The accessible chromatin landscape of the human genome.

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

Caring for affective subjects produced in intimate healthcare examinations.

This article is about the feelings - affect - induced by the digital rectal exam of the prostate and the gynaecological bimanual pelvic exam, and the care doctors are or are not instructed to give. The exams are both invasive, intimate exams located at a part of the body often charged with norms and emotions related to gender and sexuality. By using the concept affective subject, we analyse how these examinations are taught to medical students, bringing attention to how bodies and affect are cared for as patients are observed and touched. Our findings show both the role care practices play in generating and handling affect in the students' learning and the importance of the affect that the exam is (or is not) imagined to produce in the patient. Ours is a material-discursive analysis that includes the material affordances of the patient and doctor bodies in the affective work spaces observed.

Analysis of the DNA sequence and duplication history of human chromosome 15.

Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplications in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.

Gay men's experiences of sexual changes after prostate cancer treatment-a qualitative study in Sweden.

Background: The needs of gay men after prostate cancer treatment are becoming visible. This patient group reports a more negative impact of treatment than heterosexual men. Yet, gay men's experiences of post-treatment sexual changes are still little explored. This study aims to determine specific concerns of gay men's post-treatment sexual practices. Methods: A qualitative study design was deployed using semi-structured interviews as data. Participants were purposefully sampled through advertisements and the snowball method. Eleven self-identifying gay men aged 58-81 years and treated for prostate cancer participated in interviews during 2016-2017. The interviews were transcribed, coded and thematically analysed. Results: The analysis highlights sexual changes in relation to the physical body, identity and relations. Problematic physical changes included loss of ejaculate and erectile dysfunction. Some respondents reported continued pleasure from anal stimulation and were uncertain about the role of the prostate. These physical changes prompted reflections on age and (dis)ability. Relationship status also impacted perception of physical changes, with temporary sexual contacts demanding more of the men in terms of erection and ejaculations. Conclusions: Gay prostate cancer survivors' narratives about sexual changes circle around similar bodily changes as heterosexual men's, such as erectile problems and weaker orgasms. The loss of ejaculate was experienced as more debilitating for gay men. Men who had anal sex were concerned about penetration difficulties as well as sensations of anal stimulation. Additional studies are required to better understand the role of the prostate among a diversity of men, regardless of sexuality.

Surgical simulators and simulated surgeons: reconstituting medical practice and practitioners in simulations.

Simulators that represent human patients are being integrated into medical education. This study examines the use of a haptic-enabled, virtual reality simulator designed to allow training in minimally invasive surgery (MIS) techniques. The paper shows how medical practices and practitioners are constructed during a simulation. By using the theoretical tools that situated learning and communities of practice provide, combined with the concept of reconstituting, I broaden the discussion of medical simulators from a concern with discrete skills and individual knowledge to an examination of how medical knowledge is created around and with computer simulators. The concept of reconstitution is presented as a theoretical term for understanding the interplay between simulators and people in practice. Rather than merely enacting simulator training, reconstituting creates a different context, different actors and different techniques during the simulation.

Viagra selfhood: pharmaceutical advertising and the visual formation of Swedish masculinity.

Using material from the Pfizer sponsored website providing health information on erectile dysfunction to potential Swedish Viagra customers (www.potenslinjen.se), this article explores the public image of masculinity in relation to sexual health and the cultural techniques for creating pharmaceutical appeal. We zoom in on the targeted ideal users of Viagra, and the nationalized, racialized and sexualized identities they are assigned. As part of Pfizer's marketing strategy of adjustments to fit the local consumer base, the ways in which Viagra is promoted for the Swedish setting is telling of what concepts of masculinity are so stable and unassailable that they can withstand the association with a drug that is, in essence, an acknowledgement of 'failed' masculinity and 'dysfunctional' sexuality. With comparative national examples, this study presents an interdisciplinary take on the 'glocalized' cultural imaginary of Viagra, and the masculine subject positions it engenders.

Genome-scale mapping of DNase I sensitivity in vivo using tiling DNA microarrays.

Localized accessibility of critical DNA sequences to the regulatory machinery is a key requirement for regulation of human genes. Here we describe a high-resolution, genome-scale approach for quantifying chromatin accessibility by measuring DNase I sensitivity as a continuous function of genome position using tiling DNA microarrays (DNase-array). We demonstrate this approach across 1% ( approximately 30 Mb) of the human genome, wherein we localized 2,690 classical DNase I hypersensitive sites with high sensitivity and specificity, and also mapped larger-scale patterns of chromatin architecture. DNase I hypersensitive sites exhibit marked aggregation around transcriptional start sites (TSSs), though the majority mark nonpromoter functional elements. We also developed a computational approach for visualizing higher-order features of chromatin structure. This revealed that human chromatin organization is dominated by large (100-500 kb) 'superclusters' of DNase I hypersensitive sites, which encompass both gene-rich and gene-poor regions. DNase-array is a powerful and straightforward approach for systematic exposition of the cis-regulatory architecture of complex genomes.