56 research outputs found

    Finishing the euchromatic sequence of the human genome

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    The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

    CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length

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    The CCCTC-binding factor (CTCF) organises the genome in 3D through DNA loops and in 1D by setting boundaries isolating different chromatin states, but these processes are not well understood. Here we focus on the relationship between CTCF binding and the decrease of the Nucleosome Repeat Length (NRL) for ∼20 adjacent nucleosomes, affecting up to 10% of the mouse genome. We found that the chromatin boundary near CTCF is created by the nucleosome-depleted region (NDR) asymmetrically located >40 nucleotides 5’-upstream from the centre of CTCF motif. The strength of CTCF binding to DNA is correlated with the decrease of NRL near CTCF and anti-correlated with the level of asymmetry of the nucleosome array. Individual chromatin remodellers have different contributions, with Snf2h having the strongest effect on the NRL decrease near CTCF and Chd4 playing a major role in the symmetry breaking. Upon differentiation of embryonic stem cells to neural progenitor cells and embryonic fibroblasts, a subset of common CTCF sites preserved in all three cell types maintains a relatively small local NRL despite genome-wide NRL increase. The sites which lost CTCF upon differentiation are characterised by nucleosome rearrangement 3’-downstream, but the boundary defined by the NDR 5’-upstream of CTCF motif remains

    Dopamine and reward hypersensitivity in Parkinson's disease with impulse control disorder.

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    Impulse control disorders in Parkinson's disease are common neuropsychiatric complications associated with dopamine replacement therapy. Some patients treated with dopamine agonists develop pathological behaviours, such as gambling, compulsive eating, shopping, or disinhibited sexual behaviours, which can have a severe impact on their lives and that of their families. In this study we investigated whether hypersensitivity to reward might contribute to these pathological behaviours and how this is influenced by dopaminergic medication. We asked participants to shift their gaze to a visual target as quickly as possible, in order to obtain reward. Critically, the reward incentive on offer varied over trials. Motivational effects were indexed by pupillometry and saccadic velocity, and patients were tested ON and OFF dopaminergic medication, allowing us to measure the effect of dopaminergic medication changes on reward sensitivity. Twenty-three Parkinson's disease patients with a history of impulse control disorders were compared to 26 patients without such behaviours, and 31 elderly healthy controls. Intriguingly, behavioural apathy was reported alongside impulsivity in the majority of patients with impulse control disorders. Individuals with impulse control disorders also exhibited heightened sensitivity to exogenous monetary rewards cues both ON and OFF (overnight withdrawal) dopamine medication, as indexed by pupillary dilation in anticipation of reward. Being OFF dopaminergic medication overnight did not modulate pupillary reward sensitivity in impulse control disorder patients, whereas in control patients reward sensitivity was significantly reduced when OFF dopamine. These effects were independent of cognitive impairment or total levodopa equivalent dose. Although dopamine agonist dose did modulate pupillary responses to reward, the pattern of results was replicated even when patients with impulse control disorders on dopamine agonists were excluded from the analysis. The findings suggest that hypersensitivity to rewards might be a contributing factor to the development of impulse control disorders in Parkinson's disease. However, there was no difference in reward sensitivity between patient groups when ON dopamine medication, suggesting that impulse control disorders may not emerge simply because of a direct effect of dopaminergic drug level on reward sensitivity. The pupillary reward sensitivity measure described here provides a means to differentiate, using a physiological measure, Parkinson's disease patients with impulse control disorder from those who do not experience such symptoms. Moreover, follow-up of control patients indicated that increased pupillary modulation by reward can be predictive of the risk of future emergence of impulse control disorders and may thereby provide the potential for early identification of patients who are more likely to develop these symptoms

    Establishing Need and Buy-in Prior to SWPBIS

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    Identification of Candidate Regulators of Embryonic Stem Cell Differentiation by Comparative Phosphoprotein Affinity Profiling: Mol.Cell Proteomics.

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    Embryonic stem cells are a unique cell population capable both of self-renewal and of differentiation into all tissues in the adult organism. Despite the central importance of these cells, little information is available regarding the intracellular signaling pathways that govern self-renewal or early steps in the differentiation program. Embryonic stem cell growth and differentiation correlates with kinase activities, but with the exception of the JAK/STAT3 pathway, the relevant substrates are unknown. To identify candidate phosphoproteins with potential relevance to embryonic stem cell differentiation, a systems biology approach was used. Proteins were purified using phosphoprotein affinity columns, then separated by two-dimensional gel electrophoresis, and detected by silver stain before being identified by tandem mass spectrometry. By comparing preparations from undifferentiated and differentiating mouse embryonic stem cells, a set of proteins was identified that exhibited altered post-translational modifications that correlated with differentiation state. Evidence for altered post-translational modification included altered gel mobility, altered recovery after affinity purification, and direct mass spectra evidence. Affymetrix microarray analysis indicated that gene expression levels of these same proteins had minimal variability over the same differentiation period. Bioinformatic annotations indicated that this set of proteins is enriched with chromatin remodeling, catabolic, and chaperone functions. This set of candidate phosphoprotein regulators of stem cell differentiation includes products of genes previously noted to be enriched in embryonic stem cells at the mRNA expression level as well as proteins not associated previously with stem cell differentiation statusNRC publication: Ye

    Assessing Intern Impact Factors for Program Evaluation and Improvement

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    We present the results of a program evaluation system for examining school psychology interns\u27 impact on the academic and behavioral functioning of children. Outcome data from a variety of single-case problem-solving interventions conducted from 2008-2012 indicated overall moderate, positive effects. Global supervisor ratings indicated strong perceptions of the interns\u27 positive impact on the children they served

    When ‘‘3’’ is a Jerk and ‘‘E’’ is a King: Personifying Inanimate Objects in Synesthesia

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    Abstract & We report a case study of an individual (TE) for whom inanimate objects, such as letters, numbers, simple shapes, and even furniture, are experienced as having rich and detailed personalities. TE reports that her object-personality pairings are stable over time, occur independent of her intentions, and have been there for as long as she can remember. In these respects, her experiences are indicative of synesthesia. Here we show that TE's object-personality pairings are very consistent across test-retest, even for novel objects. A qualitative analysis of TE's personality descriptions revealed that her personifications are extremely detailed and multidimensional, and that her personifications of familiar and novel objects differ in specific ways. We also found that TE's eye movements can be biased by the emotional associations she has with letters and numbers. These findings demonstrate that synesthesia can involve complex semantic personifications, which can influence visual attention. Finally, we propose a neural model of normal personification and the unusual personifications that accompany object-personality synesthesia. &amp

    Recent advances and trends in subsea technologies and seafloor properties characterization

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    Following the 2012 SEG Annual Meeting in Las Vegas, the SEG Research Committee sponsored a post-convention research workshop on subsea technologies, in general, and on seafloor characterization in particular. The goal of the workshop was to share experiences in acquisition, processing and applications of geotechnical and geophysical measurements for seafloor property characterization. This includes: To help geophysicists in better understanding geotechnical seafloor measurements, e.g., when and how they are collected as well as their actual field applications; To help geotechnical specialists in better understanding geophysical seafloor measurements, how they are derived, and their importance for accurate seismic waveform modeling and inversion; To discuss technology and application trends, and how the geophysical community can participate in the fast-growing market for subsea operations in the oil and gas industry
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