Distinct phase-amplitude couplings distinguish cognitive processes in human attention

Abstract Spatial attention is the cognitive function that coordinates the selection of visual stimuli with appropriate behavioral responses. Recent studies have reported that phase-amplitude coupling (PAC) of low and high frequencies covaries with spatial attention, but differ on the direction of covariation and the frequency ranges involved. We hypothesized that distinct phase-amplitude frequency pairs have differentiable contributions during tasks that manipulate spatial attention. We investigated this hypothesis with electrocorticography (ECoG) recordings from participants who engaged in a cued spatial attention task. To understand the contribution of PAC to spatial attention we classified cortical sites by their relationship to spatial variables or behavioral performance. Local neural activity in spatial sites was sensitive to spatial variables in the task, while local neural activity in behavioral sites correlated with reaction time. We found two PAC frequency clusters that covaried with different aspects of the task. During a period of cued attention, delta-phase/high-gamma (DH) PAC was sensitive to cue direction in spatial sites. In contrast, theta-alpha-phase/beta-low-gamma-amplitude (TABL) PAC robustly correlated with future reaction times in behavioral sites. Finally, we investigated the origins of TABL PAC and found it corresponded to behaviorally relevant, sharp waveforms, which were also coupled to a low frequency rhythm. We conclude that TABL and DH PAC correspond to distinct mechanisms during spatial attention tasks and that sharp waveforms are elements of a coupled dynamical process

Variable contexts and levels of hypermutation in HIV-1 proviral genomes recovered from primary peripheral blood mononuclear cells

APOBEC-mediated cytidine cleamination of HIV-1 genomes during reverse transcription has been shown to be a potent mechanism of host restriction for HIV-1 infection ex vivo and in vitro. However, this defense system can be overcome by the viral protein Vif. Unlike other mechanisms of host restriction, the APOCEC-Vif interaction leaves an imprint on integrated proviruses in the form of G-A hypermutation. in the current work we systematically studied levels, contexts, and patterns of HIV-1 hypermutation in vivo. the analysis of 24 full-genome HIV-1 sequences retrieved from primary PBMCs, representing infections with several HIV-1 clades, and the inclusion of 7 cognate pairs of hypermutated/non-hypermutated sequences derived from the same patient sample, provided a comprehensive view of the characteristics of APOBEC-mediated restriction in vivo. Levels of hypermutation varied nearly 5-fold among the studied proviruses. GpG motifs were most frequently affected (22/24 proviruses). Levels of hypermutation varied across the genome. the reported twin peak pattern of hypermutation was observed in 18/24 hypermutants, but the remainder exhibited singular non-conforming patterns. These data suggest considerable complexity in the interplay of host restriction and viral defense during HIV-1 infection. (c) 2008 Elsevier Inc. All rights reserved.Henry M Jackson Fdn Advancement Mil Med, US Mil HIV Res Program, Rockville, MD 20850 USAUniversidade Federal de São Paulo, Paulista Sch Med, Div Infect Dis, BR-04039 São Paulo, BrazilWalter Reed Army Inst Res, Div Retrovirol, Rockville, MD 20850 USAUniversidade Federal de São Paulo, Paulista Sch Med, Div Infect Dis, BR-04039 São Paulo, BrazilWeb of Scienc

Adaptive Evolution and the Birth of CTCF Binding Sites in the Drosophila Genome

Changes in the physical interaction between cis-regulatory DNA sequences and proteins drive the evolution of gene expression. However, it has proven difficult to accurately quantify evolutionary rates of such binding change or to estimate the relative effects of selection and drift in shaping the binding evolution. Here we examine the genome-wide binding of CTCF in four species of Drosophila separated by between ~2.5 and 25 million years. CTCF is a highly conserved protein known to be associated with insulator sequences in the genomes of human and Drosophila. Although the binding preference for CTCF is highly conserved, we find that CTCF binding itself is highly evolutionarily dynamic and has adaptively evolved. Between species, binding divergence increased linearly with evolutionary distance, and CTCF binding profiles are diverging rapidly at the rate of 2.22% per million years (Myr). At least 89 new CTCF binding sites have originated in the Drosophila melanogaster genome since the most recent common ancestor with Drosophila simulans. Comparing these data to genome sequence data from 37 different strains of Drosophila melanogaster, we detected signatures of selection in both newly gained and evolutionarily conserved binding sites. Newly evolved CTCF binding sites show a significantly stronger signature for positive selection than older sites. Comparative gene expression profiling revealed that expression divergence of genes adjacent to CTCF binding site is significantly associated with the gain and loss of CTCF binding. Further, the birth of new genes is associated with the birth of new CTCF binding sites. Our data indicate that binding of Drosophila CTCF protein has evolved under natural selection, and CTCF binding evolution has shaped both the evolution of gene expression and genome evolution during the birth of new genes

Global MYCN Transcription Factor Binding Analysis in Neuroblastoma Reveals Association with Distinct E-Box Motifs and Regions of DNA Hypermethylation

BACKGROUND: Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is a major cause of childhood cancer related deaths. The single most important prognostic indicator of poor clinical outcome in this disease is genomic amplification of MYCN, a member of a family of oncogenic transcription factors. METHODOLOGY: We applied MYCN chromatin immunoprecipitation to microarrays (ChIP-chip) using MYCN amplified/non-amplified cell lines as well as a conditional knockdown cell line to determine the distribution of MYCN binding sites within all annotated promoter regions. CONCLUSION: Assessment of E-box usage within consistently positive MYCN binding sites revealed a predominance for the CATGTG motif (p\u3c0.0016), with significant enrichment of additional motifs CATTTG, CATCTG, CAACTG in the MYCN amplified state. For cell lines over-expressing MYCN, gene ontology analysis revealed enrichment for the binding of MYCN at promoter regions of numerous molecular functional groups including DNA helicases and mRNA transcriptional regulation. In order to evaluate MYCN binding with respect to other genomic features, we determined the methylation status of all annotated CpG islands and promoter sequences using methylated DNA immunoprecipitation (MeDIP). The integration of MYCN ChIP-chip and MeDIP data revealed a highly significant positive correlation between MYCN binding and DNA hypermethylation. This association was also detected in regions of hemizygous loss, indicating that the observed association occurs on the same homologue. In summary, these findings suggest that MYCN binding occurs more commonly at CATGTG as opposed to the classic CACGTG E-box motif, and that disease associated over expression of MYCN leads to aberrant binding to additional weaker affinity E-box motifs in neuroblastoma. The co-localization of MYCN binding and DNA hypermethylation further supports the dual role of MYCN, namely that of a classical transcription factor affecting the activity of individual genes, and that of a mediator of global chromatin structure

Dynamic Oscillatory Interactions Between Neural Attention and Sensorimotor Systems

The adaptive and flexible ability of the human brain to preference the processing of salient environmental features in the visual space is essential to normative cognitive function, and various neurologically afflicted patient groups report negative impacts on visual attention. While the brain-bases of human attentional processing have begun to be unraveled, very little is known regarding the interactions between attention systems and systems supporting sensory and motor processing. This is essential, as these interactions are dynamic; evolving rapidly in time and across a wide range of functionally defined rhythmic frequencies. Using magnetoencephalography (MEG) and a range of novel cognitive paradigms and analytical techniques, this work attempts to fill critical gaps in this knowledge. Specifically, we unravel the role of dynamic oscillatory interactions between attention and three sensorimotor systems. First, we establish the importance of sub-second occipital alpha (8 – 14 Hz) oscillatory responses in visual distractor suppression during selective attention (Chapter 1) and their essential role in fronto-parietal attention networks during visual orienting (Chapter 2). Next, we examine the divergent effects of directed attention on multi-frequency primary somatosensory neural oscillations in the theta (4 – 8 Hz), alpha, and beta (18 – 26 Hz) bands (Chapter 3). Finally, we extend these findings to the motor system (Chapter 4), and find that the frontal and parietal beta-frequency oscillations known to support motor planning and execution are modulated equivalently by differing subtypes of attentional interference, whereas frontal gamma (64 – 84 Hz) oscillations specifically index the superadditive effect of this interference. These findings provide new insight into the dynamic nature of attention-sensorimotor interactions in the human brain, and will be the foundation for groundbreaking new studies of attentional deficits in patients with common neurological disorders (e.g., Alzheimer’s disease, HIV-associated neurocognitive disorders, Parkinson’s disease). With an enhanced knowledge of the temporal and spectral definitions of these impairments, new therapeutic interventions utilizing frequency-targeted neural stimulation can be developed

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10\u2009m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that \u3b1-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that \u3b1-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients

Adaptive Evolution and the Birth of CTCF Binding Sites in the <i>Drosophila</i> Genome

Changes in the physical interaction between cis-regulatory DNA sequences and proteins drive the evolution of gene expression. However, it has proven difficult to accurately quantify evolutionary rates of such binding change or to estimate the relative effects of selection and drift in shaping the binding evolution. Here we examine the genome-wide binding of CTCF in four species of Drosophila separated by between ∼2.5 and 25 million years. CTCF is a highly conserved protein known to be associated with insulator sequences in the genomes of human and Drosophila. Although the binding preference for CTCF is highly conserved, we find that CTCF binding itself is highly evolutionarily dynamic and has adaptively evolved. Between species, binding divergence increased linearly with evolutionary distance, and CTCF binding profiles are diverging rapidly at the rate of 2.22% per million years (Myr). At least 89 new CTCF binding sites have originated in the Drosophila melanogaster genome since the most recent common ancestor with Drosophila simulans. Comparing these data to genome sequence data from 37 different strains of Drosophila melanogaster, we detected signatures of selection in both newly gained and evolutionarily conserved binding sites. Newly evolved CTCF binding sites show a significantly stronger signature for positive selection than older sites. Comparative gene expression profiling revealed that expression divergence of genes adjacent to CTCF binding site is significantly associated with the gain and loss of CTCF binding. Further, the birth of new genes is associated with the birth of new CTCF binding sites. Our data indicate that binding of Drosophila CTCF protein has evolved under natural selection, and CTCF binding evolution has shaped both the evolution of gene expression and genome evolution during the birth of new genes.</p

Ultraviolet and Infrared Spectroscopy of Synthetic Foldamers, Aib Homopeptides, and Solvated 1,2-Diphenylethane in the Gas Phase

The work presented here implements a supersonic jet expansion source to funnel the population of model peptides and solvated-bichromophore clusters into their low lying structural minima and to collisionally cool these minima to their respective zero-point vibrational levels. Single-conformation ultraviolet and infrared spectroscopy techniques are then used to probe these systems and investigate their electronic properties and uncover their intrinsic conformational preferences in the gas phase. Model β/γ-peptides known as synthetic foldamers and aminoisobutyric acid (Aib) homopeptides incorporate structural constraints that are designed/known to impose particular structural motifs. Here the ability of a β/γ-dipeptide to replicate the backbone length of an α-tripeptide and subsequently form the first portion of an α-helix is presented. Additionally, tests of the propensity for (Aib)n homopeptides to form 310-helices, in spite of accumulation of a macrodipole moment are shown. In fact, Aib is a strong 310-helix former, but there appears to be a point around n = 6 where competing forces funnel the population into a competing conformational family. 1,2-Diphenylethane (DPE) is a model, flexible bichromophore comprising two phenyl rings bound by an ethane bridge. By complexing DPE with (H 2O)n (n = 1-3) the effects of step-wise solvation on the electronic spectroscopy (i.e. the impact of water on vibronically coupled chromophores) and the conformational preferences of both the DPE monomer and the (H2O)n structures were investigated. In three of the four resultant clusters, the water molecule(s) were found to bind symmetrically to the DPE host, and an S0-S2 origin transition was not observed. However, in the fourth case, in which the anti conformation of the DPE monomer serves as host, localization is observed, and the S0-S2 origin is detected. Also of note is that the water-trimer, which almost always adopts a cycle geometry, was found to exclusively adopt a chain-geometry in the presence of DPE