PPARG SIGNALING IN THE NUCLEUS ACCUMBENS REGULATES MESOLIMBIC DOPAMINE ACTIVITY

Background: The mesolimbic dopamine system consists of dopamine neuron projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). The NAc regulates VTA dopamine release through inhibitory GABA projections to the VTA. Hyperactive mesolimbic dopamine signaling is implicated in anxiety. Cannabidiol, a compound found in cannabis, demonstrates promising therapeutic potential for anxiety through the regulation of the mesolimbic dopamine system. Previous studies have revealed that cannabidiol infusions into the NAc decreases mesolimbic dopamine activity - potentially through the inhibitory GABA signaling to the VTA. However, the receptor mechanism in the NAc through which CBD produces its effects is unknown. Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear transcription factor that binds to CBD and colocalizes with GABA neurons. Recent evidence suggests that PPARG activation can decrease mesolimbic dopamine activity through inhibitory GABA signaling. Considering that the NAc expresses high levels of PPARG, intra-NAc CBD may regulate mesolimbic dopamine activity through PPARG activation. Hypothesis: PPARG activation in the NAc regulates mesolimbic dopamine transmission through the modulation of the GABAergic inhibition of the VTA. Methods: In-vivo electrophysiology was used to investigate the effects of intra-NAc PPARG activation on mesolimbic dopamine activity. The anxiolytic effects of intra-NAc PPARG activation was measured using the light-dark box and elevated plus maze behavioural tests. Results: We report that PPARG activation in the NAc significantly decreases mesolimbic dopamine activity whereas PPARG antagonists block this effect. Additionally, we reveal that intra-NAc PPARG activation produces anxiolytic effects as measured in the light-dark box and elevated plus maze behavioural tests

Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma

Rationale: Bronchial thermoplasty (BT) is designed to reduce airway smooth muscle and improve asthma control. Objectives: This study was conducted to determine the safety and efficacy of this procedure in subjects with symptomatic, severe asthma. Methods: Adults who were symptomatic despite treatment with fluticasone or equivalent at more than 750 μg/day, a long-acting β2-agonist, and other medications, which could include 30 mg or less of oral prednisolone/day, were randomized to BT or to a control group. After treatment, subjects entered a 16-week steroid stable phase (Weeks 6–22), a 14-week steroid wean phase (Weeks 22–36), and a 16-week reduced steroid phase (Weeks 36–52). Measurements and Main Results: BT resulted in a transient worsening of asthma symptoms. Seven hospitalizations for respiratory symptoms occurred in 4 of 15 BT subjects during the treatment period. Five hospitalizations were within 3 days of treatment. Two subjects had segmental collapse involving the most recently treated lobe; one required bronchoscopy and aspiration of a mucus plug. There were no hospitalizations during this period in the 17 control subjects. The rate of hospitalizations was similar in both groups in the post-treatment period. At 22 weeks, BT subjects had significant improvements versus control subjects in rescue medication use (−26.6 ± 40.1 vs. −1.5 ± 11.7 puffs/7 d, P &lt; 0.05), prebronchodilator FEV1% predicted (14.9 ± 17.4 vs. −0.94 ± 22.3%, P = 0.04), and Asthma Control Questionnaire scores (−1.04 ± 1.03 vs. −0.13 ± 1.00, P = 0.02). Improvements in rescue medication use and Asthma Control Questionnaire scores remained significantly different from those of controls at 52 weeks. Conclusions: BT is associated with a short-term increase in asthma-related morbidity. However, there is preliminary evidence of long-lasting improvement in asthma control.</p

Assemblathon 2: evaluating de novo methods of genome assembly in three vertebrate species

International audienceBackgroundThe process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly.ResultsIn Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies.ConclusionsMany current genome assemblers produced useful assemblies, containing a significant representation of their genes and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another