Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice

INTRODUCTION Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome. METHODS Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues. RESULTS Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both nulliparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and nulliparous donors. CONCLUSION Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.This work was supported by grants from the US Army Medical Research and Materiel Command (W81XWH0410385 to KAD and DAMD17-01-1-0315 to ACB) and the National Institutes of Health (RO1-CA095164 to DJJ)

Electronic Footprints in the Sand: Technologies for Assisting Domestic Violence Survivors

With the rapid growth and spread of Internet-based social support systems, the impact that these systems can make to society – be it good or bad – has become more significant and can make a real difference to people’s lives. As such, various aspects of these systems need to be carefully investigated and analysed, including their security/privacy issues. In this paper, we present our work in designing and implementing various technological features that can be used to assist domestic violence survivors in obtaining help without leaving traces which might lead to further violence from their abuser. This case study serves as the core of our paper, in which we outline our approach, various de- sign considerations – including difficulties in keeping browsing history private, our currently implemented solutions (single use URL, targeted history sanitita- tion agent, and secret graphical gateway), as well as novel ideas for future work (including location-based service advertising and deployment in the wild)

Transportation Energy Futures Series. Effects of the Built Environment on Transportation. Energy Use, Greenhouse Gas Emissions, and Other Factors

Planning initiatives in many regions and communities aim to reduce transportation energy use, decrease emissions, and achieve related environmental benefits by changing land use. This report reviews and summarizes findings from existing literature on the relationship between the built environment and transportation energy use and greenhouse gas emissions, identifying results trends as well as potential future actions. The indirect influence of federal transportation and housing policies, as well as the direct impact of municipal regulation on land use are examined for their effect on transportation patterns and energy use. Special attention is given to the 'four D' factors of density, diversity, design and accessibility. The report concludes that policy-driven changes to the built environment could reduce transportation energy and GHG emissions from less than 1% to as much as 10% by 2050, the equivalent of 16%-18% of present-day urban light-duty-vehicle travel. This is one of a series of reports produced as a result of the Transportation Energy Futures (TEF) project, a Department of Energy-sponsored multi-agency project initiated to pinpoint underexplored strategies for abating GHGs and reducing petroleum dependence related to transportation

Mapping Children's Discussions of Evidence in Science to Assess Collaboration and Argumentation

The research reported in this paper concerns the development of children's skills of interpreting and evaluating evidence in science. Previous studies have shown that school teaching often places limited emphasis on the development of these skills, which are necessary for children to engage in scientific debate and decision-making. The research, undertaken in the UK, involved four collaborative decision-making activities to stimulate group discussion, each was carried out with five groups of four children (10-11 years old). The research shows how the children evaluated evidence for possible choices and judged whether their evidence was sufficient to support a particular conclusion or the rejection of alternative conclusions. A mapping technique was developed to analyse the discussions and identify different "levels" of argumentation. The authors conclude that suitable collaborative activities that focus on the discussion of evidence can be developed to exercise children's ability to argue effectively in making decisions

Multiphoton Lithography of Nanocrystalline Platinum and Palladium for Site-Specific Catalysis in 3D Microenvironments

Integration of catalytic nanostructured platinum and palladium within 3D microscale structures or fluidic environments is important for systems ranging from micropumps to microfluidic chemical reactors and energy converters. We report a straightforward procedure to fabricate microscale patterns of nanocrystalline platinum and palladium using multiphoton lithography. These materials display excellent catalytic, electrical, and electrochemical properties, and we demonstrate high-resolution integration of catalysts within 3D defined microenvironments to generate directed autonomous particle and fluid transport.Engineering and Applied Science

Bio-inspired Murray materials for mass transfer and activity

Both plants and animals possess analogous tissues containing hierarchical networks of pores, with pore size ratios that have evolved to maximize mass transport and rates of reactions. The underlying physical principles of this optimized hierarchical design are embodied in Murray’s law. However, we are yet to realize the benefit of mimicking nature’s Murray networks in synthetic materials due to the challenges in fabricating vascularized structures. Here we emulate optimum natural systems following Murray’s law using a bottom-up approach. Such bio-inspired materials, whose pore sizes decrease across multiple scales and finally terminate in size-invariant units like plant stems, leaf veins and vascular and respiratory systems provide hierarchical branching and precise diameter ratios for connecting multi-scale pores from macro to micro levels. Our Murray material mimics enable highly enhanced mass exchange and transfer in liquid–solid, gas–solid and electrochemical reactions and exhibit enhanced performance in photocatalysis, gas sensing and as Li-ion battery electrodes.B.-L.S. acknowledges the Chinese Central Government for an ‘Expert of the State’ position in the Program of the ‘Thousand Talents’ and a Life membership at Clare Hall, University of Cambridge. Y.L. acknowledges Hubei Provincial Department of Education for the ‘Chutian Scholar’ program. T.H. acknowledges support from the Royal Academy of Engineering (Graphlex). This work is financially supported by the National Key Research and Development Program of China (2016YFA0202602), Chinese Ministry of Education in a framework of the Changjiang Scholar Innovative Research Team Program (IRT_15R52) and the International Science & Technology Cooperation Program of China (2015DFE52870). This work is also supported by the project supported by State Key Laboratory of Advanced Technology for Materials Synthesis and Processing (Wuhan University of Technology), and Shenzhen Basic Research Program (No. JCYJ20160422091418366). C.J.B. and D.D. acknowledge support from the Department of Energy Office of Science Basic Energy Sciences Catalysis and Materials Science and Engineering programs, the Air Force Office of Scientific Research, and the Sandia National Laboratories Lab Directed R&D program

Was Sinn Féin dying? A quantitative post-mortem of the party's decline and the emergence of Fianna Fáil

This article calls for a reappraisal of the consensus surrounding the split within Sinn Féin in 1926 that led to the foundation of Fianna Fáil. It demonstrates that quantitative factors cited to demonstrate Sinn Féin’s “terminal” decline – finances, cumann numbers, and election results – and to explain de Valera’s decision to leave Sinn Féin and establish a rival republican organisation, Fianna Fáil, do not provide sufficient objective grounds to explain the republican leader’s actions. This article demonstrates that Sinn Féin’s election results during the period in question (1923-1926) were encouraging and the decline in finances and cumann numbers can be explained by the fact that the base year used to compare progress was 1923, an election year. Moreover, this article compares the performance of Sinn Féin to the first five years of Fianna Fáil (1926-1931) to show that what has been interpreted as terminal decline can also be attributed to normal inter-election lulls in party activity. Correspondingly, subjective factors – e.g. personal rivalries, differences in ideology, organisational style and levels of patience in terms of achieving political power – were most likely the determining factors rather than organisational decline

Building a Sustainable Approach to Mental Health Work in Schools

Sustainability is a major challenge to mental health work in schools, and many initiatives started by well-meaning individuals and agencies fade quickly. This paper outlines some key actions that can be taken to ensure that mental health work is sustained, as well as introduced, in schools. These actions include demonstrating that mental health work meets educational goals such as learning and the management of behaviour, using a positive model of mental well-being to which it is easy for those who work in schools to relate, using mentalhealth experts as part of a team, forging alliances with other agencies and working with a whole-school approach. Such approaches are more likely to meet the needs of people with more severe mental problems and provide a more stable platform for specialist interventions than targeted programmes. The paper goes on to suggest some practical steps to sustain work at the school level. These steps include assessing the current position, developing the vision, identifying the gaps, determining readiness and assessing the scene for change, securing consensus, planning the change, establishing criteria, and managing, evaluating and maintaining the change

Observations of Electrons from the Decay of Solar Flare Neutrons

We have found evidence for fluxes of energetic electrons in interplanetary space on board the ISEE-3 spacecraft which we interpret as the decay products of neutrons generated in a solar flare on 1980 June 21. The decay electrons arrived at the s/c shortly before the electrons from the flare and can be distinguished from the latter by their distinctive energy spectrum. The time profile of the decay electrons is in good agreement with the results from a simulation based on a scattering mean free path derived from a fit to the flare electron data. The comparison with simultaneously observed decay protons and a published direct measurement of high-energy neutrons places important constraints on the parent neutron spectrum.Comment: 4 pages (postscript), accepted by Astrophysical Journal Letter

The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM

The activation of ATR-ATRIP in response to double-stranded DNA breaks (DSBs) depends upon ATM in human cells and Xenopus egg extracts. One important aspect of this dependency involves regulation of TopBP1 by ATM. In Xenopus egg extracts, ATM associates with TopBP1 and thereupon phosphorylates it on S1131. This phosphorylation enhances the capacity of TopBP1 to activate the ATR-ATRIP complex. We show that TopBP1 also interacts with the Mre11-Rad50-Nbs1 (MRN) complex in egg extracts in a checkpoint-regulated manner. This interaction involves the Nbs1 subunit of the complex. ATM can no longer interact with TopBP1 in Nbs1-depleted egg extracts, which suggests that the MRN complex helps to bridge ATM and TopBP1 together. The association between TopBP1 and Nbs1 involves the first pair of BRCT repeats in TopBP1. In addition, the two tandem BRCT repeats of Nbs1 are required for this binding. Functional studies with mutated forms of TopBP1 and Nbs1 suggested that the BRCT-dependent association of these proteins is critical for a normal checkpoint response to DSBs. These findings suggest that the MRN complex is a crucial mediator in the process whereby ATM promotes the TopBP1-dependent activation of ATR-ATRIP in response to DSBs