Hypothesis driven single nucleotide polymorphism search (HyDn-SNP-S)

The advent of complete-genome genotyping across phenotype cohorts has provided a rich source of information for bioinformaticians. However the search for SNPs from this data is generally performed on a study-by-study case without any specific hypothesis of the location for SNPs that are predictive for the phenotype. We have designed a method whereby very large SNP lists (several gigabytes in size), combining several genotyping studies at once, can be sorted and traced back to their ultimate consequence in protein structure. Given a working hypothesis, researchers are able to easily search whole genome genotyping data for SNPs that link genetic locations to phenotypes. This allows a targeted search for cor- relations between phenotypes and potentially relevant systems, rather than utilizing statistical methods only. HyDn-SNP-S returns results that are less data dense, allowing more thorough analysis, including haplotype analysis. We have applied our method to correlate DNA polymerases to cancer phenotypes using four of the available cancer databases in dbGaP. Logistic regression and derived haplotype analysis indicates that ∼80 SNPs, previously overlooked, are statistically significant. Derived haplotypes from this work link POLL to breast cancer and POLG to prostate cancer with an increase in incidence of 3.01- and 9.6-fold, respectively. Molecular dynamics simulations on wild-type and one of the SNP mutants from the haplotype of POLL provide insights at the atomic level on the functional impact of this cancer related SNP. Furthermore, HyDn-SNP-S has been designed to allow application to any system. The program is available upon request from the authors

Regulating the anticancer properties of organometallic dendrimers using pyridylferrocene entities: synthesis, cytotoxicity and DNA binding studies

A new series of eight first- and second-generation heterometallic ferrocenyl-derived metal-arene metallodendrimers, containing ruthenium(II) p-cymene, ruthenium(II)-hexamethylbenzene, rhodium(III)-cyclopentadienyl or iridium(III)-cyclopentadienyl moieties have been prepared. The metallodendrimers were synthesized by first reacting DAB-(NH2)(n), (where n = 4 or 8, DAB = diaminobutane) with salicylaldehyde, and then the Schiff-base dendritic ligands were reacted in a one-pot reaction with the appropriate [(eta(6)-p-iPrC(6)H(4)Me)RuCl2](2), [(eta(6)-C6Me6)RuCl2](2), [(eta(5)-C5Me5)IrCl2](2) or [(eta(5)-C5Me5)RhCl2](2) dimers, in the presence of 4-pyridylferrocene. Heterometallic binuclear analogues were prepared as models of the larger metallodendrimers. All complexes have been characterized using analytical and spectroscopic methods. The cytotoxicity of the heterometallic metallodendrimers and their binuclear analogues were evaluated against A2780 cisplatin-sensitive and A2780cisR cisplatin-resistant human ovarian cancer cell lines and against a non-tumorigenic HEK-293 human embryonic kidney cell tine. The second generation Ru(II)-eta(6)-C6Me6 metallodendrimer is the most cytotoxic and selective compound. DNA binding experiments reveal that a possible mode-of-action of these compounds involves non-covalent interactions with DNA

Policy initiatives to address low-income households’ nutritional needs in the UK

Members of low-income households in the UK are more likely to have patterns of food and nutrient intakes that are less inclined to lead to good health outcomes in the short and long term. Health inequalities, including the likelihood of child and adulthood obesity, have long been documented in the UK and show little sign of improving so far, despite 10 years of attention from a government that has committed itself to addressing them. Following the Acheson Inquiry into Inequalities in Health (1998) in England a number of initiatives to tackle inequalities in food and diet were established, both nationally and within the devolved nations of Scotland, Wales and Northern Ireland. Nevertheless, until recently, there has been no overall strategic policy addressing the food and nutritional needs of low-income households. The present paper reviews how the problems have been constructed and understood and how they have been addressed, briefly drawing on recent evaluations of food and nutrition policies in Scotland and Wales. The contemporary challenge is to frame cross-cutting policy initiatives that move beyond simple targeting and local actions, encompass a life-course approach and recognise both the diversity of households that fall into ‘low-income’ categories and the need for ‘upstream’ intervention

The joint evolutionary histories of Wolbachia and mitochondria in Hypolimnas bolina

Background. The interaction between the Blue Moon butterfly, Hypolimnas bolina, and Wolbachia has attracted interest because of the high prevalence of male-killing achieved within the species, the ecological consequences of this high prevalence, the intensity of selection on the host to suppress the infection, and the presence of multiple Wolbachia infections inducing different phenotypes. We examined diversity in the co-inherited marker, mtDNA, and the partitioning of this between individuals of different infection status, as a means to investigate the population biology and evolutionary history of the Wolbachia infections. Results. Part of the mitochondrial COI gene was sequenced from 298 individuals of known infection status revealing ten different haplotypes. Despite very strong biological evidence that the sample represents a single species, the ten haplotypes did not fall within a monophyletic clade within the Hypolimnas genus, with one haplotype differing by 5% from the other nine. There were strong associations between infection status and mtDNA haplotype. The presence of wBol1 infection in association with strongly divergent haplotypes prompted closer examination of wBol1 genetic variation. This revealed the existence of two cryptic subtypes, wBol1a and wBol1b. The wBol1a infection, by far the most common, was in strict association with the single divergent mtDNA haplotype. The wBol1b infection was found with two haplotypes that were also observed in uninfected specimens. Finally, the wBol2 infection was associated with a large diversity of mtDNA haplotypes, most often shared with uninfected sympatric butterflies. Conclusion. This data overall supports the hypothesis that high prevalence of male-killing Wolbachia (wBol1) in H. bolina is associated with very high transmission efficiency rather than regular horizontal transmission. It also suggests this infection has undergone a recent selective sweep and was introduced in this species through introgression. In contrast, the sharing of haplotypes between wBol2-infected and uninfected individuals indicates that this strain is not perfectly transmitted and/or shows a significant level of horizontal transmission

Consciousness and the Physical World

The main file in this deposition is a pdf file containing the scanned pages of the Proceedings. Additional files OCR.txt and OCR.pdf (the latter having the same pagination as the book) are included to simplify search, etc. Because of their automated creation using software, the accuracy of the OCR files cannot be guaranteed, though some checking has been carried out. In the scanned version, entering 'go to page n' in a pdf reader will access the pair of pages 2n and 2n+1. Alternatively, go to the contents pages (accessible via 'go to page', entering 'contents' at the prompt) for the numbers to use with 'go to' for specific chapters. © By arrangement with the publishers, the editors (Brian D Josephson and Vilayanur S Ramachandran) are the present copyright holders. They grant permission for the use of the material in this book in accord with the terms of the CC licence below.Edited proceedings of an interdisciplinary symposium on consciousness held at the University of Cambridge in January 1978. The purpose of the Cambridge conference was to encourage distinguished scientists to express their views on the relationship of conscious experience to the physical world.The conference was supported by a grant from Research Corporation of New York

Translations: effects of viewpoint, feature, naming and context on identifying repeatedly copied drawings

We explored the tension between bottom – up and top – down contributions to object recognition in a collaboration between a visual artist and a cognitive psychologist. Initial pictorial renderings of objects and animals from various viewpoints were iteratively copied, and a series of drawings that changed from highly concrete images into highly abstract images was produced. In drawing identification in which sets were shown in reverse order, participants were more accurate, more confident, and quicker to correctly identify the evolving image when it was originally displayed from a canonical viewpoint with all salient features present. In drawing identification in which images were shown in random order, more abstract images could be resolved as a result of previously identifying a more concrete iteration of the same drawing. The results raise issues about the influence of viewpoint and feature on the preservation of pictorial images and about the role of labelling in the interpretation of ambiguous stimuli. In addition, the study highlights a procedure in which visual stimuli can degrade without necessitating a substantial loss of complexity

Evolution of Male-Killer Suppression in a Natural Population

Male-killing bacteria are widespread in arthropods, and can profoundly alter the reproductive biology of their host species. Here we detail the first case of complete suppression of a male killer. The nymphalid butterfly Hypolimnas bolina is infected with a strain of the bacterium Wolbachia, wBol1, which kills male host embryos in Polynesian populations, but does not do so in many areas of Southeast Asia, where both males and female adults are naturally infected, and wBol1-infected females produce a 1:1 sex ratio. We demonstrate that absence of male killing by wBol1 is associated with dominant zygotic suppression of the action of the male killer. Simulations demonstrate host suppressors of male-killer action can spread very rapidly, and historical data indicating the presence of male killing in Southeast Asia in the very recent past suggests suppressor spread has been a very recent occurrence. Thus, male killer/host interactions are much more dynamic than previously recognised, with rapid and dramatic loss of the phenotype. Our results also indicate that suppression can render male killers completely quiescent, leading to the conclusion that some species that do not currently express a male killer may have done so in the past, and thus that more species have had their biology affected by these parasites than previously believed

Galileon Hairs of Dyson Spheres, Vainshtein's Coiffure and Hirsute Bubbles

We study the fields of spherically symmetric thin shell sources, a.k.a. Dyson spheres, in a {\it fully nonlinear covariant} theory of gravity with the simplest galileon field. We integrate exactly all the field equations once, reducing them to first order nonlinear equations. For the simplest galileon, static solutions come on {\it six} distinct branches. On one, a Dyson sphere surrounds itself with a galileon hair, which far away looks like a hair of any Brans-Dicke field. The hair changes below the Vainshtein scale, where the extra galileon terms dominate the minimal gradients of the field. Their hair looks more like a fuzz, because the galileon terms are suppressed by the derivative of the volume determinant. It shuts off the `hair bunching' over the `angular' 2-sphere. Hence the fuzz remains dilute even close to the source. This is really why the Vainshtein's suppression of the modifications of gravity works close to the source. On the other five branches, the static solutions are all {\it singular} far from the source, and shuttered off from asymptotic infinity. One of them, however, is really the self-accelerating branch, and the singularity is removed by turning on time dependence. We give examples of regulated solutions, where the Dyson sphere explodes outward, and its self-accelerating side is nonsingular. These constructions may open channels for nonperturbative transitions between branches, which need to be addressed further to determine phenomenological viability of multi-branch gravities.Comment: 29+1 pages, LaTeX, 2 .pdf figure

COPD- dependent effects of genetic variation in key inflammation pathway genes on lung cancer risk

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155975/1/ijc32780.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155975/2/ijc32780-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155975/3/ijc32780_am.pd