Heat protection behaviour in the UK: Results of an online survey after the 2013 heatwave

Background: The Heatwave Plan for England provides guidance for personal and home protection measures during heatwaves. Although studies in the USA, Australia and Europe have surveyed heat-related behaviours during heatwaves, few have been conducted in the UK. This study assesses personal and housing (at-home) behaviour and housing characteristics of the UK population during the 2013 heatwave. Methods: This paper analyses data from 1497 respondents of an online survey on heat protection measures and behaviour. Participants were asked questions about their behaviour during the 2013 heatwave, the characteristics of their current housing as well as about any negative health outcomes experienced due to the hot weather. We used multinomial logit regression to analyse personal and home heat protection behaviour and logistic regression to analyse characteristics of participants' current home (installed air conditioner, curtains etc.). We stratified the outcomes by age, sex, ethnicity, income, education and regional location. Results: In 2013, for all heat-related illness (except tiredness), a higher proportion of those in the younger age groups reported symptoms compared with those in the older age groups. Women, higher income groups and those with higher education levels were found to be more likely to report always/often taking personal heat protective measures. The elderly were less likely to take some personal and home protective measures but were more likely to live in insulated homes and open windows at night to keep their home cool. Conclusion: Our study has found a high level of awareness of the actions to take during heatwaves in the UK, and has identified important demographic indicators of sections of the UK population that might benefit from additional or more targeted information. The health agencies should attempt to provide better information about heatwaves to those vulnerable (elderly, those at risk living in London, low income earners) or identify any barriers that might be preventing them from undertaking protective behaviour

Structure of the hDmc1-ssDNA filament reveals the principles of its architecture

In eukaryotes, meiotic recombination is a major source of genetic diversity, but its defects in humans lead to abnormalities such as Down's, Klinefelter's and other syndromes. Human Dmc1 (hDmc1), a RecA/Rad51 homologue, is a recombinase that plays a crucial role in faithful chromosome segregation during meiosis. The initial step of homologous recombination occurs when hDmc1 forms a filament on single-stranded (ss) DNA. However the structure of this presynaptic complex filament for hDmc1 remains unknown. To compare hDmc1-ssDNA complexes to those known for the RecA/Rad51 family we have obtained electron microscopy (EM) structures of hDmc1-ssDNA nucleoprotein filaments using single particle approach. The EM maps were analysed by docking crystal structures of Dmc1, Rad51, RadA, RecA and DNA. To fully characterise hDmc1-DNA complexes we have analysed their organisation in the presence of Ca2+, Mg2+, ATP, AMP-PNP, ssDNA and dsDNA. The 3D EM structures of the hDmc1-ssDNA filaments allowed us to elucidate the principles of their internal architecture. Similar to the RecA/Rad51 family, hDmc1 forms helical filaments on ssDNA in two states: extended (active) and compressed (inactive). However, in contrast to the RecA/Rad51 family, and the recently reported structure of hDmc1-double stranded (ds) DNA nucleoprotein filaments, the extended (active) state of the hDmc1 filament formed on ssDNA has nine protomers per helical turn, instead of the conventional six, resulting in one protomer covering two nucleotides instead of three. The control reconstruction of the hDmc1-dsDNA filament revealed 6.4 protein subunits per helical turn indicating that the filament organisation varies depending on the DNA templates. Our structural analysis has also revealed that the N-terminal domain of hDmc1 accomplishes its important role in complex formation through domain swapping between adjacent protomers, thus providing a mechanistic basis for coordinated action of hDmc1 protomers during meiotic recombination

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children

Using Multiple Microenvironments to Find Similar Ligand-Binding Sites: Application to Kinase Inhibitor Binding

The recognition of cryptic small-molecular binding sites in protein structures is important for understanding off-target side effects and for recognizing potential new indications for existing drugs. Current methods focus on the geometry and detailed chemical interactions within putative binding pockets, but may not recognize distant similarities where dynamics or modified interactions allow one ligand to bind apparently divergent binding pockets. In this paper, we introduce an algorithm that seeks similar microenvironments within two binding sites, and assesses overall binding site similarity by the presence of multiple shared microenvironments. The method has relatively weak geometric requirements (to allow for conformational change or dynamics in both the ligand and the pocket) and uses multiple biophysical and biochemical measures to characterize the microenvironments (to allow for diverse modes of ligand binding). We term the algorithm PocketFEATURE, since it focuses on pockets using the FEATURE system for characterizing microenvironments. We validate PocketFEATURE first by showing that it can better discriminate sites that bind similar ligands from those that do not, and by showing that we can recognize FAD-binding sites on a proteome scale with Area Under the Curve (AUC) of 92%. We then apply PocketFEATURE to evolutionarily distant kinases, for which the method recognizes several proven distant relationships, and predicts unexpected shared ligand binding. Using experimental data from ChEMBL and Ambit, we show that at high significance level, 40 kinase pairs are predicted to share ligands. Some of these pairs offer new opportunities for inhibiting two proteins in a single pathway

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Fine-scale spatial variability of heat-related mortality in Philadelphia County, USA, from 1983-2008: a case-series analysis

<p>Abstract</p> <p>Background</p> <p>High temperature and humidity conditions are associated with short-term elevations in the mortality rate in many United States cities. Previous research has quantified this relationship in an aggregate manner over large metropolitan areas, but within these areas the response may differ based on local-scale variability in climate, population characteristics, and socio-economic factors.</p> <p>Methods</p> <p>We compared the mortality response for 48 Zip Code Tabulation Areas (ZCTAs) comprising Philadelphia County, PA to determine if certain areas are associated with elevated risk during high heat stress conditions. A randomization test was used to identify mortality exceedances for various apparent temperature thresholds at both the city and local scale. We then sought to identify the environmental, demographic, and social factors associated with high-risk areas via principal components regression.</p> <p>Results</p> <p>Citywide mortality increases by 9.3% on days following those with apparent temperatures over 34°C observed at 7:00 p.m. local time. During these conditions, elevated mortality rates were found for 10 of the 48 ZCTAs concentrated in the west-central portion of the County. Factors related to high heat mortality risk included proximity to locally high surface temperatures, low socioeconomic status, high density residential zoning, and age.</p> <p>Conclusions</p> <p>Within the larger Philadelphia metropolitan area, there exists statistically significant fine-scale spatial variability in the mortality response to high apparent temperatures. Future heat warning systems and mitigation and intervention measures could target these high risk areas to reduce the burden of extreme weather on summertime morbidity and mortality.</p

Three New Structures of Left-Handed RadA Helical Filaments: Structural Flexibility of N-Terminal Domain Is Critical for Recombinase Activity

RecA family proteins, including bacterial RecA, archaeal RadA, and eukaryotic Dmc1 and Rad51, mediate homologous recombination, a reaction essential for maintaining genome integrity. In the presence of ATP, these proteins bind a single-strand DNA to form a right-handed nucleoprotein filament, which catalyzes pairing and strand exchange with a homologous double-stranded DNA (dsDNA), by as-yet unknown mechanisms. We recently reported a structure of RadA left-handed helical filament, and here present three new structures of RadA left-handed helical filaments. Comparative structural analysis between different RadA/Rad51 helical filaments reveals that the N-terminal domain (NTD) of RadA/Rad51, implicated in dsDNA binding, is highly flexible. We identify a hinge region between NTD and polymerization motif as responsible for rigid body movement of NTD. Mutant analysis further confirms that structural flexibility of NTD is essential for RadA's recombinase activity. These results support our previous hypothesis that ATP-dependent axial rotation of RadA nucleoprotein helical filament promotes homologous recombination

A functional perspective on machine learning via programmable induction and abduction

We present a programming language for machine learning based on the concepts of ‘induction’ and ‘abduction’ as encountered in Peirce’s logic of science. We consider the desirable features such a language must have, and we identify the ‘abductive decoupling’ of parameters as a key general enabler of these features. Both an idealised abductive calculus and its implementation as a PPX extension of OCaml are presented, along with several simple examples