Increased sister chromatid cohesion and DNA damage response factor localization at an enzyme-induced DNA double-strand break in vertebrate cells

The response to DNA damage in vertebrate cells involves successive recruitment of DNA signalling and repair factors. We used light microscopy to monitor the genetic dependencies of such localization to a single, induced DNA double strand break (DSB) in vertebrate cells. We used an inducible version of the rare-cutting I-SceI endonuclease to cut a chromosomally integrated I-SceI site beside a Tet operator array that was visualized by binding a Tet repressor-GFP fusion. Formation of γ-H2AX foci at a single DSB was independent of ATM or Ku70. ATM-deficient cells showed normal kinetics of 53Bp1 recruitment to DSBs, but Rad51 localization was retarded. 53Bp1 and Rad51 foci formation at a single DSB was greatly reduced in H2AX-null DT40 cells. We also observed decreased inter-sister chromatid distances after DSB induction, suggesting that cohesin loading at DSBs causes elevated sister chromatid cohesion. Loss of ATM reduced DSB-induced cohesion, consistent with cohesin being an ATM target in the DSB response. These data show that the same genetic pathways control how cells respond to single DSBs and to multiple lesions induced by whole-cell DNA damage

Spitzer Observations of the Predicted Eddington Flare from Blazar OJ 287

Binary black hole (BH) central engine description for the unique blazar OJ 287 predicted that the next secondary BH impact-induced bremsstrahlung flare should peak on 2019 July 31. This prediction was based on detailed general relativistic modeling of the secondary BH trajectory around the primary BH and its accretion disk. The expected flare was termed the Eddington flare to commemorate the centennial celebrations of now-famous solar eclipse observations to test general relativity by Sir Arthur Eddington. We analyze the multi-epoch Spitzer observations of the expected flare between 2019 July 31 and 2019 September 6, as well as baseline observations during 2019 February-March. Observed Spitzer flux density variations during the predicted outburst time display a strong similarity with the observed optical pericenter flare from OJ 287 during 2007 September. The predicted flare appears comparable to the 2007 flare after subtracting the expected higher base-level Spitzer flux densities at 3.55 and 4.49 $\mu$m compared to the optical R-band. Comparing the 2019 and 2007 outburst lightcurves and the previously calculated predictions, we find that the Eddington flare arrived within 4 hours of the predicted time. Our Spitzer observations are well consistent with the presence of a nano-Hertz gravitational wave emitting spinning massive binary BH that inspirals along a general relativistic eccentric orbit in OJ 287. These multi-epoch Spitzer observations provide a parametric constraint on the celebrated BH no-hair theorem.Comment: 8 pages, 4 figures, 1 table, to appear in ApJ

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Positive and Negative Parenting in Conduct Disorder with High versus Low Levels of Callous-Unemotional Traits

Less is known about the relationship between conduct disorder (CD), callous-unemotional (CU) traits, and positive and negative parenting in youth compared to early childhood. We combined traditional univariate analyses with a novel machine learning classifier (Angle-based Generalized Matrix Learning Vector Quantization) to classify youth (N = 756; 9-18 years) into typically developing (TD) or CD groups with or without elevated CU traits (CD/HCU, CD/LCU, respectively) using youth- A nd parent-reports of parenting behavior. At the group level, both CD/HCU and CD/LCU were associated with high negative and low positive parenting relative to TD. However, only positive parenting differed between the CD/HCU and CD/LCU groups. In classification analyses, performance was best when distinguishing CD/HCU from TD groups and poorest when distinguishing CD/HCU from CD/LCU groups. Positive and negative parenting were both relevant when distinguishing CD/HCU from TD, negative parenting was most relevant when distinguishing between CD/LCU and TD, and positive parenting was most relevant when distinguishing CD/HCU from CD/LCU groups. These findings suggest that while positive parenting distinguishes between CD/HCU and CD/LCU, negative parenting is associated with both CD subtypes. These results highlight the importance of considering multiple parenting behaviors in CD with varying levels of CU traits in late childhood/adolescence

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation. To better understand their malignancy, we investigated how AT/RT-specific DNA hyper-methylation was associated with gene expression and altered transcription factor binding and how it is linked to upstream regulation. Medulloblastomas, choroid plexus tumors, pluripo-tent stem cells, and fetal brain were used as references. A part of the genomic regions, which were hypermethylated in AT/RTs similarly as in pluripotent stem cells and demethylated in the fetal brain, were targeted by neural transcriptional regulators. AT/RT-unique DNA hypermethylation was associated with poly-comb repressive complex 2 and linked to suppressed genes with a role in neural development and tumorigenesis. Activity of the several NEUROG/NEUROD pioneer factors, which are unable to bind to methylated DNA, was compromised via the suppressed expression or DNA hypermethylation of their target sites, which was also experimentally validated for NEUROD1 in medullo-blastomas and AT/RT samples. These results highlight and characterize the role of DNA hypermethylation in AT/RT malignancy and halted neural cell differentiation.Peer reviewe

Accretion Disk Parameters Determined from the Great 2015 Flare of OJ 287

In the binary black hole model of OJ. 287, the secondary black hole orbits a much more massive primary, and impacts on the primary accretion disk at predictable times. We update the parameters of the disk, the viscosity, alpha, and the mass accretion rate, . We find alpha = 0.26 +/- 0.1 and = 0.08 +/- 0.04 in Eddington units. The former value is consistent with Coroniti, and the latter with Marscher & Jorstad. Predictions are made for the 2019 July 30 superflare in OJ. 287. We expect that it will take place simultaneously at the Spitzer infrared channels, as well as in the optical, and that therefore the timing of the flare in optical can be accurately determined from Spitzer observations. We also discuss in detail the light curve of the 2015 flare, and find that the radiating volume has regions where bremsstrahlung dominates, as well as regions that radiate primarily in synchrotron radiation. The former region produces the unpolarized first flare, while the latter region gives rise to a highly polarized second flare.Peer reviewe

Accretion Disk Parameters Determined from the Great 2015 Flare of OJ 287

In the binary black hole model of OJ 287, the secondary black hole orbits a much more massive primary, and impacts on the primary accretion disk at predictable times. We update the parameters of the disk, the viscosity, α, and the mass accretion rate, m. We find α = 0.26±0.1 and m=0.08±0.04 in Eddington units. The former value is consistent with Coroniti, and the latter with Marscher & Jorstad. Predictions are made for the 2019 July 30 superflare in OJ 287. We expect that it will take place simultaneously at the Spitzer infrared channels, as well as in the optical, and that therefore the timing of the flare in optical can be accurately determined from Spitzer observations. We also discuss in detail the light curve of the 2015 flare, and find that the radiating volume has regions where bremsstrahlung dominates, as well as regions that radiate primarily in synchrotron radiation. The former region produces the unpolarized first flare, while the latter region gives rise to a highly polarized second flare

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention