A Specific Point Mutant at Position 1 of the Influenza Hemagglutinin Fusion Peptide Displays a Hemifusion Phenotype

We showed previously that substitution of the first residue of the influenza hemagglutinin (HA) fusion peptide Gly1 with Glu abolishes fusion activity. In the present study we asked whether this striking phenotype was due to the charge or side-chain volume of the substituted Glu. To do this we generated and characterized six mutants with substitutions at position 1: Gly1 to Ala, Ser, Val, Glu, Gln, or Lys. We found the following. All mutants were expressed at the cell surface, could be cleaved from the precursor (HA0) to the fusion permissive form (HA1-S-S-HA2), bound antibodies against the major antigenic site, bound red blood cells, and changed conformation at low pH. Only Gly, Ala, and Ser supported lipid mixing during fusion with red blood cells. Only Gly and Ala supported content mixing. Ser HA, therefore, displayed a hemifusion phenotype. The hemifusion phenotype of Ser HA was confirmed by electrophysiological studies. Our findings indicate that the first residue of the HA fusion peptide must be small (e.g., Gly, Ala, or Ser) to promote lipid mixing and must be small and apolar (e.g., Gly or Ala) to support both lipid and content mixing. The finding that Val HA displays no fusion activity underscores the idea that hydrophobicity is not the sole factor dictating fusion peptide function. The surprising finding that Ser HA displays hemifusion suggests that the HA ectodomain functions not only in the first stage of fusion, lipid mixing, but also, either directly or indirectly, in the second stage of fusion, content mixing.

Role of adenine functional groups in the recognition of the 3′-splice-site AG during the second step of pre-mRNA splicing

The AG dinucleotide at the 3′ splice sites of metazoan nuclear pre-mRNAs plays a critical role in catalytic step II of the splicing reaction. Previous studies have shown that replacement of the guanine by adenine in the AG (AG → GG) inhibits this step. We find that the second step was even more severely inhibited by cytosine (AG → CG) or uracil (AG → UG) substitutions at this position. By contrast, a relatively moderate inhibition was observed with a hypoxanthine substitution (AG → HG). When adenine was replaced by a purine base (AG → PG) or by 7-deazaadenine (AG → c7AG), little effect on the second step was observed, suggesting that the 6-NH2 and N7 groups do not play a critical role in adenine recognition. Finally, replacement of adenine by 2-aminopurine (AG → 2-APG) had no effect on the second step. Taken together, our results suggest that the N1 group of adenine functions as an essential determinant in adenine recognition during the second step of pre-mRNA splicing.

The shape of the banking union confirms Berlin's privileged position in the eurozone. OSW Commentary No. 123, 10.01.2014

On 18 December 2013, EU finance ministers reached agreement on the structure of a banking union. The body will be tasked with oversight of the largest banks across the EU. It will also devise recovery and resolution programmes for institutions at risk of bankruptcy, and it will handle wind-up arrangements and decide on the allocation of resulting costs. The proposals are expected to be approved by March of this year by the governments of the eurozone states, by other EU members interested in joining the banking union, and by the European Parliament. A compromise on the supervision of the largest banks in the eurozone was reached several months ago. The most recent negotiations focused on the second pillar of the banking union: a Single Resolution Mechanism. The parties successfully negotiated a set of procedures for rescuing banks capable of recovery and for the closure of institutions that cannot be rescued. A joint position was also agreed on the allocation of costs resulting from such actions.

Russia's position on the events in Kyrgyzstan (April-June 2010). OSW Commentary No. 38, 2010-07-27

Russia was the first state in the world to de facto recognise the regime change in Kyrgyzstan that took place on 7 April 2010. This recognition, along with a previous campaign by the Russian media against the then President Kurmanbek Bakiyev, has given rise to suspicion that the events of April were provoked by Russia. However, it seems no more than reasonable to say that Russia provided some inspiration and lobbying in that direction. Russia offered support to the new Kyrgyz government almost immediately, albeit conditionally. Russia’s relations with Roza Otunbayeva’s government have been changing in nature; they are currently much cooler than they had been immediately after the coup. There are many indications that this change was a reaction to the extension of the lease agreement for the American military base in the Manas airport. At the same time, Moscow remains in contact with the political rivals to the current regime, which suggests that the Kremlin is preparing for different developments, and does not regard the current crisis as having been fully resolved. Despite the interim government’s plea for help, Russia refused to undertake military intervention in southern Kyrgyzstan, which plunged into ethnic unrest in June. This shows that Russia is wary of being dragged into a long-standing and bloody conflict in the region, which could entail considerable expenses and jeopardise Russia’s authority. It should be expected that after the October parliamentary elections in Kyrgyzstan, Russia will return to its plans to establish a second military base in this country (in addition to the Kant base) to reinforce its dominant position in the region. This is the first time that Russia has had a real chance to play a stabilising role in the CIS area. How Russia copes with this challenge may decide its position in post-Soviet Central Asia – and in a wider context, its relations with NATO, the USA and China.

North Caucasus: the Russian Gordian knot. The key problems and conflicts in the region and the effect thereof on the future of Russia; Putin after re-election: The Kremlin's policy in Vladimir Putin's second term. OSW Study 16/2004

North Caucasus: North Caucasus is the most instable part of the Russian Federation: since the early 90's, there has been going on the military conflict in Chechnya, which is gradually spilling over into the other republics of the region, terrorism seems to have occupied its regular position in the political life of Caucasus, organized crime is flourishing, the tension persists there and military incidents and attacks are breaking out every now and again. During the recent year, the destabilization of the region, which affects many fields of Russian political and social life, has grown to an alarming size. Putin after re-election: Vladimir Putin's first term as President was a period of submitting political, regional and economic lobbies to the Kremlin. The actions Putin has taken since being re-elected are aimed at consolidating the Kremlin's control over the political, economic and social spheres. Further liquidation of political and informational pluralism, an increase of the ruling group's control over state and private property, and an intensification of state propaganda aimed at generating social support for the Kremlin's initiatives have all proceeded apace. These processes reinforce authoritarian tendencies and strengthen the emerging monocentric political system, with the President's strong domination over political, economic and social life.

Is socioeconomic position early in life associated with physical activity during adulthood following the accumulation of risk model with additive effects?

L'activité physique améliore la santé, mais seulement 4.8% des Canadiens atteignent le niveau recommandé. La position socio-économique est un des déterminants de l'activité physique les plus importants. Elle est associée à l’activité physique de manière transversale à l’adolescence et à l’âge adulte. Cette thèse a tenté de déterminer s'il y a une association à long terme entre la position socio-économique au début du parcours de vie et l’activité physique à l’âge adulte. S'il y en avait une, un deuxième objectif était de déterminer quel modèle théorique en épidémiologie des parcours de vie décrivait le mieux sa forme. Cette thèse comprend trois articles: une recension systématique et deux recherches originales. Dans la recension systématique, des recherches ont été faites dans Medline et EMBASE pour trouver les études ayant mesuré la position socio-économique avant l'âge de 18 ans et l'activité physique à ≥18 ans. Dans les deux recherches originales, la modélisation par équations structurelles a été utilisée pour comparer trois modèles alternatifs en épidémiologie des parcours de vie: le modèle d’accumulation de risque avec effets additifs, le modèle d’accumulation de risque avec effet déclenché et le modèle de période critique. Ces modèles ont été comparés dans deux cohortes prospectives représentatives à l'échelle nationale: la 1970 British birth cohort (n=16,571; première recherche) et l’Enquête longitudinale nationale sur les enfants et les jeunes (n=16,903; deuxième recherche). Dans la recension systématique, 10 619 articles ont été passés en revue par deux chercheurs indépendants et 42 ont été retenus. Pour le résultat «activité physique» (tous types et mesures confondus), une association significative avec la position socio-économique durant l’enfance fut trouvée dans 26/42 études (61,9%). Quand seulement l’activité physique durant les loisirs a été considérée, une association significative fut trouvée dans 21/31 études (67,7%). Dans un sous-échantillon de 21 études ayant une méthodologie plus forte, les proportions d’études ayant trouvé une association furent plus hautes : 15/21 (71,4%) pour tous les types et toutes les mesures d’activité physique et 12/15 (80%) pour l’activité physique de loisir seulement. Dans notre première recherche originale sur les données de la British birth cohort, pour la classe sociale, nous avons trouvé que le modèle d’accumulation de risque avec effets additifs s’est ajusté le mieux chez les hommes et les femmes pour l’activité physique de loisir, au travail et durant les transports. Dans notre deuxième recherche originale sur les données canadiennes sur l'activité physique de loisir, nous avons trouvé que chez les hommes, le modèle de période critique s’est ajusté le mieux aux données pour le niveau d’éducation et le revenu, alors que chez les femmes, le modèle d’accumulation de risque avec effets additifs s’est ajusté le mieux pour le revenu, tandis que le niveau d’éducation ne s’est ajusté à aucun des modèles testés. En conclusion, notre recension systématique indique que la position socio-économique au début du parcours de vie est associée à la pratique d'activité physique à l'âge adulte. Les résultats de nos deux recherches originales suggèrent un patron d’associations le mieux représenté par le modèle d’accumulation de risque avec effets additifs.

The second Belgian grey book.

"The translation contains only those portions of the book which are material to the position of Great Britain, namely, the whole of the first part and section 10 of the second part, which deals with the accusations brought against Belgium of having concluded a military agreement with Great Britain." cf. Prefatory note.

Continuous-variable Einstein-Podolsky-Rosen paradox with traveling-wave second-harmonic generation

The Einstein-Podolsky-Rosen paradox and quantum entanglement are at the heart of quantum mechanics. Here we show that single-pass traveling-wave second-harmonic generation can be used to demonstrate both entanglement and the paradox with continuous variables that are analogous to the position and momentum of the original proposal.

Novel strategies in feedforward adaptation to a position-dependent perturbation

To investigate the control mechanisms used in adapting to position-dependent forces, subjects performed 150 horizontal reaching movements over 25 cm in the presence of a position-dependent parabolic force field (PF). The PF acted only over the first 10 cm of the movement. On every fifth trial, a virtual mechanical guide (double wall) constrained subjects to move along a straight-line path between the start and target positions. Its purpose was to register lateral force to track formation of an internal model of the force field, and to look for evidence of possible alternative adaptive strategies. The force field produced a force to the right, which initially caused subjects to deviate in that direction. They reacted by producing deviations to the left, into the force field, as early as the second trial. Further adaptation resulted in rapid exponential reduction of kinematic error in the latter portion of the movement, where the greatest perturbation to the handpath was initially observed, whereas there was little modification of the handpath in the region where the PF was active. Significant force directed to counteract the PF was measured on the first guided trial, and was modified during the first half of the learning set. The total force impulse in the region of the PF increased throughout the learning trials, but it always remained less than that produced by the PF. The force profile did not resemble a mirror image of the PF in that it tended to be more trapezoidal than parabolic in shape. As in previous studies of force-field adaptation, we found that changes in muscle activation involved a general increase in the activity of all muscles, which increased arm stiffness, and selectively-greater increases in the activation of muscles which counteracted the PF. With training, activation was exponentially reduced, albeit more slowly than kinematic error. Progressive changes in kinematics and EMG occurred predominantly in the region of the workspace beyond the force field. We suggest that constraints on muscle mechanics limit the ability of the central nervous system to employ an inverse dynamics model to nullify impulse-like forces by generating mirror-image forces. Consequently, subjects adopted a strategy of slightly overcompensating for the first half of the force field, then allowing the force field to push them in the opposite direction. Muscle activity patterns in the region beyond the boundary of the force field were subsequently adjusted because of the relatively-slow response of the second-order mechanics of muscle impedance to the force impulse.

Position information but not force information is used in adapting to changes in environmental dynamics

This study investigated how movement error is evaluated and used to change feedforward commands following a change in the environmental dynamics. In particular, we addressed the question of whether only position-error information is used or whether information about the force-field direction can also be used for rapid adaptation to changes in the environmental dynamics. Subjects learned to move in a position-dependent force field (PF) with a parabolic profile and the dynamics of a negative spring, which produced lateral force to the left of the target hand path. They adapted very rapidly, dramatically reducing lateral error after a single trial. Several times during training, the strength of the PF was unexpectedly doubled (PF2) for two trials. This again created a large leftward deviation, which was greatly reduced on the second PF2 trial, and an aftereffect when the force field subsequently returned to its original strength. The aftereffect was abolished if the second PF2 trial was replaced by an oppositely directed velocity-dependent force field (VF). During subsequent training in the VF, immediately after having adapted to the PF, subjects applied a force that assisted the force field for similar to 15 trials, indicating that they did not use information about the force-field direction. We concluded that the CNS uses only the position error for updating the internal model of the environmental dynamics and modifying feedforward commands. Although this strategy is not necessarily optimal, it may be the most reliable strategy for iterative improvement in performance.

Testing the protracted lexical restructuring hypothesis: The effects of position and acoustic-phonetic clarity on sensitivity to mispronunciations in children and adults

Although developmental increases in the size of the position effect within a mispronunciation detection task have been interpreted as consistent with a view of the lexical restructuring process as protracted, the position effect itself might not be reliable. The current research examined the effects of position and clarity of acoustic-phonetic information on sensitivity to mispronounced onsets in 5- and 6-year-olds and adults. Both children and adults showed a position effect only when mispronunciations also differed in the amount of relevant acoustic-phonetic information. Adults' sensitivity to mispronounced second-syllable onsets also reflected the availability of acoustic-phonetic information. The implications of these findings are discussed in relation to the lexical restructuring hypothesis. (c) 2006 Elsevier Inc. All rights reserved.

The second intracellular loop of the calcitonin gene-related peptide receptor provides molecular determinants for signal transduction and cell surface expression

The calcitonin gene-related peptide (CGRP) receptor is a heterodimer of a family B G-protein-coupled receptor, calcitonin receptor-like receptor (CLR), and the accessory protein receptor activity modifying protein 1. It couples to Gs, but it is not known which intracellular loops mediate this. We have identified the boundaries of this loop based on the relative position and length of the juxtamembrane transmembrane regions 3 and 4. The loop has been analyzed by systematic mutagenesis of all residues to alanine, measuring cAMP accumulation, CGRP affinity, and receptor expression. Unlike rhodopsin, ICL2 of the CGRP receptor plays a part in the conformational switch after agonist interaction. His-216 and Lys-227 were essential for a functional CGRP-induced cAMP response. The effect of (H216A)CLR is due to a disruption to the cell surface transport or surface stability of the mutant receptor. In contrast, (K227A)CLR had wild-type expression and agonist affinity, suggesting a direct disruption to the downstream signal transduction mechanism of the CGRP receptor. Modeling suggests that the loop undergoes a significant shift in position during receptor activation, exposing a potential G-protein binding pocket. Lys-227 changes position to point into the pocket, potentially allowing it to interact with bound G-proteins. His-216 occupies a position similar to that of Tyr-136 in bovine rhodopsin, part of the DRY motif of the latter receptor. This is the first comprehensive analysis of an entire intracellular loop within the calcitonin family of G-protein-coupled receptor. These data help to define the structural and functional characteristics of the CGRP-receptor and of family B G-protein-coupled receptors in general. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Back from the future:the second chance in the past of aller + infinitive

Typological studies (Bybee et al. 1994, Dahl 2000, Bourdin 2008 among many others) have shown a tendency for spatial elements (such as movement verbs) to grammaticalise into temporal expressions. The periphrasis made of aller + infinitive has been very productive in Romance languages. If in French, Spanish or Portuguese, it refers to future, it refers to a simple past in Catalan. fr.: je vais aller au cinéma esp.: voy a ir al cine pt. Vou ira o cine cat.: vaig anar al cine Barceló & Bres (2005:168) indicate that, In French, «vers le XVIème siècle, […] la périphrase a brièvement fonctionné comme un temps du passé (alors même que l’emploi comme temps du futur émergeait)»: (1) Sur ces propos, firent leur accord et, en regardant le lieu le plus propre pour faire cette belle œuvre, elle va dire qu’elle n’en savait point de meilleure ni plus loin de tout soupçon, qu’une petite maison qui était dedans le parc, où il y avait chambre et lit tout à propos. (Marguerite de Navarre, L’Heptaméron) The future value took over so much so that Damourette & Pichon (1911-1936 :117) claimed the past value had disappeared»: Un second tour, encore plus aberrant, n’a plus, que nous sachions, aucune position en pays d’Oui. Nous voulons parler de l’expression d’un passé au moyen de l’auxiliaire aller, suivi de l’infinitif. Ce tour a eu une grande fortune dans le provençal ancien et le catalan […] En français, on n’en trouve que des traces, notamment du XIVe au XVIe siècles . Ex.:[…] Adoncques s’arrêtèrent le conte et Raimondin soubz un grand arbre ; lors va dire le conte à Raimondin: […]. Et Raimondin va lui dire : Sire, ce qu’il vous plaira. That allegedly extinct use is nonetheless alive and kicking in Contemporary French. Larreya (2005:349)notes that it is « très courant dans les récits – en particulier dans les récits oraux» and it is also found in newspaper language as shown by this except from an obituary for Loulou Gasté (Le Monde 1995): (2) Celle-ci se déroule aux Editions Micro, où il a un bureau. Séduit par la jeune interprète, il commence à lui écrire des chansons sur mesure et leur complicité va mettre cinq ans à se transformer en amour. Au début de leur rencontre, Loulou est neurasthénique parce qu’il vient de divorcer et la future Line, exclusivement préoccupée par son métier, ne songe à rien d’autre. Line et Loulou vont rattraper le temps perdu et créer ensemble un millier de petites chansons dont la plupart sont devenues immortelles. Jusqu’à ces derniers mois, il ne va pas se passer une journée sans que Loulou s’empare de sa guitare pour créer un refrain. Would we be witnessing a linguistic resurrection? The same structure seems therefore to have grammaticalised in diverging and even diametrically opposite ways in different Romance languages. In this talk, we shall try to explain how the phrase aller + infinitive is able to function both as a future and a past. We will especially concentrate on the case of contemporary French where, while the future interpretation has obtained the status of tense as futur proche or périphrastique, a past interpretation is now commonplace. Our reflection will be supported by a personal corpus of authentic examples.

Surviving in violent conflicts: Chinese interpreters in the second Sino-Japanese War (1931-1945)

In the past decade interpreting studies has gradually adopted a sociological perspective, taking into account social and cultural factors that affect interpreters actual behaviour in different settings. However, there have been few studies of interpreters practices as forms of social interaction, especially of the ways in which they become professionals and operate as social agents. Drawing upon Pierre Bourdieus theory of practice, this thesis aims to offer a contribution to the history of interpreting by examining the professional training and practices of Chinese interpreters during the Second Sino-Japanese War (1931-1945). On the basis of Bourdieus concept of field, this thesis reconstructs three competing fields dominated by three political and military powers: the Chinese Kuomingtang (KMT) government, the Chinese Communist Party, and the Japanese forces. By investigating interpreters training, employment and practices within these three fields, the thesis examines how the interpreting profession was affected by shifts in foreign policy, and how interpreters professional habitus were formed through their training and interaction with other social agents and institutions. It then highlights the interpreters active position-taking in pursuit of individual interests by examining particular interpreters career development through case studies of two interpreters, Xia Wenyun and Yan Jiarui, who served the Japanese forces and the Chinese KMT government, respectively. The study shows that the practices of the interpreters were broader than the scope of language transfer. In order to survive violent conflicts, interpreters often intertwined their interpreting with other political and professional activities. For them, interpreting was not a mere linguistic practice, but a strategy for self-protection, a route to power, or just a chance for a better life. Frequently crossing social, political and military borders, interpreters sometimes played a crucial cushioning role by protecting local residents from loss of life and property during the war.

Mach bands and multiscale models of spatial vision:the role of first, second, and third derivative operators in encoding bars and edges

Ernst Mach observed that light or dark bands could be seen at abrupt changes of luminance gradient in the absence of peaks or troughs in luminance. Many models of feature detection share the idea that bars, lines, and Mach bands are found at peaks and troughs in the output of even-symmetric spatial filters. Our experiments assessed the appearance of Mach bands (position and width) and the probability of seeing them on a novel set of generalized Gaussian edges. Mach band probability was mainly determined by the shape of the luminance profile and increased with the sharpness of its corners, controlled by a single parameter (n). Doubling or halving the size of the images had no significant effect. Variations in contrast (20%-80%) and duration (50-300 ms) had relatively minor effects. These results rule out the idea that Mach bands depend simply on the amplitude of the second derivative, but a multiscale model, based on Gaussian-smoothed first- and second-derivative filtering, can account accurately for the probability and perceived spatial layout of the bands. A key idea is that Mach band visibility depends on the ratio of second- to first-derivative responses at peaks in the second-derivative scale-space map. This ratio is approximately scale-invariant and increases with the sharpness of the corners of the luminance ramp, as observed. The edges of Mach bands pose a surprisingly difficult challenge for models of edge detection, but a nonlinear third-derivative operation is shown to predict the locations of Mach band edges strikingly well. Mach bands thus shed new light on the role of multiscale filtering systems in feature coding. © 2012 ARVO.