A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome

DNA topoisomerases are required to resolve DNA topological stress. Despite this essential role, abortive topoisomerase activity generates aberrant protein-linked DNA breaks, jeopardising genome stability. Here, to understand the genomic distribution and mechanisms underpinning topoisomerase-induced DNA breaks, we map Top2 DNA cleavage with strand-specific nucleotide resolution across the S. cerevisiae and human genomes—and use the meiotic Spo11 protein to validate the broad applicability of this method to explore the role of diverse topoisomerase family members. Our data characterises Mre11-dependent repair in yeast and defines two strikingly different fractions of Top2 activity in humans: tightly localised CTCF-proximal, and broadly distributed transcription-proximal, the latter correlated with gene length and expression. Moreover, single nucleotide accuracy reveals the influence primary DNA sequence has upon Top2 cleavage—distinguishing sites likely to form canonical DNA double-strand breaks (DSBs) from those predisposed to form strand-biased DNA single-strand breaks (SSBs) induced by etoposide (VP16) in vivo

Reduced expression of the presynaptic co-chaperone cysteine string protein alpha (CSP?) does not exacerbate experimentally-induced ME7 prion disease

Infection of mice with the ME7 prion agent results in well-characterised neuropathological changes, which includes vacuolation, neurodegeneration and synaptic degeneration. Presynaptic dysfunction and degeneration is apparent through the progressive reduction in synaptic vesicle proteins and eventual loss of synapses. Cysteine string protein alpha (CSP?), which regulates refolding pathways at the synapse, exhibits an early decline during chronic neurodegeneration implicating it as a mediator of disease mechanisms. CSP? null mice develop a progressive neuronal dysfunction through disruption of the integrity of presynaptic function. In this study, we investigated whether reduced expression of CSP? would exacerbate ME7 prion disease. Wild type (+/+) and heterozygous (+/-) mice, which express about a ?50% reduction in CSP?, were used as a distinct genetic background on which to impose prion disease. +/+ and +/ - mice were inoculated with brain homogenate from either a normal mouse brain (NBH) or from the brain of a mouse which displayed clinical signs of prion disease (ME7). Behavioural tests, western blotting and immunohistochemistry, which resolve key elements of synaptic dysfunction, were used to assess the effect of reduced CSP? on disease. Behavioural tests revealed no change in the progression of disease in ME7-CSP? +/- animals compared to ME7-CSP? +/+ animals. In addition, the accumulation of misfolded PrP(Sc), the diseased associated gliosis or synaptic loss were not different. Thus, the misfolding events that generate synaptic dysfunction and lead to synaptic loss are unlikely to be mediated by a disease associated decrease in the refolding pathways associated with CSP?

Meiotic DSB patterning: A multifaceted process

Meiosis is a specialized two-step cell division responsible for genome haploidization and the generation of genetic diversity during gametogenesis. An integral and distinctive feature of the meiotic program is the evolutionarily conserved initiation of homologous recombination (HR) by the developmentally programmed induction of DNA double-strand breaks (DSBs). The inherently dangerous but essential act of DSB formation is subject to multiple forms of stringent and self-corrective regulation that collectively ensure fruitful and appropriate levels of genetic exchange without risk to cellular survival. Within this article we focus upon an emerging element of this control—spatial regulation—detailing recent advances made in understanding how DSBs are evenly distributed across the genome, and present a unified view of the underlying patterning mechanisms employed

Psychological interventions for autistic adolescentswith co-occurring anxiety and depression: considerations linked to autism social identity and masking

Adolescence marks a time of increased vulnerability to developing mental health difficulties. Recent literature has pointed towards both risk and protective factors that contribute to the development and maintenance of co-occurring mental health difficulties amongst autistic adolescents. For example, autistic individuals may mask their autistic traits to fit in with neurotypical peers, but prolonged masking may negatively influence the development of one’s autistic identity and increase vulnerability to developing mental health difficulties. In this commentary, we focus our efforts on highlighting how 1) autistic identity and 2) masking behaviours may be considered within a holistic and person-centred formulation to guide treatment for mental health difficulties in autistic adolescents. In current clinical practice, mental health practitioners may not explicitly enquire about potential construct overlap between these autism related factors and other cognitive and behavioural factors that perpetuate mental health difficulties. We propose a series of assessment questions that clinical professionals may use when developing a shared understanding with autistic adolescents of how they perceive the relationship between autism and co-occurring mental health difficulties. Our goal is to support clinical professionals to consider ways of integrating advances in autistic identity and masking literature in autism to inform the assessment and formulation of co-occurring mental health difficulties when supporting autistic children and young people

Chandra Discovery of 10 New X-Ray Jets Associated With FR II Radio Core-Selected AGNs in the MOJAVE Sample

The Chandra X-ray observatory has proven to be a vital tool for studying high-energy emission processes in jets associated with Active Galactic Nuclei (AGN).We have compiled a sample of 27 AGN selected from the radio flux-limited MOJAVE (Monitoring of Jets in AGN with VLBA Experiments) sample of highly relativistically beamed jets to look for correlations between X-ray and radio emission on kiloparsec scales. The sample consists of all MOJAVE quasars which have over 100 mJy of extended radio emission at 1.4 GHz and a radio structure of at least 3" in size. Previous Chandra observations have revealed X-ray jets in 11 of 14 members of the sample, and we have carried out new observations of the remaining 13 sources. Of the latter, 10 have Xray jets, bringing the overall detection rate to ~ 78%. Our selection criteria, which is based on highly compact, relativistically beamed jet emission and large extended radio flux, thus provides an effective method of discovering new X-ray jets associated with AGN. The detected X-ray jet morphologies are generally well correlated with the radio emission, except for those displaying sharp bends in the radio band. The X-ray emission mechanism for these powerful FR II (Fanaroff-Riley type II) jets can be interpreted as inverse Compton scattering off of cosmic microwave background (IC/CMB) photons by the electrons in the relativistic jets. We derive viewing angles for the jets, assuming a non-bending, non-decelerating model, by using superluminal parsec scale speeds along with parameters derived from the inverse Compton X-ray model. We use these angles to calculate best fit Doppler and bulk Lorentz factors for the jets, as well as their possible ranges, which leads to extreme values for the bulk Lorentz factor in some cases. When both the non-bending and non-decelerating assumptions are relaxed [abridged]Comment: 38 Pages, 4 Figures, 5 Tables, accepted for publication in Ap

Physical characteristics and non-keplerian orbital motion of "propeller" moons embedded in Saturn's rings

We report the discovery of several large "propeller" moons in the outer part of Saturn's A ring, objects large enough to be followed over the 5-year duration of the Cassini mission. These are the first objects ever discovered that can be tracked as individual moons, but do not orbit in empty space. We infer sizes up to 1--2 km for the unseen moonlets at the center of the propeller-shaped structures, though many structural and photometric properties of propeller structures remain unclear. Finally, we demonstrate that some propellers undergo sustained non-keplerian orbit motion. (Note: This arXiv version of the paper contains supplementary tables that were left out of the ApJL version due to lack of space).Comment: 9 pages, 4 figures; Published in ApJ