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

Insights into the structure-function relationships of dimeric C3d fragments

Cleavage of C3 to C3a and C3b plays a central role in the generation of complement-mediated defences. Although the thioester-mediated surface deposition of C3b has been well-studied, fluid phase dimers of C3 fragments remain largely unexplored. Here we show C3 cleavage results in the spontaneous formation of C3b dimers and present the first X-ray crystal structure of a disulphide-linked human C3d dimer. Binding studies reveal these dimers are capable of crosslinking complement receptor 2 and preliminary cell-based analyses suggest they could modulate B cell activation to influence tolerogenic pathways. Altogether, insights into the physiologically-relevant functions of C3d(g) dimers gained from our findings will pave the way to enhancing our understanding surrounding the importance of complement in the fluid phase and could inform the design of novel therapies for immune system disorders in the future

Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel

The impact of topical antiretrovirals for pre-exposure prophylaxis on humoral responses following HIV infection is unknown. Using a binding antibody multiplex assay, we investigated HIV-specific IgG and IgA responses to envelope glycoproteins, p24 Gag and p66, in the genital tract (GT) and plasma following HIV acquisition in women assigned to tenofovir gel (n=24) and placebo gel (n=24) in the CAPRISA 004 microbicide trial to assess if this topical antiretroviral had an impact on mucosal and systemic antibody responses. Linear mixed effect modeling and partial least squares discriminant analysis was used to identify multivariate antibody signatures associated with tenofovir use. There were significantly higher response rates to gp120 Env (P=0.03), p24 (P=0.002), and p66 (P=0.009) in plasma and GT in women assigned to tenofovir than placebo gel at multiple time points post infection. Notably, p66 IgA titers in the GT and plasma were significantly higher in the tenofovir compared with the placebo arm (P<0.05). Plasma titers for 9 of the 10 HIV-IgG specificities predicted GT levels. Taken together, these data suggest that humoral immune responses are increased in blood and GT of individuals who acquire HIV infection in the presence of tenofovir gel.United States. National Institutes of Health (AI51794)United States. National Institutes of Health (AI104387)United States. National Institutes of Health (AI115981)United States. National Institutes of Health (AI116086)United States. Agency for International Development (GP00-08-00005-00 subproject agreement PPA-09-046

Exendin-4 Improves Glycemic Control, Ameliorates Brain and Pancreatic Pathologies, and Extends Survival in a Mouse Model of Huntington's Disease

OBJECTIVE—The aim of this study was to find an effective treatment for the genetic form of diabetes that is present in some Huntington's disease patients and in Huntington's disease mouse models. Huntington's disease is a neurodegenerative disorder caused by a polyglutamine expansion within the huntingtin protein. Huntington's disease patients exhibit neuronal dysfunction/degeneration, chorea, and progressive weight loss. Additionally, they suffer from abnormalities in energy metabolism affecting both the brain and periphery. Similarly to Huntington's disease patients, mice expressing the mutated human huntingtin protein also exhibit neurodegenerative changes, motor dysfunction, perturbed energy metabolism, and elevated blood glucose levels

Towards a Learning System for University Campuses as Living Labs for Sustainability

Universities, due to their sizeable estates and populations of staff and students, as well as their connections with, and impact within, their local and wider communities, have significant environmental, social and economic impacts. There is a strong movement for universities to become leaders in driving society towards a more sustainable future, through improving the sustainability of the built environment and the universities’ practices and operations, and through their educational, research and wider community engagement missions. Around the globe the concept of ‘Living Labs’ has emerged as an instrument to integrate these different aspects to deliver sustainability improvements, through engaging multiple stakeholders in all of these areas, and through the co-creation of projects to improve the sustainability of the campus environment and operations, and to link these to the education, research, and wider community missions of the institution. This chapter describes a living, shared framework and methodology, the ‘Campus as Living Lab’ learning system, created through global participatory workshops and Living Lab literature, aimed at supporting universities and their Sustainability (Coordinating) Offices in the development and monitoring of Living Lab projects. The framework includes seven categories of supportive data collection and three levels of details to meet different requirements of potential users. The Living Lab framework presented in this chapter, aims to create value and help universities maximise the benefit of Living Lab projects within an institution, support monitoring, reflection and learning from projects, and facilitate communication with stakeholders, and the sharing of practices and learning between peers across the globe. As a living shared, framework and learning system, the framework will adapt and develop over time and within different contexts. To provide feedback and fast (practical) learning from users, the system will be further developed to facilitate transparent peer reviewing

Rad17 Plays a Central Role in Establishment of the Interaction between TopBP1 and the Rad9-Hus1-Rad1 Complex at Stalled Replication Forks

Rad17 is critical for the ATR-dependent activation of Chk1 during checkpoint responses. It is known that Rad17 loads the Rad9-Hus1-Rad1 (9-1-1) complex onto DNA. We show that Rad17 also mediates the interaction of 9-1-1 with the ATR-activating protein TopBP1 in Xenopus egg extracts. Studies with Rad17 mutants indicate that binding of ATP to Rad17 is essential for the association of 9-1-1 and TopBP1. Furthermore, hydrolysis of ATP by Rad17 is necessary for the loading of 9-1-1 onto DNA and the elevated, checkpoint-dependent accumulation of TopBP1 on chromatin. Significantly, a mutant 9-1-1 complex that cannot bind TopBP1 has a normal capacity to promote elevated accumulation of TopBP1 on chromatin. Taken together, we propose the following mechanism. First, Rad17 loads 9-1-1 onto DNA. Second, TopBP1 accumulates on chromatin in a manner that depends on both Rad17 and 9-1-1. Finally, 9-1-1 and TopBP1 dock in a Rad17-dependent manner before activation of Chk1

The Roles of Cyclin A2, B1, and B2 in Early and Late Mitotic Events

This paper presents evidence that chromatin condensation, like nuclear envelope breakdown, is brought about through the combined effects of cyclins A2 and B1, and that cyclins B1 and B2 are largely responsible for maintenance of a spindle assembly checkpoint arrest