Age-associated modulations of cerebral oscillatory patterns related to attention control.

Visual attention depends on bottom-up sensory activation and top-down attentional guidance. Although aging is known to affect sensory processing, its impact on the top-down control of attention remains a matter of debate. We investigated age-related modulations of brain oscillatory activity during visual attention using a variant of the attention network test (ANT) in 20 young and 28 elderly adults. We examined the EEG oscillatory responses to warning and target signals, and explored the correlates of temporal and spatial orienting as well as conflict resolution at target presentation. Time-frequency analysis was performed between 4 and 30Hz, and the relationship between behavioral and brain oscillatory responses was analyzed. Whereas temporal cueing and conflict had similar reaction time effects in both age groups, spatial cueing was more beneficial to older than younger subjects. In the absence of cue, posterior alpha activation was drastically reduced in older adults, pointing to an age-related decline in anticipatory attention. Following both cues and targets, older adults displayed pronounced motor-related activation in the low beta frequency range at the expense of attention-related posterior alpha activation prominent in younger adults. These findings support the recruitment of alternative motor-related circuits in the elderly, in line with the dedifferentiation hypothesis. Furthermore, older adults showed reduced midparietal alpha inhibition induced by temporal orienting as well as decreased posterior alpha activation associated with both spatial orienting and conflict resolution. Altogether, the results are consistent with an overall reduction of task-related alpha activity in the elderly, and provide functional evidence that younger and older adults engage distinct brain circuits at different oscillatory frequencies during attentional functions.

THE ROLE OF SPINDLES FOR SLEEP: MANIPULATING OSCILLATORY ACTIVITY IN THE THALAMOCORTICAL NETWORK

Modern urban lifestyle encourages the prolongation of wakefulness, leaving less and less time for sleep. Although the exact functions of sleep remain one of the biggest mysteries in neuroscience, the society is well aware of the negative consequences of sleep loss on human physical and mental health and performance. Enhancing sleep's recuperative functions might allow shortening sleep duration while preserving the beneficial effects of sleep. During sleep, brain activity oscillates across a continuum of frequencies. Individual oscillations have been suggested to underlie distinct functions for sleep and cognition. Gaining control about individual oscillations might allow boosting their specific functions. Sleep spindles are 11 - 15 Hz oscillations characteristic for light non-rapid-eye-movement sleep (NREMS) and have been proposed to play a role in memory consolidation and sleep protection against environmental stimuli. The reticular thalamic nucleus (nRt) has been identified as the major pacemaker of spindles. Intrinsic oscillatory burst discharge in nRt neurons, arising from the interplay of low-threshold (T-type) Ca2+ channels (T channels) and small conductance type 2 (SK2) K+ channels (SK2 channels), underlies this pacemaking function. In the present work we investigated the impact of altered nRt bursting on spindle generation during sleep by studying mutant mice for SK2 channels and for CaV3.3 channels, a subtype of T channels. Using in vitro electrophysiology I showed that nRt bursting was abolished in CaV3.3 knock out (CaV3.3 KO) mice. In contrast, in SK2 channel over-expressing (SK2-OE) nRt cells, intrinsic repetitive bursting was prolonged. Compared to wildtype (WT) littermates, altered nRt burst discharge lead to weakened thalamic network oscillations in vitro in CaV3.3 KO mice, while oscillatory activity was prolonged in SK2-OE mice. Sleep electroencephalographic recordings in CaV3.3 KO and SK2-OE mice revealed that reduced or potentiated nRt bursting respectively weakened or prolonged sleep spindle activity at the NREMS - REMS transition. Furthermore, SK2-OE mice showed more consolidated NREMS and increased arousal thresholds, two correlates of good sleep quality. This thesis work suggests that CaV3.3 and SK2 channels may be targeted in order to modulate sleep spindle activity. Furthermore, it proposes a novel function for spindles in NREMS consolidation. Finally, it provides evidence that sleep quality may be improved by promoting spindle activity, thereby supporting the hypothesis that sleep quality can be enhanced by modulating oscillatory activity in the brain. Le style de vie moderne favorise la prolongation de l'éveil, laissant de moins en moins de temps pour le sommeil. Même si le rôle exact du sommeil reste un des plus grands mystères des neurosciences, la société est bien consciente des conséquences négatives que provoque un manque de sommeil, à la fois sur le plan de la santé physique et mentale ainsi qu'au niveau des performances cognitives. Augmenter les fonctions récupératrices du sommeil pourrait permettre de raccourcir la durée du sommeil tout en en conservant les effets bénéfiques. Durant le sommeil, on observe des oscillations à travers un continuum de fréquences. Il a été proposé que chaque oscillation pourrait être à l'origine de fonctions spécifiques pour le sommeil et la cognition. Pouvoir de contrôler les oscillations individuelles permettrait d'augmenter leurs fonctions respectives. Les fuseaux sont des oscillations de 11 à 15 Hz caractéristiques du sommeil à ondes lentes léger et il a été suggéré qu'elles jouent un rôle majeur pour la consolidation de la mémoire ainsi que dans la protection du sommeil contre les stimuli environnementaux. Le nucleus réticulaire du thalamus (nRt) a été identifié en tant que générateur de rythme des fuseaux. Les bouffées oscillatoires intrinsèques des neurones du nRt, provenant de l'interaction de canaux calciques à bas seuil de type T (canaux T) et de canaux potassiques à faible conductance de type 2 (canaux SK2), sont à l'origine de la fonction de générateur de rythme. Dans ce travail, j'ai étudié l'impact de la modulation de bouffées de nRT sur la génération des fuseaux pendant le sommeil en investiguant des souris génétiquement modifiées pour les canaux SK2 et les canaux CaV3.3, un sous-type de canaux T. En utilisant l'électrophysiologie in vitro j'ai démontré que les bouffées du nRT étaient abolies dans les souris knock-out du type CaV3.3 (CaV3.3 KO). D'autre part, dans les cellules nRT sur-exprimant les canaux SK2 (SK2-OE), les bouffées oscillatoires intrinsèques étaient prolongées. Par rapport aux souris wild type, les souris CaV3.3 KO ont montré un affaiblissement des oscillations thalamiques en réponse à un changement des bouffées de nRT, alors que l'activité oscillatoire était prolongée dans les souris SK2-OE. Des enregistrements EEG du sommeil dans des souris de type CaV3.3 KO et SK2-OE ont révélé qu'une réduction ou augmentation des bouffées nRT ont respectivement affaibli ou prolongé l'activité des fuseaux durant les transitions du sommeil à ondes lentes au sommeil paradoxal. De plus, les souris SK2-OE ont montré des signes de consolidation du sommeil à ondes lentes et un seuil augmenté pour le réveil, deux mesures qui corrèlent avec une bonne qualité du sommeil. Le travail de cette thèse propose que les canaux CaV3.3 et SK2 pourrait être ciblés pour moduler l'activité des fuseaux. De plus, je propose une fonction nouvelle pour les fuseaux dans la consolidation du sommeil à ondes lentes. Finalement je suggère que la qualité du sommeil peut être améliorée en promouvant l'activité des fuseaux, soutenant ainsi l'idée que la qualité du sommeil peut être améliorée en modulant l'activité oscillatoire dans le cerveau.

Repeated Double-Poling Sprint Training in Hypoxia by Competitive Cross-country Skiers.

PURPOSE: Repeated-sprint training in hypoxia (RSH) was recently shown to improve repeated-sprint ability (RSA) in cycling. This phenomenon is likely to reflect fiber type-dependent, compensatory vasodilation, and therefore, our hypothesis was that RSH is even more beneficial for activities involving upper body muscles, such as double poling during cross-country skiing. METHODS: In a double-blinded fashion, 17 competitive cross-country skiers performed six sessions of repeated sprints (each consisting of four sets of five 10-s sprints, with 20-s intervals of recovery) either in normoxia (RSN, 300 m; FiO2, 20.9%; n = 8) or normobaric hypoxia (RSH, 3000 m; FiO2, 13.8 %; n = 9). Before (pre) and after (post) training, performance was evaluated with an RSA test (10-s all-out sprints-20-s recovery, until peak power output declined by 30%) and a simulated team sprint (team sprint, 3 × 3-min all-out with 3-min rest) on a double-poling ergometer. Triceps brachii oxygenation was measured by near-infrared spectroscopy. RESULTS: From pretraining to posttraining, peak power output in the RSA was increased (P < 0.01) to the same extent (29% ± 13% vs 26% ± 18%, nonsignificant) in RSH and in RSN whereas the number of sprints performed was enhanced in RSH (10.9 ± 5.2 vs 17.1 ± 6.8, P < 0.01) but not in RSN (11.6 ± 5.3 vs 11.7 ± 4.3, nonsignificant). In addition, the amplitude in total hemoglobin variations during sprints throughout RSA rose more in RSH (P < 0.01). Similarly, the average power output during all team sprints improved by 11% ± 9% in RSH and 15% ± 7% in RSN. CONCLUSIONS: Our findings reveal greater improvement in the performance of repeated double-poling sprints, together with larger variations in the perfusion of upper body muscles in RSH compared with those in RSN.

Beneficial effects of strontium ranelate compared to alendronate on bone micro-structure - a 2-year study

Aims: In a head-to-head study, we compared the effects of strontium ranelate (SrRan) and alendronate (ALN), anti-osteoporotic agents with antifracture efficacy, on bone microstructure, a component of bone quality, hence of bone strength. Methods: In a randomised, double-dummy, double-blind controlled trial, 88 postmenopausal osteoporotic women were randomised to SrRan 2g/day or ALN 70mg/week for 2 years. Microstructure of the distal radius and distal tibia were assessed by HR-pQCT after 3,6,12,18 and 24 months of treatment. Primary endpoint was HR-pQCT variables relative changes from baseline. An ITT analysis was applied. Results: Baseline characteristics were similar in both groups (mean ±SD): age: 63.6±7.5 vs. 63.7±7.6 yrs; L1-L4T Score: -2.7±0.8 vs. -2.8±0.8g/cm², Cortical Thickness (CTh), trabecular bone fraction (BV/TV) and cortical density=721±242 vs. 753±263μm, 9.5±2.5 vs. 9.3±2.7%, and 750±87 vs. 745±78mg/cm3 respectively. Over 2 yrs, distal radius values changes were within 1 to 2% without significant differences except cortical density. In contrast distal tibia CTh, BV/TV, trabecular and cortical densities increased significantly more in the SrRan group than in the ALN group (Table). No significant between-group differences were observed for the remaining measured parameter (trabecular number, trabecular spacing, and trabecular thickness). After 2 years, L1- L4 and hip aBMD increases were similar to results from pivotal trials (L1-L4:+6.5% and +5.6%;total hip:+4.1% and +2.9%, in Sr- Ran and ALN groups, respectively). In the SrRan group, bALP increased by a median of 18% (p<0.001) and sCTX decreased by a median of -16% (p=0.005) while in the ALN group, bALP and CTX decreased by median of -31% (p<0.001) and -59% (p<0.001) respectively. Relative changes from baseline to last observation (%) SrRan ALN Estimated between group difference p value CTh (μm) 6.29±9.53 0.93±6.23 5.411±1.836 0.004 BV/TV (%) 2.48±5.13 0.84±3.81 1.783±0.852 0.040 Trabecular density (mgHA/cm3) 2.47±5.07 0.88±4.00 1.729±0.859 0.048 Cortical density (mgHA/cm3) 1.43±2.77 0.36±2.14 1.137±0.530 0.045 The two treatments were well tolerated. Conclusions: Within the constraints related to HRpQCT technology, it appears that strontium ranelate has greater effects than alendronate on distal tibia cortical thickness, trabecular and cortical bone densities in women with postmenopausal osteoporosis after two years of treatment. A concomitant significant increase in bone formation marker is observed in the SrRan group.

Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.

Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events-mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

Nonshivering thermogenesis capacity associated to mitochondrial DNA haplotypes and gender in the greater white-toothed shrew, Crocidura russula.

A selection gradient was recently suggested as one possible cause for a clinal distribution of mitochondrial DNA (mtDNA) haplotypes along an altitudinal transect in the greater white-toothed shrew, Crocidura russula (Ehinger et al. 2002). One mtDNA haplotype (H1) rare in lowland, became widespread when approaching the altitudinal margin of the distribution. As H1 differs from the main lowland haplotype by several nonsynonymous mutations (including on ATP6), and as mitochondria play a crucial role in metabolism and thermogenesis, distribution patterns might stem from differences in the thermogenic capacity of different mtDNA haplotypes. In order to test this hypothesis, we measured the nonshivering thermogenesis (NST) associated with different mtDNA haplotypes. Sixty-two shrews, half of which had the H1 haplotype, were acclimated in November at semioutdoor conditions and measured for NST throughout winter. Our results showed the crucial role of NST for winter survival in C. russula. The individuals that survived winter displayed a higher significant increase in NST during acclimation, associated with a significant gain in body mass, presumably from brown fat accumulation. The NST capacity (ratio of NST to basal metabolic rate) was exceptionally high for such a small species. NST was significantly affected by a gender x haplotype interaction after winter-acclimation: females bearing the H1 haplotype displayed a better thermogenesis at the onset of the breeding season, while the reverse was true for males. Altogether, our results suggest a sexually antagonistic cyto-nuclear selection on thermogenesis.

Domain shuffling in a sensor protein contributed to the evolution of insect pathogenicity in plant-beneficial Pseudomonas protegens.

Pseudomonas protegens is a biocontrol rhizobacterium with a plant-beneficial and an insect pathogenic lifestyle, but it is not understood how the organism switches between the two states. Here, we focus on understanding the function and possible evolution of a molecular sensor that enables P. protegens to detect the insect environment and produce a potent insecticidal toxin specifically during insect infection but not on roots. By using quantitative single cell microscopy and mutant analysis, we provide evidence that the sensor histidine kinase FitF is a key regulator of insecticidal toxin production. Our experimental data and bioinformatic analyses indicate that FitF shares a sensing domain with DctB, a histidine kinase regulating carbon uptake in Proteobacteria. This suggested that FitF has acquired its specificity through domain shuffling from a common ancestor. We constructed a chimeric DctB-FitF protein and showed that it is indeed functional in regulating toxin expression in P. protegens. The shuffling event and subsequent adaptive modifications of the recruited sensor domain were critical for the microorganism to express its potent insect toxin in the observed host-specific manner. Inhibition of the FitF sensor during root colonization could explain the mechanism by which P. protegens differentiates between the plant and insect host. Our study establishes FitF of P. protegens as a prime model for molecular evolution of sensor proteins and bacterial pathogenicity.

Gene-flow in a mosaic hybrid zone: is local introgression adaptive?

Genome-wide scans of genetic differentiation between hybridizing taxa can identify genome regions with unusual rates of introgression. Regions of high differentiation might represent barriers to gene flow, while regions of low differentiation might indicate adaptive introgression-the spread of selectively beneficial alleles between reproductively isolated genetic backgrounds. Here we conduct a scan for unusual patterns of differentiation in a mosaic hybrid zone between two mussel species, Mytilus edulis and M. galloprovincialis. One outlying locus, mac-1, showed a characteristic footprint of local introgression, with abnormally high frequency of edulis-derived alleles in a patch of M. galloprovincialis enclosed within the mosaic zone, but low frequencies outside of the zone. Further analysis of DNA sequences showed that almost all of the edulis allelic diversity had introgressed into the M. galloprovincialis background in this patch. We then used a variety of approaches to test the hypothesis that there had been adaptive introgression at mac-1. Simulations and model fitting with maximum-likelihood and approximate Bayesian computation approaches suggested that adaptive introgression could generate a "soft sweep," which was qualitatively consistent with our data. Although the migration rate required was high, it was compatible with the functioning of an effective barrier to gene flow as revealed by demographic inferences. As such, adaptive introgression could explain both the reduced intraspecific differentiation around mac-1 and the high diversity of introgressed alleles, although a localized change in barrier strength may also be invoked. Together, our results emphasize the need to account for the complex history of secondary contacts in interpreting outlier loci.

Blood pressure and low-density lipoprotein-cholesterol lowering for prevention of strokes and cognitive decline: a review of available trial evidence.

BACKGROUND AND OBJECTIVES: It is well established by a large number of randomized controlled trials that lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) by drugs are powerful means to reduce stroke incidence, but the optimal BP and LDL-C levels to be achieved are largely uncertain. Concerning BP targets, two hypotheses are being confronted: first, the lower the BP, the better the treatment outcome, and second, the hypothesis that too low BP values are accompanied by a lower benefit and even higher risk. It is also unknown whether BP lowering and LDL-C lowering have additive beneficial effects for the primary and secondary prevention of stroke, and whether these treatments can prevent cognitive decline after stroke. RESULTS: A review of existing data from randomized controlled trials confirms that solid evidence on optimal BP and LDL-C targets is missing, possible interactions between BP and LDL-C lowering treatments have never been directly investigated, and evidence in favour of a beneficial effect of BP or LDL-C lowering on cognitive decline is, at best, very weak. CONCLUSION: A new, large randomized controlled trial is needed to determine the optimal level of BP and LDL-C for the prevention of recurrent stroke and cognitive decline.

Spatially selective implementation of the adiabatic T2 prep sequence for magnetic resonance angiography of the coronary arteries.

In coronary magnetic resonance angiography, a magnetization-preparation scheme for T2 -weighting (T2 Prep) is widely used to enhance contrast between the coronary blood-pool and the myocardium. This prepulse is commonly applied without spatial selection to minimize flow sensitivity, but the nonselective implementation results in a reduced magnetization of the in-flowing blood and a related penalty in signal-to-noise ratio. It is hypothesized that a spatially selective T2 Prep would leave the magnetization of blood outside the T2 Prep volume unaffected and thereby lower the signal-to-noise ratio penalty. To test this hypothesis, a spatially selective T2 Prep was implemented where the user could freely adjust angulation and position of the T2 Prep slab to avoid covering the ventricular blood-pool and saturating the in-flowing spins. A time gap of 150 ms was further added between the T2 Prep and other prepulses to allow for in-flow of a larger volume of unsaturated spins. Consistent with numerical simulation, the spatially selective T2 Prep increased in vivo human coronary artery signal-to-noise ratio (42.3 ± 2.9 vs. 31.4 ± 2.2, n = 22, P < 0.0001) and contrast-to-noise-ratio (18.6 ± 1.5 vs. 13.9 ± 1.2, P = 0.009) as compared to those of the nonselective T2 Prep. Additionally, a segmental analysis demonstrated that the spatially selective T2 Prep was most beneficial in proximal and mid segments where the in-flowing blood volume was largest compared to the distal segments. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Mononuclear cell transcriptome response after sustained virgin olive oil consumption in humans: an exploratory nutrigenomics study

Virgin olive oil (VOO) is considered to be one of the main components responsible for the health benefits of the Mediterranean diet, particularly against atherosclerosis where peripheral blood mononuclear cells (PBMNCs) play a crucial role in atherosclerosis development and progression. The objective of this article was to identify the PBMNC genes that respond to VOO consumption in order to ascertain the molecular mechanisms underlying the beneficial action of VOO in the prevention of atherosclerosis. Gene expression profiles of PBMNCs from healthy individuals were examined in pooled RNA samples by microarrays after 3 weeks of moderate and regular consumption of VOO, as the main fat source in a diet controlled for antioxidant content. Gene expression was verified by qPCR. The response to VOO consumption was confirmed for individual samples (n = 10) by qPCR for 10 upregulated genes (ADAM17, ALDH1A1, BIRC1, ERCC5, LIAS, OGT, PPARBP, TNFSF10, USP48, and XRCC5). Their putative role in the molecular mechanisms involved in atherosclerosis development and progression is discussed, focusing on a possible relation with VOO consumption. Our data support the hypothesis that 3 weeks of nutritional intervention with VOO supplementation, at doses common in the Mediterranean diet, can alter the expression of genes related to atherosclerosis development and progression.

Attribution and reciprocity in a simulated labor market: An experimental investigation

While papers such as Akerlof and Yellen (1990) and Rabin (1993) argue that psychological considerations such as fairness and reciprocity are important in individual decision-making, there is little explicit empirical evidence of reciprocal altruism in economic environments. This paper tests whether attribution of volition in choosing a wage has a significant effect on subsequent costly effort provision. An experiment was conducted in which subjects are first randomly divided into groups of employers and employees. Wages were selected and employees asked to choose an effort level, where increased effort is costly to the employee, but highly beneficial to the employer. The wage-determination process was common knowledge and wages were chosen either by the employer or by an external process. There is evidence for both distributional concerns and reciprocal altruism. The slope of the effort/wage profile is clearly positive in all cases, but is significantly higher when wages are chosen by the employer, offering support for the hypothesis of reciprocity. There are implications for models of utility and a critique of some current models is presented.

The algebraic equality of two asymptotic tests for the hypothesis that a normal distribution has a specified correlation matrix

It is proved the algebraic equality between Jennrich's (1970) asymptotic$X^2$ test for equality of correlation matrices, and a Wald test statisticderived from Neudecker and Wesselman's (1990) expression of theasymptoticvariance matrix of the sample correlation matrix.