Electron-Transfer from H-2 and Ar to Stored Multiply Charged Argon Ions Produced by Synchrotron Radiation

Journals published by the American Physical Society can be found at http://publish.aps.org/The rate coefficients for electron transfer from Ar and H-2 to Ar(q+) ions (3 less-than-or-equal-to q less-than-or-equal-to 6) have been measured using an ion-storage technique in a Penning ion trap. The ions were produced in the trap by K-shell photoionization of Ar atoms, using broadband synchrotron x-ray radiation. K-electron removal resulted in vacancy cascading, yielding a distribution of argon-ion charge states peaked near Ar4+. The stored ion gas had an initial temperature near 480 K. The basic data determining the rate coefficients k(Ar(q+)) are the storage time constants of each charge state in the trap, in the presence of a measured pressure of target gas. The results of the measurements (in units of 10(-9) cm3 s-1) are k(Ar3+, H-2) = 4.3(0.7), k(Ar3+, Ar) = 1.6(0.2), k(Ar4+, H-2) = 5.2(0.6), k(Ar4+, Ar) = 2.5(0.3), k(Ar5+, H-2) = 5.9(0.7), k(Ar5+, Ar) = 2.9(0.3), k(Ar6+, H-2) = 8.5(l.2), and k(Ar6+, Ar) = 2.5(0.3)

Targeted treatments for fragile X syndrome

Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders

Confined Thermal Multicharged Ions Produced by Synchrotron Radiation

Journals published by the American Physical Society can be found at http://publish.aps.org

Mavoglurant in Fragile X Syndrome:Results of two open-label, extension trials in adults and adolescents

Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions. Adolescent (n = 119, aged 12-19 years) and adult (n = 148, aged 18-45 years) participants received up to 100 mg bid mavoglurant for up to 34 months. Both extension studies were terminated prematurely due to lack of proven efficacy in the core studies. Mavoglurant was well tolerated with no new safety signal. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Gradual and consistent behavioral improvements as measured by the ABC-C <sub>FX</sub> scale were observed, which were numerically superior to those seen in the placebo arm of the core studies. These two extension studies confirm the long-term safety of mavoglurant in FXS, but further investigations are required to determine whether and under which conditions the significant preclinical results obtained with mGluR5 inhibition can translate to humans

Utility of the Hebb–Williams maze paradigm for translational research in Fragile X syndrome: A direct comparison of mice and humans

To generate meaningful information, translational research must employ paradigms that allow extrapolation from animal models to humans. However, few studies have evaluated translational paradigms on the basis of defined validation criteria. We outline three criteria for validating translational paradigms. We then evaluate the Hebb–Williams maze paradigm (Hebb and Williams, 1946; Rabinovitch and Rosvold, 1951) on the basis of these criteria using Fragile X syndrome (FXS) as model disease. We focuse

FMR1 premutation and full mutation molecular mechanisms related to autism

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5′ un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism

The question of access to the Japanese market

This survey focuses on the question of how market structure and different corporate organisational forms might affect access to the Japanese market for industrial goods. The question is how and whether keiretsu corporate structures in Japan constitute an important unofficial barrier in access to the Japanese market for manufactured goods