SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State

SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1) in ESCs, the related POU family member BRN2 (Pou3f2) co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors

Cognitive Behavior Therapy for Anxious Adolescents: Developmental Influences on Treatment Design and Delivery

Anxiety disorders in adolescence are common and disruptive, pointing to a need for effective treatments for this age group. Cognitive behavior therapy (CBT) is one of the most popular interventions for adolescent anxiety, and there is empirical support for its application. However, a significant proportion of adolescent clients continue to report anxiety symptoms post-treatment. This paper underscores the need to attend to the unique developmental characteristics of the adolescent period when designing and delivering treatment, in an effort to enhance treatment effectiveness. Informed by the literature from developmental psychology, developmental psychopathology, and clinical child and adolescent psychology, we review the ‘why’ and the ‘how’ of developmentally appropriate CBT for anxious adolescents. ‘Why’ it is important to consider developmental factors in designing and delivering CBT for anxious adolescents is addressed by examining the age-related findings of treatment outcome studies and exploring the influence of developmental factors, including cognitive capacities, on engagement in CBT. ‘How’ clinicians can developmentally tailor CBT for anxious adolescents in six key domains of treatment design and delivery is illustrated with suggestions drawn from both clinically and research-oriented literature. Finally, recommendations are made for research into developmentally appropriate CBT for anxious adolescents

Modèles ecologiques pour l'extrapolation des effets écotoxicologiques enregistrés lors de biotests in situ cheZ Gammarus

[Departement_IRSTEA]Eaux [TR1_IRSTEA]BELCAInternational audienceEvaluating the effects of chemical contamination on populations and ecological communities still constitutes a challenging necessity in environmental management. However the toxic effects of contaminants are commonly measured by means of organism-level responses. Linking such effects measures with ecological models is a promising way to apprehend population-level impacts. In this way, population models are currently increasingly used in predictive risk assessment procedures, but their use in environmental diagnostic framework remains limited due to their lack of ecological realism. The present study with the crustacean amphipod Gammarus fossarum, a sentinel species in freshwater monitoring, combines a dual field and laboratory experimental approach with a population modelling framework. In this way, we developed an ecologically-relevant periodic matrix population model for Gammarus. This model allowed us to capture the population dynamics in the field, and to understand the particular pattern of demographic sensitivities induced by Gammarus life-history phenology. The model we developed provided a robust population-level assessment of in situ-based effects measures recorded during a biomonitoring program on a French watershed impacted by past mining activities. Thus, our study illustrates the potential of population modelling when seeking to decipher the role of environmental toxic contamination in ecological perturbations

Binding properties to nicotinic acetylcholine receptors can explain differential toxicity of neonicotinoid insecticides in Chironomidae

International audienc

Optimization of Vibration Absorbers: A Graphical Method^ for Use on Idealized Systems With Restricted Damping

can be used on complex real-world problems. It can also provide additional insight into the physical behavior of a transient system. References 1 Aggarwal, T. C, and Hasz, J. R., "Designing Optimum Dampers Against Self-Excited Chatter," ASME Paper No. 68-WA/ Prod-25. 2 Bartel, D. L., Haug, E. J., and Rim, K., "The Optimum Design of Spatial Frames Using the Method of Constrained Steepest Descent With State Equations," to be published in Journal of Engineering for Industry, TRANS. ASME, Series B, Vol. 93, 1971. 3 Falcon, K. C, Stone, B. J., Simcock, W. D., anaSAndrew, C, "Optimization of Vibration Absorbers: A Graphical Method^ for Use on Idealized Systems With Restricted Damping," Journal of Mechanical Engineering Science, Vol. 9, No. 5, 1967, pp. 374-381. 4 The authors have presented two applications of an optimization program involving low order linear mechanical systems. The results are of some interest although the paper is hard to follow due to misprints (Figs. 1 and 4 seem to be interchanged) and unusual notation (s is called a state vector while z, a vector of displacements and velocities, though typically called a state vector in dynamics, is not called a state vector in the paper). The reference to "time domain optimization" in the title may be misleading. Another way to describe what the authors have done is by the phrase "parameter optimization" since the computer program apparently varied a damping parameter and a spring constant to optimize some aspects of the transient response of a particular 2 degree-of-freedom linear system model subject to inequality constraints. In related work, a group at I.I.T. investigated several possible methods of optimizing vibratory systems. Included were not only parameter optimization but also a true time domain optimization in which dynamic programming techniques were used to determine the optimal time history of forces which would achieve a minimum of a performance criterion subject to constraints, independent of the manner in which the force would actually be realized The authors have demonstrated their ability to achieve parameter optimization using a gradient technique, but it is not entirely clear that the method should be used on "complex realworld problems." The authors' examples are hardly complex nor do they necessarily represent the real world. Would anyone realistically construct a car bumper by trying to match it to a linear spring and dashpot combination? The potential of the technique might be better illustrated by using it to optimize nonlinear devices which, though suboptimal in the true time domain sense, yield responses closer to optimal than could be achieved with linear devices. Even in the vibration absorber problem, the proposed criterion of time-optimal energy dissipation is not so easy to justify. This criterion evidently yields a different optimal system for every different initial condition and indeed for every choice of percent energy remaining, t. This phenomenon might be explained by realizing that the response of the system in question can at least roughly be considered the sum of the responses of two normal modes. Each modal velocity is described 2 Professor and Graduate Student, respectively, Department of Mechanical Engineering, University of California, Davis, Calif. 3 Numbers in brackets designate Additional References at end of discussion. by an exponentially decaying sinusoid whose initial value is a function of all initial conditions. The rate of exponential decay for each mode can be different functions of the design parameters. For e ->-1 the tradeoff between the fast decay of a mode with high initial conditions and the slow decay of the mode with lower initial conditions is very critical. In the extreme one could hypothesize the mode with large initial value decaying very rapidly and the low initial condition mode never decaying in order for values of 6 close to one to be achieved in optimum time. The exact nature of the trade off is a function of initial conditions and e. When e ->-0, the responses of both modes are forced to be small as soon as possible. When t-*T for this case, the difference due to initial conditions in the values of the modal responses must be small because the responses are small. Hence, initial conditions have little effect, and the main concern of the optimization process becomes making both responses small as soon as possible. This is the most reasonable criteria for optimization. Surely for most vibration absorber design techniques one desires a useful criterion which will produce a single isolation design which is optimal for a broad class of inputs or initial conditions. The authors' results for e ->• 0 suggest the sort of result in optimal linear regulator design in which an infinite time integral square criteria yields an optimal design independent of initial conditions. Finally, the paper illustrates the difficulties in interpretation which often arise in parameter optimization. Computed optimal parameters may be nearly useless unless supplemented by an understanding of the influence of small changes in the optimization criterion on the system parameters. In equation In another instance, the authors have taken a specific result and made a rather broad generalization from it which may not be justified. The statement that "an optimum steady state absorber will also be nearly optimum for transient conditions when e is small" surely must be qualified. Though the statement is true for the authors' specific case, many other constraints and criteria might be used, and it would be amazing if the statement were universally true. Only when the systems remain entirely in the domain of linear optimum systems can one expect simple relations between optimal systems designed on the basis of transient and forced response [3]