The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

Replication fork stalling and accumulation of single-stranded DNA trigger the S phase checkpoint, a signalling cascade that, in budding yeast, leads to the activation of the Rad53 kinase. Rad53 is essential in maintaining cell viability, but its targets of regulation are still partially unknown. Here we show that Rad53 drives the hyper-SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε, principally following replication forks stalling induced by nucleotide depletion. Pol2 is the main target of SUMOylation within the replisome and its modification requires the SUMO-ligase Mms21, a subunit of the Smc5/6 complex. Moreover, the Smc5/6 complex co-purifies with Pol ε, independently of other replisome components. Finally, we map Pol2 SUMOylation to a single site within the N-terminal catalytic domain and identify a SUMO-interacting motif at the C-terminus of Pol2. These data suggest that the S phase checkpoint regulate Pol ε during replication stress through Pol2 SUMOylation and SUMO-binding abilit

Kinematic Sunyaev-Zel'dovich effect with ACT, DES, and BOSS: A novel hybrid estimator

The kinematic and thermal Sunyaev-Zel'dovich (kSZ and tSZ) effects probe the abundance and thermodynamics of ionized gas in galaxies and clusters. We present a new hybrid estimator to measure the kSZ effect by combining cosmic microwave background temperature anisotropy maps with photometric and spectroscopic optical survey data. The method interpolates a velocity reconstruction from a spectroscopic catalog at the positions of objects in a photometric catalog, which makes it possible to leverage the high number density of the photometric catalog and the precision of the spectroscopic survey. Combining this hybrid kSZ estimator with a measurement of the tSZ effect simultaneously constrains the density and temperature of free electrons in the photometrically selected galaxies. Using the 1000 deg2 of overlap between the Atacama Cosmology Telescope (ACT) Data Release 5, the first three years of data from the Dark Energy Survey (DES), and the Baryon Oscillation Spectroscopic Survey (BOSS) Data Release 12, we detect the kSZ signal at 4.8σ and reject the null (no-kSZ) hypothesis at 5.1σ. This corresponds to 2.0σ per 100,000 photometric objects with a velocity field based on a spectroscopic survey with 1/5th the density of the photometric catalog. For comparison, a recent ACT analysis using exclusively spectroscopic data from BOSS measured the kSZ signal at 2.1σ per 100,000 objects. Our derived constraints on the thermodynamic properties of the galaxy halos are consistent with previous measurements. With future surveys, such as the Dark Energy Spectroscopic Instrument and the Rubin Observatory Legacy Survey of Space and Time, we expect that this hybrid estimator could result in measurements with significantly better signal-to-noise than those that rely on spectroscopic data alone

Measurement of the mean central optical depth of galaxy clusters via the pairwise kinematic Sunyaev-Zel'dovich effect with SPT-3G and des

We infer the mean optical depth of a sample of optically selected galaxy clusters from the Dark Energy Survey via the pairwise kinematic Sunyaev-Zel'dovich (KSZ) effect. The pairwise KSZ signal between pairs of clusters drawn from the Dark Energy Survey Year-3 cluster catalog is detected at 4.1σ in cosmic microwave background temperature maps from two years of observations with the SPT-3G camera on the South Pole Telescope. After cuts, there are 24,580 clusters in the ∼1,400 deg2 of the southern sky observed by both experiments. We infer the mean optical depth of the cluster sample with two techniques. The optical depth inferred from the pairwise KSZ signal is τ¯e=(2.97±0.73)×10-3, while that inferred from the thermal SZ signal is τ¯e=(2.51±0.55stat±0.15syst)×10-3. The two measures agree at 0.6σ. We perform a suite of systematic checks to test the robustness of the analysis

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave transient was identified in data recorded by the Advanced LIGO detectors on 2015 September 14. The event candidate, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the gravitational wave data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network Circulars, giving an overview of the participating facilities, the gravitational wave sky localization coverage, the timeline and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the electromagnetic data and results of the electromagnetic follow-up campaign will be disseminated in the papers of the individual teams

Clinical management and outcome of patients with advanced NSCLC carrying EGFR mutations in Spain

BACKGROUND: Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) over chemotherapy has been demonstrated in several clinical trials, data from clinical practice is lacking and the optimal EGFR TKI to be used remains unclear. This study aims to assess the real-life diagnostic and clinical management and outcome of patients with advanced non-small-cell lung cancer (NSCLC) carrying EGFR mutations in Spain. METHODS: All consecutive patients recently diagnosed with advanced or metastatic NSCLC from April 2010 to December 2011 in 18 Spanish hospitals and carrying EGFR mutations were retrospectively evaluated. RESULTS: Between March and November 2013, a total of 187 patients were enrolled (98.3% Caucasian, 61.9% female, 54.9% never-smokers, 89.0% adenocarcinoma). Mutation testing was mainly performed on biopsy tumour tissue specimens (69.0%) using a qPCR-based test (90%) (47.0% Therascreen EGFR PCR Kit). Common sensitising mutations were detected in 79.8% of patients: 57.1% had exon 19 deletions and 22.6% exon 21 L858R point mutations. The vast majority of patients received first-line therapy (n = 168; 92.8%). EGFR TKIs were the most commonly used first-line treatment (81.5%), while chemotherapy was more frequently administered as a second- and third-line option (51.9% and 56.0%, respectively). Of 141 patients who experienced disease progression, 79 (56.0%) received second-line treatment. After disease progression on first-line TKIs (n = 112), 33.9% received chemotherapy, 8.9% chemotherapy and a TKI, and 9.8% continued TKI therapy. Most patients received first-line gefitinib (83.0%), while erlotinib was more frequently used in the second-line setting (83.0%). Progression-free survival (PFS) and overall survival (OS) in patients harbouring common mutations were 11.1 months and 20.1 months respectively (exon 19 deletions: 12.4 and 21.4 months; L858R: 8.3 and 14.5 months), and 3.9 months and 11.1 months respectively for those with rare mutations. CONCLUSION: EGFR TKIs (gefitinib and erlotinib) are used as the preferred first-line treatment while chemotherapy is more frequently administered as a second- and third-line option in routine clinical practice in Spain. In addition, efficacy data obtained in the real-life setting seem to concur with data from EGFR TKI phase III pivotal studies in NSCLC

Evidence for color dichotomy in the primordial Neptunian Trojan population

In the current model of early Solar System evolution, the stable members of the Jovian and Neptunian Trojan populations were captured into resonance from the leftover reservoir of planetesimals during the outward migration of the giant planets. As a result, both Jovian and Neptunian Trojans share a common origin with the primordial disk population, whose other surviving members constitute today’s trans-Neptunian object (TNO) populations. The cold (low inclination and small eccentricity) classical TNOs are ultra-red, while the dynamically excited “hot” (high inclination and larger eccentricity) population of TNOs contains a mixture of ultra-red and blue objects. In contrast, Jovian and Neptunian Trojans are observed to be blue. While the absence of ultra-red Jovian Trojans can be readily explained by the sublimation of volatile material from their surfaces due to the high flux of solar radiation at 5 AU, the lack of ultra-red Neptunian Trojans presents both a puzzle and a challenge to formation models. In this work we report the discovery by the Dark Energy Survey (DES) of two new dynamically stable L4 Neptunian Trojans, 2013 VX30 and 2014 UU240, both with inclinations i > 30°, making them the highest-inclination known stable Neptunian Trojans. We have measured the colors of these and three other dynamically stable Neptunian Trojans previously observed by DES, and find that 2013 VX30 is ultra-red, the first such Neptunian Trojan in its class. As such, 2013 VX30 may be a “missing link” between the Trojan and TNO populations. Using a simulation of the DES TNO detection efficiency, we find that there are 162  ±  73 Trojans with Hr  <  10 at the L4 Lagrange point of Neptune. Moreover, the blue-to-red Neptunian Trojan population ratio should be higher than 17:1. Based on this result, we discuss the possible origin of the ultra-red Neptunian Trojan population and its implications for the formation history of Neptunian Trojans