129 research outputs found
An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission
Get PDFAdvances in genome sequencing technologies have favored the identification of rare de novo mutations linked to neurological disorders in humans. Recently, a de novo autosomal dominant mutation in NACC1 was identified (NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp), associated with severe neurological symptoms including intellectual disability, microcephaly, and epilepsy. As NACC1 had never before been associated with neurological diseases, we investigated how this mutation might lead to altered brain function. We examined neurotransmission in autaptic glutamatergic mouse neurons expressing the murine homolog of the human mutant NACC1, i.e., Nacc1-R284W. We observed that expression of Nacc1-R284W impaired glutamatergic neurotransmission in a cell-autonomous manner, likely through a dominant negative mechanism. Furthermore, by screening for Nacc1 interaction targets in the brain, we identified SynGAP1, GluK2A, and several SUMO E3 ligases as novel Nacc1 interaction partners. At a biochemical level, Nacc1-R284W exhibited reduced binding to SynGAP1 and GluK2A, and also showed greatly increased SUMOylation. Ablating the SUMOylation of Nacc1-R284W partially restored its interaction with SynGAP1 but did not restore binding to GluK2A. Overall, these data indicate a role for Nacc1 in regulating glutamatergic neurotransmission, which is substantially impaired by the expression of a disease-associated Nacc1 mutant. This study provides the first functional insights into potential deficits in neuronal function in patients expressing the de novo mutant NACC1 protein
Kirsti Aasen: Alle mine kilder
Get PDFKirsti Aasen: A ll M y Springs. Gyldendal Norsk Forlag, Oslo 1986.Reviewed by Helge Baden NielsenThe title of the book are the first words of one of Grundtvig’s hymns. The reviewer sees this essay collection by a Norwegian woman minister first and foremost as an expression of the new interest in Grundtvig in Norway, as was proved by the establishment in 1983 of a special Norwegian branch of the Grundtvig Society. According to Kirsti Aasen this takes its origin in the liberation, under Grundtvig’s inspiration, from the pietistic view of Christianity in Norway. In her own case she discovered that Christianity could easily be combined with love of the Norwegian countryside and the life of the people. The author was born in .sterdalen, studied theology at Oslo University, and is now rector of a parish in Oslo
Identification of a catalytic active but non-aggregating MDM2 RING domain variant
Get PDFAs a key regulator of the tumour suppressor protein p53, MDM2 is involved in various types of cancer and has thus been an attractive drug target. So far, small molecule design has primarily focussed on the N-terminal p53-binding domain although on-target toxicity effects have been reported. Targeting the catalytic RING domain of MDM2 resembles an alternative approach to drug MDM2 with the idea to prevent MDM2-mediated ubiquitination of p53 while retaining MDM2's ability to bind p53. The design of RING inhibitors has been limited by the extensive aggregation tendency of the RING domain, making it challenging to undertake co-crystallization attempts with potential inhibitors. Here we compare the purification profiles of the MDM2 RING domain from several species and show that the MDM2 RING domain of other species than human is much less prone to aggregate although the overall structure of the RING domain is conserved. Through sequence comparison and mutagenesis analyses, we identify a single point mutation, G443T, which greatly enhances the dimeric fraction of human MDM2 RING domain during purification. Neither does the mutation alter the structure of the RING domain, nor does it affect E2(UbcH5B)-Ub binding and activity. Hence, MDM2-G443T facilitates studies involving binding partners that would be hampered by the low solubility of the wild-type RING domain. Furthermore, it will be valuable for the development of MDM2 RING inhibitors
Grundtvigs symbolverden. Af Helge Toldberg
Get PDFHelge Toldberg: Grundtvigs symbolverden (Grundtvig s Universe of Symbols), Skrifter udgivet af Grundtvig-Selskabet II. Copenhagen, 1950. Grundtvig’s copious use of images and symbols has given him the reputation of being an obscure and often incomprehensible writer. Only a few research students have ventured to approach Grundtvig on this side of his nature, whether it is a question of the exhaustive interpretation of particular works or of reading “ right through” his whole literary output for the purpose of establishing the underlying connections in his world of ideas and symbols. Dr. Helge Toldberg belongs to the latter group. In his book (the thesis for his Doctorate at the University of Copenhagen in 1950) he has undertaken the task of analysing the symbols employed by Grundtvig, in the belief that the frequent use of the same symbols by an author has a significance of its own, apart from the context in which they appear. The consequence of the acceptance of this principle by Dr. Toldberg is that in his study of Grundtvig’s writings the particular text is of minor interest; it is only in the comparatively few cases where the symbol constitutes its whole content that an analysis of any particular text is given. But, apart from this, the author’s method is the opposite of the genetical one. He is emphatically a systematiser and “ structuralist”, who works with clear concepts and wide ranges, and who embodies his results in definite schematic forms. In his book he attempts the immense task of finding his way down through the outward forms of Grundtvig’s literary output to its omnipresent foundation, its substratum, i. e., Grundtvig’s fundamental attitude to life or fundamental philosophy, and to the symbols employed by Grundtvig to express this fundamental philosophy. This substratum is determined by religious rather than by aesthetic factors, and Grundtvig’s choice of symbols is determined in great measure by this circumstance. Dr. Toldberg divides Grundtvig’s symbols into two groups: the symbols of life and faith which are closely connected with the substratum, and the legendary and traditional symbols taken from mythology and history which are more arbitrary and independent of the substratum. But even the last-named group of symbols is also strictly determined by the substratum, and the author’s division must therefore be regarded as a weakness ind the book and as serving an expository rather than a descriptive purpose. And indeed in practice he does not invariably keep to the sharp division he himself has made. Dr. Toldberg also makes use of the following fundamental concepts (borrowed from John Stuart M ill) : denotation, i. e., interpretation, direct signification, and connotation, i. e., connected or subsidiary ideas, the associative element. The principle of denotation is posited as the distinguishing mark of the poetry whose strength — as well as its limitations — lies in definite meanings of words, in classical clarity (typical author: Virgil). If a poem is rich in connotations, it may be characterised as romantic (in the wider sense); a poem of this kind aims first and foremost not at clarity but at plenitude (typical authors: Shakespeare, Grundtvig). Grundtvig, who despised Virgil and loved Shakespeare, is romantic in the sense that his symbolism points away from that which symbolises towards that which is symbolised (in contradistinction to that of the classical writers). Dr. Toldberg’s interpretation of Grundtvig is thus principally concerned with the subsidiary meanings which accompany the symbols, and here his philological and mythological scholarship achieves many triumphs. Thanks to an excellent index, the book can be used as a regular reference book for the interpretation of Grundtvig. The constant and the changing elements in the connotations are acutely observed, and where the symbols of life and faith are in question we are shown the coincidence between the changes in their connotations and the mutations in Grundtvig’s religious experience. The wide survey taken by Dr. Toldberg and his sense for the recurrent symbols as such can, however, cause him sometimes to overlook obvious connections and details within a particular text. From the point of view of pure literary scholarship his method can become dangerous in its denial of the organic microcosm of the particular work taken in isolation. But his system gives his grandly-conceived attempt at interpretation a firm structure which is admirable and instructive. However, the fact that the distinction between connotations and denotations may sometimes appear to be effaced raises a problem which the author has not recognised or discussed. Many of Grundtvig’s connotations really derive their character from what might be called “ private denotations” . A recognition of this problem could have given occasion for fruitful aesthetic and critical reflections. Does not a great deal of Grundtvig’s writing show traces of stiffening into a routine of conventional phraseology? And does not the recognition of this create the background for an even higher appreciation of his finest passages which reach the heights of inspiration? In the valuable chapters on Grundtvig’s symbolic language and symbolic vision (P. 37—72) two central concepts in Grundtvig’s writing are brought to light: “ spejl” = “mirror” (or “ spejling” = “mirroring”), and “ gaacfe” = “mystery” . Man (i. e. Grundtvig) must apprehend synthetically, not analytically. And the synthesis which must be apprehended everywhere is “God’s purpose in the historical and mythological context” (P. 64). The world, history and human life mirror the Divine Being, and the poet’s work is to interpret this mirroring and nothing else. Thus Grundtvig regards science as being in subordination to faith, which must reject every scientific interpretation that is incompatible with this. (Grundtvig was therefore opposed to the astronomical theories of Copernicus.) For Grundtvig existence, history, and the origin of Christianity are a series of mysteries, which can only be solved with the help of the Christian faith. The task is the interpretation of visions, and this is only possible through adopting a prophetic standpoint in relation to present and past events (P. 68). Words like “wondrous” , “wonderful” and “ to illumine” are therefore favourite words for Grundtvig. Dr. Toldbergs book is written in an exact and technical scholarly language which makes it difficult for non-specialists, and indeed for specialists as well. There seems to be something tragic in the fact that while the book’s terminology and method are addressed to readers who may be regarded as being out of touch with Grundtvig’s world of ideas, its content is concerned in great measure with what is most centrally Grundtvigian! Dr. Toldberg has begun by discussing the symbols of life and faith, and has afterwards discussed the traditional historical and mythological symbols. To have discussed them in the reverse order would have been better, and would have led the reader in clearer fashion and along an ascending path into the centre of Grundtvig’s spiritual world. The long section about legendary and traditional symbols is the most imposing from the point of view of scholarship, with its wealth of observation and power of combination. But the deepest perspectives are to be found in the section about the symbols of life and faith. The notes with which the book is liberally provided contain a wealth of information and suggestions for further study
Stress - Regulation of SUMO conjugation and of other Ubiquitin-Like Modifiers
No full textStress is unavoidable and essential to cellular and organismal evolution and failure to adapt or restore homeostasis can lead to severe diseases or even death. At the cellular level, stress drives a plethora of molecular changes, of which variations in the profile of protein post-translational modifications plays a key role in mediating the adaptative response of the genome and proteome to stress. In this context, post-translational modification of proteins by ubiquitin-like modifiers, (Ubl), notably SUMO, is an essential stress response mechanism. In this review, aiming to draw universal concepts of the Ubls stress response, we will decipher how stress alters the expression level, activity, specificity and/or localization of the proteins involved in the conjugation pathways of the various type-I Ubls, and how this result in the modification of particular Ubl targets that will translate an adaptive physiological stress response and allow cells to restore homeostasis.</p
Mapping groups associated with real-valued function spaces and direct limits of Sobolev-Lie groups
Get PDFLet be a compact smooth manifold of dimension (without boundary) and
be a finite-dimensional Lie group, with Lie algebra . Let
be the group of all mappings which are
for some . We show that can be made a regular Lie
group in Milnor's sense, modelled on the Silva space which is
the locally convex direct limit of the Hilbert spaces for ,
such that is the direct limit of the Hilbert-Lie groups
for as a smooth Lie group. We also explain how the (known)
Lie group structure on can be obtained as a special case of a
general construction of Lie groups whenever real-valued function
spaces on open subsets of are given, subject to simple
axioms.Comment: Extended preprint version, 37 pages. Starting point for first author
was earlier project "Regularity in Milnor's sense for direct limits of
infinite-dimensional Lie groups'
The development of virtual libraries in Commonwealth Libraries in Australia
Get PDFThis research examines the development of virtual libraries in Commonwealth libraries in Australia in 1998-1999. The background to the study lies in some of the current issues in the information sector, and government responses to those issues. The study begins by considering the nature of the Australian Commonwealth Government, reviewing what government libraries are and whom they serve, and examining the future trends expected to affect Commonwealth libraries. The current state of virtual library research is then reviewed, and the need for research in the Commonwealth library sector examined. The author reviews the virtual library concept as expressed in the literature in the field, determines what a virtual library is, and gives consideration to why virtual libraries are being developed. The issues that affect and are affected by virtual library development are then examined. Based on this, a model of virtual libraries is formulated, along with a brief consideration of the possible application, importance and problems associated with each element of the model. The research design and methods that were used to gather information for this study are then outlined, along with the inherent limitations of the research model. Following this, the findings from a survey of virtual library development in Commonwealth libraries are discussed. The author then conducts some analysis of these responses, and makes comparisons between different Commonwealth library responses, as well as comparisons with virtual library studies conducted in American and Australian academic libraries. The research concludes by attempting to reach some conclusions about Commonwealth virtual library development and the validity of the proposed model of virtual libraries. Flowing from this, recommendations are made for further research in this field
Waldökologie online, Heft 3 (2006)
No full textDiesmal konnten Sie auf unserer Homepage (www.afsv.de) mitverfolgen, wie Heft 3 langsam bis zu seiner Endversion gewachsen ist. Mit unserer neuen Rubrik "Vorabveröffentlichungen" haben wir uns von der starren Jahrbuch-Periodik gelöst. Es gibt keinen offiziellen Redaktionsschluss mehr. Manuskripte, die bereits frühzeitig im Jahr eingereicht werden und ein erfolgreiches Review- Prozess durchlaufen, stehen i.d.R. acht Wochen später online. Sobald 100 Seiten Umfang erreicht sind, ist automatisch ein neues Heft abgeschlossen
Structural Optimization Of A Vertical Axis Wind Turbine With Aeroelastic Analysis
No full textCurrently, the price per kW of offshore wind energy is 55% larger than onshore [38, 52]. Of this price, the rotor corresponds to 22%. To reduce the price of wind energy, it is necessary to investigate wind turbine concepts with scales above 10 MW. The commonly known Horizontal Axis Wind Turbine (HAWT) requires offshore a large support structure. If the turbine is designed to be floating, a deep floater is needed to limit the tilt angle. A possible concept to meet this challenges is the lift-driven Vertical Axis Wind Turbine (VAWT). This thesis aims to optimize the structural design of a VAWT rotor blade and to decrease the mass to area ratio by varying blade shape and structural layout. The choice of mass to rotor area ratio as an optimization function follows from the fact that this area is directly proportional to the energy output while mass drives production and installation costs. The VAWT is defined by an axis perpendicular to the unperturbed flow direction. The rotor geometry is described through a Troposkein shape. It is assumed that the blades carry their own weight leading to a reinforced root region. During operation the blades experience aerodynamic and inertia forces, which are deflecting the blades outwards, leading to an alternation of the aerodynamic loads.The interplay of load alternation and blade deflection could lead to a diverging flutter motion. After a fitting design is obtained, the blade motion has to be inspected for a safe use during operation. The rotor is designed with an adjusted optimizer, originally written by M. Schelbergen [62]. The optimizer uses the Matlab optimization toolbox in combination with Nastran. The modification allows a smooth transition of the thickness of skin, shear web and girder. The airfoil section is varied along the blade. The optimization is based on load cases such as a parked rotor and the maximum up- and downwind forces. These loads are simplified and assumed to vary neither by the motion nor the deflections of the blade. In addition, an aeroelastic model is required to observe the blades’ motion. Through out thisthesis two aeroelastic codes were used. The VAWT AeroElastic Multibody Panel Solver (VÆMPS) was created by coupling Sandia National Laboratories OWENS and the near wake panel solver UMPM. However, its computational performance was not satisfying and it was decided to use HAWC2 coupled with an actuator cylinder model to determine the induction.European Wind Energy Masters (EWEM
From the 'Rescue of the Nation State' to the Emergence of European Spaces. EUIJ-Kansai Workshop on "New Research Horizons of the History of European Integration", May 10, 2008, Toyonaka (Osaka)
Get PDFThe aim of this paper is to make some contribution to the discussion on the future direction of the historical research on the European integration processes. What I intend to do here is, broadly, to link the contemporary European studies to the Historical studies, and concretely, to emphasise the transnational dimension of European integration. This exercise should be read as presenting my "wish list" to the Integration Historians
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