Bcl-xL (S49) and (S62) sequential phosphorylation/dephosphorylation during mitosis prevents chromosome instability and aneuploidy

Une caractéristique intéressante de la protéine Bcl-xL est la présence d'un domaine en boucle non-structurée entre les hélices α1 and α2 de la protéine. Ce domaine protéique n'est pas essentiel pour sa fonction anti-apoptotique et absent chez CED-9, la protéine orthologue chez Caenorhabditis elegans. A l'intérieur de ce domaine, Bcl-xL subit une phosphorylation et déphosphorylation dynamique sur les résidus Ser49 et Ser62 en phase G2 du cycle cellulaire et lors de la mitose. Lorsque ces résidus sont mutés et les protéines exprimées dans des cellules cancéreuses, les cellules démontrent plusieurs défauts mitotiques liés à l'instabilité chromosomique. Pour analyser les effets de Bcl-xL Ser49 et Ser62 dans les cellules normales, les présentes études ont été réalisées dans des cellules diploïdes humaines normales, et in vivo chez Caenorhabditis elegans. Dans une première étude, nous avons utilisé la lignée cellulaire de cellules fibroblastiques diploïdes humaines normales BJ, exprimant Bcl-xL (type sauvage), (S49A), (S49D), (S62A), (S62D) et les double (S49/62A) et (S49/62D) mutants. Les cellules exprimant les mutants de phosphorylation ont montré des cinétiques de doublement de la population cellulaire réduites. Ces effets sur la cinétique de doublement de la population cellulaire corrèle avec l'apparition de la sénescence cellulaire, sans impact sur les taux de mort cellulaire. Ces cellules sénescentes affichent des phénotypes typiques de sénescence associés notamment à haut niveau de l'activité β-galactosidase associée à la sénescence, la sécrétion d' interleukine-6, l'activation de p53 et de p21WAF1/ Cip1, un inhibiteur des complexes kinase cycline-dépendant, ainsi que la formation de foyers de chromatine nucléaire associés à γH2A.X. Les analyses de fluorescence par hybridation in situ et des caryotypes par coloration au Giemsa ont révélé que l'expression des mutants de phosphorylation de Bcl-xL provoquent de l'instabilité chromosomique et l'aneuploïdie. Ces résultats suggèrent que les cycles de phosphorylation et déphosphorylation dynamiques de Bcl-xL Ser49 et Ser62 sont importants dans le maintien de l'intégrité des chromosomes lors de la mitose dans les cellules normales. Dans une deuxième étude, nous avons entrepris des expériences chez Caenorhabditis elegans pour comprendre l'importance des résidus Ser49 et Ser62 de Bcl-xL in vivo. Les vers transgéniques portant les mutations de Bcl-xL (S49A, S62A, S49D, S62D et S49/62A) ont été générés et leurs effets ont été analysés sur les cellules germinales des jeunes vers adultes. Les vers portant les mutations de Bcl-xL ont montré une diminution de ponte et d'éclosion des oeufs, des variations de la longueur de leurs régions mitotiques et des zones de transition, des anomalies chromosomiques à leur stade de diplotène, et une augmentation de l'apoptose des cellules germinales. Certaines de ces souches transgéniques, en particulier les variants Ser/Ala, ont également montré des variations de durée de vie par rapport aux vers témoins. Ces observations in vivo ont confirmé l'importance de Ser49 et Ser62 à l'intérieur du domaine à boucle de Bcl-xL pour le maintien de la stabilité chromosomique. Ces études auront une incidence sur les futures stratégies visant à développer et à identifier des composés qui pourraient cibler non seulement le domaine anti-apoptotique de la protéine Bcl-xL, mais aussi son domaine mitotique pour la thérapie du cancer.

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Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability

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Is the meander growth in the Brazil Current system off Southeast Brazil due to baroclinic instability?

Temporally-growing frontal meandering and occasional eddy-shedding is observed in the Brazil Current (BC) as it flows adjacent to the Brazilian Coast. No study of the dynamics of this phenomenon has been conducted to date in the region between 22 degrees S and 25 degrees S. Within this latitude range, the flow over the intermediate continental slope is marked by a current inversion at a depth that is associated with the Intermediate Western Boundary Current (IWBC). A time series analysis of 10-current-meter mooring data was used to describe a mean vertical profile for the BC-IWBC jet and a typical meander vertical structure. The latter was obtained by an empirical orthogonal function (EOF) analysis that showed a single mode explaining 82% of the total variance. This mode structure decayed sharply with depth, revealing that the meandering is much more vigorous within the BC domain than it is in the IWBC region. As the spectral analysis of the mode amplitude time series revealed no significant periods, we searched for dominant wavelengths. This search was done via a spatial EOF analysis on 51 thermal front patterns derived from digitized AVHRR images. Four modes were statistically significant at the 95% confidence level. Modes 3 and 4, which together explained 18% of the total variance, are associated with 266 and 338-km vorticity waves, respectively. With this new information derived from the data, the [Johns, W.E., 1988. One-dimensional baroclinically unstable waves on the Gulf Stream potential vorticity gradient near Cape Hatteras. Dyn. Atmos. Oceans 11, 323-350] one-dimensional quasi-geostrophic model was applied to the interpolated mean BC-IWBC jet. The results indicated that the BC system is indeed baroclinically unstable and that the wavelengths depicted in the thermal front analysis are associated with the most unstable waves produced by the model. Growth rates were about 0.06 (0.05) days(-1) for the 266-km (338-km) wave. Moreover, phase speeds for these waves were low compared to the surface BC velocity and may account for remarks in the literature about growing standing or stationary meanders off southeast Brazil. The theoretical vertical structure modes associated with these waves resembled very closely to the one obtained for the current-meter mooring EOF analysis. We interpret this agreement as a confirmation that baroclinic instability is an important mechanism in meander growth in the BC system. (C) 2008 Elsevier B.V. All rights reserved.

Low cost 3D global instability analysis and flow sensitivity based on dynamic mode decomposition and high-order numerical tools

We explore the recently developed snapshot-based dynamic mode decomposition (DMD) technique, a matrix-free Arnoldi type method, to predict 3D linear global flow instabilities. We apply the DMD technique to flows confined in an L-shaped cavity and compare the resulting modes to their counterparts issued from classic, matrix forming, linear instability analysis (i.e. BiGlobal approach) and direct numerical simulations. Results show that the DMD technique, which uses snapshots generated by a 3D non-linear incompressible discontinuous Galerkin Navier?Stokes solver, provides very similar results to classical linear instability analysis techniques. In addition, we compare DMD results issued from non-linear and linearised Navier?Stokes solvers, showing that linearisation is not necessary (i.e. base flow not required) to obtain linear modes, as long as the analysis is restricted to the exponential growth regime, that is, flow regime governed by the linearised Navier?Stokes equations, and showing the potential of this type of analysis based on snapshots to general purpose CFD codes, without need of modifications. Finally, this work shows that the DMD technique can provide three-dimensional direct and adjoint modes through snapshots provided by the linearised and adjoint linearised Navier?Stokes equations advanced in time. Subsequently, these modes are used to provide structural sensitivity maps and sensitivity to base flow modification information for 3D flows and complex geometries, at an affordable computational cost. The information provided by the sensitivity study is used to modify the L-shaped geometry and control the most unstable 3D mode.

Is financial instability male-driven? Gender and cognitive skills in experimental asset markets

The hypothesis that price stability would reliably increase with the fraction of women operating in financial markets has been frequently suggested in policy discussions. To test this hypothesis we conducted 10 male-only, 10 female-only and 10 mixed-gender experimental asset markets, and compared the effects of gender composition, confidence, risk attitude and cognitive skills. Male and female markets have comparable volatility and deviations from fundamentals, whereas mixed-gender markets are substantially more stable. On the other hand, higher average cognitive skills of the group are associated with reduced market volatility. Individual-level analysis shows that subjects with higher cognitive skills trade at prices closer to fundamental values and earn significantly higher profits; similarly, mixed markets exhibit lower mispricing, particularly for traders with lower cognitive skills. Our results are demonstrated to hold in other experimental asset market studies, suggesting that a mixed-gender composition reduces mispricing across different types of asset markets.

Exploring the relationship between educational mismatch, earnings and job satisfaction in the tourism industry

This article analyses the interrelationship between educational mismatch, wages and job satisfaction in the Spanish tourism sector in the first years of the global economic crisis. It is shown that there is a much higher incidence of over-education among workers in the Spanish tourism sector than in the rest of the economy despite this sector recording lower educational levels. This study estimates two models to analyse the influence of the educational mismatch on wages and job satisfaction for workers in the tourism industry and for the Spanish economy as a whole. The first model shows that in the tourism sector, the wage penalty associated with over-education is approximately 10%. The second reveals that in the tourism sector the levels of satisfaction of over-educated workers are considerably lower than those corresponding to workers well assigned. With respect to the differences between tourism and the overall economy in both aspects, the wage penalty is substantially lower in the case of tourism industries and the effect of over-education on job satisfaction is very similar to that of the economy as a whole in a context where both wages and the private returns to education are considerably lower in the tourism sector.

The role of instability rehabilitative resistance training for the core musculature

Neuromuscular training of the spinal stabilizing musculature is relevant for lower back pain prevention and treatment. instability resistance exercises promote cocontractions, increasing joint stability. of greatest importance to joint stability is not necessarily strength or endurance but motor control. dynamic provocative calisthenic exercises may improve core stabilizing functions. higher core muscle activation is possible with stable ground-based exercises. performing resistance exercises on unstable surfaces may have benefits in joint injury prevention and improving balance; however, strength gains could be compromised. higher levels of dynamic stabilization may be recommended with rehabilitation but should only be one component of a periodized plan.

Canadian Society for Exercise Physiology position stand : the use of instability to train the core in athletic and nonathletic conditioning

The use of instability devices and exercises to train the core musculature is an essential feature of many training centres and programs. It was the intent of this position stand to provide recommendations regarding the role of instability in resistance training programs designed to train the core musculature. The core is defined as the axial skeleton and all soft tissues with a proximal attachment originating on the axial skeleton, regardless of whether the soft tissue terminates on the axial or appendicular skeleton. Core stability can be achieved with a combination of muscle activation and intra-abdominal pressure. Abdominal bracing has been shown to be more effective than abdominal hollowing in optimizing spinal stability. When similar exercises are performed, core and limb muscle activation are reported to be higher under unstable conditions than under stable conditions. However, core muscle activation that is similar to or higher than that achieved in unstable conditions can also be achieved with ground-based free-weight exercises, such as Olympic lifts, squats, and dead lifts. Since the addition of unstable bases to resistance exercises can decrease force, power, velocity, and range of motion, they are not recommended as the primary training mode for athletic conditioning. However, the high muscle activation with the use of lower loads associated with instability resistance training suggests they can play an important role within a periodized training schedule, in rehabilitation programs, and for nonathletic individuals who prefer not to use ground-based free weights to achieve musculoskeletal health benefits.

The use of instability to train the core musculature

Training of the trunk or core muscles for enhanced health, rehabilitation, and athletic performance has received renewed emphasis. Instability resistance exercises have become a popular means of training the core and improving balance. Whether instability resistance training is as, more, or less effective than traditional ground-based resistance training is not fully resolved. The purpose of this review is to address the effectiveness of instability resistance training for athletic, nonathletic, and rehabilitation conditioning. The anatomical core is defined as the axial skeleton and all soft tissues with a proximal attachment on the axial skeleton. Spinal stability is an interaction of passive and active muscle and neural subsystems. Training programs must prepare athletes for a wide variety of postures and external forces, and should include exercises with a destabilizing component. While unstable devices have been shown to be effective in decreasing the incidence of low back pain and increasing the sensory efficiency of soft tissues, they are not recommended as the primary exercises for hypertrophy, absolute strength, or power, especially in trained athletes. For athletes, ground-based free-weight exercises with moderate levels of instability should form the foundation of exercises to train the core musculature. Instability resistance exercises can play an important role in periodization and rehabilitation, and as alternative exercises for the recreationally active individual with less interest or access to ground-based free-weight exercises. Based on the relatively high proportion of type I fibers, the core musculature might respond well to multiple sets with high repetitions (e.g., >15 per set); however, a particular sport may necessitate fewer repetitions.

Effect of instability and resistance on unintentional squat lifting kinetics

Context: Resistance training while using an instability-training device is known to increase activation of stabilizing muscle groups while decreasing the force generated by the prime movers during isometric contractions. Purpose: To investigate differences in squat kinetics during dynamic resistance training in an increasingly unstable training environment. Methods: Fourteen active men participated in this study. In each testing session, each participant performed 3 repetitions of squats with a 10-repetition maximum (10-RM) resistance, 40% of their 10-RM resistance, and 20.45 kg. The 3 testing session consisted of standing on a stable floor, foam pads, or BOSU balls. All repetitions were recorded with an optical encoder to record barbell kinetics. Results: The transition from stable (floor) to very unstable (BOSU) resulted in high likelihoods (>75%) of clinically meaningful differences ranging from small to large (effect size [ES] 0.31–1.73) in factors relating to concentric kinetics, eccentric power, and squat depth, regardless of the resistance used for training. There were also likely differences at the heaviest resistance in peak concentric power (stable to foam: ES 2.06; foam to BOSU: ES 0.38), eccentric power (stable to foam: ES 1.88; foam to BOSU: ES 0.74), and squat depth (stable to foam: ES 0.50; foam to BOSU: ES 0.67). Conclusions: Resistance training in an unstable environment at an intensity sufficient to elicit strength gains of the prime movers results in deleterious effects in concentric squat kinetics and squat technique. Such observations are particularly evident on very unstable platforms.

Non-audit services, auditor quality and the value relevance of earnings

This paper tests the hypothesis that there is an inverse relation between non-audit services (NAS) provided by a firm auditor and the value relevance of earnings(measured as the earnings response coefficient) and that this relation is weaker for firms with Big 6 auditors. The hypothesis is based on anecdotal evidence and previous research that suggests that the provision of NAS by the external auditor is likely to adversely affect investors’ perceptions of the credibility of financial reports, and that Big 6 auditors, because of reputational capital and litigation costs,are likely to mitigate the adverse effects of NAS. Results using 840 firm-year observations of Australian companies document a statistically significant inverse relationship between NAS and the value relevance of earnings, and this inverse relationship is weaker for Big 6 auditors, therefore supporting the hypothesis.

Mathematical models for cellular aggregation: the chemotactic instability and clustering formation

In this thesis we present a mathematical formulation of the interaction between microorganisms such as bacteria or amoebae and chemicals, often produced by the organisms themselves. This interaction is called chemotaxis and leads to cellular aggregation. We derive some models to describe chemotaxis. The first is the pioneristic Keller-Segel parabolic-parabolic model and it is derived by two different frameworks: a macroscopic perspective and a microscopic perspective, in which we start with a stochastic differential equation and we perform a mean-field approximation. This parabolic model may be generalized by the introduction of a degenerate diffusion parameter, which depends on the density itself via a power law. Then we derive a model for chemotaxis based on Cattaneo's law of heat propagation with finite speed, which is a hyperbolic model. The last model proposed here is a hydrodynamic model, which takes into account the inertia of the system by a friction force. In the limit of strong friction, the model reduces to the parabolic model, whereas in the limit of weak friction, we recover a hyperbolic model. Finally, we analyze the instability condition, which is the condition that leads to aggregation, and we describe the different kinds of aggregates we may obtain: the parabolic models lead to clusters or peaks whereas the hyperbolic models lead to the formation of network patterns or filaments. Moreover, we discuss the analogy between bacterial colonies and self gravitating systems by comparing the chemotactic collapse and the gravitational collapse (Jeans instability).

Earnings quality : some evidence on the role of auditor tenure and auditors' industry expertise

Prior studies suggest that auditors with short tenure are associated with lower earnings quality because of the lack of client-specific knowledge and/or low balling. In this study, we examine whether industry specialization of auditors and low balling affect the association between auditor tenure and earnings quality. We find that the association between shorter auditor tenure and lower earnings quality is weaker for firms audited by industry specialists compared to non-specialists. In addition, we do not find results consistent with the low balling explanation.

Family control, board independence and earnings management : evidence based on Hong Kong firms

In this study, we document that independent corporate boards of Hong Kong firms provide effective monitoring of earnings management, which suggests that despite differences in institutional environments, corporate board independence is important to ensure high-quality financial reporting. The findings also show that the monitoring effectiveness of corporate boards is moderated in family-controlled firms, either through ownership concentration or the presence of family members on corporate boards. The results based on firms reporting small earnings increases provide additional support for our finding that the monitoring effectiveness of independent corporate boards is moderated in family-controlled firms.