsp40 Sis1 cooperates with Hsp70 and the E3 ligase Ubr1 to promote degradation of terminally misfolded cytosolic protein.

    Directory of Open Access Journals (Sweden)

    Daniel W Summers

    Full Text Available Mechanisms for cooperation between the cytosolic Hsp70 system and the ubiquitin proteasome system during protein triage are not clear. Herein, we identify new mechanisms for selection of misfolded cytosolic proteins for degradation via defining functional interactions between specific cytosolic Hsp70/Hsp40 pairs and quality control ubiquitin ligases. These studies revolved around the use of S. cerevisiae to elucidate the degradation pathway of a terminally misfolded reporter protein, short-lived GFP (slGFP. The Type I Hsp40 Ydj1 acts with Hsp70 to suppress slGFP aggregation. In contrast, the Type II Hsp40 Sis1 is required for proteasomal degradation of slGFP. Sis1 and Hsp70 operate sequentially with the quality control E3 ubiquitin ligase Ubr1 to target slGFP for degradation. Compromise of Sis1 or Ubr1 function leads slGFP to accumulate in a Triton X-100-soluble state with slGFP degradation intermediates being concentrated into perinuclear and peripheral puncta. Interestingly, when Sis1 activity is low the slGFP that is concentrated into puncta can be liberated from puncta and subsequently degraded. Conversely, in the absence of Ubr1, slGFP and the puncta that contain slGFP are relatively stable. Ubr1 mediates proteasomal degradation of slGFP that is released from cytosolic protein handling centers. Pathways for proteasomal degradation of misfolded cytosolic proteins involve functional interplay between Type II Hsp40/Hsp70 chaperone pairs, PQC E3 ligases, and storage depots for misfolded proteins.

  19. Human stefin B role in cell's response to misfolded proteins and autophagy.

    Directory of Open Access Journals (Sweden)

    Mira Polajnar

    Full Text Available Alternative functions, apart from cathepsins inhibition, are being discovered for stefin B. Here, we investigate its role in vesicular trafficking and autophagy. Astrocytes isolated from stefin B knock-out (KO mice exhibited an increased level of protein aggregates scattered throughout the cytoplasm. Addition of stefin B monomers or small oligomers to the cell medium reverted this phenotype, as imaged by confocal microscopy. To monitor the identity of proteins embedded within aggregates in wild type (wt and KO cells, the insoluble cell lysate fractions were isolated and analyzed by mass spectrometry. Chaperones, tubulins, dyneins, and proteosomal components were detected in the insoluble fraction of wt cells but not in KO aggregates. In contrast, the insoluble fraction of KO cells exhibited increased levels of apolipoprotein E, fibronectin, clusterin, major prion protein, and serpins H1 and I2 and some proteins of lysosomal origin, such as cathepsin D and CD63, relative to wt astrocytes. Analysis of autophagy activity demonstrated that this pathway was less functional in KO astrocytes. In addition, synthetic dosage lethality (SDL gene interactions analysis in Saccharomyces cerevisiae expressing human stefin B suggests a role in transport of vesicles and vacuoles These activities would contribute, directly or indirectly to completion of autophagy in wt astrocytes and would account for the accumulation of protein aggregates in KO cells, since autophagy is a key pathway for the clearance of intracellular protein aggregates.

  20. Random amino acid mutations and protein misfolding lead to Shannon limit in sequence-structure communication.

    Directory of Open Access Journals (Sweden)

    Andreas Martin Lisewski

    2008-09-01

    Full Text Available The transmission of genomic information from coding sequence to protein structure during protein synthesis is subject to stochastic errors. To analyze transmission limits in the presence of spurious errors, Shannon's noisy channel theorem is applied to a communication channel between amino acid sequences and their structures established from a large-scale statistical analysis of protein atomic coordinates. While Shannon's theorem confirms that in close to native conformations information is transmitted with limited error probability, additional random errors in sequence (amino acid substitutions and in structure (structural defects trigger a decrease in communication capacity toward a Shannon limit at 0.010 bits per amino acid symbol at which communication breaks down. In several controls, simulated error rates above a critical threshold and models of unfolded structures always produce capacities below this limiting value. Thus an essential biological system can be realistically modeled as a digital communication channel that is (a sensitive to random errors and (b restricted by a Shannon error limit. This forms a novel basis for predictions consistent with observed rates of defective ribosomal products during protein synthesis, and with the estimated excess of mutual information in protein contact potentials.

  1. Toward unfolding the prion misfolding mystery: protein free radical chemistry in transmissible spongiform encephalopathies

    International Nuclear Information System (INIS)

    Yang Chiming

    2003-01-01

    Owing to the high oxygen-respiration in the brain of mammals, oxidative damage to prion protein has been suggested to be an additional factor. A large body of intriguing features of scrapie and prion diseases have provided multiple lines of indirect chemistry evidence, suggesting that the infectious agents may be putative forms of sequence-specific prion radicals (SSPR) and/or their immediate precursors in the transmissible spongiform encephalopathies (TSE). Here a molecular mechanism corresponding to the self-replication of scrapie protein mediated by prion free-radical processes, consonant with 'protein-only' hypotheses is proposed. This new theory may not only aid our understanding of the occurrence of prions, but also provides new insight into the possible chemistry principles underlying the neutrodegenerative disorders. It is anticipated that future studies based on this suggestion and chemistry principles of genetic diseases may allow us to determine an effective approach to stop mad cow disease and its human version, new variant of Creutzfeldt-Jakob disease (v CJD)

  2. Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.

    Directory of Open Access Journals (Sweden)

    Victoria A Lawson

    Full Text Available BACKGROUND: The accumulation of protease resistant conformers of the prion protein (PrP(res is a key pathological feature of prion diseases. Polyanions, including RNA and glycosaminoglycans have been identified as factors that contribute to the propagation, transmission and pathogenesis of prion disease. Recent studies have suggested that the contribution of these cofactors to prion propagation may be species specific. METHODOLOGY/PRINCIPAL FINDING: In this study a cell-free assay was used to investigate the molecular basis of polyanion stimulated PrP(res formation using brain tissue or cell line derived murine PrP. Enzymatic depletion of endogenous nucleic acids or heparan sulphate (HS from the PrP(C substrate was found to specifically prevent PrP(res formation seeded by mouse derived PrP(Sc. Modification of the negative charge afforded by the sulphation of glycosaminoglycans increased the ability of a familial PrP mutant to act as a substrate for PrP(res formation, while having no effect on PrP(res formed by wildtype PrP. This difference may be due to the observed differences in the binding of wild type and mutant PrP for glycosaminoglycans. CONCLUSIONS/SIGNIFICANCE: Cofactor requirements for PrP(res formation are host species and prion strain specific and affected by disease associated mutations of the prion protein. This may explain both species and strain dependent propagation characteristics and provide insights into the underlying mechanisms of familial prion disease. It further highlights the challenge of designing effective therapeutics against a disease which effects a range of mammalian species, caused by range of aetiologies and prion strains.

  3. The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum membrane for degradation of misfolded proteins.

    Directory of Open Access Journals (Sweden)

    Louise Madsen

    Full Text Available The protein known as p97 or VCP in mammals and Cdc48 in yeast is a versatile ATPase complex involved in several biological functions including membrane fusion, protein folding, and activation of membrane-bound transcription factors. In addition, p97 plays a central role in degradation of misfolded secretory proteins via the ER-associated degradation pathway. This functional diversity of p97 depends on its association with various cofactors, and to further our understanding of p97 function it is important that these cofactors are identified and analyzed. Here, we isolate and characterize the human protein named Rep8 or Ubxd6 as a new cofactor of p97. Mouse Rep8 is highly tissue-specific and abundant in gonads. In testes, Rep8 is expressed in post-meiotic round spermatids, whereas in ovaries Rep8 is expressed in granulosa cells. Rep8 associates directly with p97 via its UBX domain. We show that Rep8 is a transmembrane protein that localizes to the ER membrane with its UBX domain facing the cytoplasm. Knock-down of Rep8 expression in human cells leads to a decreased association of p97 with the ER membrane and concomitantly a retarded degradation of misfolded ER-derived proteasome substrates. Thus, Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation.

  4. The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum membrane for degradation of misfolded proteins

    DEFF Research Database (Denmark)

    Madsen, Louise; Kriegenburg, Franziska; Lages Lino Vala, Andrea

    2011-01-01

    is a transmembrane protein that localizes to the ER membrane with its UBX domain facing the cytoplasm. Knock-down of Rep8 expression in human cells leads to a decreased association of p97 with the ER membrane and concomitantly a retarded degradation of misfolded ER-derived proteasome substrates. Thus, Rep8 tethers p......The protein known as p97 or VCP in mammals and Cdc48 in yeast is a versatile ATPase complex involved in several biological functions including membrane fusion, protein folding, and activation of membrane-bound transcription factors. In addition, p97 plays a central role in degradation of misfolded...... protein named Rep8 or Ubxd6 as a new cofactor of p97. Mouse Rep8 is highly tissue-specific and abundant in gonads. In testes, Rep8 is expressed in post-meiotic round spermatids, whereas in ovaries Rep8 is expressed in granulosa cells. Rep8 associates directly with p97 via its UBX domain. We show that Rep8...

  5. Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism.

    Science.gov (United States)

    Muntau, Ania C; Gersting, Søren W

    2010-12-01

    The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life. Important milestones were the successful development of a low-phenylalanine diet for phenylketonuria patients, the recognition of tetrahydrobiopterin as an option to treat these individuals pharmacologically, and finally market approval of this drug. The work related to the discovery of a pharmacological treatment led metabolic researchers and pediatricians to new insights into the molecular processes linked to mutations in the phenylalanine hydroxylase gene at the cellular and structural level. Again, phenylketonuria became a prototype disorder for a previously underestimated but now rapidly expanding group of diseases: protein misfolding disorders with loss of function. Due to potential general biological mechanisms underlying these disorders, the door may soon open to a systematic development of a new class of pharmaceutical products. These pharmacological chaperones are likely to correct misfolding of proteins involved in numerous genetic and nongenetic diseases.

  6. Rapid and Highly Sensitive Detection of Variant Creutzfeldt-Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies.

    Directory of Open Access Journals (Sweden)

    Maxime Belondrade

    Full Text Available The prevalence of variant Creutzfeldt-Jakob disease (vCJD in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA. This assay allowed the specific detection of minute quantities (10-8 brain dilution of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions.

  7. Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency

    DEFF Research Database (Denmark)

    Pedersen, Christina Bak; Bross, P.; Winter, V.S.

    2003-01-01

    and aggregation of variant SCAD proteins. In this study we investigated the processing of a set of disease-causing variant SCAD proteins (R22W, G68C, W153R, R359C, and Q341H) and two common variant proteins (R147W and G185S) that lead to reduced SCAD activity. All SCAD proteins, including the wild type, associate...... proteolytic degradation by mitochondrial proteases or, especially at elevated temperature, aggregation of non-native conformers. The latter finding may indicate that accumulation of aggregated SCAD proteins may play a role in the pathogenesis of SCAD deficiency.......Short chain acyl-CoA dehydrogenase (SCAD) deficiency is an inborn error of the mitochondrial fatty acid metabolism caused by rare variations as well as common susceptibility variations in the SCAD gene. Earlier studies have shown that a common variant SCAD protein (R147W) was impaired in folding...

  8. The unfolded protein response in melanocytes: activation in response to chemical stressors of the endoplasmic reticulum and tyrosinase misfolding.

    Science.gov (United States)

    Manga, Prashiela; Bis, Sabina; Knoll, Kristen; Perez, Beremis; Orlow, Seth J

    2010-10-01

    Accumulation of proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), comprising three signaling pathways initiated by Ire1, Perk and Atf6 respectively. Unfolded protein response activation was compared in chemically stressed murine wildtype melanocytes and mutant melanocytes that retain tyrosinase in the ER. Thapsigargin, an ER stressor, activated all pathways in wildtype melanocytes, triggering Caspase 12-mediated apoptosis at toxic doses. Albino melanocytes expressing mutant tyrosinase showed evidence of ER stress with increased Ire1 expression, but the downstream effector, Xbp1, was not activated even following thapsigargin treatment. Attenuation of Ire1 signaling was recapitulated in wildtype melanocytes treated with thapsigargin for 8 days, with diminished Xbp1 activation observed after 4 days. Atf6 was also activated in albino melanocytes, with no response to thapsigargin, while the Perk pathway was not activated and thapsigargin treatment elicited robust expression of the downstream effector CCAAT-enhancer-binding protein homologous protein. Thus, melanocytes adapt to ER stress by attenuating two UPR pathways.

  9. Insight into PreImplantation Factor (PIF* mechanism for embryo protection and development: target oxidative stress and protein misfolding (PDI and HSP through essential RIKP [corrected] binding site.

    Directory of Open Access Journals (Sweden)

    Eytan R Barnea

    Full Text Available Endogenous PIF, upon which embryo development is dependent, is secreted only by viable mammalian embryos, and absent in non-viable ones. Synthetic PIF (sPIF administration promotes singly cultured embryos development and protects against their demise caused by embryo-toxic serum. To identify and characterize critical sPIF-embryo protein interactions novel biochemical and bio-analytical methods were specifically devised.FITC-PIF uptake/binding by cultured murine and equine embryos was examined and compared with scrambled FITC-PIF (control. Murine embryo (d10 lysates were fractionated by reversed-phase HPLC, fractions printed onto microarray slides and probed with Biotin-PIF, IDE and Kv1.3 antibodies, using fluorescence detection. sPIF-based affinity column was developed to extract and identify PIF-protein interactions from lysates using peptide mass spectrometry (LC/MS/MS. In silico evaluation examined binding of PIF to critical targets, using mutation analysis.PIF directly targets viable cultured embryos as compared with control peptide, which failed to bind. Multistep Biotin-PIF targets were confirmed by single-step PIF-affinity column based isolation. PIF binds protein disulfide isomerases a prolyl-4-hydroxylase β-subunit, (PDI, PDIA4, PDIA6-like containing the antioxidant thioredoxin domain. PIF also binds protective heat shock proteins (70&90, co-chaperone, BAG-3. Remarkably, PIF targets a common RIKP [corrected] site in PDI and HSP proteins. Further, single PIF amino acid mutation significantly reduced peptide-protein target bonding. PIF binds promiscuous tubulins, neuron backbones and ACTA-1,2 visceral proteins. Significant anti-IDE, while limited anti-Kv1.3b antibody-binding to Biotin-PIF positive lysates HPLC fractions were documented.Collectively, data identifies PIF shared targets on PDI and HSP in the embryo. Such are known to play a critical role in protecting against oxidative stress and protein misfolding. PIF-affinity-column is a

  10. C-E1 fusion protein synthesized by rubella virus DI RNAs maintained during serial passage

    International Nuclear Information System (INIS)

    Tzeng, W.-P.; Frey, Teryl K.

    2006-01-01

    Rubella virus (RUB) replicons are derivatives of the RUB infectious cDNA clone that retain the nonstructural open reading frame (NS-ORF) that encodes the replicase proteins but not the structural protein ORF (SP-ORF) that encodes the virion proteins. RUB defective interfering (DI) RNAs contain deletions within the SP-ORF and thus resemble replicons. DI RNAs often retain the 5' end of the capsid protein (C) gene that has been shown to modulate virus-specific RNA synthesis. However, when replicons either with or without the C gene were passaged serially in the presence of wt RUB as a source of the virion proteins, it was found that neither replicon was maintained and DI RNAs were generated. The majority DI RNA species contained in-frame deletions in the SP-ORF leading to a fusion between the 5' end of the C gene and the 3' end of the E1 glycoprotein gene. DI infectious cDNA clones were constructed and transcripts from these DI infectious cDNA clones were maintained during serial passage with wt RUB. The C-E1 fusion protein encoded by the DI RNAs was synthesized and was required for maintenance of the DI RNA during serial passage. This is the first report of a functional novel gene product resulting from deletion during DI RNA generation. Thus far, the role of the C-E1 fusion protein in maintenance of DI RNAs during serial passage remained elusive as it was found that the fusion protein diminished rather than enhanced DI RNA synthesis and was not incorporated into virus particles

  11. Raster-scanning serial protein crystallography using micro- and nano-focused synchrotron beams

    Energy Technology Data Exchange (ETDEWEB)

    Coquelle, Nicolas [Université Grenoble Alpes, IBS, 38044 Grenoble (France); CNRS, IBS, 38044 Grenoble (France); CEA, IBS, 38044 Grenoble (France); Brewster, Aaron S. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Kapp, Ulrike; Shilova, Anastasya; Weinhausen, Britta [European Synchrotron Radiation Facility, BP 220, 38043 Grenoble (France); Burghammer, Manfred, E-mail: burgham@esrf.fr [European Synchrotron Radiation Facility, BP 220, 38043 Grenoble (France); Ghent University, Ghent B-9000 (Belgium); Colletier, Jacques-Philippe, E-mail: burgham@esrf.fr [Université Grenoble Alpes, IBS, 38044 Grenoble (France); CNRS, IBS, 38044 Grenoble (France); CEA, IBS, 38044 Grenoble (France)

    2015-05-01

    A raster scanning serial protein crystallography approach is presented, that consumes as low ∼200–700 nl of sedimented crystals. New serial data pre-analysis software, NanoPeakCell, is introduced. High-resolution structural information was obtained from lysozyme microcrystals (20 µm in the largest dimension) using raster-scanning serial protein crystallography on micro- and nano-focused beamlines at the ESRF. Data were collected at room temperature (RT) from crystals sandwiched between two silicon nitride wafers, thereby preventing their drying, while limiting background scattering and sample consumption. In order to identify crystal hits, new multi-processing and GUI-driven Python-based pre-analysis software was developed, named NanoPeakCell, that was able to read data from a variety of crystallographic image formats. Further data processing was carried out using CrystFEL, and the resultant structures were refined to 1.7 Å resolution. The data demonstrate the feasibility of RT raster-scanning serial micro- and nano-protein crystallography at synchrotrons and validate it as an alternative approach for the collection of high-resolution structural data from micro-sized crystals. Advantages of the proposed approach are its thriftiness, its handling-free nature, the reduced amount of sample required, the adjustable hit rate, the high indexing rate and the minimization of background scattering.

  12. Protein Turnover Measurements in Human Serum by Serial Immunoaffinity LC-MS/MS.

    Science.gov (United States)

    Farrokhi, Vahid; Chen, Xiaoying; Neubert, Hendrik

    2018-02-01

    The half-life of target proteins is frequently an important parameter in mechanistic pharmacokinetic and pharmacodynamic (PK/PD) modeling of biotherapeutics. Clinical studies for accurate measurement of physiologically relevant protein turnover can reduce the uncertainty in PK/PD model-based predictions, for example, of the therapeutic dose and dosing regimen in first-in-human clinical trials. We used a targeted mass spectrometry work flow based on serial immunoaffinity enrichment ofmultiple human serum proteins from a [5,5,5- 2 H 3 ]-L-leucine tracer pulse-chase study in healthy volunteers. To confirm the reproducibility of turnover measurements from serial immunoaffinity enrichment, multiple aliquots from the same sample set were subjected to protein turnover analysis in varying order. Tracer incorporation was measured by multiple-reaction-monitoring mass spectrometry and target turnover was calculated using a four-compartment pharmacokinetic model. Five proteins of clinical or therapeutic relevance including soluble tumor necrosis factor receptor superfamily member 12A, tissue factor pathway inhibitor, soluble interleukin 1 receptor like 1, soluble mucosal addressin cell adhesion molecule 1, and muscle-specific creatine kinase were sequentially subjected to turnover analysis from the same human serum sample. Calculated half-lives ranged from 5-15 h; however, no tracer incorporation was observed for mucosal addressin cell adhesion molecule 1. The utility of clinical pulse-chase studies to investigate protein turnover can be extended by serial immunoaffinity enrichment of target proteins. Turnover analysis from serum and subsequently from remaining supernatants provided analytical sensitivity and reproducibility for multiple human target proteins in the same sample set, irrespective of the order of analysis. © 2017 American Association for Clinical Chemistry.

  13. Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review.

    Science.gov (United States)

    Thelin, Eric Peter; Zeiler, Frederick Adam; Ercole, Ari; Mondello, Stefania; Büki, András; Bellander, Bo-Michael; Helmy, Adel; Menon, David K; Nelson, David W

    2017-01-01

    The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term "effective half-life" ( t 1/2 ) in order to describe the "fall" rate in serum. Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations. Following screening (10,389 papers), n  = 122 papers were included. The proteins S100B ( n  = 66) and NSE ( n  = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t 1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1-2 h) though possibly of non-cerebral origin. In contrast, the t 1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP ( n  = 18) appears to have t 1/2 of about 24-48 h in severe TBI. The protein UCH-L1 ( n  = 9) presents a t 1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L ( n  = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use. Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be

  14. Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Eric Peter Thelin

    2017-07-01

    Full Text Available BackgroundThe proteins S100B, neuron-specific enolase (NSE, glial fibrillary acidic protein (GFAP, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1, and neurofilament light (NF-L have been serially sampled in serum of patients suffering from traumatic brain injury (TBI in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term “effective half-life” (t1/2 in order to describe the “fall” rate in serum.Materials and methodsThrough searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations.ResultsFollowing screening (10,389 papers, n = 122 papers were included. The proteins S100B (n = 66 and NSE (n = 27 were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1–2 h though possibly of non-cerebral origin. In contrast, the t1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP (n = 18 appears to have t1/2 of about 24–48 h in severe TBI. The protein UCH-L1 (n = 9 presents a t1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n = 2 only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use.ConclusionSerial sampling of brain-specific proteins in serum reveals

  15. The Copper Metabolism MURR1 Domain protein 1 (COMMD1) modulates the aggregation of misfolded protein species in a client-specific manner

    NARCIS (Netherlands)

    W.I.M. Vonk (Willianne I.); V. Kakkar (Vaishali); P. Bartuzi (Paulina); D. Jaarsma (Dick); R. Berger (Ruud); M.A. Hofker (Marten); L.W.J. Klomp (Leo W.); C. Wijmenga (Cisca); H. Kampinga (Harm); B. van de Sluis (Bart)

    2014-01-01

    textabstractThe Copper Metabolism MURR1 domain protein 1 (COMMD1) is a protein involved in multiple cellular pathways, including copper homeostasis, NF-κB and hypoxia signalling. Acting as a scaffold protein, COMMD1 mediates the levels, stability and proteolysis of its substrates (e.g. the

  16. In meso in situ serial X-ray crystallography of soluble and membrane proteins

    International Nuclear Information System (INIS)

    Huang, Chia-Ying; Olieric, Vincent; Ma, Pikyee; Panepucci, Ezequiel; Diederichs, Kay; Wang, Meitian; Caffrey, Martin

    2015-01-01

    A method for performing high-throughput in situ serial X-ray crystallography with soluble and membrane proteins in the lipid cubic phase is described. It works with microgram quantities of protein and lipid (and ligand when present) and is compatible with the most demanding sulfur SAD phasing. The lipid cubic phase (LCP) continues to grow in popularity as a medium in which to generate crystals of membrane (and soluble) proteins for high-resolution X-ray crystallographic structure determination. To date, the PDB includes 227 records attributed to the LCP or in meso method. Among the listings are some of the highest profile membrane proteins, including the β 2 -adrenoreceptor–G s protein complex that figured in the award of the 2012 Nobel Prize in Chemistry to Lefkowitz and Kobilka. The most successful in meso protocol to date uses glass sandwich crystallization plates. Despite their many advantages, glass plates are challenging to harvest crystals from. However, performing in situ X-ray diffraction measurements with these plates is not practical. Here, an alternative approach is described that provides many of the advantages of glass plates and is compatible with high-throughput in situ measurements. The novel in meso in situ serial crystallography (IMISX) method introduced here has been demonstrated with AlgE and PepT (alginate and peptide transporters, respectively) as model integral membrane proteins and with lysozyme as a test soluble protein. Structures were solved by molecular replacement and by experimental phasing using bromine SAD and native sulfur SAD methods to resolutions ranging from 1.8 to 2.8 Å using single-digit microgram quantities of protein. That sulfur SAD phasing worked is testament to the exceptional quality of the IMISX diffraction data. The IMISX method is compatible with readily available, inexpensive materials and equipment, is simple to implement and is compatible with high-throughput in situ serial data collection at macromolecular

  17. Serial millisecond crystallography of membrane and soluble protein microcrystals using synchrotron radiation.

    Science.gov (United States)

    Martin-Garcia, Jose M; Conrad, Chelsie E; Nelson, Garrett; Stander, Natasha; Zatsepin, Nadia A; Zook, James; Zhu, Lan; Geiger, James; Chun, Eugene; Kissick, David; Hilgart, Mark C; Ogata, Craig; Ishchenko, Andrii; Nagaratnam, Nirupa; Roy-Chowdhury, Shatabdi; Coe, Jesse; Subramanian, Ganesh; Schaffer, Alexander; James, Daniel; Ketwala, Gihan; Venugopalan, Nagarajan; Xu, Shenglan; Corcoran, Stephen; Ferguson, Dale; Weierstall, Uwe; Spence, John C H; Cherezov, Vadim; Fromme, Petra; Fischetti, Robert F; Liu, Wei

    2017-07-01

    Crystal structure determination of biological macromolecules using the novel technique of serial femtosecond crystallography (SFX) is severely limited by the scarcity of X-ray free-electron laser (XFEL) sources. However, recent and future upgrades render microfocus beamlines at synchrotron-radiation sources suitable for room-temperature serial crystallography data collection also. Owing to the longer exposure times that are needed at synchrotrons, serial data collection is termed serial millisecond crystallography (SMX). As a result, the number of SMX experiments is growing rapidly, with a dozen experiments reported so far. Here, the first high-viscosity injector-based SMX experiments carried out at a US synchrotron source, the Advanced Photon Source (APS), are reported. Microcrystals (5-20 µm) of a wide variety of proteins, including lysozyme, thaumatin, phycocyanin, the human A 2A adenosine receptor (A 2A AR), the soluble fragment of the membrane lipoprotein Flpp3 and proteinase K, were screened. Crystals suspended in lipidic cubic phase (LCP) or a high-molecular-weight poly(ethylene oxide) (PEO; molecular weight 8 000 000) were delivered to the beam using a high-viscosity injector. In-house data-reduction (hit-finding) software developed at APS as well as the SFX data-reduction and analysis software suites Cheetah and CrystFEL enabled efficient on-site SMX data monitoring, reduction and processing. Complete data sets were collected for A 2A AR, phycocyanin, Flpp3, proteinase K and lysozyme, and the structures of A 2A AR, phycocyanin, proteinase K and lysozyme were determined at 3.2, 3.1, 2.65 and 2.05 Å resolution, respectively. The data demonstrate the feasibility of serial millisecond crystallography from 5-20 µm crystals using a high-viscosity injector at APS. The resolution of the crystal structures obtained in this study was dictated by the current flux density and crystal size, but upcoming developments in beamline optics and the planned APS

  18. Serial millisecond crystallography of membrane and soluble protein microcrystals using synchrotron radiation

    Directory of Open Access Journals (Sweden)

    Jose M. Martin-Garcia

    2017-07-01

    Full Text Available Crystal structure determination of biological macromolecules using the novel technique of serial femtosecond crystallography (SFX is severely limited by the scarcity of X-ray free-electron laser (XFEL sources. However, recent and future upgrades render microfocus beamlines at synchrotron-radiation sources suitable for room-temperature serial crystallography data collection also. Owing to the longer exposure times that are needed at synchrotrons, serial data collection is termed serial millisecond crystallography (SMX. As a result, the number of SMX experiments is growing rapidly, with a dozen experiments reported so far. Here, the first high-viscosity injector-based SMX experiments carried out at a US synchrotron source, the Advanced Photon Source (APS, are reported. Microcrystals (5–20 µm of a wide variety of proteins, including lysozyme, thaumatin, phycocyanin, the human A2A adenosine receptor (A2AAR, the soluble fragment of the membrane lipoprotein Flpp3 and proteinase K, were screened. Crystals suspended in lipidic cubic phase (LCP or a high-molecular-weight poly(ethylene oxide (PEO; molecular weight 8 000 000 were delivered to the beam using a high-viscosity injector. In-house data-reduction (hit-finding software developed at APS as well as the SFX data-reduction and analysis software suites Cheetah and CrystFEL enabled efficient on-site SMX data monitoring, reduction and processing. Complete data sets were collected for A2AAR, phycocyanin, Flpp3, proteinase K and lysozyme, and the structures of A2AAR, phycocyanin, proteinase K and lysozyme were determined at 3.2, 3.1, 2.65 and 2.05 Å resolution, respectively. The data demonstrate the feasibility of serial millisecond crystallography from 5–20 µm crystals using a high-viscosity injector at APS. The resolution of the crystal structures obtained in this study was dictated by the current flux density and crystal size, but upcoming developments in beamline optics and the

  19. Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases

    OpenAIRE

    Adnan, Humaira; Zhang, Zhenbo; Park, Hyun-Joo; Tailor, Chetankumar; Che, Clare; Kamani, Mustafa; Spitalny, George; Binnington, Beth; Lingwood, Clifford

    2016-01-01

    Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER) 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD), to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant) subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization. The A subu...

  20. Neurodegeneration in D-bifunctional protein deficiency: diagnostic clues and natural history using serial magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Aneal [University of Calgary, Department of Medical Genetics and Pediatrics, Alberta Children' s Hospital, Calgary, AB (Canada); Wei, Xing-Chang [University of Calgary, Department of Radiology, Alberta Children' s Hospital, Calgary, AB (Canada); Snyder, Floyd F. [Alberta Children' s Hospital, Biochemical Genetics Laboratory, Calgary, AB (Canada); Mah, Jean K. [University of Calgary, Division of Neurology, Department of Pediatrics, Calgary, AB (Canada); Waterham, Hans; Wanders, Ronald J.A. [University of Amsterdam, Academic Medical Center, Lab Genetic Metabolic Diseases, Amsterdam (Netherlands)

    2010-12-15

    We report serial neurodegenerative changes on neuroimaging in a rare peroxisomal disease called D-bifunctional protein deficiency. The pattern of posterior to anterior demyelination with white matter disease resembles X-linked adrenoleukodystrophy. We feel this case is important to (1) highlight that D-bifunctional protein deficiency should be considered in cases where the neuroimaging resembles X-linked adrenoleukodystrophy, (2) to show different stages of progression to help identify this disease using neuroimaging in children, and (3) to show that neuroimaging suggesting a leukodystrophy can warrant peroxisomal beta-oxidation studies in skin fibroblasts even when plasma very long chain fatty acids are normal. (orig.)

  1. Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis?

    Science.gov (United States)

    Kabashi, Edor; Valdmanis, Paul N; Dion, Patrick; Rouleau, Guy A

    2007-12-01

    The identification in 1993 of superoxide dismutase-1 (SOD1) mutations as the cause of 10 to 20% of familial amyotrophic lateral sclerosis cases, which represents 1 to 2% of all amyotrophic lateral sclerosis (ALS) cases, prompted a substantial amount of research into the mechanisms of SOD1-mediated toxicity. Recent experiments have demonstrated that oxidation of wild-type SOD1 leads to its misfolding, causing it to gain many of the same toxic properties as mutant SOD1. In vitro studies of oxidized/misfolded SOD1 and in vivo studies of misfolded SOD1 have indicated that these protein species are selectively toxic to motor neurons, suggesting that oxidized/misfolded SOD1 could lead to ALS even in individuals who do not carry an SOD1 mutation. It has also been reported that glial cells secrete oxidized/misfolded mutant SOD1 to the extracellular environment, where it can trigger the selective death of motor neurons, offering a possible explanation for the noncell autonomous nature of mutant SOD1 toxicity and the rapid progression of disease once the first symptoms develop. Therefore, considering that sporadic (SALS) and familial ALS (FALS) cases are clinically indistinguishable, the toxic properties of mutated SOD1 are similar to that of oxidized/misfolded wild-type SOD1 (wtSOD1), and secreted/extracellular misfolded SOD1 is selectively toxic to motor neurons, we propose that oxidized/misfolded SOD1 is the cause of most forms of classic ALS and should be a prime target for the design of ALS treatments.

  2. Import and Export of Misfolded α-Synuclein

    Directory of Open Access Journals (Sweden)

    Lilia Rodriguez

    2018-05-01

    Full Text Available In Parkinson's disease, intracellular α-synuclein (α-syn inclusions form in neurons and are referred to as Lewy bodies. These aggregates spread through the brain following a specific pattern leading to the hypothesis that neuron-to-neuron transfer is critical for the propagation of Lewy body pathology. Here we review recent studies employing pre-formed fibrils generated from recombinant α-syn to evaluate the uptake, trafficking, and release of α-syn fibrils. We outline methods of internalization as well as cell surface receptors that have been described in the literature as regulating α-syn fibril uptake. Pharmacological and genetic studies indicate endocytosis is the primary method of α-syn internalization. Once α-syn fibrils have crossed the plasma membrane they are typically trafficked through the endo-lysosomal system with autophagy acting as the dominant method of α-syn clearance. Interestingly, both chaperone-mediated autophagy and macroautophagy have been implicated in the degradation of α-syn, although it remains unclear which system is chiefly responsible for the removal of α-syn fibrils. The major hallmark of α-syn spreading is the templating of misfolded properties onto healthy protein resulting in a conformational change; we summarize the evidence indicating misfolded α-syn can seed endogenous α-syn to form new aggregates. Finally, recent studies demonstrate that cells release misfolded and aggregated α-syn and that these processes may involve different chaperones. Nonetheless, the exact mechanism for the release of fibrillar α-syn remains unclear. This review highlights what is known, and what requires further clarification, regarding each step of α-syn transmission.

  3. Experimental sheep BSE prions generate the vCJD phenotype when serially passaged in transgenic mice expressing human prion protein.

    Science.gov (United States)

    Joiner, Susan; Asante, Emmanuel A; Linehan, Jacqueline M; Brock, Lara; Brandner, Sebastian; Bellworthy, Susan J; Simmons, Marion M; Hope, James; Collinge, John; Wadsworth, Jonathan D F

    2018-03-15

    The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), causes variant Creutzfeldt-Jakob disease (vCJD) in humans following dietary exposure. While it is assumed that all cases of vCJD attributed to a dietary aetiology are related to cattle BSE, sheep and goats are susceptible to experimental oral challenge with cattle BSE prions and farmed animals in the UK were undoubtedly exposed to BSE-contaminated meat and bone meal during the late 1980s and early 1990s. Although no natural field cases of sheep BSE have been identified, it cannot be excluded that some BSE-infected sheep might have entered the European human food chain. Evaluation of the zoonotic potential of sheep BSE prions has been addressed by examining the transmission properties of experimental brain isolates in transgenic mice that express human prion protein, however to-date there have been relatively few studies. Here we report that serial passage of experimental sheep BSE prions in transgenic mice expressing human prion protein with methionine at residue 129 produces the vCJD phenotype that mirrors that seen when the same mice are challenged with vCJD prions from patient brain. These findings are congruent with those reported previously by another laboratory, and thereby strongly reinforce the view that sheep BSE prions could have acted as a causal agent of vCJD within Europe. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Membrane protein structure determination by SAD, SIR, or SIRAS phasing in serial femtosecond crystallography using an iododetergent

    Science.gov (United States)

    Nakane, Takanori; Hanashima, Shinya; Suzuki, Mamoru; Saiki, Haruka; Hayashi, Taichi; Kakinouchi, Keisuke; Sugiyama, Shigeru; Kawatake, Satoshi; Matsuoka, Shigeru; Matsumori, Nobuaki; Nango, Eriko; Kobayashi, Jun; Shimamura, Tatsuro; Kimura, Kanako; Mori, Chihiro; Kunishima, Naoki; Sugahara, Michihiro; Takakyu, Yoko; Inoue, Shigeyuki; Masuda, Tetsuya; Hosaka, Toshiaki; Tono, Kensuke; Joti, Yasumasa; Kameshima, Takashi; Hatsui, Takaki; Inoue, Tsuyoshi; Nureki, Osamu; Iwata, So; Murata, Michio; Mizohata, Eiichi

    2016-01-01

    The 3D structure determination of biological macromolecules by X-ray crystallography suffers from a phase problem: to perform Fourier transformation to calculate real space density maps, both intensities and phases of structure factors are necessary; however, measured diffraction patterns give only intensities. Although serial femtosecond crystallography (SFX) using X-ray free electron lasers (XFELs) has been steadily developed since 2009, experimental phasing still remains challenging. Here, using 7.0-keV (1.771 Å) X-ray pulses from the SPring-8 Angstrom Compact Free Electron Laser (SACLA), iodine single-wavelength anomalous diffraction (SAD), single isomorphous replacement (SIR), and single isomorphous replacement with anomalous scattering (SIRAS) phasing were performed in an SFX regime for a model membrane protein bacteriorhodopsin (bR). The crystals grown in bicelles were derivatized with an iodine-labeled detergent heavy-atom additive 13a (HAD13a), which contains the magic triangle, I3C head group with three iodine atoms. The alkyl tail was essential for binding of the detergent to the surface of bR. Strong anomalous and isomorphous difference signals from HAD13a enabled successful phasing using reflections up to 2.1-Å resolution from only 3,000 and 4,000 indexed images from native and derivative crystals, respectively. When more images were merged, structure solution was possible with data truncated at 3.3-Å resolution, which is the lowest resolution among the reported cases of SFX phasing. Moreover, preliminary SFX experiment showed that HAD13a successfully derivatized the G protein-coupled A2a adenosine receptor crystallized in lipidic cubic phases. These results pave the way for de novo structure determination of membrane proteins, which often diffract poorly, even with the brightest XFEL beams. PMID:27799539

  5. Room-temperature serial crystallography using a kinetically optimized microfluidic device for protein crystallization and on-chip X-ray diffraction

    Directory of Open Access Journals (Sweden)

    Michael Heymann

    2014-09-01

    Full Text Available An emulsion-based serial crystallographic technology has been developed, in which nanolitre-sized droplets of protein solution are encapsulated in oil and stabilized by surfactant. Once the first crystal in a drop is nucleated, the small volume generates a negative feedback mechanism that lowers the supersaturation. This mechanism is exploited to produce one crystal per drop. Diffraction data are measured, one crystal at a time, from a series of room-temperature crystals stored on an X-ray semi-transparent microfluidic chip, and a 93% complete data set is obtained by merging single diffraction frames taken from different unoriented crystals. As proof of concept, the structure of glucose isomerase was solved to 2.1 Å, demonstrating the feasibility of high-throughput serial X-ray crystallography using synchrotron radiation.

  6. An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis

    Directory of Open Access Journals (Sweden)

    Melissa S Rotunno

    2013-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disorder that targets motor neurons, leading to paralysis and death within a few years of disease onset. While several genes have been linked to the inheritable, or familial, form of ALS, much less is known about the cause(s of sporadic ALS, which accounts for approximately 90% of ALS cases. Due to the clinical similarities between familial and sporadic ALS, it is plausible that both forms of the disease converge on a common pathway and, therefore, involve common factors. Recent evidence suggests the Cu,Zn-superoxide dismutase (SOD1 protein to be one such factor that is common to both sporadic and familial ALS. In 1993, mutations were uncovered in SOD1 that represent the first known genetic cause of familial ALS. While the exact mechanism of mutant-SOD1 toxicity is still not known today, most evidence points to a gain of toxic function that stems, at least in part, from the propensity of this protein to misfold. In the wild-type SOD1 protein, non-genetic perturbations such as metal depletion, disruption of the quaternary structure, and oxidation, can also induce SOD1 to misfold. In fact, these aforementioned post-translational modifications cause wild-type SOD1 to adopt a toxic conformation that is similar to familial ALS-linked SOD1 variants. These observations, together with the detection of misfolded wild-type SOD1 within human post-mortem sporadic ALS samples, have been used to support the controversial hypothesis that misfolded forms of wild-type SOD1 contribute to sporadic ALS pathogenesis. In this review, we present data from the literature that both support and contradict this hypothesis. We also discuss SOD1 as a potential therapeutic target for both familial and sporadic ALS.

  7. Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy

    Science.gov (United States)

    Cortes, Constanza J.; Qin, Kefeng; Norstrom, Eric M.; Green, William N.; Bindokas, Vytautas P.; Mastrianni, James A.

    2013-01-01

    Prion diseases are linked to the accumulation of a misfolded isoform (PrPSc) of prion protein (PrP). Evidence suggests that lysosomes are degradation endpoints and sites of the accumulation of PrPSc. We questioned whether lysosomes participate in the early quality control of newly generated misfolded PrP. We found PrP carrying the disease-associated T182A mutation (Mut-PrP) was delivered to lysosomes in a Golgi-independent manner. Time-lapse live cell imaging revealed early formation and uptake of GFP-tagged Mut-PrP aggregates into LysoTracker labeled vesicles. Compared with Wt-PrP, Mut-PrP expression was associated with an elevation in several markers of the autophagy-lysosomal pathway, and it extensively colocalized with the autophagosome-specific marker, LC3B. In autophagy deficient (ATG5−/−) mouse embryonic fibroblasts, or in normal cells treated with the autophagy-inhibitor 3-MA, Mut-PrP colocalization with lysosomes was reduced to a similar extent. Additionally, 3-MA selectively impaired the degradation of insoluble Mut-PrP, resulting in an increase in protease-resistant PrP, whereas the induction of autophagy by rapamycin reduced it. These findings suggest that autophagy might function as a quality control mechanism to limit the accumulation of misfolded PrP that normally leads to the generation of PrPSc. PMID:24454378

  8. Diagnostic Value of Serial Measurement of C-Reactive Protein in the Detection of a Surgical Complication after Laparoscopic Bowel Resection for Endometriosis

    DEFF Research Database (Denmark)

    Riiskjær, Mads; Forman, Axel; Kesmodel, Ulrik Schiøler

    2016-01-01

    AIMS: The study aimed to assess the diagnostic value of serial monitoring of biochemical inflammatory markers (C-reactive protein (CRP) and white blood cell (WBC) count) in the postoperative diagnosis of anastomotic leakage or ureteral injury after bowel resection for deep infiltrating endometrio......AIMS: The study aimed to assess the diagnostic value of serial monitoring of biochemical inflammatory markers (C-reactive protein (CRP) and white blood cell (WBC) count) in the postoperative diagnosis of anastomotic leakage or ureteral injury after bowel resection for deep infiltrating...... endometriosis. METHODS: This is a review of prospectively collected data from 217 patients who underwent laparoscopic bowel resection for endometriosis from January 2009 to April 2015. Patients with an anastomotic leakage or ureteral injury were identified and classified. RESULTS: The frequency of anastomotic...... leakage requiring reoperation was 8.3%. The frequency of ureteral injury was 4.6%. Median time to diagnosis was 6 days for anastomotic leakage and 8 days for ureteral injury. The daily mean values of serum CRP were significantly higher in patients with a surgical complication starting at the second...

  9. Common features in the unfolding and misfolding of PDZ domains and beyond: the modulatory effect of domain swapping and extra-elements.

    Science.gov (United States)

    Murciano-Calles, Javier; Güell-Bosch, Jofre; Villegas, Sandra; Martinez, Jose C

    2016-01-12

    PDZ domains are protein-protein interaction modules sharing the same structural arrangement. To discern whether they display common features in their unfolding/misfolding behaviour we have analyzed in this work the unfolding thermodynamics, together with the misfolding kinetics, of the PDZ fold using three archetypical examples: the second and third PDZ domains of the PSD95 protein and the Erbin PDZ domain. Results showed that all domains passed through a common intermediate, which populated upon unfolding, and that this in turn drove the misfolding towards worm-like fibrillar structures. Thus, the unfolding/misfolding behaviour appears to be shared within these domains. We have also analyzed how this landscape can be modified upon the inclusion of extra-elements, as it is in the nNOS PDZ domain, or the organization of swapped species, as happens in the second PDZ domain of the ZO2 protein. Although the intermediates still formed upon thermal unfolding, the misfolding was prevented to varying degrees.

  10. Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways.

    Science.gov (United States)

    Zilka, Norbert; Kazmerova, Zuzana; Jadhav, Santosh; Neradil, Peter; Madari, Aladar; Obetkova, Dominika; Bugos, Ondrej; Novak, Michal

    2012-03-07

    Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD) and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease.

  11. Highly efficient proteome analysis with combination of protein pre-fractionation by preparative microscale solution isoelectric focusing and identification by μRPLC-MS/MS with serially coupled long microcolumn.

    Science.gov (United States)

    Tao, Dingyin; Sun, Liangliang; Zhu, Guijie; Liang, Yu; Liang, Zhen; Zhang, Lihua; Zhang, Yukui

    2011-01-01

    To improve the efficiency of proteome analysis, a strategy with the combination of protein pre-fractionation by preparative microscale solution isoelectric focusing, peptide separation by μRPLC with serially coupled long microcolumn and protein identification by ESI-MS/MS was proposed. By preparative microscale solution isoelectric focusing technique, proteins extracted from whole cell lysates of Escherichia coli were fractionated into five chambers divided by isoelectric membranes, respectively with pH range from 3.0 to 4.6, 4.6 to 5.4, 5.4 to 6.2, 6.2 to 7.0 and 7.0 to 10.0. Compared to the traditional on-gel IFF, the protein recovery could be obviously improved to over 95%. Subsequently, the enriched and fractionated proteins in each chamber were digested, and further separated by a 30-cm long serially coupled RP microcolumn. Through the detection by ESI-MS/MS, about 200 proteins were identified in each fraction, and in total 835 proteins were identified even with one-dimensional μRPLC-MS/MS system. All these results demonstrate that by such a combination strategy, highly efficient proteome analysis could be achieved, not only due to the in-solution protein enrichment and pre-fractionation with improved protein recovery but also owing to the increased separation capacity of serially coupled long μRPLC columns. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Nanoflow electrospinning serial femtosecond crystallography

    Energy Technology Data Exchange (ETDEWEB)

    Sierra, Raymond G.; Laksmono, Hartawan [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Kern, Jan [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Tran, Rosalie; Hattne, Johan [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Alonso-Mori, Roberto [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Lassalle-Kaiser, Benedikt [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Glöckner, Carina; Hellmich, Julia [Technische Universität Berlin, Strasse des 17 Juni 135, 10623 Berlin (Germany); Schafer, Donald W. [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Echols, Nathaniel; Gildea, Richard J.; Grosse-Kunstleve, Ralf W. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Sellberg, Jonas [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Stockholm University, S-106 91 Stockholm (Sweden); McQueen, Trevor A. [Stanford University, Stanford, CA 94025 (United States); Fry, Alan R.; Messerschmidt, Marc M.; Miahnahri, Alan; Seibert, M. Marvin; Hampton, Christina Y.; Starodub, Dmitri; Loh, N. Duane; Sokaras, Dimosthenis; Weng, Tsu-Chien [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Zwart, Petrus H. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Glatzel, Pieter [European Synchrotron Radiation Facility, Grenoble (France); Milathianaki, Despina; White, William E. [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Adams, Paul D. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Williams, Garth J.; Boutet, Sébastien [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Zouni, Athina [Technische Universität Berlin, Strasse des 17 Juni 135, 10623 Berlin (Germany); Messinger, Johannes [Umeå Universitet, Umeå (Sweden); Sauter, Nicholas K. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Bergmann, Uwe [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); Yano, Junko; Yachandra, Vittal K. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Bogan, Michael J., E-mail: mbogan@slac.stanford.edu [SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States); SLAC National Accelerator Laboratory, Menlo Park, CA 94025 (United States)

    2012-11-01

    A low flow rate liquid microjet method for delivery of hydrated protein crystals to X-ray lasers is presented. Linac Coherent Light Source data demonstrates serial femtosecond protein crystallography with micrograms, a reduction of sample consumption by orders of magnitude. An electrospun liquid microjet has been developed that delivers protein microcrystal suspensions at flow rates of 0.14–3.1 µl min{sup −1} to perform serial femtosecond crystallography (SFX) studies with X-ray lasers. Thermolysin microcrystals flowed at 0.17 µl min{sup −1} and diffracted to beyond 4 Å resolution, producing 14 000 indexable diffraction patterns, or four per second, from 140 µg of protein. Nanoflow electrospinning extends SFX to biological samples that necessitate minimal sample consumption.

  13. Nanoflow electrospinning serial femtosecond crystallography

    International Nuclear Information System (INIS)

    Sierra, Raymond G.; Laksmono, Hartawan; Kern, Jan; Tran, Rosalie; Hattne, Johan; Alonso-Mori, Roberto; Lassalle-Kaiser, Benedikt; Glöckner, Carina; Hellmich, Julia; Schafer, Donald W.; Echols, Nathaniel; Gildea, Richard J.; Grosse-Kunstleve, Ralf W.; Sellberg, Jonas; McQueen, Trevor A.; Fry, Alan R.; Messerschmidt, Marc M.; Miahnahri, Alan; Seibert, M. Marvin; Hampton, Christina Y.; Starodub, Dmitri; Loh, N. Duane; Sokaras, Dimosthenis; Weng, Tsu-Chien; Zwart, Petrus H.; Glatzel, Pieter; Milathianaki, Despina; White, William E.; Adams, Paul D.; Williams, Garth J.; Boutet, Sébastien; Zouni, Athina; Messinger, Johannes; Sauter, Nicholas K.; Bergmann, Uwe; Yano, Junko; Yachandra, Vittal K.; Bogan, Michael J.

    2012-01-01

    A low flow rate liquid microjet method for delivery of hydrated protein crystals to X-ray lasers is presented. Linac Coherent Light Source data demonstrates serial femtosecond protein crystallography with micrograms, a reduction of sample consumption by orders of magnitude. An electrospun liquid microjet has been developed that delivers protein microcrystal suspensions at flow rates of 0.14–3.1 µl min −1 to perform serial femtosecond crystallography (SFX) studies with X-ray lasers. Thermolysin microcrystals flowed at 0.17 µl min −1 and diffracted to beyond 4 Å resolution, producing 14 000 indexable diffraction patterns, or four per second, from 140 µg of protein. Nanoflow electrospinning extends SFX to biological samples that necessitate minimal sample consumption

  14. Crossed wires: 3D genome misfolding in human disease.

    Science.gov (United States)

    Norton, Heidi K; Phillips-Cremins, Jennifer E

    2017-11-06

    Mammalian genomes are folded into unique topological structures that undergo precise spatiotemporal restructuring during healthy development. Here, we highlight recent advances in our understanding of how the genome folds inside the 3D nucleus and how these folding patterns are miswired during the onset and progression of mammalian disease states. We discuss potential mechanisms underlying the link among genome misfolding, genome dysregulation, and aberrant cellular phenotypes. We also discuss cases in which the endogenous 3D genome configurations in healthy cells might be particularly susceptible to mutation or translocation. Together, these data support an emerging model in which genome folding and misfolding is critically linked to the onset and progression of a broad range of human diseases. © 2017 Norton and Phillips-Cremins.

  15. A hydrophobic gold surface triggers misfolding and aggregation of the amyloidogenic Josephin domain in monomeric form, while leaving the oligomers unaffected.

    Directory of Open Access Journals (Sweden)

    Alessandra Apicella

    Full Text Available Protein misfolding and aggregation in intracellular and extracellular spaces is regarded as a main marker of the presence of degenerative disorders such as amyloidoses. To elucidate the mechanisms of protein misfolding, the interaction of proteins with inorganic surfaces is of particular relevance, since surfaces displaying different wettability properties may represent model systems of the cell membrane. Here, we unveil the role of surface hydrophobicity/hydrophilicity in the misfolding of the Josephin domain (JD, a globular-shaped domain of ataxin-3, the protein responsible for the spinocerebellar ataxia type 3. By means of a combined experimental and theoretical approach based on atomic force microscopy, Fourier transform infrared spectroscopy and molecular dynamics simulations, we reveal changes in JD morphology and secondary structure elicited by the interaction with the hydrophobic gold substrate, but not by the hydrophilic mica. Our results demonstrate that the interaction with the gold surface triggers misfolding of the JD when it is in native-like configuration, while no structural modification is observed after the protein has undergone oligomerization. This raises the possibility that biological membranes would be unable to affect amyloid oligomeric structures and toxicity.

  16. Developments in Serials: 1977

    Science.gov (United States)

    James, John R.

    1978-01-01

    Discusses issues and developments relating to several aspects of serials, including economics and acquisitions; bibliographic control; automation; education; serials literature and bibliographies; and copyrights. A bibliography is included. (Author/MBR)

  17. Decreasing Serial Cost Sharing

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Østerdal, Lars Peter

    The increasing serial cost sharing rule of Moulin and Shenker [Econometrica 60 (1992) 1009] and the decreasing serial rule of de Frutos [Journal of Economic Theory 79 (1998) 245] have attracted attention due to their intuitive appeal and striking incentive properties. An axiomatic characterization...... of the increasing serial rule was provided by Moulin and Shenker [Journal of Economic Theory 64 (1994) 178]. This paper gives an axiomatic characterization of the decreasing serial rule...

  18. Decreasing serial cost sharing

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Østerdal, Lars Peter Raahave

    2009-01-01

    The increasing serial cost sharing rule of Moulin and Shenker (Econometrica 60:1009-1037, 1992) and the decreasing serial rule of de Frutos (J Econ Theory 79:245-275, 1998) are known by their intuitive appeal and striking incentive properties. An axiomatic characterization of the increasing serial...... rule was provided by Moulin and Shenker (J Econ Theory 64:178-201, 1994). This paper gives an axiomatic characterization of the decreasing serial rule....

  19. Misfolded Gβ is recruited to cytoplasmic dynein by Nudel for efficient clearance

    Institute of Scientific and Technical Information of China (English)

    Yihan Wan; Zhenye Yang; Jing Guo; Qiangge Zhang; Liyong Zeng; Wei Song; Yue Xiao; Xueliang Zhu

    2012-01-01

    The Gβγ heterodimer is an important signal transducer.Gβ,however,is prone to misfolding due to its requirement for Gγ and chaperones for proper folding.How cells dispose of misfolded Gβ (mfGβ) is not clear.Here,we showed that mfGβ was able to be polyubiquitinated and subsequently degraded by the proteasome.It was sequestered in aggresomes after the inhibition of the proteasome activity with MG132.Sustained activation of Gβγ signaling further elevated cellular levels of the ubiquitinated Gβ.Moreover,Nudel,a regulator of cytoplasmic dynein,the microtubule minus end-directed motor,directly interacted with both the unubiquitinated and ubiquitinated mfGβ.Increasing the levels of both mfGβ and Nudel promoted the association of Gβ with both Nudel and dynein,resulting in robust aggresome formation in a dynein-dependent manner.Depletion of Nudel by RNAi reduced the dynein-associated mfGβ,impaired the MG132-induced aggresome formation,and markedly prolonged the half-life of nascent Gβ.Therefore,cytosolic mfGβ is recruited to dynein by Nudel and transported to the centrosome for rapid sequestration and degradation.Such a process not only eliminates mfGβ efficiently for the control of protein quality,but may also help to terminate the Gβγ signaling.

  20. Serial MRI in early Creutzfeldt-Jacob disease with a point mutation of prion protein at codon 180

    International Nuclear Information System (INIS)

    Ishida, S.; Sugino, M.; Shinoda, K.; Ohsawa, N.; Koizumi, N.; Ohta, T.; Kitamoto, T.; Tateishi, J.

    1995-01-01

    We report a 66-year-old woman with histologically diagnosed Creutzfeld-Jacob disease (CJD), followed with MRI from an early clinical stage. MRI demonstrated expansion of the high cortical signal on T2-weighted images, which differs from previous MRI reports of CJD. This patient followed an atypical clinical course: 16 months had passed before she developed akinetic mutism, and periodic sharp waves had not been detected on EEG after 2 years in spite of her akinetic mutism. Brain biopsy showed primary spongiform changes in the grey matter, and a point mutation of the prion protein gene at codon 180 was discovered using polymerase chain reaction direct sequencing and Tth 111 I cutting. This is the first case with the point mutation of the codon 180 variant with an atypical clinical course and characteristic MRI findings. (orig.)

  1. Dual Role of Ancient Ubiquitous Protein 1 (AUP1) in Lipid Droplet Accumulation and Endoplasmic Reticulum (ER) Protein Quality Control

    OpenAIRE

    Klemm, Elizabeth J.; Spooner, Eric; Ploegh, Hidde L.

    2011-01-01

    Quality control of endoplasmic reticulum proteins involves the identification and engagement of misfolded proteins, dislocation of the misfolded protein across the endoplasmic reticulum (ER) membrane, and ubiquitin-mediated targeting to the proteasome for degradation. Ancient ubiquitous protein 1 (AUP1) physically associates with the mammalian HRD1-SEL1L complex, and AUP1 depletion impairs degradation of misfolded ER proteins. One of the functions of AUP1 in ER quality control is to recruit t...

  2. The biology of non-native proteins

    NARCIS (Netherlands)

    Herczenik, E.

    2007-01-01

    Protein misfolding diseases are linked by common principles of protein aggregation, plaque development and tissue damage. There is no adequate therapy for these highly debilitating diseases. This thesis aims to increase the understanding of protein misfolding diseases, which will hopefully lead to

  3. ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations.

    Directory of Open Access Journals (Sweden)

    Benfeard Williams

    2015-10-01

    Full Text Available The increased risk of developing Alzheimer's disease (AD is associated with the APOE gene, which encodes for three variants of Apolipoprotein E, namely E2, E3, E4, differing only by two amino acids at positions 112 and 158. ApoE4 is known to be the strongest risk factor for AD onset, while ApoE3 and ApoE2 are considered to be the AD-neutral and AD-protective isoforms, respectively. It has been hypothesized that the ApoE isoforms may contribute to the development of AD by modifying the homeostasis of ApoE physiological partners and AD-related proteins in an isoform-specific fashion. Here we find that, despite the high sequence similarity among the three ApoE variants, only ApoE4 exhibits a misfolded intermediate state characterized by isoform-specific domain-domain interactions in molecular dynamics simulations. The existence of an ApoE4-specific intermediate state can contribute to the onset of AD by altering multiple cellular pathways involved in ApoE-dependent lipid transport efficiency or in AD-related protein aggregation and clearance. We present what we believe to be the first structural model of an ApoE4 misfolded intermediate state, which may serve to elucidate the molecular mechanism underlying the role of ApoE4 in AD pathogenesis. The knowledge of the structure for the ApoE4 folding intermediate provides a new platform for the rational design of alternative therapeutic strategies to fight AD.

  4. Nanoflow electrospinning serial femtosecond crystallography

    Science.gov (United States)

    Sierra, Raymond G.; Laksmono, Hartawan; Kern, Jan; Tran, Rosalie; Hattne, Johan; Alonso-Mori, Roberto; Lassalle-Kaiser, Benedikt; Glöckner, Carina; Hellmich, Julia; Schafer, Donald W.; Echols, Nathaniel; Gildea, Richard J.; Grosse-Kunstleve, Ralf W.; Sellberg, Jonas; McQueen, Trevor A.; Fry, Alan R.; Messerschmidt, Marc M.; Miahnahri, Alan; Seibert, M. Marvin; Hampton, Christina Y.; Starodub, Dmitri; Loh, N. Duane; Sokaras, Dimosthenis; Weng, Tsu-Chien; Zwart, Petrus H.; Glatzel, Pieter; Milathianaki, Despina; White, William E.; Adams, Paul D.; Williams, Garth J.; Boutet, Sébastien; Zouni, Athina; Messinger, Johannes; Sauter, Nicholas K.; Bergmann, Uwe; Yano, Junko; Yachandra, Vittal K.; Bogan, Michael J.

    2012-01-01

    An electrospun liquid microjet has been developed that delivers protein microcrystal suspensions at flow rates of 0.14–3.1 µl min−1 to perform serial femtosecond crystallography (SFX) studies with X-ray lasers. Thermolysin microcrystals flowed at 0.17 µl min−1 and diffracted to beyond 4 Å resolution, producing 14 000 indexable diffraction patterns, or four per second, from 140 µg of protein. Nanoflow electrospinning extends SFX to biological samples that necessitate minimal sample consumption. PMID:23090408

  5. CRNL library serials list

    International Nuclear Information System (INIS)

    Alburger, T.P.

    1982-04-01

    A list of 1900 serial publications (periodicals, society transactions and proceedings, annuals and directories, indexes, newspapers, etc.) is presented with volumes and years held by the Main Library. This library is the largest in AECL as well as one of the largest scientific and technical libraries in North America, and functions as a Canadian resource for nuclear information. A main alphabetical list is followed by broad subject field lists representing research interests, and lists of abstract and index serials, general bibliographic serials, conference indexes, press releases, English translations, and original language journals

  6. Playing at Serial Acquisitions

    NARCIS (Netherlands)

    J.T.J. Smit (Han); T. Moraitis (Thras)

    2010-01-01

    textabstractBehavioral biases can result in suboptimal acquisition decisions-with the potential for errors exacerbated in consolidating industries, where consolidators design serial acquisition strategies and fight escalating takeover battles for platform companies that may determine their future

  7. Classifying serial killers.

    Science.gov (United States)

    Promish, D I; Lester, D

    1999-11-08

    We attempted to match the appearance and demeanor of 27 serial killers to the postmortem 'signatures' found on their victims' bodies. Our results suggest that a link may exist between postmortem signatures and two complementary appearance-demeanor types.

  8. Na+/K+-ATPase is present in scrapie-associated fibrils, modulates PrP misfolding in vitro and links PrP function and dysfunction.

    Directory of Open Access Journals (Sweden)

    James F Graham

    Full Text Available Transmissible spongiform encephalopathies are characterised by widespread deposition of fibrillar and/or plaque-like forms of the prion protein. These aggregated forms are produced by misfolding of the normal prion protein, PrP(C, to the disease-associated form, PrP(Sc, through mechanisms that remain elusive but which require either direct or indirect interaction between PrP(C and PrP(Sc isoforms. A wealth of evidence implicates other non-PrP molecules as active participants in the misfolding process, to catalyse and direct the conformational conversion of PrP(C or to provide a scaffold ensuring correct alignment of PrP(C and PrP(Sc during conversion. Such molecules may be specific to different scrapie strains to facilitate differential prion protein misfolding. Since molecular cofactors may become integrated into the growing protein fibril during prion conversion, we have investigated the proteins contained in prion disease-specific deposits by shotgun proteomics of scrapie-associated fibrils (SAF from mice infected with 3 different strains of mouse-passaged scrapie. Concomitant use of negative control preparations allowed us to identify and discount proteins that are enriched non-specifically by the SAF isolation protocol. We found several proteins that co-purified specifically with SAF from infected brains but none of these were reproducibly and demonstrably specific for particular scrapie strains. The α-chain of Na(+/K(+-ATPase was common to SAF from all 3 strains and we tested the ability of this protein to modulate in vitro misfolding of recombinant PrP. Na(+/K(+-ATPase enhanced the efficiency of disease-specific conversion of recombinant PrP suggesting that it may act as a molecular cofactor. Consistent with previous results, the same protein inhibited fibrillisation kinetics of recombinant PrP. Since functional interactions between PrP(C and Na(+/K(+-ATPase have previously been reported in astrocytes, our data highlight this molecule as

  9. Cellular strategies to cope with protein aggregation

    NARCIS (Netherlands)

    Scior, Annika; Juenemann, Katrin; Kirstein, Janine

    2016-01-01

    Nature has evolved several mechanisms to detoxify intracellular protein aggregates that arise upon proteotoxic challenges. These include the controlled deposition of misfolded proteins at distinct cellular sites, the protein disaggregation and refolding by molecular chaperones and/or degradation of

  10. Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset.

    Directory of Open Access Journals (Sweden)

    Christine Vande Velde

    Full Text Available Mutations in superoxide dismutase (SOD1 are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced green fluorescent protein is selectively expressed in motor neurons, we demonstrate that axonal mitochondria of motor neurons are primary in vivo targets for misfolded SOD1. Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning pre-symptomatically and increasing in severity as disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape. These data indicate that mutant SOD1 binding to mitochondria disrupts normal mitochondrial distribution and size homeostasis as early pathogenic features of SOD1 mutant-mediated ALS.

  11. The Windows serial port programming handbook

    CERN Document Server

    Bai, Ying

    2004-01-01

    The fundamentals of serial port communications. Serial port programming in ANSI C and Assembly languages for MS-DOS. Serial ports interface developed in VC++ 6.0. Serial port programming in Visual Basic. Serial port programming in LabVIEW. Serial port programming in MATLAB. Serial port programming in Smalltalk. Serial port programming in Java.

  12. Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin

    Energy Technology Data Exchange (ETDEWEB)

    Hill, Shannon E.; Nguyen, Elaine; Donegan, Rebecca K.; Patterson-Orazem, Athéna C.; Hazel, Anthony; Gumbart, James C.; Lieberman, Raquel L.

    2017-11-01

    Glaucoma-associated myocilin is a member of the olfactomedins, a protein family involved in neuronal development and human diseases. Molecular studies of the myocilin N-terminal coiled coil demonstrate a unique tripartite architecture: a Y-shaped parallel dimer-of-dimers with distinct tetramer and dimer regions. The structure of the dimeric C-terminal 7-heptad repeats elucidates an unexpected repeat pattern involving inter-strand stabilization by oppositely charged residues. Molecular dynamics simulations reveal an alternate accessible conformation in which the terminal inter-strand disulfide limits the extent of unfolding and results in a kinked configuration. By inference, full-length myocilin is also branched, with two pairs of C-terminal olfactomedin domains. Selected variants within the N-terminal region alter the apparent quaternary structure of myocilin but do so without compromising stability or causing aggregation. In addition to increasing our structural knowledge of naturally occurring extracellular coiled coils and biomedically important olfactomedins, this work broadens the scope of protein misfolding in the pathogenesis of myocilin-associated glaucoma.

  13. Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin.

    Science.gov (United States)

    Hill, Shannon E; Nguyen, Elaine; Donegan, Rebecca K; Patterson-Orazem, Athéna C; Hazel, Anthony; Gumbart, James C; Lieberman, Raquel L

    2017-11-07

    Glaucoma-associated myocilin is a member of the olfactomedins, a protein family involved in neuronal development and human diseases. Molecular studies of the myocilin N-terminal coiled coil demonstrate a unique tripartite architecture: a Y-shaped parallel dimer-of-dimers with distinct tetramer and dimer regions. The structure of the dimeric C-terminal 7-heptad repeats elucidates an unexpected repeat pattern involving inter-strand stabilization by oppositely charged residues. Molecular dynamics simulations reveal an alternate accessible conformation in which the terminal inter-strand disulfide limits the extent of unfolding and results in a kinked configuration. By inference, full-length myocilin is also branched, with two pairs of C-terminal olfactomedin domains. Selected variants within the N-terminal region alter the apparent quaternary structure of myocilin but do so without compromising stability or causing aggregation. In addition to increasing our structural knowledge of naturally occurring extracellular coiled coils and biomedically important olfactomedins, this work broadens the scope of protein misfolding in the pathogenesis of myocilin-associated glaucoma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Serial interprocessor communications system

    International Nuclear Information System (INIS)

    Labiak, W.; Siemens, P.; Bailey, C.

    1980-01-01

    A serial communications system based on the EIA RS232-C standard with modem control lines has been developed. The DLV11-E interface is used for this purpose. All handshaking is done with the modem control lines. This allows totally independent full duplex communication. The message format consists of eight bit data with odd parity and a sixteen bit checksum on the whole message. All communications are fully interrupt driven. A program was written to load a program into a remote LSI-11 using the serial line without bootstrap ROM

  15. Selection and Serial Entrepreneurs

    DEFF Research Database (Denmark)

    Chen, Jing

    2013-01-01

    There is substantial evidence that serial entrepreneurs outperform de novo entrepreneurs. But is this positive association between prior experience and performance the result of learning by doing or of selection on ability? This paper proposes a strategy that combines the fixed-effects model and IV...... when the analysis focuses on founding new startups in sectors closely related to entrepreneurs' previous ventures....

  16. Selection and Serial Entrepreneurs

    DEFF Research Database (Denmark)

    Chen, Jing

    2011-01-01

    Although it has been broadly evidenced that entrepreneurial experience plays a substantial role in the emergence of serial entrepreneurship, the debate is still going on about whether this relationship should be attributed to learning by doing or instead be explained by selection on ability. This...

  17. Serial private infrastructures

    NARCIS (Netherlands)

    van den Berg, V.A.C.

    2013-01-01

    This paper investigates private supply of two congestible infrastructures that are serial, where the consumer has to use both in order to consume. Four market structures are analysed: a monopoly and 3 duopolies that differ in how firms interact. It is well known that private supply leads too high

  18. Stress in Harmonic Serialism

    Science.gov (United States)

    Pruitt, Kathryn Ringler

    2012-01-01

    This dissertation proposes a model of word stress in a derivational version of Optimality Theory (OT) called Harmonic Serialism (HS; Prince and Smolensky 1993/2004, McCarthy 2000, 2006, 2010a). In this model, the metrical structure of a word is derived through a series of optimizations in which the "best" metrical foot is chosen…

  19. Suicide in serial killers.

    Science.gov (United States)

    Lester, David; White, John

    2010-02-01

    In a sample of 248 killers of two victims in America from 1900 to 2005, obtained from an encyclopedia of serial killers by Newton (2006), those completing suicide did not differ in sex, race, or the motive for the killing from those who were arrested.

  20. Malaysian Serials: Issues and Problems.

    Science.gov (United States)

    Bahri, Che Norma

    This paper analyzes the issues and problems while looking at the trends and developments of serials publishing in Malaysia. The first section provides background; topics addressed include the country and people of Malaysia, the history of serials publishing in Malaysia, categories and formats of serials publishing, academic publications,…

  1. Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients.

    Directory of Open Access Journals (Sweden)

    Isil Keskin

    Full Text Available Mutations in superoxide dismutase-1 (SOD1 are a common known cause of amyotrophic lateral sclerosis (ALS. The neurotoxicity of mutant SOD1s is most likely caused by misfolded molecular species, but disease pathogenesis is still not understood. Proposed mechanisms include impaired mitochondrial function, induction of endoplasmic reticulum stress, reduction in the activities of the proteasome and autophagy, and the formation of neurotoxic aggregates. Here we examined whether perturbations in these cellular pathways in turn influence levels of misfolded SOD1 species, potentially amplifying neurotoxicity. For the study we used fibroblasts, which express SOD1 at physiological levels under regulation of the native promoter. The cells were derived from ALS patients expressing 9 different SOD1 mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in C9orf72 and from non-disease controls. A specific ELISA was used to quantify soluble, misfolded SOD1, and aggregated SOD1 was analysed by western blotting. Misfolded SOD1 was detected in all lines. Levels were found to be much lower in non-disease control and the non-SOD1 C9orf72 ALS lines. This enabled us to validate patient fibroblasts for use in subsequent perturbation studies. Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded SOD1 and in most cases, detergent-resistant SOD1 aggregates were not detected. However, proteasome inhibition led to uniformly large increases in misfolded SOD1 levels in all cell lines and an increase in SOD1 aggregation in some. Thus the ubiquitin-proteasome pathway is a principal determinant of misfolded SOD1 levels in cells derived both from patients and controls and a decline in activity with aging could be one of the factors behind the mid-to late-life onset of inherited ALS.

  2. Delaware's first serial killer.

    Science.gov (United States)

    Inguito, G B; Sekula-Perlman, A; Lynch, M J; Callery, R T

    2000-11-01

    The violent murder of Shirley Ellis on November 29, 1987, marked the beginning of the strange and terrible tale of Steven Bryan Pennell's reign as the state of Delaware's first convicted serial killer. Three more bodies followed the first victim, and all had been brutally beaten and sadistically tortured. The body of a fifth woman has never been found. State and county police collaborated with the FBI to identify and hunt down their suspect, forming a task force of over 100 officers and spending about one million dollars. Through their knowledge and experience with other serial killers, the FBI was able to make an amazingly accurate psychological profile of Delaware's serial killer. After months of around-the-clock surveillance, Steven Pennell was arrested on November 29, 1988, one year to the day after the first victim was found. Pennell was found guilty in the deaths of the first two victims on November 29, 1989, and plead no contest to the murder of two others on October 30, 1991. Still maintaining his innocence, he asked for the death penalty so that he could spare his family further agony. Steven Pennell was executed by lethal injection on March 15, 1992.

  3. Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin.

    Science.gov (United States)

    He, Bin Z; Ludwig, Michael Z; Dickerson, Desiree A; Barse, Levi; Arun, Bharath; Vilhjálmsson, Bjarni J; Jiang, Pengyao; Park, Soo-Young; Tamarina, Natalia A; Selleck, Scott B; Wittkopp, Patricia J; Bell, Graeme I; Kreitman, Martin

    2014-02-01

    The identification and validation of gene-gene interactions is a major challenge in human studies. Here, we explore an approach for studying epistasis in humans using a Drosophila melanogaster model of neonatal diabetes mellitus. Expression of the mutant preproinsulin (hINS(C96Y)) in the eye imaginal disc mimics the human disease: it activates conserved stress-response pathways and leads to cell death (reduction in eye area). Dominant-acting variants in wild-derived inbred lines from the Drosophila Genetics Reference Panel produce a continuous, highly heritable distribution of eye-degeneration phenotypes in a hINS(C96Y) background. A genome-wide association study (GWAS) in 154 sequenced lines identified a sharp peak on chromosome 3L, which mapped to a 400-bp linkage block within an intron of the gene sulfateless (sfl). RNAi knockdown of sfl enhanced the eye-degeneration phenotype in a mutant-hINS-dependent manner. RNAi against two additional genes in the heparan sulfate (HS) biosynthetic pathway (ttv and botv), in which sfl acts, also modified the eye phenotype in a hINS(C96Y)-dependent manner, strongly suggesting a novel link between HS-modified proteins and cellular responses to misfolded proteins. Finally, we evaluated allele-specific expression difference between the two major sfl-intronic haplotypes in heterozygtes. The results showed significant heterogeneity in marker-associated gene expression, thereby leaving the causal mutation(s) and its mechanism unidentified. In conclusion, the ability to create a model of human genetic disease, map a QTL by GWAS to a specific gene, and validate its contribution to disease with available genetic resources and the potential to experimentally link the variant to a molecular mechanism demonstrate the many advantages Drosophila holds in determining the genetic underpinnings of human disease.

  4. Comparing the Folding and Misfolding Energy Landscapes of Phosphoglycerate Kinase

    OpenAIRE

    Agocs, Gergely; Szabo, Bence T.; Koehler, Gottfried; Osvath, Szabolcs

    2012-01-01

    Partitioning of polypeptides between protein folding and amyloid formation is of outstanding pathophysiological importance. Using yeast phosphoglycerate kinase as model, here we identify the features of the energy landscape that decide the fate of the protein: folding or amyloidogenesis. Structure formation was initiated from the acid-unfolded state, and monitored by fluorescence from 10 ms to 20 days. Solvent conditions were gradually shifted between folding and amyloidogenesis, and the prop...

  5. Diagnostic value of serial measurement of C-reactive protein in serum and matrix metalloproteinase-9 in drainage fluid in the detection of infectious complications and anastomotic leakage in patients with colorectal resection.

    Science.gov (United States)

    Kostić, Zoran; Panišić, Marina; Milev, Boško; Mijušković, Zoran; Slavković, Damjan; Ignjatović, Mile

    2015-10-01

    Postoperative infectious complications are one of the most important problems in surgical treatment of colorectal cancer (CRC), being present in up to 40% of patients. The aim of this paper was to establish the significance of serial measurement of C-reactive protein (CRP) in serum and matrix metalloproteinase-9 (MMP-9) in drainage fluid for the detection of infectious complications and anastomotic leakage (AL) in patients with colorectal resection. CRP and MMP-9 values in serum and drainage fluid, respectively, were measured on the first, third, fifth, and seventh postoperative day (POD) in 150 patients with colorectal resection and primary anastomosis. The values obtained were compared between the patients without complicatons and those with surgical site and remote infections and AL. Surgical site infections (SSIs) were observed in 41 (27.3%), and remote infections in 10 (6.7%) patients. Clinically evident AL was observed in 15 (10/6) patients. In 82% of the patients with SSIs, serum CRP value on POD 5 exceeded 82 mg/L, with 81% specificity. AL was reported in 85% and 92% of the patients on PODs 5 and 7, respectively, with CRP values of 77 mg/L and 90 mg/L, respectively. The specificity was 77% for POD 5 and 88% for POD 7. All the patients with CRP values exceeding 139 mg/L on POD 5 had some of SSIs and/or AL. The mean values of MMP-9 were not statistically different between the group without complications (n = 99) and the group with AL (n = 15). Serial measurement of CRP is recommended for screening of infectious complications of colorectal resection. Patients with CRP values above 139 mg/L on POD 5 cannot be discharged from hospital, and require an intensive search for infectious complications, particularly AL. MMP-9 measurement in drainage fluid is not relevant in the detection of AL in patients with colorectal resection.

  6. Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers

    NARCIS (Netherlands)

    Mannini, Benedetta; Cascella, Roberta; Zampagni, Mariagioia; Van Waarde-Verhagen, Maria; Meehan, Sarah; Roodveldt, Cintia; Campioni, Silvia; Boninsegna, Matilde; Penco, Amanda; Relini, Annalisa; Kampinga, Harm H.; Dobson, Christopher M.; Wilson, Mark R.; Cecchi, Cristina; Chiti, Fabrizio

    2012-01-01

    Chaperones are the primary regulators of the proteostasis network and are known to facilitate protein folding, inhibit protein aggregation, and promote disaggregation and clearance of misfolded aggregates inside cells. We have tested the effects of five chaperones on the toxicity of misfolded

  7. Noncoding RNAs in protein clearance pathways: implications in ...

    Indian Academy of Sciences (India)

    Several studies from model organisms suggest upregulation of pathways that clear this toxic protein may provide .... part of UPS have been genetically linked to neurodegener- ... tionally modified or any other misfolded protein are poten-.

  8. Cytosolic protein quality control of the orphan protein Fas2, a novel physiological substrate of the E3 ligase Ubr1

    OpenAIRE

    Scazzari, Mario

    2013-01-01

    Cellular protein quality control (PQC) monitors the proper folding of polypeptides, assembly of protein subunits into protein complexes as well as the delivery of terminally misfolded proteins to degradation. The components of PQC known best at the moment are molecular chaperones and the ubiquitin proteasome system. In contrast to the well-described protein quality control system of the endoplasmic reticulum (ERAD), less is known about how misfolded proteins in the cytosol are recognized and ...

  9. Serial Network Flow Monitor

    Science.gov (United States)

    Robinson, Julie A.; Tate-Brown, Judy M.

    2009-01-01

    Using a commercial software CD and minimal up-mass, SNFM monitors the Payload local area network (LAN) to analyze and troubleshoot LAN data traffic. Validating LAN traffic models may allow for faster and more reliable computer networks to sustain systems and science on future space missions. Research Summary: This experiment studies the function of the computer network onboard the ISS. On-orbit packet statistics are captured and used to validate ground based medium rate data link models and enhance the way that the local area network (LAN) is monitored. This information will allow monitoring and improvement in the data transfer capabilities of on-orbit computer networks. The Serial Network Flow Monitor (SNFM) experiment attempts to characterize the network equivalent of traffic jams on board ISS. The SNFM team is able to specifically target historical problem areas including the SAMS (Space Acceleration Measurement System) communication issues, data transmissions from the ISS to the ground teams, and multiple users on the network at the same time. By looking at how various users interact with each other on the network, conflicts can be identified and work can begin on solutions. SNFM is comprised of a commercial off the shelf software package that monitors packet traffic through the payload Ethernet LANs (local area networks) on board ISS.

  10. Native sulfur/chlorine SAD phasing for serial femtosecond crystallography

    International Nuclear Information System (INIS)

    Nakane, Takanori; Song, Changyong; Suzuki, Mamoru; Nango, Eriko; Kobayashi, Jun; Masuda, Tetsuya; Inoue, Shigeyuki; Mizohata, Eiichi; Nakatsu, Toru; Tanaka, Tomoyuki; Tanaka, Rie; Shimamura, Tatsuro; Tono, Kensuke; Joti, Yasumasa; Kameshima, Takashi; Hatsui, Takaki; Yabashi, Makina; Nureki, Osamu; Iwata, So; Sugahara, Michihiro

    2015-01-01

    Sulfur SAD phasing facilitates the structure determination of diverse native proteins using femtosecond X-rays from free-electron lasers via serial femtosecond crystallography. Serial femtosecond crystallography (SFX) allows structures to be determined with minimal radiation damage. However, phasing native crystals in SFX is not very common. Here, the structure determination of native lysozyme from single-wavelength anomalous diffraction (SAD) by utilizing the anomalous signal of sulfur and chlorine at a wavelength of 1.77 Å is successfully demonstrated. This sulfur SAD method can be applied to a wide range of proteins, which will improve the determination of native crystal structures

  11. Development of isothermal-isobaric replica-permutation method for molecular dynamics and Monte Carlo simulations and its application to reveal temperature and pressure dependence of folded, misfolded, and unfolded states of chignolin

    Science.gov (United States)

    Yamauchi, Masataka; Okumura, Hisashi

    2017-11-01

    We developed a two-dimensional replica-permutation molecular dynamics method in the isothermal-isobaric ensemble. The replica-permutation method is a better alternative to the replica-exchange method. It was originally developed in the canonical ensemble. This method employs the Suwa-Todo algorithm, instead of the Metropolis algorithm, to perform permutations of temperatures and pressures among more than two replicas so that the rejection ratio can be minimized. We showed that the isothermal-isobaric replica-permutation method performs better sampling efficiency than the isothermal-isobaric replica-exchange method and infinite swapping method. We applied this method to a β-hairpin mini protein, chignolin. In this simulation, we observed not only the folded state but also the misfolded state. We calculated the temperature and pressure dependence of the fractions on the folded, misfolded, and unfolded states. Differences in partial molar enthalpy, internal energy, entropy, partial molar volume, and heat capacity were also determined and agreed well with experimental data. We observed a new phenomenon that misfolded chignolin becomes more stable under high-pressure conditions. We also revealed this mechanism of the stability as follows: TYR2 and TRP9 side chains cover the hydrogen bonds that form a β-hairpin structure. The hydrogen bonds are protected from the water molecules that approach the protein as the pressure increases.

  12. Protein quality control in the nucleus

    DEFF Research Database (Denmark)

    Nielsen, Sofie V.; Poulsen, Esben Guldahl; Rebula, Caio A.

    2014-01-01

    to aggregate, cells have evolved several elaborate quality control systems to deal with these potentially toxic proteins. First, various molecular chaperones will seize the misfolded protein and either attempt to refold the protein or target it for degradation via the ubiquitin-proteasome system...... to be particularly active in protein quality control. Thus, specific ubiquitin-protein ligases located in the nucleus, target not only misfolded nuclear proteins, but also various misfolded cytosolic proteins which are transported to the nucleus prior to their degradation. In comparison, much less is known about...... these mechanisms in mammalian cells. Here we highlight recent advances in our understanding of nuclear protein quality control, in particular regarding substrate recognition and proteasomal degradation....

  13. Union Listing via OCLC's Serials Control Subsystem.

    Science.gov (United States)

    O'Malley, Terrence J.

    1984-01-01

    Describes library use of Conversion of Serials Project's (CONSER) online national machine-readable database for serials to create online union lists of serials via OCLC's Serial Control Subsystem. Problems in selection of appropriate, accurate, and authenticated records and prospects for the future are discussed. Twenty sources and sample records…

  14. Serial Femtosecond Crystallography

    OpenAIRE

    Chapman, Henry N.

    2015-01-01

    X-ray free-electron lasers produce brief flashes of X-rays that are of about a billion times higher peak brightness than achievable from storage ring sources. Such a tremendous jump in X-ray source capabilities, which came in 2009 when the Linac Coherent Light Source began operations, was unprecedented in the history of X-ray science. Protein structure determination through the method of macromolecular crystallography has consistently benefited from the many increases in source performance fr...

  15. Differential effects of divalent cations on elk prion protein fibril formation and stability

    Science.gov (United States)

    Misfolding of the normally folded prion protein of mammals (PrPC) into infectious fibrils causes a variety of different diseases, from scrapie in sheep to bovine spongiform encephalopathy in cattle to chronic wasting disease (CWD) in deer and elk. The misfolded form of PrPC, termed PrPSc, or in this...

  16. Serial murder: An unusual stereotype.

    Science.gov (United States)

    Sane, Mandar R; Mugadlimath, Anand B; Farooqui, Jamebaseer M; Janagond, Anand B; Mishra, Pradeep K

    2017-12-01

    Serial murders attract attention from the media, mental health experts, academia, and the general public. We present a case of serial murders that took place in a limited area and which caused public anxiety and anguish in central India. All the victims were homeless beggars, who were bludgeoned to death (crush injury). Individual murders were initially investigated by different police stations; fortunately, since they sent all the bodies to a common autopsy centre, a forensic pathologist was able to link all the cases, the first person to do so. This emphasises the need for sharing information among police stations and autopsy centres.

  17. Prefoldin Promotes Proteasomal Degradation of Cytosolic Proteins with Missense Mutations by Maintaining Substrate Solubility.

    Directory of Open Access Journals (Sweden)

    Sophie A Comyn

    2016-07-01

    Full Text Available Misfolded proteins challenge the ability of cells to maintain protein homeostasis and can accumulate into toxic protein aggregates. As a consequence, cells have adopted a number of protein quality control pathways to prevent protein aggregation, promote protein folding, and target terminally misfolded proteins for degradation. In this study, we employed a thermosensitive allele of the yeast Guk1 guanylate kinase as a model misfolded protein to investigate degradative protein quality control pathways. We performed a flow cytometry based screen to identify factors that promote proteasomal degradation of proteins misfolded as the result of missense mutations. In addition to the E3 ubiquitin ligase Ubr1, we identified the prefoldin chaperone subunit Gim3 as an important quality control factor. Whereas the absence of GIM3 did not impair proteasomal function or the ubiquitination of the model substrate, it led to the accumulation of the poorly soluble model substrate in cellular inclusions that was accompanied by delayed degradation. We found that Gim3 interacted with the Guk1 mutant allele and propose that prefoldin promotes the degradation of the unstable model substrate by maintaining the solubility of the misfolded protein. We also demonstrated that in addition to the Guk1 mutant, prefoldin can stabilize other misfolded cytosolic proteins containing missense mutations.

  18. Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases

    NARCIS (Netherlands)

    Hickman, D.T.; Nand, D.; Baldus, M.; Muhs, A.

    2011-01-01

    Synthetic peptide immunogens which mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters

  19. TDP-43 or FUS-induced misfolded human wild-type SOD1 can propagate intercellularly in a prion-like fashion.

    Science.gov (United States)

    Pokrishevsky, Edward; Grad, Leslie I; Cashman, Neil R

    2016-03-01

    Amyotrophic lateral sclerosis (ALS), which appears to spread through the neuroaxis in a spatiotemporally restricted manner, is linked to heritable mutations in genes encoding SOD1, TDP-43, FUS, C9ORF72, or can occur sporadically without recognized genetic mutations. Misfolded human wild-type (HuWt) SOD1 has been detected in both familial and sporadic ALS patients, despite mutations in SOD1 accounting for only 2% of total cases. We previously showed that accumulation of pathological TDP-43 or FUS coexist with misfolded HuWtSOD1 in patient motor neurons, and can trigger its misfolding in cultured cells. Here, we used immunocytochemistry and immunoprecipitation to demonstrate that TDP-43 or FUS-induced misfolded HuWtSOD1 can propagate from cell-to-cell via conditioned media, and seed cytotoxic misfolding of endogenous HuWtSOD1 in the recipient cells in a prion-like fashion. Knockdown of SOD1 using siRNA in recipient cells, or incubation of conditioned media with misfolded SOD1-specific antibodies, inhibits intercellular transmission, indicating that HuWtSOD1 is an obligate seed and substrate of propagated misfolding. In this system, intercellular spread of SOD1 misfolding is not accompanied by transmission of TDP-43 or FUS pathology. Our findings argue that pathological TDP-43 and FUS may exert motor neuron pathology in ALS through the initiation of propagated misfolding of SOD1.

  20. α-Synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded α-Synuclein and Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Hien T. Tran

    2014-06-01

    Full Text Available Accumulation of misfolded alpha-synuclein (α-syn into Lewy bodies (LBs and Lewy neurites (LNs is a major hallmark of Parkinson’s disease (PD and dementia with LBs (DLB. Recent studies showed that synthetic preformed fibrils (pffs recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p. administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.

  1. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect cattle transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-Type bovine spongiform encephalopathy.

    Science.gov (United States)

    Hwang, Soyoun; Greenlee, Justin J; Nicholson, Eric M

    2017-01-01

    Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from the normal cellular prion protein to the pathogenic misfolded conformation (PrPSc). This conversion has been used for in vitro assays including serial protein misfolding amplification and real-time quaking induced conversion (RT-QuIC). RT-QuIC can be used for the detection of prions in a variety of biological tissues from humans and animals. Extensive work has been done to demonstrate that RT-QuIC is a rapid, specific, and highly sensitive prion detection assay. RT-QuIC uses recombinant prion protein to detect minute amounts of PrPSc. RT-QuIC has been successfully used to detect PrPSc from different prion diseases with a variety of substrates including hamster, human, sheep, bank vole, bovine and chimeric forms of prion protein. However, recombinant bovine prion protein has not been used to detect transmissible mink encephalopathy (TME) or to differentiate types of bovine spongiform encephalopathy (BSE) in samples from cattle. We evaluated whether PrPSc from TME and BSE infected cattle can be detected with RT-QuIC using recombinant bovine prion proteins, and optimized the reaction conditions to specifically detect cattle TME and to discriminate between classical and atypical BSE by conversion efficiency. We also found that substrate composed of the disease associated E211K mutant protein can be effective for the detection of TME in cattle and that wild type prion protein appears to be a practical substrate to discriminate between the different types of BSEs.

  2. Tevatron serial data repeater system

    International Nuclear Information System (INIS)

    Ducar, R.J.

    1981-01-01

    A ten megabit per second serial data repeater system has been developed for the 6.28km Tevatron accelerator. The repeaters are positioned at each of the thirty service buildings and accommodate control and abort system communications as well as distribution of the Tevatron time and energy clocks. The repeaters are transparent to the particular protocol of the transmissions. Serial data are encoded locally as unipolar two volt signals employing the self-clocking Manchester Bi-Phase code. The repeaters modulate the local signals to low-power bursts of 50 MHz rf carrier for the 260m transmission between service buildings. The repeaters also demodulate the transmission and restructure the data for local utilization. The employment of frequency discrimination techniques yields high immunity to the characteristic noise spectrum

  3. Serial killer: il database mondiale

    Directory of Open Access Journals (Sweden)

    Gaetano parente

    2016-07-01

    Full Text Available The complex and multisided study of serial killers is partly made difficult by the current level of progress that has led these deviant people to evolve in relation to the aspects of shrewdness (concerning the staging and mobility. Despite the important work of some scholars who proposed important theories, all this shows that, concerning serial murders, it is still particularly frequent not to pay attention to links among homicides committed by the same person but in different parts of the world. It is therefore crucial to develop a worldwide database that allows all police forces to access information collected on crime scenes of murders which are particularly absurd and committed without any apparent reason. It will then be up to the profiler, through ad hoc and technologically advanced tools, to collect this information on the crime scene that would be made available to all police forces thanks to the worldwide database.

  4. Serial Austen. Mashingups with Zombies

    Directory of Open Access Journals (Sweden)

    Eleonora Federici

    2017-01-01

    Full Text Available Jane Austen sells. She sells in all possible ways, her novels have been adapted for the cinema and the stage, they have been rewritten as comics and graphic novels. Jane austen is a cultural icon. The interest in her life is so strong that many biographies have been written in order to recover new facts and details. The places where she has lived and the places depicted in her novels have become tourist sites for literary pilgrims. Austen is a cross-over phenomenon, with regency costume balls recreated in her name and an endless proliferation of her works in all media. My essay will investigate Jane Austen and Seth Grahame-Smith’s Pride and Prejudice and Zombies (2009, a mash-up novel which has become a real cultural phenomenon of the last decade and will demonstrate how it can be considered a serial narrative. If as Henry Jenkins asserts, seriality implies the unfolding of a story over time through a process of “chunking” (that is creating meaningful parts of the same story and of “dispersal” (that is breaking the story into more parts and in more genres and media, mash-ups seems to do this.  Austen’s story remains as a “story hook” which pushes the reader to come back to different products for a continuation of the same story. So, if on the one hand, seriality occurs within the same text, the story-telling of Austen’s stories across genres and media is part of a seriality process.

  5. Notorious Cases of Serial Killers

    Directory of Open Access Journals (Sweden)

    Iosub Elena-Cătălina

    2014-05-01

    Full Text Available The reconstruction of a death scene provides an overall picture of the crime and will indicate the murder as an event or one of a series of events and also the criminal. But when the criminal is declared a serial killer, many questions are raised up. How could a person kill some else without a reason or why people react in such a disorganized way and become so brutal or what made them act like that and so many questions with also so many answers. This project explains the psychology of a murderer, his own way of thinking and acting by presuming that we may accurately discover what is in their minds when they kill. It is about a very complex issue regarding murder investigations, biological factors and psychological profile of a serial killer. Dealing with this problem we will at last reach to the question that could solve finally the puzzle: ―Are serial murderers distorted reflections of society's own values?

  6. Serial murder by healthcare professionals.

    Science.gov (United States)

    Yorker, Beatrice Crofts; Kizer, Kenneth W; Lampe, Paula; Forrest, A R W; Lannan, Jacquetta M; Russell, Donna A

    2008-01-01

    The prosecution of Charles Cullen, a nurse who killed at least 40 patients over a 16-year period, highlights the need to better understand the phenomenon of serial murder by healthcare professionals. The authors conducted a LexisNexis search which yielded 90 criminal prosecutions of healthcare providers that met inclusion criteria for serial murder of patients. In addition we reviewed epidemiologic studies, toxicology evidence, and court transcripts, to provide data on healthcare professionals who have been prosecuted between 1970 and 2006. Fifty-four of the 90 have been convicted; 45 for serial murder, four for attempted murder, and five pled guilty to lesser charges. Twenty-four more have been indicted and are either awaiting trial or the outcome has not been published. The other 12 prosecutions had a variety of legal outcomes. Injection was the main method used by healthcare killers followed by suffocation, poisoning, and tampering with equipment. Prosecutions were reported from 20 countries with 40% taking place in the United States. Nursing personnel comprised 86% of the healthcare providers prosecuted; physicians 12%, and 2% were allied health professionals. The number of patient deaths that resulted in a murder conviction is 317 and the number of suspicious patient deaths attributed to the 54 convicted caregivers is 2113. These numbers are disturbing and demand that systemic changes in tracking adverse patient incidents associated with presence of a specific healthcare provider be implemented. Hiring practices must shift away from preventing wrongful discharge or denial of employment lawsuits to protecting patients from employees who kill.

  7. Extracting knowledge from protein structure geometry

    DEFF Research Database (Denmark)

    Røgen, Peter; Koehl, Patrice

    2013-01-01

    potential from geometric knowledge extracted from native and misfolded conformers of protein structures. This new potential, Metric Protein Potential (MPP), has two main features that are key to its success. Firstly, it is composite in that it includes local and nonlocal geometric information on proteins...

  8. Viscous hydrophilic injection matrices for serial crystallography

    Directory of Open Access Journals (Sweden)

    Gabriela Kovácsová

    2017-07-01

    Full Text Available Serial (femtosecond crystallography at synchrotron and X-ray free-electron laser (XFEL sources distributes the absorbed radiation dose over all crystals used for data collection and therefore allows measurement of radiation damage prone systems, including the use of microcrystals for room-temperature measurements. Serial crystallography relies on fast and efficient exchange of crystals upon X-ray exposure, which can be achieved using a variety of methods, including various injection techniques. The latter vary significantly in their flow rates – gas dynamic virtual nozzle based injectors provide very thin fast-flowing jets, whereas high-viscosity extrusion injectors produce much thicker streams with flow rates two to three orders of magnitude lower. High-viscosity extrusion results in much lower sample consumption, as its sample delivery speed is commensurate both with typical XFEL repetition rates and with data acquisition rates at synchrotron sources. An obvious viscous injection medium is lipidic cubic phase (LCP as it is used for in meso membrane protein crystallization. However, LCP has limited compatibility with many crystallization conditions. While a few other viscous media have been described in the literature, there is an ongoing need to identify additional injection media for crystal embedding. Critical attributes are reliable injection properties and a broad chemical compatibility to accommodate samples as heterogeneous and sensitive as protein crystals. Here, the use of two novel hydrogels as viscous injection matrices is described, namely sodium carboxymethyl cellulose and the thermo-reversible block polymer Pluronic F-127. Both are compatible with various crystallization conditions and yield acceptable X-ray background. The stability and velocity of the extruded stream were also analysed and the dependence of the stream velocity on the flow rate was measured. In contrast with previously characterized injection media, both new

  9. Serial-omics characterization of equine urine.

    Directory of Open Access Journals (Sweden)

    Min Yuan

    Full Text Available Horse urine is easily collected and contains molecules readily measurable using mass spectrometry that can be used as biomarkers representative of health, disease or drug tampering. This study aimed at analyzing microliter levels of horse urine to purify, identify and quantify proteins, polar metabolites and non-polar lipids. Urine from a healthy 12 year old quarter horse mare on a diet of grass hay and vitamin/mineral supplements with limited pasture access was collected for serial-omics characterization. The urine was treated with methyl tert-butyl ether (MTBE and methanol to partition into three distinct layers for protein, non-polar lipid and polar metabolite content from a single liquid-liquid extraction and was repeated two times. Each layer was analyzed by high performance liquid chromatography-high resolution tandem mass spectrometry (LC-MS/MS to obtain protein sequence and relative protein levels as well as identify and quantify small polar metabolites and lipids. The results show 46 urine proteins, many related to normal kidney function, structural and circulatory proteins as well as 474 small polar metabolites but only 10 lipid molecules. Metabolites were mostly related to urea cycle and ammonia recycling as well as amino acid related pathways, plant diet specific molecules, etc. The few lipids represented triglycerides and phospholipids. These data show a complete mass spectrometry based-omics characterization of equine urine from a single 333 μL mid-stream urine aliquot. These omics data help serve as a baseline for healthy mare urine composition and the analyses can be used to monitor disease progression, health status, monitor drug use, etc.

  10. Serial position learning in honeybees.

    Directory of Open Access Journals (Sweden)

    Randolf Menzel

    Full Text Available Learning of stimulus sequences is considered as a characteristic feature of episodic memory since it contains not only a particular item but also the experience of preceding and following events. In sensorimotor tasks resembling navigational performance, the serial order of objects is intimately connected with spatial order. Mammals and birds develop episodic(-like memory in serial spatio-temporal tasks, and the honeybee learns spatio-temporal order when navigating between the nest and a food source. Here I examine the structure of the bees' memory for a combined spatio-temporal task. I ask whether discrimination and generalization are based solely on simple forms of stimulus-reward learning or whether they require sequential configurations. Animals were trained to fly either left or right in a continuous T-maze. The correct choice was signaled by the sequence of colors (blue, yellow at four positions in the access arm. If only one of the possible 4 signals is shown (either blue or yellow, the rank order of position salience is 1, 2 and 3 (numbered from T-junction. No learning is found if the signal appears at position 4. If two signals are shown, differences at positions 1 and 2 are learned best, those at position 3 at a low level, and those at position 4 not at all. If three or more signals are shown these results are corroborated. This salience rank order again appeared in transfer tests, but additional configural phenomena emerged. Most of the results can be explained with a simple model based on the assumption that the four positions are equipped with different salience scores and that these add up independently. However, deviations from the model are interpreted by assuming stimulus configuration of sequential patterns. It is concluded that, under the conditions chosen, bees rely most strongly on memories developed during simple forms of associative reward learning, but memories of configural serial patterns contribute, too.

  11. Accumulation of Misfolded SOD1 in Dorsal Root Ganglion Degenerating Proprioceptive Sensory Neurons of Transgenic Mice with Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Javier Sábado

    2014-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is an adult-onset progressive neurodegenerative disease affecting upper and lower motoneurons (MNs. Although the motor phenotype is a hallmark for ALS, there is increasing evidence that systems other than the efferent MN system can be involved. Mutations of superoxide dismutase 1 (SOD1 gene cause a proportion of familial forms of this disease. Misfolding and aggregation of mutant SOD1 exert neurotoxicity in a noncell autonomous manner, as evidenced in studies using transgenic mouse models. Here, we used the SOD1G93A mouse model for ALS to detect, by means of conformational-specific anti-SOD1 antibodies, whether misfolded SOD1-mediated neurotoxicity extended to neuronal types other than MNs. We report that large dorsal root ganglion (DRG proprioceptive neurons accumulate misfolded SOD1 and suffer a degenerative process involving the inflammatory recruitment of macrophagic cells. Degenerating sensory axons were also detected in association with activated microglial cells in the spinal cord dorsal horn of diseased animals. As large proprioceptive DRG neurons project monosynaptically to ventral horn MNs, we hypothesise that a prion-like mechanism may be responsible for the transsynaptic propagation of SOD1 misfolding from ventral horn MNs to DRG sensory neurons.

  12. Serial CT scannings in herpes simplex encephalitis

    Energy Technology Data Exchange (ETDEWEB)

    Fukushima, M.; Sawada, T.; Kuriyama, Y.; Kinugawa, H.; Yamaguchi, T. (National Cardivascular Center, Osaka (Japan))

    1981-10-01

    Two patients with serologically confirmed herpes simplex encephalitis were studied by serial CT scannings. Case 1, a 60-year-old woman, was admitted to National Cardiovascular Center because of headache, fever, and attacks of Jacksonian seizure. Case 2, a 54-year-old man, was admitted because of fever, consciousness disturbance and right hemiparesis. Pleocytosis (mainly lymphocytes) and elevation of protein content in cerebrospinal fluid were observed in both cases. Both patients presented ''das apallische Syndrom'' one month after admission. The diagnosis of herpes simplex encephalitis was confirmed by typical clinical courses and by greater than fourfold rises in serum antibody titer for herpes simplex virus as well as that in cerebrospinal fluid in case 1. Characteristic CT findings observed in these two cases were summarized as follows: Within a week after the onset, no obvious abnormalities could be detected on CT scans (Case 1). Two weeks after the onset, a large low-density area appeared in the left temporal lobe and in the contralateral insular cortex with midline shift toward the right side (Case 2). One month later, an ill-defined linear and ring-like high-density area (Case 1), or a well-defined high-density area (Case 2), that was enhanced after contrast administration, was observed in the large low-density area in the temporal lobe. These findings were considered as characteristic for hemorrhagic encephalitis. These high-density areas disappeared two months later, however, widespread and intensified low-density areas still remained. In both cases, the basal ganglia and thalamus were completely spared on CT scans. From these observations, it can be concluded that serial CT scannings are quite useful for diagnosis of herpes simplex encephalitis.

  13. Serial CT scannings in herpes simplex encephalitis

    International Nuclear Information System (INIS)

    Fukushima, Masashi; Sawada, Tohru; Kuriyama, Yoshihiro; Kinugawa, Hidekazu; Yamaguchi, Takenori

    1981-01-01

    Two patients with serologically confirmed herpes simplex encephalitis were studied by serial CT scannings. Case 1, a 60-year-old woman, was admitted to National Cardiovascular Center because of headache, fever, and attacks of Jacksonian seizure. Case 2, a 54-year-old man, was admitted because of fever, consciousness disturbance and right hemipare sis. Pleocytosis (mainly lymphocytes) and elevation of protein content in cerebrospinal fluid were observed in both cases. Both patients presented ''das apallische Syndrom'' one month after admission. The diagnosis of herpes simplex encephalitis was confirmed by typical clinical courses and by greater than fourfold rises in serum antibody titer for herpes simplex virus as well as that in cerebrospinal fluid in case 1. Characteristic CT findings observed in these two cases were summarized as follows: Within a week after the onset, no obvious abnormalities could be detected on CT scans (Case 1). Two weeks after the onset, a large low-density area appeared in the left temporal lobe and in the contralateral insular cortex with midline shift toward the right side (Case 2). One month later, an ill-defined linear and ring-like high-density area (Case 1), or a well-defined high-density area (Case 2), that was enhanced after contrast administration, was observed in the large low-density area in the temporal lobe. These findings were considered as characteristic for hemorrhagic encephalitis. These high-density areas disappeared two months later, however, widespread and intensified low-density areas still remained. In both cases, the basal ganglia and thalamus were completely spared on CT scans. From these observations, it can be concluded that serial CT scannings are quite useful for diagnosis of herpes simplex encephalitis. (author)

  14. Proteomic Data From Human Cell Cultures Refine Mechanisms of Chaperone-Mediated Protein homeostasis

    OpenAIRE

    Finka, Andrija; Goloubinoff, Andrija Finka and Pierre

    2013-01-01

    In the crowded environment of human cells, folding of nascent polypeptides and refolding of stress-unfolded proteins is error prone. Accumulation of cytotoxic misfolded and aggregated species may cause cell death, tissue loss, degenerative conformational diseases, and aging. Nevertheless, young cells effectively express a network of molecular chaperones and folding enzymes, termed here “the chaperome,” which can prevent formation of potentially harmful misfolded protein conformers and use the...

  15. SMALL SERIAL AND SERIAL PRODUCTION MANAGEMENT IN UNSTABLE DEMAND ENVIROUMENT

    Directory of Open Access Journals (Sweden)

    Tsomaeva I. V.

    2014-03-01

    Full Text Available The work presents the methodological approach to production program of the enterprise serial engineering for the current period in the conditions of uncertainty of demand. Here are two problems with this. The first is connected with the formation of the production program of the next quarter, year. Objective could be to stochastic programming, but this task is difficult. Therefore, in this paper we proposed a simple solution. On the basis of statistical historical information about the deviation of actual sales data products from predicted by Monte Carlo generated a lot of production programs. Fixed worst key performance (sales, profit etc. The difference between the values of the planned target and the settlement defines stochastic reserve, to be established at the expense of additional innovations. The second problem is connected with the formation of the production program production in the planned month, taking into account the creation of stocks of production in the conditions when for a short period of time is difficult to build a pattern of change in the quantity demanded by month for serial production, as in some months of the year the products are not produced nor sold. To justify the level of inventories of finished products is information on deviations from the fact plan for past periods. Built function of frequency distribution of the values of deviations. This allows you to further build the methodology for determining the level of production (taking into account the reserves and sales of products that deliver maximum economic effect from the sales in the conditions of a random process of realization of production.

  16. Native sulfur/chlorine SAD phasing for serial femtosecond crystallography.

    Science.gov (United States)

    Nakane, Takanori; Song, Changyong; Suzuki, Mamoru; Nango, Eriko; Kobayashi, Jun; Masuda, Tetsuya; Inoue, Shigeyuki; Mizohata, Eiichi; Nakatsu, Toru; Tanaka, Tomoyuki; Tanaka, Rie; Shimamura, Tatsuro; Tono, Kensuke; Joti, Yasumasa; Kameshima, Takashi; Hatsui, Takaki; Yabashi, Makina; Nureki, Osamu; Iwata, So; Sugahara, Michihiro

    2015-12-01

    Serial femtosecond crystallography (SFX) allows structures to be determined with minimal radiation damage. However, phasing native crystals in SFX is not very common. Here, the structure determination of native lysozyme from single-wavelength anomalous diffraction (SAD) by utilizing the anomalous signal of sulfur and chlorine at a wavelength of 1.77 Å is successfully demonstrated. This sulfur SAD method can be applied to a wide range of proteins, which will improve the determination of native crystal structures.

  17. Whole-pattern fitting technique in serial femtosecond nanocrystallography

    Directory of Open Access Journals (Sweden)

    Ruben A. Dilanian

    2016-03-01

    Full Text Available Serial femtosecond X-ray crystallography (SFX has created new opportunities in the field of structural analysis of protein nanocrystals. The intensity and timescale characteristics of the X-ray free-electron laser sources used in SFX experiments necessitate the analysis of a large collection of individual crystals of variable shape and quality to ultimately solve a single, average crystal structure. Ensembles of crystals are commonly encountered in powder diffraction, but serial crystallography is different because each crystal is measured individually and can be oriented via indexing and merged into a three-dimensional data set, as is done for conventional crystallography data. In this way, serial femtosecond crystallography data lie in between conventional crystallography data and powder diffraction data, sharing features of both. The extremely small sizes of nanocrystals, as well as the possible imperfections of their crystallite structure, significantly affect the diffraction pattern and raise the question of how best to extract accurate structure-factor moduli from serial crystallography data. Here it is demonstrated that whole-pattern fitting techniques established for one-dimensional powder diffraction analysis can be feasibly extended to higher dimensions for the analysis of merged SFX diffraction data. It is shown that for very small crystals, whole-pattern fitting methods are more accurate than Monte Carlo integration methods that are currently used.

  18. Criminal psychological profiling of serial arson crimes.

    Science.gov (United States)

    Kocsis, Richard N; Cooksey, Ray W

    2002-12-01

    The practice of criminal psychological profiling is frequently cited as being applicable to serial arson crimes. Despite this claim, there does not appear to be any empirical research that examines serial arson offence behaviors in the context of profiling. This study seeks to develop an empirical model of serial arsonist behaviors that can be systematically associated with probable offender characteristics. Analysis has produced a model of offence behaviors that identify four discrete behavior patterns, all of which share a constellation of common nondiscriminatory behaviors. The inherent behavioral themes of each of these patterns are explored with discussion of their broader implications for our understanding of serial arson and directions for future research.

  19. Mitochondrial Dysfunction in Protein Conformational Disorders

    Indian Academy of Sciences (India)

    EstherShlomi

    protein misfolding of α-synuclein involves conformational changes in the protein .... upon association with a membrane surface its can adopt a helical form with an 11/3 ... case of α-synuclein electrostatic interactions exist between positively ...

  20. Genetic complexity in a Drosophila model of diabetes-associated misfolded human proinsulin.

    Science.gov (United States)

    Park, Soo-Young; Ludwig, Michael Z; Tamarina, Natalia A; He, Bin Z; Carl, Sarah H; Dickerson, Desiree A; Barse, Levi; Arun, Bharath; Williams, Calvin L; Miles, Cecelia M; Philipson, Louis H; Steiner, Donald F; Bell, Graeme I; Kreitman, Martin

    2014-02-01

    Drosophila melanogaster has been widely used as a model of human Mendelian disease, but its value in modeling complex disease has received little attention. Fly models of complex disease would enable high-resolution mapping of disease-modifying loci and the identification of novel targets for therapeutic intervention. Here, we describe a fly model of permanent neonatal diabetes mellitus and explore the complexity of this model. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINS(C96Y), which is a cause of permanent neonatal diabetes. When expressed in fly imaginal discs, hINS(C96Y) causes a reduction of adult structures, including the eye, wing, and notum. Eye imaginal discs exhibit defects in both the structure and the arrangement of ommatidia. In the wing, expression of hINS(C96Y) leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild-type signaling processes regulating cell fates. These readily measurable "disease" phenotypes are sensitive to temperature, gene dose, and sex. Mutant (but not wild-type) proinsulin expression in the eye imaginal disc induces IRE1-mediated XBP1 alternative splicing, a signal for endoplasmic reticulum stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel, produce F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L), when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease has, therefore, its own distinct signature. The genetic dominance

  1. Scientific and Technical Serials Holdings Optimization in an Inefficient Market: A LSU Serials Redesign Project Exercise.

    Science.gov (United States)

    Bensman, Stephen J.; Wilder, Stanley J.

    1998-01-01

    Analyzes the structure of the library market for scientific and technical (ST) serials. Describes an exercise aimed at a theoretical reconstruction of the ST-serials holdings of Louisiana State University (LSU) Libraries. Discusses the set definitions, measures, and algorithms necessary in the design of a computer program to appraise ST serials.…

  2. Serial Position Functions in General Knowledge

    Science.gov (United States)

    Kelley, Matthew R.; Neath, Ian; Surprenant, Aimée M.

    2015-01-01

    Serial position functions with marked primacy and recency effects are ubiquitous in episodic memory tasks. The demonstrations reported here explored whether bow-shaped serial position functions would be observed when people ordered exemplars from various categories along a specified dimension. The categories and dimensions were: actors and age;…

  3. The Serial Murderer's Motivations: An Interdisciplinary Review.

    Science.gov (United States)

    DeHart, Dana D.; Mahoney, John M.

    1994-01-01

    Defines serial killer as individual who murders two or more victims over an extended period of time, ranging from days to years, with the crimes often being sexually motivated. Reviews existing motivational theories of serial murder and proposes additional explications from range of disciplines. Presents suggestions for future research and…

  4. Modus operandi of female serial killers.

    Science.gov (United States)

    Wilson, W; Hilton, T

    1998-04-01

    The modus operandi of female serial killers was examined from a chronology of 58 cases in America and 47 cases in 17 other countries, compiled over 25-year intervals. Female serial killers in other countries accounted for a disproportionately greater number of victims, but those in America managed a longer killing career when associated with a low profile modus operandi.

  5. Female serial killing: review and case report.

    Science.gov (United States)

    Frei, Andreas; Völlm, Birgit; Graf, Marc; Dittmann, Volker

    2006-01-01

    Single homicide committed by women is rare. Serial killing is very infrequent, and the perpetrators are usually white, intelligent males with sadistic tendencies. Serial killing by women has, however, also been described. To conduct a review of published literature on female serial killers and consider its usefulness in assessing a presenting case. A literature review was conducted, after searching EMBASE, MEDLINE and PsycINFO. The presenting clinical case is described in detail in the context of the literature findings. Results The literature search revealed few relevant publications. Attempts to categorize the phenomenon of female serial killing according to patterns of and motives for the homicides have been made by some authors. The most common motive identified was material gain or similar extrinsic gratification while the 'hedonistic' sadistic or sexual serial killer seems to be extremely rare in women. There is no consistent theory of serial killing by women, but psychopathic personality traits and abusive childhood experiences have consistently been observed. The authors' case did not fit the description of a 'typical' female serial killer. In such unusual circumstances as serial killing by a woman, detailed individual case formulation is required to make sense of the psychopathology in each case. Publication of cases in scientific journals should be encouraged to advance our understanding of this phenomenon. Copyright (c) 2006 John Wiley & Sons, Ltd.

  6. Reframing Serial Murder Within Empirical Research.

    Science.gov (United States)

    Gurian, Elizabeth A

    2017-04-01

    Empirical research on serial murder is limited due to the lack of consensus on a definition, the continued use of primarily descriptive statistics, and linkage to popular culture depictions. These limitations also inhibit our understanding of these offenders and affect credibility in the field of research. Therefore, this comprehensive overview of a sample of 508 cases (738 total offenders, including partnered groups of two or more offenders) provides analyses of solo male, solo female, and partnered serial killers to elucidate statistical differences and similarities in offending and adjudication patterns among the three groups. This analysis of serial homicide offenders not only supports previous research on offending patterns present in the serial homicide literature but also reveals that empirically based analyses can enhance our understanding beyond traditional case studies and descriptive statistics. Further research based on these empirical analyses can aid in the development of more accurate classifications and definitions of serial murderers.

  7. Serial killers with military experience: applying learning theory to serial murder.

    Science.gov (United States)

    Castle, Tammy; Hensley, Christopher

    2002-08-01

    Scholars have endeavored to study the motivation and causality behind serial murder by researching biological, psychological, and sociological variables. Some of these studies have provided support for the relationship between these variables and serial murder. However, the study of serial murder continues to be an exploratory rather than explanatory research topic. This article examines the possible link between serial killers and military service. Citing previous research using social learning theory for the study of murder, this article explores how potential serial killers learn to reinforce violence, aggression, and murder in military boot camps. As with other variables considered in serial killer research, military experience alone cannot account for all cases of serial murder. Future research should continue to examine this possible link.

  8. Lipidic cubic phase serial millisecond crystallography using synchrotron radiation

    Directory of Open Access Journals (Sweden)

    Przemyslaw Nogly

    2015-03-01

    Full Text Available Lipidic cubic phases (LCPs have emerged as successful matrixes for the crystallization of membrane proteins. Moreover, the viscous LCP also provides a highly effective delivery medium for serial femtosecond crystallography (SFX at X-ray free-electron lasers (XFELs. Here, the adaptation of this technology to perform serial millisecond crystallography (SMX at more widely available synchrotron microfocus beamlines is described. Compared with conventional microcrystallography, LCP-SMX eliminates the need for difficult handling of individual crystals and allows for data collection at room temperature. The technology is demonstrated by solving a structure of the light-driven proton-pump bacteriorhodopsin (bR at a resolution of 2.4 Å. The room-temperature structure of bR is very similar to previous cryogenic structures but shows small yet distinct differences in the retinal ligand and proton-transfer pathway.

  9. Serial powering of pixel modules

    International Nuclear Information System (INIS)

    Stockmanns, Tobias; Fischer, Peter; Huegging, Fabian; Peric, Ivan; Runolfsson, O.; Wermes, Norbert

    2003-01-01

    Modern pixel detectors for the next generation of high-energy collider experiments like LHC use readout electronics in deep sub-micron technology. Chips in this technology need a low supply voltage of 2-2.5 V alongside high current consumption to achieve the desired performance. The high supply current leads to significant voltage drops in the long and low mass supply cables so that voltage fluctuations at the chips are induced, when the supply current changes. This problem scales with the number of modules when connected in parallel to the power supplies. An alternative powering scheme connects several modules in series resulting in a higher supply voltage but a lower current consumption of the chain and therefore a much lower voltage drop in the cables. In addition the amount of cables needed to supply the detector is vastly reduced. The concept and features of serial powering are presented and studies of the implementation of this technology as an alternative for the ATLAS pixel detector are shown. In particular, it is shown that the potential risk of powering in series can be addressed and eliminated

  10. Serial powering of pixel modules

    CERN Document Server

    Stockmanns, Tobias; Hügging, Fabian Georg; Peric, I; Runólfsson, O; Wermes, Norbert

    2003-01-01

    Modern pixel detectors for the next generation of high-energy collider experiments like LHC use readout electronics in deep sub- micron technology. Chips in this technology need a low supply voltage of 2-2.5 V alongside high current consumption to achieve the desired performance. The high supply current leads to significant voltage drops in the long and low mass supply cables so that voltage fluctuations at the chips are induced, when the supply current changes. This problem scales with the number of modules when connected in parallel to the power supplies. An alternative powering scheme connects several modules in series resulting in a higher supply voltage but a lower current consumption of the chain and therefore a much lower voltage drop in the cables. In addition the amount of cables needed to supply the detector is vastly reduced. The concept and features of serial powering are presented and studies of the implementation of this technology as an alternative for the ATLAS pixel detector are shown. In par...

  11. The Productivity Advantage of Serial Entrepreneurs

    DEFF Research Database (Denmark)

    Shaw, Kathryn L.; Sørensen, Anders

    Serial entrepreneurs, who open more than one business, are found to have higher sales and higher productivity than novice entrepreneurs, who open one business. Using panel data on entrepreneurs and their firms from Denmark for 2001-2013, the serial entrepreneur has 67% higher sales than the novice......, but also opens firms that are larger in terms of the initial capital and labor, and thus is 39% more productive. There are subsets of firms that perform especially well – serial entrepreneurs that hold a portfolio of overlapping ongoing firms perform the best, as do those that open as limited liability...

  12. The American Serialization of Lord Jim

    Directory of Open Access Journals (Sweden)

    Stephen Donovan

    2017-12-01

    Full Text Available This essay presents the discovery of the American serialization of Joseph Conrad’s Lord Jim in New York’s Evening Telegram in 1903. This ‘lost’ serialization, it argues, invites a new perspective on Conrad’s early career by foregrounding the role of newspaper serialization and syndication in establishing his literary standing. After surveying the principal differences in the respective reading experiences of the periodical versus the book, it concludes by proposing that the prominence of women among Conrad’s first audiences requires us to reassess the basis for his success in North America and elsewhere.

  13. Some Considerations on Seriality and Synchronicity

    OpenAIRE

    Elena Nechita

    2010-01-01

    This paper presents an overview of the results that have been obtained lately on seriality and synchronicity and their link, in the light of the new theories and within the frame of complexity science.

  14. Some Considerations on Seriality and Synchronicity

    Directory of Open Access Journals (Sweden)

    Elena Nechita

    2010-01-01

    Full Text Available This paper presents an overview of the results that have been obtained lately on seriality and synchronicity and their link, in the light of the new theories and within the frame of complexity science.

  15. Serial interactome capture of the human cell nucleus.

    Science.gov (United States)

    Conrad, Thomas; Albrecht, Anne-Susann; de Melo Costa, Veronica Rodrigues; Sauer, Sascha; Meierhofer, David; Ørom, Ulf Andersson

    2016-04-04

    Novel RNA-guided cellular functions are paralleled by an increasing number of RNA-binding proteins (RBPs). Here we present 'serial RNA interactome capture' (serIC), a multiple purification procedure of ultraviolet-crosslinked poly(A)-RNA-protein complexes that enables global RBP detection with high specificity. We apply serIC to the nuclei of proliferating K562 cells to obtain the first human nuclear RNA interactome. The domain composition of the 382 identified nuclear RBPs markedly differs from previous IC experiments, including few factors without known RNA-binding domains that are in good agreement with computationally predicted RNA binding. serIC extends the number of DNA-RNA-binding proteins (DRBPs), and reveals a network of RBPs involved in p53 signalling and double-strand break repair. serIC is an effective tool to couple global RBP capture with additional selection or labelling steps for specific detection of highly purified RBPs.

  16. De novo generation of infectious prions with bacterially expressed recombinant prion protein.

    Science.gov (United States)

    Zhang, Zhihong; Zhang, Yi; Wang, Fei; Wang, Xinhe; Xu, Yuanyuan; Yang, Huaiyi; Yu, Guohua; Yuan, Chonggang; Ma, Jiyan

    2013-12-01

    The prion hypothesis is strongly supported by the fact that prion infectivity and the pathogenic conformer of prion protein (PrP) are simultaneously propagated in vitro by the serial protein misfolding cyclic amplification (sPMCA). However, due to sPMCA's enormous amplification power, whether an infectious prion can be formed de novo with bacterially expressed recombinant PrP (rPrP) remains to be satisfactorily resolved. To address this question, we performed unseeded sPMCA with rPrP in a laboratory that has never been exposed to any native prions. Two types of proteinase K (PK)-resistant and self-perpetuating recombinant PrP conformers (rPrP-res) with PK-resistant cores of 17 or 14 kDa were generated. A bioassay revealed that rPrP-res(17kDa) was highly infectious, causing prion disease in wild-type mice with an average survival time of about 172 d. In contrast, rPrP-res(14kDa) completely failed to induce any disease. Our findings reveal that sPMCA is sufficient to initiate various self-perpetuating PK-resistant rPrP conformers, but not all of them possess in vivo infectivity. Moreover, generating an infectious prion in a prion-free environment establishes that an infectious prion can be formed de novo with bacterially expressed rPrP.

  17. A novel inert crystal delivery medium for serial femtosecond crystallography

    Directory of Open Access Journals (Sweden)

    Chelsie E. Conrad

    2015-07-01

    Full Text Available Serial femtosecond crystallography (SFX has opened a new era in crystallography by permitting nearly damage-free, room-temperature structure determination of challenging proteins such as membrane proteins. In SFX, femtosecond X-ray free-electron laser pulses produce diffraction snapshots from nanocrystals and microcrystals delivered in a liquid jet, which leads to high protein consumption. A slow-moving stream of agarose has been developed as a new crystal delivery medium for SFX. It has low background scattering, is compatible with both soluble and membrane proteins, and can deliver the protein crystals at a wide range of temperatures down to 4°C. Using this crystal-laden agarose stream, the structure of a multi-subunit complex, phycocyanin, was solved to 2.5 Å resolution using 300 µg of microcrystals embedded into the agarose medium post-crystallization. The agarose delivery method reduces protein consumption by at least 100-fold and has the potential to be used for a diverse population of proteins, including membrane protein complexes.

  18. 11C-L-methyl methionine dynamic PET/CT of skeletal muscle: response to protein supplementation compared to L-[ring 13C6] phenylalanine infusion with serial muscle biopsy.

    Science.gov (United States)

    Arentson-Lantz, Emily J; Saeed, Isra H; Frassetto, Lynda A; Masharani, Umesh; Harnish, Roy J; Seo, Youngho; VanBrocklin, Henry F; Hawkins, Randall A; Mari-Aparici, Carina; Pampaloni, Miguel H; Slater, James; Paddon-Jones, Douglas; Lang, Thomas F

    2017-05-01

    The objective of this study was to determine if clinical dynamic PET/CT imaging with 11 C-L-methyl-methionine ( 11 C-MET) in healthy older women can provide an estimate of tissue-level post-absorptive and post-prandial skeletal muscle protein synthesis that is consistent with the more traditional method of calculating fractional synthesis rate (FSR) of muscle protein synthesis from skeletal muscle biopsies obtained during an infusion of L-[ring 13 C 6 ] phenylalanine ( 13 C 6 -Phe). Healthy older women (73 ± 5 years) completed both dynamic PET/CT imaging with 11 C-MET and a stable isotope infusion of 13 C 6 -Phe with biopsies to measure the skeletal muscle protein synthetic response to 25 g of a whey protein supplement. Graphical estimation of the Patlak coefficient K i from analysis of the dynamic PET/CT images was employed as a measure of incorporation of 11 C-MET in the mid-thigh muscle bundle. Post-prandial values [mean ± standard error of the mean (SEM)] were higher than post-absorptive values for both K i (0.0095 ± 0.001 vs. 0.00785 ± 0.001 min -1 , p Dynamic PET/CT imaging with 11 C-MET provides an estimate of the post-prandial anabolic response that is consistent with a traditional, invasive stable isotope, and muscle biopsy approach. These results support the potential future use of 11 C-MET imaging as a non-invasive method for assessing conditions affecting skeletal muscle protein synthesis.

  19. Broad ion beam serial section tomography

    Energy Technology Data Exchange (ETDEWEB)

    Winiarski, B., E-mail: b.winiarski@manchester.ac.uk [School of Materials, University of Manchester, Manchester M13 9PL (United Kingdom); Materials Division, National Physical Laboratory, Teddington TW11 0LW (United Kingdom); Gholinia, A. [School of Materials, University of Manchester, Manchester M13 9PL (United Kingdom); Mingard, K.; Gee, M. [Materials Division, National Physical Laboratory, Teddington TW11 0LW (United Kingdom); Thompson, G.E.; Withers, P.J. [School of Materials, University of Manchester, Manchester M13 9PL (United Kingdom)

    2017-01-15

    Here we examine the potential of serial Broad Ion Beam (BIB) Ar{sup +} ion polishing as an advanced serial section tomography (SST) technique for destructive 3D material characterisation for collecting data from volumes with lateral dimensions significantly greater than 100 µm and potentially over millimetre sized areas. Further, the associated low level of damage introduced makes BIB milling very well suited to 3D EBSD acquisition with very high indexing rates. Block face serial sectioning data registration schemes usually assume that the data comprises a series of parallel, planar slices. We quantify the variations in slice thickness and parallelity which can arise when using BIB systems comparing Gatan PECS and Ilion BIB systems for large volume serial sectioning and 3D-EBSD data acquisition. As a test case we obtain 3D morphologies and grain orientations for both phases of a WC-11%wt. Co hardmetal. In our case we have carried out the data acquisition through the manual transfer of the sample between SEM and BIB which is a very slow process (1–2 slice per day), however forthcoming automated procedures will markedly speed up the process. We show that irrespective of the sectioning method raw large area 2D-EBSD maps are affected by distortions and artefacts which affect 3D-EBSD such that quantitative analyses and visualisation can give misleading and erroneous results. Addressing and correcting these issues will offer real benefits when large area (millimetre sized) automated serial section BIBS is developed. - Highlights: • In this work we examine how microstructures can be reconstructed in three-dimensions (3D) by serial argon broad ion beam (BIB) milling, enabling much larger volumes (>250×250×100µm{sup 3}) to be acquired than by serial section focused ion beam-scanning electron microscopy (FIB-SEM). • The associated low level of damage introduced makes BIB milling very well suited to 3D-EBSD acquisition with very high indexing rates. • We explore

  20. [The serial murder: a few theoretical perspectives].

    Science.gov (United States)

    Leistedt, S; Linkowski, P

    2011-01-01

    Despite numbers of publications and effort to try to establish the definition, the classification, the epidemiology, the clinical aspects and the psychopathology of serial killers, a universal consensus seems to say the least. Crime, though reduced in some countries, appears to impact more and more consistent worldwide, generating controversial ideas and a multitude of possible explanations. The serial killer usually presents as a caucasian man, aged between 20 and 40 years, often embedded socially and in his family, but with serious psychiatric, personal and especially family history. Usually acting alone, the serial killer plans a crime well in advance, but sometimes within the scope of impulsivity for a minority, the victim not being previously selected. In the latter case, an actual mental illness like psychosis is found. It is clear from numerous psychopathological studies conducted so far that most serial killers are defined as psychopathic sexual sadists, whose childhood was difficult, if not flouted, punctuated by physical and psychological violence situations. In addition, pervasive fantasies combined with thoughts of death, sex and violence are as much in common with the original acts of which they are the instigators. Beyond a relentless media that is constantly watering the public with stories and pictures depicting them as such, serial killers remain an enigma. We can therefore attempt to answer the various questions raised by this phenomenon, the way these people operate and how we can curb the rise, thanks to the neurobiological and neurophysiological approaches that science offers us.

  1. Serial Expression Analysis: a web tool for the analysis of serial gene expression data

    Science.gov (United States)

    Nueda, Maria José; Carbonell, José; Medina, Ignacio; Dopazo, Joaquín; Conesa, Ana

    2010-01-01

    Serial transcriptomics experiments investigate the dynamics of gene expression changes associated with a quantitative variable such as time or dosage. The statistical analysis of these data implies the study of global and gene-specific expression trends, the identification of significant serial changes, the comparison of expression profiles and the assessment of transcriptional changes in terms of cellular processes. We have created the SEA (Serial Expression Analysis) suite to provide a complete web-based resource for the analysis of serial transcriptomics data. SEA offers five different algorithms based on univariate, multivariate and functional profiling strategies framed within a user-friendly interface and a project-oriented architecture to facilitate the analysis of serial gene expression data sets from different perspectives. SEA is available at sea.bioinfo.cipf.es. PMID:20525784

  2. The Role of the Heat Shock Protein B8 (HSPB8 in Motoneuron Diseases

    Directory of Open Access Journals (Sweden)

    Paola Rusmini

    2017-06-01

    Full Text Available Amyotrophic lateral sclerosis (ALS and spinal and bulbar muscular atrophy (SBMA are two motoneuron diseases (MNDs characterized by aberrant protein behavior in affected cells. In familial ALS (fALS and in SBMA specific gene mutations lead to the production of neurotoxic proteins or peptides prone to misfold, which then accumulate in form of aggregates. Notably, some of these proteins accumulate into aggregates also in sporadic ALS (sALS even if not mutated. To prevent proteotoxic stresses detrimental to cells, misfolded and/or aggregated proteins must be rapidly removed by the protein quality control (PQC system. The small heat shock protein B8 (HSPB8 is a chaperone induced by harmful events, like proteasome inhibition. HSPB8 is expressed both in motoneuron and muscle cells, which are both targets of misfolded protein toxicity in MNDs. In ALS mice models, in presence of the mutant proteins, HSPB8 is upregulated both in spinal cord and muscle. HSPB8 interacts with the HSP70 co-chaperone BAG3 and enhances the degradation of misfolded proteins linked to sALS, or causative of fALS and of SBMA. HSPB8 acts by facilitating autophagy, thereby preventing misfolded protein accumulation in affected cells. BAG3 and BAG1 compete for HSP70-bound clients and target them for disposal to the autophagy or proteasome, respectively. Enhancing the selective targeting of misfolded proteins by HSPB8-BAG3-HSP70 to autophagy may also decrease their delivery to the proteasome by the BAG1-HSP70 complex, thereby limiting possible proteasome overwhelming. Thus, approaches aimed at potentiating HSPB8-BAG3 may contribute to the maintenance of proteostasis and may delay MNDs progression.

  3. Stochastic modeling of a serial killer.

    Science.gov (United States)

    Simkin, M V; Roychowdhury, V P

    2014-08-21

    We analyze the time pattern of the activity of a serial killer, who during 12 years had murdered 53 people. The plot of the cumulative number of murders as a function of time is of "Devil's staircase" type. The distribution of the intervals between murders (step length) follows a power law with the exponent of 1.4. We propose a model according to which the serial killer commits murders when neuronal excitation in his brain exceeds certain threshold. We model this neural activity as a branching process, which in turn is approximated by a random walk. As the distribution of the random walk return times is a power law with the exponent 1.5, the distribution of the inter-murder intervals is thus explained. We illustrate analytical results by numerical simulation. Time pattern activity data from two other serial killers further substantiate our analysis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Converting serial networks to Ethernet communications

    Energy Technology Data Exchange (ETDEWEB)

    Rosado, Elroy [Freewave Technologies, Inc., Boulder, CO (United States). Latin America

    2008-07-01

    Many oil and gas producers and pipeline companies find themselves in an awkward position. They have invested millions of dollars in legacy serial communications systems and in most cases, millions more in older SCADA remote terminal units and electronic flow meters. There is a desire throughout most of the industry to convert these systems to Ethernet. This presentation will explore how Ethernet protocol offers advantages over the older serial communications in terms of peer to peer communication, faster polling cycles, and the ability to poll multiple devices at the same time. (author)

  5. Multistage parallel-serial time averaging filters

    International Nuclear Information System (INIS)

    Theodosiou, G.E.

    1980-01-01

    Here, a new time averaging circuit design, the 'parallel filter' is presented, which can reduce the time jitter, introduced in time measurements using counters of large dimensions. This parallel filter could be considered as a single stage unit circuit which can be repeated an arbitrary number of times in series, thus providing a parallel-serial filter type as a result. The main advantages of such a filter over a serial one are much less electronic gate jitter and time delay for the same amount of total time uncertainty reduction. (orig.)

  6. Serial position effects in mild cognitive impairment.

    Science.gov (United States)

    Howieson, Diane B; Mattek, Nora; Seeyle, Adriana M; Dodge, Hiroko H; Wasserman, Dara; Zitzelberger, Tracy; Jeffrey, Kaye

    2011-03-01

    Mild cognitive impairment (MCI) is often associated with the preclinical phase of Alzheimer's disease (AD). Special scoring of word-list recall data for serial position has been suggested to improve discrimination of normal aging from dementia. We examined serial position effects in word-list recall for MCI participants compared to Alzheimer patients and controls. Individuals with MCI, like Alzheimer patients, had a diminished primacy effect in recalling words from a list. No alternative scoring system was better than standard scoring of word-list recall in distinguishing MCI patients from controls. Retention weighted scoring improved the discrimination of MCI and AD groups.

  7. The eyeball killer: serial killings with postmortem globe enucleation.

    Science.gov (United States)

    Coyle, Julie; Ross, Karen F; Barnard, Jeffrey J; Peacock, Elizabeth; Linch, Charles A; Prahlow, Joseph A

    2015-05-01

    Although serial killings are relatively rare, they can be the cause of a great deal of anxiety while the killer remains at-large. Despite the fact that the motivations for serial killings are typically quite complex, the psychological analysis of a serial killer can provide valuable insight into how and why certain individuals become serial killers. Such knowledge may be instrumental in preventing future serial killings or in solving ongoing cases. In certain serial killings, the various incidents have a variety of similar features. Identification of similarities between separate homicidal incidents is necessary to recognize that a serial killer may be actively killing. In this report, the authors present a group of serial killings involving three prostitutes who were shot to death over a 3-month period. Scene and autopsy findings, including the unusual finding of postmortem enucleation of the eyes, led investigators to recognize the serial nature of the homicides. © 2015 American Academy of Forensic Sciences.

  8. Barcoding heat shock proteins to human diseases : looking beyond the heat shock response

    NARCIS (Netherlands)

    Kakkar, Vaishali; Meister-Broekema, Melanie; Minoia, Melania; Carra, Serena; Kampinga, Harm H.

    There are numerous human diseases that are associated with protein misfolding and the formation of toxic protein aggregates. Activating the heat shock response (HSR) - and thus generally restoring the disturbed protein homeostasis associated with such diseases - has often been suggested as a

  9. Serial femtosecond X-ray diffraction of enveloped virus microcrystals

    Directory of Open Access Journals (Sweden)

    Robert M. Lawrence

    2015-07-01

    Full Text Available Serial femtosecond crystallography (SFX using X-ray free-electron lasers has produced high-resolution, room temperature, time-resolved protein structures. We report preliminary SFX of Sindbis virus, an enveloped icosahedral RNA virus with ∼700 Å diameter. Microcrystals delivered in viscous agarose medium diffracted to ∼40 Å resolution. Small-angle diffuse X-ray scattering overlaid Bragg peaks and analysis suggests this results from molecular transforms of individual particles. Viral proteins undergo structural changes during entry and infection, which could, in principle, be studied with SFX. This is an important step toward determining room temperature structures from virus microcrystals that may enable time-resolved studies of enveloped viruses.

  10. Recalling visual serial order for verbal sequences

    NARCIS (Netherlands)

    Logie, R.H.; Saito, S.; Morita, A.; Varma, S.; Norris, D.

    2016-01-01

    We report three experiments in which participants performed written serial recall of visually presented verbal sequences with items varying in visual similarity. In Experiments 1 and 2 native speakers of Japanese recalled visually presented Japanese Kanji characters. In Experiment 3, native speakers

  11. Serial analysis of gene expression (SAGE)

    NARCIS (Netherlands)

    van Ruissen, Fred; Baas, Frank

    2007-01-01

    In 1995, serial analysis of gene expression (SAGE) was developed as a versatile tool for gene expression studies. SAGE technology does not require pre-existing knowledge of the genome that is being examined and therefore SAGE can be applied to many different model systems. In this chapter, the SAGE

  12. Facial rejuvenation: Serial fat graft transfer

    African Journals Online (AJOL)

    Saad Mohamed Saad Ibrahiem

    2016-02-01

    Feb 1, 2016 ... This a clinical study carried out to test the aesthetic outcome of serial injection of the cryo-preserved fat cells for both aesthetic and reconstructive purposes. Methods: Clinical ..... ucts, devices, or drugs mentioned in this manuscript that might create a ... Adipose stem cells and regenerative medicine. 7th ed.

  13. Advances in Serials Management. Volume 6.

    Science.gov (United States)

    Hepfer, Cindy, Ed.; Gammon, Julia, Ed.; Malinowski, Teresa, Ed.

    In order to further discussion and support constructive change, this volume presents the following eight papers on various dimensions of serials management: (1) "CD-ROMs, Surveys, and Sales: The OSA [Optical Society of America] Experience" (Frank E. Harris and Alan Tourtlotte); (2) "Management and Integration of Electronic Journals into the…

  14. Amyloid-β Peptide Induces Prion Protein Amyloid Formation: Evidence for Its Widespread Amyloidogenic Effect.

    Science.gov (United States)

    Honda, Ryo

    2018-04-12

    Transmissible spongiform encephalopathy is associated with misfolding of prion protein (PrP) into an amyloid β-rich aggregate. Previous studies have indicated that PrP interacts with Alzheimer's disease amyloid-β peptide (Aβ), but it remains elusive how this interaction impacts on the misfolding of PrP. This study presents the first in vitro evidence that Aβ induces PrP-amyloid formation at submicromolar concentrations. Interestingly, systematic mutagenesis of PrP revealed that Aβ requires no specific amino acid sequences in PrP, and induces the misfolding of other unrelated proteins (insulin and lysozyme) into amyloid fibrils in a manner analogous to PrP. This unanticipated nonspecific amyloidogenic effect of Aβ indicates that this peptide might be involved in widespread protein aggregation, regardless of the amino acid sequences of target proteins, and exacerbate the pathology of many neurodegenerative diseases. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Interaction between -Synuclein and Other Proteins in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Kurt A. Jellinger

    2011-01-01

    Full Text Available Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.

  16. Determination of motive of serial invaders as a stage of serial murders investigation

    Directory of Open Access Journals (Sweden)

    Davydov A.B.

    2017-04-01

    Full Text Available the article discusses the existing classification of motives of serial murderers. The author provides the classification, which is based on the technique of extreme meanings offered by D.A. Leontyev.

  17. Serial position markers in space: visuospatial priming of serial order working memory retrieval.

    Directory of Open Access Journals (Sweden)

    Maya De Belder

    Full Text Available Most general theories on serial order working memory (WM assume the existence of position markers that are bound to the to-be-remembered items to keep track of the serial order. So far, the exact cognitive/neural characteristics of these markers have remained largely underspecified, while direct empirical evidence for their existence is mostly lacking. In the current study we demonstrate that retrieval from verbal serial order WM can be facilitated or hindered by spatial cuing: begin elements of a verbal WM sequence are retrieved faster after cuing the left side of space, while end elements are retrieved faster after cuing the right side of space. In direct complement to our previous work--where we showed the reversed impact of WM retrieval on spatial processing--we argue that the current findings provide us with a crucial piece of evidence suggesting a direct and functional involvement of space in verbal serial order WM. We outline the idea that serial order in verbal WM is coded within a spatial coordinate system with spatial attention being involved when searching through WM, and we discuss how this account can explain several hallmark observations related to serial order WM.

  18. Serial crystallography captures enzyme catalysis in copper nitrite reductase at atomic resolution from one crystal

    Directory of Open Access Journals (Sweden)

    Sam Horrell

    2016-07-01

    Full Text Available Relating individual protein crystal structures to an enzyme mechanism remains a major and challenging goal for structural biology. Serial crystallography using multiple crystals has recently been reported in both synchrotron-radiation and X-ray free-electron laser experiments. In this work, serial crystallography was used to obtain multiple structures serially from one crystal (MSOX to study in crystallo enzyme catalysis. Rapid, shutterless X-ray detector technology on a synchrotron MX beamline was exploited to perform low-dose serial crystallography on a single copper nitrite reductase crystal, which survived long enough for 45 consecutive 100 K X-ray structures to be collected at 1.07–1.62 Å resolution, all sampled from the same crystal volume. This serial crystallography approach revealed the gradual conversion of the substrate bound at the catalytic type 2 Cu centre from nitrite to nitric oxide, following reduction of the type 1 Cu electron-transfer centre by X-ray-generated solvated electrons. Significant, well defined structural rearrangements in the active site are evident in the series as the enzyme moves through its catalytic cycle, namely nitrite reduction, which is a vital step in the global denitrification process. It is proposed that such a serial crystallography approach is widely applicable for studying any redox or electron-driven enzyme reactions from a single protein crystal. It can provide a `catalytic reaction movie' highlighting the structural changes that occur during enzyme catalysis. The anticipated developments in the automation of data analysis and modelling are likely to allow seamless and near-real-time analysis of such data on-site at some of the powerful synchrotron crystallographic beamlines.

  19. An Investigation of Selective College and University Libraries' Serial Arrangement.

    Science.gov (United States)

    Kesler, Elizabeth Gates; Teborek, Gay

    Data from a survey on serials arrangement procedures and policies at academic libraries was used by the University of Rhode Island (URI) Library in changing current serials policies. Ten libraries, four of which have similar serial holdings and user populations to URI, responded to a questionnaire. Information was obtained on classification versus…

  20. Sensing the Opaque : Seriality and the Aesthetics of Televisual Form

    NARCIS (Netherlands)

    Dasgupta, S.; Kelleter, F.

    2017-01-01

    Recent work on TV seriality focuses on the deference of meaning through narrative extension. Contemporary seriality, it has been argued, exploits this expanding textuality to construct complicated narratives that tip the pleasures of seriality toward detecting the meaning of the plot's

  1. Serial SPECT in children with partial epilepsy

    International Nuclear Information System (INIS)

    Hosoya, Machiko; Ushiku, Hideo

    1995-01-01

    We performed serial single-photon emission CT (SPECT) with N-isopropyl-p-( 123 I)-Iodoamphetamine to measure the regional cerebral blood flow (rCBF) in 15 children with partial epilepsy. SPECT showed focal changes in 14 cases. Ten cases had abnormalities in the initial SPECT and another four cases in the second test. The cases with normal rCBF in initial SPECT had been tested in an early phase after the onset, and then decreased rCBF were observed in the second SPECT. The cases with both abnormal rCBF in the initial SPECT and improved rCBF in the second SPECT showed good prognosis in clinico-electrophysiological evolutions. In cases with abnormal changes of rCBF in the second SPECT, clinical prognosis was found to be not so good. These findings suggest that serial SPECT may be used to follow the course of epilepsy. (author)

  2. [Personality disorders, psychopathy and serial killers].

    Science.gov (United States)

    Morana, Hilda C P; Stone, Michael H; Abdalla-Filho, Elias

    2006-10-01

    To illustrate the basic characteristics of several specific personality disorders, focusing mainly in antisocial personality disorder. The differences between antisocial personality disorder and psychopathy are highlighted. Serial killers and its psychopathic aspects are also discussed. A bibliographic review was completed in order to outline convergences and divergences among different authors about this controversial issue, especially those concerning the possibility of treatment. While anti-social personality disorder is a medical diagnosis, the term "psychopathy" (which belongs to the sphere of forensic psychiatry) may be understood as a "legal diagnosis". It is not still possible to identify an effective treatment for serial killers. Personality disorders, especially of the antisocial type, still represent a formidable challenge to forensic psychiatry today. Questions as yet unanswered include the best and most humane place for patients with this condition and the nature of a standardised treatment recommendation.

  3. A Survey of Electronic Serials Managers Reveals Diversity in Practice

    Directory of Open Access Journals (Sweden)

    Laura Costello

    2014-09-01

    Full Text Available A Review of: Branscome, B. A. (2013. Management of electronic serials in academic libraries: The results of an online survey. Serials Review, 39(4, 216-226. http://dx.doi.org/10.1016/j.serrev.2013.10.004 Abstract Objective – To examine industry standards for the management of electronic serials and measure the adoption of electronic serials over print. Design – Survey questionnaire. Setting – Email lists aimed at academic librarians working in serials management. Subjects – 195 self-selected subscribers to serials email lists. Methods – The author created a 20 question survey that consisted primarily of closed-ended questions pertaining to the collection demographics, staff, budget, and tools of serials management groups in academic libraries. The survey was conducted via Survey Monkey and examined using the analytical features of the tool. Participants remained anonymous and the survey questions did not ask them to reveal identifiable information about their libraries. Main Results – Collection demographics questions revealed that 78% of surveyed librarians estimated that print-only collections represented 40% or fewer of their serials holdings. The author observed diversity in the factors that influence print to digital transitions in academic libraries. However 71.5% of participants indicated that publisher technology support like IP authentication was required before adopting digital subscriptions. A lack of standardization also marked serials workflows, department responsibilities, and department titles. The author did not find a correlation between serials budget and the enrollment size of the institution. Participants reported that they used tools from popular serials management vendors like Serials Solutions, Innovative Interfaces, EBSCO, and Ex Libris, but most indicated that they used more than one tool for serials management. Participants specified 52 unique serials management products used in their libraries. Conclusion

  4. Fungal myositis in children: serial ultrasonographic findings

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Jung Hwa; Lee, Hee Jung; Choi, Jin Soo [Keimyung University School of Medicine, Daegu (Korea, Republic of)

    2003-08-01

    To evaluate serial ultrasonographic findings of fungal myositis in children. Eleven lesions caused by fungal myositis and occurring in six children were included in this study. Eight lesions in five children were histopathologically proven and the other three were clinically diagnosed. Serial ultrasonographic findings were retrospectively evaluated in terms of size, location, margin, internal echotexture and adjacent cortical change occurring during the follow-up period ranging from five days to two months. Three patients (50%) had multiple lesions. The sites of involvment were the thigh (n=4), calf (n=3), chest wall (n=2), abdominal wall (n=1) and forearm (n=1). Initially, diffuse muscular swelling was revealed, with ill-defined hypoechoic lesions confined to the muscle layer (n=8). Follow-up examination of eight lesions over a period of 5-10 days showed that round central echogenic lesions were surrounded by previous slightly echogenic lesions (n=6, 75%). Long-term follow-up of five lesions over a two-month period revealed periosteal thickening in one case (20%), and the peristence of echogenic solid nodules in four (80%). Pathologic examination showed that the central lesions correlated with a fungus ball and the peripheral slightly echogenic lesions corresponded to hematoma and necrosis. Serial ultrasonographic findings of fungal myositis in children revealed relatively constant features in each case. In particular, the findings of muscular necrosis and a fungus ball over a period of 5-14 days were thought to be characteristic.

  5. Fungal myositis in children: serial ultrasonographic findings

    International Nuclear Information System (INIS)

    Kwon, Jung Hwa; Lee, Hee Jung; Choi, Jin Soo

    2003-01-01

    To evaluate serial ultrasonographic findings of fungal myositis in children. Eleven lesions caused by fungal myositis and occurring in six children were included in this study. Eight lesions in five children were histopathologically proven and the other three were clinically diagnosed. Serial ultrasonographic findings were retrospectively evaluated in terms of size, location, margin, internal echotexture and adjacent cortical change occurring during the follow-up period ranging from five days to two months. Three patients (50%) had multiple lesions. The sites of involvment were the thigh (n=4), calf (n=3), chest wall (n=2), abdominal wall (n=1) and forearm (n=1). Initially, diffuse muscular swelling was revealed, with ill-defined hypoechoic lesions confined to the muscle layer (n=8). Follow-up examination of eight lesions over a period of 5-10 days showed that round central echogenic lesions were surrounded by previous slightly echogenic lesions (n=6, 75%). Long-term follow-up of five lesions over a two-month period revealed periosteal thickening in one case (20%), and the peristence of echogenic solid nodules in four (80%). Pathologic examination showed that the central lesions correlated with a fungus ball and the peripheral slightly echogenic lesions corresponded to hematoma and necrosis. Serial ultrasonographic findings of fungal myositis in children revealed relatively constant features in each case. In particular, the findings of muscular necrosis and a fungus ball over a period of 5-14 days were thought to be characteristic

  6. Proteins interacting with the 26S proteasome

    DEFF Research Database (Denmark)

    Hartmann-Petersen, R; Gordon, C

    2004-01-01

    The 26S proteasome is the multi-protein protease that recognizes and degrades ubiquitinylated substrates targeted for destruction by the ubiquitin pathway. In addition to the well-documented subunit organization of the 26S holoenzyme, it is clear that a number of other proteins transiently...... associate with the 26S complex. These transiently associated proteins confer a number of different roles such as substrate presentation, cleavage of the multi-ubiquitin chain from the protein substrate and turnover of misfolded proteins. Such activities are essential for the 26S proteasome to efficiently...... fulfill its intracellular function in protein degradation....

  7. Serial analysis of gene expression (SAGE) in rat liver regeneration

    International Nuclear Information System (INIS)

    Cimica, Velasco; Batusic, Danko; Haralanova-Ilieva, Borislava; Chen, Yonglong; Hollemann, Thomas; Pieler, Tomas; Ramadori, Giuliano

    2007-01-01

    We have applied serial analysis of gene expression for studying the molecular mechanism of the rat liver regeneration in the model of 70% partial hepatectomy. We generated three SAGE libraries from a normal control liver (NL library: 52,343 tags), from a sham control operated liver (Sham library: 51,028 tags), and from a regenerating liver (PH library: 53,061 tags). By SAGE bioinformatics analysis we identified 40 induced genes and 20 repressed genes during the liver regeneration. We verified temporal expression of such genes by real time PCR during the regeneration process and we characterized 13 induced genes and 3 repressed genes. We found connective tissue growth factor transcript and protein induced very early at 4 h after PH operation before hepatocytes proliferation is triggered. Our study suggests CTGF as a growth factor signaling mediator that could be involved directly in the mechanism of liver regeneration induction

  8. From animal cruelty to serial murder: applying the graduation hypothesis.

    Science.gov (United States)

    Wright, Jeremy; Hensley, Christopher

    2003-02-01

    Although serial murder has been recorded for centuries, limited academic attention has been given to this important topic. Scholars have attempted to examine the causality and motivations behind the rare phenomenon of serial murder. However, scant research exists which delves into the childhood characteristics of serial murderers. Using social learning theory, some of these studies present supporting evidence for a link between childhood animal cruelty and adult aggression toward humans. Based on five case studies of serial murderers, we contribute to the existing literature by exploring the possible link between childhood cruelty toward animals and serial murder with the application of the graduation hypothesis.

  9. Implementation of a Multichannel Serial Data Streaming Algorithm using the Xilinx Serial RapidIO Solution

    Science.gov (United States)

    Doxley, Charles A.

    2016-01-01

    In the current world of applications that use reconfigurable technology implemented on field programmable gate arrays (FPGAs), there is a need for flexible architectures that can grow as the systems evolve. A project has limited resources and a fixed set of requirements that development efforts are tasked to meet. Designers must develop robust solutions that practically meet the current customer demands and also have the ability to grow for future performance. This paper describes the development of a high speed serial data streaming algorithm that allows for transmission of multiple data channels over a single serial link. The technique has the ability to change to meet new applications developed for future design considerations. This approach uses the Xilinx Serial RapidIO LOGICORE Solution to implement a flexible infrastructure to meet the current project requirements with the ability to adapt future system designs.

  10. Energy Information Data Base: serial titles

    International Nuclear Information System (INIS)

    1980-06-01

    The Department of Energy Technical Information Center (TIC) is responsible for creating bibliographic data bases that are used in the announcement and retrieval of publications dealing with all phases of energy. The TIC interactive information processing system makes use of a number of computerized authorities so that consistency can be maintained and indexes can be produced. One such authority is the Energy Information Data Base: Serial Titles. This authority contains the full and abbreviated journal title, country of publication, CODEN, and certain codes. This revision replaces previous revisions of this document

  11. Serials collection management in recessionary times

    CERN Document Server

    Lawson, Karen G

    2015-01-01

    Strategic planning, collaboration, continual stewardship, best practices, and re-engineering can provide librarians with a toolkit of innovative strategies that meets the worst of economic times with bold, persistent experimentation. This book covers the implications for libraries of a broad range of technological and economic challenges. These challenges include the fallout from the global economic crisis, the positioning of usage statistics, the advent of open access scholarship, database management, responding to budgetary constrictions and general access to serials. Taken as a whole, this

  12. Inverse Kinematics of a Serial Robot

    Directory of Open Access Journals (Sweden)

    Amici Cinzia

    2016-01-01

    Full Text Available This work describes a technique to treat the inverse kinematics of a serial manipulator. The inverse kinematics is obtained through the numerical inversion of the Jacobian matrix, that represents the equation of motion of the manipulator. The inversion is affected by numerical errors and, in different conditions, due to the numerical nature of the solver, it does not converge to a reasonable solution. Thus a soft computing approach is adopted to mix different traditional methods to obtain an increment of algorithmic convergence.

  13. Rapid serial visual presentation design for cognition

    CERN Document Server

    Spence, Robert

    2013-01-01

    A powerful new image presentation technique has evolved over the last twenty years, and its value demonstrated through its support of many and varied common tasks. Conceptually, Rapid Serial Visual Presentation (RSVP) is basically simple, exemplified in the physical world by the rapid riffling of the pages of a book in order to locate a known image. Advances in computation and graphics processing allow RSVP to be applied flexibly and effectively to a huge variety of common tasks such as window shopping, video fast-forward and rewind, TV channel selection and product browsing. At its heart is a

  14. CAR-T cells are serial killers.

    Science.gov (United States)

    Davenport, Alexander J; Jenkins, Misty R; Ritchie, David S; Prince, H Miles; Trapani, Joseph A; Kershaw, Michael H; Darcy, Phillip K; Neeson, Paul J

    2015-12-01

    Chimeric antigen receptor (CAR) T cells have enjoyed unprecedented clinical success against haematological malignancies in recent years. However, several aspects of CAR T cell biology remain unknown. We recently compared CAR and T cell receptor (TCR)-based killing in the same effector cell and showed that CAR T cells can not only efficiently kill single tumor targets, they can also kill multiple tumor targets in a sequential manner. Single and serial killing events were not sustained long term due to CAR down-regulation after 20 hours.

  15. Personality disorders, psychopathy and serial killers

    OpenAIRE

    Morana, Hilda C P; Stone, Michael H; Abdalla-Filho, Elias

    2006-01-01

    OBJETIVO: Apresentar as características básicas dos diversos transtornos específicos de personalidade, mas centrando-se no transtorno de personalidade anti-social, fazendo sua diferenciação com psicopatia. O estudo ainda se propõe a abordar a figura do serial killer, apontando a presença de aspectos psicopáticos no homicídio seriado. MÉTODO: Uma revisão bibliográfica foi feita no sentido de se abordar convergências e divergências entre diversos autores sobre um assunto tão polêmico, sobretudo...

  16. Galileo - The Serial-Production AIT Challenge

    Science.gov (United States)

    Ragnit, Ulrike; Brunner, Otto

    2008-01-01

    The Galileo Project is one of the most demanding projects of ESA, being Europe's autarkic navigation system and a constellation composed of 30 satellites. This presentation points out the different phases of the project up to the full operational capability and the corresponding launch options with respect to launch vehicles as well as launch configurations. One of the biggest challenges is to set up a small serial 'production line' for the overall integration and test campaign of satellites. This production line demands an optimization of all relevant tasks, taking into account also backup and recovery actions. A comprehensive AIT concept is required, reflecting a tightly merged facility layout and work flow design. In addition a common data management system is needed to handle all spacecraft related documentation and to have a direct input-out flow for all activities, phases and positions at the same time. Process optimization is a well known field of engineering in all small high tech production lines, nevertheless serial production of satellites are still not the daily task in space business and therefore new concepts have to be put in place. Therefore, and in order to meet the satellites overall system optimization, a thorough interface between unit/subsystem manufacturing and satellite AIT must be realized to ensure a smooth flow and to avoid any process interruption, which would directly lead to a schedule impact.

  17. Spatial serial order processing in schizophrenia.

    Science.gov (United States)

    Fraser, David; Park, Sohee; Clark, Gina; Yohanna, Daniel; Houk, James C

    2004-10-01

    The aim of this study was to examine serial order processing deficits in 21 schizophrenia patients and 16 age- and education-matched healthy controls. In a spatial serial order working memory task, one to four spatial targets were presented in a randomized sequence. Subjects were required to remember the locations and the order in which the targets were presented. Patients showed a marked deficit in ability to remember the sequences compared with controls. Increasing the number of targets within a sequence resulted in poorer memory performance for both control and schizophrenia subjects, but the effect was much more pronounced in the patients. Targets presented at the end of a long sequence were more vulnerable to memory error in schizophrenia patients. Performance deficits were not attributable to motor errors, but to errors in target choice. The results support the idea that the memory errors seen in schizophrenia patients may be due to saturating the working memory network at relatively low levels of memory load.

  18. Serial position curves in free recall.

    Science.gov (United States)

    Laming, Donald

    2010-01-01

    The scenario for free recall set out in Laming (2009) is developed to provide models for the serial position curves from 5 selected sets of data, for final free recall, and for multitrial free recall. The 5 sets of data reflect the effects of rate of presentation, length of list, delay of recall, and suppression of rehearsal. Each model accommodates the serial position curve for first recalls (where those data are available) as well as that for total recalls. Both curves are fit with the same parameter values, as also (with 1 exception) are all of the conditions compared within each experiment. The distributions of numbers of recalls are also examined and shown to have variances increased above what would be expected if successive recalls were independent. This is taken to signify that, in those experiments in which rehearsals were not recorded, the retrieval of words for possible recall follows the same pattern that is observed following overt rehearsal, namely, that retrieval consists of runs of consecutive elements from memory. Finally, 2 sets of data are examined that the present approach cannot accommodate. It is argued that the problem with these data derives from an interaction between the patterns of (covert) rehearsal and the parameters of list presentation.

  19. Malingering, coaching, and the serial position effect.

    Science.gov (United States)

    Suhr, Julie A

    2002-01-01

    The normal pattern of performance on list-learning tasks is to recall more words from the beginning (primacy) and end (recency) of the list. This pattern is also seen in patients with closed head injury, but malingerers tend to recall less words from the beginning of word lists, leading to a suppressed primacy effect. The present study examined this pattern on both learning trials and delayed recall of the Auditory Verbal Learning Test (AVLT) in 34 persons performing with normal effort, 38 naive malingerers, 33 warned malingerers, and 29 head-injured patients. Both malingering groups had lower scores on the primacy portion of the list during learning trials, while normals and head-injured patients had normal serial position curves. During delayed recall, normals and head-injured patients did better than the two malingering groups on middle and recency portions of the list. Findings suggest that the serial position effect during learning trials may be a useful pattern of performance to watch for when suspicious of malingering.

  20. Rapid-Sequence Serial Sexual Homicides.

    Science.gov (United States)

    Schlesinger, Louis B; Ramirez, Stephanie; Tusa, Brittany; Jarvis, John P; Erdberg, Philip

    2017-03-01

    Serial sexual murderers have been described as committing homicides in a methodical manner, taking substantial time between offenses to elude the authorities. The results of our study of the temporal patterns (i.e., the length of time between homicides) of a nonrandom national sample of 44 serial sexual murderers and their 201 victims indicate that this representation may not always be accurate. Although 25 offenders (56.8%) killed with longer than a 14-day period between homicides, a sizeable subgroup was identified: 19 offenders (43.2%) who committed homicides in rapid-sequence fashion, with fewer than 14 days between all or some of the murders. Six offenders (13.6%) killed all their victims in one rapid-sequence, spree-like episode, with homicides just days apart or sometimes two murders in the same day. Thirteen offenders (29.5%) killed in one or two rapid-sequence clusters (i.e., more than one murder within a 14-day period, as well as additional homicides with greater than 14 days between each). The purpose of our study was to describe this subgroup of rapid-sequence offenders who have not been identified until now. These findings argue for accelerated forensic assessments of dangerousness and public safety when a sexual murder is detected. Psychiatric disorders with rapidly occurring symptom patterns, or even atypical mania or mood dysregulation, may serve as exemplars for understanding this extraordinary group of offenders. © 2017 American Academy of Psychiatry and the Law.

  1. CMOS serial link for fully duplexed data communication

    Science.gov (United States)

    Lee, Kyeongho; Kim, Sungjoon; Ahn, Gijung; Jeong, Deog-Kyoon

    1995-04-01

    This paper describes a CMOS serial link allowing fully duplexed 500 Mbaud serial data communication. The CMOS serial link is a robust and low-cost solution to high data rate requirements. A central charge pump PLL for generating multiphase clocks for oversampling is shared by several serial link channels. Fully duplexed serial data communication is realized in the bidirectional bridge by separating incoming data from the mixed signal on the cable end. The digital PLL accomplishes process-independent data recovery by using a low-ratio oversampling, a majority voting, and a parallel data recovery scheme. Mostly, digital approach could extend its bandwidth further with scaled CMOS technology. A single channel serial link and a charge pump PLL are integrated in a test chip using 1.2 micron CMOS process technology. The test chip confirms upto 500 Mbaud unidirectional mode operation and 320 Mbaud fully duplexed mode operation with pseudo random data patterns.

  2. CAMAC serial highway interface for the LSI-11

    International Nuclear Information System (INIS)

    Lau, N.H.

    1980-01-01

    A CAMAC Serial Highway Interface has been designed for the Local Control and Instrumentation System of the Mirror Fusion Test Facility. There are over 50 distinguishable systems in the facility, each of which consists of the LSI-11 computer, fiber optic communication links, and the CAMAC system. The LSI-11 computer includes a 32k memory, serial modem interface and the CAMAC Serial Highway Interface

  3. Implementation of Serial and Parallel Bubble Sort on Fpga

    OpenAIRE

    Purnomo, Dwi Marhaendro Jati; Arinaldi, Ahmad; Priyantini, Dwi Teguh; Wibisono, Ari; Febrian, Andreas

    2016-01-01

    Sorting is common process in computational world. Its utilization are on many fields from research to industry. There are many sorting algorithm in nowadays. One of the simplest yet powerful is bubble sort. In this study, bubble sort is implemented on FPGA. The implementation was taken on serial and parallel approach. Serial and parallel bubble sort then compared by means of its memory, execution time, and utility which comprises slices and LUTs. The experiments show that serial bubble sort r...

  4. SERIAL TELEVISI DEXTER SEBAGAI ANAKRONISME DALAM SASTRA POPULER

    OpenAIRE

    Ida Rochani Adi

    2014-01-01

    In the popular literature context, this study aims to investigate: (1) how the formulation of the characterization of Dexter in the television serial Dexter violates the tradition of literary characterization, and (2) how the formula of moral values is dramatized through Dexter, who is a sociopath, psychopath, serial killer, and person without moral. The research object was the television serial Dexter, which ranks five in popularity in the world. The data were collected by documenting 84 epi...

  5. Representation of the serial killer on the Italian Internet.

    Science.gov (United States)

    Villano, P; Bastianoni, P; Melotti, G

    2001-10-01

    The representation of serial killers was examined from the analysis of 317 Web pages in the Italian language to study how the psychological profiles of serial killers are described on the Italian Internet. The correspondence analysis of the content of these Web pages shows that in Italy the serial killer is associated with words such as "monster" and "horror," which suggest and imply psychological perversion and aberrant acts. These traits are peculiar for the Italian scenario.

  6. IMPLEMENTATION OF SERIAL AND PARALLEL BUBBLE SORT ON FPGA

    Directory of Open Access Journals (Sweden)

    Dwi Marhaendro Jati Purnomo

    2016-06-01

    Full Text Available Sorting is common process in computational world. Its utilization are on many fields from research to industry. There are many sorting algorithm in nowadays. One of the simplest yet powerful is bubble sort. In this study, bubble sort is implemented on FPGA. The implementation was taken on serial and parallel approach. Serial and parallel bubble sort then compared by means of its memory, execution time, and utility which comprises slices and LUTs. The experiments show that serial bubble sort required smaller memory as well as utility compared to parallel bubble sort. Meanwhile, parallel bubble sort performed faster than serial bubble sort

  7. A psychological profile of a serial killer: a case report.

    Science.gov (United States)

    Dogra, T D; Leenaars, Antoon A; Chadha, R K; Manju, Mehta; Lalwani, Sanjeev; Sood, Mamta; Lester, David; Raina, Anupuma; Behera, C

    2012-01-01

    Serial killers have always fascinated society. A serial killer is typically defined as a perpetrator who murders three or more people over a period of time. Most reported cases of serial killers come from the United States and Canada. In India, there are few reported cases. We present, to the best of our knowledge, the first Indian case in the literature. The present case is of a 28-year-old man, Surinder Koli. The Department of Forensic Medicine & Toxicology, All India Institute of Medical Sciences, New Delphi handled the forensic study. We present a most unique psychological investigation into the mind of a serial killer.

  8. Malignant sex and aggression: an overview of serial sexual homicide.

    Science.gov (United States)

    Myers, W C; Reccoppa, L; Burton, K; McElroy, R

    1993-01-01

    Serial murderers have attracted considerable attention in the popular press and criminal justice field, but scientific literature about these individuals is limited. This article provides an overview, from a psychiatric perspective, of serial sexual homicide, one type of serial killing. Characteristics of this type of murder and of these offenders are discussed. Defining qualities and diagnoses applicable to serial sexual killers are reviewed. Various etiologic theories are discussed, with emphasis on the role of fantasy and psychodynamic explanations. Governmental agencies involved in combating this type of crime, along with the role of mental health professionals in criminal profiling, are presented. Finally, the authors explore the reaction of society to this phenomenon.

  9. Woody Allen, serial schlemiel ?

    Directory of Open Access Journals (Sweden)

    Frédérique Brisset

    2011-04-01

    Full Text Available Woody Allen a développé au fil des années une persona cinématographique de schlemiel new-yorkais aisément reconnaissable par le spectateur. Elle marque nombre de ses films, qu’il y apparaisse en tant qu’acteur ou y dirige des substituts comédiens comme déclinaisons de lui-même. Si cette figure prototypique est le fondement de la sérialité dans sa filmographie, il est des traits stylistiques qui en portent trace tout au long de son œuvre : la récurrence annuelle de ses réalisations, la signature formelle symbolisée par ses génériques à la typographie singulière, le rythme de ses dialogues ponctués d’interjections et l’usage de l’autocitation sont autant de procédés qui marquent son cinéma d’un sceau très personnel. Ils fonctionnent comme des clins d’œil au spectateur qui reçoit dès lors LE Woody Allen millésimé comme une invitation à retrouver son microcosme. Ainsi la sérialité se pose comme à la fois initiale et conséquentielle de son système filmique, processus de création unique dans le cinéma américain.Woody Allen has long constructed a cinematographic persona of schlemiel New- Yorker that the audience can easily identify. It impacts most of his films, whether he stars in them or directs “substitute” actors to impersonate his character. If this prototypical figure is the basis of seriality in his cinematography, serial stylistic features can also be found all along his career: the annual recurrence of his productions, the formal signature symbolised by the typography of his singular credit titles, his rhythmical interjection-punctuated dialogues and the use of self-quotation imprint a very personal seal upon his movies. They all work as a recognition signals for the audience who thus receive THE Woody Allen vintage as an invitation to re-enter his microcosm. Seriality is then both initial and consequential to his cinematographic system, a unique creative process in American film history.

  10. Serial binary interval ratios improve rhythm reproduction.

    Science.gov (United States)

    Wu, Xiang; Westanmo, Anders; Zhou, Liang; Pan, Junhao

    2013-01-01

    Musical rhythm perception is a natural human ability that involves complex cognitive processes. Rhythm refers to the organization of events in time, and musical rhythms have an underlying hierarchical metrical structure. The metrical structure induces the feeling of a beat and the extent to which a rhythm induces the feeling of a beat is referred to as its metrical strength. Binary ratios are the most frequent interval ratio in musical rhythms. Rhythms with hierarchical binary ratios are better discriminated and reproduced than rhythms with hierarchical non-binary ratios. However, it remains unclear whether a superiority of serial binary over non-binary ratios in rhythm perception and reproduction exists. In addition, how different types of serial ratios influence the metrical strength of rhythms remains to be elucidated. The present study investigated serial binary vs. non-binary ratios in a reproduction task. Rhythms formed with exclusively binary (1:2:4:8), non-binary integer (1:3:5:6), and non-integer (1:2.3:5.3:6.4) ratios were examined within a constant meter. The results showed that the 1:2:4:8 rhythm type was more accurately reproduced than the 1:3:5:6 and 1:2.3:5.3:6.4 rhythm types, and the 1:2.3:5.3:6.4 rhythm type was more accurately reproduced than the 1:3:5:6 rhythm type. Further analyses showed that reproduction performance was better predicted by the distribution pattern of event occurrences within an inter-beat interval, than by the coincidence of events with beats, or the magnitude and complexity of interval ratios. Whereas rhythm theories and empirical data emphasize the role of the coincidence of events with beats in determining metrical strength and predicting rhythm performance, the present results suggest that rhythm processing may be better understood when the distribution pattern of event occurrences is taken into account. These results provide new insights into the mechanisms underlining musical rhythm perception.

  11. Serial binary interval ratios improve rhythm reproduction

    Directory of Open Access Journals (Sweden)

    Xiang eWu

    2013-08-01

    Full Text Available Musical rhythm perception is a natural human ability that involves complex cognitive processes. Rhythm refers to the organization of events in time, and musical rhythms have an underlying hierarchical metrical structure. The metrical structure induces the feeling of a beat and the extent to which a rhythm induces the feeling of a beat is referred to as its metrical strength. Binary ratios are the most frequent interval ratio in musical rhythms. Rhythms with hierarchical binary ratios are better discriminated and reproduced than rhythms with hierarchical non-binary ratios. However, it remains unclear whether a superiority of serial binary over non-binary ratios in rhythm perception and reproduction exists. In addition, how different types of serial ratios influence the metrical strength of rhythms remains to be elucidated. The present study investigated serial binary vs. non-binary ratios in a reproduction task. Rhythms formed with exclusively binary (1:2:4:8, non-binary integer (1:3:5:6, and non-integer (1:2.3:5.3:6.4 ratios were examined within a constant meter. The results showed that the 1:2:4:8 rhythm type was more accurately reproduced than the 1:3:5:6 and 1:2.3:5.3:6.4 rhythm types, and the 1:2.3:5.3:6.4 rhythm type was more accurately reproduced than the 1:3:5:6 rhythm type. Further analyses showed that reproduction performance was better predicted by the distribution pattern of event occurrences within an inter-beat interval, than by the coincidence of events with beats, or the magnitude and complexity of interval ratios. Whereas rhythm theories and empirical data emphasize the role of the coincidence of events with beats in determining metrical strength and predicting rhythm performance, the present results suggest that rhythm processing may be better understood when the distribution pattern of event occurrences is taken into account. These results provide new insights into the mechanisms underlining musical rhythm perception.

  12. Mimicking the action of GroEL in molecular dynamics simulations : Application to the refinement of protein structures

    NARCIS (Netherlands)

    Fan, H; Mark, AE

    Bacterial chaperonin, GroEL, together with its co-chaperonin, GroES, facilitates the folding of a variety of polypeptides. Experiments suggest that GroEL stimulates protein folding by multiple cycles of binding and release. Misfolded proteins first bind to an exposed hydrophobic surface on GroEL.

  13. KANBAN allocation in a serial suply chain

    Directory of Open Access Journals (Sweden)

    Guillermo Andrés Sánchez C.

    2012-06-01

    Full Text Available The aim of this project is to simulate a Kanban system using N stages with the objective of maintaining an acceptable throughput and mean system time. The document shows the production systems where Kanban is applicable and what the potential benefits are. A serial of simulations will be done using a demand given by a poison distribution with rate λ ^ ext. The simulation aimed to find the best number of withdrawal Kanban on all stages when the values of μ (for exponential distribution of the process and λ ^ ext increase and decrease. At the end of this simulation, the best way to allocate the withdrawal Kanban over N stages with the objective of maintaining acceptable throughput and mean system time will be clearer thus the conclusions of this work will be done.

  14. Handbook of serial communications interfaces a comprehensive compendium of serial digital input/output (I/O) standards

    CERN Document Server

    Frenzel, Louis

    2015-01-01

    This book catalogs the most popular and commonly used serial-port interfaces and provides details on the specifications and the latest standards, enabling you to select an interface for a new design or verify that an interface is working correctly. Each chapter is based on a different interface and is written in an easy to follow, standard format. With this book you will learn: The most widely used serial interfacesHow to select the best serial interface for a specific application or designThe trade-offs between data rate and distance (length or range)The operation and benefits of serial

  15. Polymer Directed Protein Assemblies

    Directory of Open Access Journals (Sweden)

    Patrick van Rijn

    2013-05-01

    Full Text Available Protein aggregation and protein self-assembly is an important occurrence in natural systems, and is in some form or other dictated by biopolymers. Very obvious influences of biopolymers on protein assemblies are, e.g., virus particles. Viruses are a multi-protein assembly of which the morphology is dictated by poly-nucleotides namely RNA or DNA. This “biopolymer” directs the proteins and imposes limitations on the structure like the length or diameter of the particle. Not only do these bionanoparticles use polymer-directed self-assembly, also processes like amyloid formation are in a way a result of directed protein assembly by partial unfolded/misfolded biopolymers namely, polypeptides. The combination of proteins and synthetic polymers, inspired by the natural processes, are therefore regarded as a highly promising area of research. Directed protein assembly is versatile with respect to the possible interactions which brings together the protein and polymer, e.g., electrostatic, v.d. Waals forces or covalent conjugation, and possible combinations are numerous due to the large amounts of different polymers and proteins available. The protein-polymer interacting behavior and overall morphology is envisioned to aid in clarifying protein-protein interactions and are thought to entail some interesting new functions and properties which will ultimately lead to novel bio-hybrid materials.

  16. Role of Prion Protein Aggregation in Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Tullio Florio

    2012-07-01

    Full Text Available In several neurodegenerative diseases, such as Parkinson, Alzheimer’s, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP, the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126 and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death.

  17. Functional Rescue of a Misfolded Drosophila melanogaster Dopamine Transporter Mutant Associated with a Sleepless Phenotype by Pharmacological Chaperones.

    Science.gov (United States)

    Kasture, Ameya; El-Kasaby, Ali; Szöllősi, Daniel; Asjad, H M Mazhar; Grimm, Alexandra; Stockner, Thomas; Hummel, Thomas; Freissmuth, Michael; Sucic, Sonja

    2016-09-30

    Folding-defective mutants of the human dopamine transporter (DAT) cause a syndrome of infantile dystonia/parkinsonism. Here, we provide a proof-of-principle that the folding deficit is amenable to correction in vivo by two means, the cognate DAT ligand noribogaine and the HSP70 inhibitor, pifithrin-μ. We examined the Drosophila melanogaster (d) mutant dDAT-G108Q, which leads to a sleepless phenotype in flies harboring this mutation. Molecular dynamics simulations suggested an unstable structure of dDAT-G108Q consistent with a folding defect. This conjecture was verified; heterologously expressed dDAT-G108Q and the human (h) equivalent hDAT-G140Q were retained in the endoplasmic reticulum in a complex with endogenous folding sensors (calnexin and HSP70-1A). Incubation of the cells with noribogaine (a DAT ligand selective for the inward-facing state) and/or pifithrin-μ (an HSP70 inhibitor) restored folding of, and hence dopamine transport by, dDAT-G108Q and hDAT-G140Q. The mutated versions of DAT were confined to the cell bodies of the dopaminergic neurons in the fly brain and failed to reach the axonal compartments. Axonal delivery was restored, and sleep time was increased to normal length (from 300 to 1000 min/day) if the dDAT-G108Q-expressing flies were treated with noribogaine and/or pifithrin-μ. Rescuing misfolded versions of DAT by pharmacochaperoning is of therapeutic interest; it may provide opportunities to remedy disorders arising from folding-defective mutants of human DAT and of other related SLC6 transporters. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Short- and long-term memory contributions to immediate serial recognition: evidence from serial position effects.

    Science.gov (United States)

    Purser, Harry; Jarrold, Christopher

    2010-04-01

    A long-standing body of research supports the existence of separable short- and long-term memory systems, relying on phonological and semantic codes, respectively. The aim of the current study was to measure the contribution of long-term knowledge to short-term memory performance by looking for evidence of phonologically and semantically coded storage within a short-term recognition task, among developmental samples. Each experimental trial presented 4-item lists. In Experiment 1 typically developing children aged 5 to 6 years old showed evidence of phonologically coded storage across all 4 serial positions, but evidence of semantically coded storage at Serial Positions 1 and 2. In a further experiment, a group of individuals with Down syndrome was investigated as a test case that might be expected to use semantic coding to support short-term storage, but these participants showed no evidence of semantically coded storage and evidenced phonologically coded storage only at Serial Position 4, suggesting that individuals with Down syndrome have a verbal short-term memory capacity of 1 item. Our results suggest that previous evidence of semantic effects on "short-term memory performance" does not reflect semantic coding in short-term memory itself, and provide an experimental method for researchers wishing to take a relatively pure measure of verbal short-term memory capacity, in cases where rehearsal is unlikely.

  19. Dual Role of Ancient Ubiquitous Protein 1 (AUP1) in Lipid Droplet Accumulation and Endoplasmic Reticulum (ER) Protein Quality Control

    Science.gov (United States)

    Klemm, Elizabeth J.; Spooner, Eric; Ploegh, Hidde L.

    2011-01-01

    Quality control of endoplasmic reticulum proteins involves the identification and engagement of misfolded proteins, dislocation of the misfolded protein across the endoplasmic reticulum (ER) membrane, and ubiquitin-mediated targeting to the proteasome for degradation. Ancient ubiquitous protein 1 (AUP1) physically associates with the mammalian HRD1-SEL1L complex, and AUP1 depletion impairs degradation of misfolded ER proteins. One of the functions of AUP1 in ER quality control is to recruit the soluble E2 ubiquitin-conjugating enzyme UBE2G2. We further show that the CUE domain of AUP1 regulates polyubiquitylation and facilitates the interaction of AUP1 with the HRD1 complex and with dislocation substrates. AUP1 localizes both to the ER and to lipid droplets. The AUP1 expression level affects the abundance of cellular lipid droplets and as such represents the first protein with lipid droplet regulatory activity to be linked to ER quality control. These findings indicate a possible connection between ER protein quality control and lipid droplets. PMID:21857022

  20. Utilization of serial resources in libraries of selected tertiary ...

    African Journals Online (AJOL)

    Information Impact: Journal of Information and Knowledge Management ... security personnel for adequate monitoring of the serial materials, as well as the need for authors and stakeholders in education to donate more serial materials in order to enrich the collections in the library and enhance academic performance.

  1. The Effect of Concurrent Semantic Categorization on Delayed Serial Recall

    Science.gov (United States)

    Acheson, Daniel J.; MacDonald, Maryellen C.; Postle, Bradley R.

    2011-01-01

    The influence of semantic processing on the serial ordering of items in short-term memory was explored using a novel dual-task paradigm. Participants engaged in 2 picture-judgment tasks while simultaneously performing delayed serial recall. List material varied in the presence of phonological overlap (Experiments 1 and 2) and in semantic content…

  2. Effects of Serial Rehearsal Training on Memory Search

    Science.gov (United States)

    McCauley, Charley; And Others

    1976-01-01

    Half the subjects were trained to use a serial rehearsal strategy during target set storage and half were given no strategy training. The results indicate that the rate of memory search is IQ-related, and that serial rehearsal training facilitates memory search when rehearsal is covert. (Author/BW)

  3. Indexing Serialized Fiction: May the Force Be with You.

    Science.gov (United States)

    Barr, Melissa M.

    The adult novel offers indexers an unusual opportunity to create a serialized fiction index. This research paper involved designing and creating a Character Index, Thesaurus, Glossary, and Abstract (with descriptors) for 21 novels based on the "Star Wars" movies. The novels are an unusual example of serialized fiction featuring main…

  4. Infants' Memory Processing of a Serial List: List Length Effects.

    Science.gov (United States)

    Gulya, Michele; Sweeney, Becky; Rovee-Collier, Carolyn

    1999-01-01

    Three experiments demonstrated that increasing the length of a mobile serial list impaired 6-month olds' memory for serial order. Findings indicated that the primacy effect was absent on a 24-hour delayed recognition test and was exhibited on a reactivation test, adding to growing evidence that young infants possess two functionally distinct…

  5. Antisocial personality disorder, sexual sadism, malignant narcissism, and serial murder.

    Science.gov (United States)

    Geberth, V J; Turco, R N

    1997-01-01

    This paper examines the research on serial murder and its relationship to antisocial personality disorder and sexual sadism. The concept of malignant narcissism is also discussed. Case studies of serial killers are examined regarding the nature of sexual violation and crime scene behavior.

  6. Highlights in radiation measuring technique's - Serial Micro Channel SMC 2100

    International Nuclear Information System (INIS)

    Kandler, M.; Hoffmann, Ch.

    2002-01-01

    The Serial Micro Channel SMC 2100 offers an ''intelligent stand alone'' electronics for the radiation measuring technique's. First it is designed of being connected to a serial interface RS232 of a PC. With a RS485 serial interface on a PC, a network structure can be generated. It has all functional modules which are necessary for the measurement of detector signals. Hence it is possible to directly connect any detector for radiation measurement to a PC, laptop, or notebook. All variations can be operated without PC support too. It has a modular structure and consists of two blocks, the functional modules and the basic modules. The Serial Micro Channel SMC 2100 may be directly coupled to a detector, which therefore makes the realisation of an ''intelligent radiation detector'' with serial link RS232 or RS485. (orig.)

  7. Serial Entrepreneurship, Learning by Doing and Self-selection

    DEFF Research Database (Denmark)

    Rocha, Vera; Carneiro, Anabela; Varum, Celeste

    2015-01-01

    of the person-specific effect, using information on individuals’ past histories in paid employment, confirm that serial entrepreneurs exhibit, on average, a larger person-specific effect than non-serial business owners. Moreover, ignoring serial entrepreneurs’ self-selection overestimates learning by doing......It remains a question whether serial entrepreneurs typically perform better than their novice counterparts owing to learning by doing effects or mostly because they are a selected sample of higher-than-average ability entrepreneurs. This paper tries to unravel these two effects by exploring a novel...... empirical strategy based on continuous time duration models with selection. We use a large longitudinal matched employer-employee dataset that allows us to identify about 220,000 individuals who have left their first entrepreneurial experience, out of which over 35,000 became serial entrepreneurs. We...

  8. SERIAL TELEVISI DEXTER SEBAGAI ANAKRONISME DALAM SASTRA POPULER

    Directory of Open Access Journals (Sweden)

    Ida Rochani Adi

    2014-06-01

    Full Text Available In the popular literature context, this study aims to investigate: (1 how the formulation of the characterization of Dexter in the television serial Dexter violates the tradition of literary characterization, and (2 how the formula of moral values is dramatized through Dexter, who is a sociopath, psychopath, serial killer, and person without moral. The research object was the television serial Dexter, which ranks five in popularity in the world. The data were collected by documenting 84 episodes of the serial having been broadcast since 2006. They were analyzed by means of content analysis and qualitative descriptive techniques. Based on the findings, the conclusions are as follows. First, there is a violation or anachronism of characterization through the main character in the serial. Second, the dramatized moral values still contain conventional values although they are in different forms.

  9. Endoplasmic reticulum proteins SDF2 and SDF2L1 act as components of the BiP chaperone cycle to prevent protein aggregation.

    Science.gov (United States)

    Fujimori, Tsutomu; Suno, Ryoji; Iemura, Shun-Ichiro; Natsume, Tohru; Wada, Ikuo; Hosokawa, Nobuko

    2017-08-01

    The folding of newly synthesized proteins in the endoplasmic reticulum (ER) is assisted by ER-resident chaperone proteins. BiP (immunoglobulin heavy-chain-binding protein), a member of the HSP70 family, plays a central role in protein quality control. The chaperone function of BiP is regulated by its intrinsic ATPase activity, which is stimulated by ER-resident proteins of the HSP40/DnaJ family, including ERdj3. Here, we report that two closely related proteins, SDF2 and SDF2L1, regulate the BiP chaperone cycle. Both are ER-resident, but SDF2 is constitutively expressed, whereas SDF2L1 expression is induced by ER stress. Both luminal proteins formed a stable complex with ERdj3 and potently inhibited the aggregation of different types of misfolded ER cargo. These proteins associated with non-native proteins, thus promoting the BiP-substrate interaction cycle. A dominant-negative ERdj3 mutant that inhibits the interaction between ERdj3 and BiP prevented the dissociation of misfolded cargo from the ERdj3-SDF2L1 complex. Our findings indicate that SDF2 and SDF2L1 associate with ERdj3 and act as components in the BiP chaperone cycle to prevent the aggregation of misfolded proteins, partly explaining the broad folding capabilities of the ER under various physiological conditions. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

  10. Fixed target matrix for femtosecond time-resolved and in situ serial micro-crystallography

    Directory of Open Access Journals (Sweden)

    C. Mueller

    2015-09-01

    Full Text Available We present a crystallography chip enabling in situ room temperature crystallography at microfocus synchrotron beamlines and X-ray free-electron laser (X-FEL sources. Compared to other in situ approaches, we observe extremely low background and high diffraction data quality. The chip design is robust and allows fast and efficient loading of thousands of small crystals. The ability to load a large number of protein crystals, at room temperature and with high efficiency, into prescribed positions enables high throughput automated serial crystallography with microfocus synchrotron beamlines. In addition, we demonstrate the application of this chip for femtosecond time-resolved serial crystallography at the Linac Coherent Light Source (LCLS, Menlo Park, California, USA. The chip concept enables multiple images to be acquired from each crystal, allowing differential detection of changes in diffraction intensities in order to obtain high signal-to-noise and fully exploit the time resolution capabilities of XFELs.

  11. Molecular dynamics study of the dominant-negative E219K polymorphism in human prion protein

    NARCIS (Netherlands)

    Jahandideh, Samad; Jamalan, Mostafa; Faridounnia, Maryam|info:eu-repo/dai/nl/338666923

    2015-01-01

    Human prion diseases are associated with misfolding or aggregation of the Human Prion Protein (HuPrP). Missense mutations in the HuPrP gene, contribute to conversion of HuPrP(C) to HuPrP(Sc) and amyloid formation. Based on our previous comprehensive study, three missense mutations, from two

  12. Task based synthesis of serial manipulators

    Directory of Open Access Journals (Sweden)

    Sarosh Patel

    2015-05-01

    Full Text Available Computing the optimal geometric structure of manipulators is one of the most intricate problems in contemporary robot kinematics. Robotic manipulators are designed and built to perform certain predetermined tasks. There is a very close relationship between the structure of the manipulator and its kinematic performance. It is therefore important to incorporate such task requirements during the design and synthesis of the robotic manipulators. Such task requirements and performance constraints can be specified in terms of the required end-effector positions, orientations and velocities along the task trajectory. In this work, we present a comprehensive method to develop the optimal geometric structure (DH parameters of a non-redundant six degree of freedom serial manipulator from task descriptions. In this work we define, develop and test a methodology to design optimal manipulator configurations based on task descriptions. This methodology is devised to investigate all possible manipulator configurations that can satisfy the task performance requirements under imposed joint constraints. Out of all the possible structures, the structures that can reach all the task points with the required orientations are selected. Next, these candidate structures are tested to see whether they can attain end-effector velocities in arbitrary directions within the user defined joint constraints, so that they can deliver the best kinematic performance. Additionally least power consuming configurations are also identified.

  13. Serial neuroradiological studies in focal cerebritis

    International Nuclear Information System (INIS)

    Hatta, S.; Mochizuki, H.; Kuru, Y.; Miwa, H.; Kondo, T.; Mori, H.; Mizuno, Y.

    1994-01-01

    We report serial neuroradiological studies in a patient with focal cerebritis in the head of the left caudate nucleus. On the day after the onset of symptoms, CT showed an ill-defined low density lesion. The lack of contrast enhancement appeared to be the most important finding for differentiating focal cerebritis from an encapsulated brain abscess or a tumour. MRI two days later revealed the centre of the lesion to be of slightly low intensity on T1-weighted inversion recovery (IR) images and very low intensity on T2-weighted spin echo images, which appeared to correspond to the early cerebritis stage of experimentally induced cerebritis and brain abscess. Ten days after the onset of symptoms, CT revealed a thin ring of enhancement in the head of the caudate nucleus, and a similar small ring was seen in the hypothalamus 16 days after the onset, corresponding to the late cerebritis stage. MRI nine days later revealed ill-defined high signal lesions within the involved area on the T1-weighted IR images. To our knowledge, this is the first published MRI documentation of the early cerebritis stage developing into an encapsulated brain abscess. The mechanisms underlying of these radiographic changes are discussed. (orig.)

  14. PORNOGRAFI DALAM SERIAL ANIME ANAK (ANALISIS SEMIOTIKA DALAM SERIAL CRAYON SHIN CHAN

    Directory of Open Access Journals (Sweden)

    - Sangidun

    2017-01-01

    Full Text Available Crayon Shin Chan, a Japanese two-dimension animation series broadcast in one of private Indonesian TVs, is categorized into child’s program since it is broadcast at child’s prime time, Sunday 08.30 a.m. In spite of its broadcast time, this series consist of symbols directed not for children, such as some acts that are not appropriate to be done by children, especially in Indonesia. Moreover, adult symbols of sex are also found in the program. For this reason it will be interesting to analyze it using semiotic analysis. Semiotics is the study of symbol and its meaning which its principle concept is that both signifier and signified consist of symbols and are related to denotation and connotation.   Crayon Shin Chan merupakan serial animasi dua dimensi yang tayang di salah satu stasiun televisi swasta di Indonesia. Ini merupakan produk animasi 2 dimensi yang diimpor dari Jepang. Di Indonesia, serial ini masuk dalam kategori acara anak. Hal ini dapat dilihat dari jam penayangannya yang merupakan waktu prime time bagi anak, yakni pada hari minggu pukul 08.30. Akan tetapi, pada serial ini banyak simbol-simbol yang mengarah pada tayangan yang bukan untuk anak-anak, yakni adeganadegan yang tidak pantas dilakukan oleh anak khususnya di Indonesia. Serta adanya pula simbol-simbol yang mengarah pada tayangan berbau dewasa. Tentu akan menarik jika tayangan ini diteliti menggunakan analisis semiotika. Semiotika sendiri merupakan kajian ilmu mengenai tanda dan makna. Yang pada prinsipnya, konsep penting seperti penanda (signifier dan petanda (signified sama-sama terdiri dari tanda dan terkait dengan denotasi dan konotasi.

  15. Transtornos de personalidade, psicopatia e serial killers Personality disorders, psychopathy and serial killers

    Directory of Open Access Journals (Sweden)

    Hilda C P Morana

    2006-10-01

    Full Text Available OBJETIVO: Apresentar as características básicas dos diversos transtornos específicos de personalidade, mas centrando-se no transtorno de personalidade anti-social, fazendo sua diferenciação com psicopatia. O estudo ainda se propõe a abordar a figura do serial killer, apontando a presença de aspectos psicopáticos no homicídio seriado. MÉTODO: Uma revisão bibliográfica foi feita no sentido de se abordar convergências e divergências entre diversos autores sobre um assunto tão polêmico, sobretudo quanto à viabilidade de tratamento dessa clientela forense. RESULTADOS: Enquanto o transtorno de personalidade anti-social é um diagnóstico médico, pode-se entender o termo "psicopatia", pertencente à esfera psiquiátrico-forense, como um "diagnóstico legal". Não se pode falar ainda de tratamento eficaz para os chamados "serial killers". CONCLUSÃO: Os transtornos de personalidade, especialmente o tipo anti-social, representam ainda hoje um verdadeiro desafio para a psiquiatria forense. O local mais adequado e justo para seus portadores, bem como recomendação homogênea e padronizada de tratamento são questões ainda não respondidas.OBJECTIVE: To illustrate the basic characteristics of several specific personality disorders, focusing mainly in antisocial personality disorder. The differences between antisocial personality disorder and psychopathy are highlighted. Serial killers and its psychopathic aspects are also discussed. METHOD: A bibliographic review was completed in order to outline convergences and divergences among different authors about this controversial issue, especially those concerning the possibility of treatment. RESULTS: While anti-social personality disorder is a medical diagnosis, the term "psychopathy" (which belongs to the sphere of forensic psychiatry may be understood as a "legal diagnosis". It is not still possible to identify an effective treatment for serial killers. CONCLUSION: Personality disorders

  16. Serial forced displacement in American cities, 1916-2010.

    Science.gov (United States)

    Fullilove, Mindy Thompson; Wallace, Rodrick

    2011-06-01

    Serial forced displacement has been defined as the repetitive, coercive upheaval of groups. In this essay, we examine the history of serial forced displacement in American cities due to federal, state, and local government policies. We propose that serial forced displacement sets up a dynamic process that includes an increase in interpersonal and structural violence, an inability to react in a timely fashion to patterns of threat or opportunity, and a cycle of fragmentation as a result of the first two. We present the history of the policies as they affected one urban neighborhood, Pittsburgh's Hill District. We conclude by examining ways in which this problematic process might be addressed.

  17. Serials cataloging at the turn of the century

    CERN Document Server

    Williams, James W

    2014-01-01

    An overview of the research topics and trends that have appeared over the last five years, Serials Cataloging at the Turn of the Century doesn't just tell you that there has been a lot of change--that the information environment is something of a chameleon, always beguiling and slipping out of grasp. Instead, it gives you the plain facts on the specific challenges serials catalogers have been facing and how they're meeting adversity head-on, ready to gain the advantage in the rumble with proliferating information and formats.Comprehensive, resource-packed, and easy-to-digest, Serials Catalogin

  18. The serial message-passing schedule for LDPC decoding algorithms

    Science.gov (United States)

    Liu, Mingshan; Liu, Shanshan; Zhou, Yuan; Jiang, Xue

    2015-12-01

    The conventional message-passing schedule for LDPC decoding algorithms is the so-called flooding schedule. It has the disadvantage that the updated messages cannot be used until next iteration, thus reducing the convergence speed . In this case, the Layered Decoding algorithm (LBP) based on serial message-passing schedule is proposed. In this paper the decoding principle of LBP algorithm is briefly introduced, and then proposed its two improved algorithms, the grouped serial decoding algorithm (Grouped LBP) and the semi-serial decoding algorithm .They can improve LBP algorithm's decoding speed while maintaining a good decoding performance.

  19. Serial CSTR digester configuration for improving biogas production from manure

    DEFF Research Database (Denmark)

    Boe, Kanokwan; Angelidaki, Irini

    2009-01-01

    distribution ratio of 80/20 and 90/10, and total HRT of 15 days. The results showed that the serial CSTR could obtain 11% higher biogas yield compared to the single CSTR. The increased biogas yield in the serial CSTR was mainly from the second reactor, which accounted for 16% and 12% of total biogas yield......A new configuration of manure digesters for improving biogas production has been investigated in laboratory scale. A single thermophilic continuous-flow stirred tank reactor (CSTR) operated with a hydraulic retention time (HRT) of 15 days was compared to a serial CSTR configuration with volume...

  20. Abutment region dosimetry for serial tomotherapy

    International Nuclear Information System (INIS)

    Low, Daniel A.; Mutic, Sasa; Dempsey, James F.; Markman, Jerry; Goddu, S. Murty; Purdy, James A.

    1999-01-01

    Purpose: A commercial intensity modulated radiation therapy system (Corvus, NOMOS Corp.) is presently used in our clinic to generate optimized dose distributions delivered using a proprietary dynamic multileaf collimator (DMLC) (MIMiC) composed of 20 opposed leaf pairs. On our accelerator (Clinac 600C/D, Varian Associates, Inc.) each MIMiC leaf projects to either 1.00 x 0.84 or 1.00 x 1.70 cm 2 (depending on the treatment plan and termed 1 cm or 2 cm mode, respectively). The MIMiC is used to deliver serial (axial) tomotherapy treatment plans, in which the beam is delivered to a nearly cylindrical volume as the DMLC is rotated about the patient. For longer targets, the patient is moved (indexed) between treatments a distance corresponding to the projected leaf width. The treatment relies on precise indexing and a method was developed to measure the precision of indexing devices. A treatment planning study of the dosimetric effects of incorrect patient indexing and concluded that a dose heterogeneity of 10% mm -1 resulted. Because the results may be sensitive to the dose model accuracy, we conducted a measurement-based investigation of the consequences of incorrect indexing using our accelerator. Although the indexing provides an accurate field abutment along the isocenter, due to beam divergence, hot and cold spots will be produced below and above isocenter, respectively, when less than 300 deg. arcs were used. A preliminary study recently determined that for a 290 deg. rotation in 1 cm mode, 15% cold and 7% hot spots were delivered to 7 cm above and below isocenter, respectively. This study completes the earlier work by investigating the dose heterogeneity as a function of position relative to the axis of rotation, arc length, and leaf width. The influence of random daily patient positioning errors is also investigated. Methods and Materials: Treatment plans were generated using 8.0 cm diameter cylindrical target volumes within a homogeneous rectilinear film

  1. Serial rotatostereography - A new diagnostic method

    International Nuclear Information System (INIS)

    Ottomo, Michinori; Nakanishi, Takeshi.

    1986-01-01

    In the previous study using cine, a cine film stereoprojector showed the adjacent two frames of cine film simultaneously, such as frames 1 and 2, 2 and 3, 3 and 4, and so on, consecutively. Because some intracranial lesions require emergency surgery immediately after angiography, a real time display method of serial rotatostereography was necessary. In order to show the consecutive adjacent two frames of a video disc simultaneously, using the same method as with the cine stereoprojector, a video disc recorder (VDR) (VM-1000M) and two video memories (Image Σ) were required. This VDR has the ability of advancing, stopping, and reversing the display of memories. A control unit was manufactured in order to display these memories advancing and reversing continuously. As a result of this continuous semirotation stereo display, the anteroposterior projection was reversed, showing the posteroanterior view during ''reversing mode''. Thus a lead relay circuit was manufactured to prevent this phenomenon. Recording was done using a memory disc recorder (FOM 2200F), which has the ability of recording 10,000 frames per disc. Each frame can also be recorded on imaging film using O · X Multi Camera 400X. Finally, stereoscopic views of cerebral circulation, using a single injection of contrast media and rapid rotation of the gantry, were obtained using two cathode-ray tubes (CRTs) and a stereoviewer (Continuous Semi-rotation Classical Stereo Display Method). Stereoscopic views were also obtained using a single CRT, which displayed the images in a semirotating fashion similar to a oscillating fan head (Continuous Semi-rotation New Stereo Display Method). (J.P.N.)

  2. Opportunity recognition: delineating the process and motivators for serial entrepreneurs

    Directory of Open Access Journals (Sweden)

    Boris Urban

    2011-04-01

    Full Text Available Opportunity recognition is a fundamental research issue in entrepreneurship which this paper empirically investigates for serial entrepreneurs. Initially key definitions and boundary conditions of opportunity recognition are explored to elucidate the relevant motivators driving serial entrepreneurs. After operationalising the various concepts, data is collected by surveying serial entrepreneurs (n= 77 based on pre-determined selection criteria. Since the study’s objective is to build solid theory on these new phenomena, descriptive analysis on the empirical results is provided. To test the hypotheses inferential statistics employing parametric and non-parametric tests are used. The findings reveal that the opportunity recognition behaviours are manifest among serial entrepreneurs, with few significant differences on how many new, major businesses have been pursued, or whether they can be said to be successes.

  3. Attractive Serial Dependence in the Absence of an Explicit Task.

    Science.gov (United States)

    Fornaciai, Michele; Park, Joonkoo

    2018-03-01

    Attractive serial dependence refers to an adaptive change in the representation of sensory information, whereby a current stimulus appears to be similar to a previous one. The nature of this phenomenon is controversial, however, as serial dependence could arise from biased perceptual representations or from biased traces of working memory representation at a decisional stage. Here, we demonstrated a neural signature of serial dependence in numerosity perception emerging early in the visual processing stream even in the absence of an explicit task. Furthermore, a psychophysical experiment revealed that numerosity perception is biased by a previously presented stimulus in an attractive way, not by repulsive adaptation. These results suggest that serial dependence is a perceptual phenomenon starting from early levels of visual processing and occurring independently from a decision process, which is consistent with the view that these biases smooth out noise from neural signals to establish perceptual continuity.

  4. Fast Grasp Contact Computation for a Serial Robot

    Science.gov (United States)

    Shi, Jianying (Inventor); Hargrave, Brian (Inventor); Diftler, Myron A. (Inventor)

    2015-01-01

    A system includes a controller and a serial robot having links that are interconnected by a joint, wherein the robot can grasp a three-dimensional (3D) object in response to a commanded grasp pose. The controller receives input information, including the commanded grasp pose, a first set of information describing the kinematics of the robot, and a second set of information describing the position of the object to be grasped. The controller also calculates, in a two-dimensional (2D) plane, a set of contact points between the serial robot and a surface of the 3D object needed for the serial robot to achieve the commanded grasp pose. A required joint angle is then calculated in the 2D plane between the pair of links using the set of contact points. A control action is then executed with respect to the motion of the serial robot using the required joint angle.

  5. BRAIN Journal - Some Considerations on Seriality and Synchronicity

    OpenAIRE

    Elena Nechita

    2017-01-01

    ABSTRACT This paper presents an overview of the results that have been obtained lately on seriality and synchronicity and their link, in the light of the new theories and within the frame of complexity science.

  6. Serials Management In Polytechnic Libraries in Nigeria: A ...

    African Journals Online (AJOL)

    Serials Management In Polytechnic Libraries in Nigeria: A Comparative Study of Kaduna Polytechnic And Yaba College of Technology Libraries. ... Samaru Journal of Information Studies. Journal Home · ABOUT THIS JOURNAL · Advanced ...

  7. Energy information data base. Serial titles, February 1978--June 1979

    International Nuclear Information System (INIS)

    1979-06-01

    This supplement contains changes and additions to TID-4579-R10 (the authority list for serial titles used by TIC), and is intended to be used with that publication. Supplements are cumulative until another revision is issued

  8. Fault tolerance based on serial communication of FPGA

    International Nuclear Information System (INIS)

    Peng Jing; Fang Zongliang; Xu Quanzhou; Hu Jiewei; Ma Guizhen

    2012-01-01

    There maybe appear mistake in serial communication. This paper was described the intellectual detector of γ dose ratemeter communication with FPGA. The software of FPGA designed the code about fault tolerance, prevented mistake effectively. (authors)

  9. Using Behavior Sequence Analysis to Map Serial Killers' Life Histories.

    Science.gov (United States)

    Keatley, David A; Golightly, Hayley; Shephard, Rebecca; Yaksic, Enzo; Reid, Sasha

    2018-03-01

    The aim of the current research was to provide a novel method for mapping the developmental sequences of serial killers' life histories. An in-depth biographical account of serial killers' lives, from birth through to conviction, was gained and analyzed using Behavior Sequence Analysis. The analyses highlight similarities in behavioral events across the serial killers' lives, indicating not only which risk factors occur, but the temporal order of these factors. Results focused on early childhood environment, indicating the role of parental abuse; behaviors and events surrounding criminal histories of serial killers, showing that many had previous convictions and were known to police for other crimes; behaviors surrounding their murders, highlighting differences in victim choice and modus operandi; and, finally, trial pleas and convictions. The present research, therefore, provides a novel approach to synthesizing large volumes of data on criminals and presenting results in accessible, understandable outcomes.

  10. How Do We Write about Performance in Serial Television?

    OpenAIRE

    Elliott Logan

    2015-01-01

    Television studies has produced few sustained analyses of performance in serial television. Yet film studies scholarship has shown how attending to the integration of performances with other aspects of film style is crucial to the interpretation and appreciation of expression and meaning in filmed narrative fictions. However, as a particle form of filmed serial narrative, series television raises a number of questions about performance that will not necessarily be satisfyingly addressed by th...

  11. Three more semantic serial position functions and a SIMPLE explanation.

    Science.gov (United States)

    Kelley, Matthew R; Neath, Ian; Surprenant, Aimée M

    2013-05-01

    There are innumerable demonstrations of serial position functions-with characteristic primacy and recency effects-in episodic tasks, but there are only a handful of such demonstrations in semantic memory tasks, and those demonstrations have used only two types of stimuli. Here, we provide three more examples of serial position functions when recalling from semantic memory. Participants were asked to reconstruct the order of (1) two cartoon theme song lyrics, (2) the seven Harry Potter books, and (3) two sets of movies, and all three demonstrations yielded conventional-looking serial position functions with primacy and recency effects. The data were well-fit by SIMPLE, a local distinctiveness model of memory that was originally designed to account for serial position effects in short- and long-term episodic memory. According to SIMPLE, serial position functions in both episodic and semantic memory tasks arise from the same type of processing: Items that are more separated from their close neighbors in psychological space at the time of recall will be better remembered. We argue that currently available evidence suggests that serial position functions observed when recalling items that are presumably in semantic memory arise because of the same processes as those observed when recalling items that are presumably in episodic memory.

  12. How Do We Write about Performance in Serial Television?

    Directory of Open Access Journals (Sweden)

    Elliott Logan

    2015-05-01

    Full Text Available Television studies has produced few sustained analyses of performance in serial television. Yet film studies scholarship has shown how attending to the integration of performances with other aspects of film style is crucial to the interpretation and appreciation of expression and meaning in filmed narrative fictions. However, as a particle form of filmed serial narrative, series television raises a number of questions about performance that will not necessarily be satisfyingly addressed by the direct adoption and application of approaches to writing about performance that have been honed in regard to film. How, then, do we write about performance in television serials in ways that recognise and accommodate the form’s relationship to film, while at the same time appropriately acknowledging and responding to long-form television’s serial status? To examine the difficulties and opportunities of approaching performance in serial television this way, the article conducts close readings of various pieces of television studies writing on performance, by scholars such as Jason Mittell, Sue Turnbull, George Toles, and Steven Peacock. Their work brings into view film and television’s points of common relation, and the distinctive challenges, achievements, and rewards of appreciating the best television serials, and the performances in them.

  13. Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis.

    Science.gov (United States)

    Parone, Philippe A; Da Cruz, Sandrine; Han, Joo Seok; McAlonis-Downes, Melissa; Vetto, Anne P; Lee, Sandra K; Tseng, Eva; Cleveland, Don W

    2013-03-13

    Mitochondria have been proposed as targets for toxicity in amyotrophic lateral sclerosis (ALS), a progressive, fatal adult-onset neurodegenerative disorder characterized by the selective loss of motor neurons. A decrease in the capacity of spinal cord mitochondria to buffer calcium (Ca(2+)) has been observed in mice expressing ALS-linked mutants of SOD1 that develop motor neuron disease with many of the key pathological hallmarks seen in ALS patients. In mice expressing three different ALS-causing SOD1 mutants, we now test the contribution of the loss of mitochondrial Ca(2+)-buffering capacity to disease mechanism(s) by eliminating ubiquitous expression of cyclophilin D, a critical regulator of Ca(2+)-mediated opening of the mitochondrial permeability transition pore that determines mitochondrial Ca(2+) content. A chronic increase in mitochondrial buffering of Ca(2+) in the absence of cyclophilin D was maintained throughout disease course and was associated with improved mitochondrial ATP synthesis, reduced mitochondrial swelling, and retention of normal morphology. This was accompanied by an attenuation of glial activation, reduction in levels of misfolded SOD1 aggregates in the spinal cord, and a significant suppression of motor neuron death throughout disease. Despite this, muscle denervation, motor axon degeneration, and disease progression and survival were unaffected, thereby eliminating mutant SOD1-mediated loss of mitochondrial Ca(2+) buffering capacity, altered mitochondrial morphology, motor neuron death, and misfolded SOD1 aggregates, as primary contributors to disease mechanism for fatal paralysis in these models of familial ALS.

  14. “It’s Always the Same, and It’s Always Different” Mythologisation and the Serial Killer in Henry: Portrait of a Serial Killer.

    OpenAIRE

    Smyth, David A.

    2015-01-01

    Serial killers are important in American horror because of their ability to exist between ‘myth’ and ‘reality’. The serial killer is one of the most important American myths, but it is one firmly rooted in real life: unlike Paul Bunyan or Superman, serial killers do exist. This essay examines the relationship between the ‘myth’ and the ‘reality’ of serial killers, and the complex relationship between the American public and the serial killer, using Henry: Portrait of a Serial K...

  15. The contribution of different prion protein types and host polymorphisms to clinicopathological variations in Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Head, Mark W; Ironside, James W

    2012-07-01

    Creutzfeldt-Jakob disease is a fatal neurodegenerative disease that primarily affects the central nervous system. In this respect, it can be considered alongside the more frequently occurring neurodegenerative diseases, such as Alzheimer's disease. Creutzfeldt-Jakob disease is perhaps the paradigmatic protein misfolding disorder, so comparisons between the mechanisms involved in Creutzfeldt-Jakob disease and other neurodegenerative diseases associated with protein misfolding (such as the tauopathies and synucleinopathies) may also be informative. Like many of these diseases, Creutzfeldt-Jakob disease occurs sporadically or can, more rarely, be associated with mutations. However, Creutzfeldt-Jakob disease can also be acquired and is experimentally transmissible. These properties have had profound public health implications and made the disease of interest to virologists, in addition to those interested in protein misfolding disorders and neurodegeneration. The possible causes for the pronounced phenotypic variation among different forms of Creutzfeldt-Jakob disease are beginning to become understood, and these appear to depend in large measure on the genetics of the host (specifically the sequence of the prion protein gene, PRNP) and the epigenetic aspects of the agent (thought to be a misfolded and aggregated form of the PRNP gene product, termed a prion). This review will examine whether this model in its present form has sufficient complexity and subtlety to account for the clinicopathological variation evident in Creutzfeldt-Jakob disease and will outline the ways in which a more complete and informative molecular definition of human prions are currently being sought. Copyright © 2012 John Wiley & Sons, Ltd.

  16. Clinical features in prion protein-deficient and wild-type cattle inoculated with transmissible mink encephalopathy (TME)

    Science.gov (United States)

    Background: Transmissible spongiform encephalopathies (TSEs) or prion diseases are caused by the propagation of a misfolded form (PrP**d) of the normal cellular prion protein, PrP**c. Recently, we have reported the generation and characterization of PrP**C-deficient cattle (PrP-/-) produced by a seq...

  17. Room-temperature macromolecular serial crystallography using synchrotron radiation

    Directory of Open Access Journals (Sweden)

    Francesco Stellato

    2014-07-01

    Full Text Available A new approach for collecting data from many hundreds of thousands of microcrystals using X-ray pulses from a free-electron laser has recently been developed. Referred to as serial crystallography, diffraction patterns are recorded at a constant rate as a suspension of protein crystals flows across the path of an X-ray beam. Events that by chance contain single-crystal diffraction patterns are retained, then indexed and merged to form a three-dimensional set of reflection intensities for structure determination. This approach relies upon several innovations: an intense X-ray beam; a fast detector system; a means to rapidly flow a suspension of crystals across the X-ray beam; and the computational infrastructure to process the large volume of data. Originally conceived for radiation-damage-free measurements with ultrafast X-ray pulses, the same methods can be employed with synchrotron radiation. As in powder diffraction, the averaging of thousands of observations per Bragg peak may improve the ratio of signal to noise of low-dose exposures. Here, it is shown that this paradigm can be implemented for room-temperature data collection using synchrotron radiation and exposure times of less than 3 ms. Using lysozyme microcrystals as a model system, over 40 000 single-crystal diffraction patterns were obtained and merged to produce a structural model that could be refined to 2.1 Å resolution. The resulting electron density is in excellent agreement with that obtained using standard X-ray data collection techniques. With further improvements the method is well suited for even shorter exposures at future and upgraded synchrotron radiation facilities that may deliver beams with 1000 times higher brightness than they currently produce.

  18. Analysis of assembly serial number usage in domestic light-water reactors

    International Nuclear Information System (INIS)

    Reich, W.J.; Moore, R.S.

    1991-05-01

    Domestic light-water reactor (LWR) fuel assemblies are identified by a serial number that is placed on each assembly. These serial numbers are used as identifiers throughout the life of the fuel. The uniqueness of assembly serial numbers is important in determining their effectiveness as unambiguous identifiers. The purpose of this study is to determine what serial numbering schemes are used, the effectiveness of these schemes, and to quantify how many duplicate serial numbers occur on domestic LWR fuel assemblies. The serial numbering scheme adopted by the American National Standards Institute (ANSI) ensures uniqueness of assembly serial numbers. The latest numbering scheme adopted by General Electric (GE), was also found to be unique. Analysis of 70,971 fuel assembly serial numbers from permanently discharged fuel identified 11,948 serial number duplicates. Three duplicate serial numbers were found when analysis focused on duplication within the individual fuel inventory at each reactor site, but these were traced back to data entry errors and will be corrected by the Energy Information Administration (EIA). There were also three instances where the serial numbers used to identify assemblies used for hot cell studies differed from the serial numbers reported to the EIA. It is recommended that fuel fabricators and utilities adhere to the ANSI serial numbering scheme to ensure serial number uniqueness. In addition, organizations collecting serial number information, should request that all known serial numbers physically attached or associated with each assembly be reported and identified by the corresponding number scheme. 10 refs., 5 tabs

  19. Overexpression and purification of halophilic proteins in Haloferax volcanii

    OpenAIRE

    Allers, Thorsten

    2010-01-01

    Halophilic enzymes function optimally at high salt concentrations and are active at low water availability. Such conditions are encountered at elevated concentrations of solutes such as salts and sugars, and at high concentrations of organic solvents. However, expression in heterologous hosts such as Escherichia coli can cause problems, since halophilic proteins typically misfold and aggregate in conditions of low ionic strength. We have harnessed the sophisticated genetic tools available for...

  20. Virulence-associated genome mutations of murine rotavirus identified by alternating serial passages in mice and cell cultures.

    Science.gov (United States)

    Tsugawa, Takeshi; Tatsumi, Masatoshi; Tsutsumi, Hiroyuki

    2014-05-01

    Although significant clinical efficacy and safety of rotavirus vaccines were recently revealed in many countries, the mechanism of their attenuation is not well understood. We passaged serially a cell culture-adapted murine rotavirus EB strain in mouse pups or in cell cultures alternately and repeatedly and fully sequenced all 11 genes of 21 virus samples passaged in mice or in cell cultures. Sequence analysis revealed that mouse-passaged viruses that regained virulence almost consistently acquired four kinds of amino acid (aa) substitutions in VP4 and substitution in aa 37 (Val to Ala) in NSP4. In addition, they gained and invariably conserved the 3' consensus sequence in NSP1. The molecular changes occurred along with the acquisition of virulence during passages in mice and then disappeared following passages in cell cultures. Intraperitoneal injection of recombinant NSP4 proteins confirmed the aa 37 site as important for its diarrheagenic activity in mice. These genome changes are likely to be correlated with rotavirus virulence. Serial passage of a virulent wild-type virus in vitro often results in loss of virulence of the virus in an original animal host, while serial passage of a cell culture-adapted avirulent virus in vivo often gains virulence in an animal host. Actually, live attenuated virus vaccines were originally produced by serial passage in cell cultures. Although clinical efficacy and safety of rotavirus vaccines were recently revealed, the mechanism of their attenuation is not well understood. We passaged serially a murine rotavirus by alternating switch of host (mice or cell cultures) repeatedly and sequenced the eleven genes of the passaged viruses to identify mutations associated with the emergence or disappearance of virulence. Sequence analysis revealed that changes in three genes (VP4, NSP1, and NSP4) were associated with virulence in mice. Intraperitoneal injection of recombinant NSP4 proteins confirmed its diarrheagenic activity in mice

  1. Virulence-Associated Genome Mutations of Murine Rotavirus Identified by Alternating Serial Passages in Mice and Cell Cultures

    Science.gov (United States)

    Tatsumi, Masatoshi; Tsutsumi, Hiroyuki

    2014-01-01

    ABSTRACT Although significant clinical efficacy and safety of rotavirus vaccines were recently revealed in many countries, the mechanism of their attenuation is not well understood. We passaged serially a cell culture-adapted murine rotavirus EB strain in mouse pups or in cell cultures alternately and repeatedly and fully sequenced all 11 genes of 21 virus samples passaged in mice or in cell cultures. Sequence analysis revealed that mouse-passaged viruses that regained virulence almost consistently acquired four kinds of amino acid (aa) substitutions in VP4 and substitution in aa 37 (Val to Ala) in NSP4. In addition, they gained and invariably conserved the 3′ consensus sequence in NSP1. The molecular changes occurred along with the acquisition of virulence during passages in mice and then disappeared following passages in cell cultures. Intraperitoneal injection of recombinant NSP4 proteins confirmed the aa 37 site as important for its diarrheagenic activity in mice. These genome changes are likely to be correlated with rotavirus virulence. IMPORTANCE Serial passage of a virulent wild-type virus in vitro often results in loss of virulence of the virus in an original animal host, while serial passage of a cell culture-adapted avirulent virus in vivo often gains virulence in an animal host. Actually, live attenuated virus vaccines were originally produced by serial passage in cell cultures. Although clinical efficacy and safety of rotavirus vaccines were recently revealed, the mechanism of their attenuation is not well understood. We passaged serially a murine rotavirus by alternating switch of host (mice or cell cultures) repeatedly and sequenced the eleven genes of the passaged viruses to identify mutations associated with the emergence or disappearance of virulence. Sequence analysis revealed that changes in three genes (VP4, NSP1, and NSP4) were associated with virulence in mice. Intraperitoneal injection of recombinant NSP4 proteins confirmed its

  2. The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases.

    Science.gov (United States)

    Victoria, Guiliana Soraya; Zurzolo, Chiara

    2017-09-04

    Progression of pathology in neurodegenerative diseases is hypothesized to be a non-cell-autonomous process that may be mediated by the productive spreading of prion-like protein aggregates from a "donor cell" that is the source of misfolded aggregates to an "acceptor cell" in which misfolding is propagated by conversion of the normal protein. Although the proteins involved in the various diseases are unrelated, common pathways appear to be used for their intercellular propagation and spreading. Here, we summarize recent evidence of the molecular mechanisms relevant for the intercellular trafficking of protein aggregates involved in prion, Alzheimer's, Huntington's, and Parkinson's diseases. We focus in particular on the common roles that lysosomes and tunneling nanotubes play in the formation and spreading of prion-like assemblies. © 2017 Victoria and Zurzolo.

  3. Hemispatial neglect and serial order in verbal working memory.

    Science.gov (United States)

    Antoine, Sophie; Ranzini, Mariagrazia; van Dijck, Jean-Philippe; Slama, Hichem; Bonato, Mario; Tousch, Ann; Dewulf, Myrtille; Bier, Jean-Christophe; Gevers, Wim

    2018-01-09

    Working memory refers to our ability to actively maintain and process a limited amount of information during a brief period of time. Often, not only the information itself but also its serial order is crucial for good task performance. It was recently proposed that serial order is grounded in spatial cognition. Here, we compared performance of a group of right hemisphere-damaged patients with hemispatial neglect to healthy controls in verbal working memory tasks. Participants memorized sequences of consonants at span level and had to judge whether a target consonant belonged to the memorized sequence (item task) or whether a pair of consonants were presented in the same order as in the memorized sequence (order task). In line with this idea that serial order is grounded in spatial cognition, we found that neglect patients made significantly more errors in the order task than in the item task compared to healthy controls. Furthermore, this deficit seemed functionally related to neglect severity and was more frequently observed following right posterior brain damage. Interestingly, this specific impairment for serial order in verbal working memory was not lateralized. We advance the hypotheses of a potential contribution to the deficit of serial order in neglect patients of either or both (1) reduced spatial working memory capacity that enables to keep track of the spatial codes that provide memorized items with a positional context, (2) a spatial compression of these codes in the intact representational space. © 2018 The British Psychological Society.

  4. Development of serial magnification angiography and its clinical significance

    International Nuclear Information System (INIS)

    Sasaki, Tsuneo; Matsubara, Kazuhito; Ishiguchi, Tsuneo; Mashita, Shinichi; Kaii, Osamu

    1979-01-01

    In order to apply serial magnification angiography to clinical examinations so easily, a serial cardioangiography apparatus was equipped with a tube having 0.1 mm focal spot and with DRX-431HD diode. A CAT-FK Type catheter bed (Toshiba) was used as a roentgenographic table and a PUCK film changer was used. Thus, serial magnification angiography can be easily used to clinical examinations, and can be set in a usual x-ray photographic studio. Serial magnification angiography was used to examine the cerebral vessels in 6 patients, vessels of the pulmonary circulation in 1 patient, bronchial arteries in 6 patients, the celiac artery in 18 patients, the superior mesenteric artery in 2 patients, inferior mesenteric artery in 2 patients, the renal artery in 2 patients, and the adrenal vein in 7 patients. Owing to this angiography, minute changes in the vessel in the lesion can be observed and fine neovascularity can be detected. Thus, serial magnification angiography makes diagnoses of vascular disorders easier. (Ichikawa, K.)

  5. The relationship between serial sexual murder and autoerotic asphyxiation.

    Science.gov (United States)

    Myers, Wade C; Bukhanovskiy, Alexandr; Justen, Elle; Morton, Robert J; Tilley, John; Adams, Kenneth; Vandagriff, Virgil L; Hazelwood, Robert R

    2008-04-07

    This case series documents and examines the association between autoerotic asphyxiation, sadomasochism, and serial sexual murderers. Autoerotic asphyxiation, along with other paraphilias found in this population, is reviewed. Five cases of serial sexual killers who engaged in autoerotic asphyxiation were identified worldwide: four from the United States and one from Russia. Case reports for each are provided. All (100%) were found to have sexual sadism in addition to autoerotic asphyxiation. Furthermore, two (40%) had bondage fetishism, and two (40%) had transvestic fetishism, consistent with these paraphilias co-occurring in those with autoerotic asphyxiation. Overall the group averaged 4.0 lifetime paraphilias. Some possible relationships were observed between the offenders' paraphilic orientation and their modus operandi, e.g., all of these serial killers strangled victims-suggesting an association between their sadistic and asphyxiative paraphilic interests. The overlap of seemingly polar opposite paraphilias in this sample--sexual sadism and autoerotic asphyxiation--is explored from a historical and clinical perspective. Multiple commonalities shared between these five offenders and serial sexual murderers in general are addressed. A primary limitation of this study is its small sample size and empirical basis; the results may not be generalizable beyond the sample. The findings from this study support the supposition that crime scene behaviors often reflect paraphilic disturbances in those who commit serial sexual homicides.

  6. Piezoelectric micromotor based on the structure of serial bending arms.

    Science.gov (United States)

    Tong, Jianhua; Cui, Tianhong; Shao, Peige; Wang, Liding

    2003-09-01

    This paper presents a new piezoelectric micromotor based on the structure of serial bending arms. Serial bending arms are composed of two piezoelectric bimorphs with one end fixed and the other end free, driven by two signals of a biased square wave with a phase difference of pi/2. The free end of a cantilever arm will move along an elliptic orbit so that the cantilever is used to drive a cylinder rotor. The rotor's end surface contacts the free end of the cantilever, resulting in the rotor's rotation. There are six serial bending arms anchored on the base. The driving mechanism of the micromotor is proposed and analyzed. A new micromotor prototype, 5 mm in diameter, has been fabricated and characterized. The maximum rotational speed reaches 325 rpm, and the output torque is about 36.5 microNm.

  7. Numerical discrepancy between serial and MPI parallel computations

    Directory of Open Access Journals (Sweden)

    Sang Bong Lee

    2016-09-01

    Full Text Available Numerical simulations of 1D Burgers equation and 2D sloshing problem were carried out to study numerical discrepancy between serial and parallel computations. The numerical domain was decomposed into 2 and 4 subdomains for parallel computations with message passing interface. The numerical solution of Burgers equation disclosed that fully explicit boundary conditions used on subdomains of parallel computation was responsible for the numerical discrepancy of transient solution between serial and parallel computations. Two dimensional sloshing problems in a rectangular domain were solved using OpenFOAM. After a lapse of initial transient time sloshing patterns of water were significantly different in serial and parallel computations although the same numerical conditions were given. Based on the histograms of pressure measured at two points near the wall the statistical characteristics of numerical solution was not affected by the number of subdomains as much as the transient solution was dependent on the number of subdomains.

  8. A combination strategy for tracking the serial criminal

    Science.gov (United States)

    He, Chuan; Zhang, Yuan-Biao; Wan, Jiadi; Yu, Wenjing

    2010-08-01

    We build a Geographic Profiling Model to generate the criminal's geographical profile, by combining two complementary strategies: the Spatial Distribution Strategy and the Probability Distance Strategy. In the first strategy, we designate the mean of all the known crime sites as the anchor point, and build a Standard Deviational Ellipse Model, considering the effect of landscape. In the second strategy, we take many factors such as the buffer zone and distance decay theory into consideration and calculate the probability of the offender's residence in a certain area by using the Bayesian Theorem and the Rossmo Algorithm. Then, we combine the result of two strategies and get three search areas suit different conditions of the police to track the serial criminal. Apply the model to the English serial killer Peter Sutcliffe's case, the calculation result shows that the model can effectively be used to track serial criminal.

  9. S3-1: The Serial Dependence of Visual Perception

    Directory of Open Access Journals (Sweden)

    David Whitney

    2012-10-01

    Full Text Available In our moment-to-moment perceptual experience, visual scenes can change, but objects rarely spontaneously come into or out of existence. The visual system may therefore delicately balance the need to optimize sensitivity to image changes (e.g., by adapting to changes in color, orientation, object identity, etc with the desire to represent the temporal continuity of objects—the likelihood that objects perceived at this moment tend to exist in subsequent moments. One way that the visual system may promote such stability is through the introduction of serial dependence to visual perception: by biasing the current percept toward what was seen at previous moments, the brain could compensate for variability in visual input that might otherwise disrupt perceptual continuity. Here, in two sets of experiments, we tested for serial dependence in visual perception of orientation and facial expression. We found that on a given trial, a subject's perception of the orientation of a grating reflected not only the currently viewed stimulus, but also a systematic attraction toward the orientations of the previously viewed stimuli. We found the same serial dependence in the perception of facial expression. This perceptual attraction extended over several trials and seconds, and displayed clear tuning to the difference (in orientation or facial expression between the sequential stimuli. Furthermore, serial dependence in object perception was spatially specific and selective to the attended object within a scene. Several control experiments showed that the perceptual serial dependence we report cannot be explained by effects of priming, known hysteresis effects, visual short-term memory, or expectation. Our results reveal a systematic influence of recent visual experiences on perception at any given moment: visual percepts, even of unambiguous stimuli, are attracted toward what was previously seen. We propose that such serial dependence helps to maintain

  10. Effect of impurities and post-experimental purification in SAD phasing with serial femtosecond crystallography data.

    Science.gov (United States)

    Zhang, Tao; Gu, Yuanxin; Fan, Haifu

    2016-06-01

    In serial crystallography (SX) with either an X-ray free-electron laser (XFEL) or synchrotron radiation as the light source, huge numbers of micrometre-sized crystals are used in diffraction data collection. For a SAD experiment using a derivative with introduced heavy atoms, it is difficult to completely exclude crystals of the native protein from the sample. In this paper, simulations were performed to study how the inclusion of native crystals in the derivative sample could affect the result of SAD phasing and how the post-experimental purification proposed by Zhang et al. [(2015), Acta Cryst. D71, 2513-2518] could be used to remove the impurities. A gadolinium derivative of lysozyme and the corresponding native protein were used in the test. Serial femtosecond crystallography (SFX) diffraction snapshots were generated by CrystFEL. SHELXC/D, Phaser, DM, ARP/wARP and REFMAC were used for automatic structure solution. It is shown that a small amount of impurities (snapshots from native crystals) in the set of derivative snapshots can strongly affect the SAD phasing results. On the other hand, post-experimental purification can efficiently remove the impurities, leading to results similar to those from a pure sample.

  11. Synchronic Seriality: The Dissolving of Diegetic Borders Through Metalepsis

    Directory of Open Access Journals (Sweden)

    Paige M. Piper

    2015-12-01

    Full Text Available In dialogue with Gérard Genette’s literary concept of metalepsis to television, this paper considers instances of meta-textual actor/character portrayals in serial narratives to show that meta-narrative intrusion fosters a greater empathetic link between the spectator and character, whilst simultaneously inviting the viewer to appreciate the technique as an artifice-aware gesture. The fluidity of diegetic borders brought on by the conflation of performer/performance replicates Baudrillard’s simulacra, creating a synchronic form of seriality and transcending rigid genre classifications.

  12. Quick, sensitive serial NMR experiments with Radon transform.

    Science.gov (United States)

    Dass, Rupashree; Kasprzak, Paweł; Kazimierczuk, Krzysztof

    2017-09-01

    The Radon transform is a potentially powerful tool for processing the data from serial spectroscopic experiments. It makes it possible to decode the rate at which frequencies of spectral peaks shift under the effect of changing conditions, such as temperature, pH, or solvent. In this paper we show how it also improves speed and sensitivity, especially in multidimensional experiments. This is particularly important in the case of low-sensitivity techniques, such as NMR spectroscopy. As an example, we demonstrate how Radon transform processing allows serial measurements of 15 N-HSQC spectra of unlabelled peptides that would otherwise be infeasible. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Serial MRI studies using gadolinium DTPA in active multiple sclerosis

    International Nuclear Information System (INIS)

    Miller, D.H.; Johnson, G.; Barnes, D.; Rudge, P.; McDonald, W.I.

    1988-01-01

    It has been suggested that blood brain barrier (BBB) impairment is a necessary early event in the pathogenesis of the multiple sclerosis (MS) lesions. To evaluate such an hypothesis in vivo would require: (1) serial imaging studies using a modality with high sensitivity for detecting plaques; (2) a contrast enhancing agent which demonstrates BBB impairment. A serial magnetic resonance imaging (MRI) study was undertaken of a group of MS patients using the contrast agent gadolinium-DTPA. As it has been suggested that T 1 and T 2 relaxation times are longer in acute than chronic MS lesions, these were also measured. 3 refs.; 1 figure

  14. IT-based Value Creation in Serial Acquisitions

    DEFF Research Database (Denmark)

    Henningsson, Stefan; Yetton, Philip

    2013-01-01

    serial acquirers realize IT-based value, we integrate and model the findings on individual acquisitions from the extant literature, and extend that model to explain the effects of sequential acquisitions in a growth-by-acquisition strategy. This extended model, drawing on the Resource-Based Theory......The extant research on post-acquisition IT integration analyzes how acquirers realize IT-based value in individual acquisitions. However, serial acquirers make 60% of acquisitions. These acquisitions are not isolated events, but are components in growth-by-acquisition programs. To explain how...

  15. Biophysics of protein evolution and evolutionary protein biophysics

    Science.gov (United States)

    Sikosek, Tobias; Chan, Hue Sun

    2014-01-01

    The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence–structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by ‘hidden’ conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution. PMID:25165599

  16. Cellular Handling of Protein Aggregates by Disaggregation Machines.

    Science.gov (United States)

    Mogk, Axel; Bukau, Bernd; Kampinga, Harm H

    2018-01-18

    Both acute proteotoxic stresses that unfold proteins and expression of disease-causing mutant proteins that expose aggregation-prone regions can promote protein aggregation. Protein aggregates can interfere with cellular processes and deplete factors crucial for protein homeostasis. To cope with these challenges, cells are equipped with diverse folding and degradation activities to rescue or eliminate aggregated proteins. Here, we review the different chaperone disaggregation machines and their mechanisms of action. In all these machines, the coating of protein aggregates by Hsp70 chaperones represents the conserved, initializing step. In bacteria, fungi, and plants, Hsp70 recruits and activates Hsp100 disaggregases to extract aggregated proteins. In the cytosol of metazoa, Hsp70 is empowered by a specific cast of J-protein and Hsp110 co-chaperones allowing for standalone disaggregation activity. Both types of disaggregation machines are supported by small Hsps that sequester misfolded proteins. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Autophagy Proteins ATG5 and ATG7 Are Essential for the Maintenance of Human CD34+ Hematopoietic Stem-Progenitor Cells

    NARCIS (Netherlands)

    Gomez Puerto, Maria Catalina; Folkerts, Hendrik; Wierenga, Albertus T J; Schepers, Koen; Schuringa, Jan Jacob; Coffer, Paul J.; Vellenga, Edo

    2016-01-01

    Autophagy is a highly regulated catabolic process that involves sequestration and lysosomal degradation of cytosolic components such as damaged organelles and misfolded proteins. While autophagy can be considered to be a general cellular housekeeping process, it has become clear that it may also

  18. Overexpression of binding protein and disruption of the PMR1 gene synergistically stimulate secretion of bovine prochymosin but not plant thaumatin in yeast.

    NARCIS (Netherlands)

    Harmsen, M.M.; Bruyne, M.I.; Raué, H.A.; Maat, J.

    1996-01-01

    When the heterologous proteins thaumatin and bovine prochymosin are produced in yeast cells as a fusion with the yeast invertase secretory signal peptide, less than 2% of the product is secreted in a biologically active form into the medium. The remainder accumulates intracellularly in a misfolded

  19. Recommendations for CAMAC Serial Highway drivers and LAM Graders for the SCC-L2 Serial Crate Controller

    International Nuclear Information System (INIS)

    1978-01-01

    The functional requirements of Drivers for the CAMAC Serial Highway defined in IEEE Standard 595-1976 are described. The description is independent of the implementation, and in particular no assumption is made about the boundary between hardware and software within the Driver. Topics covered are the user interface, the supporting system services required, demand handling, and a detailed discussion of the message analysis for various levels of error recovery. An appendix describes the recommended features of LAM Graders for use with the Serial Crate Controller Type L2 of IEEE Std 595-1976

  20. Protein damage and repair controlling seed vigor and longevity.

    Science.gov (United States)

    Ogé, Laurent; Broyart, Caroline; Collet, Boris; Godin, Béatrice; Jallet, Denis; Bourdais, Gildas; Job, Dominique; Grappin, Philippe

    2011-01-01

    The formation of abnormal isoaspartyl residues derived from aspartyl or asparaginyl residues is a major source of spontaneous protein misfolding in cells. The repair enzyme protein L: -isoaspartyl methyltransferase (PIMT) counteracts such damage by catalyzing the conversion of abnormal isoaspartyl residues to their normal aspartyl forms. Thus, this enzyme contributes to the survival of many organisms, including plants. Analysis of the accumulation of isoaspartyl-containing proteins and its modulation by the PIMT repair pathway, using germination tests, immunodetection, enzymatic assays, and HPLC analysis, gives new insights in understanding controlling mechanisms of seed longevity and vigor.

  1. Kiondo Bag Boutique: A Serial Case for Introductory Financial Accounting

    Science.gov (United States)

    Siriwardane, Harshini P.

    2014-01-01

    Kiondo Bag Boutique is a hypothetical serial case involving a start-up retail business. The case evolves from an ambitious business idea to a successful business. Through the evolving business, the importance of accounting information is highlighted. Different iterations are used to illustrate the role of accounting in serving and managing…

  2. 'American Psycho': a double portrait of serial yuppie Patrick Bateman

    NARCIS (Netherlands)

    Kooijman, J.; Laine, T.

    2003-01-01

    Kooijman and Laine analyze Mary Harron's "American Psycho," a 2000 film adaptation of the 1980s satirical novel by Bret Easton Ellis in which Patrick Bateman, a narcissistic Wall Street young urban professional ("yuppie"), assumes an alternate identity as a serial killer. The authors examine the

  3. The stand-alone test and decreasing serial cost sharing

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Thorlund-Petersen, Lars

    2000-01-01

    The rule of decreasing serial cost sharing defined in de Frutos [1] over the class of concave cost functions may violate the important stand-alone test. Sufficient conditions for the test to be satisfied are given, in terms of individual rationality as well as coalitional stability...

  4. Serial Comparison Processes and Sex Differences in Clerical Speed.

    Science.gov (United States)

    Majeres, Raymond L.

    1988-01-01

    Three experiments were conducted with 91 male and 91 female university students to assess sex differences in performance on speeded matching tests and theory on same-different judgments. Results are interpreted via the dual-process hypothesis of same-difference judgments with sex differences explained in terms of serial comparison processes rather…

  5. Serials Management by Microcomputer: The Potential of DBMS.

    Science.gov (United States)

    Vogel, J. Thomas; Burns, Lynn W.

    1984-01-01

    Describes serials management at Philadelphia College of Textiles and Science library via a microcomputer, a file manager called PFS, and a relational database management system called dBase II. Check-in procedures, programing with dBase II, "static" and "active" databases, and claim procedures are discussed. Check-in forms are…

  6. Phonological Similarity in Serial Recall: Constraints on Theories of Memory

    Science.gov (United States)

    Lewandowsky, Stephan; Farrell, Simon

    2008-01-01

    In short-term serial recall, similar-sounding items are remembered more poorly than items that do not sound alike. When lists mix similar and dissimilar items, performance on the dissimilar items is of considerable theoretical interest. Farrell and Lewandowsky [Farrell, S., & Lewandowsky, S. (2003). Dissimilar items benefit from phonological…

  7. Development of parallel/serial program analyzing tool

    International Nuclear Information System (INIS)

    Watanabe, Hiroshi; Nagao, Saichi; Takigawa, Yoshio; Kumakura, Toshimasa

    1999-03-01

    Japan Atomic Energy Research Institute has been developing 'KMtool', a parallel/serial program analyzing tool, in order to promote the parallelization of the science and engineering computation program. KMtool analyzes the performance of program written by FORTRAN77 and MPI, and it reduces the effort for parallelization. This paper describes development purpose, design, utilization and evaluation of KMtool. (author)

  8. Auditory distraction and serial memory: The avoidable and the ineluctable

    Directory of Open Access Journals (Sweden)

    Dylan M Jones

    2010-01-01

    Full Text Available One mental activity that is very vulnerable to auditory distraction is serial recall. This review of the contemporary findings relating to serial recall charts the key determinants of distraction. It is evident that there is one form of distraction that is a joint product of the cognitive characteristics of the task and of the obligatory cognitive processing of the sound. For sequences of sound, distraction appears to be an ineluctable product of similarity-of-process, specifically, the serial order processing of the visually presented items and the serial order coding that is the by-product of the streaming of the sound. However, recently emerging work shows that the distraction from a single sound (one deviating from a prevailing sequence results in attentional capture and is qualitatively distinct from that of a sequence in being restricted in its action to encoding, not to rehearsal of list members. Capture is also sensitive to the sensory task load, suggesting that it is subject to top-down control and therefore avoidable. These two forms of distraction-conflict of process and attentional capture-may be two consequences of auditory perceptual organization processes that serve to strike the optimal balance between attentional selectivity and distractability.

  9. Asymmetric binding in serial memory for verbal and spatial information

    NARCIS (Netherlands)

    Guerard, Katherine; Morey, Candice C.; Lagace, Sebastien; Tremblay, Sebastien

    As the number of studies showing that items can be retained as bound representations in memory increases, researchers are beginning to investigate how the different features are bound together. In the present study, we examined the relative importances of the verbal and spatial features in serial

  10. FPGA based fast synchronous serial multi-wire links synchronization

    Science.gov (United States)

    Pozniak, Krzysztof T.

    2013-10-01

    The paper debates synchronization method of multi-wire, serial link of constant latency, by means of pseudo-random numbers generators. The solution was designed for various families of FPGA circuits. There were debated synchronization algorithm and functional structure of parameterized transmitter and receiver modules. The modules were realized in VHDL language in a behavioral form.

  11. Asymmetrical learning between a tactile and visual serial RT task

    NARCIS (Netherlands)

    Abrahamse, E.L.; van der Lubbe, Robert Henricus Johannes; Verwey, Willem B.

    2007-01-01

    According to many researchers, implicit learning in the serial reaction-time task is predominantly motor based and therefore should be independent of stimulus modality. Previous research on the task, however, has focused almost completely on the visual domain. Here we investigated sequence learning

  12. Serial assessment of doxorubicin cardiomyopathy with the computerized scintillation probe

    International Nuclear Information System (INIS)

    Strashun, A.; Goldsmith, S.J.; Horowitz, S.F.

    1982-01-01

    Cardiac function was serially monitored in 55 patients receiving adriamycin chemotherapy over 18 months with quantitative radionuclide assessment by both a nonimaging computerized scintillation probe and gamma camera-computer imaging. Interval ejection fraction change was comparable with both techniques and predicted incipient cardiotoxicity. Probe data revealed ejection fraction decline was antedated by decline left ventricular emptying and filling rates

  13. Using identification in entertainment-education drama serials to ...

    African Journals Online (AJOL)

    The study used two entertainment-education drama serials which were designed using Albert Bandura's theoretical framework to communicate positive messages of women's rights to real life audiences in select communities. The study sought to find out if there was any significant relationship i.e. identification between TV ...

  14. Counterbalancing for Serial Order Carryover Effects in Experimental Condition Orders

    Science.gov (United States)

    Brooks, Joseph L.

    2012-01-01

    Reactions of neural, psychological, and social systems are rarely, if ever, independent of previous inputs and states. The potential for serial order carryover effects from one condition to the next in a sequence of experimental trials makes counterbalancing of condition order an essential part of experimental design. Here, a method is proposed…

  15. Mixed-List Phonological Similarity Effects in Delayed Serial Recall

    Science.gov (United States)

    Farrell, Simon

    2006-01-01

    Recent experiments have shown that placing dissimilar items on lists of phonologically similar items enhances accuracy of ordered recall of the dissimilar items [Farrell, S., & Lewandowsky, S. (2003). Dissimilar items benefit from phonological similarity in serial recall. "Journal of Experimental Psychology: Learning, Memory, and Cognition," 29,…

  16. Electronic conductance of quantum wire with serial periodic potential structures

    International Nuclear Information System (INIS)

    Fayad, Hisham M.; Shabat, Mohammed M.; Abdus Salam International Centre for Theoretical Physics, Trieste

    2000-08-01

    A theory based on the total transfer matrix is presented to investigate the electronic conductance in a quantum wire with serial periodic potentials. We apply the formalism in computation of the electronic conductance in a wire with different physical parameters of the wire structure. The numerical results could be used in designing some future quantum electronic devices. (author)

  17. Analysis of aging in lager brewing yeast during serial repitching.

    Science.gov (United States)

    Bühligen, Franziska; Lindner, Patrick; Fetzer, Ingo; Stahl, Frank; Scheper, Thomas; Harms, Hauke; Müller, Susann

    2014-10-10

    Serial repitching of brewing yeast inoculates is an important economic factor in the brewing industry, as their propagation is time and resource intensive. Here, we investigated whether replicative aging and/or the population distribution status changed during serial repitching in three different breweries with the same brewing yeast strain but different abiotic backgrounds and repitching regimes with varying numbers of reuses. Next to bud scar numbers the DNA content of the Saccharomyces pastorianus HEBRU cells was analyzed. Gene expression patterns were investigated using low-density microarrays with genes for aging, stress, storage compound metabolism and cell cycle. Two breweries showed a stable rejuvenation rate during serial repitching. In a third brewery the fraction of virgin cells varied, which could be explained with differing wort aeration rates. Furthermore, the number of bud scars per cell and cell size correlated in all 3 breweries throughout all runs. Transcriptome analyses revealed that from the 6th run on, mainly for the cells positive gene expression could be seen, for example up-regulation of trehalose and glycogen metabolism genes. Additionally, the cells' settling in the cone was dependent on cell size, with the lowest and the uppermost cone layers showing the highest amount of dead cells. In general, cells do not progressively age during extended serial repitching. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Benchmarking Usage Statistics in Collection Management Decisions for Serials

    Science.gov (United States)

    Tucker, Cory

    2009-01-01

    Usage statistics are an important metric for making decisions on serials. Although the University of Nevada, Las Vegas (UNLV) Libraries have been collecting usage statistics, the statistics had not frequently been used to make decisions and had not been included in collection development policy. After undergoing a collection assessment, the…

  19. Serials use in a College of Agriculture Education Library | Adzobu ...

    African Journals Online (AJOL)

    Serials use in a College of Agriculture Education Library. J Adzobu, JA Opare. Abstract. No Abstract. Ghana Library Journal Vol. 20 (1) 2008: pp. 81-88. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Article Metrics. Metrics Loading ... Metrics powered by PLOS ALM

  20. Child serial murder-psychodynamics: closely watched shadows.

    Science.gov (United States)

    Turco, R

    2001-01-01

    There is a malignant transformation in object relations resulting in an identification with an omnipotent and cruel object resulting in an identity transformation. If the tension, desperation, and dissociation increase, serial murder becomes spree murder. The presence of pathological narcissism and psychopathic tendencies are of diagnostic significance in understanding the murderer's personality functioning and motivation to kill. Meloy (1988) considered the degree of sadism and aggression combined with narcissistic qualities to reflect the "malignancy" of the psychopathic disturbance where gratification (of aggression) occurs in the service of narcissistic functioning--that is, cruelty toward others in the form of a triumphant victory over a rejecting object. Meloy also believes that dissociation is ubiquitious in the psychopath. The initial murder of the serial murderer may reflect a "new identity." The pathological object-relations of narcissism and the malignant narcissism are important diagnostic indicators in the personality functioning of serial killers and the occurrence of these phenomena is a significant factor in the formation of the personalities of serial killers, their inner motivations, and their pattern of commission.

  1. Serial Killers: Academic Libraries Respond to Soaring Costs.

    Science.gov (United States)

    McCarthy, Paul

    1994-01-01

    Discusses ways in which academic libraries are responding to rising costs of serials. Topics addressed include pricing by publishers; the effect of journal cancellations on research activities; interlibrary loans and document delivery services; coordinated cancelling; electronic journals; and experiences at the University of Arizona. (LRW)

  2. The Rise in Consumerism: The Year's Work in Serials, 1990.

    Science.gov (United States)

    Lonberger, Jana

    1991-01-01

    Examines major issues and trends in serials management represented in the literature published during 1990. Topics covered include the pricing crisis; publishing and scholarly communication; cancellation projects; technological developments and alternatives to print; claiming and replacement activities; acquisitions and collection development;…

  3. Chromosome driven spatial patterning of proteins in bacteria.

    Directory of Open Access Journals (Sweden)

    Saeed Saberi

    Full Text Available The spatial patterning of proteins in bacteria plays an important role in many processes, from cell division to chemotaxis. In the asymmetrically dividing bacteria Caulobacter crescentus, a scaffolding protein, PopZ, localizes to both poles and aids the differential patterning of proteins between mother and daughter cells during division. Polar patterning of misfolded proteins in Escherichia coli has also been shown, and likely plays an important role in cellular ageing. Recent experiments on both of the above systems suggest that the presence of chromosome free regions along with protein multimerization may be a mechanism for driving the polar localization of proteins. We have developed a simple physical model for protein localization using only these two driving mechanisms. Our model reproduces all the observed patterns of PopZ and misfolded protein localization--from diffuse, unipolar, and bipolar patterns and can also account for the observed patterns in a variety of mutants. The model also suggests new experiments to further test the role of the chromosome in driving protein patterning, and whether such a mechanism is responsible for helping to drive the differentiation of the cell poles.

  4. Proteins aggregation and human diseases

    Science.gov (United States)

    Hu, Chin-Kun

    2015-04-01

    Many human diseases and the death of most supercentenarians are related to protein aggregation. Neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), frontotemporallobar degeneration, etc. Such diseases are due to progressive loss of structure or function of neurons caused by protein aggregation. For example, AD is considered to be related to aggregation of Aβ40 (peptide with 40 amino acids) and Aβ42 (peptide with 42 amino acids) and HD is considered to be related to aggregation of polyQ (polyglutamine) peptides. In this paper, we briefly review our recent discovery of key factors for protein aggregation. We used a lattice model to study the aggregation rates of proteins and found that the probability for a protein sequence to appear in the conformation of the aggregated state can be used to determine the temperature at which proteins can aggregate most quickly. We used molecular dynamics and simple models of polymer chains to study relaxation and aggregation of proteins under various conditions and found that when the bending-angle dependent and torsion-angle dependent interactions are zero or very small, then protein chains tend to aggregate at lower temperatures. All atom models were used to identify a key peptide chain for the aggregation of insulin chains and to find that two polyQ chains prefer anti-parallel conformation. It is pointed out that in many cases, protein aggregation does not result from protein mis-folding. A potential drug from Chinese medicine was found for Alzheimer's disease.

  5. Reconstructing genealogies of serial samples under the assumption of a molecular clock using serial-sample UPGMA.

    Science.gov (United States)

    Drummond, A; Rodrigo, A G

    2000-12-01

    Reconstruction of evolutionary relationships from noncontemporaneous molecular samples provides a new challenge for phylogenetic reconstruction methods. With recent biotechnological advances there has been an increase in molecular sequencing throughput, and the potential to obtain serial samples of sequences from populations, including rapidly evolving pathogens, is fast being realized. A new method called the serial-sample unweighted pair grouping method with arithmetic means (sUPGMA) is presented that reconstructs a genealogy or phylogeny of sequences sampled serially in time using a matrix of pairwise distances. The resulting tree depicts the terminal lineages of each sample ending at a different level consistent with the sample's temporal order. Since sUPGMA is a variant of UPGMA, it will perform best when sequences have evolved at a constant rate (i.e., according to a molecular clock). On simulated data, this new method performs better than standard cluster analysis under a variety of longitudinal sampling strategies. Serial-sample UPGMA is particularly useful for analysis of longitudinal samples of viruses and bacteria, as well as ancient DNA samples, with the minimal requirement that samples of sequences be ordered in time.

  6. Smart grid serialization comparison: Comparision of serialization for distributed control in the context of the Internet of Things

    DEFF Research Database (Denmark)

    Petersen, Bo Søborg; Bindner, Henrik W.; You, Shi

    2017-01-01

    within a given timeframe, especially in the context of the Internet of Things, using low-bandwidth data connections and constrained devices. The paper shows that there are better alternatives than XML & JAXB and gives guidance in choosing the most appropriate serialization format and library depending...

  7. Cuz1/Ynl155w, a Zinc-dependent Ubiquitin-binding Protein, Protects Cells from Metalloid-induced Proteotoxicity*

    Science.gov (United States)

    Hanna, John; Waterman, David; Isasa, Marta; Elsasser, Suzanne; Shi, Yuan; Gygi, Steven; Finley, Daniel

    2014-01-01

    Protein misfolding is a universal threat to cells. The ubiquitin-proteasome system mediates a cellular stress response capable of eliminating misfolded proteins. Here we identify Cuz1/Ynl155w as a component of the ubiquitin system, capable of interacting with both the proteasome and Cdc48. Cuz1/Ynl155w is regulated by the transcription factor Rpn4, and is required for cells to survive exposure to the trivalent metalloids arsenic and antimony. A related protein, Yor052c, shows similar phenotypes, suggesting a multicomponent stress response pathway. Cuz1/Ynl155w functions as a zinc-dependent ubiquitin-binding protein. Thus, Cuz1/Ynl155w is proposed to protect cells from metalloid-induced proteotoxicity by delivering ubiquitinated substrates to Cdc48 and the proteasome for destruction. PMID:24297164

  8. Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription.

    Directory of Open Access Journals (Sweden)

    Goran Periz

    2015-04-01

    Full Text Available Protein quality control is essential for clearing misfolded and aggregated proteins from the cell, and its failure is associated with many neurodegenerative disorders. Here, we identify two genes, ufd-2 and spr-5, that when inactivated, synergistically and robustly suppress neurotoxicity associated with misfolded proteins in Caenorhabditis elegans. Loss of human orthologs ubiquitination factor E4 B (UBE4B and lysine-specific demethylase 1 (LSD1, respectively encoding a ubiquitin ligase and a lysine-specific demethylase, promotes the clearance of misfolded proteins in mammalian cells by activating both proteasomal and autophagic degradation machineries. An unbiased search in this pathway reveals a downstream effector as the transcription factor p53, a shared substrate of UBE4B and LSD1 that functions as a key regulator of protein quality control to protect against proteotoxicity. These studies identify a new protein quality control pathway via regulation of transcription factors and point to the augmentation of protein quality control as a wide-spectrum antiproteotoxicity strategy.

  9. The unfolded protein response and the role of protein disulphide isomerase in neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Emma ePerri

    2016-01-01

    Full Text Available The maintenance and regulation of proteostasis is a critical function for post-mitotic neurons and dysregulation of proteostasis is increasingly implicated in neurodegenerative diseases. Despite having different clinical manifestations, these disorders share similar pathology; an accumulation of misfolded proteins in neurons and subsequent disruption to cellular proteostasis. The endoplasmic reticulum (ER is an important component of proteostasis, and when the accumulation of misfolded proteins occurs within the ER, this disturbs ER homeostasis, giving rise to ER stress. This triggers the unfolded protein response (UPR, distinct signalling pathways that whilst initially protective, are pro-apoptotic if ER stress is prolonged. ER stress is increasingly implicated in neurodegenerative diseases, and emerging evidence highlights the complexity of the UPR in these disorders, with both protective and detrimental components being described. Protein Disulphide Isomerase (PDI is an ER chaperone induced during ER stress that is responsible for the formation of disulphide bonds in proteins. Whilst initially considered to be protective, recent studies have revealed unconventional roles for PDI in neurodegenerative diseases, distinct from its normal function in the UPR and the ER, although these mechanisms remain poorly defined. However specific aspects of PDI function may offer the potential to be exploited therapeutically in the future. This review will focus on the evidence linking ER stress and the UPR to neurodegenerative diseases, with particular emphasis on the emerging functions ascribed to PDI in these conditions.

  10. Failure of protein quality control in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Kabashi, Edor; Durham, Heather D

    2006-01-01

    The protein chaperoning and ubiquitin-proteasome systems perform many homeostatic functions within cells involving protein folding, transport and degradation. Of paramount importance is ridding cells of mutant or post-translationally modified proteins that otherwise tend to aggregate into insoluble complexes and form inclusions. Such inclusions are characteristic of many neurodegenerative diseases and implicate protein misfolding and aggregation as common aspects of pathogenesis. In the most common familial form of ALS, mutations in SOD1 promote misfolding of the protein and target it for degradation by proteasomes. Although proteasomes can degrade the mutant proteins efficiently, altered solubility and aggregation of mutant SOD1 are features of the disease and occur most prominently in the most vulnerable cells and tissues. Indeed, lumbar spinal cord of mutant SOD1 transgenic mice show early reduction in their capacity for protein chaperoning and proteasome-mediated hydrolysis of substrates, and motor neurons are particularly vulnerable to aggregation of mutant SOD1. A high threshold for upregulating key pathways in response to the stress of added substrate load may contribute to this vulnerability. The broad spectrum neuroprotective capability and efficacy of some chaperone-based therapies in preclinical models makes these pathways attractive as targets for therapy in ALS, as well as other neurodegenerative diseases. A better understanding of the mechanisms governing the regulation of protein chaperones and UPS components would facilitate development of treatments that upregulate these pathways in a coordinated manner in neural tissue without long term toxicity.

  11. Measurement of the unfolded protein response (UPR) in monocytes.

    LENUS (Irish Health Repository)

    Carroll, Tomás P

    2011-01-01

    In mammalian cells, the primary function of the endoplasmic reticulum (ER) is to synthesize and assemble membrane and secreted proteins. As the main site of protein folding and posttranslational modification in the cell, the ER operates a highly conserved quality control system to ensure only correctly assembled proteins exit the ER and misfolded and unfolded proteins are retained for disposal. Any disruption in the equilibrium of the ER engages a multifaceted intracellular signaling pathway termed the unfolded protein response (UPR) to restore normal conditions in the cell. A variety of pathological conditions can induce activation of the UPR, including neurodegenerative disorders such as Parkinson\\'s disease, metabolic disorders such as atherosclerosis, and conformational disorders such as cystic fibrosis. Conformational disorders are characterized by mutations that modify the final structure of a protein and any cells that express abnormal protein risk functional impairment. The monocyte is an important and long-lived immune cell and acts as a key immunological orchestrator, dictating the intensity and duration of the host immune response. Monocytes expressing misfolded or unfolded protein may exhibit UPR activation and this can compromise the host immune system. Here, we describe in detail methods and protocols for the examination of UPR activation in peripheral blood monocytes. This guide should provide new investigators to the field with a broad understanding of the tools required to investigate the UPR in the monocyte.

  12. Measurement of the unfolded protein response (UPR) in monocytes.

    LENUS (Irish Health Repository)

    Carroll, Tomas P

    2012-02-01

    In mammalian cells, the primary function of the endoplasmic reticulum (ER) is to synthesize and assemble membrane and secreted proteins. As the main site of protein folding and posttranslational modification in the cell, the ER operates a highly conserved quality control system to ensure only correctly assembled proteins exit the ER and misfolded and unfolded proteins are retained for disposal. Any disruption in the equilibrium of the ER engages a multifaceted intracellular signaling pathway termed the unfolded protein response (UPR) to restore normal conditions in the cell. A variety of pathological conditions can induce activation of the UPR, including neurodegenerative disorders such as Parkinson\\'s disease, metabolic disorders such as atherosclerosis, and conformational disorders such as cystic fibrosis. Conformational disorders are characterized by mutations that modify the final structure of a protein and any cells that express abnormal protein risk functional impairment. The monocyte is an important and long-lived immune cell and acts as a key immunological orchestrator, dictating the intensity and duration of the host immune response. Monocytes expressing misfolded or unfolded protein may exhibit UPR activation and this can compromise the host immune system. Here, we describe in detail methods and protocols for the examination of UPR activation in peripheral blood monocytes. This guide should provide new investigators to the field with a broad understanding of the tools required to investigate the UPR in the monocyte.

  13. Serial Learning Process: Test of Chaining, Position, and Dual-Process Hypotheses

    Science.gov (United States)

    Giurintano, S. L.

    1973-01-01

    The chaining, position, and dual-process hypotheses of serial learning (SL) as well as serial recall, reordering, and relearning of paired-associate learning were examined to establish learning patterns. Results provide evidence for dual-process hypothesis. (DS)

  14. Ranking serials in oceanography: An analysis based on the Indian contributions and their citations

    Digital Repository Service at National Institute of Oceanography (India)

    Tapaswi, M.P.; Maheswarappa, B.S.

    An analysis of serials preferred and cited in various communications by the Indian oceanographers during 1963 to 1992 is presented. A shift in preference of serials from general sciences to oceanography (interdisciplinary) and to core subject...

  15. cDNA Microarray Analysis of Serially Sampled Cervical Cancer Specimens From Patients Treated With Thermochemoradiotherapy

    International Nuclear Information System (INIS)

    Borkamo, Erling Dahl; Schem, Baard-Christian; Fluge, Oystein; Bruland, Ove; Dahl, Olav; Mella, Olav

    2009-01-01

    Purpose: To elucidate changes in gene expression after treatment with regional thermochemoradiotherapy in locally advanced squamous cell cervical cancer. Methods and Materials: Tru-Cut biopsy specimens were serially collected from 16 patients. Microarray gene expression levels before and 24 h after the first and second trimodality treatment sessions were compared. Pathway and network analyses were conducted by use of Ingenuity Pathways Analysis (IPA; Ingenuity Systems, Redwood City, CA). Single gene expressions were analyzed by quantitative real-time reverse transcription-polymerase chain reaction. Results: We detected 53 annotated genes that were differentially expressed after trimodality treatment. Central in the three top networks detected by IPA were interferon alfa, interferon beta, and interferon gamma receptor; nuclear factor κB; and tumor necrosis factor, respectively. These genes encode proteins that are important in regulation cell signaling, proliferation, gene expression, and immune stimulation. Biological processes over-represented among the 53 genes were fibrosis, tumorigenesis, and immune response. Conclusions: Microarrays showed minor changes in gene expression after thermochemoradiotherapy in locally advanced cervical cancer. We detected 53 differentially expressed genes, mainly involved in fibrosis, tumorigenesis, and immune response. A limitation with the use of serial biopsy specimens was low quality of ribonucleic acid from tumors that respond to highly effective therapy. Another 'key limitation' is timing of the post-treatment biopsy, because 24 h may be too late to adequately assess the impact of hyperthermia on gene expression.

  16. Sodium 4-phenylbutyrate acts as a chemical chaperone on misfolded myocilin to rescue cells from endoplasmic reticulum stress and apoptosis.

    Science.gov (United States)

    Yam, Gary Hin-Fai; Gaplovska-Kysela, Katarina; Zuber, Christian; Roth, Jürgen

    2007-04-01

    To evaluate the effect of chemical chaperones on the trafficking of secretion-incompetent primary open-angle glaucoma-associated mutant myocilin and the possibility to rescue cells coexpressing mutant and wild-type myocilin from endoplasmic reticulum (ER) stress and apoptosis. CHO-K1, HEK293 and human trabecular meshwork cells were transfected to express wild-type or mutant (C245Y, G364V, P370L, Y437H) myocilin-green fluorescent protein fusion protein and were treated or not with various chemical chaperones (glycerol, dimethylsulfoxide, or sodium 4-phenylbutyrate) for different time periods. The secretion, Triton X-100 solubility, and intracellular distribution of wild-type and mutant myocilin were analyzed by immunoprecipitation, Western blotting, and confocal double immunofluorescence. The effect of sodium 4-phenylbutyrate on ER stress proteins and apoptosis was examined in cells coexpressing mutant and wild-type myocilin. Treatment with sodium 4-phenylbutyrate, but not with glycerol or dimethylsulfoxide, reduced the amount of detergent-insoluble myocilin aggregates, diminished myocilin interaction with calreticulin, and restored the secretion of mutant myocilin. Heteromeric complexes formed by mutant and wild-type myocilin induced the ER stress-associated phosphorylated form of ER-localized eukaryotic initiation factor (eIF)-2alpha kinase and the active form of caspase 3, which resulted in an increased rate of apoptosis. Sodium 4-phenylbutyrate treatment of cells coexpressing mutant and wild-type myocilin relieved ER stress and significantly reduced the rate of apoptosis. These findings indicate that sodium 4-phenylbutyrate protects cells from the deleterious effects of ER-retained aggregated mutant myocilin. These data point to the possibility of a chemical chaperone treatment for myocilin-caused primary open-angle glaucoma.

  17. The Intrinsically Disordered Domain of the Antitoxin Phd Chaperones the Toxin Doc against Irreversible Inactivation and Misfolding*

    Science.gov (United States)

    De Gieter, Steven; Konijnenberg, Albert; Talavera, Ariel; Butterer, Annika; Haesaerts, Sarah; De Greve, Henri; Sobott, Frank; Loris, Remy; Garcia-Pino, Abel

    2014-01-01

    The toxin Doc from the phd/doc toxin-antitoxin module targets the cellular translation machinery and is inhibited by its antitoxin partner Phd. Here we show that Phd also functions as a chaperone, keeping Doc in an active, correctly folded conformation. In the absence of Phd, Doc exists in a relatively expanded state that is prone to dimerization through domain swapping with its active site loop acting as hinge region. The domain-swapped dimer is not capable of arresting protein synthesis in vitro, whereas the Doc monomer is. Upon binding to Phd, Doc becomes more compact and is secured in its monomeric state with a neutralized active site. PMID:25326388

  18. Expression of three topologically distinct membrane proteins elicits unique stress response pathways in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Buck, Teresa M; Jordan, Rick; Lyons-Weiler, James; Adelman, Joshua L; Needham, Patrick G; Kleyman, Thomas R; Brodsky, Jeffrey L

    2015-06-01

    Misfolded membrane proteins are retained in the endoplasmic reticulum (ER) and are subject to ER-associated degradation, which clears the secretory pathway of potentially toxic species. While the transcriptional response to environmental stressors has been extensively studied, limited data exist describing the cellular response to misfolded membrane proteins. To this end, we expressed and then compared the transcriptional profiles elicited by the synthesis of three ER retained, misfolded ion channels: The α-subunit of the epithelial sodium channel, ENaC, the cystic fibrosis transmembrane conductance regulator, CFTR, and an inwardly rectifying potassium channel, Kir2.1, which vary in their mass, membrane topologies, and quaternary structures. To examine transcriptional profiles in a null background, the proteins were expressed in yeast, which was previously used to examine the degradation requirements for each substrate. Surprisingly, the proteins failed to induce a canonical unfolded protein response or heat shock response, although messages encoding several cytosolic and ER lumenal protein folding factors rose when αENaC or CFTR was expressed. In contrast, the levels of these genes were unaltered by Kir2.1 expression; instead, the yeast iron regulon was activated. Nevertheless, a significant number of genes that respond to various environmental stressors were upregulated by all three substrates, and compared with previous microarray data we deduced the existence of a group of genes that reflect a novel misfolded membrane protein response. These data indicate that aberrant proteins in the ER elicit profound yet unique cellular responses. Copyright © 2015 the American Physiological Society.

  19. Impact of Serials Management, Access and Use on Publication Output of Lecturers in Nigerian Universities

    Science.gov (United States)

    Akinbode, Rahmon O. Onaolapo; Nwalo, Kenneth Ivo Ngozi

    2017-01-01

    This study investigates serials management in university libraries, determines the extent to which serials are accessed and used and appraises the influence of availability, accessibility and use of serials on publications output of lecturers in federal universities in Nigeria. Questionnaire administration method was adopted to accumulate data for…

  20. A constrained rasch model of trace redintegration in serial recall.

    Science.gov (United States)

    Roodenrys, Steven; Miller, Leonie M

    2008-04-01

    The notion that verbal short-term memory tasks, such as serial recall, make use of information in long-term as well as in short-term memory is instantiated in many models of these tasks. Such models incorporate a process in which degraded traces retrieved from a short-term store are reconstructed, or redintegrated (Schweickert, 1993), through the use of information in long-term memory. This article presents a conceptual and mathematical model of this process based on a class of item-response theory models. It is demonstrated that this model provides a better fit to three sets of data than does the multinomial processing tree model of redintegration (Schweickert, 1993) and that a number of conceptual accounts of serial recall can be related to the parameters of the model.

  1. Plastic optical fiber serial communications link for distributed control system

    Science.gov (United States)

    Saxena, Piyush; Sharangpani, K. K.; Vora, H. S.; Nakhe, S. V.; Jain, R.; Shenoy, N. M.; Bhatnagar, R.; Shirke, N. D.

    2001-09-01

    One of the most common interface for communications specified is RS 232C standard. Though widely accepted, RS232 has limited transmission speed, range and networking capabilities. RS 422 standard overcomes limitations by using differential signal lines. In automation of the operation of gas discharge lasers, multiple processors are used for control of lasers, cooling system, vacuum system etc. High EMI generated by lasers interfere through galvanic transmission or by radiation over the length of cables, and hang up operation of processors or control PC. A serial communications link was designed eliminating copper transmission media, using plastic optical fiber cables and components, to connect local controllers with the master PC working on RS232 protocols. The paper discusses the design and implementation of a high ly reliable EMI harden serial communications link.

  2. Serial network simplifies the design of multiple microcomputer systems

    Energy Technology Data Exchange (ETDEWEB)

    Folkes, D.

    1981-01-01

    Recently there has been a lot of interest in developing network communication schemes for carrying digital data between locally distributed computing stations. Many of these schemes have focused on distributed networking techniques for data processing applications. These applications suggest the use of a serial, multipoint bus, where a number of remote intelligent units act as slaves to a central or host computer. Each slave would be serially addressable from the host and would perform required operations upon being addressed by the host. Based on an MK3873 single-chip microcomputer, the SCU 20 is designed to be such a remote slave device. The capabilities of the SCU 20 and its use in systems applications are examined.

  3. Serial murder in America: case studies of seven offenders.

    Science.gov (United States)

    Beasley, James O

    2004-01-01

    This article summarizes and compares information on seven interviewed serial killers in an ongoing project designed to study similarities and differences among these individuals. The aim of this article is to increase our collective knowledge of the dynamics of serial murder by examining the perpetrators' backgrounds, as well as the unique ways in which they view themselves and the world around them. Although qualitative interview research alone is not sufficient to fully understand such behavior, it is useful in many ways. Some of the information discussed based on the seven offenders interviewed is compared with broader epidemiological studies, and the strengths and limitations of each type of research are discussed. Published in 2004 by John Wiley & Sons, Ltd.

  4. [Some criminological and psychopathologic reflexions about serial crimes].

    Science.gov (United States)

    Romi, Juan Carlos

    2011-01-01

    This article reviews the concept of serial crime, including murder as well as any action for the purpose of inflicting bodily harm upon any person. It characterizes three types of multi-murderers: serial killers, mass murderers, and spree killers. These offenders often have a specific (ritual) behavior that is idiosyncratic and repeated on each crime, which allows the psychological profiling of the murderer. Examples, a psychopathological background, and a description of both their criminal behavior and dynamics are provided for each of these criminals. They are further classified according to their different motivations: psychotic, prophetic or enlightened, pleasure, secondary or pecuniary profits, power or control. Finally, the author shares his personal experience over 20 years in the assessment of sexual offenders.

  5. Counterbalancing for serial order carryover effects in experimental condition orders

    OpenAIRE

    Brooks, Joseph L

    2012-01-01

    Reactions of neural, psychological, and social systems are rarely, if ever, independent of previous inputs and states. The potential for serial order carryover effects from one condition to the next in a sequence of experimental trials makes counterbalancing of condition order an essential part of experimental design. Here, a method is proposed for generating counterbalanced sequences for repeated-measures designs including those with multiple observations of each condition on one participant...

  6. A matter of emphasis: Linguistic stress habits modulate serial recall

    OpenAIRE

    Taylor, John C.; Macken, Bill; Jones, Dylan M.

    2014-01-01

    Models of short-term memory for sequential information rely on item-level, feature-based descriptions to account for errors in serial recall. Transposition errors within alternating similar/dissimilar letter sequences derive from interactions between overlapping features. However, in two experiments, we demonstrated that the characteristics of the sequence are what determine the fates of items, rather than the properties ascribed to the items themselves. Performance in alternating sequences i...

  7. Serial MR imaging in Creutzfeldt-Jakob disease

    Energy Technology Data Exchange (ETDEWEB)

    Uchino, A.; Hata, H.; Ohno, M. (Kyushu Rosai Hospital, Kitakyushu (Japan). Dept. of Radiology); Yoshinaga, M.; Shiokawa, O. (Kyushu Rosai Hospital, Kitakyushu (Japan). Stroke Care Unit)

    1991-08-01

    Serial magnetic resonance (MR) imagings of two autopsied patients with Creutzfeldt-Jakob disease (CJD) are presented. Both patients showed a dramatic progression of brain atrophy. The initial MR imagings were, however, interpreted as normal except for localized mild cortical atrophy in one patient. When a normal MR image is obtained in a demented middle-aged or aged patient, CJD may still need to be ruled out: follow up MR imaging may be useful. (orig.).

  8. Serial MR imaging in Creutzfeldt-Jakob disease

    International Nuclear Information System (INIS)

    Uchino, A.; Hata, H.; Ohno, M.; Yoshinaga, M.; Shiokawa, O.

    1991-01-01

    Serial magnetic resonance (MR) imagings of two autopsied patients with Creutzfeldt-Jakob disease (CJD) are presented. Both patients showed a dramatic progression of brain atrophy. The initial MR imagings were, however, interpreted as normal except for localized mild cortical atrophy in one patient. When a normal MR image is obtained in a demented middle-aged or aged patient, CJD may still need to be ruled out: follow up MR imaging may be useful. (orig.)

  9. Which serial killers commit suicide? An exploratory study.

    Science.gov (United States)

    Lester, David; White, John

    2012-11-30

    In a sample of 483 serial killers, 6.2% were documented to have committed suicide. Those who committed suicide were found to come from more dysfunctional homes characterized by more psychiatric disturbance in the parents. The sexual acts involved in the murders by the suicides seemed to be more deviant in some aspects, such as committing more bizarre sexual acts or more often taping the murder. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. The intrinsically disordered domain of the antitoxin Phd chaperones the toxin Doc against irreversible inactivation and misfolding.

    Science.gov (United States)

    De Gieter, Steven; Konijnenberg, Albert; Talavera, Ariel; Butterer, Annika; Haesaerts, Sarah; De Greve, Henri; Sobott, Frank; Loris, Remy; Garcia-Pino, Abel

    2014-12-05

    The toxin Doc from the phd/doc toxin-antitoxin module targets the cellular translation machinery and is inhibited by its antitoxin partner Phd. Here we show that Phd also functions as a chaperone, keeping Doc in an active, correctly folded conformation. In the absence of Phd, Doc exists in a relatively expanded state that is prone to dimerization through domain swapping with its active site loop acting as hinge region. The domain-swapped dimer is not capable of arresting protein synthesis in vitro, whereas the Doc monomer is. Upon binding to Phd, Doc becomes more compact and is secured in its monomeric state with a neutralized active site. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Taking serial correlation into account in tests of the mean

    International Nuclear Information System (INIS)

    Zwiers, F.W.; Storch, H. von

    1993-01-01

    The comparison of means derived from samples of noisy data is a standard part of climatology. When the data are not serially correlated the appropriate statistical tool for this task is usually the conventional Student's t-test. However, data frequently are serially correlated in climatological applications with the result that the t-tests in its standard form is not applicable. The usual solution to this problem is to scale the t-statistic by a factor which depends upon the equivalent sample size n e . We show, by means of simulations, that the revised t-test is often conservative (the actual significance level is smaller than the specified significance level) when the equivalent sample size is known. However, in most practical cases the equivalent sample size is not known. Then the test becomes liberal (the actual significance level is greater than the specified significance level). This systematic error becomes small when the true equivalent sample size is large (greater than approximately 30). We re-examine the difficulties inherent in difference of means tests when there is serial dependence. We provide guidelines for the application of the 'usual' t-test and propose two alternative tests which substantially improve upon the 'usual' t-test when samples are small. (orig.)

  12. Cognitive, emotional and social markers of serial murdering.

    Science.gov (United States)

    Angrilli, Alessandro; Sartori, Giuseppe; Donzella, Giovanna

    2013-01-01

    Although criminal psychopathy is starting to be relatively well described, our knowledge of the characteristics and scientific markers of serial murdering is still very poor. A serial killer who murdered more than five people, KT, was administered a battery of standardized tests aimed at measuring neuropsychological impairment and social/emotional cognition deficits. KT exhibited a striking dissociation between a high level of emotional detachment and a low score on the antisocial behavior scale on the Psychopathy Checklist-Revised (PCL-R). The Minnesota Multiphasic Personality Inventory-2 showed a normal pattern with the psychotic triad at borderline level. KT had a high intelligence score and showed almost no impairment in cognitive tests sensitive to frontal lobe dysfunction (Wisconsin Card Sorting Test, Theory of Mind, Tower of London, this latter evidenced a mild impairment in planning performance). In the tests on moral, emotional and social cognition, his patterns of response differed from matched controls and from past reports on criminal psychopaths as, unlike these individuals, KT exhibited normal recognition of fear and a relatively intact knowledge of moral rules but he was impaired in the recognition of anger, embarrassment and conventional social rules. The overall picture of KT suggests that serial killing may be closer to normality than psychopathy defined according to either the DSM IV or the PCL-R, and it would be characterized by a relatively spared moral cognition and selective deficits in social and emotional cognition domains.

  13. DDCMP protocol on a DMA serial-line board

    International Nuclear Information System (INIS)

    Hunt, D.N.; Kessler, G.C.

    1982-01-01

    The Nuclear Chemistry Division of Lawrence Livermore National Laboratory is in the midst of an upgrade to their radiation counting facility. The result of this upgrade wil be a computer-based data acquisition network, the Nuclear Chemistry Counting Facility Network (NCCF-NET). This network will consist of forty dedicated LSI-11/2 based controllers, ten interactive LSI-11/23 based workstations and a VAX-11/750 central node for data reduction and storage. One of the data acquisition instruments used in this network is a Nuclear Data pulse-height analyzer, the ND66L. This analyzer communicates to a host system over a 9600-baud serial line, using the DDCMP link level protocol. In order to relieve the host computer from the overhead of handling the DDCMP protocol, an in-house designed DMA serial line board was implemented to communicate with the ND66L. The hardware used and its environment will be duscussed along with the design and implementation of the firmware, which implements the serial DDCMP link

  14. A matter of emphasis: Linguistic stress habits modulate serial recall.

    Science.gov (United States)

    Taylor, John C; Macken, Bill; Jones, Dylan M

    2015-04-01

    Models of short-term memory for sequential information rely on item-level, feature-based descriptions to account for errors in serial recall. Transposition errors within alternating similar/dissimilar letter sequences derive from interactions between overlapping features. However, in two experiments, we demonstrated that the characteristics of the sequence are what determine the fates of items, rather than the properties ascribed to the items themselves. Performance in alternating sequences is determined by the way that the sequences themselves induce particular prosodic rehearsal patterns, and not by the nature of the items per se. In a serial recall task, the shapes of the canonical "saw-tooth" serial position curves and transposition error probabilities at successive input-output distances were modulated by subvocal rehearsal strategies, despite all item-based parameters being held constant. We replicated this finding using nonalternating lists, thus demonstrating that transpositions are substantially influenced by prosodic features-such as stress-that emerge during subvocal rehearsal.

  15. The Effect of Concurrent Semantic Categorization on Delayed Serial Recall

    Science.gov (United States)

    Acheson, Daniel J.; MacDonald, Maryellen C.; Postle, Bradley R.

    2010-01-01

    The influence of semantic processing on the serial ordering of items in short-term memory was explored using a novel dual-task paradigm. Subjects engaged in two picture judgment tasks while simultaneously performing delayed serial recall. List material varied in the presence of phonological overlap (Experiments 1 and 2) and in semantic content (concrete words in Experiment 1 and 3; nonwords in Experiments 2 and 3). Picture judgments varied in the extent to which they required accessing visual semantic information (i.e., semantic categorization and line orientation judgments). Results showed that, relative to line orientation judgments, engaging in semantic categorization judgments increased the proportion of item ordering errors for concrete lists but did not affect error proportions for nonword lists. Furthermore, although more ordering errors were observed for phonologically similar relative to dissimilar lists, no interactions were observed between the phonological overlap and picture judgment task manipulations. These results thus demonstrate that lexical-semantic representations can affect the serial ordering of items in short-term memory. Furthermore, the dual-task paradigm provides a new method for examining when and how semantic representations affect memory performance. PMID:21058880

  16. Voltage balancing strategies for serial connection of microbial fuel cells

    Science.gov (United States)

    Khaled, Firas; Ondel, Olivier; Allard, Bruno; Buret, François

    2015-07-01

    The microbial fuel cell (MFC) converts electrochemically organic matter into electricity by means of metabolisms of bacteria. The MFC power output is limited by low voltage and low current characteristics in the range of microwatts or milliwatts per litre. In order to produce a sufficient voltage level (>1.5 V) and sufficient power to supply real applications such as autonomous sensors, it is necessary to either scale-up one single unit or to connect multiple units together. Many topologies of connection are possible as the serial association to improve the output voltage, or the parallel connection to improve the output current or the series/parallel connection to step-up both voltage and current. The association of MFCs in series is a solution to increase the voltage to an acceptable value and to mutualize the unit's output power. The serial association of a large number of MFCs presents several issues. The first one is the hydraulic coupling among MFCs when they share the same substrate. The second one is the dispersion between generators that lead to a non-optimal stack efficiency because the maximum power point (MPP) operation of all MFCs is not permitted. Voltage balancing is a solution to compensate non-uniformities towards MPP. This paper presents solutions to improve the efficiency of a stack of serially connected MFCs through a voltage-balancing circuit. Contribution to the topical issue "Electrical Engineering Symposium (SGE 2014)", edited by Adel Razek

  17. Evidence for spontaneous serial refreshing in verbal working memory?

    Science.gov (United States)

    Vergauwe, Evie; Langerock, Naomi; Cowan, Nelson

    2018-04-01

    Working memory (WM) keeps information temporarily accessible for ongoing cognition. One proposed mechanism to keep information active in WM is refreshing. This mechanism is assumed to operate by bringing memory items into the focus of attention, thereby serially refreshing the content of WM. We report two experiments in which we examine evidence for the spontaneous occurrence of serial refreshing in verbal WM. Participants had to remember series of red letters, while black probe letters were presented between these memory items, with each probe to be judged present in or absent from the list presented so far, as quickly as possible (i.e., the probe-span task). Response times to the probes were used to infer the status of the representations in WM and, in particular, to examine whether the content of the focus of attention changed over time, as would be expected if serial refreshing occurs spontaneously during inter-item pauses. In sharp contrast with this hypothesis, our results indicate that the last-presented memory item remained in the focus of attention during the inter-item pauses of the probe-span task. We discuss how these findings help to define the boundary conditions of spontaneous refreshing of verbal material in WM, and discuss implications for verbal WM maintenance and forgetting.

  18. Efficient multitasking: parallel versus serial processing of multiple tasks.

    Science.gov (United States)

    Fischer, Rico; Plessow, Franziska

    2015-01-01

    In the context of performance optimizations in multitasking, a central debate has unfolded in multitasking research around whether cognitive processes related to different tasks proceed only sequentially (one at a time), or can operate in parallel (simultaneously). This review features a discussion of theoretical considerations and empirical evidence regarding parallel versus serial task processing in multitasking. In addition, we highlight how methodological differences and theoretical conceptions determine the extent to which parallel processing in multitasking can be detected, to guide their employment in future research. Parallel and serial processing of multiple tasks are not mutually exclusive. Therefore, questions focusing exclusively on either task-processing mode are too simplified. We review empirical evidence and demonstrate that shifting between more parallel and more serial task processing critically depends on the conditions under which multiple tasks are performed. We conclude that efficient multitasking is reflected by the ability of individuals to adjust multitasking performance to environmental demands by flexibly shifting between different processing strategies of multiple task-component scheduling.

  19. Simple measuring rod method for the coaxiality of serial holes

    Science.gov (United States)

    Wang, Lei; Yang, Tongyu; Wang, Zhong; Ji, Yuchen; Liu, Changjie; Fu, Luhua

    2017-11-01

    Aiming at the rapid coaxiality measurement of serial hole part with a small diameter, a coaxiality measuring rod for each layer hole with a single LDS (laser displacement sensor) is proposed. This method does not require the rotation angle information of the rod, and the coaxiality of serial holes can be calculated from the measured values of LDSs after randomly rotating the measuring rod several times. With the mathematical model of the coaxiality measuring rod, each factor affecting the accuracy of coaxiality measurement is analyzed by simulation, and the installation accuracy requirements of the measuring rod and LDSs are presented. In the tolerance of a certain installation error of the measuring rod, the relative center of the hole is calculated by setting the over-determined nonlinear equations of the fitting circles of the multi-layer holes. In experiment, coaxiality measurement accuracy is realized by a 16 μm precision LDS, and the validity of the measurement method is verified. The manufacture and measurement requirements of the coaxiality measuring rod are low, by changing the position of LDSs in the measuring rod, the serial holes with different sizes and numbers can be measured. The rapid coaxiality measurement of parts can be easily implemented in industrial sites.

  20. A network-based Macintosh serial host interface program

    International Nuclear Information System (INIS)

    Wight, J.

    1991-03-01

    A program has been written for the Apple Macintosh to replace conventional host RS232 terminals with customizable user interfaces. Serial port NuBus cards in the Macintosh allow many simultaneous sessions to be maintained. A powerful system is attained by connecting multiple Macintoshes on a network, each running this program. Each is then able to share incoming data from any of its serial ports with any other Macintosh, as well as accept data from any other Macintosh for output to any of its serial ports. The program has been used to eliminate multiple host terminals, modernize the user interface, and to centralize operation of a complex control system. Minimal changes to host software have been required. By making extensive use of Macintosh resources, the same executable code serves in a variety of roles. An object oriented C language with a class library made the development straightforward and easy to modify. This program is used to control a 2 MW neutral beam system on the DIII-D magnetic fusion tokamak. 7 figs

  1. The neural signature of emotional memories in serial crimes.

    Science.gov (United States)

    Chassy, Philippe

    2017-10-01

    Neural plasticity is the process whereby semantic information and emotional responses are stored in neural networks. It is hypothesized that the neural networks built over time to encode the sexual fantasies that motivate serial killers to act should display a unique, detectable activation pattern. The pathological neural watermark hypothesis posits that such networks comprise activation of brain sites that reflect four cognitive components: autobiographical memory, sexual arousal, aggression, and control over aggression. The neural sites performing these cognitive functions have been successfully identified by previous research. The key findings are reviewed to hypothesise the typical pattern of activity that serial killers should display. Through the integration of biological findings into one framework, the neural approach proposed in this paper is in stark contrast with the many theories accounting for serial killers that offer non-medical taxonomies. The pathological neural watermark hypothesis offers a new framework to understand and detect deviant individuals. The technical and legal issues are briefly discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. AMYPdb: A database dedicated to amyloid precursor proteins

    Directory of Open Access Journals (Sweden)

    Delamarche Christian

    2008-06-01

    Full Text Available Abstract Background Misfolding and aggregation of proteins into ordered fibrillar structures is associated with a number of severe pathologies, including Alzheimer's disease, prion diseases, and type II diabetes. The rapid accumulation of knowledge about the sequences and structures of these proteins allows using of in silico methods to investigate the molecular mechanisms of their abnormal conformational changes and assembly. However, such an approach requires the collection of accurate data, which are inconveniently dispersed among several generalist databases. Results We therefore created a free online knowledge database (AMYPdb dedicated to amyloid precursor proteins and we have performed large scale sequence analysis of the included data. Currently, AMYPdb integrates data on 31 families, including 1,705 proteins from nearly 600 organisms. It displays links to more than 2,300 bibliographic references and 1,200 3D-structures. A Wiki system is available to insert data into the database, providing a sharing and collaboration environment. We generated and analyzed 3,621 amino acid sequence patterns, reporting highly specific patterns for each amyloid family, along with patterns likely to be involved in protein misfolding and aggregation. Conclusion AMYPdb is a comprehensive online database aiming at the centralization of bioinformatic data regarding all amyloid proteins and their precursors. Our sequence pattern discovery and analysis approach unveiled protein regions of significant interest. AMYPdb is freely accessible 1.

  3. Cellular Chaperones As Therapeutic Targets in ALS to Restore Protein Homeostasis and Improve Cellular Function

    Directory of Open Access Journals (Sweden)

    Bernadett Kalmar

    2017-09-01

    Full Text Available Heat shock proteins (Hsps are ubiquitously expressed chaperone proteins that enable cells to cope with environmental stresses that cause misfolding and denaturation of proteins. With aging this protein quality control machinery becomes less effective, reducing the ability of cells to cope with damaging environmental stresses and disease-causing mutations. In neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS, such mutations are known to result in protein misfolding, which in turn results in the formation of intracellular aggregates cellular dysfunction and eventual neuronal death. The exact cellular pathology of ALS and other neurodegenerative diseases has been elusive and thus, hindering the development of effective therapies. However, a common scheme has emerged across these “protein misfolding” disorders, in that the mechanism of disease involves one or more aspects of proteostasis; from DNA transcription, RNA translation, to protein folding, transport and degradation via proteosomal and autophagic pathways. Interestingly, members of the Hsp family are involved in each of these steps facilitating normal protein folding, regulating the rate of protein synthesis and degradation. In this short review we summarize the evidence that suggests that ALS is a disease of protein dyshomeostasis in which Hsps may play a key role. Overwhelming evidence now indicates that enabling protein homeostasis to cope with disease-causing mutations might be a successful therapeutic strategy in ALS, as well as other neurodegenerative diseases. Novel small molecule co-inducers of Hsps appear to be able to achieve this aim. Arimoclomol, a hydroxylamine derivative, has shown promising results in cellular and animal models of ALS, as well as other protein misfolding diseases such as Inclusion Body Myositis (IBM. Initial clinical investigations of Arimoclomol have shown promising results. Therefore, it is possible that the long series of

  4. A versatile diffractive maskless lithography for single-shot and serial microfabrication.

    Science.gov (United States)

    Jenness, Nathan J; Hill, Ryan T; Hucknall, Angus; Chilkoti, Ashutosh; Clark, Robert L

    2010-05-24

    We demonstrate a diffractive maskless lithographic system that is capable of rapidly performing both serial and single-shot micropatterning. Utilizing the diffractive properties of phase holograms displayed on a spatial light modulator, arbitrary intensity distributions were produced to form two and three dimensional micropatterns/structures in a variety of substrates. A straightforward graphical user interface was implemented to allow users to load templates and change patterning modes within the span of a few minutes. A minimum resolution of approximately 700 nm is demonstrated for both patterning modes, which compares favorably to the 232 nm resolution limit predicted by the Rayleigh criterion. The presented method is rapid and adaptable, allowing for the parallel fabrication of microstructures in photoresist as well as the fabrication of protein microstructures that retain functional activity.

  5. Serial measurements of serum human placental lactogen (hPL) and serial ultrasound examinations in the evaluation of fetal growth

    DEFF Research Database (Denmark)

    Sørensen, Steen; von Tabouillot, D; Schioler, V

    2000-01-01

    Serial serum hPL measurements and serial ultrasound fetometry were compared in the evaluation of fetal growth by relating these two parameters to size at birth and to clinical factors known to influence size at birth. The data were from a prospective study of 1000 consecutive pregnant women...... considered to be at risk for fetal growth retardation with retrospective analysis. Serum hPL was measured by radioimmunoassay and fetal weight estimated by ultrasound every 3 weeks during the last trimester. hPL values were expressed as multiples of the median (MoM) and linear regression analysis of the h......PL MoM values was carried out for each pregnancy to find the slope of the line (hPL-slope); at least 3 serum hPL values were required. The estimated fetal weight and weight-for-age at birth was expressed in Z-scores. The individual intrauterine growth velocity was calculated by regression analysis...

  6. Rehosting of Bacterial Chaperones for High-Quality Protein Production▿

    Science.gov (United States)

    Martínez-Alonso, Mónica; Toledo-Rubio, Verónica; Noad, Rob; Unzueta, Ugutz; Ferrer-Miralles, Neus; Roy, Polly; Villaverde, Antonio

    2009-01-01

    Coproduction of DnaK/DnaJ in Escherichia coli enhances solubility but promotes proteolytic degradation of their substrates, minimizing the yield of unstable polypeptides. Higher eukaryotes have orthologs of DnaK/DnaJ but lack the linked bacterial proteolytic system. By coexpression of DnaK and DnaJ in insect cells with inherently misfolding-prone recombinant proteins, we demonstrate simultaneous improvement of soluble protein yield and quality and proteolytic stability. Thus, undesired side effects of bacterial folding modulators can be avoided by appropriate rehosting in heterologous cell expression systems. PMID:19820142

  7. Vitamin k3 inhibits protein aggregation: Implication in the treatment of amyloid diseases

    OpenAIRE

    Parvez Alam; Sumit Kumar Chaturvedi; Mohammad Khursheed Siddiqi; Ravi Kant Rajpoot; Mohd Rehan Ajmal; Masihuz Zaman; Rizwan Hasan Khan

    2016-01-01

    Protein misfolding and aggregation have been associated with several human diseases such as Alzheimer?s, Parkinson?s and familial amyloid polyneuropathy etc. In this study, anti-fibrillation activity of vitamin k3 and its effect on the kinetics of amyloid formation of hen egg white lysozyme (HEWL) and A?-42 peptide were investigated. Here, in combination with Thioflavin T (ThT) fluorescence assay, circular dichroism (CD), transmission electron microscopy and cell cytotoxicity assay, we demons...

  8. Production of membrane proteins without cells or detergents.

    Science.gov (United States)

    Rajesh, Sundaresan; Knowles, Timothy; Overduin, Michael

    2011-04-30

    The production of membrane proteins in cellular systems is besieged by several problems due to their hydrophobic nature which often causes misfolding, protein aggregation and cytotoxicity, resulting in poor yields of stable proteins. Cell-free expression has emerged as one of the most versatile alternatives for circumventing these obstacles by producing membrane proteins directly into designed hydrophobic environments. Efficient optimisation of expression and solubilisation conditions using a variety of detergents, membrane mimetics and lipids has yielded structurally and functionally intact membrane proteins, with yields several fold above the levels possible from cell-based systems. Here we review recently developed techniques available to produce functional membrane proteins, and discuss amphipols, nanodisc and styrene maleic acid lipid particle (SMALP) technologies that can be exploited alongside cell-free expression of membrane proteins. Copyright © 2010 Elsevier B.V. All rights reserved.

  9. Role of the Disulfide Bond in Prion Protein Amyloid Formation: A Thermodynamic and Kinetic Analysis.

    Science.gov (United States)

    Honda, Ryo

    2018-02-27

    Prion diseases are associated with the structural conversion of prion protein (PrP) to a β-sheet-rich aggregate, PrP Sc . Previous studies have indicated that a reduction of the disulfide bond linking C179 and C214 of PrP yields an amyloidlike β-rich aggregate in vitro. To gain mechanistic insights into the reduction-induced aggregation, here I characterized how disulfide bond reduction modulates the protein folding/misfolding landscape of PrP, by examining 1) the equilibrium stabilities of the native (N) and aggregated states relative to the unfolded (U) state, 2) the transition barrier separating the U and aggregated states, and 3) the final structure of amyloidlike misfolded aggregates. Kinetic and thermodynamic experiments revealed that disulfide bond reduction decreases the equilibrium stabilities of both the N and aggregated states by ∼3 kcal/mol, without changing either the amyloidlike aggregate structure, at least at the secondary structural level, or the transition barrier of aggregation. Therefore, disulfide bond reduction modulates the protein folding/misfolding landscape by entropically stabilizing disordered states, including the U and transition state of aggregation. This also indicates that the equilibrium stability of the N state, but not the transition barrier of aggregation, is the dominant factor determining the reduction-induced aggregation of PrP. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  10. Word-serial Architectures for Filtering and Variable Rate Decimation

    Directory of Open Access Journals (Sweden)

    Eugene Grayver

    2002-01-01

    Full Text Available A new flexible architecture is proposed for word-serial filtering and variable rate decimation/interpolation. The architecture is targeted for low power applications requiring medium to low data rate and is ideally suited for implementation on either an ASIC or an FPGA. It combines the small size and low power of an ASIC with the programmability and flexibility of a DSP. An efficient memory addressing scheme eliminates the need for power hungry shift registers and allows full reconfiguration. The decimation ratio, filter length and filter coefficients can all be changed in real time. The architecture takes advantage of coefficient symmetries in linear phase filters and in polyphase components.

  11. Diffusion thermopower of a serial double quantum dot

    International Nuclear Information System (INIS)

    Thierschmann, H; Henke, M; Knorr, J; Maier, L; Buhmann, H; Molenkamp, L W; Heyn, C; Hansen, W

    2013-01-01

    We have experimentally studied the diffusion thermopower of a serial double quantum dot, defined electrostatically in a GaAs/AlGaAs heterostructure. We present the thermopower stability diagram for a temperature difference ΔT = (20 ± 10) mK across the device and find a maximum thermovoltage signal of several μV in the vicinity of the triple points. Along a constant energy axis in this regime, the data show a characteristic pattern which is in agreement with Mott's relation and can be well understood within a model of sequential transport. (paper)

  12. Hi-speed versatile serial crate controller for CAMAC

    International Nuclear Information System (INIS)

    Horelick, D.

    1984-10-01

    A serial crate controller, primarily for use in the SLC CAMAC control system, has been designed, and has been in use for about 2 years. The design supports a party line approach, with up to 16 crates on a single twisted pair for data transfers, plus another pair for prompt L response. The bit rate is 5 megabits/s, and complete transaction times of about 10 μs are achieved for 16-bit data transfers over cables up to 1000 feet long. One of the primary objects of the design was simplicity - there are approximately 60 chips in the two-board unit

  13. Lean buffering in serial production lines with Bernoulli machines

    Directory of Open Access Journals (Sweden)

    A. B. Hu

    2006-01-01

    Full Text Available Lean buffering is the smallest buffer capacity necessary to ensure the desired production rate of a manufacturing system. In this paper, analytical methods for selecting lean buffering in serial production lines are developed under the assumption that the machines obey the Bernoulli reliability model. Both closed-form expressions and recursive approaches are investigated. The cases of identical and nonidentical machines are analyzed. Results obtained can be useful for production line designers and production managers to maintain the required production rate with the smallest possible inventories.

  14. Key Conditions for Successful Serial Entrepreneurship in Healthcare.

    Science.gov (United States)

    Piron, Cameron

    2017-01-01

    As a serial entrepreneur in the medical device industry, the author embraces Snowdon's (2017) effort to create and stimulate dialogue among experts in health system innovation in an effort to define and support Canada's innovation agenda. In this paper, he outlines some of the attributes and skills that companies need to launch their products and scale their companies. He also identifies the main conditions of an innovation ecosystem that create the necessary infrastructure to enable and support highly successful companies while allowing them to accelerate their growth.

  15. Serial computed tomography findings in Creutzfeldt-Jakob disease

    International Nuclear Information System (INIS)

    Schlenska, G.K.; Walter, G.F.

    1989-01-01

    Serial CT investigations of 3 patients with histologically confirmed Creutzfeldt-Jakob disease revealed persisting slight brain atrophy to progressive extreme atrophy corresponding to the absolute, not the individual duration of illness. No correlation was observed between CT findings and the patients condition or electroencephalographic results. In one case with a duration of about 16 months and a terminal brain weight of 750 g a massive bilateral, later unilateral subdural hygroma appeared which probably was caused by retraction of the brain showing an enormous atrophy. (orig.)

  16. Serial computed tomography findings in Creutzfeldt-Jakob disease

    Energy Technology Data Exchange (ETDEWEB)

    Schlenska, G.K.; Walter, G.F.

    1989-09-01

    Serial CT investigations of 3 patients with histologically confirmed Creutzfeldt-Jakob disease revealed persisting slight brain atrophy to progressive extreme atrophy corresponding to the absolute, not the individual duration of illness. No correlation was observed between CT findings and the patients condition or electroencephalographic results. In one case with a duration of about 16 months and a terminal brain weight of 750 g a massive bilateral, later unilateral subdural hygroma appeared which probably was caused by retraction of the brain showing an enormous atrophy. (orig.).

  17. Serial radionuclide quantitative function studies for evaluation of renal transplants

    International Nuclear Information System (INIS)

    Martin, D.C.; Hunter, J.L.; Lawton, M.B.; Berke, R.A.; Morton, M.E.

    1974-01-01

    A new method of assessing renal function following transplantation has been presented. The calculated rate of transfer to the kidney expressed as percent per minute, effective renal blood flow in milliliters per minute and the percentage of the dose in the urine at 20 minutes are calculated from data derived from a scintillation probe over the heart following a single injection of radiohippuran. These indices provide a means of interpreting serial determinations of renal function in states in which the more conventional parameters of renal function are not reliable. (U.S.)

  18. Freeform Optics: current challenges for future serial production

    Science.gov (United States)

    Schindler, C.; Köhler, T.; Roth, E.

    2017-10-01

    One of the major developments in optics industry recently is the commercial manufacturing of freeform surfaces for optical mid- and high performance systems. The loss of limitation on rotational symmetry enables completely new optical design solutions - but causes completely new challenges for the manufacturer too. Adapting the serial production from radial-symmetric to freeform optics cannot be done just by the extension of machine capabilities and software for every process step. New solutions for conventional optics productions or completely new process chains are necessary.

  19. Long-distance configuration of FPGA based on serial communication

    International Nuclear Information System (INIS)

    Liu Xiang; Song Kezhu; Zhang Sifeng

    2010-01-01

    To solve FPGA configuration in some nuclear electronics, which works in radioactivity environment, the article introduces a way of long-distance configuration with PC and CPLD, based on serial communication. Taking CYCLONE series FPGA and EPCS configuration chip from ALTERA for example, and using the AS configuration mode, we described our design from the aspects of basic theory, hardware connection, software function and communication protocol. With this design, we could configure several FPGAs in the distance of 100 meters, or we could configure on FPGA in the distance of 150 meters. (authors)

  20. The essential guide to Serial ATA and SATA express

    CERN Document Server

    Deming, David A

    2014-01-01

    Used in laptop and desktop computers, low-end servers, and mobile devices, Serial ATA (Advance Technology Attachment), or SATA, is the pervasive disk storage technology in use today. SATA has also penetrated the enterprise computing environment by adding hardware components for fail-over, extending command processing capabilities, and increasing device performance and link speeds. If you work in a data center or manage your company's storage resources, you will likely encounter storage solutions that require SATA software or hardware.In this book, leading storage networking technologist David

  1. POSSIBILITIES OF INCREASING EFFICIENCY WITHIN SERIAL PRODUCTION MANAGEMENT

    Directory of Open Access Journals (Sweden)

    CODRUŢA DURA

    2010-01-01

    Full Text Available Under the impact of transition to the new post-industrial society, massproduction recently faced the most numerous difficulties. They are caused by turbulences in theexternal environment in which companies operate, manifested in particular by enhancing thedynamism of markets and by deep changes in the structure of consumers’ demands. In thiscontext, specialized literature records the concerns for increasing the efficiency and flexibilityof products, elements involving radical changes of management and manufacturingtechnologies methods. Given these issues, the paper approaches two separate ways to improvethe management of serial production: increasing economic efficiency by optimizing the size ofbatches and flexible production systems by implementing techniques to reduce the change-overtime.

  2. Engineering and Characterization of a Superfolder Green Fluorescent Protein

    International Nuclear Information System (INIS)

    Pedelacq, J.; Cabantous, S.; Tran, T.; Terwilliger, T.; Waldo, G.

    2006-01-01

    Existing variants of green fluorescent protein (GFP) often misfold when expressed as fusions with other proteins. We have generated a robustly folded version of GFP, called 'superfolder' GFP, that folds well even when fused to poorly folded polypeptides. Compared to 'folding reporter' GFP, a folding-enhanced GFP containing the 'cycle-3' mutations and the 'enhanced GFP' mutations F64L and S65T, superfolder GFP shows improved tolerance of circular permutation, greater resistance to chemical denaturants and improved folding kinetics. The fluorescence of Escherichia coli cells expressing each of eighteen proteins from Pyrobaculum aerophilum as fusions with superfolder GFP was proportional to total protein expression. In contrast, fluorescence of folding reporter GFP fusion proteins was strongly correlated with the productive folding yield of the passenger protein. X-ray crystallographic structural analyses helped explain the enhanced folding of superfolder GFP relative to folding reporter GFP

  3. The Unfolded Protein Response in Chronic Obstructive Pulmonary Disease.

    Science.gov (United States)

    Kelsen, Steven G

    2016-04-01

    Accumulation of nonfunctional and potentially cytotoxic, misfolded proteins in chronic obstructive pulmonary disease (COPD) is believed to contribute to lung cell apoptosis, inflammation, and autophagy. Because of its fundamental role as a quality control system in protein metabolism, the "unfolded protein response" (UPR) is of potential importance in the pathogenesis of COPD. The UPR comprises a series of transcriptional, translational, and post-translational processes that decrease protein synthesis while enhancing protein folding capacity and protein degradation. Several studies have suggested that the UPR contributes to lung cell apoptosis and lung inflammation in at least some subjects with human COPD. However, information on the prevalence of the UPR in subjects with COPD, the lung cells that manifest a UPR, and the role of the UPR in the pathogenesis of COPD is extremely limited and requires additional study.

  4. Implementation of Bluetooth serial port based profiles in embedded systems

    Science.gov (United States)

    Liu, Guanglei; Qiu, Zhengding; Wang, Quanping; Gao, Qiang

    2001-10-01

    Bluetooth is a new short-range wireless communication technology developing rapidly in recent years. Bluetooth software architecture consists of stack and profiles. Serial Port Profile (SPP) is an underlying profile that emulates RS232 serial cable connections between two peer devices. Based on SPP, Dial-up Networking (DUN) Profile establishes PPP connection with remote dial-up server, Fax Profile realizes document facsimile function and LAN Access Profile (LAP) provides local area network access service. When it comes to their implementation in embedded systems, there are several challenges such as memory consumption, code efficiency, code reliability, and code portability onto different OS and hardware platforms to be attacked. In this paper, we propose integrated software architecture after discussing the great similarities shared among the three SPP based profiles. Then implementation of the architecture is given, in which OS-dependent and OS-independent parts are clearly separated. Profile interfaces with stack and OS are specified respectively so that the three profiles as a whole can be ported onto various software and hardware platforms easily. As a result, policy of transplanting our implementation onto different platforms is addressed at the end of the paper.

  5. Rethinking Conceptual Definitions of the Criminal Career and Serial Criminality.

    Science.gov (United States)

    Edelstein, Arnon

    2016-01-01

    Since Cesare Lombroso's days, criminology seeks to define, explain, and categorize the various types of criminals, their behaviors, and motives. This aim has theoretical as well as policy-related implications. One of the important areas in criminological thinking focuses chiefly on recidivist offenders who perform large numbers of crimes and/or commit the most dangerous crimes in society (rape, murder, arson, and armed robbery). These criminals have been defined as "habitual offenders," "professional criminals," "career criminals," and "serial offenders." The interest in these criminals is a rational one, given the perception that they present a severe threat to society. The main challenge in this area of research is a conceptual problem that has significant effects across the field. To this day, scholars have reused and misused titles to define and explain different concepts. The aim of this article is 3-fold. First, to review the concepts of criminal career, professional crime, habitual offenses, and seriality with a critical attitude on confusing terms. Second, to propose the redefinition of concepts mentioned previously, mainly on the criminal career. Third, to propose a theoretical model to enable a better understanding of, and serve as a basis for, further research in this important area of criminology. © The Author(s) 2015.

  6. Automated detection of multiple sclerosis lesions in serial brain MRI

    International Nuclear Information System (INIS)

    Llado, Xavier; Ganiler, Onur; Oliver, Arnau; Marti, Robert; Freixenet, Jordi; Valls, Laia; Vilanova, Joan C.; Ramio-Torrenta, Lluis; Rovira, Alex

    2012-01-01

    Multiple sclerosis (MS) is a serious disease typically occurring in the brain whose diagnosis and efficacy of treatment monitoring are vital. Magnetic resonance imaging (MRI) is frequently used in serial brain imaging due to the rich and detailed information provided. Time-series analysis of images is widely used for MS diagnosis and patient follow-up. However, conventional manual methods are time-consuming, subjective, and error-prone. Thus, the development of automated techniques for the detection and quantification of MS lesions is a major challenge. This paper presents an up-to-date review of the approaches which deal with the time-series analysis of brain MRI for detecting active MS lesions and quantifying lesion load change. We provide a comprehensive reference source for researchers in which several approaches to change detection and quantification of MS lesions are investigated and classified. We also analyze the results provided by the approaches, discuss open problems, and point out possible future trends. Lesion detection approaches are required for the detection of static lesions and for diagnostic purposes, while either quantification of detected lesions or change detection algorithms are needed to follow up MS patients. However, there is not yet a single approach that can emerge as a standard for the clinical practice, automatically providing an accurate MS lesion evolution quantification. Future trends will focus on combining the lesion detection in single studies with the analysis of the change detection in serial MRI. (orig.)

  7. Serial album validation for promotion of infant body weight control

    Directory of Open Access Journals (Sweden)

    Nathalia Costa Gonzaga Saraiva

    2018-05-01

    Full Text Available ABSTRACT Objective: to validate the content and appearance of a serial album for children aged from 7 to 10 years addressing the topic of prevention and control of body weight. Method: methodological study with descriptive nature. The validation process was attended by 33 specialists in educational technologies and/or in excess of infantile weight. The agreement index of 80% was the minimum considered to guarantee the validation of the material. Results: most of the specialists had a doctoral degree and a graduate degree in nursing. Regarding content, illustrations, layout and relevance, all items were validated and 69.7% of the experts considered the album as great. The overall agreement validation index for the educational technology was 0.88. Only the script-sheet 3 did not reach the cutoff point of the content validation index. Changes were made to the material, such as title change, inclusion of the school context and insertion of nutritionist and physical educator in the story narrated in the album. Conclusion: the proposed serial album was considered valid by experts regarding content and appearance, suggesting that this technology has the potential to contribute in health education by promoting healthy weight in the age group of 7 to 10 years.

  8. Forgetting in immediate serial recall: decay, temporal distinctiveness, or interference?

    Science.gov (United States)

    Oberauer, Klaus; Lewandowsky, Stephan

    2008-07-01

    Three hypotheses of forgetting from immediate memory were tested: time-based decay, decreasing temporal distinctiveness, and interference. The hypotheses were represented by 3 models of serial recall: the primacy model, the SIMPLE (scale-independent memory, perception, and learning) model, and the SOB (serial order in a box) model, respectively. The models were fit to 2 experiments investigating the effect of filled delays between items at encoding or at recall. Short delays between items, filled with articulatory suppression, led to massive impairment of memory relative to a no-delay baseline. Extending the delays had little additional effect, suggesting that the passage of time alone does not cause forgetting. Adding a choice reaction task in the delay periods to block attention-based rehearsal did not change these results. The interference-based SOB fit the data best; the primacy model overpredicted the effect of lengthening delays, and SIMPLE was unable to explain the effect of delays at encoding. The authors conclude that purely temporal views of forgetting are inadequate. Copyright (c) 2008 APA, all rights reserved.

  9. Automated detection of multiple sclerosis lesions in serial brain MRI

    Energy Technology Data Exchange (ETDEWEB)

    Llado, Xavier; Ganiler, Onur; Oliver, Arnau; Marti, Robert; Freixenet, Jordi [University of Girona, Computer Vision and Robotics Group, Girona (Spain); Valls, Laia [Dr. Josep Trueta University Hospital, Department of Radiology, Girona (Spain); Vilanova, Joan C. [Girona Magnetic Resonance Center, Girona (Spain); Ramio-Torrenta, Lluis [Dr. Josep Trueta University Hospital, Institut d' Investigacio Biomedica de Girona, Multiple Sclerosis and Neuroimmunology Unit, Girona (Spain); Rovira, Alex [Vall d' Hebron University Hospital, Magnetic Resonance Unit, Department of Radiology, Barcelona (Spain)

    2012-08-15

    Multiple sclerosis (MS) is a serious disease typically occurring in the brain whose diagnosis and efficacy of treatment monitoring are vital. Magnetic resonance imaging (MRI) is frequently used in serial brain imaging due to the rich and detailed information provided. Time-series analysis of images is widely used for MS diagnosis and patient follow-up. However, conventional manual methods are time-consuming, subjective, and error-prone. Thus, the development of automated techniques for the detection and quantification of MS lesions is a major challenge. This paper presents an up-to-date review of the approaches which deal with the time-series analysis of brain MRI for detecting active MS lesions and quantifying lesion load change. We provide a comprehensive reference source for researchers in which several approaches to change detection and quantification of MS lesions are investigated and classified. We also analyze the results provided by the approaches, discuss open problems, and point out possible future trends. Lesion detection approaches are required for the detection of static lesions and for diagnostic purposes, while either quantification of detected lesions or change detection algorithms are needed to follow up MS patients. However, there is not yet a single approach that can emerge as a standard for the clinical practice, automatically providing an accurate MS lesion evolution quantification. Future trends will focus on combining the lesion detection in single studies with the analysis of the change detection in serial MRI. (orig.)

  10. Serial sectioning methods for 3D investigations in materials science.

    Science.gov (United States)

    Zankel, Armin; Wagner, Julian; Poelt, Peter

    2014-07-01

    A variety of methods for the investigation and 3D representation of the inner structure of materials has been developed. In this paper, techniques based on slice and view using scanning microscopy for imaging are presented and compared. Three different methods of serial sectioning combined with either scanning electron or scanning ion microscopy or atomic force microscopy (AFM) were placed under scrutiny: serial block-face scanning electron microscopy, which facilitates an ultramicrotome built into the chamber of a variable pressure scanning electron microscope; three-dimensional (3D) AFM, which combines an (cryo-) ultramicrotome with an atomic force microscope, and 3D FIB, which delivers results by slicing with a focused ion beam. These three methods complement one another in many respects, e.g., in the type of materials that can be investigated, the resolution that can be obtained and the information that can be extracted from 3D reconstructions. A detailed review is given about preparation, the slice and view process itself, and the limitations of the methods and possible artifacts. Applications for each technique are also provided. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Working memory capacity and controlled serial memory search.

    Science.gov (United States)

    Mızrak, Eda; Öztekin, Ilke

    2016-08-01

    The speed-accuracy trade-off (SAT) procedure was used to investigate the relationship between working memory capacity (WMC) and the dynamics of temporal order memory retrieval. High- and low-span participants (HSs, LSs) studied sequentially presented five-item lists, followed by two probes from the study list. Participants indicated the more recent probe. Overall, accuracy was higher for HSs compared to LSs. Crucially, in contrast to previous investigations that observed no impact of WMC on speed of access to item information in memory (e.g., Öztekin & McElree, 2010), recovery of temporal order memory was slower for LSs. While accessing an item's representation in memory can be direct, recovery of relational information such as temporal order information requires a more controlled serial memory search. Collectively, these data indicate that WMC effects are particularly prominent during high demands of cognitive control, such as serial search operations necessary to access temporal order information from memory. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Improved Software to Browse the Serial Medical Images for Learning.

    Science.gov (United States)

    Kwon, Koojoo; Chung, Min Suk; Park, Jin Seo; Shin, Byeong Seok; Chung, Beom Sun

    2017-07-01

    The thousands of serial images used for medical pedagogy cannot be included in a printed book; they also cannot be efficiently handled by ordinary image viewer software. The purpose of this study was to provide browsing software to grasp serial medical images efficiently. The primary function of the newly programmed software was to select images using 3 types of interfaces: buttons or a horizontal scroll bar, a vertical scroll bar, and a checkbox. The secondary function was to show the names of the structures that had been outlined on the images. To confirm the functions of the software, 3 different types of image data of cadavers (sectioned and outlined images, volume models of the stomach, and photos of the dissected knees) were inputted. The browsing software was downloadable for free from the homepage (anatomy.co.kr) and available off-line. The data sets provided could be replaced by any developers for their educational achievements. We anticipate that the software will contribute to medical education by allowing users to browse a variety of images. © 2017 The Korean Academy of Medical Sciences.

  13. Volume imaging NDE and serial sectioning of carbon fiber composites

    Science.gov (United States)

    Hakim, Issa; Schumacher, David; Sundar, Veeraraghavan; Donaldson, Steven; Creuz, Aline; Schneider, Rainer; Keller, Juergen; Browning, Charles; May, Daniel; Ras, Mohamad Abo; Meyendorf, Norbert

    2018-04-01

    A composite material is a combination of two or more materials with very different mechanical, thermal and electrical properties. The various forms of composite materials, due to their high material properties, are widely used as structural materials in the aviation, space, marine, automobile, and sports industries. However, some defects like voids, delamination, or inhomogeneous fiber distribution that form during the fabricating processes of composites can seriously affect the mechanical properties of the composite material. In this study, several imaging NDE techniques such as: thermography, high frequency eddy current, ultrasonic, x-ray radiography, x-ray laminography, and high resolution x-ray CT were conducted to characterize the microstructure of carbon fiber composites. Then, a 3D analysis was implemented by the destructive technique of serial sectioning for the same sample tested by the NDE methods. To better analyze the results of this work and extract a clear volume image for all features and defects contained in the composite material, an intensive comparison was conducted among hundreds of 3D-NDE and multi serial sections' scan images showing the microstructure variation.

  14. Nonlinear Process Fault Diagnosis Based on Serial Principal Component Analysis.

    Science.gov (United States)

    Deng, Xiaogang; Tian, Xuemin; Chen, Sheng; Harris, Chris J

    2018-03-01

    Many industrial processes contain both linear and nonlinear parts, and kernel principal component analysis (KPCA), widely used in nonlinear process monitoring, may not offer the most effective means for dealing with these nonlinear processes. This paper proposes a new hybrid linear-nonlinear statistical modeling approach for nonlinear process monitoring by closely integrating linear principal component analysis (PCA) and nonlinear KPCA using a serial model structure, which we refer to as serial PCA (SPCA). Specifically, PCA is first applied to extract PCs as linear features, and to decompose the data into the PC subspace and residual subspace (RS). Then, KPCA is performed in the RS to extract the nonlinear PCs as nonlinear features. Two monitoring statistics are constructed for fault detection, based on both the linear and nonlinear features extracted by the proposed SPCA. To effectively perform fault identification after a fault is detected, an SPCA similarity factor method is built for fault recognition, which fuses both the linear and nonlinear features. Unlike PCA and KPCA, the proposed method takes into account both linear and nonlinear PCs simultaneously, and therefore, it can better exploit the underlying process's structure to enhance fault diagnosis performance. Two case studies involving a simulated nonlinear process and the benchmark Tennessee Eastman process demonstrate that the proposed SPCA approach is more effective than the existing state-of-the-art approach based on KPCA alone, in terms of nonlinear process fault detection and identification.

  15. In vivo serial sampling of epididymal sperm in mice.

    Science.gov (United States)

    Del Val, Gonzalo Moreno; Robledano, Patricia Muñoz

    2013-07-01

    This study was undertaken to refine the techniques of in vivo collection of sperm in the mouse. The principal objective was to offer a viable, safe and reliable method for serial collection of in vivo epididimary sperm through the direct puncture of the epididymis. Six C57Bl/6J males were subjected to the whole experiment. First we obtain a sperm sample of the right epididymis, and perform a vasectomy on the left side. This sample was used in an in vitro fertilization (IVF) experiment while the males were individually housed for 10 days to let them recover from the surgery, and then their fertility was tested with natural matings until we obtained a litter of each one. After that, the animals were subjected another time to the same process (sampling, recover and natural mating). The results of these experiments were a fertilization average value of 56.7%, and that all the males had a litter in the first month after the natural matings. This study documented the feasibility of the epididimary puncture technique to in vivo serial sampling of sperm in the mouse.

  16. Serial Contradictions. The Italian Debate on Tv Series

    Directory of Open Access Journals (Sweden)

    Daniela Cardini

    2016-06-01

    Full Text Available In the last decade the academic debate on television seriality has become lively and often quite animated, in the US as well as in Italy. The traditional hierarchic relation between cinema and television is clearly represented by the form of the most recent tv drama, whose boundaries are more and more difficult to locate. The main questions at stake seem to be the so-called “cinematic television” (Mills, 2013; Jaramillo, 2013, the umbrella definition of “quality tv” (McCabe and Akass, 2007 and its relation with the broadest concept of “complex tv” (Mittell, 2009, 2015. The essay will take into consideration these oxymorons, which are deeply rooted in the Italian tv series debate, with the aim of considering both their risks and their opportunities. A great variety of texts are grouped under the “tv series” label, but they are very different as far as content, production values and audience reactions are concerned. The academic discourse, however, only recently has tried to identify the differences between longstanding mainstream shows (such as, for instance, Grey’s Anatomy or CSI and some more recent, and supposedly “cinematic” series like True Detective or Fargo. Together with the analysis of the oxymoric nature of recent television seriality, the essay will explore the need to historicising what is proving to be one of the most dense and fruitful domains of recent television studies.

  17. Forgiveness and Suicidal Behavior: Cynicism and Psychache as Serial Mediators.

    Science.gov (United States)

    Dangel, Trever J; Webb, Jon R; Hirsch, Jameson K

    2018-02-17

    Research is burgeoning regarding the beneficial association of forgiveness with numerous health-related outcomes; however, its particular relationship to suicidal behavior has received relatively little attention. Both cynicism and psychache, or agonizing psychological pain, have displayed deleterious associations with suicidal behavior, but have rarely been incorporated into more comprehensive models of suicidal behavior. Consistent with the recent development of a theoretical model regarding the forgiveness-suicidal behavior association, the present study utilized an undergraduate sample of college students (N = 312) to test a mediation-based model of the cross-sectional association of forgiveness with suicidal behavior, as serially mediated by cynicism and psychache. Dispositional forgiveness of self and forgiveness of uncontrollable situations were each indirectly associated with less suicidal behavior via less psychache. Also, dispositional forgiveness of others was indirectly associated with less suicidal behavior via less cynicism and less psychache, in a serial fashion. The present results are consistent with the extent literature on the forgiveness-suicidal behavior association, cynicism, and psychache, and pending future studies, may be utilized to inform further treatment efforts for individuals at a high risk of attempting suicide.

  18. Injection Methods and Instrumentation for Serial X-ray Free Electron Laser Experiments

    Science.gov (United States)

    James, Daniel

    Scientists have used X-rays to study biological molecules for nearly a century. Now with the X-ray free electron laser (XFEL), new methods have been developed to advance structural biology. These new methods include serial femtosecond crystallography, single particle imaging, solution scattering, and time resolved techniques. The XFEL is characterized by high intensity pulses, which are only about 50 femtoseconds in duration. The intensity allows for scattering from microscopic particles, while the short pulses offer a way to outrun radiation damage. XFELs are powerful enough to obliterate most samples in a single pulse. While this allows for a "diffract and destroy" methodology, it also requires instrumentation that can position microscopic particles into the X-ray beam (which may also be microscopic), continuously renew the sample after each pulse, and maintain sample viability during data collection. Typically these experiments have used liquid microjets to continuously renew sample. The high flow rate associated with liquid microjets requires large amounts of sample, most of which runs to waste between pulses. An injector designed to stream a viscous gel-like material called lipidic cubic phase (LCP) was developed to address this problem. LCP, commonly used as a growth medium for membrane protein crystals, lends itself to low flow rate jetting and so reduces the amount of sample wasted significantly. This work discusses sample delivery and injection for XFEL experiments. It reviews the liquid microjet method extensively, and presents the LCP injector as a novel device for serial crystallography, including detailed protocols for the LCP injector and anti-settler operation.

  19. Evaluation of Esophageal Anastomotic Integrity With Serial Pleural Amylase Levels.

    Science.gov (United States)

    Miller, Daniel L; Helms, Gerald A; Mayfield, William R

    2018-01-01

    An anastomotic leak is the most devastating and potentially fatal complication after esophagectomy. Current detection methods can be inaccurate and place patients at risk of other complications. Analysis of pleural fluid for amylase may be more accurate and place patients at less of a risk for evaluating the integrity of an esophageal anastomosis. We retrospectively reviewed prospective data of 45 consecutive patients who underwent an Ivor Lewis esophagectomy over an 18-month period and evaluated their anastomotic integrity with serial pleural amylase levels (PAL). There were 40 men (89%), and median age was 63 years (range, 35 to 79). Indication for esophagectomy was cancer in 38 patients (84%); 27 (71%) underwent neoadjuvant chemoradiation. A barium swallow was performed in the first 25 patients at median postoperative day (POD) 5 (range, 5 to 10); the swallow was negative in 23 patients (93%). Serial PALs were obtained starting on POD 3 and stopped 1 day after toleration of clear liquids. The PALs in the no-leak patients were highest on POD 3 (median 42 IU/L; range, 20 to 102 IU/L) and decreased (median 15 IU/L; range, 8 to 34 IU/L) to the lowest levels 1 day after clear liquid toleration (p = 0.04). Two patients had a leak and had peak PALs of 227 IU/L and 630 IU/L, respectively; both leaks occurred on POD 4, 1 day before their scheduled swallow test. The last 20 patients underwent serial PALs only, without a planned swallow test or computed tomography scan for anastomotic integrity evaluation. One of these patients had a leak on POD 5 with a low PAL of 55 IU/L the day before the spike of more than 4,000 IU/L. Two of the leaks were treated with esophageal stent placement and intravenous antibiotics, and the remaining patient's leak resolved with intravenous antibiotics, no oral intake, and observation only. None of the leak patients required transthoracic esophageal repair or drainage of an empyema. There was 1 postoperative death (2%) secondary to aspiration

  20. Serial-order short-term memory predicts vocabulary development: evidence from a longitudinal study.

    Science.gov (United States)

    Leclercq, Anne-Lise; Majerus, Steve

    2010-03-01

    Serial-order short-term memory (STM), as opposed to item STM, has been shown to be very consistently associated with lexical learning abilities in cross-sectional study designs. This study investigated longitudinal predictions between serial-order STM and vocabulary development. Tasks maximizing the temporary retention of either serial-order or item information were administered to kindergarten children aged 4 and 5. At age 4, age 5, and from age 4 to age 5, serial-order STM capacities, but not item STM capacities, were specifically associated with vocabulary development. Moreover, the increase of serial-order STM capacity from age 4 to age 5 predicted the increase of vocabulary knowledge over the same time period. These results support a theoretical position that assumes an important role for serial-order STM capacities in vocabulary acquisition.

  1. Identification of novel putative-binding proteins for cellular prion protein and a specific interaction with the STIP1 homology and U-Box-containing protein 1

    OpenAIRE

    Gimenez, Ana Paula Lappas; Richter, Larissa Morato Luciani; Atherino, Mariana Campos; Beirão, Breno Castello Branco; Fávaro, Celso; Costa, Michele Dietrich Moura; Zanata, Silvio Marques; Malnic, Bettina; Mercadante, Adriana Frohlich

    2015-01-01

    Prion diseases involve the conversion of the endogenous cellular prion protein, PrPC, into a misfolded infectious isoform, PrPSc. Several functions have been attributed to PrPC, and its role has also been investigated in the olfactory system. PrPC is expressed in both the olfactory bulb (OB) and olfactory epithelium (OE) and the nasal cavity is an important route of transmission of diseases caused by prions. Moreover, Prnp−/− mice showed impaired behavior in olfactory tests. Given the high Pr...

  2. Pharmacological chaperone reshapes the energy landscape for folding and aggregation of the prion protein

    Science.gov (United States)

    Gupta, Amar Nath; Neupane, Krishna; Rezajooei, Negar; Cortez, Leonardo M.; Sim, Valerie L.; Woodside, Michael T.

    2016-06-01

    The development of small-molecule pharmacological chaperones as therapeutics for protein misfolding diseases has proven challenging, partly because their mechanism of action remains unclear. Here we study Fe-TMPyP, a tetrapyrrole that binds to the prion protein PrP and inhibits misfolding, examining its effects on PrP folding at the single-molecule level with force spectroscopy. Single PrP molecules are unfolded with and without Fe-TMPyP present using optical tweezers. Ligand binding to the native structure increases the unfolding force significantly and alters the transition state for unfolding, making it more brittle and raising the barrier height. Fe-TMPyP also binds the unfolded state, delaying native refolding. Furthermore, Fe-TMPyP binding blocks the formation of a stable misfolded dimer by interfering with intermolecular interactions, acting in a similar manner to some molecular chaperones. The ligand thus promotes native folding by stabilizing the native state while also suppressing interactions driving aggregation.

  3. Smart grid communication comparison: Distributed control middleware and serialization comparison for the Internet of Things

    DEFF Research Database (Denmark)

    Petersen, Bo Søborg; Bindner, Henrik W.; Poulsen, Bjarne

    2017-01-01

    To solve the problems caused by intermittent renewable energy production, communication between Distributed Energy Resources (DERs) and system operators is necessary. The communication middleware and serialization used for communication are essential to ensure delivery of the messages within...... communication middleware and serialization format/library, aided by the authors' earlier work, which investigates the performance and characteristics of communication middleware and serialization independently. Given the performance criteria of the paper, ZeroMQ, YAMI4, and ICE are the middleware that performs...

  4. The Organized/Disorganized Typology of Serial Murder: Myth or Model?

    OpenAIRE

    Canter, David V.; Alison, Laurence J.; Alison, Emily; Wentink, Natalia

    2004-01-01

    Despite weaknesses in the organized/disorganized classification of serial killers, it is drawn on for "offender profiles," theories of offending, and in murder trials. This dichotomy was therefore tested by the multidimensional scaling of the co-occurrence of 39 aspects of serial killings derived 100 murders committed by 100 U.S. serial killers. Results revealed no distinct subsets of offense characteristics reflecting the dichotomy. They showed a subset of organized features typical of most ...

  5. The mitochondrial translocator protein, TSPO, inhibits HIV-1 envelope glycoprotein biosynthesis via the endoplasmic reticulum-associated protein degradation pathway.

    Science.gov (United States)

    Zhou, Tao; Dang, Ying; Zheng, Yong-Hui

    2014-03-01

    The HIV-1 Env glycoprotein is folded in the endoplasmic reticulum (ER), which is necessary for viral entry and replication. Currently, it is still unclear how this process is regulated. The glycoprotein folding in the ER is controlled by the ER-associated protein degradation (ERAD) pathway, which specifically targets misfolded proteins for degradation. Previously, we reported that HIV-1 replication is restricted in the human CD4(+) T cell line CEM.NKR (NKR). To understand this mechanism, we first analyzed cellular protein expression in NKR cells and discovered that levels of the mitochondrial translocator protein TSPO were upregulated by ∼64-fold. Notably, when NKR cells were treated with TSPO antagonist PK-11195, Ro5-4864, or diazepam, HIV restriction was completely disrupted, and TSPO knockdown by short hairpin RNAs (shRNAs) achieved a similar effect. We next analyzed viral protein expression, and, interestingly, we discovered that Env expression was specifically inhibited. Both TSPO knockdown and treatment with TSPO antagonist could restore Env expression in NKR cells. We further discovered that Env proteins were rapidly degraded and that kifunensine, an ERAD pathway inhibitor, could restore Env expression and viral replication, indicating that Env proteins were misfolded and degraded through the ERAD pathway in NKR cells. We also knocked out the TSPO gene in 293T cells using CRISPR/Cas9 (clustered, regularly interspaced, short palindromic repeat [CRISPR]/CRISPR-associated-9) technology and found that TSPO could similarly inhibit Env expression in these cells. Taken together, these results demonstrate that TSPO inhibits Env protein expression through the ERAD pathway and suggest that mitochondria play an important role in regulating the Env folding process. The HIV-1 Env glycoprotein is absolutely required for viral infection, and an understanding of its expression pathway in infected cells will identify new targets for antiretroviral therapies. Env proteins

  6. A comparison of serial order short-term memory effects across verbal and musical domains.

    Science.gov (United States)

    Gorin, Simon; Mengal, Pierre; Majerus, Steve

    2018-04-01

    Recent studies suggest that the mechanisms involved in the short-term retention of serial order information may be shared across short-term memory (STM) domains such as verbal and visuospatial STM. Given the intrinsic sequential organization of musical material, the study of STM for musical information may be particularly informative about serial order retention processes and their domain-generality. The present experiment examined serial order STM for verbal and musical sequences in participants with no advanced musical expertise and experienced musicians. Serial order STM for verbal information was assessed via a serial order reconstruction task for digit sequences. In the musical domain, serial order STM was assessed using a novel melodic sequence reconstruction task maximizing the retention of tone order information. We observed that performance for the verbal and musical tasks was characterized by sequence length as well as primacy and recency effects. Serial order errors in both tasks were characterized by similar transposition gradients and ratios of fill-in:infill errors. These effects were observed for both participant groups, although the transposition gradients and ratios of fill-in:infill errors showed additional specificities for musician participants in the musical task. The data support domain-general serial order STM effects but also suggest the existence of additional domain-specific effects. Implications for models of serial order STM in verbal and musical domains are discussed.

  7. Respiratory epithelial cell responses to cigarette smoke: the unfolded protein response.

    Science.gov (United States)

    Kelsen, Steven G

    2012-12-01

    Cigarette smoking exposes the respiratory epithelium to highly toxic, reactive oxygen nitrogen species which damage lung proteins in the endoplasmic reticulum (ER), the cell organelle in which all secreted and membrane proteins are processed. Accumulation of damaged or misfolded proteins in the ER, a condition termed ER stress, activates a complex cellular process termed the unfolded protein responses (UPR). The UPR acts to restore cellular protein homeostasis by regulating all aspects of protein metabolism including: protein translation and syntheses; protein folding; and protein degradation. However, activation of the UPR may also induce signaling pathways which induce inflammation and cell apoptosis. This review discusses the role of UPR in the respiratory epithelial cell response to cigarette smoke and the pathogenesis of lung diseases like COPD. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Heat shock response improves heterologous protein secretion in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Hou, Jin; Österlund, Tobias; Liu, Zihe

    2013-01-01

    The yeast Saccharomyces cerevisiae is a widely used platform for the production of heterologous proteins of medical or industrial interest. However, heterologous protein productivity is often low due to limitations of the host strain. Heat shock response (HSR) is an inducible, global, cellular...... stress response, which facilitates the cell recovery from many forms of stress, e.g., heat stress. In S. cerevisiae, HSR is regulated mainly by the transcription factor heat shock factor (Hsf1p) and many of its targets are genes coding for molecular chaperones that promote protein folding and prevent...... the accumulation of mis-folded or aggregated proteins. In this work, we over-expressed a mutant HSF1 gene HSF1-R206S which can constitutively activate HSR, so the heat shock response was induced at different levels, and we studied the impact of HSR on heterologous protein secretion. We found that moderate and high...

  9. Heat shock protein 72: release and biological significance during exercise.

    Science.gov (United States)

    Whitham, Martin; Fortes, Matthew Benjamin

    2008-01-01

    The cumulative stressors of exercise manifest themselves at a cellular level by threatening the protein homeostasis of the cell. In these conditions, Heat Shock Proteins (HSP) are synthesised to chaperone mis-folded and denatured proteins. As such, the intracellular HSP response is thought to aid cell survival in the face of otherwise lethal cellular stress. Recently, the inducible isoform of the 70 Kda heat shock protein family, Hsp72 has been detected in the extracellular environment. Furthermore, the release of this protein into the circulation has been shown to occur in response to a range of exercise bouts. The present review summarises the current research on the exercise Hsp72 response, the possible mediators and mechanisms of extracellular (e)Hsp72 release, and the possible biological significance of this systemic response. In particular, the possible role of eHsp72 in the modulation of immunity during exercise is discussed.

  10. Closed-Loop Analysis of Soft Decisions for Serial Links

    Science.gov (United States)

    Lansdowne, Chatwin A.; Steele, Glen F.; Zucha, Joan P.; Schlesinger, Adam M.

    2013-01-01

    We describe the benefit of using closed-loop measurements for a radio receiver paired with a counterpart transmitter. We show that real-time analysis of the soft decision output of a receiver can provide rich and relevant insight far beyond the traditional hard-decision bit error rate (BER) test statistic. We describe a Soft Decision Analyzer (SDA) implementation for closed-loop measurements on single- or dual- (orthogonal) channel serial data communication links. The analyzer has been used to identify, quantify, and prioritize contributors to implementation loss in live-time during the development of software defined radios. This test technique gains importance as modern receivers are providing soft decision symbol synchronization as radio links are challenged to push more data and more protocol overhead through noisier channels, and software-defined radios (SDRs) use error-correction codes that approach Shannon's theoretical limit of performance.

  11. Serial ultrasonographic appearance of postpartum uterine involution in beagle dogs.

    Science.gov (United States)

    Yeager, A E; Concannon, P W

    1990-09-01

    Postpartum changes in uterine shape, architecture, echogenicity and diameter were determined during the serial examinations of five beagle bitches. During postpartum Week 1, the uterine horns were tubular structures composed of multiple layers of various echogenicity and had multiple, discrete enlargements with hypoechoic centers at placental sites. Diameters ranged from 1.1 to 3.8 cm at placental site enlargements, and 0.5 to 1.4 cm between enlargements. Uterine involution appeared to be completed by 15 wk post partum. At 15 weeks the uterine horns of each dog were uniform hypoechoic, tubular structures without enlargements and had a reduced diameter of 0.3 to 0.6 cm. These ultrasonographic findings are similar to previously reported gross and light microscopic descriptions of canine uterine involution.

  12. The primacy model: a new model of immediate serial recall.

    Science.gov (United States)

    Page, M P; Norris, D

    1998-10-01

    A new model of immediate serial recall is presented: the primacy model. The primacy model stores order information by means of the assumption that the strength of activation of successive list items decreases across list position to form a primacy gradient. Ordered recall is supported by a repeated cycle of operations involving a noisy choice of the most active item followed by suppression of the chosen item. Word-length and list-length effects are attributed to a decay process that occurs both during input, when effective rehearsal is prevented, and during output. The phonological similarity effect is attributed to a second stage of processing at which phonological confusions occur. The primacy model produces accurate simulations of the effects of word length, list length, and phonological similarity.

  13. Analysis of XFEL serial diffraction data from individual crystalline fibrils

    Directory of Open Access Journals (Sweden)

    David H. Wojtas

    2017-11-01

    Full Text Available Serial diffraction data collected at the Linac Coherent Light Source from crystalline amyloid fibrils delivered in a liquid jet show that the fibrils are well oriented in the jet. At low fibril concentrations, diffraction patterns are recorded from single fibrils; these patterns are weak and contain only a few reflections. Methods are developed for determining the orientation of patterns in reciprocal space and merging them in three dimensions. This allows the individual structure amplitudes to be calculated, thus overcoming the limitations of orientation and cylindrical averaging in conventional fibre diffraction analysis. The advantages of this technique should allow structural studies of fibrous systems in biology that are inaccessible using existing techniques.

  14. Modelling and Forecasting Stock Price Movements with Serially Dependent Determinants

    Directory of Open Access Journals (Sweden)

    Rasika Yatigammana

    2018-05-01

    Full Text Available The direction of price movements are analysed under an ordered probit framework, recognising the importance of accounting for discreteness in price changes. By extending the work of Hausman et al. (1972 and Yang and Parwada (2012,This paper focuses on improving the forecast performance of the model while infusing a more practical perspective by enhancing flexibility. This is achieved by extending the existing framework to generate short term multi period ahead forecasts for better decision making, whilst considering the serial dependence structure. This approach enhances the flexibility and adaptability of the model to future price changes, particularly targeting risk minimisation. Empirical evidence is provided, based on seven stocks listed on the Australian Securities Exchange (ASX. The prediction success varies between 78 and 91 per cent for in-sample and out-of-sample forecasts for both the short term and long term.

  15. Whole brain imaging with Serial Two-Photon Tomography

    Directory of Open Access Journals (Sweden)

    Stephen P Amato

    2016-03-01

    Full Text Available Imaging entire mouse brains at submicron resolution has historically been a challenging undertaking and largely confined to the province of dedicated atlasing initiatives. The has limited systematic investigations into important areas of neuroscience, such as neural circuits, brain mapping and neurodegeneration. In this paper, we describe in detail Serial Two-Photon (STP tomography, a robust, reliable method for imaging entire brains with histological detail. We provide examples of how the basic methodology can be extended to other imaging modalities, such as optical coherence tomography, in order to provide unique contrast mechanisms. Furthermore we provide a survey of the research that STP tomography has enabled in the field of neuroscience, provide examples of how this technology enables quantitative whole brain studies, and discuss the current limitations of STP tomography-based approaches

  16. New method for designing serial resonant power converters

    Science.gov (United States)

    Hinov, Nikolay

    2017-12-01

    In current work is presented one comprehensive method for design of serial resonant energy converters. The method is based on new simplified approach in analysis of such kind power electronic devices. It is grounded on supposing resonant mode of operation when finding relation between input and output voltage regardless of other operational modes (when controlling frequency is below or above resonant frequency). This approach is named `quasiresonant method of analysis', because it is based on assuming that all operational modes are `sort of' resonant modes. An estimation of error was made because of the a.m. hypothesis and is compared to the classic analysis. The `quasiresonant method' of analysis gains two main advantages: speed and easiness in designing of presented power circuits. Hence it is very useful in practice and in teaching Power Electronics. Its applicability is proven with mathematic modelling and computer simulation.

  17. Split-plot designs for robotic serial dilution assays.

    Science.gov (United States)

    Buzas, Jeffrey S; Wager, Carrie G; Lansky, David M

    2011-12-01

    This article explores effective implementation of split-plot designs in serial dilution bioassay using robots. We show that the shortest path for a robot to fill plate wells for a split-plot design is equivalent to the shortest common supersequence problem in combinatorics. We develop an algorithm for finding the shortest common supersequence, provide an R implementation, and explore the distribution of the number of steps required to implement split-plot designs for bioassay through simulation. We also show how to construct collections of split plots that can be filled in a minimal number of steps, thereby demonstrating that split-plot designs can be implemented with nearly the same effort as strip-plot designs. Finally, we provide guidelines for modeling data that result from these designs. © 2011, The International Biometric Society.

  18. Continuous Heterogeneous Photocatalysis in Serial Micro-Batch Reactors.

    Science.gov (United States)

    Pieber, Bartholomäus; Shalom, Menny; Antonietti, Markus; Seeberger, Peter H; Gilmore, Kerry

    2018-01-29

    Solid reagents, leaching catalysts, and heterogeneous photocatalysts are commonly employed in batch processes but are ill-suited for continuous-flow chemistry. Heterogeneous catalysts for thermal reactions are typically used in packed-bed reactors, which cannot be penetrated by light and thus are not suitable for photocatalytic reactions involving solids. We demonstrate that serial micro-batch reactors (SMBRs) allow for the continuous utilization of solid materials together with liquids and gases in flow. This technology was utilized to develop selective and efficient fluorination reactions using a modified graphitic carbon nitride heterogeneous catalyst instead of costly homogeneous metal polypyridyl complexes. The merger of this inexpensive, recyclable catalyst and the SMBR approach enables sustainable and scalable photocatalysis. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Cinema 4D Dalam Pipeline Produksi Serial Animasi

    Directory of Open Access Journals (Sweden)

    Ardiyansah Ardiyansah

    2011-04-01

    Full Text Available Cinema 4D is best known as software that is efficient in render time. This is very beneficial especially for those who engaged in animated projects with tight deadlines and require work time efficiency, such as serial project. In addition to time, in the animated series production pipeline also generally require various items of work that involves a lot of resources implemented in parallel. This is to avoid delays to the overall project progress whenever a work item suffers setback due to any reason. Cinema 4D as a tool, allowing a project carried out with the most efficient method in accordance with needs, and flexibility that is the appeal of Cinema 4D as well as strength in the context of the animated series production. 

  20. Cortical laminar necrosis in brain infarcts: serial MRI

    Energy Technology Data Exchange (ETDEWEB)

    Siskas, N.; Lefkopoulos, A.; Ioannidis, I.; Charitandi, A.; Dimitriadis, A.S. [Radiology Department, AHEPA University Hospital, Aristotele University of Thessaloniki (Greece)

    2003-05-01

    High-signal cortical lesions are observed on T1-weighted images in cases of brain infarct. Histological examination has demonstrated these to be ''cortical laminar necrosis'', without haemorrhage or calcification. We report serial MRI in this condition in 12 patients with brain infarcts. We looked at high-signal lesions on T1-weighted images, chronological changes in signal intensity and contrast enhancement. High-signal cortical lesions began to appear about 2 weeks after the ictus, were prominent at 1 - 2 months, then became less evident, but occasionally remained for up to 1.5 years. They gave high signal or were isointense on T2-weighted images and did not give low signal at any stage. Contrast enhancement of these lesions was prominent at 1 - 2 months, and less apparent from 3 months, but was seen up to 5 months. (orig.)

  1. Unequal Input Voltages Distribution Between the Serial Connected Halfbridges

    Directory of Open Access Journals (Sweden)

    Radovan Ovcarcik

    2006-01-01

    Full Text Available This paper describes a topology of DC-DC converter consisting in two serial connected half-bridges. Secondary circuit is realized like a conventional full-wave rectifier. The main advantage of this topology is the possibility of dividing the input voltage between the half-bridges. The converter is controlled using the phase-shift modulation, which allows a ZVSoperation mode. The voltage unbalance between the inputs causes an important problem of the presented topology. It is necessary to avoid it by the control algorithm, which is described in the text. The practical results show a zero voltage switching technique and the limits of the chosen topology and of the control.

  2. Linguistic ostracism causes prejudice: Support for a serial mediation effect.

    Science.gov (United States)

    Hitlan, Robert Thomas; A Zárate, Michael; Kelly, Kristine M; Catherine DeSoto, M

    2016-01-01

    This research investigated the effects of linguistic ostracism, defined as any communication setting in which a target individual (or group) is ostracized by another individual (or group) in a language that the target has extremely limited ability to understand. Participants were included or ostracized by their group members during a computer-mediated group discussion. Half of the ostracized participants were linguistically ostracized via their group members conversing with one another in a language the participant did not know well (Spanish Ostracism: SO), or in a language the participant did know well (English Ostracism: EO). SO participants reported feeling less similar than both included and EO participants. SO participants also reported being angrier and expressed more prejudice than included participants (and EO participants using effect size estimates). Results also provided support for the hypothesized serial mediation model. Findings are discussed in terms of implications for intergroup relations.

  3. Serial cultivation of human scalp hair follicle keratinocytes.

    Science.gov (United States)

    Weterings, P J; Roelofs, H M; Vermorken, A J; Bloemendal, H

    1983-01-01

    A method is described for the serial cultivation of adult human hair follicle keratinocytes. Plucked scalp hair follicles, placed on bovine eye lens capsules as a growth substrate, give rise to quickly expanding colonies within a few days. After trypsinization, the cells are replated with irradiated 3T3 cells as 'feeders'. Using this combination of techniques the keratinocytes can be subcultured up to four times. In this way about 10(7) keratinocytes can be generated from one single hair follicle. Moreover, the technique enables cryogenic storage of the cells, allowing for instance, convenient transportation. Subcultured hair follicle keratinocytes can be plated on glass coverslips. This allows immunofluorescence studies. The keratin cytoskeletons visualized using an antiserum against human keratin.

  4. Serialization and persistent objects turning data structures into efficient databases

    CERN Document Server

    Soukup, Jiri

    2014-01-01

    Recently, the pressure for fast processing and efficient storage of large data with complex?relations increased beyond the capability of traditional databases. Typical examples include iPhone applications, computer aided design - both electrical and mechanical, biochemistry applications, and incremental compilers. Serialization, which is sometimes used in such situations is notoriously tedious and error prone.In this book, Jiri Soukup and Petr Macha?ek show in detail how to write programs which store their internal data automatically and transparently to disk. Together with special data structure libraries which treat relations among objects as first-class entities, and with a UML class-diagram generator, the core application code is much simplified. The benchmark chapter shows a typical example where persistent data is faster by the order of magnitude than with a traditional database, in both traversing and accessing the data.The authors explore and exploit advanced features of object-oriented languages in a...

  5. Bit-Serial Adder Based on Quantum Dots

    Science.gov (United States)

    Fijany, Amir; Toomarian, Nikzad; Modarress, Katayoon; Spotnitz, Mathew

    2003-01-01

    A proposed integrated circuit based on quantum-dot cellular automata (QCA) would function as a bit-serial adder. This circuit would serve as a prototype building block for demonstrating the feasibility of quantum-dots computing and for the further development of increasingly complex and increasingly capable quantum-dots computing circuits. QCA-based bit-serial adders would be especially useful in that they would enable the development of highly parallel and systolic processors for implementing fast Fourier, cosine, Hartley, and wavelet transforms. The proposed circuit would complement the QCA-based circuits described in "Implementing Permutation Matrices by Use of Quantum Dots" (NPO-20801), NASA Tech Briefs, Vol. 25, No. 10 (October 2001), page 42 and "Compact Interconnection Networks Based on Quantum Dots" (NPO-20855), which appears elsewhere in this issue. Those articles described the limitations of very-large-scale-integrated (VLSI) circuitry and the major potential advantage afforded by QCA. To recapitulate: In a VLSI circuit, signal paths that are required not to interact with each other must not cross in the same plane. In contrast, for reasons too complex to describe in the limited space available for this article, suitably designed and operated QCA-based signal paths that are required not to interact with each other can nevertheless be allowed to cross each other in the same plane without adverse effect. In principle, this characteristic could be exploited to design compact, coplanar, simple (relative to VLSI) QCA-based networks to implement complex, advanced interconnection schemes. To enable a meaningful description of the proposed bit-serial adder, it is necessary to further recapitulate the description of a quantum-dot cellular automation from the first-mentioned prior article: A quantum-dot cellular automaton contains four quantum dots positioned at the corners of a square cell. The cell contains two extra mobile electrons that can tunnel (in the

  6. Depression and pain: testing of serial multiple mediators.

    Science.gov (United States)

    Wongpakaran, Tinakon; Wongpakaran, Nahathai; Tanchakvaranont, Sitthinant; Bookkamana, Putipong; Pinyopornpanish, Manee; Wannarit, Kamonporn; Satthapisit, Sirina; Nakawiro, Daochompu; Hiranyatheb, Thanita; Thongpibul, Kulvadee

    2016-01-01

    Despite the fact that pain is related to depression, few studies have been conducted to investigate the variables that mediate between the two conditions. In this study, the authors explored the following mediators: cognitive function, self-sacrificing interpersonal problems, and perception of stress, and the effects they had on pain symptoms among patients with depressive disorders. An analysis was performed on the data of 346 participants with unipolar depressive disorders. The 17-item Hamilton Depression Rating Scale, Mini-Mental State Examination, the pain subscale of the health-related quality of life (SF-36), the self-sacrificing subscale of the Inventory of Interpersonal Problems, and the Perceived Stress Scale were used. Parallel multiple mediator and serial multiple mediator models were used. An alternative model regarding the effect of self-sacrificing on pain was also proposed. Perceived stress, self-sacrificing interpersonal style, and cognitive function were found to significantly mediate the relationship between depression and pain, while controlling for demographic variables. The total effect of depression on pain was significant. This model, with an additional three mediators, accounted for 15% of the explained variance in pain compared to 9% without mediators. For the alternative model, after controlling for the mediators, a nonsignificant total direct effect level of self-sacrificing was found, suggesting that the effect of self-sacrificing on pain was based only on an indirect effect and that perceived stress was found to be the strongest mediator. Serial mediation may help us to see how depression and pain are linked and what the fundamental mediators are in the chain. No significant, indirect effect of self-sacrificing on pain was observed, if perceived stress was not part of the depression and/or cognitive function mediational chain. The results shown here have implications for future research, both in terms of testing the model and in

  7. Examining the relationship between free recall and immediate serial recall: the serial nature of recall and the effect of test expectancy.

    Science.gov (United States)

    Bhatarah, Parveen; Ward, Geoff; Tan, Lydia

    2008-01-01

    In two experiments, we examined the relationship between free recall and immediate serial recall (ISR), using a within-subjects (Experiment 1) and a between-subjects (Experiment 2) design. In both experiments, participants read aloud lists of eight words and were precued or postcued to respond using free recall or ISR. The serial position curves were U-shaped for free recall and showed extended primacy effects with little or no recency for ISR, and there was little or no difference between recall for the precued and the postcued conditions. Critically, analyses of the output order showed that although the participants started their recall from different list positions in the two tasks, the degree to which subsequent recall was serial in a forward order was strikingly similar. We argue that recalling in a serial forward order is a general characteristic of memory and that performance on ISR and free recall is underpinned by common memory mechanisms.

  8. Methamphetamine increases Prion Protein and induces dopamine-dependent expression of protease resistant PrPsc.

    Science.gov (United States)

    Ferrucci, M; Ryskalin, L; Biagioni, F; Gambardella, S; Busceti, C L; Falleni, A; Lazzeri, G; Fornai, F

    2017-07-01

    The cellular prion protein (PrPc) is physiologically expressed within selective brain areas of mammals. Alterations in the secondary structure of this protein lead to scrapie-like prion protein (PrPsc), which precipitates in the cell. PrPsc has been detected in infectious, inherited or sporadic neurodegenerative disorders. Prion protein metabolism is dependent on autophagy and ubiquitin proteasome. Despite not being fully elucidated, the physiological role of prion protein relates to chaperones which rescue cells under stressful conditions.Methamphetamine (METH) is a widely abused drug which produces oxidative stress in various brain areas causing mitochondrial alterations and protein misfolding. These effects produce a compensatory increase of chaperones while clogging cell clearing pathways. In the present study, we explored whether METH administration modifies the amount of PrPc. Since high levels of PrPc when the clearing systems are clogged may lead to its misfolding into PrPsc, we further tested whether METH exposure triggers the appearance of PrPsc. We analysed the effects of METH and dopamine administration in PC12 and striatal cells by using SDS-PAGE Coomassie blue, immune- histochemistry and immune-gold electron microscopy. To analyze whether METH administration produces PrPsc aggregates we used antibodies directed against PrP following exposure to proteinase K or sarkosyl which digest folded PrPc but misfolded PrPsc. We fond that METH triggers PrPsc aggregates in DA-containing cells while METH is not effective in primary striatal neurons which do not produce DA. In the latter cells exogenous DA is needed to trigger PrPsc accumulation similarly to what happens in DA containing cells under the effects of METH. The present findings, while fostering novel molecular mechanisms involving prion proteins, indicate that, cell pathology similar to prion disorders can be mimicked via a DA-dependent mechanism by a drug of abuse.

  9. Proteins aggregation and human diseases

    International Nuclear Information System (INIS)

    Hu, Chin-Kun

    2015-01-01

    Many human diseases and the death of most supercentenarians are related to protein aggregation. Neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), frontotemporallobar degeneration, etc. Such diseases are due to progressive loss of structure or function of neurons caused by protein aggregation. For example, AD is considered to be related to aggregation of Aβ40 (peptide with 40 amino acids) and Aβ42 (peptide with 42 amino acids) and HD is considered to be related to aggregation of polyQ (polyglutamine) peptides. In this paper, we briefly review our recent discovery of key factors for protein aggregation. We used a lattice model to study the aggregation rates of proteins and found that the probability for a protein sequence to appear in the conformation of the aggregated state can be used to determine the temperature at which proteins can aggregate most quickly. We used molecular dynamics and simple models of polymer chains to study relaxation and aggregation of proteins under various conditions and found that when the bending-angle dependent and torsion-angle dependent interactions are zero or very small, then protein chains tend to aggregate at lower temperatures. All atom models were used to identify a key peptide chain for the aggregation of insulin chains and to find that two polyQ chains prefer anti-parallel conformation. It is pointed out that in many cases, protein aggregation does not result from protein mis-folding. A potential drug from Chinese medicine was found for Alzheimer's disease. (paper)

  10. Dendrimer effects on peptide and protein fibrillation

    DEFF Research Database (Denmark)

    Heegaard, Peter M. H.; Boas, Ulrik; Otzen, Daniel E.

    2007-01-01

    involved in a range of serious and irreversibly progressive pathological conditions (protein-misfolding diseases). Interesting as this may be, the interaction of dendrimers with such generic peptidic aggregates also offers a new perspective on the molecular mechanisms governing assembly and disassembly......, they offer numerous possibilities for interactions with and responses to biological macromolecules and biostructures including cell membranes and proteins. By way of their multiple functional surface groups, they allow the design of surfaces carrying a multitude of biological motifs and/or charges giving...... rise to quite significant biological and physico-chemical effects. Here we describe the surprising ability of dendrimers to interact with and perturb polypeptide conformations, particularly efficiently towards amyloid structures; that is, the structures of highly insoluble polypeptide aggregates...

  11. The Locus of Serial Processing in Reading Aloud: Orthography-to-Phonology Computation or Speech Planning?

    Science.gov (United States)

    Mousikou, Petroula; Rastle, Kathleen; Besner, Derek; Coltheart, Max

    2015-01-01

    Dual-route theories of reading posit that a sublexical reading mechanism that operates serially and from left to right is involved in the orthography-to-phonology computation. These theories attribute the masked onset priming effect (MOPE) and the phonological Stroop effect (PSE) to the serial left-to-right operation of this mechanism. However,…

  12. The effects of nidopallium caudolaterale inactivation on serial-order behaviour in pigeons (Columba livia).

    Science.gov (United States)

    Johnston, Melissa Jane; Clarkson, Andrew N; Gowing, Emma K; Scarf, Damian; Colombo, Mike

    2018-06-06

    Serial-order behaviour is the ability to complete a sequence of responses in a predetermined order to achieve a reward. In birds, serial-order behaviour is thought to be impaired by damage to the nidopallium caudolaterale (NCL). In the current study, we examined the role of the NCL in serial-order behaviour by training pigeons on a 4-item serial-order task and a go/no-go discrimination task. Following training, pigeons were received infusions of 1μl of either tetrodotoxin (TTX) or saline. Saline infusions had no impact on serial-order behaviour whereas TTX infusions resulted in a significant decrease in performance. The serial-order impairments, however, were not the results of errors of any specific error at any specific list item. With respect to the go/no-go discrimination task, saline infusions also had no impact on performance whereas TTX infusions impaired pigeons' discrimination abilities. Given the impairments on the go/no-go discrimination task, which does not require processing of serial-order information, we tentatively conclude that damage to the NCL does not impair serial-order behaviour per se, but rather results in a more generalised impairment that may impact performance across a range of tasks.

  13. Serial Position Effects in the Identification of Letters, Digits, and Symbols

    Science.gov (United States)

    Tydgat, Ilse; Grainger, Jonathan

    2009-01-01

    In 6 experiments, the authors investigated the form of serial position functions for identification of letters, digits, and symbols presented in strings. The results replicated findings obtained with the target search paradigm, showing an interaction between the effects of serial position and type of stimulus, with symbols generating a distinct…

  14. Visual and Phonological Similarity Effects in Verbal Immediate Serial Recall: A Test with Kanji Materials

    Science.gov (United States)

    Saito, Satoru; Logie, Robert H.; Morita, Aiko; Law, Anna

    2008-01-01

    In a series of three experiments, native speakers of Japanese performed serial ordered written recall of visually presented Japanese kanji characters that varied systematically in visual and phonological similarity. Overall effects of phonological similarity were observed for retention of serial order under silent reading in Experiments 1 and 3…

  15. A study on the utilization of serial resources in selected tertiary ...

    African Journals Online (AJOL)

    A study on the utilization of serial resources in selected tertiary institutions in Ogun State. ... Lagos Journal of Library and Information Science ... Serial resources are publications either in printed form or electronic format issued in successive parts usually having numerical or chronological designations and intended to be ...

  16. What's Your Money Worth? Materials Budgets and the Selection and Evaluation of Book and Serial Vendors.

    Science.gov (United States)

    Barker, Joseph W.

    1992-01-01

    Discusses budgets for library materials and how to select and evaluate book and serial vendors. Trends in automation, publishing, and economics that affect both libraries and vendors are discussed; and examples from the University of California at Berkeley that include serials service charges and approval plan discounts are presented. (six…

  17. 3D Topography of the Young Adult Anal Sphincter Complex Reconstructed from Undeformed Serial Anatomical Sections

    NARCIS (Netherlands)

    Wu, Yi; Dabhoiwala, Noshir F.; Hagoort, Jaco; Shan, Jin-Lu; Tan, Li-Wen; Fang, Bin-Ji; Zhang, Shao-Xiang; Lamers, Wouter H.

    2015-01-01

    Pelvic-floor anatomy is usually studied by artifact-prone dissection or imaging, which requires prior anatomical knowledge. We used the serial-section approach to settle contentious issues and an interactive 3D-pdf to make the results widely accessible. 3D reconstructions of undeformed thin serial

  18. Serial MR findings of metaphyseal cyst in Legg-Calve-Perthes disease: a case report

    International Nuclear Information System (INIS)

    Shim, Chang Min; Na, Jae Boem; Moon, Haeng Jin

    2001-01-01

    Metaphyseal cysts are common findings in Lee-Calve-Perthes(LCP) disease, though usually disappear within 6-12 months several studies have described the MR imaging findings of these cysts, though serial MRI findings have not been documented. In this report, therefore, we report the serial MRI results of metaphyseal cyst in LCP patients

  19. A high speed serializer ASIC for ATLAS Liquid Argon calorimeter upgrade

    CERN Document Server

    Liu, T; The ATLAS collaboration

    2011-01-01

    The current front-end electronics of the ATLAS Liquid Argon calorimeters need to be upgraded to sustain the higher radiation levels and data rates expected at the upgraded LHC machine (HL-LHC), which will have 5 times more luminosity than the LHC in its ultimate configuration. This upgrade calls for an optical link system of 100 Gbps per front-end board (FEB). A high speed, low power, radiation tolerant serializer is the critical component in this system. In this paper, we present the design and test results of a single channel 16:1 serializer and the design of a double-channel 16:1 serializer. Both designs are based on a commercial 0.25 μm silicon-on-sapphire CMOS technology. The single channel serializer consists of a serializing unit, a PLL clock generator and a line driver implemented in current mode logic (CML). The serializing unit multiplexes 16 bit parallel LVDS data into 1-bit width serial CMOS data. The serializing unit is composed of a cascade of 2:1 multiplexing circuits based on static D-flip-fl...

  20. Subject-Verb Agreement in Children and Adults: Serial or Hierarchical Processing?

    Science.gov (United States)

    Negro, Isabelle; Chanquoy, Lucile; Fayol, Michel; Louis-Sidney, Maryse

    2005-01-01

    Two processes, serial and hierarchical, are generally opposed to account for grammatical encoding in language production. In a developmental perspective, the question addressed here is whether the subject-verb agreement during writing is computed serially, once the words are linearly ordered in the sentence, or hierarchically, as soon as the…

  1. Juvenility and serial vegetative propagation of Norway spruce clones (Picea abies Karst.).

    Science.gov (United States)

    J.B. St. Clair; J. Kleinschmit; J. Svolba

    1985-01-01

    Effects associated with progressive maturation of clones are of greatest concern in clonal tree improvement programs. Serial propagation has been in use at the Lower Saxony Forest Research Institute since 1968 to arrest maturation in Norway spruce clones. By 1980 cuttings were established in the nursery that had been serially propagated from one to five cycles. This...

  2. Race as Seriality: A Response to David Benatar and Zimitri Erasmus

    Science.gov (United States)

    Gouws, A.

    2010-01-01

    In this article I draw on the Sarte's notion of "seriality" as theorized in his book "Dialectic of Reason" and as interpreted by Iris Marion Young. I argue that seriality can be used to escape the false essentialism and identity politics of race as a category for admissions to universities. A series is a social collective whose members are unified…

  3. Serial cranial ultrasonography or early MRI for detecting preterm brain injury?

    NARCIS (Netherlands)

    Plaisier, Annemarie; Raets, Marlou M A; Ecury-Goossen, Ginette M; Govaert, Paul; Feijen-Roon, Monique; Reiss, Irwin K M; Smit, Liesbeth S; Lequin, Maarten H; Dudink, Jeroen

    OBJECTIVE: To investigate detection ability and feasibility of serial cranial ultrasonography (CUS) and early MRI in preterm brain injury. DESIGN: Prospective cohort study. SETTING: Level III neonatal intensive care unit. PATIENTS: 307 infants, born below 29 weeks of gestation. METHODS: Serial CUS

  4. Cross-domain interference costs during concurrent verbal and spatial serial memory tasks are asymmetric

    NARCIS (Netherlands)

    Morey, Candice C.; Mall, Jonathan T.

    2012-01-01

    Some evidence suggests that memory for serial order is domain-general. Evidence also points to asymmetries in interference between verbal and visual-spatial tasks. We confirm that concurrently remembering verbal and spatial serial lists provokes substantial interference compared with remembering a

  5. The effects of serial intravascular transfusions in ascitic/hydropic RhD-alloimmunized fetuses.

    Science.gov (United States)

    Craparo, F J; Bonati, F; Gementi, P; Nicolini, U

    2005-02-01

    To evaluate the effects of serial intravascular transfusions on RhD-alloimmunized fetuses with ascites/hydrops at the time of the first transfusion by measuring multiple hematological/biochemical blood variables. Thirty-one singleton pregnancies were referred for management of RhD alloimmunization. Seven fetuses had hydrops on presentation and were transfused immediately. The remainder underwent weekly ultrasound examinations, and fetal blood sampling and transfusion were performed on development of ascites. In the 104 samples collected overall from the 31 fetuses, glucose, uric acid, urea, creatinine, total protein, total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase, alkaline phosphatase, lactic dehydrogenase, amylase, pseudocholinesterase (PCHE), creatine kinase, triglycerides and cholesterol were measured and compared with a reference range for non-anemic fetuses. The median gestational age at first transfusion was 26 (range, 18-34) weeks. There were three fetal losses after the first transfusion, two of which were due to procedure-related complications; one further loss occurred. At the first transfusion fetal hematocrit, pO2, total protein, PCHE, creatinine and urea concentrations were significantly decreased compared to reference data, while total and direct bilirubin, AST, ALT, amylase, triglyceride and uric acid concentrations were increased. In all surviving fetuses ascites/hydrops had disappeared by the second transfusion. Fetal pO2, total protein, AST, ALT and PCHE concentrations had normalized by the third transfusion. Correction of fetal anemia did not affect the other variables. RhD-alloimmunized fetuses with ascites/hydrops at the time of the first transfusion had a survival rate of 87%. Alterations of several biochemical fetal blood indices are present at the first sampling/transfusion, but most variables normalize with intravascular transfusions. Copyright 2005 ISUOG.

  6. Kinematics and dynamics analysis of a novel serial-parallel dynamic simulator

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Bo; Zhang, Lian Dong; Yu, Jingjing [Parallel Robot and Mechatronic System Laboratory of Hebei Province, Yanshan University, Qinhuangdao, Hebei (China)

    2016-11-15

    A serial-parallel dynamics simulator based on serial-parallel manipulator is proposed. According to the dynamics simulator motion requirement, the proposed serial-parallel dynamics simulator formed by 3-RRS (active revolute joint-revolute joint-spherical joint) and 3-SPR (Spherical joint-active prismatic joint-revolute joint) PMs adopts the outer and inner layout. By integrating the kinematics, constraint and coupling information of the 3-RRS and 3-SPR PMs into the serial-parallel manipulator, the inverse Jacobian matrix, velocity, and acceleration of the serial-parallel dynamics simulator are studied. Based on the principle of virtual work and the kinematics model, the inverse dynamic model is established. Finally, the workspace of the (3-RRS)+(3-SPR) dynamics simulator is constructed.

  7. Changing Series: Narrative Models and the Role of the Viewer in Contemporary Television Seriality

    Directory of Open Access Journals (Sweden)

    Veronica Innocenti

    2015-04-01

    Full Text Available In the past few years television serial narratives have gone through some severe changes in the way they are organized from a narrative point of view, as well as in the way they are perceived by the audiences. Our article originates from the necessity of investigating the products of this new wave of serial production, with the purpose of focusing on narrative formulas and on the relationships that serial products establish with their users. Vast serialized narratives are not just texts anymore, they have become complex universes of meaning that last for long time and that have a strong influence on the audiences. The article aims to investigate serial narratives as usable objects, that are not just seen by the public, but that are part of a complex experience.

  8. Kinematics and dynamics analysis of a novel serial-parallel dynamic simulator

    International Nuclear Information System (INIS)

    Hu, Bo; Zhang, Lian Dong; Yu, Jingjing

    2016-01-01

    A serial-parallel dynamics simulator based on serial-parallel manipulator is proposed. According to the dynamics simulator motion requirement, the proposed serial-parallel dynamics simulator formed by 3-RRS (active revolute joint-revolute joint-spherical joint) and 3-SPR (Spherical joint-active prismatic joint-revolute joint) PMs adopts the outer and inner layout. By integrating the kinematics, constraint and coupling information of the 3-RRS and 3-SPR PMs into the serial-parallel manipulator, the inverse Jacobian matrix, velocity, and acceleration of the serial-parallel dynamics simulator are studied. Based on the principle of virtual work and the kinematics model, the inverse dynamic model is established. Finally, the workspace of the (3-RRS)+(3-SPR) dynamics simulator is constructed

  9. Female serial murderers: directions for future research on a hidden population.

    Science.gov (United States)

    Gurian, Elizabeth A

    2011-02-01

    This comprehensive overview on a sample of 65 cases (134 total offenders, including some partnered teams of more than 2 offenders) provides information on female serial murderers who either work in a mixed-sex offending group or alone. These female serial homicide offenders have a distinct set of offender-victim characteristics, including specific victim preferences, methods, and motivations: Partnered serial homicide offenders are more likely to target adult strangers and dispatch them using a combination of methods, whereas solo female serial murderers are most likely to target adult family members and murder them with poison. These patterns have the potential to add to our understanding of the possible similarities and differences of serial homicide cases by building on established offender characteristics. Convictions and sentences for the offenders are included and areas of future research and implications for treatment with this sample are also explored.

  10. Testing Cross-Sectional Correlation in Large Panel Data Models with Serial Correlation

    Directory of Open Access Journals (Sweden)

    Badi H. Baltagi

    2016-11-01

    Full Text Available This paper considers the problem of testing cross-sectional correlation in large panel data models with serially-correlated errors. It finds that existing tests for cross-sectional correlation encounter size distortions with serial correlation in the errors. To control the size, this paper proposes a modification of Pesaran’s Cross-sectional Dependence (CD test to account for serial correlation of an unknown form in the error term. We derive the limiting distribution of this test as N , T → ∞ . The test is distribution free and allows for unknown forms of serial correlation in the errors. Monte Carlo simulations show that the test has good size and power for large panels when serial correlation in the errors is present.

  11. IEEE 1394/firewire a low cost, high speed, digital serial bus

    Energy Technology Data Exchange (ETDEWEB)

    Gaunt, R.

    1997-05-01

    Does the world need yet another 1/0 bus standard? If you need fast and cheap serial video communication, then the answer is yes. As technology advances, so too must data transport mechanisms advance. You can`t expect RS-232 to support real-time digital video, and if you can`t afford expensive professional serial video interfaces, (such as Sony`s Serial Digital Interface), Firewire may be a good solution. IEEE 1394, or commonly known as Firewire, is a general purpose serial bus that meets many of the 1/0 needs of today`s video and multimedia developers. For those of you who only read the first paragraph, here`s Firewire in a nutshell: It provides a guaranteed transfer rate of 10OMbps or 20OMbps of digital data (such as video direct from camera to computer), over an inexpensive, non-proprietary serial bus. Here is a list of its features.

  12. Virus-Induced Chaperone-Enriched (VICE domains function as nuclear protein quality control centers during HSV-1 infection.

    Directory of Open Access Journals (Sweden)

    Christine M Livingston

    2009-10-01

    Full Text Available Virus-Induced Chaperone-Enriched (VICE domains form adjacent to nuclear viral replication compartments (RC during the early stages of HSV-1 infection. Between 2 and 3 hours post infection at a MOI of 10, host protein quality control machinery such as molecular chaperones (e.g. Hsc70, the 20S proteasome and ubiquitin are reorganized from a diffuse nuclear distribution pattern to sequestration in VICE domains. The observation that VICE domains contain putative misfolded proteins suggests that they may be similar to nuclear inclusion bodies that form under conditions in which the protein quality control machinery is overwhelmed by the presence of misfolded proteins. The detection of Hsc70 in VICE domains, but not in nuclear inclusion bodies, indicates that Hsc70 is specifically reorganized by HSV-1 infection. We hypothesize that HSV-1 infection induces the formation of nuclear protein quality control centers to remodel or degrade aberrant nuclear proteins that would otherwise interfere with productive infection. Detection of proteolytic activity in VICE domains suggests that substrates may be degraded by the 20S proteasome in VICE domains. FRAP analysis reveals that GFP-Hsc70 is dynamically associated with VICE domains, suggesting a role for Hsc70 in scanning the infected nucleus for misfolded proteins. During 42 degrees C heat shock, Hsc70 is redistributed from VICE domains into RC perhaps to remodel viral replication and regulatory proteins that have become insoluble in these compartments. The experiments presented in this paper suggest that VICE domains are nuclear protein quality control centers that are modified by HSV-1 to promote productive infection.

  13. Depression and pain: testing of serial multiple mediators

    Directory of Open Access Journals (Sweden)

    Wongpakaran T

    2016-07-01

    Full Text Available Tinakon Wongpakaran,1 Nahathai Wongpakaran,1 Sitthinant Tanchakvaranont,2 Putipong Bookkamana,3 Manee Pinyopornpanish,1 Kamonporn Wannarit,4 Sirina Satthapisit,5 Daochompu Nakawiro,6 Thanita Hiranyatheb,6 Kulvadee Thongpibul7 1Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Kingdom of Thailand; 2Department of Psychiatry, Queen Savang Vadhana Memorial Hospital, Chonburi, Kingdom of Thailand; 3Department of Statistics, Faculty of Science, Chiang Mai University, Chiang Mai, Kingdom of Thailand; 4Department of Psychiatry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Kingdom of Thailand; 5Department of Psychiatry, Khon Kaen Regional Hospital, Khon Kaen, Kingdom of Thailand; 6Department of Psychiatry, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Kingdom of Thailand; 7Department of Psychology, Faculty of Humanities, Chiang Mai University, Chiang Mai, Kingdom of Thailand Purpose: Despite the fact that pain is related to depression, few studies have been conducted to investigate the variables that mediate between the two conditions. In this study, the authors explored the following mediators: cognitive function, self-sacrificing interpersonal problems, and perception of stress, and the effects they had on pain symptoms among patients with depressive disorders.Participants and methods: An analysis was performed on the data of 346 participants with unipolar depressive disorders. The 17-item Hamilton Depression Rating Scale, Mini-Mental State Examination, the pain subscale of the health-related quality of life (SF-36, the self-sacrificing subscale of the Inventory of Interpersonal Problems, and the Perceived Stress Scale were used. Parallel multiple mediator and serial multiple mediator models were used. An alternative model regarding the effect of self-sacrificing on pain was also proposed.Results: Perceived stress, self-sacrificing interpersonal style, and cognitive

  14. Using Serial and Discrete Digit Naming to Unravel Word Reading Processes.

    Science.gov (United States)

    Altani, Angeliki; Protopapas, Athanassios; Georgiou, George K

    2018-01-01

    During reading acquisition, word recognition is assumed to undergo a developmental shift from slow serial/sublexical processing of letter strings to fast parallel processing of whole word forms. This shift has been proposed to be detected by examining the size of the relationship between serial- and discrete-trial versions of word reading and rapid naming tasks. Specifically, a strong association between serial naming of symbols and single word reading suggests that words are processed serially, whereas a strong association between discrete naming of symbols and single word reading suggests that words are processed in parallel as wholes. In this study, 429 Grade 1, 3, and 5 English-speaking Canadian children were tested on serial and discrete digit naming and word reading. Across grades, single word reading was more strongly associated with discrete naming than with serial naming of digits, indicating that short high-frequency words are processed as whole units early in the development of reading ability in English. In contrast, serial naming was not a unique predictor of single word reading across grades, suggesting that within-word sequential processing was not required for the successful recognition for this set of words. Factor mixture analysis revealed that our participants could be clustered into two classes, namely beginning and more advanced readers. Serial naming uniquely predicted single word reading only among the first class of readers, indicating that novice readers rely on a serial strategy to decode words. Yet, a considerable proportion of Grade 1 students were assigned to the second class, evidently being able to process short high-frequency words as unitized symbols. We consider these findings together with those from previous studies to challenge the hypothesis of a binary distinction between serial/sublexical and parallel/lexical processing in word reading. We argue instead that sequential processing in word reading operates on a continuum

  15. TDP-43 Proteinopathies: A New Player in Neurodegenerative Diseases with Defective Protein Folding

    Directory of Open Access Journals (Sweden)

    Suna Lahut

    2012-03-01

    Full Text Available The proteome is the sum of all proteins inside a cell, and proteostasis (protein homeostasis is the stable condition of the proteome. Proteostasis is essential for the cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins challenge the proteostasis machinery and the vitality of the cell. There is increasing evidence that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but, when not corrected, that they initiate a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation, referred to as proteinopathies. Alzheimer’s Disease (AD, Parkinson’s Disease (PD, Huntington’s Disease (HD, Amyotrophic Lateral Sclerosis (ALS, cancer and diabetes, whose frequencies have drastically increased in countries with aging populations, are all consequences of misfolded proteins. This paper focuses on TDP-43, which excelled as a key protein in neurodegenerative processes because of its association with different diseases, especially with ALS and Frontotemporal Lobar Dementia (FTLD, the two best studied examples of TDP-43 proteinopathies

  16. Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis.

    Science.gov (United States)

    Finka, Andrija; Goloubinoff, Pierre

    2013-09-01

    In the crowded environment of human cells, folding of nascent polypeptides and refolding of stress-unfolded proteins is error prone. Accumulation of cytotoxic misfolded and aggregated species may cause cell death, tissue loss, degenerative conformational diseases, and aging. Nevertheless, young cells effectively express a network of molecular chaperones and folding enzymes, termed here "the chaperome," which can prevent formation of potentially harmful misfolded protein conformers and use the energy of adenosine triphosphate (ATP) to rehabilitate already formed toxic aggregates into native functional proteins. In an attempt to extend knowledge of chaperome mechanisms in cellular proteostasis, we performed a meta-analysis of human chaperome using high-throughput proteomic data from 11 immortalized human cell lines. Chaperome polypeptides were about 10% of total protein mass of human cells, half of which were Hsp90s and Hsp70s. Knowledge of cellular concentrations and ratios among chaperome polypeptides provided a novel basis to understand mechanisms by which the Hsp60, Hsp70, Hsp90, and small heat shock proteins (HSPs), in collaboration with cochaperones and folding enzymes, assist de novo protein folding, import polypeptides into organelles, unfold stress-destabilized toxic conformers, and control the conformal activity of native proteins in the crowded environment of the cell. Proteomic data also provided means to distinguish between stable components of chaperone core machineries and dynamic regulatory cochaperones.

  17. Protein aggregates as depots for the release of biologically active compounds.

    Science.gov (United States)

    Artemova, Natalya V; Kasakov, Alexei S; Bumagina, Zoya M; Lyutova, Elena M; Gurvits, Bella Ya

    2008-12-12

    Protein misfolding and aggregation is one of the most serious problems in cell biology, molecular medicine, and biotechnology. Misfolded proteins interact with each other or with other proteins in non-productive or damaging ways. However, a new paradigm arises that protein aggregation may be exploited by nature to perform specific functions in different biological contexts. From this consideration, acceleration of stress-induced protein aggregation triggered by any factor resulting in the formation of soluble aggregates may have paradoxical positive consequences. Here, we suggest that amorphous aggregates can act as a source for the release of biologically active proteins after removal of stress conditions. To address this concept, we investigated the kinetics of thermal aggregation in vitro of yeast alcohol dehydrogenase (ADH) as a model substrate in the presence of two amphiphilic peptides: Arg-Phe or Ala-Phe-Lys. Using dynamic light scattering (DLS) and turbidimetry, we have demonstrated that under mild stress conditions the concentration-dependent acceleration of ADH aggregation by these peptides results in formation of large but soluble complexes of proteins prone to refolding.

  18. Modulation of the maladaptive stress response to manage diseases of protein folding.

    Directory of Open Access Journals (Sweden)

    Daniela Martino Roth

    2014-11-01

    Full Text Available Diseases of protein folding arise because of the inability of an altered peptide sequence to properly engage protein homeostasis components that direct protein folding and function. To identify global principles of misfolding disease pathology we examined the impact of the local folding environment in alpha-1-antitrypsin deficiency (AATD, Niemann-Pick type C1 disease (NPC1, Alzheimer's disease (AD, and cystic fibrosis (CF. Using distinct models, including patient-derived cell lines and primary epithelium, mouse brain tissue, and Caenorhabditis elegans, we found that chronic expression of misfolded proteins not only triggers the sustained activation of the heat shock response (HSR pathway, but that this sustained activation is maladaptive. In diseased cells, maladaptation alters protein structure-function relationships, impacts protein folding in the cytosol, and further exacerbates the disease state. We show that down-regulation of this maladaptive stress response (MSR, through silencing of HSF1, the master regulator of the HSR, restores cellular protein folding and improves the disease phenotype. We propose that restoration of a more physiological proteostatic environment will strongly impact the management and progression of loss-of-function and gain-of-toxic-function phenotypes common in human disease.

  19. TDP-43 Proteinopathies: A New Player in Neurodegenerative Diseases with Defective Protein Folding

    Directory of Open Access Journals (Sweden)

    Suna Lahut

    2012-03-01

    Full Text Available The proteome is the sum of all proteins inside a cell, and proteostasis (protein homeostasis is the stable condition of the proteome. Proteostasis is essential for the cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins challenge the proteostasis machinery and the vitality of the cell. There is increasing evidence that the accumulation of damaged proteins not only has direct consequences on the efficiency and fidelity of cellular processes but, when not corrected, that they initiate a cascade of dysfunction, which in humans is associated with a plethora of diseases of protein conformation, referred to as proteinopathies. Alzheimer’s Disease (AD, Parkinson’s Disease (PD, Huntington’s Disease (HD, Amyotrophic Lateral Sclerosis (ALS, cancer and diabetes, whose frequencies have drastically increased in countries with aging populations, are all consequences of misfolded proteins. This paper focuses on TDP-43, which excelled as a key protein in neurodegenerative processes because of its association with different diseases, especially with ALS and Frontotemporal Lobar Dementia (FTLD, the two best studied examples of TDP-43 proteinopathies.

  20. Porcine prion protein amyloid.

    Science.gov (United States)

    Hammarström, Per; Nyström, Sofie

    2015-01-01

    Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

  1. Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels.

    Science.gov (United States)

    Hantouche, Christine; Williamson, Brittany; Valinsky, William C; Solomon, Joshua; Shrier, Alvin; Young, Jason C

    2017-02-10

    Cardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Technical refolding of proteins: Do we have freedom to operate?

    Science.gov (United States)

    Eiberle, Maria K; Jungbauer, Alois

    2010-06-01

    Expression as inclusion bodies in Escherichia coli is a widely used method for the large-scale production of therapeutic proteins that do not require post-translational modifications. High expression yields and simple recovery steps of inclusion bodies from the host cells are attractive features industrially. However, the value of an inclusion body-based process is dominated by the solubilization and refolding technologies. Scale-invariant technologies that are economical and applicable for a wide range of proteins are requested by industry. The main challenge is to convert the denatured protein into its native conformation at high yields. Refolding competes with misfolding and aggregation. Thus, the yield of native monomer depends strongly on the initial protein concentrations in the refolding solution. Reasonable yields are attained at low concentrations (freedom to operate.

  3. Protein evolution via amino acid and codon elimination

    DEFF Research Database (Denmark)

    Goltermann, Lise; Larsen, Marie Sofie Yoo; Banerjee, Rajat

    2010-01-01

    BACKGROUND: Global residue-specific amino acid mutagenesis can provide important biological insight and generate proteins with altered properties, but at the risk of protein misfolding. Further, targeted libraries are usually restricted to a handful of amino acids because there is an exponential...... correlation between the number of residues randomized and the size of the resulting ensemble. Using GFP as the model protein, we present a strategy, termed protein evolution via amino acid and codon elimination, through which simplified, native-like polypeptides encoded by a reduced genetic code were obtained...... simultaneously), while retaining varying levels of activity. Combination of these substitutions to generate a Phe-free variant of GFP abolished fluorescence. Combinatorial re-introduction of five Phe residues, based on the activities of the respective single amino acid replacements, was sufficient to restore GFP...

  4. Vascular smooth muscle cells exhibit a progressive loss of rigidity with serial culture passaging.

    Science.gov (United States)

    Dinardo, Carla Luana; Venturini, Gabriela; Omae, Samantha Vieira; Zhou, Enhua H; da Motta-Leal-Filho, Joaquim Maurício; Dariolli, Rafael; Krieger, José Eduardo; Alencar, Adriano Mesquita; Costa Pereira, Alexandre

    2012-01-01

    One drawback of in vitro cell culturing is the dedifferentiation process that cells experience. Smooth muscle cells (SMC) also change molecularly and morphologically with long term culture. The main objective of this study was to evaluate if culture passages interfere in vascular SMC mechanical behavior. SMC were obtained from five different porcine arterial beds. Optical magnetic twisting cytometry (OMTC) was used to characterize mechanically vascular SMC from different cultures in distinct passages and confocal microscopy/western blotting, to evaluate cytoskeleton and extracellular matrix proteins. We found that vascular SMC rigidity or viscoelastic complex modulus (G) decreases with progression of passages. A statistically significant negative correlation between G and passage was found in four of our five cultures studied. Phalloidin-stained SMC from higher passages exhibited lower mean signal intensity per cell (confocal microscopy) and quantitative western blotting analysis showed a decrease in collagen I content throughout passages. We concluded that vascular SMC progressively lose their stiffness with serial culture passaging. Thus, limiting the number of passages is essential for any experiment measuring viscoelastic properties of SMC in culture.

  5. Low-Z polymer sample supports for fixed-target serial femtosecond X-ray crystallography

    Energy Technology Data Exchange (ETDEWEB)

    Feld, Geoffrey K. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); National Institute of Environmental Health Science, Research Triangle Park, NC (United States); Heymann, Michael [Brandeis Univ., Waltham, MA (United States); Univ. of Hamburg and DESY, Hamburg (Germany); Benner, W. Henry [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Pardini, Tommaso [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Tsai, Ching -Ju [Paul Scherrer Inst. (PSI), Villigen (Switzerland); Boutet, Sebastien [SLAC National Accelerator Lab., Menlo Park, CA (United States); Coleman, Matthew A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Hunter, Mark S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States); Li, Xiaodan [Paul Scherrer Inst. (PSI), Villigen (Switzerland); Messerschmidt, Marc [SLAC National Accelerator Lab., Menlo Park, CA (United States); BioXFEL Science and Technology Center, Buffalo, NY (United States); Opathalage, Achini [Brandeis Univ., Waltham, MA (United States); Pedrini, Bill [Paul Scherrer Inst. (PSI), Villigen (Switzerland); Williams, Garth J. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Krantz, Bryan A. [Univ. of California, Berkeley, CA (United States); Fraden, Seth [Brandeis Univ., Waltham, MA (United States); Hau-Riege, Stefan [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Evans, James E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Segelke, Brent W. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Frank, Matthias [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-06-27

    X-ray free-electron lasers (XFELs) offer a new avenue to the structural probing of complex materials, including biomolecules. Delivery of precious sample to the XFEL beam is a key consideration, as the sample of interest must be serially replaced after each destructive pulse. The fixed-target approach to sample delivery involves depositing samples on a thin-film support and subsequent serial introduction via a translating stage. Some classes of biological materials, including two-dimensional protein crystals, must be introduced on fixed-target supports, as they require a flat surface to prevent sample wrinkling. A series of wafer and transmission electron microscopy (TEM)-style grid supports constructed of low-Z plastic have been custom-designed and produced. Aluminium TEM grid holders were engineered, capable of delivering up to 20 different conventional or plastic TEM grids using fixed-target stages available at the Linac Coherent Light Source (LCLS). As proof-of-principle, X-ray diffraction has been demonstrated from two-dimensional crystals of bacteriorhodopsin and three-dimensional crystals of anthrax toxin protective antigen mounted on these supports at the LCLS. In conclusion, the benefits and limitations of these low-Z fixed-target supports are discussed; it is the authors' belief that they represent a viable and efficient alternative to previously reported fixed-target supports for conducting diffraction studies with XFELs.

  6. Serial ammonia measurement in patients poisoned with glufosinate ammonium herbicide.

    Science.gov (United States)

    Moon, J M; Chun, B J

    2016-05-01

    This study investigated whether ammonia concentrations can predict delayed neurotoxicity development and neurotoxicity latency in glufosinate ammonium (GLA) herbicide-poisoned patients presenting with an alert mental state and stable hemodynamics. This retrospective observational case study included 26 patients divided into 2 groups: neurotoxicity during hospitalization (complicated group) and without neurotoxicity (noncomplicated group). Thirteen patients (50.0%) experienced neurotoxicity at 16 h post-ingestion. Although ammonia concentrations at presentation did not differ significantly between the two groups, the ammonia level in the complicated group increased significantly at the next measurement and remained significantly higher than that in the noncomplicated group until 48 h after ingestion. The peak ammonia concentration before neurotoxicity development was an independent predictor of neurotoxicity (odds ratio: 1.047, 95% confidence interval: 1.010-1.087, p value = 0.014), and the optimal cutoff value of peak ammonia concentration for predicting neurotoxicity was 101.5 μg/dL. The rate of ammonia increase was not associated with the time latency from ingestion to neurotoxicity development. This study showed that serial ammonia measurements in GLA-poisoned patients may identify those who are at high risk of developing neurotoxicity. However, as this study enrolled few patients, further qualified trials are required to confirm our results and to reveal the etiology of hyperammonemia and its causality in neurotoxicity. © The Author(s) 2015.

  7. Phonological and semantic strategies in immediate serial recall.

    Science.gov (United States)

    Campoy, Guillermo; Baddeley, Alan

    2008-05-01

    It has been suggested that certain theoretically important anomalous results in the area of verbal short-term memory could be attributable to differences in strategy. However there are relatively few studies that investigate strategy directly. We describe four experiments, each involving the immediate serial recall of word sequences under baseline control conditions, or preceded by instruction to use a phonological or semantic strategy. Two experiments varied phonological similarity at a presentation rate of one item every 1 or 2 seconds. Both the control and the phonologically instructed group showed clear effects of similarity at both presentation rates, whereas these were largely absent under semantic encoding conditions. Two further experiments manipulated word length at the same two rates. The phonologically instructed groups showed clear effects at both rates, the control group showed a clear effect at the rapid rate which diminished with the slower presentation, while the semantically instructed group showed a relatively weak effect at the rate of one item per second, and a significant reverse effect with slower presentation. The latter finding is interpreted in terms of fortuitous differences in inter-item rated associability between the two otherwise matched word pools, reinforcing our conclusion that the semantically instructed group were indeed encoding semantically. Implications for controlling strategy by instruction are discussed.

  8. High speed serial link for UA1 microprocessor network

    CERN Document Server

    Cittolin, S; Zurfluh, E

    1981-01-01

    The UA1 data acquisition system consists of a set of distributed microprocessor units. An interprocessor link, independent of the CAMAC data readout, has been developed in order to have continuous remote control and run-time data handling, e.g. transmission of calibration programs/parameters, equipment test/status and histogram accumulation. The data transmission system is designed to be used in a loop configuration equipped with transceivers for twisted pair cables (RS-422). As an economical system, it is running as an ancillary serial loop-link between microprocessors, like Data Acquisition Crate Controllers and systems with distributed intelligence. The software driver consists of a loop-controller package, which may run in a BAMBI Computer Language environment and a fully interrupt controlled program for all other secondary stations. A special single-character mode provides a handy link for remote debugging in a pseudo-full-duplex mode. The format is based on the HDLC protocol without sequence numbering. ...

  9. High speed serial link for UA1 microprocessor network

    International Nuclear Information System (INIS)

    Cittolin, S.; Loefstedt, B.; Zurfluh, E.

    1981-01-01

    The UA1 data acquisition system consists of a set of distributed microprocessor units. An interprocessor link, independent of the CAMAC data readout, has been developed in order to have continuous remote control and run-time data handling, e.g. transmission of calibration programs/parameters, equipment rest/status and histogram accumulation. The data transmission system is designed to be used in a loop configuration equipped with transceivers for twisted pair cables (RS-422). As an economical system it is running as an ancillary serial loop-link between microprocessors Like Data Acquisition Crate Controllers and systems with distributed intelligence. The software driver consists of a loop-controller package, which may run in a BAMBI Computer Language environment and a fully interrupt controlled program for all other secondary stations. A special single-character mode provides a handy link for remote debugging in a pseudo-full-duplex mode. The format is based on the HDLC protocol without sequence numbering. The Chip MC-6854 from Motorola, Inc. enables an implementation with few components. (orig.)

  10. High speed serial link for UA1 microprocessor network

    CERN Document Server

    Cittolin, Sergio; Zurfluh, E

    1981-01-01

    The UA1 data acquisition system consists of a set of distributed microprocessor units. An interprocessor link, independent of the CAMAC data readout, has been developed in order to have continuous remote control and run-time data handling, e.g. transmission of calibration programs/parameters, equipment test/status and histogram accumulation. The data transmission system is designed to be used in a loop configuration equipped with transceivers for twisted pair cables (RS-422). As an economical system, it is running as an ancillary serial loop-link between microprocessors, like data acquisition crate controllers and systems with distributed intelligence. The software driver consists of a loop-controller package, which may run in a BAMBI computer language environment and a fully interrupt controlled program for all other secondary stations. A special single-character mode provides a handy link for remote debugging in a pseudo-full-duplex mode. The format is based on the HDLC protocol without sequence numbering. ...

  11. Serial exercise gated radionuclide ventriculograms (RVG) in monitoring doxorubicin cardiotoxicity

    International Nuclear Information System (INIS)

    Goldstein, H.A.; Lahoda, J.; Fox, L.

    1985-01-01

    The resting RVG (Radionuclide Ventriculograms) are demonstrated to be an effective monitor of the cardiotoxicity of doxorubicin. The exercise RVG has not been as well studied to see if it yields additional information or detects toxicity effects earlier. Sixteen patients receiving doxorubicin for chemotherapy had 2-6 serial exercise studies with intervals between studies of 1 month to 15 months. The patients exercised varying amounts with cardiac work indicated by their double products (HR x Sys. BP). Although all patients started with a normal resting LVEF (>50%), 5 of the 16 did not have a normal response (≥5% increase in LVEF) with initial exercise study. Of the 11 patients with an initially normal response to exercise, on at least one subsequent study, 3 had an abnormal response to exercise. On a later follow up study 1 of these 3 patients again had a normal response to exercise. Six of these 11 patients had had RVG evidence of cardiotoxicity. Four of these 6 patients had continually normal exercise responses, while 2 of these 5 patients had had an abnormal exercise response. An initial exercise RVG may be reasonable to detect unsuspected CAD in cancer victims. These patients are reported to be more sensitive to the toxic effects of doxorubicin. Follow up exercise RVGs do not contribute useful information, do not predict cardiotoxicity, and may be misleading

  12. Prophetic Visions, Quality Serials: Twin Peaks’ new mode of storytelling

    Directory of Open Access Journals (Sweden)

    Mikhail L. Skoptsov

    2015-05-01

    Full Text Available Following the April 1990 debut of Twin Peaks on ABC, the vision - a sequence of images that relates information of the narrative future or past – has become a staple of numerous network, basic cable and premium cable serials, including Buffy the Vampire Slayer (WB, Battlestar Galactica (SyFy and Game of Thrones (HBO. This paper argues that Peaks in effect had introduced a mode of storytelling called “visio-narrative,” which draws on ancient epic poetry by focusing on main characters that receive knowledge from enigmatic, god-like figures that control his world. Their visions disrupt linear storytelling, allowing a series to embrace the formal aspects of the medium and create the impression that its disparate episodes constitute a singular whole. This helps them qualify as ‘quality TV’, while disguising instances of authorial manipulation evident within the texts as products of divine internal causality.As a result, all narrative events, no matter how coincidental or inconsequential, become part of a grand design. Close examination of Twin Peaks and Carnivàle will demonstrate how the mode operates, why it is popular among modern storytellers and how it can elevate a show’s cultural status.

  13. LabVIEW Serial Driver Software for an Electronic Load

    Science.gov (United States)

    Scullin, Vincent; Garcia, Christopher

    2003-01-01

    A LabVIEW-language computer program enables monitoring and control of a Transistor Devices, Inc., Dynaload WCL232 (or equivalent) electronic load via an RS-232 serial communication link between the electronic load and a remote personal computer. (The electronic load can operate at constant voltage, current, power consumption, or resistance.) The program generates a graphical user interface (GUI) at the computer that looks and acts like the front panel of the electronic load. Once the electronic load has been placed in remote-control mode, this program first queries the electronic load for the present values of all its operational and limit settings, and then drops into a cycle in which it reports the instantaneous voltage, current, and power values in displays that resemble those on the electronic load while monitoring the GUI images of pushbuttons for control actions by the user. By means of the pushbutton images and associated prompts, the user can perform such operations as changing limit values, the operating mode, or the set point. The benefit of this software is that it relieves the user of the need to learn one method for operating the electronic load locally and another method for operating it remotely via a personal computer.

  14. Serial functional imaging poststroke reveals visual cortex reorganization.

    Science.gov (United States)

    Brodtmann, Amy; Puce, Aina; Darby, David; Donnan, Geoffrey

    2009-02-01

    Visual cortical reorganization following injury remains poorly understood. The authors performed serial functional magnetic resonance imaging (fMRI) on patients with visual cortex infarction to evaluate early and late striate, ventral, and dorsal extrastriate cortical activation. Patients were studied with fMRI within 10 days and at 6 months. The authors used a high-level visual activation task designed to activate the ventral extrastriate cortex. These data were compared to those of age-appropriate healthy control participants. The results from 24 healthy control individuals (mean age 65.7 +/- SE 3.6 years, range 32-89) were compared to those from 5 stroke patients (mean age 73.8 +/- SE 7 years, range 49-86). Patients had infarcts involving the striate and ventral extrastriate cortex. Patient activation patterns were markedly different to controls. Bilateral striate and ventral extrastriate activation was reduced at both sessions, but dorsal extrastriate activated voxel counts remained comparable to controls. Conversely, mean percent magnetic resonance signal change increased in dorsal sites. These data provide strong evidence of bilateral poststroke functional depression of striate and ventral extrastriate cortices. Possible utilization or surrogacy of the dorsal visual system was demonstrated following stroke. This activity could provide a target for novel visual rehabilitation therapies.

  15. Serial CT scans and Menkes' kinky hair disease

    International Nuclear Information System (INIS)

    Nakada, Eizo; Kameyama, Junji; Yoshimitsu, Hajime; Mori, Mikio; Tanaka, Mutsuo; Yoshimitsu, Kazunori.

    1988-01-01

    Menkes' kinky hair disease is a sex-linked recessive disorder of copper metabolism, characterized by progressive psychomotor deterioration, seizures, and peculiar hair structure. We examined serial CT scans of patients with this disease. A 2,210-g male infant was delivered after an uneventful gestation of 36 weeks. His one-minute Apgar score was 9. His uncle had died at 1 year of age. His first cousin was also diagnosed as having Menkes' kinky hair disease when our patient was 2 years old. Shortly after birth he had mild respiratory distress. At 5 days of age, he developed setting-sun signs. The first CT scan, at 10 days of age, revealed mild posterior fossa hemorrhages. At 3 months of age, myoclonic seizures began, and the CT scan revealed subdural effusion and mild brain atrophy. The seizures were controllable by using phenobarbital, valproic acid, and nitrazepam. He did not follow light or a fixate, but the fundi were normal. He was diffusely hypotonic. At 9 months of age, the seizures became uncontrollable. The CT scans at 15 and 31 months of age showed subdural hemorrhage and/or brain atrophy. At 15 months of age, the serum copper level was 42 μ g/dl, while the serum ceruloplasmin level was 3.2 mg/dl. He exhibited severe developmental failure. At 4 years of age, he died. (author)

  16. Serial CT scans and Menkes' kinky hair disease

    Energy Technology Data Exchange (ETDEWEB)

    Nakada, Eizo; Kameyama, Junji; Yoshimitsu, Hajime; Mori, Mikio; Tanaka, Mutsuo; Yoshimitsu, Kazunori.

    1988-02-01

    Menkes' kinky hair disease is a sex-linked recessive disorder of copper metabolism, characterized by progressive psychomotor deterioration, seizures, and peculiar hair structure. We examined serial CT scans of patients with this disease. A 2,210-g male infant was delivered after an uneventful gestation of 36 weeks. His one-minute Apgar score was 9. His uncle had died at 1 year of age. His first cousin was also diagnosed as having Menkes' kinky hair disease when our patient was 2 years old. Shortly after birth he had mild respiratory distress. At 5 days of age, he developed setting-sun signs. The first CT scan, at 10 days of age, revealed mild posterior fossa hemorrhages. At 3 months of age, myoclonic seizures began, and the CT scan revealed subdural effusion and mild brain atrophy. The seizures were controllable by using phenobarbital, valproic acid, and nitrazepam. He did not follow light or a fixate, but the fundi were normal. He was diffusely hypotonic. At 9 months of age, the seizures became uncontrollable. The CT scans at 15 and 31 months of age showed subdural hemorrhage and/or brain atrophy. At 15 months of age, the serum copper level was 42 ..mu.. g/dl, while the serum ceruloplasmin level was 3.2 mg/dl. He exhibited severe developmental failure. At 4 years of age, he died.

  17. Mediamorfosi del romanzo popolare: dal 'feuilleton' al serial TV

    Directory of Open Access Journals (Sweden)

    Emanuela Piga

    2014-12-01

    Full Text Available Nel 1964, in Apocalittici e integrati Umberto Eco affermava che se l’errore degli apologeti della cultura di massa era di ritenere che la moltiplicazione dei prodotti dell’industria fosse di per sé buona, al contrario, “l’errore degli apocalittici-aristocratici” era di pensare che la cultura di massa fosse radicalmente cattiva proprio per la sua natura di “fatto industriale”, come se si potesse dare cultura al di fuori del condizionamento industriale. In una prospettiva che guarda all’evoluzione storica dei supporti mediali che accolgono e formano l’espressione dell’immaginazione, l’intento qui è di soffermarsi su un’analogia, da più parti riscontrata, tra le forme narrative del romanzo ottocentesco e alcune contemporanee serie televisive. Senza mirare a definire integralmente il rapporto tra le diverse sfere del letterario e del televisivo, lo scopo di questo contributo è  di riflettere sulle trasformazioni del romanzo popolare attraverso epoche e media, a partire dal romanzo ottocentesco Les Mystères de Paris (Eugène Sue e dal contemporaneo Serial TV Lost (J.J. Abrams, D. Lindelof, J. Lieber, C. Cuse.

  18. Serial analysis of gene expression in the silkworm, Bombyx mori.

    Science.gov (United States)

    Huang, Jianhua; Miao, Xuexia; Jin, Weirong; Couble, Pierre; Mita, Kasuei; Zhang, Yong; Liu, Wenbin; Zhuang, Leijun; Shen, Yan; Keime, Celine; Gandrillon, Olivier; Brouilly, Patrick; Briolay, Jerome; Zhao, Guoping; Huang, Yongping

    2005-08-01

    The silkworm Bombyx mori is one of the most economically important insects and serves as a model for Lepidoptera insects. We used serial analysis of gene expression (SAGE) to derive profiles of expressed genes during the developmental life cycle of the silkworm and to create a reference for understanding silkworm metamorphosis. We generated four SAGE libraries, one from each of the four developmental stages of the silkworm. In total we obtained 257,964 SAGE tags, of which 39,485 were unique tags. Sorted by copy number, 14.1% of the unique tags were detected at a median to high level (five or more copies), 24.2% at lower levels (two to four copies), and 61.7% as single copies. Using a basic local alignment search tool on the EST database, 35% of the tags matched known silkworm expressed sequence tags. SAGE demonstrated that a number of the genes were up- or down-regulated during the four developmental phases of the egg, larva, pupa, and adult. Furthermore, we found that the generation of longer cDNA fragments from SAGE tags constituted the most efficient method of gene identification, which facilitated the analysis of a large number of unknown genes.

  19. A reappraisal of serial isotope bone scans in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    O' Donoghue, J M; Rogers, E; Grimes, H; McCarthy, P; Corcoran, M; Bredin, H; Given, H F [University College Hospital, Galway (Ireland)

    1993-08-01

    The authors have evaluated prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) as alternatives to conventional serial bone scanning in 129 patients with newly diagnosed prostate cancer over a period of 3 years. Although serum PSA did not reflect local tumour burden at presentation, it was significantly elevated in those with stage D disease (p < 0.01). 45 patients presented de novo with metastatic bone deposits and a further 18 patients developed metastases during the study. The sensitivity of PSA in detecting secondary deposits at presentation for levels in excess of 100 [mu]g/l was 93.75%, the positive predictive value 95.7% and the negative predictive value for levels less than 5 [mu]g/l was 90.6%. During the follow-up period sensitivity was 94.4%, the positive predictive value 100%, the negative predictive value 100%, with a median lead time of 3 months in predicting metastases in the 18 patients with progressive disease. (author).

  20. Serial Myocardial Imaging after a Single Dose of Thallium-201

    Directory of Open Access Journals (Sweden)

    Takahiko Kamata

    2014-10-01

    Full Text Available Although thallium-201 exercise scintigraphy has been established for the detection of myocardial ischemia and viability, little is known regarding the myocardial thallium-201 kinetics during angioplasty. Herein, we report a 77-year old man with angina pectoris, in whom serial myocardial imaging after a single dose of thallium-201 was helpful in identifying not only the culprit lesion and myocardial viability, but also the dynamic changes in myocardial perfusion during angioplasty. Thallium-201 images after exercise showed a perfusion defect in the inferior wall, with a trivial redistribution 3 hours after the exercise and a marked improvement 24 hours later. Coronary angiography, performed 27 hours after exercise scintigraphy, showed severe stenosis in the right coronary artery. Guidewire crossing of the lesion interrupted the antegrade flow, which was restored after balloon dilation and stent implantation. Thallium-201 images, 2 hours after angioplasty (i.e., 30 hours after exercise, showed a decreased tracer uptake in the inferior wall, which improved the next day (i.e., 48 hours after exercise. Cardiac biomarkers were negative in the clinical course.