Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD.

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B-/- mouse model of ASD. Male and female Shank3B-/- mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions

Modelling the effects of an abolition of the EU sugar quota on internal prices, production and imports

We apply a spatial price equilibrium model of the world sugar market to simulate an abolishment of the EU quota system in 2015/16. To overcome the normative nature of the approach, we calibrate the model by attaching a non-linear cost term to each trade flow. This is in some regards similar to positive mathematical programming. We suggest an economic interpretation and an econometric specification of the cost term. Production in the EU increases to almost 16 million tons. Twelve member states increase production, seven reduce it. Preferential imports are significantly reduced. Simulated effects are found to be more pronounced the higher the world market price.CAP, structural change, sugar, TRQ, spatial modelling, trade preferences, PMP, Agricultural and Food Policy, Farm Management, Land Economics/Use,

Some issues concerning Large-Eddy Simulation of inertial particle dispersion in turbulent bounded flows

The problem of an accurate Eulerian-Lagrangian modeling of inertial particle dispersion in Large Eddy Simulation (LES) of turbulent wall-bounded flows is addressed. We run Direct Numerical Simulation (DNS) for turbulent channel flow at shear Reynolds numbers equal to 150 and 300 and corresponding a-priori and a-posteriori LES on differently coarse grids. We then tracked swarms of different inertia particles and we examined the influence of filtering and of Sub-Grid Scale (SGS) modeling for the fluid phase on particle velocity and concentration statistics. We also focused on how particle preferential segregation is predicted by LES. Results show that even ``well-resolved'' LES is unable to reproduce the physics as demonstrated by DNS, both for particle accumulation at the wall and for particle preferential segregation. Inaccurate prediction is observed for the entire range of particles considered in this study, even when the particle response time is much larger than the flow timescales not resolved in LES. Both a-priori and a-posteriori tests indicate that recovering the level of fluid and particle velocity fluctuations is not enough to have accurate prediction of near-wall accumulation and local segregation. This may suggest that reintroducing the correct amount of higher-order moments of the velocity fluctuations is also a key point for SGS closure models for the particle equation. Another important issue is the presence of possible flow Reynolds number effects on particle dispersion. Our results show that, in small Reynolds number turbulence and in the case of heavy particles, the shear fluid velocity is a suitable scaling parameter to quantify these effects

Financial Structure in Chile: Macroeconomic Developments and Microeconomic Effects

The objectives of this paper are, first, to describe the developments in Chilean financial markets at the macroeconomic level and, then, to examine their effects at the level of firms. After reviewing the main government policies towards financial markets in the last three decades, the paper describes the remarkable changes and progress in the banking sector and in various types of capital markets (bond, stock, pension and insurance markets) during the same period. This is done by evaluating changes in financial markets size, activity, and efficiency. Second, the paper analyzes the changes in both the access to financial markets and the financing (balance-sheet) decisions in a sample of Chilean firms. The sample consists of 79 firms that are quoted in the stock market and for which annual balance sheet data for the period 1985-1995 are available and complete. The paper estimates and tests econometrically three issues. The first is whether the firms' reliance on internal funds for investment has decreased in the more financially open period of the 1990s relative to the 1980s and, thus, whether investment has been more responsive to changes in the q-value of the firm. The second examines whether financial liberalization and the development of the banking, stock and bond markets at the aggregate level have affected the importance of debt relative to equity and the maturity of debt in the balance sheet of firms. The third studies the extent to which firm-specific and aggregate financial market developments have impacted on firm growth, measured by the percentage increase in operational revenues. In general, we conclude that financial developments at the macro level have indeed had an impact on the firms' access to capital markets, their financial structure, and their rate of growth.

Managing the trade-off implications of global supply

The cost versus response trade-off is a growing logistics issue due to many markets being increasingly characterized by demand uncertainty and shorter product life cycles. This is exacerbated further with supply increasingly moving to low cost global sources. However, the poor response implications of global supply are often not addressed or even acknowledged when undertaking such decisions. Consequently, various practical approaches to minimising, postponing or otherwise managing the impact of the demand uncertainty are often only adopted retrospectively. Even though such generic solutions are documented through case examples we lack effective tools and concepts to support the proactive identification and resolution of such trade-offs. This paper reports on case-based theory building research, involving three cases from the UK and USA used in developing a conceptual model with associated tools, in support of such a process

Rocaglates induce gain-of-function alterations to eIF4A and eIF4F

Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.P50 GM067041 - NIGMS NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHSPublished versio

NCR+ ILC3 maintain larger STAT4 reservoir via T-BET to regulate type 1 features upon IL-23 stimulation in mice

Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 towards the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR+ ILC3) to acquire type 1 features. We observed that NCR+ ILC3 exhibited high basal expression of the signal-dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-γ, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL-23 signaling in ILC3. This article is protected by copyright. All rights reserved

17-11 Evaluation of Transit Priority Treatments in Tennessee

Many big cities are progressively implementing transit friendly corridors especially in urban areas where traffic may be increasing at an alarming rate. Over the years, Transit Signal Priority (TSP) has proven to be very effective in creating transit friendly corridors with its ability to improve transit vehicle travel time, serviceability and reliability. TSP as part of Transit Oriented Development (TOD) is associated with great benefits to community liveability including less environmental impacts, reduced traffic congestions, fewer vehicular accidents and shorter travel times among others.This research have therefore analysed the impact of TSP on bus travel times, late bus recovery at bus stop level, delay (on mainline and side street) and Level of Service (LOS) at intersection level on selected corridors and intersections in Nashville Tennessee; to solve the problem of transit vehicle delay as a result of high traffic congestion in Nashville metropolitan areas. This study also developed a flow-delay model to predict delay per vehicle for a lane group under interrupted flow conditions and compared some measure of effectiveness (MOE) before and after TSP. Unconditional green extension and red truncation active priority strategies were developed via Vehicle Actuated Programming (VAP) language which was tied to VISSIM signal controller to execute priority for transit vehicles approaching the traffic signal at 75m away from the stop line. The findings from this study indicated that TSP will recover bus lateness at bus stops 25.21% to 43.1% on the average, improve bus travel time by 5.1% to 10%, increase side street delay by 15.9%, and favour other vehicles using the priority approach by 5.8% and 11.6% in travel time and delay reduction respectively. Findings also indicated that TSP may not affect LOS under low to medium traffic condition but LOS may increase under high traffic condition