Insula-specific responses induced by dental pain: a proton magnetic resonance spectroscopy study

OBJECTIVES: To evaluate whether induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex after stimulation of the right maxillary canine and to examine whether these metabolic changes and the subjective pain intensity perception correlate. METHODS: Ten male volunteers were included in the pain group and compared with a control group of 10 other healthy volunteers. The pain group received a total of 87-92 electrically induced pain stimuli over 15 min to the right maxillary canine tooth. Contemporaneously, they evaluated the subjective pain intensity of every stimulus using an analogue scale. Neurotransmitter changes within the left insular cortex were evaluated by MR spectroscopy. RESULTS: Significant metabolic changes in glutamine (+55.1%), glutamine/glutamate (+16.4%) and myo-inositol (-9.7%) were documented during pain stimulation. Furthermore, there was a significant negative correlation between the subjective pain intensity perception and the metabolic levels of Glx, Gln, glutamate and N-acetyl aspartate. CONCLUSION: The insular cortex is a metabolically active region in the processing of acute dental pain. Induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex resulting in significant alterations in metabolites. Negative correlation between subjective pain intensity rating and specific metabolites could be observed

H2B ubiquitylation is part of chromatin architecture that marks exon-intron structure in budding yeast

<p>Abstract</p> <p>Background</p> <p>The packaging of DNA into chromatin regulates transcription from initiation through 3' end processing. One aspect of transcription in which chromatin plays a poorly understood role is the co-transcriptional splicing of pre-mRNA.</p> <p>Results</p> <p>Here we provide evidence that H2B monoubiquitylation (H2BK123ub1) marks introns in <it>Saccharomyces cerevisiae</it>. A genome-wide map of H2BK123ub1 in this organism reveals that this modification is enriched in coding regions and that its levels peak at the transcribed regions of two characteristic subgroups of genes. First, long genes are more likely to have higher levels of H2BK123ub1, correlating with the postulated role of this modification in preventing cryptic transcription initiation in ORFs. Second, genes that are highly transcribed also have high levels of H2BK123ub1, including the ribosomal protein genes, which comprise the majority of intron-containing genes in yeast. H2BK123ub1 is also a feature of introns in the yeast genome, and the disruption of this modification alters the intragenic distribution of H3 trimethylation on lysine 36 (H3K36me3), which functionally correlates with alternative RNA splicing in humans. In addition, the deletion of genes encoding the U2 snRNP subunits, Lea1 or Msl1, in combination with an <it>htb-K123R </it>mutation, leads to synthetic lethality.</p> <p>Conclusion</p> <p>These data suggest that H2BK123ub1 facilitates cross talk between chromatin and pre-mRNA splicing by modulating the distribution of intronic and exonic histone modifications.</p

Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

Objective To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Methods Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. Results We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. Interpretation Here, we have developed a public resource () which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481Peer reviewe

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered

Dopamine Agonists Diminish Value Sensitivity of the Orbitofrontal Cortex: A Trigger for Pathological Gambling in Parkinson's Disease?

International audienceThe neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson's disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences