The MRN complex in double-strand break repair and telomere maintenance

AbstractGenomes are subject to constant threat by damaging agents that generate DNA double-strand breaks (DSBs). The ends of linear chromosomes need to be protected from DNA damage recognition and end-joining, and this is achieved through protein–DNA complexes known as telomeres. The Mre11–Rad50–Nbs1 (MRN) complex plays important roles in detection and signaling of DSBs, as well as the repair pathways of homologous recombination (HR) and non-homologous end-joining (NHEJ). In addition, MRN associates with telomeres and contributes to their maintenance. Here, we provide an overview of MRN functions at DSBs, and examine its roles in telomere maintenance and dysfunction

Discrete Element Modeling of Triboelectrically Charged Particles

Tribocharging of particles is common in many processes including fine powder handling and mixing, printer toner transport and dust extraction. In a lunar environment with its high vacuum and lack of water, electrostatic forces are an important factor to consider when designing and operating equipment. Dust mitigation and management is critical to safe and predictable performance of people and equipment. The extreme nature of lunar conditions makes it difficult and costly to carry out experiments on earth which are necessary to better understand how particles gather and transfer charge between each other and with equipment surfaces. DEM (Discrete Element Modeling) provides an excellent virtual laboratory for studying tribocharging of particles as well as for design of devices for dust mitigation and for other purposes related to handling and processing of lunar regolith. Theoretical and experimental work has been performed pursuant to incorporating screened Coulombic electrostatic forces into EDEM, a commercial DEM software package. The DEM software is used to model the trajectories of large numbers of particles for industrial particulate handling and processing applications and can be coupled with other solvers and numerical models to calculate particle interaction with surrounding media and force fields. While simple Coulombic force between two particles is well understood, its operation in an ensemble of particles is more complex. When the tribocharging of particles and surfaces due to frictional contact is also considered, it is necessary to consider longer range of interaction of particles in response to electrostatic charging. The standard DEM algorithm accounts for particle mechanical properties and inertia as a function of particle shape and mass. If fluid drag is neglected, then particle dynamics are governed by contact between particles, between particles and equipment surfaces and gravity forces. Consideration of particle charge and any tribocharging and electric field effects requires calculation of the forces due to these effects

Discrete Element Modeling (DEM) of Triboelectrically Charged Particles: Revised Experiments

In a previous work, the addition of basic screened Coulombic electrostatic forces to an existing commercial discrete element modeling (DEM) software was reported. Triboelectric experiments were performed to charge glass spheres rolling on inclined planes of various materials. Charge generation constants and the Q/m ratios for the test materials were calculated from the experimental data and compared to the simulation output of the DEM software. In this paper, we will discuss new values of the charge generation constants calculated from improved experimental procedures and data. Also, planned work to include dielectrophoretic, Van der Waals forces, and advanced mechanical forces into the software will be discussed

Employee share ownership in a unionised duopoly

Profit sharing schemes have been analysed assuming Cournot competition and decentralised wage negotiations, and it has been found that firms share profits in equilibrium. This paper analyses a different remuneration system: employee share ownership. We find that whether firms choose to share ownership or not depends on both the type of competition in the product market and the way in which workers organise to negotiate wages. If wage setting is decentralised, under duopolistic Cournot competition both firms share ownership. If wage setting is centralised, only one firm shares ownership if the degree to which goods are substitutes takes an intermediate value; otherwise, the two firms share ownership. In this case, if the union sets the same wage for all workers neither firm shares ownership. Therefore, centralised wage setting discourages share ownership. Fi- nally, under Bertrand competition neither firm shares ownership regardless of how workers are organised to negotiate wages.info:eu-repo/semantics/publishedVersio

Assessment of Adverse Events From the Patient Perspective in a Phase 3 Metastatic Castration-Resistant Prostate Cancer Clinical Trial

IMPORTANCE Standard adverse event (AE) reporting in oncology clinical trials has historically relied on clinician grading, which prior research has shown can lead to underestimation of rates of symptomatic AEs. Industry sponsors are beginning to implement in trials the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), which was developed to allow patients to self-report symptomatic AEs and improve the quality of symptomatic AE detection. OBJECTIVES To evaluate the feasibility of implementing PRO-CTCAE in a prespecified correlative analysis of the phase 3 COMET-2 trial and enumerate statistically significant between-group differences in symptomatic AEs using PRO-CTCAE and the CTCAE. DESIGN, SETTING, AND PARTICIPANTS This correlative study of 119 men in the randomized, double-blind, placebo-controlled phase 3 COMET-2 trial with metastatic castration-resistant prostate cancer who had undergone at least 2 prior lines of systemic treatment was conducted from March 2012 to July 2014. Participants completed PRO-CTCAE items using an automated telephone system from home prior to treatment and every 3 weeks during treatment. Statistical analysis was performed from May 2018 to June 2019. MAIN OUTCOMES AND MEASURES The proportion of patients who completed expected PRO-CTCAE self-reports was computed as a measure of feasibility. RESULTS Among the 119 men in the study (median age, 65 years [range, 44-80 years]), 534 of 587 (91.0%) expected PRO-CTCAE self-reports were completed, with consistently high rates of completion throughout participation. Rates of self-report adherence were similar between groups (cabozantinib s-maleate, 286 of 317 [90.2%]; and mitoxantrone hydrochloride-prednisone, 248 of 270 [91.9%]). Of 12 measured, patient-reported PRO-CTCAE symptomatic AEs, 4 reached statistical significance when comparing the proportion of patients with at least 1 postbaseline score greater than 0 between groups (differences ranged from 20.1% to 34.1% with higher proportions in the cabozantinib group; all P < .05), and use of a method for accounting for preexisting symptoms at baseline yielded 7 AEs with statistically significant differences between groups (differences ranged from 20.5%to 41.2%with higher proportions in the cabozantinib group; all P < .05). In the same analysis using investigator-reported CTCAE data, no statistically significant differences were found between groups for any symptomatic AEs. CONCLUSIONS AND RELEVANCE PRO-CTCAE data collection was feasible and improved the accuracy of symptomatic AE detection in a phase 3 cancer trial. This analysis adds to mounting evidence of the feasibility and value of patient-reported AEs in oncology, which should be considered for inclusion in cancer trials that incorporate AE evaluation

A Comparison of Women of Color and Non-Hispanic White Women on Factors Related to Leaving a Violent Relationship

This study compares women of color and non-Hispanic White women regarding the influence of socioeconomic status, family investment, and psychological abuse on leaving a violent relationship. It was found that most women who left stayed away for less than a month. Women of color and non-Hispanic White women did not differ in their length or rate of leaving, although women of color left more frequently when they did leave. Factors associated with leaving for both groups were threat with a weapon, psychological abuse, being single, and having fewer adults in the household. Women of color with higher socioeconomic status were less likely to leave, which was not the case for non-Hispanic White women. Non-Hispanic White women were more likely to leave if they had lived with their partners less than 5 years and had children at home.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90886/1/Lacey-Saunders-Zhang 2011-Women of color vs white women - factors in leaving violent relationahip JIV .pd

Factors influencing publication choice: why faculty choose open access

BACKGROUND: In an attempt to identify motivating factors involved in decisions to publish in open access and open archives (OA) journals, individual interviews with biomedical faculty members at the University of North Carolina at Chapel Hill (UNC-Chapel Hill) and Duke University, two major research universities, were conducted. The interviews focused on faculty identified as early adopters of OA/free full-text publishing. METHODS: Searches conducted in PubMed and PubMed Central identified faculty from the two institutions who have published works in OA/free full-text journals. The searches targeted authors with multiple OA citations during a specified 18 month period. Semi-structured interviews were conducted with the most prolific OA authors at each university. Individual interviews attempted to determine whether the authors were aware they published in OA journals, why they chose to publish in OA journals, what factors influenced their publishing decisions, and their general attitude towards OA publishing models. RESULTS & DISCUSSION: Fourteen interviews were granted and completed. Respondents included a fairly even mix of Assistant, Associate and Full professors. Results indicate that when targeting biomedical faculty at UNC-Chapel Hill and Duke, speed of publication and copyright retention are unlikely motivating factors or incentives for the promotion of OA publishing. In addition, author fees required by some open access journals are unlikely barriers or disincentives. CONCLUSION: It appears that publication quality is of utmost importance when choosing publication venues in general, while free access and visibility are specifically noted incentives for selection of OA journals. Therefore, free public availability and increased exposure may not be strong enough incentives for authors to choose open access over more traditional and respected subscription based publications, unless the quality issue is also addressed

Attributing scientific and technical progress: the case of holography

Holography, the three-dimensional imaging technology, was portrayed widely as a paradigm of progress during its decade of explosive expansion 1964–73, and during its subsequent consolidation for commercial and artistic uses up to the mid 1980s. An unusually seductive and prolific subject, holography successively spawned scientific insights, putative applications and new constituencies of practitioners and consumers. Waves of forecasts, associated with different sponsors and user communities, cast holography as a field on the verge of success—but with the dimensions of success repeatedly refashioned. This retargeting of the subject represented a degree of cynical marketeering, but was underpinned by implicit confidence in philosophical positivism and faith in technological progressivism. Each of its communities defined success in terms of expansion, and anticipated continual progressive increase. This paper discusses the contrasting definitions of progress in holography, and how they were fashioned in changing contexts. Focusing equally on reputed ‘failures’ of some aspects of the subject, it explores the varied attributes by which success and failure were linked with progress by different technical communities. This important case illuminates the peculiar post-World War II environment that melded the military, commercial and popular engagement with scientific and technological subjects, and the competing criteria by which they assessed the products of science

Population-based emergence of unfamiliar climates

Time of emergence, which characterizes when significant signals of climate change will emerge from existing variability, is a useful and increasingly common metric. However, a more useful metric for understanding future climate change in the context of past experience may be the ratio of climate signal to noise (S/N)—a measure of the amplitude of change expressed in terms of units of existing variability. Here, we present S/N projections in the context of emergent climates (termed ‘unusual’, ‘unfamiliar’ and ‘unknown’ by reference to an individual’s lifetime), highlighting sensitivity to future emissions scenarios and geographical and human groupings. We show how for large sections of the world’s population, and for several geopolitical international groupings, mitigation can delay the onset of ‘unknown’ or ‘unfamiliar’ climates by decades, and perhaps even beyond 2100. Our results demonstrate that the benefits of mitigation accumulate over several decades, a key metric of which is reducing S/N, or keeping climate as familiar as possible. A relationship is also identified between cumulative emissions and patterns of emergent climate signals. Timely mitigation will therefore provide the greatest benefits to those facing the earliest impacts, many of whom are alive now