Position Effect Takes Precedence Over Target Sequence in Determination of Adenine Methylation Patterns in the Nuclear Genome of a Eukaryote, \u3cem\u3eTetrahymena thermophila\u3c/em\u3e

Approximately 0.8% of the adenine residues in the macronuclear DNA of the ciliated protozoan Tetrahymena thermophila are modified to N6-methyladenine. DNA methylation is site specific and the pattern of methylation is constant between clonal cell lines. In vivo, modification of adenine residues appears to occur exclusively in the sequence 5′-NAT-3′, but no consensus sequence for modified sites has been found. In this study, DNA fragments containing a site that is uniformly methylated on the 50 copies of the macronuclear chromosome were cloned into the extrachromosomal rDNA. In the novel location on the rDNA minichromosome, the site was unmethylated. The result was the same whether the sequences were introduced in a methylated or unmethylated state and regardless of the orientation of the sequence with respect to the origin of DNA replication. The data show that sequence is insufficient to account for site-specific methylation in Tetrahymena and argue that other factors determine the pattern of DNA methylation

Uncovering the Biological Basis of Control Energy: Structural and Metabolic Correlates of Energy Inefficiency in Temporal Lobe Epilepsy

Network control theory is increasingly used to profile the brain\u27s energy landscape via simulations of neural dynamics. This approach estimates the control energy required to simulate the activation of brain circuits based on structural connectome measured using diffusion magnetic resonance imaging, thereby quantifying those circuits\u27 energetic efficiency. The biological basis of control energy, however, remains unknown, hampering its further application. To fill this gap, investigating temporal lobe epilepsy as a lesion model, we show that patients require higher control energy to activate the limbic network than healthy volunteers, especially ipsilateral to the seizure focus. The energetic imbalance between ipsilateral and contralateral temporolimbic regions is tracked by asymmetric patterns of glucose metabolism measured using positron emission tomography, which, in turn, may be selectively explained by asymmetric gray matter loss as evidenced in the hippocampus. Our investigation provides the first theoretical framework unifying gray matter integrity, metabolism, and energetic generation of neural dynamics

Methylation of adenine in the nuclear DNA of Tetrahymena is internucleosomal and independent of histone H1

There are about 50 copies of each chromosome in the somatic macronucleus of the ciliated protozoan Tetrahymena. Approximately 0.8% of the adenine residues in the macronuclear DNA of Tetrahymena are methylated to N(6)-methyladenine. The degree of methylation varies between sites from a very low percentage to >90%. In this study a correlation was found between nucleosome positioning and DNA methylation. Eight GATC sites with different levels of methylation were examined. There was a direct correlation between the degree of methylation and proximity to linker DNA at these sites. Although methylation occurs preferentially in linker DNA, the patterns and extent of methylation in a histone H1 knockout strain were virtually indistinguishable from those in wild-type cells

Nucleosome Positioning Is Independent of Histone H1 \u3cem\u3ein Vivo\u3c/em\u3e

Nucleosome positioning in the somatic macronuclear genome of the ciliated protozoan Tetrahymena thermophila was analyzed by indirect end labeling. Nucleosomes were positioned nonrandomly in three different regions of theTetrahymena genome. Nucleosome repeat length varied between adjacent nucleosomes. Nucleosome positioning in a histone H1 knockout strain was indistinguishable from that in a strain with wild type histone H1

Position Effect for Adenine Methylation in the Macronuclear DNA of \u3cem\u3eTetrahymena\u3c/em\u3e

The macronucleus of the ciliate Tetrahymena contains about 45 copies of the genome. The fraction of the molecules on which an adenine residue is modified to N6-methyladenine is characteristic of the specific site, and consistent between clones. A fragment of DNA containing a site that is uniformly methylated on the macronuclear chromosome was moved to a new location on the extrachromosomal rDNA. The methylation pattern of the fragment on the rDNA was different from that on the chromosome. The data suggest that DNA sequence is not sufficient to determine the level of methylation

Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: a meta-analysis

Many theories of cognitive aging are based on evidence that dopamine (DA) declines with age. Here, we performed a systematic meta-analysis of cross-sectional positron emission tomography and single-photon emission-computed tomography studies on the average effects of age on distinct DA targets (receptors, transporters, or relevant enzymes) in healthy adults (N = 95 studies including 2611 participants). Results revealed significant moderate to large, negative effects of age on DA transporters and receptors. Age had a significantly larger effect on D1- than D2-like receptors. In contrast, there was no significant effect of age on DA synthesis capacity. The average age reductions across the DA system were 3.7%-14.0% per decade. A meta-regression found only DA target as a significant moderator of the age effect. This study precisely quantifies prior claims of reduced DA functionality with age. It also identifies presynaptic mechanisms (spared synthesis capacity and reduced DA transporters) that may partially account for previously unexplained phenomena whereby older adults appear to use dopaminergic resources effectively. Recommendations for future studies including minimum required samples sizes are provided

Subjective value representations during effort, probability and time discounting across adulthood

Every day, humans make countless decisions that require the integration of information about potential benefits (i.e. rewards) with other decision features (i.e. effort required, probability of an outcome or time delays). Here, we examine the overlap and dissociation of behavioral preferences and neural representations of subjective value in the context of three different decision features (physical effort, probability and time delays) in a healthy adult life span sample. While undergoing functional neuroimaging, participants (N = 75) made incentive compatible choices between a smaller monetary reward with lower physical effort, higher probability, or a shorter time delay versus a larger monetary reward with higher physical effort, lower probability, or a longer time delay. Behavioral preferences were estimated from observed choices, and subjective values were computed using individual hyperbolic discount functions. We found that discount rates were uncorrelated across tasks. Despite this apparent behavioral dissociation between preferences, we found overlapping subjective value-related activity in the medial prefrontal cortex across all three tasks. We found no consistent evidence for age differences in either preferences or the neural representations of subjective value across adulthood. These results suggest that while the tolerance of decision features is behaviorally dissociable, subjective value signals share a common representation across adulthood

Brain‐based ranking of cognitive domains to predict schizophrenia

Schizophrenia is a devastating brain disorder that disturbs sensory perception, motoraction, and abstract thought. Its clinical phenotype implies dysfunction of variousmental domains, which has motivated a series of theories regarding the underlyingpathophysiology. Aiming at a predictive benchmark of a catalog of cognitive functions,we developed a data-driven machine-learning strategy and provide a proof ofprinciple in a multisite clinical dataset (n = 324). Existing neuroscientific knowledge ondiverse cognitive domains was first condensed into neurotopographical maps. Wethen examined how the ensuing meta-analytic cognitive priors can distinguishpatients and controls using brain morphology and intrinsic functional connectivity.Some affected cognitive domains supported well-studied directions of research onauditory evaluation and social cognition. However, rarely suspected cognitivedomains also emerged as disease relevant, including self-oriented processing of bodilysensations in gustation and pain. Such algorithmic charting of the cognitive landscapecan be used to make targeted recommendations for future mental health research