Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat.

Marked increases in intracellular calcium may play a role in mediating cellular dysfunction and death following central nervous system trauma, in part through the activation of the calcium-dependent neutral protease calpain. In this study, we evaluated the effect of the calpain inhibitor AK295 [Z-Leu-aminobutyric acid-CONH(CH2)3-morpholine] on cognitive and motor deficits following lateral fluid percussion brain injury in rats. Before injury, male Sprague-Dawley rats (350-425 g) were trained to perform a beam-walking task and to learn a cognitive test using a Morris water maze paradigm. Animals were subjected to fluid percussion injury (2.2-2.4 atm; 1 atm = 101.3 kPa) and, beginning at 15 min postinjury, received a continuous intraarterial infusion of AK295 (120-140 mg/kg, n = 15) or vehicle (n= 16) for 48 hr. Sham (uninjured) animals received either drug (n = 5) or vehicle (n = 10). Animals were evaluated for neurobehavioral motor function at 48 hr and 7 days postinjury and were tested in the Morris water maze to evaluate memory retention at 7 days postinjury. At 48 hr, both vehicle- and AK295-treated injured animals showed significant neuromotor deficits (P< 0.005). At 7 days, injured animals that received vehicle continued to exhibit significant motor dysfunction (P< 0.01). However, brain-injured, AK295-treated animals showed markedly improved motor scores (P<0.02), which were not significantly different from sham (uninjured) animals. Vehicle-treated, injured animals demonstrated a profound cognitive deficit (P< 0.001), which was significantly attenuated by AK295 treatment (P< 0.05). To our knowledge, this study is the first to use a calpain inhibitor following brain trauma and suggests that calpain plays a role in the posttraumatic events underlying memory and neuromotor dysfunction.

Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein.

The beta-amyloid precursor protein (beta-APP), from which the beta-A4 peptide is derived, is considered to be central to the pathogenesis of Alzheimer disease (AD). Transgenic mice expressing the 751-amino acid isoform of human beta-APP (beta-APP751) have been shown to develop early AD-like histopathology with diffuse deposits of beta-A4 and aberrant tau protein expression in the brain, particularly in the hippocampus, cortex, and amygdala. We now report that beta-APP751 transgenic mice exhibit age-dependent deficits in spatial learning in a water-maze task and in spontaneous alternation in a Y maze. These deficits were mild or absent in 6-month-old transgenic mice but were severe in 12-month-old transgenic mice compared to age-matched wild-type control mice. No other behavioral abnormalities were observed. These mice therefore model the progressive learning and memory impairment that is a cardinal feature of AD. These results provide evidence for a relationship between abnormal expression of beta-APP and cognitive impairments.

Bases moléculaires et cellulaires d’un trouble neurodéveloppemental causé par l’haploinsuffisance de SYNGAP1

La déficience intellectuelle est la cause d’handicap la plus fréquente chez l’enfant. De nombreuses évidences convergent vers l’idée selon laquelle des altérations dans les gènes synaptiques puissent expliquer une fraction significative des affections neurodéveloppementales telles que la déficience intellectuelle ou encore l’autisme. Jusqu’à récemment, la majorité des mutations associées à la déficience intellectuelle a été liée au chromosome X ou à la transmission autosomique récessive. D’un autre côté, plusieurs études récentes suggèrent que des mutations de novo dans des gènes à transmission autosomique dominante, requis dans les processus de la plasticité synaptique peuvent être à la source d’une importante fraction des cas de déficience intellectuelle non syndromique. Par des techniques permettant la capture de l’exome et le séquençage de l’ADN génomique, notre laboratoire a précédemment reporté les premières mutations pathogéniques dans le gène à transmission autosomique dominante SYNGAP1. Ces dernières ont été associées à des troubles comportementaux tels que la déficience intellectuelle, l’inattention, des problèmes d’humeur, d’impulsivité et d’agressions physiques. D’autres patients sont diagnostiqués avec des troubles autistiques et/ou des formes particulières d’épilepsie généralisée. Chez la souris, le knock-out constitutif de Syngap1 (souris Syngap1+/-) résulte en des déficits comme l’hyperactivité locomotrice, une réduction du comportement associée à l’anxiété, une augmentation du réflexe de sursaut, une propension à l’isolation, des problèmes dans le conditionnement à la peur, des troubles dans les mémoires de travail, de référence et social. Ainsi, la souris Syngap1+/- représente un modèle approprié pour l’étude des effets délétères causés par l’haploinsuffisance de SYNGAP1 sur le développement de circuits neuronaux. D’autre part, il est de première importance de statuer si les mutations humaines aboutissent à l’haploinsuffisance de la protéine. SYNGAP1 encode pour une protéine à activité GTPase pour Ras. Son haploinsuffisance entraîne l’augmentation des niveaux d’activité de Ras, de phosphorylation de ERK, cause une morphogenèse anormale des épines dendritiques et un excès dans la concentration des récepteurs AMPA à la membrane postsynaptique des neurones excitateurs. Plusieurs études suggèrent que l’augmentation précoce de l’insertion des récepteurs AMPA au sein des synapses glutamatergiques contribue à certains phénotypes observés chez la souris Syngap1+/-. En revanche, les conséquences de l’haploinsuffisance de SYNGAP1 sur les circuits neuronaux GABAergiques restent inconnues. Les enjeux de mon projet de PhD sont: 1) d’identifier l’impact de mutations humaines dans la fonction de SYNGAP1; 2) de déterminer si SYNGAP1 contribue au développement et à la fonction des circuits GABAergiques; 3) de révéler comment l’haploinsuffisance de Syngap1 restreinte aux circuits GABAergiques affecte le comportement et la cognition. Nous avons publié les premières mutations humaines de type faux-sens dans le gène SYNGAP1 (c.1084T>C [p.W362R]; c.1685C>T [p.P562L]) ainsi que deux nouvelles mutations tronquantes (c.2212_2213del [p.S738X]; c.283dupC [p.H95PfsX5]). Ces dernières sont toutes de novo à l’exception de c.283dupC, héritée d’un père mosaïque pour la même mutation. Dans cette étude, nous avons confirmé que les patients pourvus de mutations dans SYNGAP1 présentent, entre autre, des phénotypes associés à des troubles comportementaux relatifs à la déficience intellectuelle. En culture organotypique, la transfection biolistique de l’ADNc de Syngap1 wild-type dans des cellules pyramidales corticales réduit significativement les niveaux de pERK, en fonction de l’activité neuronale. Au contraire les constructions plasmidiques exprimant les mutations W362R, P562L, ou celle précédemment répertoriée R579X, n’engendre aucun effet significatif sur les niveaux de pERK. Ces résultats suggèrent que ces mutations faux-sens et tronquante résultent en la perte de la fonction de SYNGAP1 ayant fort probablement pour conséquences d’affecter la régulation du développement cérébral. Plusieurs études publiées suggèrent que les déficits cognitifs associés à l’haploinsuffisance de SYNGAP1 peuvent émerger d’altérations dans le développement des neurones excitateurs glutamatergiques. Toutefois, si, et auquel cas, de quelle manière ces mutations affectent le développement des interneurones GABAergiques résultant en un déséquilibre entre l’excitation et l’inhibition et aux déficits cognitifs restent sujet de controverses. Par conséquent, nous avons examiné la contribution de Syngap1 dans le développement des circuits GABAergiques. A cette fin, nous avons généré une souris mutante knockout conditionnelle dans laquelle un allèle de Syngap1 est spécifiquement excisé dans les interneurones GABAergiques issus de l’éminence ganglionnaire médiale (souris Tg(Nkx2.1-Cre);Syngap1flox/+). En culture organotypique, nous avons démontré que la réduction de Syngap1 restreinte aux interneurones inhibiteurs résulte en des altérations au niveau de leur arborisation axonale et dans leur densité synaptique. De plus, réalisés sur des coupes de cerveau de souris Tg(Nkx2.1-Cre);Syngap1flox/+, les enregistrements des courants inhibiteurs postsynaptiques miniatures (mIPSC) ou encore de ceux évoqués au moyen de l’optogénétique (oIPSC) dévoilent une réduction significative de la neurotransmission inhibitrice corticale. Enfin, nous avons comparé les performances de souris jeunes adultes Syngap1+/-, Tg(Nkx2.1-Cre);Syngap1flox/+ à celles de leurs congénères contrôles dans une batterie de tests comportementaux. À l’inverse des souris Syngap1+/-, les souris Tg(Nkx2.1-Cre);Syngap1flox/+ ne présentent pas d’hyperactivité locomotrice, ni de comportement associé à l’anxiété. Cependant, elles démontrent des déficits similaires dans la mémoire de travail et de reconnaissance sociale, suggérant que l’haploinsuffisance de Syngap1 restreinte aux interneurones GABAergiques dérivés de l’éminence ganglionnaire médiale récapitule en partie certains des phénotypes cognitifs observés chez la souris Syngap1+/-. Mes travaux de PhD établissent pour la première fois que les mutations humaines dans le gène SYNGAP1 associés à la déficience intellectuelle causent la perte de fonction de la protéine. Mes études dévoilent, également pour la première fois, l’influence significative de ce gène dans la régulation du développement et de la fonction des interneurones. D’admettre l’atteinte des cellules GABAergiques illustre plus réalistement la complexité de la déficience intellectuelle non syndromique causée par l’haploinsuffisance de SYNGAP1. Ainsi, seule une compréhension raffinée de cette condition neurodéveloppementale pourra mener à une approche thérapeutique adéquate.

Current Account ‘Core-Periphery Dualism’ in the EMU. CEPS Working Document No. 406/March 2015

Current account dispersion within EU member states has been increasing since the 1990s. Interestingly, the persistent deficits in many peripheral countries have not been accompanied by a significant growth process that is able to stimulate a long-run rebalancing, as neoclassical theory predicts. To shed light on the issue this paper investigates the determinants of eurozone current account imbalances, focusing on the role played by financial integration. The analysis considers two samples of 22 OECD and 15 EU countries; three time horizons corresponding to various steps in European integration; different control variables; and several panel econometric methods. The results suggest that within the OECD and EU groups, financial integration helped to explain CA deterioration in the peripheral countries, especially in the post-EMU period. The business cycle seems to have played a growing role over time, whereas the role of competiveness seems to have diminished.

The grand divergence: global and European current account surpluses. Bruegel Working Paper 2015/08, 13 August 2015

Global current account imbalances widened before the 2007/2008 crisis and have narrowed since. While the post-crisis adjustment of European current account deficits was in line with global developments (though more forceful), European current account surpluses defied global trends and increased. We use panel econometric models to analyse the determinants of medium-term current account balances. Our results confirm that higher fiscal balances, higher GDP per capita, more rapidly aging populations, larger net foreign assets, larger oil rents and better legal systems increase the medium-term current account balance, while a larger growth differential and a higher old-age dependency ratio reduce it. European current account surpluses became excessive during the past twelve years according to our estimates, while they were in line with model predictions in the preceding three decades. Generally, the gap between the actual current account and its fitted value in the model has a strong predictive power for future current account changes. Excess deficits adjust more forcefully than excess surpluses. However, in the 2004-07 period, excess imbalances were amplified, which was followed by a forceful correction in 2008-15, with the exception of European surpluses.

The Drivers of Current Account Surplus in Germany and the Politics of Rebalancing in the Eurozone. EU Centre, Singapore Working Paper No. 24, April 2015

Current account deficits have caught the public’s attention as they have contributed to the European debt crisis. However, surpluses also constitute an issue as a deficit in any country must be financed through a surplus in another country. In 2013, Germany, now the world’s largest surplus economy, registered a record high US$273 billion surplus. This paper looks at what accounts for Germany’s surplus, revealing that the major driving factors include strong global demand for quality German exports, domestic wage restraint, an undervalued single currency, high domestic savings rate and interest rate convergence in the euro area. This paper echoes the US Treasury’s view that a persistent German surplus makes it harder for the eurozone as a whole and the southern peripheral economies in particular to recover from the current financial crisis by imposing a Europe-wide “deflationary bias” through pushing up the exchange rate of the euro, exporting feeble German inflation and projecting its ultra-tight macroeconomic policies onto crisis economies. This paper contends that Germany’s trade surplus is likely to endure as Germany and other eurozone countries uphold diverging views on the nature of the surplus engage in a blame-game amidst a sluggish rebalancing process. Prizing the surplus as a reflection of hard work and economic competitiveness, German authorities urge their southern eurozone colleagues to undertake bold structural reforms to correct the imbalance, while the hand-tied governments in crisis-stricken economies call on Germany to do its “homework” by boosting German demands for European goods and services.

Cognitive deficits associated with cancer: A model of subjective and objective outcomes

Cancer and its treatment can affect many different aspects of quality of life. As a construct measured subjectively, quality of life shows an inconsistent relationship with objective outcome measures. That is, sometimes subjective and objective outcomes correspond with each other and sometimes they show little or no relationship. In this article, we propose a model for the relationship between subjective and objective outcomes using the example of cognitive function in people with cancer. The model and the research findings on which it is based help demonstrate that, in some circumstances, subjective measures of cognitive function correlate more strongly with psychosocial variables such as appraisal, coping, and emotions than with objective cognitive function. The model may provide a useful framework for research and clinical practice in quality of life for people with cancer.

Pleasure, pain and procrastination:reflections on the experience of doing memory-work research

The focus of this article is the process of doing memory-work research. We tell the story of our experience of what it was like to use this approach. We were enthused to work collectively on a "discovery" project to explore a method with which we were unfamiliar. We hoped to build working relationships based on mutual respect and the desire to focus on methodology and its place in our psychological understanding. The empirical activities highlighted methodological and experiential challenges, which tested our adherence to the social constructionist premise of Haug's original description of memory work. Combined with practical difficulties of living across Europe, writing and analyzing the memories became contentious. We found ourselves having to address a number of tensions emanating from the work and our approach to it. We discuss some of these tensions alongside examples that illustrate the research process and the ways we negotiated the collective nature of the memory-work approach. © 2012 Copyright Taylor and Francis Group, LLC.

Long memory and multifractality:a joint test

The properties of statistical tests for hypotheses concerning the parameters of the multifractal model of asset returns (MMAR) are investigated, using Monte Carlo techniques. We show that, in the presence of multifractality, conventional tests of long memory tend to over-reject the null hypothesis of no long memory. Our test addresses this issue by jointly estimating long memory and multifractality. The estimation and test procedures are applied to exchange rate data for 12 currencies. In 11 cases, the exchange rate returns are accurately described by compounding a NIID series with a multifractal time-deformation process. There is no evidence of long memory.

Prudent Budget Planning and Budgetary Process Effectiveness: The Canadian Federal Government’s Experience (Working Paper 47)

In 1994, the Liberal government introduced a structured approach to prudent budgeting to provide the fiscal discipline needed to meet its debt reduction targets in which explicit prudence factors were introduced into the fiscal framework to reduce the amount of fiscal flexibility available for allocation in each annual budget. Although that framework was successful in contributing to the elimination of persistent budgetary deficits, this paper advances three linked arguments: • that additional but undisclosed prudence factors were also introduced into the fiscal framework to attenuate the political risk of missing budget targets; • that these undisclosed prudence factors are one cause of a number of unintended budgetary outcomes that put the effectiveness of the budgetary process at risk; and • that there is nothing inherently politically partisan about the Liberal’s approach to prudent budget planning and, changes to terminology and display notwithstanding, the present Conservative government has continued to apply most elements of that framework in its budgets. Moving from a single-year budget target to one that is expressed as a cumulative total over the election cycle is discussed as one option that would help preserve the merits of prudent budgeting.

Deep into fragile memory: the other secretaries of the Holy Office.

The secretaries of the secret were an essential element of the Holy Office’s district courts. They were in charge of record-ing and writing all of the official documents of these tribunals, but also of keeping the archive in order. And not only of these, so they were not the simple bureaucrats that the traditional historians wrote about. In fact, their long working hours turned a unique and much defined office into a complex taxonomy of professionals who shared the secretaries of the secret’s concerns but not their privileges. This paper aims to go in depth into these profession-als’ current life. They were not officials, but they take care of some important duties even if they were not getting paid for it.

A comparison of modality effect performance in children: how reading achievement performance is influenced by echoic memory

This study investigates if less skilled readers suffer from deficits in echoic memory, which may be responsible for limiting the progress of reading acquisition. Serial recall performance in auditory, visual, and noisy conditions was used to assess echoic memory differences between skilled and less skilled readers. Both groups showed the typical modality effect, demonstrating that each had a functioning echoic memory. Less skilled readers performed more weakly than skilled readers on noisy serial recall, suggesting that the recall of less skilled readers is more vulnerable to interference than the recall of skilled readers. Nonword repetition performance indicated that all participants had reduced recall as a function of word complexity and word length. No difference between reading groups was found on this task; however, as nonword repetition and size of modality effect did not correlate, this task may not be a measure of echoic memory.

Imaging identity: media, memory and portraiture in the digital age

Imaging Identity presents potent reflections on the human condition through the prism of portraiture. Taking digital imaging technologies and the dynamic and precarious dimensions of contemporary identity as critical reference points, these essays consider why portraits continue to have such galvanising appeal and perform fundamental work across so many social settings. This multidisciplinary enquiry brings together artists, art historians, art theorists and anthropologists working with a variety of media. Authors look beyond conventional ideas of the portrait to the wider cultural contexts, governmental practices and intimate experiences that shape relationships between persons and pictures. Their shared purpose centres on a commitment to understanding the power of images to draw people into their worlds. Imaging Identity tracks a fundamental symbiosis — to grapple with the workings of images is to understand something vital of what it is to be human.

Memory for public events in mild cognitive impairment and Alzheimer’s disease : the importance of rehearsal

Ribot’s law refers to the better preservation of remote memories compared with recent ones that presumably characterizes retrograde amnesia. Even if Ribot-type temporal gradient has been extensively studied in retrograde amnesia, particularly in Alzheimer’s disease (AD), this pattern has not been consistently found. One explanation for these results may be that rehearsal frequency rather than remoteness accounts for the better preservation of these memories. Thus, the aim of present study was to address this question by studying retrograde semantic memory in subjects with amnestic mild cognitive impairment (aMCI) (n = 20), mild AD (n = 20) and in healthy older controls (HC; n = 19). In order to evaluate the impact of repetition as well as the impact of remoteness, we used a test assessing memory for enduring and transient public events that occurred in the recent and remote past. Results show no clear temporal gradient across time periods (1960–1975; 1976–1990; 1991–2005; 2006–2011), but a better performance was observed in all three groups for enduring compared with transient events. Moreover, although deficits were globally found in both patients groups compared with HC, more specific analyses revealed that aMCI patients were only impaired on transient events while AD patients were impaired on both transient and enduring events. Exploratory analyses also revealed a tendency suggesting preservation of remote transient events in aMCI. These findings are discussed with regards to memory consolidation models.