A conserved Polϵ binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1

Defects during chromosome replication in eukaryotes activate a signaling pathway called the S-phase checkpoint, which produces a multifaceted response that preserves genome integrity at stalled DNA replication forks. Work with budding yeast showed that the ‘alternative clamp loader’ known as Ctf18-RFC acts by an unknown mechanism to activate the checkpoint kinase Rad53, which then mediates much of the checkpoint response. Here we show that budding yeast Ctf18-RFC associates with DNA polymerase epsilon, via an evolutionarily conserved ‘Pol ϵ binding module’ in Ctf18-RFC that is produced by interaction of the carboxyl terminus of Ctf18 with the Ctf8 and Dcc1 subunits. Mutations at the end of Ctf18 disrupt the integrity of the Pol ϵ binding module and block the S-phase checkpoint pathway, downstream of the Mec1 kinase that is the budding yeast orthologue of mammalian ATR. Similar defects in checkpoint activation are produced by mutations that displace Pol ϵ from the replisome. These findings indicate that the association of Ctf18-RFC with Pol ϵ at defective replication forks is a key step in activation of the S-phase checkpoint

Exploring the interactions underlying flow states: A connecting analysis of flow occurrence in European Tour golfers

Objectives: Research to date has identified a range of factors suggested to facilitate flow states in sport. However, less attention has focused on how exactly those facilitating factors influence the occurrence of flow. Therefore, this study aimed to explore the specific ways in which such facilitators influenced flow occurrence in European Tour golfers. Design: Qualitative design. Method: Ten full-time golfers from the European Tour (M age=37; SD=13.08) participated in semi-structured interviews investigating the occurrence of their flow states. Data were interpreted using an iterative process of thematic and connecting analyses. Results: Ten facilitators of flow were identified, of which commitment and the caddie have not been reported previously. Twenty four connecting links were identified in the data, through which the caddie, effective preparation, and high-quality performance appeared to be most influential for flow occurrence. Confidence and concentration also emerged as key constructs underlying the flow experience in this setting. Conclusion: A central contribution of this study is the identification of ways in which facilitating factors could influence flow occurrence in elite golf. This process adds detail to understanding of flow occurrence, and moves beyond simply identifying factors which are associated with the experience. As such, connecting analysis is proposed as an additional strategy for qualitatively investigating flow occurrence in sport. Results are discussed in relation to previous literature, and recommendations are identified for researchers, athletes, coaches and practitioners

Implementation of U.K. Earth system models for CMIP6

We describe the scientific and technical implementation of two models for a core set of experiments contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6). The models used are the physical atmosphere-land-ocean-sea ice model HadGEM3-GC3.1 and the Earth system model UKESM1 which adds a carbon-nitrogen cycle and atmospheric chemistry to HadGEM3-GC3.1. The model results are constrained by the external boundary conditions (forcing data) and initial conditions.We outline the scientific rationale and assumptions made in specifying these. Notable details of the implementation include an ozone redistribution scheme for prescribed ozone simulations (HadGEM3-GC3.1) to avoid inconsistencies with the model's thermal tropopause, and land use change in dynamic vegetation simulations (UKESM1) whose influence will be subject to potential biases in the simulation of background natural vegetation.We discuss the implications of these decisions for interpretation of the simulation results. These simulations are expensive in terms of human and CPU resources and will underpin many further experiments; we describe some of the technical steps taken to ensure their scientific robustness and reproducibility

Theta Rhythms Coordinate Hippocampal–Prefrontal Interactions in a Spatial Memory Task

Decision-making requires the coordinated activity of diverse brain structures. For example, in maze-based tasks, the prefrontal cortex must integrate spatial information encoded in the hippocampus with mnemonic information concerning route and task rules in order to direct behavior appropriately. Using simultaneous tetrode recordings from CA1 of the rat hippocampus and medial prefrontal cortex, we show that correlated firing in the two structures is selectively enhanced during behavior that recruits spatial working memory, allowing the integration of hippocampal spatial information into a broader, decision-making network. The increased correlations are paralleled by enhanced coupling of the two structures in the 4- to 12-Hz theta-frequency range. Thus the coordination of theta rhythms may constitute a general mechanism through which the relative timing of disparate neural activities can be controlled, allowing specialized brain structures to both encode information independently and to interact selectively according to current behavioral demands

Choice of forecast scenario impacts the carbon allocation at the same global warming levels

The anthropogenic carbon distribution between the atmosphere, land surface and ocean varies significantly with the choice of scenario for identical changes in mean global surface temperature. Moving to a lower CO2 emissions scenario means that warming levels occur later, and with significantly less carbon in the three main carbon reservoirs. After 2 °C of warming, the multi-model mean ocean allocation can be up to 3 % different between scenarios, or 36 Pg in total with an even larger difference in some single model means. For the UKESM1 model, the difference between the minimum and maximum atmospheric fraction at the 2 °C Global Warming Level (GWL) is 3.6 %. This is equivalent to 50 Pg of additional carbon in the atmosphere, or the equivalent of five years of our current global total emissions. In the lower CO2 concentration scenarios, SSP1-1.9 and SSP1-2.6, the ocean fraction grows over time while the the land surface fraction remains constant. In the higher CO2 concentration scenarios, SSP2-4.5, SSP3-7.0 and SSP5-8.5, the ocean fraction remains constant over time while the the land surface fraction decreases over time. Higher equilibrium climate sensitivity (ECS) models reach the GWLs sooner, and with lower atmospheric CO2 than lower sensitivity models. However, the choice of scenario has a much larger impact on the percentage carbon allocation at a given warming level than the individual model's ECS

Improving quality of breast cancer surgery through development of a national breast cancer surgical outcomes (BRCASO) research database

<p>Abstract</p> <p>Background</p> <p>Common measures of surgical quality are 30-day morbidity and mortality, which poorly describe breast cancer surgical quality with extremely low morbidity and mortality rates. Several national quality programs have collected additional surgical quality measures; however, program participation is voluntary and results may not be generalizable to all surgeons. We developed the Breast Cancer Surgical Outcomes (BRCASO) database to capture meaningful breast cancer surgical quality measures among a non-voluntary sample, and study variation in these measures across providers, facilities, and health plans. This paper describes our study protocol, data collection methods, and summarizes the strengths and limitations of these data.</p> <p>Methods</p> <p>We included 4524 women ≥18 years diagnosed with breast cancer between 2003-2008. All women with initial breast cancer surgery performed by a surgeon employed at the University of Vermont or three Cancer Research Network (CRN) health plans were eligible for inclusion. From the CRN institutions, we collected electronic administrative data including tumor registry information, Current Procedure Terminology codes for breast cancer surgeries, surgeons, surgical facilities, and patient demographics. We supplemented electronic data with medical record abstraction to collect additional pathology and surgery detail. All data were manually abstracted at the University of Vermont.</p> <p>Results</p> <p>The CRN institutions pre-filled 30% (22 out of 72) of elements using electronic data. The remaining elements, including detailed pathology margin status and breast and lymph node surgeries, required chart abstraction. The mean age was 61 years (range 20-98 years); 70% of women were diagnosed with invasive ductal carcinoma, 20% with ductal carcinoma in situ, and 10% with invasive lobular carcinoma.</p> <p>Conclusions</p> <p>The BRCASO database is one of the largest, multi-site research resources of meaningful breast cancer surgical quality data in the United States. Assembling data from electronic administrative databases and manual chart review balanced efficiency with high-quality, unbiased data collection. Using the BRCASO database, we will evaluate surgical quality measures including mastectomy rates, positive margin rates, and partial mastectomy re-excision rates among a diverse, non-voluntary population of patients, providers, and facilities.</p