Modulation of the GABAergic pathway for the treatment of fragile X syndrome.

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS

Conceptual design of thermal energy storage systems for near term electric utility applications. Volume 2: Appendices - screening of concepts

Volume 2 of this 2 volume report is represented. This volume contains three appendices: (1) bibliography and cross references; (2) taxonomy - proponents and sources; and (3) concept definitions

Conceptual design of thermal energy storage systems for near term electric utility applications. Volume 1: Screening of concepts

Over forty thermal energy storage (TES) concepts gathered from the literature and personal contacts were studied for their suitability for the electric utility application of storing energy off-peak discharge during peak hours. Twelve selections were derived from the concepts for screening; they used as storage media high temperature water (HTW), hot oil, molten salts, and packed beds of solids such as rock. HTW required pressure containment by prestressed cast-iron or concrete vessels, or lined underground cavities. Both steam generation from storage and feedwater heating from storage were studied. Four choices were made for further study during the project. Economic comparison by electric utility standard cost practices, and near-term availability (low technical risk) were principal criteria but suitability for utility use, conservation potential, and environmental hazards were considered

An eight-month climatology of marine stratocumulus cloud fraction, albedo, and integrated liquid water

As part of the FIRE/Extended Time Observations (ETO) program, extended time observations were made at San Nicolas Island (SNI) from March to October, 1987. Hourly averages of air temperature, relative humidity, wind speed and direction, solar irradiance, and downward longwave irradiance were recorded. The radiation sensors were standard Eppley pyranometers (shortwave) and pyrgeometers (longwave). The SNI data were processed in several ways to deduce properties of the stratocumulus covered marine boundary layer (MBL). For example, from the temperature and humidity the lifting condensation level, which is an estimate of the height of the cloud bottom, can be computed. A combination of longwave irradiance statistics can be used to estimate fractional cloud cover. An analysis technique used to estimate the integrated cloud liquid water content (W) and the cloud albedo from the measured solar irradiance is also described. In this approach, the cloud transmittance is computed by dividing the irradiance measured at some time by a clear sky value obtained at the same hour on a cloudless day. From the transmittance and the zenith angle, values of cloud albedo and W are computed using the radiative transfer parameterizations of Stephens (1978). These analysis algorithms were evaluated with 17 days of simultaneous and colocated mm-wave (20.6 and 31.65 GHz) radiometer measurements of W and lidar ceilometer measurements of cloud fraction and cloudbase height made during the FIRE IFO. The algorithms are then applied to the entire data set to produce a climatology of these cloud properties for the eight month period

Mind the Gap: Another look at the problem of the semantic gap in image retrieval

This paper attempts to review and characterise the problem of the semantic gap in image retrieval and the attempts being made to bridge it. In particular, we draw from our own experience in user queries, automatic annotation and ontological techniques. The first section of the paper describes a characterisation of the semantic gap as a hierarchy between the raw media and full semantic understanding of the media's content. The second section discusses real users' queries with respect to the semantic gap. The final sections of the paper describe our own experience in attempting to bridge the semantic gap. In particular we discuss our work on auto-annotation and semantic-space models of image retrieval in order to bridge the gap from the bottom up, and the use of ontologies, which capture more semantics than keyword object labels alone, as a technique for bridging the gap from the top down

Frontostriatal Maturation Predicts Cognitive Control Failure to Appetitive Cues in Adolescents

Adolescent risk-taking is a public health issue that increases the odds of poor lifetime outcomes. One factor thought to influence adolescents' propensity for risk-taking is an enhanced sensitivity to appetitive cues, relative to an immature capacity to exert sufficient cognitive control. We tested this hypothesis by characterizing interactions among ventral striatal, dorsal striatal, and prefrontal cortical regions with varying appetitive load using fMRI scanning. Child, teen, and adult participants performed a go/no-go task with appetitive (happy faces) and neutral cues (calm faces). Impulse control to neutral cues showed linear improvement with age, whereas teens showed a nonlinear reduction in impulse control to appetitive cues. This performance decrement in teens was paralleled by enhanced activity in the ventral striatum. Prefrontal cortical recruitment correlated with overall accuracy and showed a linear response with age for no-go versus go trials. Connectivity analyses identified a ventral frontostriatal circuit including the inferior frontal gyrus and dorsal striatum during no-go versus go trials. Examining recruitment developmentally showed that teens had greater between-subject ventral-dorsal striatal coactivation relative to children and adults for happy no-go versus go trials. These findings implicate exaggerated ventral striatal representation of appetitive cues in adolescents relative to an intermediary cognitive control response. Connectivity and coactivity data suggest these systems communicate at the level of the dorsal striatum differentially across development. Biased responding in this system is one possible mechanism underlying heightened risk-taking during adolescence

Behavioral Assessment of Emotion Discrimination, Emotion Regulation, and Cognitive Control in Childhood, Adolescence, and Adulthood

Emotion discrimination, emotion regulation, and cognitive control are three related, yet separable processes that emerge over the course of development. The current study tested 100 children, adolescents, and adults on an Emotional Go/Nogo task, illustrating the ability of this paradigm to identify the unique developmental patterns for each of these three processes in the context of both positive (happy) and negative emotions (fear, sad, and anger), across three different age groups. Consistent with previous literature, our findings show that emotion discrimination and regulatory abilities (both cognitive control and emotion regulation) improve steadily for each age group, with each age group showing unique patterns of performance. The findings suggest that emotion regulation is constructed from basic cognition control and emotion discrimination skills. The patterns of behavior from the Emotional Go/Nogo task provide normative benchmark data across a wide range of emotions that can be used for future behavioral and neuroimaging studies that examine the developmental construction of emotion regulatory processes

X-ray and near-infrared observations of the middle-aged pulsar B1055-52, its multiwavelength spectrum, and proper motion

Previous observations of the middle-aged $\gamma$-ray, X-ray, and radio pulsar B1055-52 indicated some peculiarities, such as a suspected changing of the X-ray flux and spectral parameters, a large excess of the alleged thermal component of the ultraviolet (UV) spectrum over the Rayleigh-Jeans extension of the X-ray thermal spectrum, and a possible double break in the nonthermal spectral component between the optical and X-ray bands. We observed PSR B1055-52 with the XMM-Newton observatory in X-rays and the Hubble Space Telescope in near-infrared (NIR). The analysis of the XMM-Newton observations does not support the notion of long-term changes in the X-ray flux and broad-band X-ray spectrum of the pulsar. Using an observing mode less affected by background noise than the previous XMM-Newton observations, we constrain the power-law (PL) spectral index as $\alpha_X=-0.57^{+0.26}_{-0.25}$ ($F_{\nu} \propto \nu^{\alpha}$) in the energy band 3-10 keV. From the NIR-optical data we obtain a PL slope $\alpha_O= -0.24 \pm 0.10$ for the color index $E(B-V)=0.03$ mag. The slopes and fluxes of the NIR-optical and X-ray nonthermal spectra suggest that the NIR through X-ray emission can be described by the same PL and is generated by the same mechanism, unlike the pulsar's $\gamma$-ray emission. The excess of the UV thermal component over the extension of the X-ray thermal component became smaller but did not disappear, indicating a non-uniformity of the bulk surface temperature. The NIR data also enable us to accurately measure the proper motion with values $\mu_\alpha =47.5\pm 0.7\,{\rm mas\,yr}^{-1}$ and $\mu_\delta = -8.7 \pm 0.7 \,{\rm mas\,yr}^{-1}$.Comment: ApJ accepted; 19 pages, 10 Figures, 5 Table