Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

Copyright © 2015, The American Society for Biochemistry and Molecular Biology. Acknowledgements-We thank Drs Timo Rager and Rolf Hilfiker (Solvias, Switzerland) for polymorph analyses.Peer reviewedPublisher PD

An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder.

OBJECTIVE: To collect pilot data assessing the safety, tolerability, and efficacy of tomoxetine, a nonstimulant norepinephrine enhancer, in pediatric attention deficit hyperactivity disorder (ADHD). METHODS: An open-label trial of tomoxetine in pediatric ADHD was conducted as part of a multisite clinical trial. Following a baseline assessment, an ascending dose titration was completed during 10 weekly visits. RESULTS: Ten subjects were enrolled at baseline, with eight completing the study. Seven of the eight remaining subjects met efficacy criteria. Significant decreases in symptom severity ratings by parents and study investigators were found. The medication was well tolerated, with transient appetite suppression the most frequently reported side effect. However, subjects\u27 weights remained stable across study visits. DISCUSSION: These preliminary findings suggest that tomoxetine may hold promise as a treatment for pediatric ADHD

Delays in Leniency Application: Is There Really a Race to the Enforcer's Door?

This paper studies cartels’ strategic behavior in delaying leniency applications, a take-up decision that has been ignored in the previous literature. Using European Commission decisions issued over a 16-year span, we show, contrary to common beliefs and the existing literature, that conspirators often apply for leniency long after a cartel collapses. We estimate hazard and probit models to study the determinants of leniency-application delays. Statistical tests find that delays are symmetrically affected by antitrust policies and macroeconomic fluctuations. Our results shed light on the design of enforcement programs against cartels and other forms of conspiracy

The Formation of the First Stars II. Radiative Feedback Processes and Implications for the Initial Mass Function

We consider the radiative feedback processes that operate during the formation of the first stars, including the photodissociation of H_2, Ly-alpha radiation pressure, formation and expansion of an HII region, and disk photoevaporation. These processes may inhibit continued accretion once the stellar mass has reached a critical value, and we evaluate this mass separately for each process. Photodissociation of H_2 in the local dark matter minihalo occurs relatively early in the growth of the protostar, but we argue this does not affect subsequent accretion since by this time the depth of the potential is large enough for accretion to be mediated by atomic cooling. However, neighboring starless minihalos can be affected. Ionization creates an HII region in the infalling envelope above and below the accretion disk. Ly-alpha radiation pressure acting at the boundary of the HII region is effective at reversing infall from narrow polar directions when the star reaches ~20-30Msun, but cannot prevent infall from other directions. Expansion of the HII region beyond the gravitational escape radius for ionized gas occurs at masses ~50-100Msun, depending on the accretion rate and angular momentum of the inflow. However, again, accretion from the equatorial regions can continue since the neutral accretion disk has a finite thickness and shields a substantial fraction of the accretion envelope from direct ionizing flux. At higher stellar masses, ~140Msun in the fiducial case, the combination of declining accretion rates and increasing photoevaporation-driven mass loss from the disk act to effectively halt the increase in the protostellar mass. We identify this process as the mechanism that terminates the growth of Population III stars... (abridged)Comment: 31 pages, including 10 figures, accepted to Ap

LSD1-mediated enhancer silencing attenuates retinoic acid signalling during pancreatic endocrine cell development.

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute to signal-induced transcriptional responses, here we manipulate the signalling environment and activity of the histone demethylase LSD1 during differentiation of hESC-gut tube intermediates into pancreatic endocrine cells. We identify a transient requirement for LSD1 in endocrine cell differentiation spanning a short time-window early in pancreas development, a phenotype we reproduced in mice. Examination of enhancer and transcriptome landscapes revealed that LSD1 silences transiently active retinoic acid (RA)-induced enhancers and their target genes. Furthermore, prolonged RA exposure phenocopies LSD1 inhibition, suggesting that LSD1 regulates endocrine cell differentiation by limiting the duration of RA signalling. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited

The PPARβ/δAgonist GW0742 Relaxes Pulmonary Vessels and Limits Right Heart Hypertrophy in Rats with Hypoxia-Induced Pulmonary Hypertension

Copyright: © 2010 Harrington et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedBackground: Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension. Methodology/Principal Findings: Here we show that the PPARβ/δ agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARβ/δ or cell surface prostacyclin (IP) receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg) for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model. Conclusions/Significance: These observations are the first to show a therapeutic benefit of 'PPARβ/δ' agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.Peer reviewedFinal Published versio