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Sample records for aprotininskintigrafi ved amyloidose

  1. Transthyretin Cardiac Amyloidoses in Older North Americans

    PubMed Central

    Dharmarajan, Kumar; Maurer, Mathew S.

    2011-01-01

    The amyloidoses are a group of hereditary or acquired disorders caused by the extracellular deposition of insoluble protein fibrils that impair tissue structure and function. All amyloidoses result from protein misfolding, a common mechanism for disorders in older persons including Alzheimer's disease and Parkinson's disease. Cardiac amyloidoses in the elderly are most often caused by abnormalities in the protein transthyretin (TTR), a serum transporter of thyroxine and retinol. Mutations in TTR can result in familial amyloidotic cardiomyopathy, and wild-type TTR can result in senile cardiac amyloidosis. These underdiagnosed disorders are much more common than previously thought. The resulting restrictive cardiomyopathy can cause congestive heart failure, arrhythmias, and advanced conduction system disease. Although historically difficult to make, the diagnosis of TTR cardiac amyloidosis has become easier in recent years with advances in cardiac imaging and more widespread use of genetic analysis. While therapy to this point has largely involved supportive medical care, avoidance of potentially toxic agents, and rarely organ transplantation, the near future brings the possibility of targeted pharmacotherapies designed to prevent TTR misfolding and amyloid deposition. As these disease modifying agents are designed to prevent disease progression, it has become increasingly important that older persons with TTR amyloidosis be expeditiously identified and considered for enrollment in clinical registries and trials. PMID:22329529

  2. A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses

    PubMed Central

    Zha, Jun; Liu, Xiang-meng; Zhu, Jie; Liu, Shu-ying; Lu, Shuai; Xu, Peng-xin; Yu, Xiao-lin; Liu, Rui-tian

    2016-01-01

    Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson’s disease and Huntington’s disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and other amyloidoses. PMID:27824125

  3. Structural Typing of Systemic Amyloidoses by Luminescent-Conjugated Polymer Spectroscopy

    PubMed Central

    Nilsson, K. Peter R.; Ikenberg, Kristian; Åslund, Andreas; Fransson, Sophia; Konradsson, Peter; Röcken, Christoph; Moch, Holger; Aguzzi, Adriano

    2010-01-01

    Most systemic amyloidoses are progressive and lethal, and their therapy depends on the identification of the offending proteins. Here we report that luminescent-conjugated thiophene polymers (LCP) sensitively detect amyloid deposits. The heterodisperse polythiophene acetic acid derivatives, polythiophene acetic acid (PTAA) and trimeric PTAA, emitted yellow-red fluorescence on binding to amyloid deposits, whereas chemically homogeneous pentameric formic thiophene acetic acid emitted green-yellow fluorescence. The geometry of LCPs modulates the spectral composition of the emitted light, thereby reporting ligand-induced steric changes. Accordingly, a screen of PTAA-stained amyloid deposits in histological tissue arrays revealed striking spectral differences between specimens. Blinded cluster assignments of spectral profiles of tissue samples from 108 tissue samples derived from 96 patients identified three nonoverlapping classes, which were found to match AA, AL, and ATTR immunotyping. We conclude that LCP spectroscopy is a sensitive and powerful tool for identifying and characterizing amyloid deposits. PMID:20035056

  4. Life and consciousness – The Vedāntic view

    PubMed Central

    Shanta, Bhakti Niskama

    2015-01-01

    In the past, philosophers, scientists, and even the general opinion, had no problem in accepting the existence of consciousness in the same way as the existence of the physical world. After the advent of Newtonian mechanics, science embraced a complete materialistic conception about reality. Scientists started proposing hypotheses like abiogenesis (origin of first life from accumulation of atoms and molecules) and the Big Bang theory (the explosion theory for explaining the origin of universe). How the universe came to be what it is now is a key philosophical question. The hypothesis that it came from Nothing (as proposed by Stephen Hawking, among others), proves to be dissembling, since the quantum vacuum can hardly be considered a void. In modern science, it is generally assumed that matter existed before the universe came to be. Modern science hypothesizes that the manifestation of life on Earth is nothing but a mere increment in the complexity of matter — and hence is an outcome of evolution of matter (chemical evolution) following the Big Bang. After the manifestation of life, modern science believed that chemical evolution transformed itself into biological evolution, which then had caused the entire biodiversity on our planet. The ontological view of the organism as a complex machine presumes life as just a chance occurrence, without any inner purpose. This approach in science leaves no room for the subjective aspect of consciousness in its attempt to know the world as the relationships among forces, atoms, and molecules. On the other hand, the Vedāntic view states that the origin of everything material and nonmaterial is sentient and absolute (unconditioned). Thus, sentient life is primitive and reproductive of itself – omne vivum ex vivo – life comes from life. This is the scientifically verified law of experience. Life is essentially cognitive and conscious. And, consciousness, which is fundamental, manifests itself in the gradational forms of all

  5. Life and consciousness - The Vedāntic view.

    PubMed

    Shanta, Bhakti Niskama

    2015-01-01

    In the past, philosophers, scientists, and even the general opinion, had no problem in accepting the existence of consciousness in the same way as the existence of the physical world. After the advent of Newtonian mechanics, science embraced a complete materialistic conception about reality. Scientists started proposing hypotheses like abiogenesis (origin of first life from accumulation of atoms and molecules) and the Big Bang theory (the explosion theory for explaining the origin of universe). How the universe came to be what it is now is a key philosophical question. The hypothesis that it came from Nothing (as proposed by Stephen Hawking, among others), proves to be dissembling, since the quantum vacuum can hardly be considered a void. In modern science, it is generally assumed that matter existed before the universe came to be. Modern science hypothesizes that the manifestation of life on Earth is nothing but a mere increment in the complexity of matter - and hence is an outcome of evolution of matter (chemical evolution) following the Big Bang. After the manifestation of life, modern science believed that chemical evolution transformed itself into biological evolution, which then had caused the entire biodiversity on our planet. The ontological view of the organism as a complex machine presumes life as just a chance occurrence, without any inner purpose. This approach in science leaves no room for the subjective aspect of consciousness in its attempt to know the world as the relationships among forces, atoms, and molecules. On the other hand, the Vedāntic view states that the origin of everything material and nonmaterial is sentient and absolute (unconditioned). Thus, sentient life is primitive and reproductive of itself - omne vivum ex vivo - life comes from life. This is the scientifically verified law of experience. Life is essentially cognitive and conscious. And, consciousness, which is fundamental, manifests itself in the gradational forms of all

  6. The transthyretin amyloidoses: advances in therapy.

    PubMed

    Dubrey, Simon; Ackermann, Elizabeth; Gillmore, Julian

    2015-08-01

    There are two forms of transthyretin (TTR) amyloidosis: non-hereditary and hereditary. The non-hereditary form (ATTRwt) is caused by native or wild-type TTR and was previously referred to as senile systemic amyloidosis. The hereditary form (ATTRm) is caused by variant TTR which results from a genetic mutation of TTR. The predominant effect of ATTRwt amyloidosis is on the heart, with patients having a greater left ventricular wall thickness at presentation than the devastating form which is light chain (AL) amyloidosis. ATTRm amyloidosis is broadly split into two categories: a type that predominantly affects the nervous system (often called familial amyloid polyneuropathy (FAP)) and one with a predilection for the heart (often called familial amyloid cardiomyopathy (FAC)). Approximately half of all TTR mutations known to express a clinical phenotype cause a cardiomyopathy. Since the introduction of orthotopic liver transplantation for ATTRm amyloidosis in 1991, several additional therapies have been developed. These therapies aim to provide a reduction or elimination of TTR from the plasma (through genetic approaches), stabilisation of the TTR molecule (to prevent deposition) and dissolution of the amyloid matrix. We describe the latest developments in these approaches to management, many of which are also applicable to wild-type amyloidosis.

  7. Performance of viscoelastic dampers (VED) under various temperatures and application of magnetorheological dampers (MRD) for seismic control of structures

    NASA Astrophysics Data System (ADS)

    Bhatti, Abdul Qadir

    2013-08-01

    A number of studies have been carried out to investigate the performance of viscoelastic dampers (VEDs) and magnetorheological dampers (MRDs) in controlling the seismic response of buildings, but very few of them regarding the effect of temperature on the behavior of those dampers. The energy absorption properties of the VEDs are dependent on the ambient temperature, excitation frequency and strain amplitude. Several mathematical models have been investigated for reproducing the experimental behavior of single degree of freedom VEDs and MEDs. Of these, only the fractional derivative model can reflect the influence of temperature which is, however, so complex that it is difficult to apply in structural analysis. In order to verify the effect of temperature, two case studies of structural element have been conducted: once using VED and once using MRD. Kelvin-Voigt mathematical model applied, they were investigated and after analyzing the results, the force vs. displacement showed that MRD achieved a high force capacity and a better performance than VED. Furthermore, the effect of the temperature in case of VED observed via plotting the dissipated energy hysteresis at different temperatures. These results validate the effect of the temperature as the lower the temperature the more viscous the dashpot element becomes, hence improving damping, but this is up to a specific low temperature.

  8. Vedāntic view of life: Reply to Gustavo Caetano-Anollés

    PubMed Central

    2016-01-01

    ABSTRACT The author would like to thank Professor Gustavo Caetano-Anollés from Department of Crop Sciences, University of Illinois for his interest in his work. We may sometimes observe that there is a noticeable difference between the anecdote people narrate about the implications of a scientific paper and the real conclusion of the paper. Prof. Gustavo Caetano-Anollés's response1 is an ideal example of the same, where he has tried to make great hay about the implications of the article “Life and consciousness – The Vedāntic view.”2 The Vedāntic view subscribes neither to the views of ‘Creationist Movement’/‘Intelligent Design’, nor it supports some splendid anti-science proposal. Vedāntic view refutes the dominant reductionistic view of life in modern biology by proposing a viable alternative concept of ‘Organic Whole’ and thus serves a scientific critique to the nescience (avidyā) that is practiced on the name of science. PMID:27195069

  9. Vedāntic view of life: Reply to Gustavo Caetano-Anollés.

    PubMed

    Shanta, Bhakti Niskama

    2016-01-01

    The author would like to thank Professor Gustavo Caetano-Anollés from Department of Crop Sciences, University of Illinois for his interest in his work. We may sometimes observe that there is a noticeable difference between the anecdote people narrate about the implications of a scientific paper and the real conclusion of the paper. Prof. Gustavo Caetano-Anollés's response(1) is an ideal example of the same, where he has tried to make great hay about the implications of the article "Life and consciousness - The Vedāntic view."(2) The Vedāntic view subscribes neither to the views of 'Creationist Movement'/'Intelligent Design', nor it supports some splendid anti-science proposal. Vedāntic view refutes the dominant reductionistic view of life in modern biology by proposing a viable alternative concept of 'Organic Whole' and thus serves a scientific critique to the nescience (avidyā) that is practiced on the name of science.

  10. Terahertz-Regime, Micro-VEDs: Evaluation of Micromachined TWT Conceptual Designs

    NASA Technical Reports Server (NTRS)

    Booske, John H.; Kory, Carol L.; Gallagher, D.; van der Weide, Daniel W.; Limbach, S; Gustafson, P; Lee, W.-J.; Gallagher, S.; Jain, K.

    2001-01-01

    Summary form only given. The Terahertz (THz) region of the electromagnetic spectrum (approx.300-3000 GHz) has enormous potential for high-data-rate communications, spectroscopy, astronomy, space research, medicine, biology, surveillance, remote sensing, industrial process control, etc. The most critical roadblock to full exploitation of the THz band is lack of coherent radiation sources that are powerful (0.01-10.0 W continuous wave), efficient (>1 %), frequency agile (instantaneously tunable over 1% bandwidths or more), reliable, and relatively inexpensive. Micro-machined Vacuum Electron Devices (micro-VEDs) represent a promising solution. We describe prospects for miniature, THz-regime TWTs fabricated using micromachining techniques. Several approx.600 GHz conceptual designs are compared. Their expected performance has been analyzed using SD, 2.51), and 3D TWT codes. A folded waveguide (FWG) TWT forward-wave amplifier design is presented based on a Northrop Grumman (NGC) optimized design procedure. This conceptual device is compared to the simulated performance of a novel, micro-VED helix TWT. Conceptual FWG TWT backward-wave amplifiers and oscillators are also discussed. A scaled (100 GHz) FWG TWT operating at a relatively low voltage (-12 kV) is under development at NGC. Also, actual-size micromachining experiments are planned to evaluate the feasibility of arrays of micro-VED TWTs. Progress and results of these efforts are described. This work was supported, in part by AFOSR, ONR, and NSF.

  11. Consciousness, Cognition and the Cognitive Apparatus in the Vedānta Tradition

    PubMed Central

    Balasubramanian, R.

    2011-01-01

    A human being is a complex entity consisting of the Self (also known as Consciousness), mind, senses and the body. The Vedānta tradition holds that the mind, the senses and the body are essentially different from the Self or Consciousness. It is through consciousness that we are able to know the things of the world, making use of the medium of the mind and the senses. Furthermore, the mind, though material, is able to reveal things, borrowing the light from consciousness. From the phenomenological point of view, we have to answer the following questions: how does one know the mind/the mental operations/the cogitations of the mind? Does the mind know itself? Is it possible? There is, again, the problem of the intentionality of consciousness. Is consciousness intentional? According to Vedānta, consciousness by its very nature is not intentional, but it becomes intentional through the mind. The mind or the ego is not part of the consciousness; on the contrary, it is transcendent to consciousness. It is difficult to spell out the relation between consciousness and the mind. How does consciousness, which is totally different from the mind, get related to the mind in such a way that it makes the latter capable of comprehending the things of the world? The Vedānta tradition provides the answer to this question in terms of the knower-known relation. Consciousness is pure light, self-luminous by its very nature, that is, although it reveals other objects, it is not revealed by anything else. When Sartre describes it as nothingness, bereft of even ego, it is to show that it is pure light revealing objects outside it. PMID:21694962

  12. Consciousness, cognition and the cognitive apparatus in the vedānta tradition.

    PubMed

    Balasubramanian, R

    2011-01-01

    A human being is a complex entity consisting of the Self (also known as Consciousness), mind, senses and the body. The Vedānta tradition holds that the mind, the senses and the body are essentially different from the Self or Consciousness. It is through consciousness that we are able to know the things of the world, making use of the medium of the mind and the senses. Furthermore, the mind, though material, is able to reveal things, borrowing the light from consciousness. From the phenomenological point of view, we have to answer the following questions: how does one know the mind/the mental operations/the cogitations of the mind? Does the mind know itself? Is it possible? There is, again, the problem of the intentionality of consciousness. Is consciousness intentional? According to Vedānta, consciousness by its very nature is not intentional, but it becomes intentional through the mind. The mind or the ego is not part of the consciousness; on the contrary, it is transcendent to consciousness. It is difficult to spell out the relation between consciousness and the mind. How does consciousness, which is totally different from the mind, get related to the mind in such a way that it makes the latter capable of comprehending the things of the world? The Vedānta tradition provides the answer to this question in terms of the knower-known relation. Consciousness is pure light, self-luminous by its very nature, that is, although it reveals other objects, it is not revealed by anything else. When Sartre describes it as nothingness, bereft of even ego, it is to show that it is pure light revealing objects outside it.

  13. Grasping at ontological straws: overcoming reductionism in the Advaita Vedānta-Neuroscience dialogue.

    PubMed

    Kaplan, Stephen

    2009-01-01

    Contemporary neuropsychology reveals that the parietal lobe contains neurons that are specifically attuned to the act of grasping and this act may be fundamental to the establishment of the phenomenal boundaries between subject and object. Furthermore, alterations to this process, such as the hypoactivation of this region during meditation or the hyperactivation associated with schizophrenia, may eliminate or confuse, respectively, the phenomenal boundaries between subject and object. Traversing disciplines, the Advaita Vedānta school of Hinduism traces some of its key terms for subject and object to the verbal root grah, to grasp. The subject is literally the grasper. Furthermore, the practice of asparśa yoga, the yoga of no-touch, is aimed at stopping, hypoactivating, the grasping process in order to transcend all subject-object boundaries. This paper will argue that while we have not uncovered an identity of thought, we have uncovered a confluence of ideas between these two disciplines. We will see that this confluence of ideas has not pitted the believer against the critic-not forced us into the great reductionism debate that has dominated so much of the interchange between religious studies and the sciences. This case study will illuminate some of the methodological ways around this reductionism battle and also the boundaries of both disciplines for the intellectual benefit of each.

  14. Modelling Aṣṭādhyāyī: An Approach Based on the Methodology of Ancillary Disciplines (Vedāṅga)

    NASA Astrophysics Data System (ADS)

    Mishra, Anand

    This article proposes a general model based on the common methodological approach of the ancillary disciplines (Vedāṅga) associated with the Vedas taking examples from Śikṣā, Chandas, Vyākaraṇa and Prātiśā khya texts. It develops and elaborates this model further to represent the contents and processes of Aṣṭādhyāyī. Certain key features are added to my earlier modelling of Pāṇinian system of Sanskrit grammar. This includes broader coverage of the Pāṇinian meta-language, mechanism for automatic application of rules and positioning the grammatical system within the procedural complexes of ancillary disciplines.

  15. Alzheimer disease and the prion disorders amyloid beta-protein and prion protein amyloidoses.

    PubMed Central

    Price, D L; Borchelt, D R; Sisodia, S S

    1993-01-01

    Alzheimer disease and the prion disorders/spongiform encephalopathies share many common features. These chronic, progressive, sometimes familial diseases of the central nervous system are characterized by the presence of different types of amyloid deposits in the brain. This review provides a perspective on these two types of neurodegenerative disorders. PMID:8101988

  16. Impact of Deuteration on the Assembly Kinetics of Transthyretin Monitored by Native Mass Spectrometry and Implications for Amyloidoses

    PubMed Central

    Yee, Ai Woon; Moulin, Martine; Breteau, Nina; Haertlein, Michael; Mitchell, Edward P.; Cooper, Jonathan B.

    2016-01-01

    Abstract It is well established that the formation of transthyretin (TTR) amyloid fibrils is linked to the destabilization and dissociation of its tetrameric structure into insoluble aggregates. Isotope labeling is used for the study of TTR by NMR, neutron diffraction, and mass spectrometry (MS). Here MS, thioflavin T fluorescence, and crystallographic data demonstrate that while the X‐ray structures of unlabeled and deuterium‐labeled TTR are essentially identical, subunit exchange kinetics and amyloid formation are accelerated for the deuterated protein. However, a slower subunit exchange is noted in deuterated solvent, reflecting the poorer solubility of non‐polar protein side chains in such an environment. These observations are important for the interpretation of kinetic studies involving deuteration. The destabilizing effects of TTR deuteration are rather similar in character to those observed for aggressive mutations of TTR such as L55P (associated with familial amyloid polyneuropathy). PMID:27311939

  17. In vitro disintegration of goat brain cystatin fibrils using conventional and gemini surfactants: Putative therapeutic intervention in amyloidoses.

    PubMed

    Bhat, Waseem Feeroze; Bhat, Imtiyaz Ahmad; Bhat, Sheraz Ahmad; Bano, Bilqees

    2016-12-01

    Many protein misfolding diseases in mammalian system are characterised by the accumulation of protein aggregates in amyloid fibrillar forms. Several therapeutic approaches include reduction in the production of the amyloidogenic form of proteins, increase in the clearance rate of misfolded or aggregated proteins, and direct inhibition of the self-assembly process have been explained. One of the possible remedial treatments for such disorders may be to identify molecules which are capable of either preventing formation of fibrils or disintegrating the formed fibrils. In this work, we have studied the effect of conventional surfactants; sodium dodecylsulphate (SDS), cetyl trimethylammonium bromide (CTAB) and dicationic gemini (16-4-16) surfactant on the disintegration of the goat brain cystatin (GBC) fibrils above their critical micelle concentrations (CMC) using ThT fluorescence, CD, TEM, Congo red and turbidity approaches. The results obtained are significant and showing the best disintegrating potency on GBC fibrils with gemini surfactant. The outcome from this work will aid in the development and/or design of potential inhibitory agents against amyloid deposits associated with amyloid diseases.

  18. Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses

    PubMed Central

    Galant, Natalie J.; Bugyei-Twum, Antoinette; Rakhit, Rishi; Walsh, Patrick; Sharpe, Simon; Arslan, Pharhad Eli; Westermark, Per; Higaki, Jeffrey N.; Torres, Ronald; Tapia, José; Chakrabartty, Avijit

    2016-01-01

    Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis® and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89–97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential. PMID:27122057

  19. [Diabetes and alternative medicine: diabetic patients experiences with Ayur-Ved, "clinical ecology" and "cellular nutrition" methods].

    PubMed

    Vanelli, M; Chiari, G; Gugliotta, M; Capuano, C; Giacalone, T; Gruppi, L; Condò, M

    2002-04-01

    In the last two years we discovered that three of our patients with type 1 diabetes mellitus (0.8%) suffered an unexpected worsening in their glycemic control due to a reduction of their insulin dosage in favour of some "alternative" diabetes treatments using herbs, vitamins, fantastic diets and trace elements prescribed by non-medical practitioners. The first patient, a 6.6 year old boy, was admitted to hospital because of a severe ketoacidosis with first degree coma as a result of his parents having reduced his insulin dosage by 77% and replacing the insulin with an ayurvedic herbal preparation (Bardana Actium Lapp). The second patient, a 10.4 year old boy, was admitted to hospital after his teachers noticed that he appeared tired, thinner and polyuric. During hospital admission for mild ketoacidosis the mother, reluctant at first, finally confessed that her son was under the care of a "clinical ecologist". Having identified several food allergies this "clinical ecologist" had placed the child on a spartan diet of bread, water and salt, and had reduced his insulin dosage by 68%. The third patient, a 21 year old male, upon transfer to the Adult Diabetic Center, reported that he had been under the care of a pranotherapist for several years. The pranotherapist had prescribed a cellular nutrition preparation (called "Madonna drops"), a meditation program and also a 50% reduction in his insulin dosage. During this period his HbAlc values had increased from 6.4% to 12%. Current orthodox diabetes treatments are considered unsatisfactory by many people and it is thus not surprising that they search for "miracle" cures. It is important, however, that hospital staff do not ridicule the patients or their parents for trying these alternative therapies. Nevertheless, it would be useful for staff to discuss in advance these "therapies" with patients, highlighting their ineffectiveness and strongly discouraging cures that call for a reduction or elimination of the insulin treatment.

  20. Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity

    PubMed Central

    Sant'Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira-Henriques, Alda; Ferreira, Nelson; Pinheiro, Francisca; Esperante, Sebastian; Pallares, Irantzu; Huertas, Oscar; Rosário Almeida, Maria; Reixach, Natàlia; Insa, Raul; Velazquez-Campoy, Adrian; Reverter, David; Reig, Núria; Ventura, Salvador

    2016-01-01

    Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists. PMID:26902880

  1. Natural polyphenols binding to amyloid: a broad class of compounds to treat different human amyloid diseases.

    PubMed

    Ngoungoure, Viviane L Ndam; Schluesener, Jan; Moundipa, Paul F; Schluesener, Hermann

    2015-01-01

    Polyphenols are a large group of phytonutrients found in herbal beverages and foods. They have manifold biological activities, including antioxidative, antimicrobial, and anti-inflammatory properties. Interestingly, some polyphenols bind to amyloid and substantially ameliorate amyloid diseases. Misfolding, aggregation, and accumulation of amyloid fibrils in tissues or organs leads to a group of disorders, called amyloidoses. Prominent diseases are Alzheimer's, Parkinson's, and Huntington's disease, but there are other, less well-known diseases wherein accumulation of misfolded protein is a prominent feature. Amyloidoses are a major burden to public health. In particular, Alzheimer's disease shows a strong increase in patient numbers. Accelerated development of effective therapies for amyloidoses is a necessity. A viable strategy can be the prevention or reduction of protein misfolding, thus reducing amyloid build-up by restoring the cellular aggretome. Amyloid-binding polyphenols affect amyloid formation on various levels, e.g. by inhibiting fibril formation or steering oligomer formation into unstructured, nontoxic pathways. Consequently, preclinical studies demonstrate reduction of amyloid-formation by polyphenols. Amyloid-binding polyphenols might be suitable lead structures for development of imaging agents for early detection of disease and monitoring amyloid deposition. Intake of dietary polyphenols might be relevant to the prevention of amyloidoses. Nutraceutical strategies might be a way to reduce amyloid diseases.

  2. Elucidation of Prion Protein Conformational Changes Associated with Infectivity by Fluorescence Spectroscopy

    DTIC Science & Technology

    2006-06-01

    diseases are fatal neurodegenerative diseases of mammals and include Creutzfeld-Jacob disease (humans), scrapie (sheep), chronic wasting disease (elk...magnetic resonance; PN, peroxynitrite; PrP, prion protein; PrP90, residues 90-232 of hamster prion protein; PrPC, cellular prion; PrPSc, scrapie prion...cow) in cows, chronic wasting in deer and elk, and scrapie in sheep. Prion diseases belong to the larger category of amyloidoses that also includes

  3. Spontaneous Splenic Rupture in Vascular Ehlers-Danlos Syndrome.

    PubMed

    Batagini, Nayara Cioffi; Gornik, Heather; Kirksey, Lee

    2015-01-01

    Vascular Ehlers-Danlos Syndrome (VEDS) is a rare autosomal dominant collagen vascular disorder. Different from other Ehler-Danlos Syndrome subtypes, VEDS has poor prognosis due to severe fragility of connective tissues and association with life-threatening vascular and gastrointestinal complications. Spontaneous splenic rupture is a rare but hazardous complication related to this syndrome. To date, only 2 cases have been reported in the literature. Here we present another case of this uncommon complication, occurring in a 54-year-old woman in clinical follow-up for VEDS who presented with sudden onset of abdominal pain and hypotension.

  4. Recurrent arterial aneurysm rupture of the upper extremity in a patient with vascular-type Ehlers-Danlos syndrome.

    PubMed

    Nakanishi, Koji; Tajiri, Nobuhisa; Nakai, Mikizo; Shimizu, Shuji

    2014-10-01

    Arterial aneurysm rupture is one of the most critical complications in patients with vascular-type Ehlers-Danlos syndrome (vEDS). Here, we report a case of recurrent aneurysm rupture successfully treated by endovascular embolization. A 38-year old woman who underwent brachial artery ligation for a ruptured aneurysm was diagnosed postoperatively with vEDS. Impending rupture of a collateral artery aneurysm was encountered 5 months after the initial open surgery. Endovascular embolization with a liquid embolic agent was successfully performed. Given that arterial rupture can occur repeatedly in patients with vEDS, careful life-long follow-up is necessary.

  5. Oral phenotype and scoring of vascular Ehlers–Danlos syndrome: a case–control study

    PubMed Central

    Frank, Michael; Gogly, Bruno; Golmard, Lisa; Naveau, Adrien; Chérifi, Hafida; Emmerich, Joseph; Gaultier, Frédérick; Berdal, Ariane; Jeunemaitre, Xavier; Fournier, Benjamin P J

    2012-01-01

    Objective Vascular Ehlers–Danlos syndrome (vEDS) is a rare genetic condition related to mutations in the COL3A1 gene, responsible of vascular, digestive and uterine accidents. Difficulty of clinical diagnosis has led to the design of diagnostic criteria, summarised in the Villefranche classification. The goal was to assess oral features of vEDS. Gingival recession is the only oral sign recognised as a minor diagnostic criterion. The authors aimed to check this assumption since bibliographical search related to gingival recession in vEDS proved scarce. Design Prospective case–control study. Setting Dental surgery department in a French tertiary hospital. Participants 17 consecutive patients with genetically proven vEDS, aged 19–55 years, were compared with 46 age- and sex-matched controls. Observations Complete oral examination (clinical and radiological) with standardised assessment of periodontal structure, temporomandibular joint function and dental characteristics were performed. COL3A1 mutations were identified by direct sequencing of genomic or complementary DNA. Results Prevalence of gingival recession was low among patients with vEDS, as for periodontitis. Conversely, patients showed marked gingival fragility, temporomandibular disorders, dentin formation defects, molar root fusion and increased root length. After logistic regression, three variables remained significantly associated to vEDS. These variables were integrated in a diagnostic oral score with 87.5% and 97% sensitivity and specificity, respectively. Conclusions Gingival recession is an inappropriate diagnostic criterion for vEDS. Several new specific oral signs of the disease were identified, whose combination may be of greater value in diagnosing vEDS. PMID:22492385

  6. Amyloidogenic Propensity of a Natural Variant of Human Apolipoprotein A-I: Stability and Interaction with Ligands

    PubMed Central

    Rosú, Silvana A.; Rimoldi, Omar J.; Prieto, Eduardo D.; Curto, Lucrecia M.; Delfino, José M.

    2015-01-01

    A number of naturally occurring mutations of human apolipoprotein A-I (apoA-I) have been associated with hereditary amyloidoses. The molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here we examined the effects of the Arg173Pro point mutation in apoA-I on the structure, stability, and aggregation propensity, as well as on the ability to bind to putative ligands. Our results indicate that the mutation induces a drastic loss of stability, and a lower efficiency to bind to phospholipid vesicles at physiological pH, which could determine the observed higher tendency to aggregate as pro-amyloidogenic complexes. Incubation under acidic conditions does not seem to induce significant desestabilization or aggregation tendency, neither does it contribute to the binding of the mutant to sodium dodecyl sulfate. While the binding to this detergent is higher for the mutant as compared to wt apoA-I, the interaction of the Arg173Pro variant with heparin depends on pH, being lower at pH 5.0 and higher than wt under physiological pH conditions. We suggest that binding to ligands as heparin or other glycosaminoglycans could be key events tuning the fine details of the interaction of apoA-I variants with the micro-environment, and probably eliciting the toxicity of these variants in hereditary amyloidoses. PMID:25950566

  7. Yeast Prions: Structure, Biology, and Prion-Handling Systems

    PubMed Central

    Shewmaker, Frank P.; Bateman, David A.; Edskes, Herman K.; Gorkovskiy, Anton; Dayani, Yaron; Bezsonov, Evgeny E.

    2015-01-01

    SUMMARY A prion is an infectious protein horizontally transmitting a disease or trait without a required nucleic acid. Yeast and fungal prions are nonchromosomal genes composed of protein, generally an altered form of a protein that catalyzes the same alteration of the protein. Yeast prions are thus transmitted both vertically (as genes composed of protein) and horizontally (as infectious proteins, or prions). Formation of amyloids (linear ordered β-sheet-rich protein aggregates with β-strands perpendicular to the long axis of the filament) underlies most yeast and fungal prions, and a single prion protein can have any of several distinct self-propagating amyloid forms with different biological properties (prion variants). Here we review the mechanism of faithful templating of protein conformation, the biological roles of these prions, and their interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling systems, and other cellular factors governing prion generation and propagation. Human amyloidoses include the PrP-based prion conditions and many other, more common amyloid-based diseases, several of which show prion-like features. Yeast prions increasingly are serving as models for the understanding and treatment of many mammalian amyloidoses. Patients with different clinical pictures of the same amyloidosis may be the equivalent of yeasts with different prion variants. PMID:25631286

  8. AMYLOID NEUROPATHIES

    PubMed Central

    Shin, Susan C.; Robinson-Papp, Jessica

    2012-01-01

    Peripheral neuropathy is a common complication of many of the systemic amyloidoses. Although the cause of neuropathy is not entirely clear, it is likely related to amyloid deposition within the nerve. This may lead to focal, multifocal, or diffuse neuropathies involving sensory, motor and/or autonomic fibers. The presenting symptoms depend on the distribution of nerves affected. One of the most common phenotypes is sensorimotor polyneuropathy, which is characterized by symptoms of neuropathic pain, numbness, and in advanced cases weakness. Symptoms begin in the feet and ultimately progress to the proximal legs and hands. The most common focal neuropathy is a median neuropathy at the wrist, or clinically known as carpal tunnel syndrome. Carpal tunnel symptoms may include pain and sensory disturbances in the lateral palm and fingers; hand weakness may ensue if the focal neuropathy is severe. Autonomic neuropathy may affect a variety of organ systems such as the cardiovascular, gastrointestinal, and genitourinary systems. Symptoms may be non-specific making the diagnosis of autonomic neuropathy more difficult to identify. However, it is important to recognize and distinguish autonomic neuropathy from diseases of the end-organs themselves. This chapter reviews the inherited and acquired amyloidoses that affect the peripheral nervous system including familial amyloid polyneuropathy, and primary, secondary and senile amyloidosis. We emphasize the clinical presentation of the neurologic aspects of these diseases, physical examination findings, appropriate diagnostic evaluation, treatment and prognosis. PMID:23239211

  9. Yeast prions: structure, biology, and prion-handling systems.

    PubMed

    Wickner, Reed B; Shewmaker, Frank P; Bateman, David A; Edskes, Herman K; Gorkovskiy, Anton; Dayani, Yaron; Bezsonov, Evgeny E

    2015-03-01

    A prion is an infectious protein horizontally transmitting a disease or trait without a required nucleic acid. Yeast and fungal prions are nonchromosomal genes composed of protein, generally an altered form of a protein that catalyzes the same alteration of the protein. Yeast prions are thus transmitted both vertically (as genes composed of protein) and horizontally (as infectious proteins, or prions). Formation of amyloids (linear ordered β-sheet-rich protein aggregates with β-strands perpendicular to the long axis of the filament) underlies most yeast and fungal prions, and a single prion protein can have any of several distinct self-propagating amyloid forms with different biological properties (prion variants). Here we review the mechanism of faithful templating of protein conformation, the biological roles of these prions, and their interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling systems, and other cellular factors governing prion generation and propagation. Human amyloidoses include the PrP-based prion conditions and many other, more common amyloid-based diseases, several of which show prion-like features. Yeast prions increasingly are serving as models for the understanding and treatment of many mammalian amyloidoses. Patients with different clinical pictures of the same amyloidosis may be the equivalent of yeasts with different prion variants.

  10. Apolipoprotein C-II Deposition Amyloidosis: A Potential Misdiagnosis as Light Chain Amyloidosis

    PubMed Central

    Schuiteman, Emily; Zarouk, Sami

    2016-01-01

    Hereditary amyloidoses are rare and pose a diagnostic challenge. We report a case of hereditary amyloidosis associated with apolipoprotein C-II deposition in a 61-year-old female presenting with renal failure and nephrotic syndrome misdiagnosed as light chain amyloidosis. Renal biopsy was consistent with amyloidosis on microscopy; however, immunofluorescence was inconclusive for the type of amyloid protein. Monoclonal gammopathy evaluation revealed kappa light chain. Bone marrow biopsy revealed minimal involvement with amyloidosis with kappa monotypic plasma cells on flow cytometry. She was started on chemotherapy for light chain amyloidosis. She was referred to the Mayo clinic where laser microdissection and liquid chromatography mass spectrometry detected high levels of apolipoprotein C-II, making a definitive diagnosis. Apolipoprotein C-II is a component of very low-density lipoprotein and aggregates in lipid-free conditions to form amyloid fibrils. The identification of apolipoprotein C-II as the cause of amyloidosis cannot be solely made with routine microscopy or immunofluorescence. Further evaluation of biopsy specimens with laser microdissection and mass spectrometry and DNA sequencing of exons should be done routinely in patients with amyloidoses for definitive diagnosis. Our case highlights the importance of determining the subtype of amyloidosis that is critical for avoiding unnecessary therapy such as chemotherapy. PMID:27840752

  11. Water Molecular System Dynamics Associated with Amyloidogenic Nucleation as Revealed by Real Time Near Infrared Spectroscopy and Aquaphotomics

    PubMed Central

    Chatani, Eri; Tsuchisaka, Yutaro; Masuda, Yuki; Tsenkova, Roumiana

    2014-01-01

    The formation of amyloid fibrils proceeds via a nucleation-dependent mechanism in which nucleation phase is generally associated with a high free energy resulting in the rate-limiting step. On the basis of this kinetic feature, the nucleation is one of the most crucial phases controlling the pathogenesis of amyloidoses, but little is known about the details of how protein molecules and surrounding environment vary at this stage. Here, we applied near infrared (NIR) spectral monitoring of water structural changes in real time during the nucleation-dependent fibrillation of insulin. Whilst multivariate spectral analysis in the 2050–2350 nm spectral region indicated cross-β formation, characteristic transformations of water structure have been detected in the spectral region 1300–1600 nm corresponding to the first overtone of water OH stretching vibrations. Furthermore, specific water spectral patterns (aquagrams) related to different water molecular conformations have been found along the course of protein nucleation and aggregation. Right in the beginning, dissociation of hydrogen-bonded network in bulk water and coinstantaneous protein and ion hydration were observed, followed by water hydrogen-bonded networks development, presumably forcing the nucleation. These specific transformations of water spectral pattern could be used further as a biomarker for early non-invasive diagnosis of amyloidoses prior to explosive amplification and deposits of amyloid fibrils. PMID:25013915

  12. Water molecular system dynamics associated with amyloidogenic nucleation as revealed by real time near infrared spectroscopy and aquaphotomics.

    PubMed

    Chatani, Eri; Tsuchisaka, Yutaro; Masuda, Yuki; Tsenkova, Roumiana

    2014-01-01

    The formation of amyloid fibrils proceeds via a nucleation-dependent mechanism in which nucleation phase is generally associated with a high free energy resulting in the rate-limiting step. On the basis of this kinetic feature, the nucleation is one of the most crucial phases controlling the pathogenesis of amyloidoses, but little is known about the details of how protein molecules and surrounding environment vary at this stage. Here, we applied near infrared (NIR) spectral monitoring of water structural changes in real time during the nucleation-dependent fibrillation of insulin. Whilst multivariate spectral analysis in the 2050-2350 nm spectral region indicated cross-β formation, characteristic transformations of water structure have been detected in the spectral region 1300-1600 nm corresponding to the first overtone of water OH stretching vibrations. Furthermore, specific water spectral patterns (aquagrams) related to different water molecular conformations have been found along the course of protein nucleation and aggregation. Right in the beginning, dissociation of hydrogen-bonded network in bulk water and coinstantaneous protein and ion hydration were observed, followed by water hydrogen-bonded networks development, presumably forcing the nucleation. These specific transformations of water spectral pattern could be used further as a biomarker for early non-invasive diagnosis of amyloidoses prior to explosive amplification and deposits of amyloid fibrils.

  13. Amyloidogenesis in Healing Wound

    PubMed Central

    Hashimoto, Ken; Brownstein, Martin H.

    1972-01-01

    Clinically and histologically typical skin lesions of macular and lichenoid amyloidoses were biopsied. Rebiopsies were performed after 2 to 16 weeks, and the sequence of amyloid reproduction in granulation tissue was followed. Initially, medium electron-dense proteinaceous substance with fine filaments was produced within or in close relation to the rough-surfaced endoplasmic reticulum of fibroblasts and subsequently discharged. Typical amyloid filaments emerged within and in the vicinity of this substance. A significant number of collagen fibrils were admixed in the centers of some amyloid islands. Predominantly amorphous amyloid substance was seen in contact with the basal laminae. No plasma cells were observed in foci of amyloid. Nonepithelialized wounds did not contain amyloid. It was suggested that, in the primary skin amyloidoses, abnormal dermal fibroblasts produce amyloid precursors under the influence of the epidermis. ImagesFig 9Fig 10Fig 4Fig 5Fig 11Fig 6Fig 7Fig 12Fig 1Fig 2Fig 8Fig 3 PMID:5049430

  14. Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis

    PubMed Central

    Ferreira, Nelson; Gonçalves, Nádia P.; Saraiva, Maria J.; Almeida, Maria R.

    2016-01-01

    Transthyretin amyloidoses encompass a variety of acquired and hereditary diseases triggered by systemic extracellular accumulation of toxic transthyretin aggregates and fibrils, particularly in the peripheral nervous system. Since transthyretin amyloidoses are typically complex progressive disorders, therapeutic approaches aiming multiple molecular targets simultaneously, might improve therapy efficacy and treatment outcome. In this study, we evaluate the protective effect of physiologically achievable doses of curcumin on the cytotoxicity induced by transthyretin oligomers in vitro by showing reduction of caspase-3 activity and the levels of endoplasmic reticulum-resident chaperone binding immunoglobulin protein. When given to an aged Familial Amyloidotic Polyneuropathy mouse model, curcumin not only reduced transthyretin aggregates deposition and toxicity in both gastrointestinal tract and dorsal root ganglia but also remodeled congophilic amyloid material in tissues. In addition, curcumin enhanced internalization, intracellular transport and degradation of transthyretin oligomers by primary macrophages from aged Familial Amyloidotic Polyneuropathy transgenic mice, suggesting an impaired activation of naïve phagocytic cells exposed to transthyretin toxic intermediate species. Overall, our results clearly support curcumin or optimized derivatives as promising multi-target disease-modifying agent for late-stage transthyretin amyloidosis. PMID:27197872

  15. In vitro binding of [³H]PIB to human amyloid deposits of different types.

    PubMed

    Hellström-Lindahl, Ewa; Westermark, Per; Antoni, Gunnar; Estrada, Sergio

    2014-03-01

    Systemic amyloidosis is caused by extracellular deposition of insoluble fibrillar proteins arranged in β-pleated sheets. [(11)C]PIB has been used in PET studies to assess Aβ deposition in brain of patients with Alzheimer's disease (AD). The possibility to visualize other types of amyloid deposits with [(11)C]PIB would be of potential clinical importance in early diagnosis and for following therapeutic effects. In the present study, we evaluated in vitro binding of [(3)H]PIB to tissues containing transthyretin (ATTR), immunoglobulin light-chain (AL), amyloid protein A (AA) and Aβ amyloid. We found significantly higher binding of [(3)H]PIB in tissue from systemic amyloidoses than in control tissue, i.e. 4.7 times higher (p < 0.05). [(3)H]PIB showed the highest affinity to cortex of AD brain (IC50 = 3.84 nM), while IC50 values were much higher for ATTR, AA and AL type of amyloidosis and large variations in affinity were observed even within tissues having the same type of amyloidosis. Extraction with guanidine-HCl, which disrupts the β-sheet structure, decreased the protein levels and, concomitantly, the binding of [(3)H]PIB in all four types of amyloidoses.

  16. Altered Dimer Interface Decreases Stability in an Amyloidogenic Protein

    SciTech Connect

    Baden, Elizabeth M.; Owen, Barbara A.L.; Peterson, Francis C.; Volkman, Brian F.; Ramirez-Alvarado, Marina; Thompson, James R.

    2008-07-21

    Amyloidoses are devastating and currently incurable diseases in which the process of amyloid formation causes fatal cellular and organ damage. The molecular mechanisms underlying amyloidoses are not well known. In this study, we address the structural basis of immunoglobulin light chain amyloidosis, which results from deposition of light chains produced by clonal plasma cells. We compare light chain amyloidosis protein AL-09 to its wild-type counterpart, the kl O18/O8 light chain germline. Crystallographic studies indicate that both proteins form dimers. However, AL-09 has an altered dimer interface that is rotated 90 degrees from the kl O18/O8 dimer interface. The three non-conservative mutations in AL-09 are located within the dimer interface, consistent with their role in the decreased stability of this amyloidogenic protein. Moreover, AL-09 forms amyloid fibrils more quickly than kl O18/O8 in vitro. These results support the notion that the increased stability of the monomer and delayed fibril formation, together with a properly formed dimer, may be protective against amyloidogenesis. This could open a new direction into rational drug design for amyloidogenic proteins.

  17. Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.

    PubMed

    Coelho, Teresa; Merlini, Giampaolo; Bulawa, Christine E; Fleming, James A; Judge, Daniel P; Kelly, Jeffery W; Maurer, Mathew S; Planté-Bordeneuve, Violaine; Labaudinière, Richard; Mundayat, Rajiv; Riley, Steve; Lombardo, Ilise; Huertas, Pedro

    2016-06-01

    Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis.

  18. [Brachial artery endothelial function in teenagers with obesity depending on severity of clinical, trophological and metabolic disorders].

    PubMed

    Maskova, G S; Chernaia, N L; Nagornova, E Iu; Fomina, O V; Byteva, T A

    2014-01-01

    We carried out complex examination of 68 adolescents aged 11-17 years with primary obesity which in addition to assessment of clinical-anamnestic, laboratory data and functional parameters of cardiovascular system included registration of reaction of brachial artery endothelium to reactive hyperemia. Vascular endothelial dysfunction (VED) was found in 66% of obese teenagers. Obesity in adolescents with VED was characterized by aggravated course with higher fat mass index (36.8 +/- 4.39%) and prevalence of hypothalamic (42%) and metabolic (8.8%) syndromes. Stable arterial hypertension (AH) found in 37% of examined adolescents was 1.5 times more often registered in those with VED. We distinguished 4 groups of adolescents with various degree of risk of development of cardiovascular disorders: with stable AH and VED (group I), with stable AH and normal function of vascular endothelium (group II), with normal or labile arterial pressure with VED (group III), with normal or labile arterial pressure with normal function of vascular endothelium. It is expedient to supplement examination of obese adolescents with assessment of the state of vascular endothelium aiming at determination of degree of risk of development of atherosclerosis and/or stable AH.

  19. Vessel enhancing diffusion: a scale space representation of vessel structures.

    PubMed

    Manniesing, Rashindra; Viergever, Max A; Niessen, Wiro J

    2006-12-01

    A method is proposed to enhance vascular structures within the framework of scale space theory. We combine a smooth vessel filter which is based on a geometrical analysis of the Hessian's eigensystem, with a non-linear anisotropic diffusion scheme. The amount and orientation of diffusion depend on the local vessel likeliness. Vessel enhancing diffusion (VED) is applied to patient and phantom data and compared to linear, regularized Perona-Malik, edge and coherence enhancing diffusion. The method performs better than most of the existing techniques in visualizing vessels with varying radii and in enhancing vessel appearance. A diameter study on phantom data shows that VED least affects the accuracy of diameter measurements. It is shown that using VED as a preprocessing step improves level set based segmentation of the cerebral vasculature, in particular segmentation of the smaller vessels of the vasculature.

  20. Spontaneous Dissection of the Renal Artery in Vascular Ehlers-Danlos Syndrome

    PubMed Central

    Pereira, Filipa; Cardoso, Teresa; Sá, Paula

    2015-01-01

    Ehlers-Danlos syndrome (EDS) is a rare heterogeneous group of connective tissue disorders. The vascular type (vEDS) is an autosomal dominant disorder caused by heterozygous mutations in the COL3A1 gene predisposing to premature arterial, intestinal, or uterine rupture. We report a case of a 38-year-old woman with a recent diagnosis of vEDS admitted in the Emergency Department with a suspicion of a pyelonephritis that evolved to a cardiopulmonary arrest. A fatal retroperitoneal hematoma related with a haemorrhagic dissection of the right renal artery was found after emergency surgery. This case highlights the need to be aware of the particular characteristics of vEDS, such as a severe vascular complication that can lead to a fatal outcome. PMID:26175915

  1. Total pleural covering technique for intractable pneumothorax in patient with Ehlers-Danlos syndrome.

    PubMed

    Kadota, Yoshihisa; Fukui, Eriko; Kitahara, Naoto; Okura, Eiji; Ohta, Mitsunori

    2016-07-01

    We report a patient with vascular-type Ehlers-Danlos syndrome (vEDS) who developed pneumothorax and was treated with a total pleural covering technique (TPC). A 24-year-old man developed repeat pneumothorax with intermittent hemo-sputum. Based on unusual radiological manifestations of lung lesions and physical findings, EDS was suspected as an underlying cause of the pneumothorax. Surgical treatment was performed using a mediastinal fat pad and TPC, and no relapse was seen up to 2 years after surgery. TPC is a less invasive surgical approach for selected patients with vEDS. Accurate underlying diagnosis of vEDS and systemic evaluation of vascular complications are necessary before planning surgery.

  2. Identification of a new hereditary amyloidosis prealbumin variant, Tyr-77, and detection of the gene by DNA analysis.

    PubMed Central

    Wallace, M R; Dwulet, F E; Williams, E C; Conneally, P M; Benson, M D

    1988-01-01

    In the last several years, five human plasma prealbumin (transthyretin) variants have been discovered in association with hereditary amyloidosis, a late-onset fatal disorder. We recently studied a patient of German descent with peripheral neuropathy and bowel dysfunction. Biopsied rectal tissue contained amyloid that stained with anti-human prealbumin. Amino acid sequence analysis of the patient's plasma prealbumin revealed both normal and variant prealbumin molecules, with the variant containing a tyrosine at position 77 instead of serine. We predicted a single nucleotide change in codon 77 of the variant prealbumin gene, which we then detected in the patient's DNA using the restriction enzyme SspI and a specifically tailored genomic prealbumin probe. DNA tests of other family members identified several gene carriers. This is the sixth prealbumin variant implicated in amyloidosis, and adds to the accumulating evidence that the prealbumin amyloidoses are more varied and prevalent than previously thought. Images PMID:2891727

  3. Cavity filling mutations at the thyroxine-binding site dramatically increase transthyretin stability and prevent its aggregation.

    PubMed

    Sant'Anna, Ricardo; Almeida, Maria Rosário; Varejāo, Nathalia; Gallego, Pablo; Esperante, Sebastian; Ferreira, Priscila; Pereira-Henriques, Alda; Palhano, Fernando L; de Carvalho, Mamede; Foguel, Debora; Reverter, David; Saraiva, Maria João; Ventura, Salvador

    2017-03-24

    More than a hundred different Transthyretin (TTR) mutations are associated with fatal systemic amyloidoses. They destabilize the protein tetrameric structure and promote the extracellular deposition of TTR as pathological amyloid fibrils. So far, only mutations R104H and T119M have been shown to stabilize significantly TTR, acting as disease suppressors. We describe a novel A108V non-pathogenic mutation found in a Portuguese subject. This variant is more stable than wild type TTR both in vitro and in human plasma, a feature that prevents its aggregation. The crystal structure of A108V reveals that this stabilization comes from novel intra and inter subunit contacts involving the thyroxine (T4) binding site. Exploiting this observation, we engineered a A108I mutation that fills the T4 binding cavity, as evidenced in the crystal structure. This synthetic protein becomes one of the most stable TTR variants described so far, with potential application in gene and protein replacement therapies.

  4. [Diabetes type 2 and Alzheimer disease - one or two diseases? Mechanisms of association].

    PubMed

    Marszałek, Małgorzata

    2013-07-23

    Some epidemiological data and pathophysiological evidence suggest similarities and connection of two amyloidoses: diabetes mellitus type 2, (DM2) (non-insulin dependent diabetes mellitus, NIDDM) and Alzheimer's disease (AD). What they have in common is insulin resistance, neurodegeneration, development and progression of dementia, and the fact that in the course of both diseases fibrillar aggregates of specific proteins are accumulated in affected organs. What is more, experimental evidence also supports the hypothesis that small prefibrillar aggregates that emerge prior to the appearance of mature fibrils are responsible for a key step in development and cytotoxicity of both diseases. They also have similar pathogenic effects. Both peptides possess the common receptor AMY3. More and more evidence is accumulating that key cell regulation processes are similar for both diseases as well. The question is raised: can Alzheimer be a new form of diabetes disease?

  5. Dietary polyphenol-derived protection against neurotoxic β-amyloid protein: from molecular to clinical.

    PubMed

    Smid, Scott D; Maag, Jesper L; Musgrave, Ian F

    2012-12-01

    Polyphenolic compounds derived mainly from plant products have demonstrated neuroprotective properties in a number of experimental settings. Such protective effects have often been ascribed to antioxidant capacity, but specific augmentation of other cellular defences and direct interactions with neurotoxic proteins have also been demonstrated. With an emphasis on neurodegenerative conditions, such as Alzheimer's disease, we highlight recent findings on the neuroprotection ascribed to bioactive polyphenols capable of directly interfering with the Alzheimer's disease hallmark toxic β-amyloid protein (Aβ), thereby inhibiting fibril and aggregate formation. This includes compounds such as the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) and the phytoalexin resveratrol. Targeted studies on the biomolecular interactions between dietary polyphenolics and Aβ have not only improved our understanding of the pathogenic role of β-amyloid, but also offer fundamentally novel treatment options for Alzheimer's disease and potentially other amyloidoses.

  6. An Overview of Predictors for Intrinsically Disordered Proteins over 2010-2014.

    PubMed

    Li, Jianzong; Feng, Yu; Wang, Xiaoyun; Li, Jing; Liu, Wen; Rong, Li; Bao, Jinku

    2015-09-29

    The sequence-structure-function paradigm of proteins has been changed by the occurrence of intrinsically disordered proteins (IDPs). Benefiting from the structural disorder, IDPs are of particular importance in biological processes like regulation and signaling. IDPs are associated with human diseases, including cancer, cardiovascular disease, neurodegenerative diseases, amyloidoses, and several other maladies. IDPs attract a high level of interest and a substantial effort has been made to develop experimental and computational methods. So far, more than 70 prediction tools have been developed since 1997, within which 17 predictors were created in the last five years. Here, we presented an overview of IDPs predictors developed during 2010-2014. We analyzed the algorithms used for IDPs prediction by these tools and we also discussed the basic concept of various prediction methods for IDPs. The comparison of prediction performance among these tools is discussed as well.

  7. Amyloid-β peptide aggregation and the influence of carbon nanoparticles

    NASA Astrophysics Data System (ADS)

    Wen-Hui, Xi; Guang-Hong, Wei

    2016-01-01

    Soluble peptides or proteins can self-aggregate into insoluble, ordered amyloid fibrils under appropriate conditions. These amyloid aggregates are the hallmarks of several human diseases ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we first introduce the common structural features of amyloid fibrils and the amyloid fibrillation kinetics determined from experimental studies. Then, we discuss the structural models of Alzheimer’s amyloid-β (Aβ) fibrils derived from solid-state nuclear magnetic resonance spectroscopy. On the computational side, molecular dynamics simulations can provide atomic details of structures and the underlying oligomerization mechanisms. We finally summarize recent progress in atomistic simulation studies on the oligomerization of Aβ (including full-length Aβ and its fragments) and the influence of carbon nanoparticles. Project supported by the National Natural Science Foundation of China (Grant Nos. 11274075 and 91227102).

  8. An Overview of Predictors for Intrinsically Disordered Proteins over 2010–2014

    PubMed Central

    Li, Jianzong; Feng, Yu; Wang, Xiaoyun; Li, Jing; Liu, Wen; Rong, Li; Bao, Jinku

    2015-01-01

    The sequence-structure-function paradigm of proteins has been changed by the occurrence of intrinsically disordered proteins (IDPs). Benefiting from the structural disorder, IDPs are of particular importance in biological processes like regulation and signaling. IDPs are associated with human diseases, including cancer, cardiovascular disease, neurodegenerative diseases, amyloidoses, and several other maladies. IDPs attract a high level of interest and a substantial effort has been made to develop experimental and computational methods. So far, more than 70 prediction tools have been developed since 1997, within which 17 predictors were created in the last five years. Here, we presented an overview of IDPs predictors developed during 2010–2014. We analyzed the algorithms used for IDPs prediction by these tools and we also discussed the basic concept of various prediction methods for IDPs. The comparison of prediction performance among these tools is discussed as well. PMID:26426014

  9. Acute saline expansion increases nephron filtration and distal flow rate but maintains tubuloglomerular feedback responsiveness: role of adenosine A1 receptors

    PubMed Central

    Singh, Prabhleen; Deng, Aihua; Thomson, Scott C.; Vallon, Volker

    2012-01-01

    Temporal adaptation of tubuloglomerular feedback (TGF) permits readjustment of the relationship of nephron filtration rate [single nephron glomerular filtration rate (SNGFR)] and early distal tubular flow rate (VED) while maintaining TGF responsiveness. We used closed-loop assessment of TGF in hydropenia and after acute saline volume expansion (SE; 10% body wt over 1 h) to determine whether 1) temporal adaptation of TGF occurs, 2) adenosine A1 receptors (A1R) mediate TGF responsiveness, and 3) inhibition of TGF affects SNGFR, VED, or urinary excretion under these conditions. SNGFR was evaluated in Fromter-Wistar rats by micropuncture in 1) early distal tubules (ambient flow at macula densa), 2) recollected from early distal tubules while 12 nl/min isotonic fluid was added to late proximal tubule (increased flow to macula densa), and 3) from proximal tubules of same nephrons (zero flow to macula densa). SE increased both ambient SNGFR and VED compared with hydropenia, whereas TGF responsiveness (proximal-distal difference in SNGFR, distal SNGFR response to adding fluid to proximal tubule) was maintained, demonstrating TGF adaptation. A1R blockade completely inhibited TGF responsiveness during SE and made VED more susceptible to perturbation in proximal tubular flow, but did not alter ambient SNGFR or VED. Greater urinary excretion of fluid and Na+ with A1R blockade may reflect additional effects on the distal nephron in hydropenia and SE. In conclusion, A1R-independent mechanisms adjust SNGFR and VED to higher values after SE, which facilitates fluid and Na+ excretion. Concurrently, TGF adapts and stabilizes early distal delivery at the new setpoint in an A1R-dependent mechanism. PMID:22622464

  10. Inventory Analysis in a Private Dental Hospital in Bangalore, India

    PubMed Central

    Krishnappa, Pushpanjali

    2016-01-01

    Introduction There are various approaches for inventory management. Of all the inventory control systems, ABC (Always, Better, Control) and VED (Vital, Essential, Desirable) matrix is most suitable for dental stores. We could not find any literature pertaining to inventory analysis in a private dental hospital. So, we conducted a study in a private dental hospital in Bangalore, Karnataka, India. Aim The present study aimed at evolving an inventory control plan for a private dental institution by categorizing the materials utilizing an ABC-VED coupling matrix. Materials and Methods The study analysed the annual consumption, the expenditure incurred for the dental consumables and developed a matrix based on ABC and VED analysis to narrow down the group of consumables for managerial monitoring. Results Of the 215 consumables used 13.5% (A category) consumed 70% of total annual expenditure. About 21% of the consumables (Category B) consumed 20% and 65.5% (C category) accounted for 10% of the annual expenditure. The VED analysis found 47% consumables as vital, 37.6% as essential and 15.4% as desirable category. ABC-VED matrix analysis categorized 51.6%, 33.5% and 14.8% of consumables as category I, II and III, respectively. Conclusion Categorization by the ABC-VED coupling matrix model helps to narrow down on fewer consumables. The management of Category I consumables was monitored by top management resulting in better control on the annual expenses and at the same time making available the vital consumables. Category II was monitored by middle and Category III at lower managerial level. PMID:28050404

  11. Preservation of penile length after radical prostatectomy: early intervention with a vacuum erection device.

    PubMed

    Dalkin, B L; Christopher, B A

    2007-01-01

    Radical prostatectomy has been shown to have a potential negative impact on penile health. Stretched penile length (SPL), which most closely correlates with erect penile length, was significantly reduced in almost half of men undergoing surgery in several studies. The purpose of this study was to test whether early intervention after surgery with a vacuum erection device could prevent the changes in penile health, as defined by SPL, found in prior studies. Forty-two men with good preoperative sexual function undergoing nerve-sparing radical prostatectomy underwent measurement of SPL preoperative and at 3 months postoperative by a single investigator. Daily use of a vacuum erection device (VED) was begun the day after catheter removal, and continued for 90 days. Men kept a log of their compliance with daily VED use. A decrease in SPL of > or = 1.0 cm was considered significant. Out of 42 men, 39 completed the study. In men who used the VED >50% of possible days, only 1/36 (3%) had a decrease in SPL of > or = 1.0 cm. Of the three men with poor VED compliance, two (67%) had a reduction in SPL of > or = 1.0 cm. When compared to prior studies where 48% of men after surgery had a significant reduction in SPL, early intervention with the daily use of a VED resulted in a significantly lower risk of loss of penile length (P<0.0001). For men wishing to preserve penile health/length after surgery, early intervention with the daily use of a VED should be strongly recommended.

  12. Structure–Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimer's Disease and Related Disorders

    PubMed Central

    Rahimi, F.; Shanmugam, A.; Bitan, G.

    2010-01-01

    Several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and prion diseases, are characterized pathognomonically by the presence of intra- and/or extracellular lesions containing proteinaceous aggregates, and by extensive neuronal loss in selective brain regions. Related non-neuropathic systemic diseases, e.g., light-chain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes mellitus, also are characterized by deposition of aberrantly folded, insoluble proteins. It is debated whether the hallmark pathologic lesions are causative. Substantial evidence suggests that these aggregates are the end state of aberrant protein folding whereas the actual culprits likely are transient, pre-fibrillar assemblies preceding the aggregates. In the context of neurodegenerative amyloidoses, the proteinaceous aggregates may eventuate as potentially neuroprotective sinks for the neurotoxic, oligomeric protein assemblies. The pre-fibrillar, oligomeric assemblies are believed to initiate the pathogenic mechanisms that lead to synaptic dysfunction, neuronal loss, and disease-specific regional brain atrophy. The amyloid β-protein (Aβ), which is believed to cause Alzheimer's disease (AD), is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Aβ assemblies. However, the dynamic and metastable nature of Aβ oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting. Here we review structural, functional, and biological experiments used to produce and study pre-fibrillar Aβ assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that contemporary

  13. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines.

    PubMed

    Sipe, Jean D; Benson, Merrill D; Buxbaum, Joel N; Ikeda, Shu-Ichi; Merlini, Giampaolo; Saraiva, Maria J M; Westermark, Per

    2016-12-01

    The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XVth Symposium of the Society, 3 July-7 July 2016, Uppsala, Sweden, to assess and formulate recommendations for nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. An amyloid fibril must exhibit affinity for Congo red and with green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. While congophilia and birefringence remain the gold standard for demonstration of amyloid deposits, new staining and imaging techniques are proving useful. To be included in the nomenclature list, in addition to congophilia and birefringence, the chemical identity of the protein must be unambiguously characterized by protein sequence analysis when possible. In general, it is insufficient to identify a mutation in the gene of a candidate amyloid protein without confirming the variant changes in the amyloid fibril protein. Each distinct form of amyloidosis is uniquely characterized by the chemical identity of the amyloid fibril protein that deposits in the extracellular spaces of tissues and organs and gives rise to the disease syndrome. The fibril proteins are designated as protein A followed by a suffix that is an abbreviation of the parent or precursor protein name. To date, there are 36 known extracellular fibril proteins in humans, 2 of which are iatrogenic in nature and 9 of which have also been identified in animals. Two newly recognized fibril proteins, AApoCII derived from apolipoprotein CII and AApoCIII derived from apolipoprotein CIII, have been added. AApoCII amyloidosis and AApoCIII amyloidosis are hereditary systemic amyloidoses. Intracellular protein inclusions displaying some of the properties of amyloid, "intracellular amyloid" have been reported. Two proteins which were previously characterized as intracellular inclusions, tau and α-synuclein, are now recognized to form extracellular

  14. Computational modeling of the relationship between amyloid and disease

    PubMed Central

    Hall, Damien; Edskes, Herman

    2013-01-01

    Amyloid is a title conferred upon a special type of linear protein aggregate that exhibits a common set of structural features and dye binding capabilities. The formation of amyloid is associated with over twenty-seven distinct human diseases which are collectively referred to as the amyloidoses. Although there is great diversity amongst the amyloidoses with regard to the polypeptide monomeric precursor, targeted tissues and the nature and time course of disease development, the common underlying link of a structurally similar amyloid aggregate has prompted the search for a unified theory of disease progression in which amyloid production is the central element. Computational modeling has allowed the formulation and testing of scientific hypotheses for exploring this relationship. However, the majority of computational studies on amyloid aggregation are pitched at the atomistic level of description, in simple ideal solution environments, with simulation time scales of the order of microseconds and system sizes limited to a hundred monomers (or less). The experimental reality is that disease related amyloid aggregation processes occur in extremely complex reaction environments (i.e. the human body), over time-scales of months to years with monitoring of the reaction achieved using extremely coarse or indirect experimental markers that yield little or no atomistic insight. Clearly a substantial gap exists between computational and experimental communities with a deficit of ‘useful’ computational methodology that can be directly related to available markers of disease progression. This Review will place its focus on the development of these latter types of computational models and discuss them in relation to disease onset and progression. PMID:23495357

  15. Identification of proteins associated with amyloidosis by polarity index method.

    PubMed

    Polanco, Carlos; Samaniego, José Lino; Uversky, Vladimir N; Castañón-González, Jorge Alberto; Buhse, Thomas; Leopold-Sordo, Marili; Madero-Arteaga, Alejandro; Morales-Reyes, Alicia; Tavera-Sierra, Lourdes; González-Bernal, Jesus A; Arias-Estrada, Miguel

    2015-01-01

    There is a natural protein form, insoluble and resistant to proteolysis, adopted by many proteins independently of their amino acid sequences via specific misfolding-aggregation process. This dynamic process occurs in parallel with or as an alternative to physiologic folding, generating toxic protein aggregates that are deposited and accumulated in various organs and tissues. These proteinaceous deposits typically represent bundles of β-sheet-enriched fibrillar species known as the amyloid fibrils that are responsible for serious pathological conditions, including but not limited to neurodegenerative diseases, grouped under the term amyloidoses. The proteins that might adopt this fibrillar conformation are some globular proteins and natively unfolded (or intrinsically disordered) proteins. Our work shows that intrinsically disordered and intrinsically ordered proteins can be reliably identified, discriminated, and differentiated by analyzing their polarity profiles generated using a computational tool known as the polarity index method (Polanco & Samaniego, 2009; Polanco et al., 2012; 2013; 2013a; 2014; 2014a; 2014b; 2014c; 2014d). We also show that proteins expressed in neurons can be differentiated from proteins in these two groups based on their polarity profiles, and also that this computational tool can be used to identify proteins associated with amyloidoses. The efficiency of the proposed method is high (i.e. 70%) as evidenced by the analysis of peptides and proteins in the APD2 database (2012), AVPpred database (2013), and CPPsite database (2013), the set of selective antibacterial peptides from del Rio et al. (2001), the sets of natively unfolded and natively folded proteins from Oldfield et al. (2005), the set of human revised proteins expressed in neurons, and non-human revised proteins expressed in neurons, from the Uniprot database (2014), and also the set of amyloidogenic proteins from the AmyPDB database (2014).

  16. Current and future treatment of amyloid diseases.

    PubMed

    Ankarcrona, M; Winblad, B; Monteiro, C; Fearns, C; Powers, E T; Johansson, J; Westermark, G T; Presto, J; Ericzon, B-G; Kelly, J W

    2016-08-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment.

  17. Structure-function relationships of pre-fibrillar protein assemblies in Alzheimer's disease and related disorders.

    PubMed

    Rahimi, F; Shanmugam, A; Bitan, G

    2008-06-01

    Several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and prion diseases, are characterized pathognomonically by the presence of intra- and/or extracellular lesions containing proteinaceous aggregates, and by extensive neuronal loss in selective brain regions. Related non-neuropathic systemic diseases, e.g., light-chain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes mellitus, also are characterized by deposition of aberrantly folded, insoluble proteins. It is debated whether the hallmark pathologic lesions are causative. Substantial evidence suggests that these aggregates are the end state of aberrant protein folding whereas the actual culprits likely are transient, pre-fibrillar assemblies preceding the aggregates. In the context of neurodegenerative amyloidoses, the proteinaceous aggregates may eventuate as potentially neuroprotective sinks for the neurotoxic, oligomeric protein assemblies. The pre-fibrillar, oligomeric assemblies are believed to initiate the pathogenic mechanisms that lead to synaptic dysfunction, neuronal loss, and disease-specific regional brain atrophy. The amyloid beta-protein (Abeta), which is believed to cause Alzheimer's disease (AD), is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Abeta assemblies. However, the dynamic and metastable nature of Abeta oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting. Here we review structural, functional, and biological experiments used to produce and study pre-fibrillar Abeta assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that

  18. Genetic factors in amyloidosis.

    PubMed Central

    Thomas, P K

    1975-01-01

    In the absence of biochemical distinctions, the nosography of the inherited amyloidoses must at present depend largely upon clinical subdivisions. In the broad classification adopted here, the disorders have for convenience been grouped according to the anatomical system that is predominantly affected. It is evident that the amyloid syndromes display considerable heterogeneity. However, they overlap. Thus in the Iowa type classified with the hereditary amyloid neuropathies (van Allen et al, 1969; Gimeno et al, 1974), renal involvement was frequent and was the usual cause of death. In the English (Zalin et al, 1974) and Scandinavian (Andersson, 1970) families with neuropathy as the predominant feature, cardiac involvement was a common finding. In certain of the conditions discussed, such as medullary carcinoma of the thyroid and Down's syndrome, amyloid deposition is merely an incidental aspect of the disorder. In those conditions in which generalized or localized amyloid deposition occupies a more central position in the clinical syndrome, an autosomal dominant inheritance has been established or suggested in the majority. An autosomal recessive inheritance has so far only been recognized in familial Mediterranean fever. In the family with hereditary amyloid heart diseases reported by Fredricksen et al (1962), the disorder was confined to a single sibship, raising the possibility of recessive inheritance. This could also be true in sporadic examples of primary amyloidosis. The dominantly inherited amyloidoses comprise a number of geographically widely scattered families with clinical pictures that do not show consistent differences between some families. The families that do not show consistent differences are not necessarily harbouring nutations at the same locus, or the same mutation at any particular locus. However, many of these dominantly inherited clinical syndromes are sufficiently different from each other and the clinical manifestations of each

  19. Cervical artery dissections and type A aortic dissection in a family with a novel missense COL3A1 mutation of vascular type Ehlers-Danlos syndrome.

    PubMed

    Makrygiannis, Georgios; Loeys, Bart; Defraigne, Jean-Olivier; Sakalihasan, Natzi

    2015-11-01

    Cervical artery dissection (CeAD) is a rare condition. One of the causes is the vascular type of Ehlers-Danlos syndrome (vEDS). A novel missense mutation in COL3A1 was found in a young patient with CeAD as the single manifestation of vEDS. This is a heterozygous c.953G > A mutation in exon 14, disrupting the normal Gly-X-Y repeats of type III procollagen, by converting glycine to aspartic acid.

  20. Hearings on Reauthorization of the Vocational Education Act of 1963. Part 10: Vocational Education Data System. Hearing before the Subcommittee on Elementary, Secondary, and Vocational Education of the Committee on Education and Labor. House of Representatives. Ninety-Seventh Congress. First Session (December 10, 1981).

    ERIC Educational Resources Information Center

    Congress of the U.S., Washington, DC. House Committee on Education and Labor.

    This is a report of a hearing on December 10, 1981, before the Subcommittee on Elementary, Secondary, and Vocational Education of the Committee on Education and Labor, House of Representatives, regarding reauthorization of the Vocational Education Act of 1963. It focuses on the vocational education data system known as VEDS. Testimony includes…

  1. Evaluation of Epoxies to Provide Stress-Free Bonding of Pyroceram Mirrors.

    DTIC Science & Technology

    1979-03-01

    re-checked for distortion. In this case, the distortion remained at 6-7 fringes with a definite saddling of the surface. The only conclusion which...intorfesorar shown n Fig’ re 53, but the quntitative dOeqrad-lio ni TF could not be, predicted. Figure 55 is a plot of the MT-.’ responsce achie’ved for the

  2. Cloud/Mesoscale Model Development and Application Studies.

    DTIC Science & Technology

    1987-09-30

    rt t udy. Since ccmp,:etirFg his thesis thisJl task has recei4ved ~essempliasis, though our analysis of Derecho -type events associated with V’CCs... ambient wind. Parcel history can te observed spatially, varying as distance from the orographic barrier. With minimum unc-rtainty, we are thus able to

  3. East Coast Air Combat Maneuvering Range (EC/ACMR) Ocean Tower Construction Completion Report.

    DTIC Science & Technology

    1978-03-01

    fahr ~cat ioni yard to the Vast -oat intallation sites was accomplished in two phases. The first phase invol!ved t ransportat ion of the derrick ha...meeting H. MEDICAl, No injuries, no serious disease . I. MORALE - Vcry Food 2. LT, MAYER, ROICC ACMR, SENDS. F. "- F-9

  4. Stressors and Coping in the Norwegian Aeromedical Detachment in Afghanistan 2008-2010

    DTIC Science & Technology

    2011-04-01

    Lärarhögskolan Stockholm. HLS Förlag. [4] Bache, M., & Hommelgaard, B. (1994). Danske FN- soldater – opplevelser og stressreaktioner. Unpublished report...College. [65] Widing, H., Davøen, L.M., Laberg, J.C., Johnsen, B.H., Brun,W. & Eid, J. (2002). Soldaters vurdering av egne militære ferdigheter ved

  5. Phylogenetic conservatism in plant phenology

    USGS Publications Warehouse

    Davies, T. Jonathan; Wolkovich, Elizabeth M.; Kraft, Nathan J. B.; Salamin, Nicolas; Allen, Jenica M.; Ault, Toby R.; Betancourt, Julio L.; Bolmgren, Kjell; Cleland, Elsa E.; Cook, Benjamin I.; Crimmins, Theresa M.; Mazer, Susan J.; McCabe, Gregory; Pau, Stephanie; Regetz, Jim; Schwartz, Mark D.; Travers, Steven E.

    2013-01-01

    Synthesis. Closely related species tend to resemble each other in the timing of their life-history events, a likely product of evolutionarily conser ved responses to environmental cues. The search for the underlying drivers of phenology must therefore account for species’ shared evolutionary histories.

  6. MICRO-VERS. Micro-computer Software for the Vocational Education Reporting System. Version 3.1. Radio Shack TRS-80 Model III.

    ERIC Educational Resources Information Center

    Illinois State Board of Education, Springfield. Dept. of Adult, Vocational and Technical Education.

    This manual is intended to accompany a software system for the TRS-80 Model III computer that is designed to aid local districts in completing vocational education enrollment claims and Vocational Education Data System (VEDS) reports. Part I, Introduction, gives a brief overview of the Microcomputer Vocational Education Reporting System…

  7. MICRO-VERS. Micro-computer Software for the Vocational Education Reporting System. User's Guide and Reference Manual. Version 3.1. Apple II.

    ERIC Educational Resources Information Center

    Illinois State Board of Education, Springfield. Dept. of Adult, Vocational and Technical Education.

    This manual is intended to accompany a software system for the Apple II microcomputer that is designed to aid local districts in completing vocational education enrollment claims and Vocational Education Data System (VEDS) reports. Part I, Introduction, gives a brief overview of the Microcomputer Vocational Education Reporting System (MICRO-VERS),…

  8. A Rate-Dependent Viscoelastic Damage Model for Simulation of Solid Propellant Impacts

    NASA Astrophysics Data System (ADS)

    Matheson, E. R.; Nguyen, D. Q.

    2006-07-01

    A viscoelastic deformation and damage model (VED) for solid rocket propellants has been developed based on an extensive set of mechanical properties experiments. Monotonic tensile tests performed at several strain rates showed rate and dilatation effects. During cyclic tensile tests, hysteresis and a rate-dependent shear modulus were observed. A tensile relaxation experiment showed significant stress decay in the sample. Taylor impact tests exhibited large dilatations without significant crack growth. Extensive modifications to a viscoelastic-viscoplastic model (VEP) necessary to capture these experimental results have led to development of the VED model. In particular, plasticity has been eliminated in the model, and the multiple Maxwell viscoelastic formulation has been replaced with a time-dependent shear modulus. Furthermore, the loading and unloading behaviors of the material are modeled independently. To characterize the damage and dilatation behavior, the Tensile Damage and Distention (TDD) model is run in conjunction with VED. The VED model is connected to a single-cell driver as well as to the CTH shock physics code. Simulations of tests show good comparisons with tensile tests and some aspects of the Taylor tests.

  9. Community College Journal for Research and Planning.

    ERIC Educational Resources Information Center

    Carter, Edith H., Ed.

    1981-01-01

    This journal, designed as a forum for the exchange of ideas among research and planning professionals, offers articles of research studies and practices. After Timothy Lightfield highlights upcoming professional association events, Janice S. Ancarrow's article, "The National Vocational Education Data Reporting and Accounting System (VEDS): Its…

  10. Simplified analysis of frame structures with viscoelastic dampers considering the effect of soil-structure interaction

    NASA Astrophysics Data System (ADS)

    Zhao, Xuefei; Wang, Shuguang; Du, Dongsheng; Liu, Weiqing

    2017-01-01

    In this study, simplified numerical models are developed to analyze the soil-structure interaction (SSI) effect on frame structures equipped with viscoelastic dampers (VEDs) based on pile group foundation. First, a single degree-of-freedom (SDOF) oscillator is successfully utilized to replace the SDOF energy dissipated structure considering the SSI effect. The equivalent period and damping ratio of the system are obtained through analogical analysis using the frequency transfer function with adoption of the modal strain energy (MSE) technique. A parametric analysis is carried out to study the SSI effect on the performance of VEDs. Then the equilibrium equations of the multi degree-of-freedom (MDOF) structure with VEDs considering SSI effect are established in the frequency domain. Based on the assumption that the superstructure of the coupled system possesses the classical normal mode, the MDOF superstructure is decoupled to a set of individual SDOF systems resting on a rigid foundation with adoption of the MSE technique through formula derivation. Numerical results demonstrate that the proposed methods have the advantage of reducing computational cost, however, retaining the satisfactory accuracy. The numerical method proposed herein can provide a fast evaluation of the efficiency of VEDs considering the SSI effect.

  11. Embolization of Life-Threatening Arterial Rupture in Patients with Vascular Ehlers–Danlos Syndrome

    SciTech Connect

    Okada, Takuya; Frank, Michael; Pellerin, Olivier Primio, Massimiliano Di Angelopoulos, Georgios; Boughenou, Marie-Fazia; Pagny, Jean-Yves; Messas, Emmanuel; Sapoval, Marc

    2013-05-09

    PurposeTo evaluate the safety and efficacy of transarterial embolization of life-threatening arterial rupture in patients with vascular Ehlers–Danlos syndrome (vEDS) in a single tertiary referral center.MethodsWe retrospectively analyzed transarterial embolization for vEDS performed at our institution from 2000 to 2012. The indication of embolization was spontaneous arterial rupture or pseudoaneurysm with acute bleeding. All interventions used a percutaneous approach through a 5F or less introducer sheath. Embolic agents were microcoils and glue in 3 procedures, glue alone in 2, and microcoils alone in 2.ResultsFive consecutive vEDS patients were treated by 7 embolization procedures (4 women, mean age 29.8 years). All procedures were successfully performed. Two patients required a second procedure for newly arterial lesions at a different site from the first procedure. Four of the five patients were still alive after a mean follow-up of 19.4 (range 1–74.7) months. One patient died of multiple organ failure 2 days after procedure. Minor procedural complications were observed in 3 procedures (43 %), all directly managed during the same session. Remote arterial lesions occurred after 3 procedures (43 %); one underwent a second embolization, and the other 2 were observed conservatively. Puncture site complication was observed in only one procedure (14 %).ConclusionEmbolization for vEDS is a safe and effective method to manage life-threatening arterial rupture.

  12. Pulsed Artificial Electrojet Generation

    NASA Astrophysics Data System (ADS)

    Papadopoulos, K.

    2008-12-01

    Traditional techniques for generating low frequency signals in the ULF/ELF range (.1-100 Hz) and rely on ground based Horizontal Electric Dipole (HED) antennas. It is, furthermore, well known that a Vertical Electric Dipole (VED) is by more than 50 dB more efficient than a HED with the same dipole current moment. However, the prohibitively long length of VED antennas in the ELF/ULF range coupled with voltage limitations due to corona discharge in the atmosphere make them totally impracticable. In this paper we discuss a novel concept, inspired by the physics of the equatorial electrojet, that allows for the conversion of a ground based HED to a VED in the E-region of the equatorial ionosphere with current moment comparable to the driving HED. The paper focuses in locations near the dip-equator, where the earth's magnetic is in predominantly in the horizontal direction. The horizontal electric field associated with a pulsed HED drives a large Hall current in the ionospheric E-region, resulting in a vertical current. It is shown that the pulsed vertical current in the altitude range 80-130 km, driven by a horizontal electric field of, approximately, .1 mV/m at 100 km altitude, is of the order of kA. This results in a pulsed VED larger than 106 A-m. Such a pulsed VED will drive ELF/ULF pulses with amplitude in excess of .1 nT at a lateral range larger than few hundred kilometers. This is by three orders of magnitude larger than the one expected by a HED with comparable current moment. The paper will conclude with the description of a sneak-through technique that allows for creating pulsed electric fields in the ionosphere much larger than expected from steady state oscillatory HED antennas.

  13. Molecular diagnosis in Vascular Ehlers-Danlos Syndrome Predicts Pattern of Arterial Involvement and Outcomes

    PubMed Central

    Shalhub, Sherene; Black, James H; Cecchi, Alana C.; Xu, Zhi; Griswold, Ben F; Safi, Hazim J; Milewicz, Dianna M.; McDonnell, Nazli B.

    2015-01-01

    OBJECTIVES The management of arterial pathology in individuals with vascular Ehlers-Danlos syndrome (vEDS) remains a challenge. Here we describe the correlation between COL3A1 gene mutation type and the clinical phenotype in individuals with vEDS. METHODS Individuals with confirmed molecular diagnoses of vEDS were enrolled in a multi institutional natural history study. Data collected included demographics, clinical and family histories, arterial pathology (aneurysm, dissection, and rupture), operative details, and autopsy reports. Individuals were classified into two cohorts based on the type of COL3A1 mutations and their effect on the amount of normal collagen produced: MIN group had mutations that lead to minimal (10–15%) production of normal type III collagen and HI group had haploinsufficiency mutations that lead to production of half the normal type III collagen. RESULTS A cohort of 68 (72%) individuals from 56 families had arterial pathology (44% male, 13% HI). The HI group was older at the time of their first vascular event (mean 42 years, range 26–58 vs. 33 years, range 8–62, P = .016). The HI group had a higher incidence of aortic pathology compared to the MIN group (56% vs. 21%. P = .025). Visceral arterial pathology was seen in 43 arteries in 23 individuals in the MIN group versus only a single artery in 5 individuals in the HI group. Emergent surgical procedures were more likely to be undertaken when vEDS diagnosis was not known (81% vs. 41%, P = .005) and the majority of these procedures were open surgical repair compared to endovascular repair (81% vs. 19%, P = .019). In the elective setting, there was equal use of open and endovascular repair. Post-operative complications were highest when the diagnosis of vEDS was not known (62% vs. 14%, P < .001) and when procedures were undertaken in an emergency setting (5% vs. 55% P < .001). There was no mortality due to arterial complications in the HI cohort and 21% in the MIN cohort (P = .132

  14. Micromachined TWTs for THz Radiation Sources

    NASA Technical Reports Server (NTRS)

    Booske, John H.; vanderWeide, Daniel W.; Kory, Carol L.; Limbach, S.; Downey, Alan (Technical Monitor)

    2001-01-01

    The Terahertz (THz) region of the electromagnetic spectrum (about 300 - 3000 GHz in frequency or about 0.1 - 1 mm free space wavelength) has enormous potential for high-data-rate communications, spectroscopy, astronomy, space research, medicine, biology, surveillance, remote sensing, industrial process control, etc. It has been characterized as the most scientifically rich, yet under-utilized, region of the electromagnetic spectrum. The most critical roadblock to full exploitation of the THz band is lack of coherent radiation sources that are powerful (0.001 - 1.0 W continuous wave), efficient (> 1%), frequency agile (instantaneously tunable over 1% bandwidths or more), reliable, and comparatively inexpensive. To develop vacuum electron device (VED) radiation sources satisfying these requirements, fabrication and packaging approaches must be heavily considered to minimize costs, in addition to the basic interaction physics and circuit design. To minimize size of the prime power supply, beam voltage must be minimized, preferably 10 kV. Solid state sources satisfy the low voltage requirement, but are many orders of magnitude below power, efficiency, and bandwidth requirements. On the other hand, typical fast-wave VED sources in this regime (e.g., gyrotrons, FELs) tend to be large, expensive, high voltage and very high power devices unsuitable for most of the applications cited above. VEDs based on grating or inter-digital (ID) circuits have been researched and developed. However, achieving forward-wave amplifier operation with instantaneous fractional bandwidths > 1% is problematic for these devices with low-energy (< 15 kV) electron beams. Moreover, the interaction impedance is quite low unless the beam-circuit spacing is kept particularly narrow, often leading to significant beam interception. One solution to satisfy the THz source requirements mentioned above is to develop micromachined VEDs, or "micro-VEDs". Among other benefits, micro-machining technologies

  15. Thermo-Mechanical Stress in High-Frequency Vacuum Electron Devices

    NASA Astrophysics Data System (ADS)

    Gamzina, Diana; Luhmann, Neville C.; Ravani, Bahram

    2017-01-01

    Analysis of the thermo-mechanical performance of high-frequency vacuum electron devices is essential to the advancement of RF sources towards high-power generation. Operation in an ultra-high vacuum environment, space restricting magnetic focusing, and limited material options are just some of the constraints that complicate thermal management in a high-power VED. An analytical method for evaluating temperature, stress, and deformation distribution in thin vacuum-to-cooling walls is presented, accounting for anisotropic material properties. Thin plate geometry is used and analytical expressions are developed for thermo-mechanical analysis that includes the microstructure effects of grain orientations. The method presented evaluates the maximum allowable heat flux that can be used to establish the power-handling limitation of high-frequency VEDs prior to full-scale design, accelerating time-to-manufacture.

  16. Introducing cholera vaccination in Asia, Africa and Haiti: a meeting report.

    PubMed

    Hall, Robert H; Sack, David A

    2015-01-15

    Orally-administered cholera vaccine (OCV) has been increasingly examined as an additional tool to intervene against endemic and epidemic cholera. In 2013, short- and long-term field experience with OCV under nine distinctive field settings was reported from India, Bangladesh, Vietnam, Guinea, Haiti, and Thailand. Lead investigators from each of these projects presented their findings at a symposium chaired by Drs. David A. Sack and Robert H. Hall at the Vaccines for Enteric Diseases (VED) Conference in Bangkok on November 7, 2013. The objective of the symposium was to describe the unique features of each setting and project, share field experience of implementing cholera vaccination, discuss results, and identify constraints to the wider use of OCV. The VED provided a forum where >200 attendees engaged with this exciting and potentially decisive new development in the cholera field.

  17. Qualification Test Report. Fuel Pump Test Stand. 3C3965G05

    DTIC Science & Technology

    1991-10-01

    ACTION REQESTS XII. OONCUB ICNS APPEDIX A. VED ORR ATION TESY D SHEETS APPENDIX B. EEFINITICN OF tUt CREA I=CN LIMITS APPENDIX C. CRREATION ETA...LO-DISCH. OPM P4-FIL OUT PSIO T4mIGV INLET - BYPASS OPM PS-DZSCH. PSI0 TSmDISCH. Q3 - IGV IN OPM P6-FIL BPV PSID T&mCELL AM1. r = SERVO RET. GPM

  18. Assessment of Benefits and Drawbacks of Using Fuzzy Logic, Especially in Fire Control Systems

    DTIC Science & Technology

    1994-03-01

    classitied by :W. Pelt classitication date :September 20, 1993 jp:op:ved ci.’ :::: - - - - title :ongerubriceerd manage mentuittreksel :Ongerubriceerd...kanonsysteem het gebruik van "fuzzy reasoning" technieken voorkwam. Dit voorstel is gedaan door SIGNAAL, in een opdracht van de KM. Het TNO-FEL had een...van bet gebruik van fuzzy logic in vergelijking met ’conventionele’ methoden. Geconcludeerd wordt dat er in principe goede mogelijkhieden voor

  19. Abstracts of AF Materials Laboratory Reports

    DTIC Science & Technology

    1975-09-01

    NO: TITLE: AUTHOR(S): CONTRACT NO; CONTRACTOR: AFML-TR-73-307 200,397 IMPROVED AUTOMATED TAPE LAYING MACHINE M. Poullos, W. J. Murray, D.L...AUTOMATED IMPROVED AUTOMATED TAPE LAYING MACHINE AUTOMATION AUTOMATION OF COATING PROCESSES FOR GAS TURBINE DLADcS AND VANES 203222/111 203072...IMP90VE0 TAPE LAYING MACHINE IMPP)VED AUTOMATED TAPE LAYING MACHINE A STUDY O^ THE STRESS-STRAIN TEHAVIOR OF GRAPHITE

  20. The CCTC Quick-Reacting General War Gaming System (QUICK) Users Manual. Volume 3. Weapon Allocation Subsystem

    DTIC Science & Technology

    1978-04-15

    GENERAL Ld WAR GAMING SYSTEM (QUICK) VOLUME III WEAFON ALLOCATION SUBSYSTEM DEFENSE USERS MANUAL COMMUNICATIONS AGENCY FTHIS 2OCUP.ENT HiAS E APP)VED... GAMING SYSTEM Volume III Weapon Allocation Subsystem. SUBMITTED Bl("--- APPROVED BY: Q)C.. IIOMPSON 1ED EI A. RAF, . " Project Officel Captain, U.S...for Military Studies and Analyses, CCTC, in response to a requirement of the Studies, Analysis, and Gaming Agency, Organization of the Joint Chiefs if

  1. The Shaped Charge Concept. Part 2. The History of Shaped Charges

    DTIC Science & Technology

    1990-09-01

    was called lde Beethoven and had a disamee of 180 an with 5,000 kg of high explosive. The Beethoven was designed for ums against ships mnd ground...foificauions. During the Normandy invasion, the Beethoven destroyed two batleships and four large uumrport ships. The Beethoven was the formunnir of die...large Gennan holov charge called the "MISTERIE?" (This is undoubtedl) the MISTEL which evo ved fhom the Beethoven charge discussed earlier). From the

  2. Moral Intuition and the Professional Military Ethic

    DTIC Science & Technology

    2011-03-14

    ndsp=17&ved=1t:429,r:7,s:15&biw=1024&bih=587 3 http://www.google.com/imgres?imgurl=http://www.blogcdn.com/www.pixcetera.com/blog/media/ 2008 /08...17 See Zajonc (1980), Bargh & Chartrand, (1999), Greenwald & Banaji, 1995) as quoted in Haidt, ibid page 818. 18 See Nisbett and...20 Williams , Blair S, Heuristics and Biases in Military Decision Making, Military Review, Sept/OCT 2010. Major

  3. Two-Dimensional Confined Jet Thrust Vector Control: Operating Mechanisms and Performance

    DTIC Science & Technology

    1989-03-01

    Avdilability Codes Nsf / AvduI and Ior 4 01st Specia Appr-ved for public release; distribution unlimited Pr ef ace In this thesis, I continued the...exceptionally high quality test articles, also with impossible deadlines. - the von Karman Institute, Dr. M. Carbonaro provided me with theoretical and...Schlieren photographs and video tapes were used to study flow separation and internal shock structures. Nozzle performance parameters were determined for

  4. Forecasting Device Effectiveness. Volume 2. Procedures

    DTIC Science & Technology

    1985-06-01

    18 months, but who have not ser- ved as gunners. Alternatively, they might be enlistees who have just finished Basic Combat Training (BCT) and on the...34 trouble-shooting a complex : piece of equipment. Consider the number of internal decisions or calculations that must be made in choosing your answer...training system chunk: the material to be learned into small blocks or steps appropriate to the complexity of the subtas:S (tasks) and the capabilities

  5. Verbal Emotional Disclosure of Traumatic Experiences in Adolescents: The Role of Social Risk Factors.

    PubMed

    Pérez, Silvia; Peñate, Wenceslao; Bethencourt, Juan M; Fumero, Ascensión

    2017-01-01

    It is well-known that traumatic events and adverse life situations are very important in both physical and psychological health. Prevalence studies suggested that adolescents experience at least one potentially traumatic event before reaching age 18. The paradigm of research centered on expressive writing has evidenced the beneficial effects that the emotional disclosure of previous traumas produces on physical health and psychological adjustment. The aims of the study are threefold: determining the prevalence of adverse or traumatic events; examining the extent to which psychopathological symptoms developed in those exposed to traumatic events; and exploring an verbal emotional disclosure (VED) paradigm in which variations on time spent talking about traumatic experiences to others resulted in a reduction of the psychological impact of trauma in a sample of Spanish adolescents. 422 volunteer adolescents participated, 226 boys and 192 girls, from 10 to 19 years old, all of them living in Tenerife. The mean age was 14.8 years (SD = 1.83). All of them completed the instruments used to assess the psychological impact of traumatic experiences and VED. The main results indicated that 77% of the participants had suffered a traumatic situation. The participants who have been exposed to traumatic events scored significantly higher in measures of post-traumatic stress, disorder, intrusive thoughts, avoidance behaviors, anxiety and depression, compared to those without trauma. Furthermore, results show a decrease in symptomatology scores as a function of time spent disclosing emotional experiences to others, particularly when disclosure occurred several times. In conclusion, stressful events or traumatic experiences and their concomitant emotional effects are highly prevalent in adolescents, and repeated VED to others appears to ameliorate their impact. VED shows greater therapeutic benefits when adolescents narrate the experience on several occasions and in an extensive way.

  6. Verbal Emotional Disclosure of Traumatic Experiences in Adolescents: The Role of Social Risk Factors

    PubMed Central

    Pérez, Silvia; Peñate, Wenceslao; Bethencourt, Juan M.; Fumero, Ascensión

    2017-01-01

    It is well-known that traumatic events and adverse life situations are very important in both physical and psychological health. Prevalence studies suggested that adolescents experience at least one potentially traumatic event before reaching age 18. The paradigm of research centered on expressive writing has evidenced the beneficial effects that the emotional disclosure of previous traumas produces on physical health and psychological adjustment. The aims of the study are threefold: determining the prevalence of adverse or traumatic events; examining the extent to which psychopathological symptoms developed in those exposed to traumatic events; and exploring an verbal emotional disclosure (VED) paradigm in which variations on time spent talking about traumatic experiences to others resulted in a reduction of the psychological impact of trauma in a sample of Spanish adolescents. 422 volunteer adolescents participated, 226 boys and 192 girls, from 10 to 19 years old, all of them living in Tenerife. The mean age was 14.8 years (SD = 1.83). All of them completed the instruments used to assess the psychological impact of traumatic experiences and VED. The main results indicated that 77% of the participants had suffered a traumatic situation. The participants who have been exposed to traumatic events scored significantly higher in measures of post-traumatic stress, disorder, intrusive thoughts, avoidance behaviors, anxiety and depression, compared to those without trauma. Furthermore, results show a decrease in symptomatology scores as a function of time spent disclosing emotional experiences to others, particularly when disclosure occurred several times. In conclusion, stressful events or traumatic experiences and their concomitant emotional effects are highly prevalent in adolescents, and repeated VED to others appears to ameliorate their impact. VED shows greater therapeutic benefits when adolescents narrate the experience on several occasions and in an extensive way

  7. Does Aid to Families with Dependent Children Displace Familial Assistance?

    DTIC Science & Technology

    1996-07-01

    RAND Does Aid to Families with Dependent Children Displace Familial Assistance? Robert F. Schoeni July 1996 ■ved id ßuclie releasaj DRU-1453-RC...cite this Working paper without permission of the author. OTIC QUALITY JQSSEEGiaa 1 DOES AID TO FAMILIES WITH DEPENDENT CHILDREN DISPLACE FAMILIAL...Public Affairs at Syracuse University for valuable comments. DOES AID TO FAMTTJES WITH DEPENDENT CHILDREN DISPLACE FAMILIAL ASSISTANCE? Abstract

  8. A Multidisciplinary Study of Ciguatoxin and Related Low Molecular Weight Toxins from Marine Source

    DTIC Science & Technology

    1986-08-01

    viscera (liver and intestines) of guinea pigs, and the fruit of the avocado . Authentic ClX ws not available at the time the experiments outlined below...iully Treatmet of the tissues with attract~s from tilapiao, kale,. guines, pig viscera and avocado produced respnes slimilar to those ctain’ved with...all ultimately caused death. Avocado extract differad only in the anmumt necessary to procduce these effects, 80 - 100 ug/kg in two animals. Copy .c

  9. Field Observations and SWAN Model Predictions of Wave Evolution in a Muddy Coastal Environment

    DTIC Science & Technology

    2009-06-01

    start of the wave observati on records. W ind speeds obser ved during the preceding and following one-hour periods did not deviate m ore than 2.8 m...from http://www.fluidmechanics.tudelft.nl/swan/default.htm Hsiao, S., & Shemdin , O. (1980). Interaction of ocean waves with a soft b ottom. J...SWAN MODEL PREDICTIONS OF WAVE EVOLUTION IN A MUDDY COASTAL ENVIRONMENT by Lincoln Thomas Trainor June 2009 Thesis Advisor

  10. Comparison of a Follow-On Analysis and Initial Findings of a Survey of the Perceived Quality of Life of Air Force People

    DTIC Science & Technology

    1979-09-07

    being, his satis- faction or dissatisfaction with life , or happiness or unhappiness [17:11]. Dr. Ben-Chieh Liu has defined QOL as: . . . the output...FOLLOW-ON ANALYSIS AND INITIAL FINDINGS OF A SURVEY OF THE PERCEIVED QUALITY OF LIFE OF AIR FORCE PEOPLE , /•’ / William L./George; Captain...A FOLLOW-ON ANALYSIS AND INITIAL FINDINGS OF A SURVEY OF THE PERCLiVED QUALITY OF LIFE OF AIR FORCE PEOPLE 5 TYPE OF REPORT & PERIOO COVERED

  11. Shift and Scale Invariant Preprocessor.

    DTIC Science & Technology

    1981-12-01

    1982 THESIS D V SHIFT AND SCALE INVARIANT ?PREPROCESSOR by Norman E. Huston, Jr. December 1981 0 Thesis Advisor: L. A. Wilson Approved for public...SCHOOL December 1981 Author: - . 4 ,/ A pp ro0ved by: rYY. ( Thesis Advisor Co-Ad isor Chairman, De artment of 4n n eing Dean of Science and...large range of problems/disciplines. Fields where it is particularly common include optical imagery, acoustic signal processing , radiology, radio

  12. A Design-Aid and Cost Estimate Model for Suppressive Shielding Structures

    DTIC Science & Technology

    1975-12-01

    Dou.-ar-tmelrit Of the Army. Tns0ni has been reviewed aniid isý -a7pro-ved for relase Fr Lurther informlation on this. pr-oject contact Dr . Ccorr--e L...5 Ivaterial Parameters ......... .. 00. .......... 5 Economic Parameters . ........ . ................... . 6 The Cost Equation...pipes, etc. (sae Appendix B) The economic value of suppressive structures must be determiined before they can replace the concrete barriers. An economic

  13. Candidate THz sources: The history and future (?) of velocity-modulated devices

    NASA Astrophysics Data System (ADS)

    Lee, Thomas H.

    2006-02-01

    Compelling applications for terahertz technology include medical diagnostics and imaging, extremely wideband communication (XWB), pollution monitoring and security threat detection. One impediment is a lack of practical sources in the 1-10THz frequency range. Room-temperature CW operation, high spectral purity, tunability, and power levels above the milliwatt range are additional requirements that compound the challenge. Continued scaling of feature sizes will enable traditional semiconductor devices to provide good small-signal performance at THz frequencies, but practically obtaining the desired output power levels is much less certain. Traditional coherent optical sources encounter downward frequency scaling difficulties as the energy state differences approach 25meV (corresponding to approximately 6THz, or 50μm free-space wavelength). Electronic devices dependent on velocity modulation obey rather different scaling laws and are strong candidates for bridging the "terahertz gap." As relatively few contemporary engineers are familiar with vacuum electronic devices (VEDs), and fewer still with velocity modulation, this paper reviews the history of velocity-modulated VEDs, starting with the observations of Barkhausen and Kurz in 1919, and proceeding to practical devices, such as the klystron, magnetron, traveling-wave tube (TWT) and backward-wave oscillator (BWO). We additionally consider how modern process technology enables a reconceiving of classical VEDs to produce devices capable of practical operation in the 1-10THz region.

  14. Vessel Enhancement and Segmentation of 4D CT Lung Image Using Stick Tensor Voting

    NASA Astrophysics Data System (ADS)

    Cong, Tan; Hao, Yang; Jingli, Shi; Xuan, Yang

    2016-12-01

    Vessel enhancement and segmentation plays a significant role in medical image analysis. This paper proposes a novel vessel enhancement and segmentation method for 4D CT lung image using stick tensor voting algorithm, which focuses on addressing the vessel distortion issue of vessel enhancement diffusion (VED) method. Furthermore, the enhanced results are easily segmented using level-set segmentation. In our method, firstly, vessels are filtered using Frangi's filter to reduce intrapulmonary noises and extract rough blood vessels. Secondly, stick tensor voting algorithm is employed to estimate the correct direction along the vessel. Then the estimated direction along the vessel is used as the anisotropic diffusion direction of vessel in VED algorithm, which makes the intensity diffusion of points locating at the vessel wall be consistent with the directions of vessels and enhance the tubular features of vessels. Finally, vessels can be extracted from the enhanced image by applying level-set segmentation method. A number of experiments results show that our method outperforms traditional VED method in vessel enhancement and results in satisfied segmented vessels.

  15. Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis

    SciTech Connect

    Wall, Jonathan; Martin, Emily B.; Richey, Tina; Stuckey, Alan C.; Macy, Sallie; Wooliver, Craig; Williams, Angela; Foster, James S.; McWilliams-Koeppen, Penney; Uberbacher, Ed; Cheng, Xiaolin; Kennel, Stephen J.

    2015-04-27

    Amyloid is a complex pathologic matrix comprised principally of para-crystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloidoses are rare (~3500 new cases per year in the US); thus, routine diagnosis is often challenging, and effective treatment options are limited, resulting in high morbidity and mortality rates. Glycosaminoglycans contribute inextricably to the formation of amyloid fibrils and foster the deposition of amyloid in tissues. Those present in amyloid deposits are biochemically and electrochemically distinct from glycosaminoglycans found in the plasma membrane and extracellular matrices of healthy tissues due to the presence of a high degree of heparin-like hypersulfation. We have exploited this unique property and evaluated heparin-reactive peptides, such as p5+14. Herein we show efficacious detection of murine systemic amyloid in vivo by using molecular imaging, and the specific targeting of the peptide to major forms of human amyloid in tissue sections. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients; thus, providing a novel technique for prognostication, patient stratification, and monitoring response to therapy.

  16. Mechanisms for the inhibition of amyloid aggregation by small ligands

    PubMed Central

    Ramazzotti, Matteo; Melani, Fabrizio; Marchi, Laura; Mulinacci, Nadia; Gestri, Stefano; Tiribilli, Bruno; Degl'Innocenti, Donatella

    2016-01-01

    The formation of amyloid aggregates is the hallmark of systemic and neurodegenerative disorders, also known as amyloidoses. Many proteins have been found to aggregate into amyloid-like fibrils and this process is recognized as a general tendency of polypeptides. Lysozyme, an antibacterial protein, is a well-studied model since it is associated in human with systemic amyloidosis and that is widely available from chicken eggs (HEWL, hen egg white lysozyme). In the present study we investigated the mechanism of interaction of aggregating HEWL with rosmarinic acid and resveratrol, that we verified to be effective and ineffective, respectively, in inhibiting aggregate formation. We used a multidisciplinary strategy to characterize such effects, combining biochemical and biophysical methods with molecular dynamics (MD) simulations on the HEWL peptide 49–64 to gain insights into the mechanisms and energy variations associated to amyloid formation and inhibition. MD revealed that neither resveratrol nor rosmarinic acid were able to compete with the initial formation of the β-sheet structure. We then tested the association of two β-sheets, representing the model of an amyloid core structure. MD showed that rosmarinic acid displayed an interaction energy and a contact map comparable to that of sheet pairings. On the contrary, resveratrol association energy was found to be much lower and its contact map largely different than that of sheet pairings. The overall characterization elucidated a possible mechanism explaining why, in this model, resveratrol is inactive in blocking fibril formation, whereas rosmarinic acid is instead a powerful inhibitor. PMID:27512096

  17. A quantitative model of the generation of N(epsilon)-(carboxymethyl)lysine in the Maillard reaction between collagen and glucose.

    PubMed Central

    Ferreira, António E N; Ponces Freire, Ana M J; Voit, Eberhard O

    2003-01-01

    The Maillard reaction between reducing sugars and amino groups of biomolecules generates complex structures known as AGEs (advanced glycation endproducts). These have been linked to protein modifications found during aging, diabetes and various amyloidoses. To investigate the contribution of alternative routes to the formation of AGEs, we developed a mathematical model that describes the generation of CML [ N(epsilon)-(carboxymethyl)lysine] in the Maillard reaction between glucose and collagen. Parameter values were obtained by fitting published data from kinetic experiments of Amadori compound decomposition and glycoxidation of collagen by glucose. These raw parameter values were subsequently fine-tuned with adjustment factors that were deduced from dynamic experiments taking into account the glucose and phosphate buffer concentrations. The fine-tuned model was used to assess the relative contributions of the reaction between glyoxal and lysine, the Namiki pathway, and Amadori compound degradation to the generation of CML. The model suggests that the glyoxal route dominates, except at low phosphate and high glucose concentrations. The contribution of Amadori oxidation is generally the least significant at low glucose concentrations. Simulations of the inhibition of CML generation by aminoguanidine show that this compound effectively blocks the glyoxal route at low glucose concentrations (5 mM). Model results are compared with literature estimates of the contributions to CML generation by the three pathways. The significance of the dominance of the glyoxal route is discussed in the context of possible natural defensive mechanisms and pharmacological interventions with the goal of inhibiting the Maillard reaction in vivo. PMID:12911334

  18. A Hydrophobic Gold Surface Triggers Misfolding and Aggregation of the Amyloidogenic Josephin Domain in Monomeric Form, While Leaving the Oligomers Unaffected

    PubMed Central

    Apicella, Alessandra; Soncini, Monica; Deriu, Marco Agostino; Natalello, Antonino; Bonanomi, Marcella; Dellasega, David; Tortora, Paolo; Regonesi, Maria Elena; Casari, Carlo Spartaco

    2013-01-01

    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. PMID:23527026

  19. Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing α/β and α/γ Hybrid Peptidomimetics

    PubMed Central

    Paul, Ashim; Kalita, Sourav; Kalita, Sujan; Sukumar, Piruthivi; Mandal, Bhubaneswar

    2017-01-01

    Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted β, γ and δ -aminobenzoic acid separately into an amyloidogenic peptide sequence, synthesized α/β, α/γ and α/δ hybrid peptidomimetics, respectively. Interestingly, we observed the aggregation inhibitory efficacy of α/β and α/γ BSBHps, but not of α/δ analogues. They also disrupt existing amyloids into non-toxic forms. Results may be useful for newer drug design against T2DM as well as other amyloidoses and understanding amyloidogenesis. PMID:28054630

  20. Amyloid β-Protein C-Terminal Fragments: Formation of Cylindrins and β-Barrels.

    PubMed

    Do, Thanh D; LaPointe, Nichole E; Nelson, Rebecca; Krotee, Pascal; Hayden, Eric Y; Ulrich, Brittany; Quan, Sarah; Feinstein, Stuart C; Teplow, David B; Eisenberg, David; Shea, Joan-Emma; Bowers, Michael T

    2016-01-20

    In order to evaluate potential therapeutic targets for treatment of amyloidoses such as Alzheimer's disease (AD), it is essential to determine the structures of toxic amyloid oligomers. However, for the amyloid β-protein peptide (Aβ), thought to be the seminal neuropathogenetic agent in AD, its fast aggregation kinetics and the rapid equilibrium dynamics among oligomers of different size pose significant experimental challenges. Here we use ion-mobility mass spectrometry, in combination with electron microscopy, atomic force microscopy, and computational modeling, to test the hypothesis that Aβ peptides can form oligomeric structures resembling cylindrins and β-barrels. These structures are hypothesized to cause neuronal injury and death through perturbation of plasma membrane integrity. We show that hexamers of C-terminal Aβ fragments, including Aβ(24-34), Aβ(25-35) and Aβ(26-36), have collision cross sections similar to those of cylindrins. We also show that linking two identical fragments head-to-tail using diglycine increases the proportion of cylindrin-sized oligomers. In addition, we find that larger oligomers of these fragments may adopt β-barrel structures and that β-barrels can be formed by folding an out-of-register β-sheet, a common type of structure found in amyloid proteins.

  1. Amyloid β-Protein C-terminal Fragments: Formation of Cylindrins and β-barrels

    PubMed Central

    Do, Thanh D.; LaPointe, Nichole E.; Nelson, Rebecca; Krotee, Pascal; Hayden, Eric Y.; Ulrich, Brittany; Quan, Sarah; Feinstein, Stuart C.; Teplow, David B.; Eisenberg, David; Shea, Joan-Emma; Bowers, Michael T.

    2016-01-01

    In order to evaluate potential therapeutic targets for treatment of amyloidoses such as Alzheimer’s disease (AD), it is essential to determine the structures of toxic amyloid oligomers. However, for the amyloid β-protein peptide (Aβ), thought to be the seminal neuropathogenetic agent in AD, its fast aggregation kinetics and the rapid equilibrium dynamics among oligomers of different size pose significant experimental challenges. Here we use ion-mobility mass spectrometry, in combination with electron microscopy, atomic force microscopy, and computational modeling, to test the hypothesis that Aβ peptides can form oligomeric structures resembling cylindrins and β-barrels. These structures are hypothesized to cause neuronal injury and death through perturbation of plasma membrane integrity. We show that hexamers of C-terminal Aβ fragments, including Aβ(24-34), Aβ(25-35) and Aβ(26-36), have collision cross-sections similar to those of cylindrins. We also show that linking two identical fragments head-to-tail using di-glycine increases the proportion of cylindrin-sized oligomers. In addition, we find that larger oligomers of these fragments may adopt β-barrel structures and that β-barrels can be formed by folding an out-of-register β-sheet, a common type of structure found in amyloid proteins. PMID:26700445

  2. Immunoglobulin light chains, glycosaminoglycans and amyloid.

    SciTech Connect

    Stevens, F. J.; Kisilevsky, R.; Biosciences Division; Queen's Univ.

    2000-03-01

    Immunoglobulin light chains are the precursor proteins for fibrils that are formed during primary amyloidosis and in amyloidosis associated with multiple myeloma. As found for the approximately 20 currently described forms of focal, localized, or systemic amyloidoses, light chain-related fibrils extracted from physiological deposits are invariably associated with glycosaminoglycans, predominantly heparan sulfate. Other amyloid-related proteins are either structurally normal, such as g2-microglobulin and islet amyloid polypeptide, fragments of normal proteins such as serum amyloid A protein or the precursor protein of the g peptide involved in Alzheimer's disease, or are inherited forms of single amino acid variants of a normal protein such as found in the familial forms of amyloid associated with transthyretin. In contrast, the primary structures of light chains involved in fibril formation exhibit extensive mutational diversity rendering some proteins highly amyloidogenic and others non-pathological. The interactions between light chains and glycosaminoglycans are also affected by amino acid variation and may influence the clinical course of disease by enhancing fibril stability and contributing to resistance to protease degradation. Relatively little is currently known about the mechanisms by which glycosaminoglycans interact with light chains and light-chain fibrils. It is probable that future studies of this uniquely diverse family of proteins will continue o shed light on the processes of amyloidosis, and contribute as well to a greater understanding of the normal physiological roles of glycosaminoglycans.

  3. Human Apolipoprotein A-I-Derived Amyloid: Its Association with Atherosclerosis

    PubMed Central

    Ramella, Nahuel A.; Rimoldi, Omar J.; Prieto, Eduardo D.; Schinella, Guillermo R.; Sanchez, Susana A.; Jaureguiberry, María S.; Vela, María E.

    2011-01-01

    Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA-I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis. PMID:21811627

  4. A comparative study on the aggregating effects of guanidine thiocyanate, guanidine hydrochloride and urea on lysozyme aggregation

    SciTech Connect

    Emadi, Saeed Behzadi, Maliheh

    2014-08-08

    Highlights: • Lysozyme aggregated in guanidine thiocyanate (1.0 and 2.0 M). • Lysozyme aggregated in guanidine hydrochloride (4 and 5 M). • Lysozyme did not aggregated at any concentration (0.5–5 M) of urea. • Unfolding pathway is more important than unfolding per se in aggregation. - Abstract: Protein aggregation and its subsequent deposition in different tissues culminate in a diverse range of diseases collectively known as amyloidoses. Aggregation of hen or human lysozyme depends on certain conditions, namely acidic pH or the presence of additives. In the present study, the effects on the aggregation of hen egg-white lysozyme via incubation in concentrated solutions of three different chaotropic agents namely guanidine thiocyanate, guanidine hydrochloride and urea were investigated. Here we used three different methods for the detection of the aggregates, thioflavin T fluorescence, circular dichroism spectroscopy and atomic force microscopy. Our results showed that upon incubation with different concentrations (0.5, 1.0, 2.0, 3.0, 4.0, 5.0 M) of the chemical denaturants, lysozyme was aggregated at low concentrations of guanidine thiocyanate (1.0 and 2.0 M) and at high concentrations of guanidine hydrochloride (4 and 5 M), although no fibril formation was detected. In the case of urea, no aggregation was observed at any concentration.

  5. Transthyretin and BRICHOS: The Paradox of Amyloidogenic Proteins with Anti-Amyloidogenic Activity for Aβ in the Central Nervous System

    PubMed Central

    Buxbaum, Joel N.; Johansson, Jan

    2017-01-01

    Amyloid fibrils are physiologically insoluble biophysically specific β-sheet rich structures formed by the aggregation of misfolded proteins. In vivo tissue amyloid formation is responsible for more than 30 different disease states in humans and other mammals. One of these, Alzheimer's disease (AD), is the most common form of human dementia for which there is currently no definitive treatment. Amyloid fibril formation by the amyloid β-peptide (Aβ) is considered to be an underlying cause of AD, and strategies designed to reduce Aβ production and/or its toxic effects are being extensively investigated in both laboratory and clinical settings. Transthyretin (TTR) and proteins containing a BRICHOS domain are etiologically associated with specific amyloid diseases in the CNS and other organs. Nonetheless, it has been observed that TTR and BRICHOS structures are efficient inhibitors of Aβ fibril formation and toxicity in vitro and in vivo, raising the possibility that some amyloidogenic proteins, or their precursors, possess properties that may be harnessed for combating AD and other amyloidoses. Herein, we review properties of TTR and the BRICHOS domain and discuss how their abilities to interfere with amyloid formation may be employed in the development of novel treatments for AD. PMID:28360830

  6. β2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

    PubMed Central

    Goodchild, Sophia C.; Sheynis, Tania; Thompson, Rebecca; Tipping, Kevin W.; Xue, Wei-Feng; Ranson, Neil A.; Beales, Paul A.; Hewitt, Eric W.; Radford, Sheena E.

    2014-01-01

    Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of β2-microglobulin (β2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which β2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of β2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that β2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between β2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of β2m amyloid-associated osteoarticular tissue destruction in DRA. PMID:25100247

  7. Amyloids: from Pathogenesis to Function.

    PubMed

    Nizhnikov, A A; Antonets, K S; Inge-Vechtomov, S G

    2015-09-01

    The term "amyloids" refers to fibrillar protein aggregates with cross-β structure. They have been a subject of intense scrutiny since the middle of the previous century. First, this interest is due to association of amyloids with dozens of incurable human diseases called amyloidoses, which affect hundreds of millions of people. However, during the last decade the paradigm of amyloids as pathogens has changed due to an increase in understanding of their role as a specific variant of quaternary protein structure essential for the living cell. Thus, functional amyloids are found in all domains of the living world, and they fulfill a variety of roles ranging from biofilm formation in bacteria to long-term memory regulation in higher eukaryotes. Prions, which are proteins capable of existing under the same conditions in two or more conformations at least one of which having infective properties, also typically have amyloid features. There are weighty reasons to believe that the currently known amyloids are only a minority of their real number. This review provides a retrospective analysis of stages in the development of amyloid biology that during the last decade resulted, on one hand, in reinterpretation of the biological role of amyloids, and on the other hand, in the development of systems biology of amyloids, or amyloidomics.

  8. Amyloidogenic potential of foie gras.

    PubMed

    Solomon, Alan; Richey, Tina; Murphy, Charles L; Weiss, Deborah T; Wall, Jonathan S; Westermark, Gunilla T; Westermark, Per

    2007-06-26

    The human cerebral and systemic amyloidoses and prion-associated spongiform encephalopathies are acquired or inherited protein folding disorders in which normally soluble proteins or peptides are converted into fibrillar aggregates. This is a nucleation-dependent process that can be initiated or accelerated by fibril seeds formed from homologous or heterologous amyloidogenic precursors that serve as an amyloid enhancing factor (AEF) and has pathogenic significance in that disease may be transmitted by oral ingestion or parenteral administration of these conformationally altered components. Except for infected brain tissue, specific dietary sources of AEF have not been identified. Here we report that commercially available duck- or goose-derived foie gras contains birefringent congophilic fibrillar material composed of serum amyloid A-related protein that acted as a potent AEF in a transgenic murine model of secondary (amyloid A protein) amyloidosis. When such mice were injected with or fed amyloid extracted from foie gras, the animals developed extensive systemic pathological deposits. These experimental data provide evidence that an amyloid-containing food product hastened the development of amyloid protein A amyloidosis in a susceptible population. On this basis, we posit that this and perhaps other forms of amyloidosis may be transmissible, akin to the infectious nature of prion-related illnesses.

  9. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis

    PubMed Central

    Ward, Jennifer Ellis; Ren, Ruiyi; Toraldo, Gianluca; SooHoo, Pam; Guan, Jian; O'Hara, Carl; Jasuja, Ravi; Trinkaus-Randall, Vickery; Liao, Ronglih; Connors, Lawreen H.

    2011-01-01

    Systemic AL amyloidosis results from the aggregation of an amyloidogenic immunoglobulin (Ig) light chain (LC) usually produced by a plasma cell clone in the bone marrow. AL is the most rapidly fatal of the systemic amyloidoses, as amyloid fibrils can rapidly accumulate in tissues including the heart, kidneys, autonomic or peripheral nervous systems, gastrointestinal tract, and liver. Chemotherapy is used to eradicate the cellular source of the amyloidogenic precursor. Currently, there are no therapies that target the process of LC aggregation, fibril formation, or organ damage. We developed transgenic mice expressing an amyloidogenic λ6 LC using the cytomegalovirus (CMV) promoter to circumvent the disruption of B cell development by premature expression of recombined LC. The CMV-λ6 transgenic mice develop neurologic dysfunction and Congophilic amyloid deposits in the stomach. Amyloid deposition was inhibited in vivo by the antibiotic doxycycline. In vitro studies demonstrated that doxycycline directly disrupted the formation of recombinant LC fibrils. Furthermore, treatment of ex vivo LC amyloid fibrils with doxycycline reduced the number of intact fibrils and led to the formation of large disordered aggregates. The CMV-λ6 transgenic model replicates the process of AL amyloidosis and is useful for testing the antifibril potential of orally available agents. PMID:21998211

  10. Amyloid-linked cellular toxicity triggered by bacterial inclusion bodies

    SciTech Connect

    Gonzalez-Montalban, Nuria; Villaverde, Antonio; Aris, Anna; E-mail: Anna.Aris@irta.es

    2007-04-13

    The aggregation of proteins in the form of amyloid fibrils and plaques is the characteristic feature of some pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. The mechanisms by which the aggregation processes result in cell damage are under intense investigation but recent data indicate that prefibrillar aggregates are the most proximate mediators of toxicity rather than mature fibrils. Since it has been shown that prefibrillar forms of the nondisease-related misfolded proteins are highly toxic to cultured mammalian cells we have studied the cytoxicity associated to bacterial inclusion bodies that have been recently described as protein deposits presenting amyloid-like structures. We have proved that bacterial inclusion bodies composed by a misfolding-prone {beta}-galactosidase fusion protein are clearly toxic for mammalian cells but the {beta}-galactosidase wild type enzyme forming more structured thermal aggregates does not impair cell viability, despite it also binds and enter into the cells. These results are in the line that the most cytotoxic aggregates are early prefibrilar assemblies but discard the hypothesis that the membrane destabilization is Key event to subsequent disruption of cellular processes, such as ion balance, oxidative state and the eventually cell death.

  11. Cavity filling mutations at the thyroxine-binding site dramatically increase transthyretin stability and prevent its aggregation

    PubMed Central

    Sant’Anna, Ricardo; Almeida, Maria Rosário; Varejāo, Nathalia; Gallego, Pablo; Esperante, Sebastian; Ferreira, Priscila; Pereira-Henriques, Alda; Palhano, Fernando L.; de Carvalho, Mamede; Foguel, Debora; Reverter, David; Saraiva, Maria João; Ventura, Salvador

    2017-01-01

    More than a hundred different Transthyretin (TTR) mutations are associated with fatal systemic amyloidoses. They destabilize the protein tetrameric structure and promote the extracellular deposition of TTR as pathological amyloid fibrils. So far, only mutations R104H and T119M have been shown to stabilize significantly TTR, acting as disease suppressors. We describe a novel A108V non-pathogenic mutation found in a Portuguese subject. This variant is more stable than wild type TTR both in vitro and in human plasma, a feature that prevents its aggregation. The crystal structure of A108V reveals that this stabilization comes from novel intra and inter subunit contacts involving the thyroxine (T4) binding site. Exploiting this observation, we engineered a A108I mutation that fills the T4 binding cavity, as evidenced in the crystal structure. This synthetic protein becomes one of the most stable TTR variants described so far, with potential application in gene and protein replacement therapies. PMID:28338000

  12. Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing α/β and α/γ Hybrid Peptidomimetics

    NASA Astrophysics Data System (ADS)

    Paul, Ashim; Kalita, Sourav; Kalita, Sujan; Sukumar, Piruthivi; Mandal, Bhubaneswar

    2017-01-01

    Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted β, γ and δ -aminobenzoic acid separately into an amyloidogenic peptide sequence, synthesized α/β, α/γ and α/δ hybrid peptidomimetics, respectively. Interestingly, we observed the aggregation inhibitory efficacy of α/β and α/γ BSBHps, but not of α/δ analogues. They also disrupt existing amyloids into non-toxic forms. Results may be useful for newer drug design against T2DM as well as other amyloidoses and understanding amyloidogenesis.

  13. Nuclear imaging of amyloidosis.

    PubMed

    Cytawa, Wojciech; Teodorczyk, Jacek; Lass, Piotr

    2014-01-01

    Summary Amyloidosis is a clinical condition caused by deposition of various protein fibrills in extracellular space. The presented symptoms depend on the type of deposits and the organ or organs involved. The correct diagnosis is often difficult, due to lack of nonivasive imaging techniques and insufficiency of morphological imaging procedures delievered by radiology. We presented a list of potential radiopharmaceuticals that can be used in detecting various types of amyloidoses. (123)I-SAP proved to have high sensitivity in imaging of AA and AL amyloidosis in visceral organs. (99m)Tc-Aprotinin was found to be useful in detecting cardiac amyloidosis. A couple of classical radiotracers, such as (201)Tl, (123)I-mIBG, together with (111)In-antimyosin were also tested for accuracy in cardiac imaging, however the main problem was low specificity. Potential applicability was also found in case of some bone-seeking agents and other radiotracers, e.g. (67)Ga-citrate and (99m)Tc-penta-DMSA. High sensitivity and specificity was achieved with β2-microglobulin labeled with (131)I or (111)In. Among PET tracers, (11)C-PIB deserves more attention, because it may have an important role in diagnosing of AD in the near future. Further clinical studies are expected to take place, because noninvasive diagnosing and monitoring of amyloidosis is still a challenge.

  14. Dynamics of oligomer formation by denatured carbonic anhydrase II.

    PubMed

    Prokhorov, Dmitry A; Timchenko, Alexander A; Uversky, Vladimir N; Khristoforov, Vladimir S; Kihara, Hiroshi; Kimura, Kazumoto; Kutyshenko, Viktor P

    2008-05-01

    Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. Many proteins unrelated to amyloidoses also fibrillate at the appropriate conditions. These proteins serve as a model for studying the processes of protein misfolding, oligomerization and fibril formation. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation. The urea-induced unfolding of bovine carbonic anhydrase II, BCA II, is characterized by a combination of high-resolution NMR, circular dichroism spectroscopy and small angle X-ray scattering. It is shown that the formation of associates of protein molecules in complex with solvent (water and urea), APS, takes place in the presence of 4-6 M urea. The subsequent increase in urea concentration to 8 M is accompanied by a disruption of APS and leads to a complete unfolding of a protein molecule. Analysis of BCA II self-association in the presence of 4.2 M urea revealed that APS are relatively large mostly beta-structural blocks with the averaged molecular mass of 190-220 kDa. This work also demonstrates some novel NMR-based methodological approaches that provide useful information on protein self-association.

  15. Celastrols as inducers of the heat shock response and cytoprotection.

    PubMed

    Westerheide, Sandy D; Bosman, Joshua D; Mbadugha, Bessie N A; Kawahara, Tiara L A; Matsumoto, Gen; Kim, Soojin; Gu, Wenxin; Devlin, John P; Silverman, Richard B; Morimoto, Richard I

    2004-12-31

    Alterations in protein folding and the regulation of conformational states have become increasingly important to the functionality of key molecules in signaling, cell growth, and cell death. Molecular chaperones, because of their properties in protein quality control, afford conformational flexibility to proteins and serve to integrate stress-signaling events that influence aging and a range of diseases including cancer, cystic fibrosis, amyloidoses, and neurodegenerative diseases. We describe here characteristics of celastrol, a quinone methide triterpene and an active component from Chinese herbal medicine identified in a screen of bioactive small molecules that activates the human heat shock response. From a structure/function examination, the celastrol structure is remarkably specific and activates heat shock transcription factor 1 (HSF1) with kinetics similar to those of heat stress, as determined by the induction of HSF1 DNA binding, hyperphosphorylation of HSF1, and expression of chaperone genes. Celastrol can activate heat shock gene transcription synergistically with other stresses and exhibits cytoprotection against subsequent exposures to other forms of lethal cell stress. These results suggest that celastrols exhibit promise as a new class of pharmacologically active regulators of the heat shock response.

  16. Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis

    DOE PAGES

    Wall, Jonathan; Martin, Emily B.; Richey, Tina; ...

    2015-04-27

    Amyloid is a complex pathologic matrix comprised principally of para-crystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloidoses are rare (~3500 new cases per year in the US); thus, routine diagnosis is often challenging, and effective treatment options are limited, resulting in high morbidity and mortality rates. Glycosaminoglycans contribute inextricably to the formation of amyloid fibrils and foster the deposition of amyloid in tissues. Those present in amyloid deposits are biochemically and electrochemically distinct from glycosaminoglycans found in the plasma membrane and extracellular matrices of healthy tissues due to the presence of a high degree of heparin-like hypersulfation. We havemore » exploited this unique property and evaluated heparin-reactive peptides, such as p5+14. Herein we show efficacious detection of murine systemic amyloid in vivo by using molecular imaging, and the specific targeting of the peptide to major forms of human amyloid in tissue sections. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients; thus, providing a novel technique for prognostication, patient stratification, and monitoring response to therapy.« less

  17. RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles

    PubMed Central

    Fernández, Cristina; Núñez-Ramírez, Rafael; Jiménez, Mercedes; Rivas, Germán; Giraldo, Rafael

    2016-01-01

    RepA-WH1 is a disease-unrelated protein that recapitulates in bacteria key aspects of human amyloid proteinopathies: i) It undergoes ligand-promoted amyloidogenesis in vitro; ii) its aggregates are able to seed/template amyloidosis on soluble protein molecules; iii) its conformation is modulated by Hsp70 chaperones in vivo, generating transmissible amyloid strains; and iv) causes proliferative senescence. Membrane disruption by amyloidogenic oligomers has been found for most proteins causing human neurodegenerative diseases. Here we report that, as for PrP prion and α-synuclein, acidic phospholipids also promote RepA-WH1 amyloidogenesis in vitro. RepA-WH1 molecules bind to liposomes, where the protein assembles oligomeric membrane pores. Fluorescent tracer molecules entrapped in the lumen of the vesicles leak through these pores and RepA-WH1 can then form large aggregates on the surface of the vesicles without inducing their lysis. These findings prove that it is feasible to generate in vitro a synthetic proteinopathy with a minimal set of cytomimetic components and support the view that cell membranes are primary targets in protein amyloidoses. PMID:26984374

  18. Homozygosity for the E526V Mutation in Fibrinogen A Alpha-Chain Amyloidosis: The First Report

    PubMed Central

    Tavares, Isabel; Lobato, Luísa; Matos, Carlos; Santos, Josefina; Moreira, Paul; Saraiva, Maria João; Castro Henriques, António

    2015-01-01

    Systemic hereditary amyloidoses are autosomal dominant diseases associated with mutations in genes encoding ten different proteins. The clinical phenotype has implications on therapeutic approach, but it is commonly variable and largely dependent on the type of mutation. Except for rare cases involving gelsolin or transthyretin, patients are heterozygous for the amyloidogenic variants. Here we describe the first patient identified worldwide as homozygous for a nephropathic amyloidosis, involving the fibrinogen variant associated with the fibrinogen alpha-chain E526V (p.Glu545Val) mutation. In 1989, a 44-year-old woman presented with hypertension, hepatosplenomegaly, nephrotic syndrome, and renal failure. She started hemodialysis in 1990 and 6 years later underwent isolated kidney transplantation from a deceased donor. Graft function and clinical status were unremarkable for 16 years, despite progressively increased left ventricular mass on echocardiography. In 2012, 4 months before death, she deteriorated rapidly with severe heart failure, precipitated by Clostridium difficile colitis and urosepsis. Affected family members developed nephropathy, on average, nearly three decades later, which may be explained by the gene dosage effects on the phenotype of E526V (p.Glu545Val) fibrinogen A alpha-chain amyloidosis. PMID:26199771

  19. Interaction of thioflavin T with amyloid fibrils of apolipoprotein A-I N-terminal fragment: resonance energy transfer study.

    PubMed

    Girych, Mykhailo; Gorbenko, Galyna; Trusova, Valeriya; Adachi, Emi; Mizuguchi, Chiharu; Nagao, Kohjiro; Kawashima, Hiroyuki; Akaji, Kenichi; Lund-Katz, Sissel; Phillips, Michael C; Saito, Hiroyuki

    2014-01-01

    Apolipoprotein A-I is amenable to a number of specific mutations associated with hereditary systemic amyloidoses. Amyloidogenic properties of apoA-I are determined mainly by its N-terminal fragment. In the present study Förster resonance energy transfer between tryptophan as a donor and Thioflavin T as an acceptor was employed to obtain structural information on the amyloid fibrils formed by apoA-I variant 1-83/G26R/W@8. Analysis of the dye-fibril binding data provided evidence for the presence of two types of ThT binding sites with similar stoichiometries (bound dye to monomeric protein molar ratio ∼10), but different association constants (∼6 and 0.1μM(-1)) and ThT quantum yields in fibril-associated state (0.08 and 0.05, respectively). A β-strand-loop-β-strand structural model of 1-83/G26R/W@8 apoA-I fibrils has been proposed, with potential ThT binding sites located in the solvent-exposed grooves of the N-terminal β-sheet layer. Reasoning from the expanded FRET analysis allowing for heterogeneity of ThT binding centers and fibril polymorphism, the most probable locations of high- and low-affinity ThT binding sites were attributed to the grooves T16_Y18 and D20_L22, respectively.

  20. Endoplasmic Reticulum Quality Control and Systemic Amyloid Disease: Impacting Protein Stability from the Inside Out

    PubMed Central

    Chen, John J.; Genereux, Joseph C.; Wiseman, R. Luke

    2015-01-01

    The endoplasmic reticulum (ER) is responsible for regulating proteome integrity throughout the secretory pathway. The ER protects downstream secretory environments such as the extracellular space by partitioning proteins between ER protein folding, trafficking and degradation pathways in a process called ER quality control. In this process, ER quality control factors identify misfolded, aggregation-prone protein conformations and direct them towards ER protein folding or degradation, reducing their secretion to the extracellular space where they could further misfold or aggregate into proteotoxic conformations. Despite the general efficiency of ER quality control, many human diseases, such as the systemic amyloidoses, involve aggregation of destabilized, aggregation-prone proteins in the extracellular space. A common feature for all systemic amyloid diseases is the ability for amyloidogenic proteins to evade ER quality control and be efficiently secreted. The efficient secretion of these amyloidogenic proteins increases their serum concentrations available for the distal proteotoxic aggregation characteristic of these diseases. This indicates that ER quality control, and the regulation thereof, is a critical determinant in defining the onset and pathology of systemic amyloid diseases. Here, we discuss the pathologic and potential therapeutic relationship between ER quality control, protein secretion and distal deposition of amyloidogenic proteins involved in systemic amyloid diseases. Furthermore, we present evidence that the Unfolded Protein Response, the stress-responsive signaling pathway that regulates ER quality control, is involved in the pathogenesis of systemic amyloid diseases and represents a promising emerging therapeutic target to intervene in this class of human disease. PMID:26018985

  1. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

    PubMed Central

    Bulawa, Christine E.; Connelly, Stephen; DeVit, Michael; Wang, Lan; Weigel, Charlotte; Fleming, James A.; Packman, Jeff; Powers, Evan T.; Wiseman, R. Luke; Foss, Theodore R.; Wilson, Ian A.; Kelly, Jeffery W.; Labaudinière, Richard

    2012-01-01

    The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (Kds ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis. PMID:22645360

  2. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.

    PubMed

    Bulawa, Christine E; Connelly, Stephen; Devit, Michael; Wang, Lan; Weigel, Charlotte; Fleming, James A; Packman, Jeff; Powers, Evan T; Wiseman, R Luke; Foss, Theodore R; Wilson, Ian A; Kelly, Jeffery W; Labaudinière, Richard

    2012-06-12

    The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A-retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K(d)s ~2 nM and ~200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.

  3. Possible vasculoprotective role of linagliptin against sodium arsenite-induced vascular endothelial dysfunction.

    PubMed

    Jyoti, Uma; Kansal, Sunil Kumar; Kumar, Puneet; Goyal, Sandeep

    2016-02-01

    Vascular endothelial dysfunction (VED) interrupts the integrity and function of endothelial lining through enhanced markers of oxidative stress and decrease endothelial nitric oxide synthase (eNOS) expression. The main aim of the present study has been designed to investigate the possible vasculoprotective role of linagliptin against sodium arsenite-induced VED. Sodium arsenite (1.5 mg/kg, i.p., 2 weeks) abrogated the acetylcholine-induced, endothelium-dependent vasorelaxation by depicting the decrease in serum nitrite/nitrate concentration, reduced glutathione level, and simultaneously enhance the thiobarbituric acid reactive substances (TBARS) level, superoxide level, and tumor necrosis factor-alpha. These elevated markers interrupt the integrity of endothelial lining of thoracic aorta which was assessed histologically. The study elicits dose dependent effect of linagliptin (1.5 mg/kg, i.p. and 3 mg/kg, i.p.) or atorvastatin (30 mg/kg, p.o.) treatment, improved the endothelium-dependent independent relaxation, improve the integrity of endothelium lining which was assessed histologically by enhancing the serum nitrite/nitrate level, reduced glutathione level and simultaneously decreasing the TBARS level, superoxide anion level and tumor necrosis factor-alpha (TNF-α) level. L-NAME (25 mg/kg, i.p.), eNOS inhibitor, abrogated the ameliorative potential of linagliptin. However, the ameliorative potential of linagliptin has been enhanced by l-arginine (200 mg/kg, i.p.) which elicits that ameliorative potential of linagliptin was through eNOS signaling cascade and it may be concluded that linagliptin 3 mg/kg, i.p. has more significantly activated the eNOS and decreased the oxidative markers than linagliptin 1.5 mg/kg, i.p. and prevented sodium arsenite-induced VED.

  4. Controlling {beta}-amyloid oligomerization by the use of naphthalene sulfonates: trapping low molecular weight oligomeric species.

    PubMed

    Ferrão-Gonzales, Astria D; Robbs, Bruno K; Moreau, Vitor Hugo; Ferreira, Aricéle; Juliano, Luiz; Valente, Ana Paula; Almeida, Fabio C L; Silva, Jerson L; Foguel, Debora

    2005-10-14

    Aggregation of proteins and peptides has been shown to be responsible for several diseases known as amyloidoses, which include Alzheimer disease (AD), prion diseases, among several others. AD is a neurodegenerative disorder caused primarily by the aggregation of beta-amyloid peptide (Abeta). Here we describe the stabilization of small oligomers of Abeta by the use of sulfonated hydrophobic molecules such as AMNS (1-amino-5-naphthalene sulfonate); 1,8-ANS (1-anilinonaphthalene-8-sulfonate) and bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonate). The experiments were performed with either Abeta-1-42 or with Abeta-13-23, a shorter version of Abeta that is still able to form amyloid fibrils in vitro and contains amino acid residues 16-20, previously shown to be essential to peptide-peptide interaction and fibril formation. All sulfonated molecules tested were able to prevent Abeta aggregation in a concentration dependent fashion in the following order of efficacy: 1,8-ANS < AMNS < bis-ANS. Size exclusion chromatography revealed that in the presence of bis-ANS, Abeta forms a heterogeneous population of low molecular weight species that proved to be toxic to cell cultures. Since the ANS compounds all have apolar rings and negative charges (sulfonate groups), both hydrophobic and electrostatic interactions may contribute to interpeptide contacts that lead to aggregation. We also performed NMR experiments to investigate the structure of Abeta-13-23 in SDS micelles and found features of an alpha-helix from Lys(16) to Phe(20). 1H TOCSY spectra of Abeta-13-23 in the presence of AMNS displayed a chemical-shift dispersion quite similar to that observed in SDS, which suggests that in the presence of AMNS this peptide might adopt a conformation similar to that reported in the presence of SDS. Taken together, our studies provide evidence for the crucial role of small oligomers and their stabilization by sulfonate hydrophobic compounds.

  5. Molecular tweezers targeting transthyretin amyloidosis.

    PubMed

    Ferreira, Nelson; Pereira-Henriques, Alda; Attar, Aida; Klärner, Frank-Gerrit; Schrader, Thomas; Bitan, Gal; Gales, Luís; Saraiva, Maria João; Almeida, Maria Rosário

    2014-04-01

    Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders. Recently, the "molecular tweezers", CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer's disease and Parkinson's disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model. In cell culture assays we found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.

  6. Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis.

    PubMed

    Gregorini, Gina; Izzi, Claudia; Obici, Laura; Tardanico, Regina; Röcken, Christoph; Viola, Battista Fabio; Capistrano, Mariano; Donadei, Simona; Biasi, Luciano; Scalvini, Tiziano; Merlini, Giampaolo; Scolari, Francesco

    2005-12-01

    Apolipoprotein A-I amyloidosis is a rare, late-onset, autosomal dominant condition characterized by systemic deposition of amyloid in tissues, the major clinical problems being related to renal, hepatic, and cardiac involvement. Described is the clinical and histologic picture of renal involvement as a result of apolipoprotein A-I amyloidosis in five families of Italian ancestry. In all of the affected family members, the disease was caused by the Leu75Pro heterozygous mutation in exon 4 of apolipoprotein A-I gene, as demonstrated by direct sequencing and RFLP analysis. Immunohistochemistry confirmed that amyloid deposits were specifically stained with an anti-apolipoprotein A-I antibody. The clinical phenotype was mainly characterized by a variable combination of kidney and liver disturbance. The occurrence of renal involvement seemed to be almost universal, although its severity varied greatly ranging from subclinical organ damage to overt, slowly progressive renal dysfunction. The renal presentation was consistent with a tubulointerstitial disease, as suggested by the findings of defective urine-concentrating capacity, moderate polyuria, negative urinalysis, and mild tubular proteinuria. Histology confirmed tubulointerstitial nephritis. Surprising, amyloid was restricted to nonglomerular regions and limited to the renal medulla. This location of apolipoprotein A-I amyloid differs sharply from other systemic amyloidoses that are mainly characterized by glomerular and vascular deposits. The tubulointerstitial nephritis as a result of hereditary apolipoprotein A-I amyloidosis is a rare disease and a challenging diagnosis to recognize. Patients who present with familial tubulointerstitial nephritis associated with liver disease require a high index of suspicion for apolipoprotein A-I amyloidosis.

  7. Familial mutations in fibrinogen Aα (FGA) chain identified in renal amyloidosis increase in vitro amyloidogenicity of FGA fragment.

    PubMed

    Sivalingam, Vishwanath; Patel, Basant K

    2016-08-01

    Amyloidoses are clinical disorders where deposition of β-sheet rich, misfolded protein aggregates called amyloid occurs in vital organs like brain, kidney, liver or heart etc. Aggregation of several proteins such as immunoglobulin light chain, fibrinogen Aα chain (FGA) and lysozyme have been found to be associated with renal amyloidosis. Fibrinogen amyloidosis (AFib) is predominantly familial and is associated with the deposition of mutant FGA amyloid, primarily in kidneys. Over ten substitution and frame-shift mutations in FGA have been identified from AFib patients. Whether wild-type FGA is also involved in AFib is yet unknown. The affected tissues from AFib patients usually show ∼10 kDA peptide from C-terminal 80 amino acid residues of mutant FGA. Notably, this region also encompasses all known disease-related mutations. Whether these point mutations increase the amyloidogenicity of FGA leading to disease progression, have not been studied yet. Here, we have investigated the role of two disease-related mutations in affecting amyloidogenic propensity of an FGA(496-581) fragment. We found that at physiological pH, the wild-type FGA(496-581) fragment remains monomeric, whereas its E540V mutant forms amyloid-like fibrils as observed by AFM. Also, FGA(496-581) harbouring another familial mutation, R554L, converts in vitro into globular, β-sheet rich aggregates, showing amyloid-like properties. These findings suggest that familial mutations in FGA may have role in renal amyloidosis via enhanced amyloid formation.

  8. Disorder in milk proteins: caseins, intrinsically disordered colloids.

    PubMed

    Redwan, Elrashdy M; Xue, Bin; Almehdar, Hussein A; Uversky, Vladimir N

    2015-01-01

    This article opens a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. The focus of this introductory article on caseins is symbolic, since caseins were among the first recognized functional unfolded proteins and since they are definitely the most disordered, the most abundant, and the most studied of all milk proteins. In eutherian milks, the casein family includes at least three and usually four major members (αs1-, αs2-, β-, and κ-caseins) that are unrelated in sequence. However, in some species, two different αS2-casein genes are active, and therefore the total number of caseins can be as high as five. These proteins have found a number of uses in food industry. The functional repertoire of caseins ranges from nutritional function to involvement in the improving and/or maintaining cardiovascular health, to crucial contribution to the milk capacity to transport calcium phosphate, to serve as molecular chaperones, and to protect the mother's mammary gland against amyloidoses and ectopic calcification. An intricate feature of caseins is their ability to assemble to colloidal protein particles, casein micelles, serving to sequester and transport amorphous calcium phosphate. These and many other functions of caseins are obviously dependent on their intrinsically disordered nature and are controlled by various posttranslational modifications. Since various aspects of casein structure and function are rather well studied and since several recent reviews emphasized the functional roles of caseins' intrinsic disorder, the major goal of this article is to show how intrinsic disorder is encoded in the amino acid sequences of these proteins.

  9. Is the prevalent human prion protein 129M/V mutation a living fossil from a Paleolithic panzootic superprion pandemic?

    PubMed

    Nyström, Sofie; Hammarström, Per

    2014-01-01

    Prion diseases are consistently associated with prion protein (PrP(C)) misfolding rendering a cascade of auto-catalytic self-perpetuation of misfolded PrP in an afflicted individual. The molecular process is intriguingly similar to all known amyloid diseases both local and systemic. The prion disease is also infectious by the transfer of misfolded PrP from one individual to the next. Transmissibility is surprisingly efficient in prion diseases and given the rapid disease progression following initial symptoms the prionoses stand out from other amyloidoses, which all may be transmissible under certain circumstances. The nature of the infectious prion as well as the genotype of the host is important for transmissibility. For hitherto unexplained reasons the majority of Europeans carry a missense mutation on one or both alleles of the PrP gene (PRNP), and hence express a variant of PrP with a substitution for valine (V) instead of methionine (M) in position 129. In fact the 129M/V variant is very common in all populations except for the Japanese. Sporadic Creutzfeldt-Jakob disease is a disease rarely striking people below the age of 60, where homozygosity especially 129MM is a very strong risk factor. Paradoxically, the 129M/V polymorphism suggestive of heterozygote advantage is one of the most clear cut disease associated traits of the human population, yet prion disease is extraordinarily rare. The genetic basis for how this trait spread with such prevalence within human populations is still target to investigations and deserves attention. This short essay represents a somewhat provocative hypothetical notion of a possible ancient significance of this polymorphism.

  10. Prion diseases: a riddle wrapped in a mystery inside an enigma.

    PubMed

    Liberski, Paweł P

    2008-01-01

    It is now widely accepted that many structurally diverse proteins can misfold and cause so-called "conformational diseases", including the most common neurodegenerations, Alzheimer's disease and Parkinson's disease. The conversion of largely a-helical or random coil proteins into cross-beta-pleated sheet conformations that form first oligomers and then fibrils underlies these disorders. However, this alpha- to beta-structure transition seems to be a generic propensity of all globular proteins, not only those involved in neurodegenerations, not to mention "prion diseases". Metaphorically, all these neurodegenerations are "infectious" in the sense that misfolded beta-sheeted conformers are formed in a nucleation process in which preformed metastable oligomer acts as a seed (a nucleus) to convert a normal into an abnormal protein. However, in none but transmissible spongiform encephalopathies (TSEs) has infectivity in a microbiological sense ever been observed, and even in TSEs the formation of misfolded protein is not necessarily accompanied by the generation of infectivity de novo. Furthermore, certain "prion diseases" are not TSEs but just "proteinopathies" caused by accumulation of abnormally misfolded PrPd. The presence of a massive amount of PrP-amyloid and no infectivity casts doubts on whether TSEs are really infectious amyloidoses. The misfolding of PrP may yet prove to be an epiphenomenon secondary to infection with a still unknown infectious agent. If, on the other hand, the purely proteinaceous character of the replicating unit of TSE infectivity is ultimately found to be correct, the critical issues become 1) the mechanism by which a misfolded PrP template induces normal protein molecules to adopt the same pathologically misfolded conformation, and 2) the intracellular conditions that are responsible for strain differences in these molecules.

  11. Incidence of hereditary amyloidosis and autoinflammatory diseases in Sweden: endemic and imported diseases

    PubMed Central

    2013-01-01

    Background Amyloidoses are a heterogeneous group of progressive diseases caused by tissue deposition of misfolded proteins. According to the International Classification of Diseases, hereditary amyloidosis is divided into neuropathic and non-neuropathic forms. In Sweden, neuropathic heredofamilial amyloidosis has been identified as familial amyloidotic polyneuropathy (FAP), a fatal disease that is treated by liver transplantation. The non-neuropathic form includes familial autoinflammatory diseases. As no incidence data on these hereditary diseases are available and as even diagnostic data on non-neuropathic forms are lacking we determined the incidence of these diseases and characterized non-neuropathic conditions. Methods Patients were identified using data from the Swedish Hospital Discharge Register and from the Outpatient Register for 2001 through 2008. All patients discharged with hereditary amyloidosis diagnoses were included and standardized incidence rates were calculated. Results Non-neuropathic disease was diagnosed in 210 patients, with an incidence of 2.83 per million. FAP was diagnosed in 221 patients, with an incidence of 2.02 per million. Two northern provinces that are home to 5% of the Swedish population accounted for 77% of FAP cases; the incidence in one of them, West Bothnia, was 100 times that in the rest of Sweden. Approximately 98% of non-neuropathic disease patients were immigrants, most of whom were from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500-fold higher than that in individuals with Swedish parents. Even the early onset of these conditions identified them as familial autoinflammatory diseases. Conclusions FAP cases were highly concentrated in the two northernmost provinces. Non-neuropathic familial autoinflammatory diseases were of early-onset and immigrant origin most likely related to periodic fever syndromes. Paradoxically, FAP has remained endemic, in spite of

  12. Advanced Technology for Improved Quantum Device Properties Using Highly Strained Materials

    DTIC Science & Technology

    1989-06-15

    PREPARED BY: W.J. Schaff S.D. OffseyI DL)L.,C ;.. $T A H. Park At~pio-ved tc- ;p7ua~ic tel-e:a~o L.F. Eastman q uoig4 04 Table of Contents Page...Graded-Index Separate-Confinement Heterostructure Single Quantum Well Lasers Grown by Molecular Beam Epitaxy", S.D. Offsey, W.J. Schaff , P.J. Tasker, H...gle Confinement Single Quantum Well Lasers Grown by Molecular Beam Epitaxy", S.D. Offsey, W.J. Schaff , P.J. Tasker and L.F. Eastman, Device Research

  13. Flying Qualities of Relaxed Static Stability Aircraft. Volume 2. Ramifications of Flight-Essential/Critical Heavily-Augmented Airplane Characteristics on Flying Qualities

    DTIC Science & Technology

    1982-09-01

    root variation am is perwltte4 to becout sort uaatlvs ( eeg ., cog. Wereeeixuly w~ved further fotowrd of the neutral potat). % w~a e t-period dh~a~a fs Cc...deg-sec) unit impulse. For sueh an input the pit~ch att.It~ tdc responses in !A’gure 11 appear with the same response shapes as those deacribed...this pair approaches the clewaical tm -degree-of-froedo. phugoid mode dwereint Z’ V/gZuAT &rglo I n this classic phugoid (Ref erence 22) the angle of

  14. Pathfinder. Volume 9, Number 1, January/February 2011

    DTIC Science & Technology

    2011-02-01

    Intelligence Agency team member Ken Brewer rece ved the Department of Defense Outstanding Employee with a Disability award Dec. 7 in Bethesda, Md...Personnel and Readiness, joined NGA Director Letitia A. Long in recognizing Brewer with this honor and presenting him with the award. “I am honored...to be named as one of the DOD’s Outstanding Employees with a Disability,” Brewer said. “This is an unforgettable moment in my life.” The award

  15. A Systems Engineering Based Methodology for Analyzing Human Electrocortical Responses.

    DTIC Science & Technology

    1987-07-20

    D f Lh modeling provided a promising approach for hiandling obse ved r n the dcita. Model Parameter values were found to relate- tr S ...designed to be similar. Due to the nature of the two 121 FiR 5 5a0 Fig 5 0 0.. .. . . LO ° s .. . " R "R " - " - ,". ’. ’Io rpc ("IM O’CY 1. - g e -lip le e...w d - A’ --- • -A N - 46 .- - Iv e s -a S8ECT 32 -400 -1100 j ’.J - 00 000 - LIGHTS ONLY DECISION EASY DECISION HARD "* - U ".. FP[OUttu Y H

  16. Controlled Growth of Parallel Oriented ZnO Nanostructural Arrays on Ga2O3 Nanowires

    DTIC Science & Technology

    2008-11-01

    been obtained by growth of ZnO ,10-13 Ga2O3, 14 SnO2 , 15 and GaAs16 nanorod branches symmetrically around the nanowire (NW) cores composed of materials...Controlled Growth of Parallel Oriented ZnO Nanostructural Arrays on Ga2O3 Nanowires Lena Mazeina,* Yoosuf N. Picard, and Sharka M. Prokes Electronics...Manuscript ReceiVed NoVember 6, 2008 ABSTRACT: Novel hierarchical ZnO -Ga2O3 nanostructures were fabricated via a two stage growth process. Nanowires of Ga2O3

  17. Procedures Used in Narcotics Airbridge Denial Program in Peru, 1995-2001

    DTIC Science & Technology

    2008-08-25

    conduct a periodic or independentch£ckregardiilgthe ABDP, + I f"ved "’I~A Leg’lidV"’" when the missionary shcotdown ~,",,’din . ApI II ZOOI, According te...outside the [uanjui Base doing drills when it occurred. He said he watched the videotape atl ~nd that nothing stood out in his mind about It. WhIle...the tape whether or not visual signals were done and it was " hard to say" if there should have been further reporting. 264·l_ ’n_nnn ,m" jsaid it was

  18. Is the daily use of vacuum erection device for a month before penile prosthesis implantation beneficial? a randomized controlled trial.

    PubMed

    Canguven, O; Talib, R A; Campbell, J; De Young, L; El Ansari, W; Al-Ansari, A

    2017-01-01

    Patient concerns about penile length after penile prosthesis (PP) implantation for erectile dysfunction (ED) have significant impact on patients and their partners. In addition, corporal fibrosis is associated with difficult PP implantation. The preoperative use of vacuum erectile devices (VED) is an uncommon physical treatment for such concerns. Therefore, the current randomized controlled study assessed two outcomes: whether pre-operative VED use for a month before surgery would significantly increase flaccid stretched penile length (SPL) on the day of surgery, and facilitate easier corporal dilatation intraoperatively. Fifty-one patients scheduled for PP implantation for ED were randomized to either intervention group (pre-operative VED use; 10-15 min/day for ≥30 days; Group A; n = 25), or control group (no intervention; Group B; n = 26). A research assistant (blinded to the treatment assignments) recorded SPL at baseline (initial consultation) and on day of surgery. The surgeons performing the PP implantation (also blinded to the treatment assignments) provided subjective assessments of the ease of corporal dilatation. Baseline patient characteristics, demographics, and comorbidities were the same in both groups. Baseline measurements (SPL-1) were 10.71 ± 1.28 and 10.87 ± 1.26 cm in Group A and Group B, respectively; and the day of surgery measurements (SPL-2) were 11.50 ± 1.33 and 11.06 ± 1.34 cm in Group A and Group B, respectively. In terms of outcomes: mean SPL increase in Group A was significantly more by a mean of 0.80 ± 0.38 cm (p < 0.05) compared to Group B; and surgeons' subjective report of surgical ease indicated smoother corporal dilatation for Group A compared to Group B. VED use (10-15 min/day during the month prior to PP implantation) was associated with significantly increased SPL on day of surgery, and facilitated easier corporal dilatation intraoperatively. Future studies should examine the long-term outcomes of

  19. CFD Techniques for Propulsion Applications Panel Symposium (77th), Held in San Antonio, Texas on 27-31 May 1991 (Les Techniques de l’Aerodynamique Numerique pour les Applications aux Propulseurs)

    DTIC Science & Technology

    1992-02-01

    numerical grid with respect to the form an initial value problem which can be sol - plane {(f-i, i(imax+ l )/ 2 ). ved numerically. When the computational...reprsentaiives de l ’&oulement seront montr~es ct analysees dans diff6rents plans successifs. Pour fixer les Wdes les plans seront rep6r~s par rapport...des fluctuations des diffdrentes grandeurs physiques, regissant l 𔄀coulement de faqon par exemple A analyser un phenom.ne local plus finement, it faut

  20. Mathematical Studies of Wavelet Inverse Reconstructions for Nondestructive Evaluation, Novel Dielectrics, and the Dispersion from Chaotic Motions in Water

    DTIC Science & Technology

    2007-11-02

    dispersion of water from a previous AFOSR grant. The wavelet studies were direct^ toward nondestructive evaluation using ultrasonic waves. The...novel dielectrics were mainly the PBGS, photonic band gap structures - periodic arrays of a dielectric with permitivity »^ embedded in a...n g au9lan°S irtHeXCePti1° nal "^ "^ *™^" °™«" much 0? Z Tnilf TeUt phaSe Space- This metn°° ^ved mucn of the noise from the

  1. Proceedings of the 14th Annual Review Conference on Atmospheric Transmission Models (14th) Held at Hanscom Air Force Base, Massachusetts on 11-12 June 1991,

    DTIC Science & Technology

    1992-02-26

    03 CO2 CH4 NO CO N,) 02 HNO3 NO NOI NH3 Sol EXPANIDEO APPLICABILITY x ,1ODTRA1 IS BETTER SUITED THfAlf LOWTRAI FOR ATMOSPHERIC PATHS ABOVE 30 KM...0 1 0 -> HI 03 (000) 11 03 (001) ->M 03 (000) 03(001) ->03(000) 1’ h v " RATE EQUATIONS SOL VED IN STEADY STATE - SSUMES RATE EQUATIONS DEPEND L...AND FAR LINE WING PROBLEM J.-M. Hartmann Laboratoire E.M2.C., de CNRS (UPR288) et de rEcole Centrale Paris, Grand voie des vignes , 92295 Chatenay

  2. Integrated Microtransducer and Neural Networks System for Distributed Control

    DTIC Science & Technology

    1997-12-01

    this burden, to Washington Head 0< 5 a \\ ved -0188 cisting data sources, other aspect of this iu neports, 1215 Jefferson L.UHGI.UUII u uiMi uu...Network Systems for Distributed Control 6. AUTHOR(S) Professor Chih-Ming Ho 5 . FUNDING NUMBERS F49620-93-1-0332 7. PERFORMING ORGANIZATION NAME(S...Waltham, Mass. U.S.A. April, 1995. 5 . Joshi, Speyer, J. and Kim, J. "A systems theory approach to the control of transitional flows", Accept by J. of

  3. Histogram Equalization with Variable Enhancement Degree for Preserving Mean Brightness

    NASA Astrophysics Data System (ADS)

    Kawakami, Takashi; Murahira, Kota; Taguchi, Akira

    The histogram equalization (HE) is one of the common methods used for improving contrast in digital images. However, this technique causes a fluctuation of mean brightness. The fluctuation leads to the flicker for video signal. In order to preserve the mean brightness, the dynamic histogram equalization (DHE) is proposed. In this letter, we propose a novel DHE which is called the DHE with variable enhancement degree (DHEwVED). This method can change from DHE to HE by turning one parameter. We also show the effectiveness of the proposed method.

  4. Bayesian Interpolation and Deconvolution

    DTIC Science & Technology

    1992-07-01

    an arbitrary input may be written as a convolution or average of the true signal ,ov1 i, ved with the iinptulse response function. Averaging loses...cntered Ile pr(oleIn. Thlese parameters were adhded •to tw prior ini a way that indicate.s that tlwir viluie’ arre given. Of c(urse iii a real...prior is written , this is not the case! The 1ik matrix has one sin.ular eiernv vatue. Apparently one of the two boundary c’oniditions was redundiant

  5. The Influence of 8 Weeks of Whey-Protein and Leucine Supplementation on Physical and Cognitive Performance

    DTIC Science & Technology

    2010-01-01

    branchecl -chain mino ac ids ( BCAA ) may a lso improve cogni t ive per formance dur ing latigue. Blornstrand, Hassmdn, Eckblorn, and News- holme (1q91...1991) and Hassmdn, Blornstrand, Eck- blom, and Newsholme (1994) observecl that participants supplemented with BCAAs scored better on both mood lcvels...whey and casein, whey and BCAAs . or’ placebo ver’ I 0 weeks of R1’. ’fhey obser"ved a significant incrcase in l-RM BP in all 3 groups with no

  6. [The Contribution of Vascular Capacity and Blood Volume to Maintain Stable Blood Circulation during General Anesthesia].

    PubMed

    Shigemi, Kenji

    2016-05-01

    To maintain proper cardiac preload is one of the most effective procedures for the systemic circulation remaining stable. In particular, the balance between vascular capacity and total blood volume must be maintained within appropriate range by the administration of fluids, blood and/or vasoactive drugs with mean circulatory filling pressure (Pmcf), central venous pressure (CVP) or stroke volume variation (SVV). End-diastolic left ventricular volume (Ved) is theoretically the best index of cardiac preload; however, without transesophageal echocardbalanceiogram we cannot directly monitor Ved during anesthesia. The infused fluid volume remaining in intravascular space, the vascular capacity controlled by autonomic nervous system and/or vasoactive agents, and the unstressed blood volume properly mobilized to excess blood volume are the crucial factors to maintain cardiac output The knowledge of vascular physiology contribute the decision making to manipulate such factors to control blood circulation during general anesthesia. For example, CVP is usually maintained in the narrow range and seems to be stable; however, it must be changed just after the circulatory disturbances, such as acute bleeding, blood transfusion, and fluid infusion, and followed by gradual returning to initial value, because of the solid mechanism to preserve cardiac output

  7. Design of Visco-Elastic Dampers for RC Frame for Site-Specific Earthquake

    NASA Astrophysics Data System (ADS)

    Kamatchi, P.; Rama Raju, K.; Ravisankar, K.; Iyer, Nagesh R.

    2016-12-01

    Number of Reinforced Concrete (RC) framed buildings have got damaged at Ahmedabad city, India located at about 240 km away from epicenter during January 2001, 7.6 moment magnitude (Mw) Bhuj earthquake. In the present study, two dimensional nonlinear time history dynamic analyses of a typical 13 storey frame assumed to be located at Ahmedabad is carried out with the rock level and surface level site-specific ground motion for scenario earthquake of Mw 7.6 from Bhuj. Artificial ground motions are generated using extended finite source stochastic model with seismological parameters reported in literature for 2001 Bhuj earthquake. Surface level ground motions are obtained for a typical soil profile of 100 m depth reported in literature through one dimensional equivalent linear wave propagation analyses. From the analyses, failure of frame is observed for surface level ground motions which indicates that, in addition to the in-adequacy of the cross sections and reinforcement of the RC members of the frame chosen, the rich energy content of the surface level ground motion near the fundamental time period of the frame has also contributed for the failure of frame. As a part of retrofitting measure, five Visco-elastic Dampers (VED) in chevron bracing are added to frame. For the frame considered in the present study, provision of VED is found to be effective to mitigate damage for the soil site considered.

  8. Assessment of Ganga river ecosystem at Haridwar, Uttarakhand, India with reference to water quality indices

    NASA Astrophysics Data System (ADS)

    Bhutiani, R.; Khanna, D. R.; Kulkarni, Dipali Bhaskar; Ruhela, Mukesh

    2016-06-01

    The river Ganges is regarded as one of the most holy and sacred rivers of the world from time immemorial. The evaluation of river water quality is a critical element in the assessment of water resources. The quality/potability of water that is consumed defines the base line of protection against many diseases and infections. The present study aimed to calculate Water Quality Index (WQI) by the analysis of sixteen physico-chemical parameters on the basis of River Ganga index of Ved Prakash, weighted arithmetic index and WQI by National sanitation foundation (NSF) to assess the suitability of water for drinking, irrigation purposes and other human uses. These three water quality indices have been used to assess variation in the quality of the River Ganga at monitored locations over an 11-year period. Application of three different indexes to assess the water quality over a period of 11 years shows minor variations in water quality. Index values as per River Ganga Index by Ved Prakash et al. from 2000 to 2010 ranged between medium to good, Index values as per NSF Index for years 2000-2010 indicate good water quality, while Index values as per the weighted arithmetic index method for the study period indicate poor water quality.

  9. Generalization of geometrical flux maximizing flow on Riemannian manifolds for improved volumetric blood vessel segmentation.

    PubMed

    Gooya, Ali; Liao, Hongen; Sakuma, Ichiro

    2012-09-01

    Geometric flux maximizing flow (FLUX) is an active contour based method which evolves an initial surface to maximize the flux of a vector field on the surface. For blood vessel segmentation, the vector field is defined as the vectors specified by vascular edge strengths and orientations. Hence, the segmentation performance depends on the quality of the detected edge vector field. In this paper, we propose a new method for level set based segmentation of blood vessels by generalizing the FLUX on a Riemannian manifold (R-FLUX). We consider a 3D scalar image I(x) as a manifold embedded in the 4D space (x, I(x)) and compute the image metric by pullback from the 4D space, whose metric tensor depends on the vessel enhancing diffusion (VED) tensor. This allows us to devise a non-linear filter which both projects and normalizes the original image gradient vectors under the inverse of local VED tensors. The filtered gradient vectors pertaining to the vessels are less sensitive to the local image contrast and more coherent with the local vessel orientation. The method has been applied to both synthetic and real TOF MRA data sets. Comparisons are made with the FLUX and vesselsness response based segmentations, indicating that the R-FLUX outperforms both methods in terms of leakage minimization and thiner vessel delineation.

  10. An aerostat-supported ELF/VLF transmitter

    NASA Astrophysics Data System (ADS)

    Field, E. C., Jr.; Kies, L. R.; Bannister, P. R.; Ingram, R. F.; Hopkins, W. D.; Roberts, M. A.

    1989-03-01

    A demonstration of an aerostat-supported extremely low frequency/very low frequency (ELF/VLF) transmitting antenna was performed. At ELF the vertical electric dipole (VED) antenna radiated at least 100,000 times more power than would a horizontal electric dipole having the same moment. That efficiency was achieved with an altitude of 12,500 feet (3810 m). Calculations show that the radiated power will increase as the fourth power of aerostat altitude. The tether antenna exhibited a corona onset voltage of 180 kV and was resistant to the degrading effects of ELF corona. Prolonged in-corona operation is therefore possible. The antenna was continuously tuned, despite changes in height and capacitance caused by the aerostat flight dynamics. The huge 300-H ELF tuning inductor posed no problem. Enhanced VED moments were achieved at ELF by operation at voltages up to 260 kV, 40% above the corona onset voltage. At VLF the antenna emulated a monopole that had a radiation efficiency greater than 90%. The measured bandwidths were large: 1.5 kHz at 23 kHz and 3.5 kHz at 34 kHz. The antenna height exceeded one-quarter wavelength at VLF, so the antenna could be tuned capacitively and required relatively low base voltages. At both VLF and ELF the measured fields agreed closely with predictions.

  11. Extracorporeal Membrane Oxygenation as Bridge-to-Decision in Acute Heart Failure due to Systemic Light-Chain Amyloidosis

    PubMed Central

    Silva, Jennifer Mancio; Fontes-Carvalho, Ricardo; Valente, Dília; Almeida, Cristiana; Cruz, António José; Tente, David; Coelho, Henrique; Oliveira, Marco; Albuquerque, Aníbal; Ribeiro, Vasco Gama

    2015-01-01

    Patient: Female, 58 Final Diagnosis: Acute hear failure Symptoms: Dispnoea • edema • fatigue Medication: — Clinical Procedure: Bone marrow biopsy • endomyocardial biopsy • abdominal subcutaneous fat biopsy under ECMO support Specialty: Cardiology Objective: Rare disease Background: Cardiac amyloidosis results from the amyloid deposition in heart tissue, either in the context of a systemic disease or as a localized form. Several pro-amyloid proteins can produce amyloid deposits in the heart. Each of these amyloidoses has characteristic clinical (cardiac and extracardiac) features, and a specific diagnosis and treatment. Case Report: A 58-year-old woman who presented with acute heart failure and echocardiographic findings strongly suggestive of infiltrative cardiomyopathy needed percutaneous veno-arterial extracorporeal membrane oxygenation (ECMO) as bridge-to-decision. Amyloid deposition was found on endomyocardial and bone marrow biopsies. Bone marrow plasma cell infiltrate with acute renal lesion and hypercalcemia confirmed the diagnosis of multiple myeloma-associated systemic light-chain amyloidosis (AL). Refractory shock with multi-organic failure syndrome persisted and no improvements in left ventricular function and structure were seen. After extensive discussion by a multidisciplinary team, and with the patients’ family, she was not considered eligible for high-dose chemotherapy and/or autologous stem cell transplantation, heart transplantation, or sequential heart with autologous stem cell transplantation. The patient died a few hours after ECMO withdrawal. During the 14 days of ECMO support no major bleeding or thrombotic complications occurred. Conclusions: The clinician must consider a diagnosis of cardiac amyloidosis in patients with heart failure, a restrictive type of cardiomyopathy with ventricular hypertrophy in the absence of valve abnormalities, or uncontrolled arterial hypertension. Although developments in chemotherapy have greatly

  12. An evaluation of the accuracy of some radar wind profiling techniques

    NASA Technical Reports Server (NTRS)

    Koscielny, A. J.; Doviak, R. J.

    1983-01-01

    Major advances in Doppler radar measurement in optically clear air have made it feasible to monitor radial velocities in the troposphere and lower stratosphere. For most applications the three dimensional wind vector is monitored rather than the radial velocity. Measurement of the wind vector with a single radar can be made assuming a spatially linear, time invariant wind field. The components and derivatives of the wind are estimated by the parameters of a linear regression of the radial velocities on functions of their spatial locations. The accuracy of the wind measurement thus depends on the locations of the radial velocities. The suitability is evaluated of some of the common retrieval techniques for simultaneous measurement of both the vertical and horizontal wind components. The techniques considered for study are fixed beam, azimuthal scanning (VAD) and elevation scanning (VED).

  13. The treatment of erectile dysfunction in patients with neurogenic disease

    PubMed Central

    Brant, William O.

    2016-01-01

    Erectile dysfunction (ED) related to compromise of the nervous system is an increasingly common occurrence. This may be due to the multifactorial nature of ED, the myriad of disorders affecting the neurotransmission of erectogenic signals, and improved awareness and diagnosis of ED. Nevertheless, neurogenic ED remains poorly understood and characterized. Disease related factors such as depression, decreased physical and mental function, the burden of chronic illness, and loss of independence may preclude sexual intimacy and lead to ED as well. The amount of data regarding treatment options in subpopulations of differing neurologic disorders remains scarce except for men with spinal cord injury. The treatment options including phosphodiesterase inhibitors, intracavernosal or intraurethral vasoactive agents, vacuum erection devices (VED) and penile prosthetic implantation remain constant. This review discusses the options in specific neurologic conditions, and briefly provides insight into new and future developments that may reshape the management of neurogenic ED. PMID:26904415

  14. Identification of GI cancers utilising rapid mid-infrared spectral imaging

    NASA Astrophysics Data System (ADS)

    Nallala, Jayakrupakar; Lloyd, Gavin R.; Kendall, Catherine; Barr, Hugh; Shepherd, Neil; Stone, Nick

    2016-03-01

    Pathologists find it notoriously difficult to provide both inter- and intra-observer agreement on a diagnosis of early gastrointestinal cancers. Vibrational spectroscopic approaches have shown their value in providing molecular compositional data from tissue samples and therefore enabling the identification of disease specific changes, when combined with multivariate techniques. Mid-infrared microscopic imaging is undergoing rapid developments in sources, detectors and spectrometers. Here we explore the use of high magnification FTIR for GI cancers and consider how the MINERVA (MId- to NEaR infrared spectroscopy for improVed medical diAgnostics) project, which is developing discrete frequency IR imaging tools will enable histopathologists to obtain rapid molecular images form unstained tissue sections.

  15. A Low Cost Traveling Wave Tube for Wireless Communications

    NASA Technical Reports Server (NTRS)

    Vancil, Bernard Kenneth; Wintucky, Edwin G.; Williams, W. D. (Technical Monitor)

    2002-01-01

    Demand for high data rate wireless communications is pushing up amplifier power, bandwidth and frequency requirements. Some systems are using vacuum electron devices again because solid-state power amplifiers are not able to efficiently meet the new requirements. The traveling wave tube is the VED of choice because of its excellent broadband capability as well as high power efficiency and frequency. But TWTs are very expensive on a per watt basis below about 200 watts of output power. We propose a new traveling wave tube that utilizes cathode ray tube construction technology and electrostatic focusing. We believe the tube can be built in quantity for under $1,000 each. We discuss several traveling wave tube slow wave circuits that lend themselves to the new construction. We will present modeling results and data on prototype devices.

  16. Feasibility Study of Improved Methods for Riverbank Stabilization

    DTIC Science & Technology

    1964-11-01

    stabilization, that of sun drying, has been used for many cen- turies in making adobe . However, the hardening which o ccu1· s during this process is...lbwn • ••lty 0. tl4-0 "* ’ · otf.J, .)to ..... ,oo t O UO ... I r -o ... . ,. l lo:•t Stl 0 1’ •• hiCh d-~Uiy 0 t41·0.M-\\ 1, •oo. r., HIO )! • SOl > 10...This does not include an~r ballast to keep the mattress in place. The problem of impermeability is one that could be sol ved by mak- ing more

  17. Vascular Ehlers-Danlos syndrome: a rare disorder presenting with focal convulsions.

    PubMed

    Ahmed, Shakeel; Ali, Syed Rehan; Nadeem, Naila; Hamid, Muhammad

    2014-11-01

    Vascular Ehlers-Danlos Syndrome (VEDS), previously called Ehlers-Danlos syndrome type-IV, is a heterogeneous group of heritable connective tissue disorders characterized by thin, translucent skin, easy bruising, arterial, intestinal, and/or uterine fragility. There is large vessel involvement that leads to arterial rupture often preceded by aneurysm, arteriovenous fistulae, or dissection. Noninvasive imaging studies such as CT angiography and MR angiography are preferred as diagnostic studies for this condition. We are reporting a 4 years old girl who was presented with right sided unilateral convulsions and hypertension. CT angiogram showed stenosis with post-stenotic dilatation of coeliac and superior mesenteric arteries. There were extensive calcified plaques with atherosclerotic changes in the segment of right common iliac artery with aneurysmal dilatation of celiac, superior mesenteric and common iliac artery. Radiological findings were consistent with vascular Ehlers-Danlos syndrome. She was successfully managed with anti-hypertensive and anticonvulsants.

  18. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.

    PubMed

    Frank, Michael; Albuisson, Juliette; Ranque, Brigitte; Golmard, Lisa; Mazzella, Jean-Michael; Bal-Theoleyre, Laurence; Fauret, Anne-Laure; Mirault, Tristan; Denarié, Nicolas; Mousseaux, Elie; Boutouyrie, Pierre; Fiessinger, Jean-Noël; Emmerich, Joseph; Messas, Emmanuel; Jeunemaitre, Xavier

    2015-12-01

    Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n=71), (2) splice-site and in-frame insertions-deletions (n=36), (3) variants leading to haplo-insufficiency (n=7), (4) non-glycine missense variants within the triple helix (n=4 variants), and (5) non-glycine missense variants or in-frame insertions-deletions, in the N- or C-terminal part of the protein (n=8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22-39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3-5, with extreme median ages at first major complication of 23-47 years. Patients of groups 3-5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care.

  19. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

    PubMed Central

    Frank, Michael; Albuisson, Juliette; Ranque, Brigitte; Golmard, Lisa; Mazzella, Jean-Michael; Bal-Theoleyre, Laurence; Fauret, Anne-Laure; Mirault, Tristan; Denarié, Nicolas; Mousseaux, Elie; Boutouyrie, Pierre; Fiessinger, Jean-Noël; Emmerich, Joseph; Messas, Emmanuel; Jeunemaitre, Xavier

    2015-01-01

    Vascular Ehlers–Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n=71), (2) splice-site and in-frame insertions–deletions (n=36), (3) variants leading to haplo-insufficiency (n=7), (4) non-glycine missense variants within the triple helix (n=4 variants), and (5) non-glycine missense variants or in-frame insertions–deletions, in the N- or C-terminal part of the protein (n=8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22–39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3–5, with extreme median ages at first major complication of 23–47 years. Patients of groups 3–5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care. PMID:25758994

  20. Eukaliuric diuresis and natriuresis in response to the KATP channel blocker U37883A: micropuncture studies on the tubular site of action.

    PubMed

    Huang, D Y; Osswald, H; Vallon, V

    1999-08-01

    1. Systemic application of U37883A, a blocker of ATP sensitive potassium (KATP) channels, elicits diuresis and natriuresis without significantly altering urinary potassium excretion. 2. To elucidate tubular sites of action upstream to the distal nephron, micropuncture experiments were performed in nephrons with superficial glomeruli of anaesthetized Munich-Wistar-Frömter rats during systemic application of U37883A (1, 5 or 15 mg kg-1 i.v.). 3. The observed eukaliuric diuresis and natriuresis in response to U37883A at 15 mg kg-1 was accompanied by an increase in early distal tubular flow rate (VED) from 10 - 18 nl min(-1) reflecting a reduction in fractional reabsorption of fluid up to this site (FR-fluid) of 13%. The latter proposed an effect on water-permeable segments such as the proximal tubule which could fully account for the observed reduction in fractional reabsorption of Na+ up to the early distal tubule (FR-Na+) of 8% and the increase in early distal tubular Na+ concentration ([Na+]ED) from 35 - 51 mM whereas [K+]ED was left unaltered. 4. In comparison, furosemide (3 mg kg-1 i.v.), which acts in the water-impermeable thick ascending limb, elicited diuresis, natriuresis and kaliuresis which were associated with a fall in FR-Na+ of 10% with no change in FR-fluid, and a rise in [Na+]ED from 42 - 117 mM and [K+]ED from 1.2 - 5.7 mM with no change in VED. 5. Direct late proximal tubular fluid collections confirmed a significant inhibition of fluid reabsorption in proximal convoluted tubule in response to systemic application of U37883A. 6. These findings suggest that the diuretic and natriuretic effect upstream to the distal tubule in response to systemic application of U37883A involves actions on water-permeable segments such as the proximal convoluted tubule.

  1. Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities.

    PubMed

    Bhardwaj, Pooja; Khanna, Deepa; Balakumar, Pitchai

    2014-03-01

    Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED), an initial event that could lead to the pathogenesis of atherosclerosis and hypertension. Previous studies showed that catechin, a key component of green tea, possesses vascular beneficial effects. We investigated the effect of catechin hydrate in diabetes mellitus-induced experimental vascular endothelial abnormalities (VEA). Streptozotocin (50 mg/kg, i.p., once) administration to rats produced diabetes mellitus, which subsequently induced VEA in 8 weeks by markedly attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentrations and impairing aortic endothelial integrity. These abnormalities in diabetic rats were accompanied with elevated aortic superoxide anion generation and serum lipid peroxidation in addition to hyperglycemia. Catechin hydrate treatment (50 mg/kg/day p.o., 3 weeks) markedly prevented diabetes mellitus-induced VEA and vascular oxidative stress. Intriguingly, in vitro incubation of L-NAME (100 μM), an inhibitor of nitric oxide synthase, or Wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), markedly prevented catechin hydrate-induced improvement in acetylcholine-provoked endothelium-dependent relaxation in the diabetic rat aorta. Moreover, catechin hydrate treatment considerably reduced the elevated level of serum glucose in diabetic rats. In conclusion, catechin hydrate treatment prevents diabetes mellitus-induced VED through the activation of endothelial PI3K signal and subsequent activation of eNOS and generation of nitric oxide. In addition, reduction in high glucose, vascular oxidative stress, and lipid peroxidation might additionally contribute to catechin hydrate-associated prevention of diabetic VEA.

  2. Comparative Evaluation of Prevalence of Upper Cervical Vertebrae Anomalies in Cleft Lip/Palate Patients: A Retrospective Study

    PubMed Central

    Datana, Sanjeev; Kumar, Prasanna; Kumar Roy, Supriya; Londhe, Sanjay

    2014-01-01

    ABSTRACT% Purpose: The patients with cleft lip and palate have a higher risk of cervical vertebrae anomalies than do patients in general population. The aim of present study was to determine the prevalence of various upper cervical spine anomalies in different type of clefts. Procedures: Lateral cephalograms of 128 patients (66 males, 62 females) with cleft lip and palate, and 125 (60 males, 65 females) non syndromic patients without cleft lip and palate were selected at random from archive. Cephalograms of the patients were traced and the diagnosis of any cervical vertebrae anomaly was noted. Anomalies were categorized as either: posterior arch deficiency or fusions. Main findings: Prevalence of cervical vertebrae anomalies in the c lef t group was 20. 3% while it was 6.4% in the control group. Further cervical vertebrae anomalies were 16.6% in the CPO group, 19.1% in the BCLP group, and 22.2% in the UCLP group. Conclusion: A higher prevalence of cervical vertebrae anomalies was observed in cleft lip and palate patients. The prevalenc e obser ved is 3 times more in clef t group than c ontrol group. How to cite this article: Datana S, Bhalla A, Kumar P, Roy SK, Londhe S. Comparative Evaluation of Prevalence of Upper Cervical Vertebrae Anomalies in Cleft Lip/Palate Patients: A Retrospective Study. Int J Clin Pediatr Dent 2014;7(3):168-171. PMID:25709295

  3. Two models of inventory control with supplier selection in case of multiple sourcing: a case of Isfahan Steel Company

    NASA Astrophysics Data System (ADS)

    Rabieh, Masood; Soukhakian, Mohammad Ali; Mosleh Shirazi, Ali Naghi

    2016-03-01

    Selecting the best suppliers is crucial for a company's success. Since competition is a determining factor nowadays, reducing cost and increasing quality of products are two key criteria for appropriate supplier selection. In the study, first the inventories of agglomeration plant of Isfahan Steel Company were categorized through VED and ABC methods. Then the models to supply two important kinds of raw materials (inventories) were developed, considering the following items: (1) the optimal consumption composite of the materials, (2) the total cost of logistics, (3) each supplier's terms and conditions, (4) the buyer's limitations and (5) the consumption behavior of the buyers. Among diverse developed and tested models—using the company's actual data within three pervious years—the two new innovative models of mixed-integer non-linear programming type were found to be most suitable. The results of solving two models by lingo software (based on company's data in this particular case) were equaled. Comparing the results of the new models to the actual performance of the company revealed 10.9 and 7.1 % reduction in total procurement costs of the company in two consecutive years.

  4. Recreational Industry in the North of European Russia: Case Assessment, Komi Republic

    NASA Astrophysics Data System (ADS)

    Yakovleva, M. P.; Kuchkina, E.; Iyevlev, N.; Lyaskovsky, S.

    2012-12-01

    At the past AGU Annual Meeting in 2011, we presented information about development of the recreation industry in European Russia within the "Silver Ring" Project (http://neespi.org/web-content/meetings/AGU_2011/Yakovleva-poster.pdf). This Project can be considered as a system of actions directed to a comprehensive socio-economic development of the Northwest of the Russian Federation that includes 11 provinces ("oblast", "republic", "okrug") of the country. Among the provinces included in the Project, The Komi Republic is one of the most interesting regions. The Komi Republic is located in the North of European Russia within the gridbox restricted by 59N - 69N latitudes and 45E - 66E longitudes. The region is populated by indigenous northern nations: Komi, Russians, Karels, Ved', Permyaks, and others. It is characterized as an ecologically clean territory, has a small population density, is rich with natural reserves, and has abundant forest and water resources. Flora and fauna of the Republic are unique and attractive. Rich biodiversity and abundance of fish and game allow hunting and sport fishing. As of January 1, 2010, The Komi Republic has 240 territories of special environmental protection ("zakazniki") with restricted human activity. This allows a diversity of field trips devoted to in-depth studies of regional ecosystems as well as tourist visits aiming to enjoy unique nature and ethnic-cultures of the North.

  5. Low cost mobile explosive/drug detection devices

    SciTech Connect

    Gozani, T.; Bendahan, J.

    1999-06-10

    Inspection technologies based on Thermal Neutron Analysis (TNA) and/or Fast Neutron Analysis (FNA) are the basis for relatively compact and low-cost, material-sensitive devices for a wide variety of inspection needs. The TNA allows the use of either isotropic neutron sources such as a {sup 252}Cf, or electronic neutron generators such as the d-T sealed neutron generator tubes. The latter could be used in a steady state mode or in slow (>{mu}s) pulsing mode, to separate the thermal neutron capture signatures following the pulse from the combination of the FNA plus TNA signatures during the pulse. Over the years, Ancore Corporation has built and is continuing to develop a variety of inspection devices based on its TNA and FNA technologies: SPEDS--an explosive detection device for small parcels, portable electronics, briefcases and other similar carry-on items; MDS - a system for the detection or confirmation of buried mines; VEDS - a system for the detection of varied amounts of explosives and/or drugs concealed in passenger vehicles, pallets, lightly loaded trucks or containers, etc.; ACD - a device to clear alarms from a primary, non-specific explosive detection system for passenger luggage. The principle and performance of these devices will be shown and discussed.

  6. Brain Enhancing Ingredients from Āyurvedic Medicine: Quintessential Example of Bacopa monniera, a Narrative Review

    PubMed Central

    Singh, Hemant K.

    2013-01-01

    Āyurveda, the science (ved) of life (ayu), owing its origin to Veda, the oldest recorded wisdom of human civilization written in 3500 BCE, contains extensive knowledge of various diseases and their therapeutic approaches. It essentially relied on nature and the immune system of an individual, and therapeutic interventions were introduced only to augment the immune system. Āyurveda had eight specialties, including psycho-neuroscience (a combination of psychology, clinical psychology and psychiatry) and a unique promotive therapy encompassing nutrition, rejuvenation and geriatrics. The symptoms of various brain disorders, including memory disorder, were well defined. The goal of Āyurveda was to help an individual to achieve his cherished goal of leading a healthy life of 100 years. To achieve this, great emphasis was laid on nutrition, diet and a good conduct by the two great exponents of Āyurveda viz. Carak and Suśruta. By following these regimens, an individual could lead a less stressful life free from emotional disturbances. Both Carak and Suśruta had believed that these in combination with rasayana (rejuvenating) plants could enable an individual to lead a healthy life of 100 years. PMID:23389306

  7. Implications of Weak Link Effects on Thermal Characteristics of Transition-Edge Sensors

    NASA Technical Reports Server (NTRS)

    Bailey, C. N.; Adams, J. S.; Bandler, S. R.; Brekosky, R. P.; Chevenak, J. A.; Eckart, M. E.; Finkbeiner, F. M.; Kelley, R. L.; Kally, D. P.; Kilbourne, C. A.; Porter, F. S.; Sadleir, J. E.; Smith, S. J.

    2012-01-01

    Weak link behavior in transition-edge sensor (TES) microcalorimeters creates the need for a more careful characterization of a device's thermal characteristics through its transition. This is particularly true for small TESs where a small change in the bias current results in large changes in effective transition temperature. To correctly interpret measurements, especially complex impedance, it is crucial to know the temperature-dependent thermal conductance, G(T), and heat capacity, C(T), at each point through the transition. We present data illustrating these effects and discuss how we overcome the challenges that are present in accurately determining G and T from I-V curves. We also show how these weak link effects vary wi.th TES size. Additionally, we use this improVed understanding of G(T) to determine that, for these TES microcalorimeters. Kaptiza boundary resistance dominates the G of devices with absorbers while the electron-phonon coupling also needs to be considered when determining G for devices without absorbers

  8. Robustness of tomographic reconstructors versus real atmospheric profiles in the ELT perspective

    NASA Astrophysics Data System (ADS)

    Gendron, E.; Morel, C.; Osborn, J.; Martin, O.; Gratadour, D.; Vidal, F.; Le Louarn, M.; Rousset, G.

    2014-08-01

    In this article we revisit a subject that has partly already been examined in previous studies: the behavior of tomographic reconstructors in adaptive optics systems, facing to an atmospheric profile (C2n(h)) different from the one they've been optimized for. We develop a new approach for that. The current usual approach is to simulate the performance of the reconstructor when slightly varying the C2n(h) profile around a nominal one, and show how far the deviation may go. This has the disadvantage that, as the parameter space for potential errors on the C2n(h) profile is basically infinite, it is particularly uneasy to span. Our approach consists in deriving a sort of sensitivity function, that we call vertical error distribution (VED), from the knowledge of any tomographic reconstructor. This function can be computed even for non-tomographic reconstructors, ground-layers reconstructors, single-conjugate AO reconstructors, etc. In any case, it allows us to derive the error when applied to a particular C2n(h) profile, have a direct, global visualization of the error variation with layer altitude, for any number at any altitude. This also allows us to understand what a given reconstructor is sensitive to, at what altitudes or altitude range, or explain why some GLAO reconstructors may perform better than optimized MMSE tomographic reconstructors if low-altitude layers pop up. We also discuss the case of ELTs and apply our approach to large scale reconstructors.

  9. Realism Assessment of Sonic Boom Simulators

    NASA Technical Reports Server (NTRS)

    Sullivan, Brenda M.; Davies, Patrica; Hodgdon, Kthleen K.; Salamone, Joseph A., III; Pilon, Anthony

    2008-01-01

    Developments in small supersonic aircraft design are predicted to result in low-intensity sonic booms. Booms generated by current aircraft are similar to those that led to the ban on commercial supersonic fli ght over the US, so are unsuitable for parametric studies of psychoac oustic response to low-intensity booms. Therefore, simulators have be en used to study the impact of predicted low-intensity sonic booms. H owever, simulators have been criticized because, when simulating conv entional-level booms, the sounds were observed to be unrealistic by p eople experienced in listening to sonic booms. Thus, two studies were conducted to measure the perceived realism of three sonic boom simul ators. Experienced listeners rated the realism of conventional sonic boom signatures when played in these simulators. The effects on percei ved realism of factors such as duration of post-boom noise, exclusion of very low frequency components, inclusion of ground reflections, a nd type of simulator were examined. Duration of post-boom noise was f ound to have a strong effect on perceived realism, while type of simu lator had a weak effect. It was determined that post-boom noise had t o be at least 1.5 seconds long for the sound to be rated very realist ic. Loudness level did not affect realism for the range of sounds pla yed in the tests (80-93 dB ASEL).

  10. Kodymirus and the case for convergence of raptorial appendages in Cambrian arthropods.

    PubMed

    Lamsdell, James C; Stein, Martin; Selden, Paul A

    2013-09-01

    Kodymirus vagans Chlupáč and Havlíček in Sb Geol Ved Paleontol 6:7-20, 1965 is redescribed as an aglaspidid-like arthropod bearing a single pair of enlarged raptorial appendages, which are shown to be the second cephalic appendage. A number of early Palaeozoic arthropods, recognized from predominantly Cambrian Konservat-Lagerstätten, are known to have borne single pairs of large raptorial appendages. They are well established for the iconic yet problematic anomalocarids, the common megacheirans, and the ubiquitous bivalved Isoxys. Further taxa, such as fuxianhuiids and Branchiocaris, have been reported to have single pairs of specialized cephalic appendages, i.e., appendages differentiated from a largely homonomous limbs series, members of which act in metachronal motion. The homology of these raptorial appendages across these Cambrian arthropods has often been assumed, despite differences in morphology. Thus, anomalocaridids, for instance, have long multiarticulate "frontal appendages" consisting of many articles bearing an armature of paired serial spines, while megacheirans and Isoxys have short "great appendages" consisting of few articles with well-developed endites or elongate fingers. Homology of these appendages would require them to belong to the same cephalic segment. We argue based on morphological evidence that, to the contrary, the raptorial appendages of some of these taxa can be shown to belong to different cephalic segments and are the result of convergence in life habits. K. vagans is yet another important example for this, representing an instance for this morphology from a marginal marine environment.

  11. Brain enhancing ingredients from Āyurvedic medicine: quintessential example of Bacopa monniera, a narrative review.

    PubMed

    Singh, Hemant K

    2013-02-06

    Āyurveda, the science (ved) of life (ayu), owing its origin to Veda, the oldest recorded wisdom of human civilization written in 3500 BCE, contains extensive knowledge of various diseases and their therapeutic approaches. It essentially relied on nature and the immune system of an individual, and therapeutic interventions were introduced only to augment the immune system. Āyurveda had eight specialties, including psycho-neuroscience (a combination of psychology, clinical psychology and psychiatry) and a unique promotive therapy encompassing nutrition, rejuvenation and geriatrics. The symptoms of various brain disorders, including memory disorder, were well defined. The goal of Āyurveda was to help an individual to achieve his cherished goal of leading a healthy life of 100 years. To achieve this, great emphasis was laid on nutrition, diet and a good conduct by the two great exponents of Āyurveda viz. Carak and Suśruta. By following these regimens, an individual could lead a less stressful life free from emotional disturbances. Both Carak and Suśruta had believed that these in combination with rasayana (rejuvenating) plants could enable an individual to lead a healthy life of 100 years.

  12. Orbiting transmitter and antenna for spaceborne communications at ELF/VLF to submerged submarines

    NASA Technical Reports Server (NTRS)

    Bannister, P. R.; Harrison, J. K.; Rupp, C. C.; King, R. W. P.; Cosmo, M. L.; Lorenzini, E. C.; Dyer, C. J.; Grossi, M. D.

    1993-01-01

    An orbital emplacement for the transmitter and the antenna of a communications link at ELF (30 to 300 Hz) and VLF (3 kHz to 30 kHz) to submerged submarines has been considered since the very inception of the space age. However, only recently has space technology reached a sufficient level of maturity for system designers to undertake serious studies of this link configuration. The optimistic outlook stems from recent space technology developments, such as the design and construction by NASA of long orbiting tethers, and the testing, onboard Shuttle Orbiter ATLANTIS, of the first spaceborne 20 km metal wire. This is known as the Tethered Satellite System-1 (TSS-1), a space mission that might be possibly followed by other flights, with tether lengths that could reach 100 km. Once deployed at a height of, say, 300 km, from a Shuttle Orbiter, or from another suitable platform, a long, thin tether aligns itself along the local vertical by virtue of the gradient of the Earth gravity field. If made of metal, the tether can function as a VED (Vertical Electric Dipole) transmitting antenna at ELF and VLF.

  13. Induction of human leukemia U937 cell apoptosis by an ethanol extract of Dendropanax morbifera Lev. through the caspase-dependent pathway.

    PubMed

    Lee, Joon Wοο; Park, Cheol; Han, Min Hο; Hong, Su Hyun; Lee, Tae Kyung; Lee, Shin Hwa; Kim, Gi-Young; Choi, Yung Hyun

    2013-09-01

    Dendropanax morbifera Leveille is found throughout southwestern Korea, and has been used in traditional medicine for various diseases, such as migraine headache, infectious diseases, skin diseases and dysmenorrhea. However, the molecular mechanisms of D. morbifera concerning its biochemical actions in cancer have not yet been clearly elucidated. In the present study, we investigated the pro-apoptotic effects of an ethanol extract of D. morbifera stem bark (EEDM) on human leukemia U937 cells. EEDM markedly inhibited the growth of U937 cells by decreasing cell proliferation and inducing apoptosis. EEDM-induced apoptosis in U937 cells was associated with the upregulation of death receptor-related protein levels and downregulation of anti-apoptotic IAP family proteins. The increase in apoptosis was also associated with proteolytic activation of caspase-8, -9 and -3, inhibition of anti‑apoptotic Bcl-2 and Bcl-xL expression, Bid cleavage, and loss of MMP suggesting that apoptosis of U937 cells induced by EEDM was through the extrinsic and intrinsic pathways. However, a pan-caspase inhibitor, z-VED-fmk, significantly inhibited EEDM-induced U937 cell apoptosis indicating that the caspases were key regulators of apoptosis in response to EEDM in U937 cells. Our data suggest that D. morbifera may be a potential anticancer agent for cancer treatment.

  14. Vitamin E deficiency reduced lumbar bone calcium content in female rats.

    PubMed

    Norazlina, M; Chua, C W; Ima-Nirwana, S

    2004-12-01

    Vitamin E deficiency has been found to impair bone calcification. This study was done to determine the effects of vitamin E deficiency and supplementation on parathyroid hormone, i.e. the hormone involved in bone regulation. Female Sprague-Dawley rats were divided into 4 groups: 1) normal rat chow (RC), 2) vitamin E deficiency (VED), vitamin E deficient rats supplemented with 3) 60 mg/kg alpha-tocotrienol (ATT) and 4) 60 mg/kg (alpha-tocopherol (ATF). Treatment was carried out for 3 months. Vitamin E deficiency caused hypocalcaemia during the first month of the treatment period, increased the parathyroid hormone level in the second month and decreased the bone calcium content in the 4th lumbar bone at the end of the treatment. Vitamin E supplementation (ATT and ATF) failed to improve these conditions. The bone formation marker, osteocalcin, and the bone resorption marker, deoxypyridinoline did not change throughout the study period. In conclusion vitamin E deficiency impaired bone calcium homeostasis with subsequent secondary hyperparathyroidism and vertebral bone loss. Replacing the vitamin E with pure ATF or pure ATT alone failed to correct the changes seen.

  15. Effects of Vitamin C or E on the Pro-inflammatory Cytokines, Heat Shock Protein 70 and Antioxidant Status in Broiler Chicks under Summer Conditions.

    PubMed

    Jang, In-Surk; Ko, Young-Hyun; Moon, Yang-Soo; Sohn, Sea-Hwan

    2014-05-01

    The present study was carried out to investigate the effects of dietary antioxidants on pro-inflammatory cytokines, heat shock protein (HSP) and antioxidant status in broiler chicks under summer conditions. A total of 162, 3-d-old broiler chicks were randomly assigned to a basal diet (CON) and the basal diet supplemented with vitamin C (200 mg/kg diet, VCD) or vitamin E (100 mg/kg, VED) until 35 day of age. All birds were exposed to summer diurnal heat stress at average daily fluctuations of temperature between 32°C to 34°C at day to 27°C to 29°C at night for the entire feeding periods. There was no significant difference in body weight, feed to gain ratio and the relative organ weight except the thymus in response to dietary vitamin C or E supplementation. However, the mRNA expression of interleukin (IL)-1β, IL-6, interferon (IFN)-γ, Toll like receptor (TLR)-4 and HSP70 in the liver of birds fed diet containing vitamin C significantly (p<0.05) decreased compared with those in birds fed basal diet. Dietary vitamin E also showed a significant (p<0.05) decrease in the mRNA expression of IL-6 and HSP70 compared with a basal diet. Total antioxidant status (TAS) in serum of birds fed vitamin C supplemented diet was significantly (p<0.05) higher with than that in birds a basal diet. Lipid peroxidation in serum and liver resulted in a significant (p<0.05) decrease in response to dietary vitamin C or E supplementation. In conclusion, dietary supplementation with antioxidant vitamins, especially vitamin C resulted in a significant decrease in the mRNA expression of pro-inflammatory cytokines and HSP70, and higher antioxidant parameters than that of birds on the basal diet under summer conditions.

  16. Competitive Low Pressure Oxygen Plasma Interactions with Different= Carbon-Carbon Double Bonds

    NASA Astrophysics Data System (ADS)

    Patiño, P.; Sifontes, A.; Gambús, G.

    1999-10-01

    Recently we have shown advances from reactions of O(^3P) with both, l ong-chain hydrocarbons and refinery residuum. The oxidation products of t he process, a mixture of alcohols, epoxides and carbonyl compounds, might have potential properties as additives in formulating fuels. This work s hows the results of the interactions of an oxygen plasma with double bond s, both olefin and aromatic, in the same compound. The reactions have bee n carried out by making the plasma, created by a high voltage glow discha rge, reach the low vapor pressure surface of liquid 4-phenyl-1-butene. Th is (3 mL) was cooled down to -45 ^oC in a glass reactor, applied power was 24 W, at an oxygen pressure of 20 Pa. Products were analyzed by IR, N MR and mass spectroscopies. Conversions were studied as a function of the reaction time, this ranging from 5 to 120 minutes. At short times the O( ^3P) atoms produced in the discharge only reacted with the alkene fra ction of the hydrocarbon, 4-phenyl-1,2-epoxibutane (52%) and 4-phenyl-bu tanal (48%) being the products. Reactions on the benzene ring were obser ved from about 30 minutes on, the corresponding phenols having being prod uced at ratios ortho:para:meta :: 4:1:0.7. At 120 minutes, the ol efin have been completely oxidized and a low fraction of the non-equivale nt two methylene groups have reacted to produce alcohols and ketones.

  17. Towards the mid-infrared optical biopsy

    NASA Astrophysics Data System (ADS)

    Seddon, Angela B.; Benson, Trevor M.; Sujecki, Slawomir; Abdel-Moneim, Nabil; Tang, Zhuoqi; Furniss, David; Sojka, Lukasz; Stone, Nick; Jayakrupakar, Nallala; Lloyd, Gavin R.; Lindsay, Ian; Ward, Jon; Farries, Mark; Moselund, Peter M.; Napier, Bruce; Lamrini, Samir; Møller, Uffe; Kubat, Irnis; Petersen, Christian R.; Bang, Ole

    2016-03-01

    We are establishing a new paradigm in mid-infrared molecular sensing, mapping and imaging to open up the midinfrared spectral region for in vivo (i.e. in person) medical diagnostics and surgery. Thus, we are working towards the mid-infrared optical biopsy (`opsy' look at, bio the biology) in situ in the body for real-time diagnosis. This new paradigm will be enabled through focused development of devices and systems which are robust, functionally designed, safe, compact and cost effective and are based on active and passive mid-infrared optical fibers. In particular, this will enable early diagnosis of external cancers, mid-infrared detection of cancer-margins during external surgery for precise removal of diseased tissue, in one go during the surgery, and mid-infrared endoscopy for early diagnosis of internal cancers and their precision removal. The mid-infrared spectral region has previously lacked portable, bright sources. We set a record in demonstrating extreme broad-band supercontinuum generated light 1.4 to 13.3 microns in a specially engineered, high numerical aperture mid-infrared optical fiber. The active mid-infrared fiber broadband supercontinuum for the first time offers the possibility of a bright mid-infrared wideband source in a portable package as a first step for medical fiber-based systems operating in the mid-infrared. Moreover, mid-infrared molecular mapping and imaging is potentially a disruptive technology to give improved monitoring of the environment, energy efficiency, security, agriculture and in manufacturing and chemical processing. This work is in part supported by the European Commission: Framework Seven (FP7) Large-Scale Integrated Project MINERVA: MId-to-NEaR- infrared spectroscopy for improVed medical diAgnostics (317803; www.minerva-project.eu).

  18. Fatigue test results of the rotating steel blades of steam turbine K-25-0.6 GEO with ion-plasma coating

    NASA Astrophysics Data System (ADS)

    Kachalin, G. V.; Mednikov, A. F.; Tkhabisimov, A. B.; Arkad'ev, D. A.; Temkin, S. G.; Senina, N. A.

    2016-12-01

    Fatigue test results of the rotating steel blades of the fourth stage of the K-25-0.6 low pressure cylinder Geo steam turbine manufactured in the Kaluga Turbine Plant (hereinafter, KTP) with the ion-plasma coating were presented. Coating formation was carried out at the National Research University (MPEI) on the Gefest vacuum pilot plant by the magnetron sputtering method. Characteristics of the obtained coating were analyzed with the use of the scientific-research equipment of the National Research University (MPEI). Fatigue tests of the rotating blades and determination of the fatigue strength of the material with the ion-plasma coating were carried out on the electrodynamic vibration machines VEDS-400A in the KTP structural laboratory. The following characteristics were obtained after tests: Ti-TiN composition, 10-11 μm thickness, 1200 HV 0.05 microhardness. Fatigue tests showed that destruction, regardless of availability or nonavailability of the coating, took place by cross-section in the root zone both on the leading and trailing edges of the blade, i.e., in the most stressed zones. It was found out that the maximum stresses during tests were revealed in the root section along the trailing edge on the blade pressure side, and the less stresses were on the leading edge. Fatigue strength of the working blades after coating formation increased by 12% minimum. Results of the fatigue tests prove the previously obtained data concerning 10-12% increase of the fatigue strength of the blade steel with the ion-plasma coating and allow claiming that the process of their formation exerts the positive influence on the fatigue characteristics of the blade materials.

  19. PREFACE: Physics and biology of neurodegenerative diseases Physics and biology of neurodegenerative diseases

    NASA Astrophysics Data System (ADS)

    Pastore, Annalisa

    2012-06-01

    In 1939, William T Astbury, who was at the time a professor at the University of Leeds, wrote a letter to Dorothy Hodgkins, a crystallographer colleague who would eventually be awarded a Nobel Prize (1964) [1]. Astbury was working on determining the structure of silk and had found that these fibres had a so-called cross-beta arrangement, with the hydrogen bonds holding a beta-sheet structure perpendicular to the fibre axis. This structure was very robust and thus would account well for the properties of the silk fibre. Being very impressed by this structural solution at a time when protein structure was just being discovered, he wrote to Dorothy Hodgkins formulating the hypothesis that all proteins could adopt a cross-beta structure similar to that found for silk as a sort of ultimate solution. Approximately 70 years later, this prediction was reconsidered and is now generally accepted to be correct: most if not all proteins seem to be able to form fibrils, commonly named amyloids, that adopt the same structural features found in silk. The field of amyloid fibres bloomed in the mid-90s when several researchers—among them Chris Dobson, a professor first at Oxford and then at Cambridge—observed that proteins could aggregate by concomitant formation of fibrillar structures (reviewed in [2]). It was certainly not news that proteins could aggregate with an irreversible mechanism. However, what nearly came as a surprise was the realization that aggregation is often accompanied by a major structural rearrangement, which almost invariably associates with protein misfolding (i.e. loss of the native structure and adoption of a beta-rich structure) and amyloid fibre formation. Even more interesting was the growing evidence that amyloid fibres have very special mechanical properties, being extremely resilient and not easily degraded. At the same time it was noticed that different diseases, generically named amyloidoses, are associated with fibrillar aggregates. Today

  20. Tango in the Mid-Jurassic: 10,000-Yr Geomagnetic Field Reversals

    NASA Astrophysics Data System (ADS)

    Steiner, M.

    2001-12-01

    A continuous magnetostratigraphic signature of Layer 2A from Jurassic Quiet Zone (JQZ) oceanic crust now is known from two separate paleo-magnetic data sets. Measurement/demagnetization along the length of the entire core at 5-cm intervals generated ~100,000 data points, whereas a suite of 472 discrete samples also were taken from throughout the core. Both data sets display the same magnetization pattern, a series of repeated sinusoidal inclination changes downhole. Six inter-vals of maximum inclination (three positive, three negative) are obser-ved. Maximum inclination intervals of +/-40° are separated by regions of smoothly varying intermediate inclination values. Despite lack of azmuithal orientation of the core, downhole magnetic logging (Larson et al., in prep.) shows full ~360° directional change in the magnetization vector. Therefore, the maximum inclination regions represent polarity intervals of the geomagnetic field, and six polarity intervals in stacked sequence are contained in the upper 400 m thickness of Layer 2A at this site. The time duration spanned by these six reversals was estimated from recent seismic studies of young ocean crustal construction on the East Pacific Rise (EPR). Estimates of completion of construction of Layer 2A within 1-3 km from the rise crest and typical EPR half-spreading rates of 5-8 cm/yr suggest that the studied 400 m of ocean crust represents 37,000-60,000 years. The fast construction of EPR crust implies that the Middle Jurassic geomagnetic field was reversing at a phenomenal rate of 5000-10,000 years. These data establish that the `quiet' signature in the oldest portion of the lineated magnetic anomaly patterns in the ocean crust is due to exceedingly rapid reversals of the geomagnetic field, because succes-sive, superposed opposite-polarity magnetic signatures will essentially cancel one another out at the sea surface. The width of the 'quiet' magnetic signature in the western Pacific Ocean implies that the 5000

  1. Misho mafic complex - A part of paleotethyan oceanic crust or a magmatism in continental rift?

    NASA Astrophysics Data System (ADS)

    Azimzadeh, Zohreh; Jahangiri, Ahmad; Saccani, Emilio; Dilek, Yildirim

    2013-04-01

    Misho Mafic Complex (NW Iran) represents a significant component of the West Cimmerian domain in Paleo-Tethys. The Misho Mafic Complex (MMC) consists of gabbro (mainly) and norıte,olivine gabbro, anorthosite and diorite with the east- west sereight. MMC has ıntrussıved ın Kahar sedımrtery Infta- Cambrıan rocks, crosscut by abundant basaltic dykes and the overlying basaltic sheeted dyke complex. Kahar sedimentary rocks are representing the northern margin of Gondwana. Misho mafic complex are covered by Permian sedimentary rocks. The gabbros and basaltic dykes have MORB affinities. MMC formed as a product of interactions between a depleted MORB-type asthenosphere and plume-type material. Mafic rocks represent an early Carboniferous magmatic event developed during the continental break-up of the northern edge of Gondwanaland that led to the opening of Paleotethys. Alternatively, these magmas may have been emplaced into the continental crust at the continental margin soon after the oceanic crust was formed (that is the oceanic crust was still narrow). There is no data for discriminating between these two hypotheses. In first hypothesis MMC is a part of ophiolites related to paleotethyan oceanic crust and the rocks that were above this crustal level should have necessarily been eroded. In another hypothesis Misho complex represents an aborted rift in a triple junction. Above a mantle plume, the continental crust breaks along three directions at 120 degrees. But, soon after, the extension proceeds along two of these three direction. Between them is formed the oceanic crust. The continental extension along the third direction is aborted. Here no oceanic crust if formed and there is only rifted, thinned continental crust. But, also in the aborted branch MORB magmatism can occur for short time. In this hypothesis, the Misho complex was never associated with oceanic crust, but was anyway associated with the opening of the Paleotethys. This magmatism was originally

  2. Morphological and functional preservation of pre-antral follicles after vitrification of macaque ovarian tissue in a closed system

    PubMed Central

    Ting, A. Y.; Yeoman, R. R.; Campos, J. R.; Lawson, M. S.; Mullen, S. F.; Fahy, G. M.; Zelinski, M. B.

    2013-01-01

    STUDY QUESTION What are the appropriate conditions to vitrify the macaque ovarian cortex in a large-volume, closed system that will preserve functional pre-antral follicles? SUMMARY ANSWER The combination of glycerol, ethylene glycol (EG) and polymers with cooling in liquid nitrogen (LN2) vapor and a two-step warming procedure was able to preserve tissue and follicle morphology as well as function of a small population of secondary follicles in the macaque ovarian cortex following vitrification in a closed system. WHAT IS KNOWN ALREADY For prepubertal cancer patients or those who require immediate cancer therapy, ovarian tissue cryopreservation offers the only hope for future fertility. However, the efficacy of live birth from the transplantation of cryopreserved ovarian tissue is still unclear. In addition, live birth from cryopreserved ovarian tissue has only been demonstrated after tissue autotransplantation, which poses the risk of transmitting metastatic cancer cells back to the cancer survivor in certain cancers. STUDY DESIGN, SIZE, DURATION Non-human primate model, n = 4, randomized, control versus treatment. End-points were collected from tissue histology, tissue culture (48 h) and isolated secondary follicle culture (6 weeks). PARTICIPANTS/MATERIALS, SETTING, METHODS Two vitrification solutions (VSs) containing EG + glycerol (VEG) and EG + dimethylsulfoxide (VED) were examined for vitrification, devitrification and thermodynamic properties. Once the optimal VS was determined, macaque ovarian cortical pieces (3 × 3 × 0.5 mm3) were divided into fresh and two vitrified groups (VEG and VED). For the vitrification groups, tissues were exposed to 1/4, 1/2 and 1× VS for 5 min/step as well as 1× VS + polymers for 1 min at 37°C, loaded into high-security straws with 1 ml of VS + polymers, heat sealed and cooled in LN2 vapor. Samples were warmed in a 40°C water bath and cryoprotective agents were diluted with 1, 0.5, 0.25 and 0 M sucrose. Tissues were fixed

  3. Anhydrobiosis vs. aging: comparative genomics of protein repair L-isoaspartyl methyltransferases in the sleeping chironomid. .

    NASA Astrophysics Data System (ADS)

    Gusev, Oleg; Kikawada, Takahiro; Shagimardanova, Elena; Suetsugu, Yoshitaka; Ayupov, Rustam

    and larval stages. Finally, the expression of Pimt1 gene in both chironomids was not changed in response to desiccation, while the clustered PvPimt2-12 showed strong up-regulation in response to water loss and other abiotic stresses. The abundance of PvPimt2-12 mRNAs was maximal in anhydrobiotic larvae, and it resembles the case of plant seeds where accumulation of PIMT provides additional protection for proteins during long dry storage. Predicted proteins of PvPimT2-12 contain conservative L-isoaspartyl methyltransferase functional domain. At the same time the length and structure of N- and C- terminals of the predicted proteins show significant variation, suggesting different substrate preferences or other specific properties of different Pv-PIMT Furthermore, the multi-member family in Pv is the first observation of drastic expansion and evolution of Pimt genes in general, and particularly in a single insect species. This work was supported by Russian Foundation for Basic Research (№ 12-08-33157 mol_a_ved and № 14-04-01657_A).

  4. Investigations of the air flow velocity field structure above the wavy surface under severe wind conditions by particle image velosimetry technique.

    NASA Astrophysics Data System (ADS)

    Troitskaya, Yuliya; Kandaurov, Alexander; Sergeev, Daniil; Ermakova, Olga

    2013-04-01

    both method were in a good agreement. The application of PIV method enabled us measuring wind velocity profiles much closer to water surface than in the case of contact method. As a result there exists the logarithmic parts in velocity profiles, which yield turbulent momentum flux from the slope and also the equivalent 10-m wind speed and the surface drag coefficient. It was shown that similarly to [2] the surface drag coefficient tends to saturate at wind velocities exceeding 25 m/s. The decrease of the water surface drag coefficient with wind velocity increase was not observed. This work was supported by RFBR (project 11-05-12047-ofi-m, 13-05-00865-a, 12-05-33070 mol-a-ved, 12-05-31435 mol-a, 12-05-01064-a). References 1. Canny, J. A. Computational approach to edge detection/ J.A. Canny// IEEE Trans. Pattern Analysis and Machine Intelligence. - 1986. - V. 8(6). - P. 679-698.. 2. Troitskaya, Y. I., D. A. Sergeev, A. A. Kandaurov, G. A. Baidakov, M. A. Vdovin, and V. I. Kazakov Laboratory and theoretical modeling of air-sea momentum transfer under severe wind conditions J.Geophys. Res., 117, C00J21, doi:10.1029/2011JC007778.

  5. Podzol development in S Norway - a soil chronosequence of 31 pedons covering soil ages from 85 to 9650 years

    NASA Astrophysics Data System (ADS)

    Sauer, Daniela; Svendgård-Stokke, Siri; Sperstad, Ragnhild; Sørensen, Rolf; Fuchs, Markus; Gebers, Henrik; Schülli-Maurer, Isabelle

    2013-04-01

    horizons. The mineralogical composition of the parent material is dominated by quartz and feldspars, whereby the feldspar grains show features of proceeding weathering with time. In addition to podzolisation features, illuvial clay is observed below the Bs horizons. Apparently, the sand is sufficiently buffered during the first millennia of soil formation so that acidification proceeds slowly enough to allow for clay translocation prior to podzolisation. Reference Sørensen, R., Høeg, H.I., Henningsmoen, K.E., Skog, G., Labowsky, S.F., Stabell, B. (2012): Utviklingen av det senglasiale og tidlig preboreale landskapet og vegetasjonen omkring steinalderboplassene ved Pauler, Larvik kommune, Vestfold. In: Jaksland, L. (Ed.), E18 Brunlaneprospektet. Varia 79. Kulturhistorisk Museum, University of Oslo.

  6. Fluid composition and evolution in coesite-bearing rocks (Dora-Maira massif, Western Alps): implications for element recycling during subduction

    NASA Astrophysics Data System (ADS)

    Philippot, Pascal; Chevallier, Pierre; Chopin, Christian; Dubessy, Jean

    1995-08-01

    Fluid inclusions and F, Cl concentration of hydrous minerals were analysed in the coesite-pyrope quartzite, the interlayered jadeite quartzite and their country-rock gneiss from the Dora-Maira massif using a combination of microthermometry, Raman spectrometry, synchrotron X-ray microfiuorescence and electron microprobe analysis. Three populations of fluid inclusions were recognized texturally and can be related to distinct metamorphic stages. A low-salinity aqueous fluid occurs in the retrogressed country gneiss and as late secondary inclusions in jadeite quartzite and chloritized pyrope. An earlier secondary population is found in matrix quartz of the jadeite- and pyro-pe-quartzites. This population can be related to the early decompression and so to incipient breakdown of garnet into phlogopite-bearing assemblages. The inclusion fluid is highly saline (up to 84 wt% equivalent NaCl) and contains Na, Ca, Fe, Cu and Zn as major cations. In pyrope quartzite, additional K was found in these brines, which locally coexist with CO2-rich inclusions. The oldest fluid inclusions are preserved in kyanite grains included in fresh pyrope and in pyrope itself. In pyrope, all inclusions have decrepitated and contain magnesite, an Mg-phosphate, sheet-silicate(s), a chloride and an opaque phase, with no fluid preser ved. In contrast, the kyanite inclusions in pyrope preserve primary H2O-CO2 low-salinity fluid inclusions, probably owing to the low compressibility of the kyanite inclusions and host garnet. In spite of in-situ re-equilibration, these inclusions can be interpreted as relics of the dehydration fluid that attended pyrope growth. These correlations between textural and chemical fluid inclusion data and metamorphic stages are consistent with the fluid composition calculated from the halogen content of different generations of phlogopite and biotite. The preservation of different fluid compositions, both in time and space, is evidence for local control and possibly origin

  7. Offshore influence of coastal upwelling off Mauritania, NW Africa, as recorded by diatoms in sediment traps at 2195 m water depth

    NASA Astrophysics Data System (ADS)

    Lange, Carina B.; Romero, Oscar E.; Wefer, Gerold; Gabric, Albert J.

    1998-06-01

    taxa in the sediments. In an attempt to contrast coastal vs. oceanic upwelling, we compared the Cap Blanc trap results (a coastal/open-ocean transition site) with the patterns recorded previously in sediment traps from the Guinea Basin (GBN3; an open-ocean equatorial upwelling site). Enhanced fluxes at both sites corresponded in time with the occurrence of upwelling (i.e. spring and early summer for CB1, and early spring and summer for GBN3). Total, opal and lithogenic mean daily fluxes were 2.4, 1.6 and 6.3 times higher at CB1 than at GBN3. Diatom and silicoflagellate fluxes were 8.9 and 1.6 times higher at GBN3. On a yearly basis, the diatom flora for CB1 can be characterized as "coastal with oceanic influence", and for GBN3 as "open ocean with moderate coastal influence". Chain-forming and colonial diatoms with individual cell diameters of >5 μm dominated the coastal upwelling site ( Thalassionema nitzschioides and Chaetoceros), while small (<5 μm) solitary diatoms ( Nitzschia bicapitata) dominated the open ocean equatorial upwelling regime. Comparable relative abundances of freshwater diatoms were noted at both trap sites; their seasonal distribution within each geographical area was attributed to the Saharan dust transport patterns involved. While diatom indicators of coastal upwelling were readily preser ved in the surface sediments off Cap Blanc, the assemblage in the Guinea Basin sediments differed greatly from that in the traps with the summer signal for equatorial upwelling being removed from the sediment. We conclude that significant differences between the assemblages trapped at both sites support the usefulness of these data as sensitive indicators of dissimilar oceanographic settings.

  8. Micromorphological changes over time observed in the Vestfold Podzol chronosequence, SE Norway

    NASA Astrophysics Data System (ADS)

    Sauer, Daniela; Musztyfaga, Elżbieta; Sørensen, Rolf; Svendgård-Stokke, Siri; Rennert, Thilo; Sperstad, Ragnhild; Fuchs, Markus

    2016-04-01

    addition, micromorphological analysis shows that clay translocation took place prior to strong acidification and podzolisation in many profiles. In some rare cases, clay coatings are observed even on top of spodic material, suggesting that - at least to minor extent - translocation of coarse clay may take place even contemporarily to podzolisation. This apparent contradiction can be explained by different depths of mobilisation of metal-organic complexes and clay. Apparently, even when the upper, strongly acid part of the soils is already subject to podzolisation, acidification and Al saturation at some depth are still not as advanced as further up in the profile and still allow for clay mobilisation. In addition, cappings of coarse clay and fine silt on top of larger grains suggest that water flushing through the coarse voids of the sandy material, e.g., after snow-melt, may sweep down also clay particles in a not completely dispersed state. In this way, clay translocation might take place also outside the pH range that is usually considered suitable for clay migration. Reference Sørensen, R., Høeg, H.I., Henningsmoen, K.E., Skog, G., Labowsky, S.F., Stabell, B., 2012. Utviklingen av det senglasiale og tidlig preboreale landskapet og vegetasjonen omkring steinalderboplassene ved Pauler, Larvik kommune, Vestfold. In: Jaksland, L. (Ed.), E18 Brunlaneprospektet. Varia 79. Kulturhistorisk Museum, University of Oslo.

  9. Objectives and Outcomes

    SciTech Connect

    Segalman, D.J.

    1998-11-30

    I have recently become involved in the ABET certification process under the new system - ABET 2000. This system relies heavily on concepts of Total Quality Management (TQM). It encourages each institution to define its objectives in terms of its own mission and then create a coherent program based on it. The prescribed steps in setting up the new system at an engineering institution are: o identification of constituencies G definition of mission. It is expected that the department's mission will be consistent with that of the overall institution, but containing some higher resolution language appropriate to that particular discipline of the engineering profession. o statement of objectives consistent with the mission 3G~~\\vED " enumeration of desired, and preferably measurable, outcomes of the process that would ~ `=. verify satisfaction of the objectives. ~~~ 07 !398 o establish performance standards for each outcome. o creation of appropriate feedback loops to assure that the objectives are still consistent with Q$YT1 the mission, that the outcomes remain consistent with the objectives, and that the curriculum and the teaching result in those outcomes. It is my assertion that once the institution verbalizes a mission, enumerated objectives naturally flow from that mission. (We shall try to demonstrate by example.) Further, if the mission uses the word "engineer", one would expect that word also to appear in at least one of the objectives. The objective of producing engineers of any sort must -by decree - involve the presence of the ABET criteria in the outcomes list. In other words, successful satisfaction of the ABET items a-k are a necessary subset of the measure of success in producing engineers. o We shall produce bachelor level engineers whose training in the core topics of chemical (or electrical, or mechanical) engineering is recognized to be among the best in the nation. o We shall provide an opportunity for our students to gain a

  10. [Macular choroidal blood flow in concurrent age-related macular degeneration and primary open-angle glaucoma].

    PubMed

    Panova, I E; Ermak, E M; Shaimova, T A; Shaimova, V A

    2016-01-01

    олическая скорость (peak systolic velocity — Vps), конечная диастолическая скорость (end-diastolic velocity — Ved), усредненная по времени максимальная скорость кровотока (time-averaged maximum velocity — Vtamax), индекс резистентности (resistive index — RI). Результаты. Установлено, что в 1-й, 3-й группах и подгруппе 2А формируется гипоперфузионный тип хориоидального кровотока в макулярной зоне (снижение Vtamax) с развитием некомпенсированного перфузионного дефицита на фоне напряжения механизмов ауторегуляции (снижение Vps, Ved, сниженные или нормальные значения RI). У больных подгруппы 2Б достоверно чаще формируется гиперперфузионный тип хориоидального кровотока (повышение Vps, Ved, Vtamax, RI). Заключение. Сочетанная патология — ВМД и ПОУГ — характеризуется гипоперфузионным типом хориоидального кровотока в макулярной зоне, что приводит к нарушению трофики нейросенсорной сетчатки и предопределяет возможность утяжеления течения ВМД с прогрессированием атрофической формы.