Kinase inhibition leads to hormesis in a dual phosphorylation-dephosphorylation cycle

This is the final version of the article. Available from the publisher via the DOI in this record.Many antimicrobial and anti-tumour drugs elicit hormetic responses characterised by low-dose stimulation and high-dose inhibition. While this can have profound consequences for human health, with low drug concentrations actually stimulating pathogen or tumour growth, the mechanistic understanding behind such responses is still lacking. We propose a novel, simple but general mechanism that could give rise to hormesis in systems where an inhibitor acts on an enzyme. At its core is one of the basic building blocks in intracellular signalling, the dual phosphorylation-dephosphorylation motif, found in diverse regulatory processes including control of cell proliferation and programmed cell death. Our analytically-derived conditions for observing hormesis provide clues as to why this mechanism has not been previously identified. Current mathematical models regularly make simplifying assumptions that lack empirical support but inadvertently preclude the observation of hormesis. In addition, due to the inherent population heterogeneities, the presence of hormesis is likely to be masked in empirical population-level studies. Therefore, examining hormetic responses at single-cell level coupled with improved mathematical models could substantially enhance detection and mechanistic understanding of hormesis.Funding bodies: BBSRC (BB/J010340/1); EPSRC (EP/I00503X/1); Wellcome Trust (ISSF to University of Exeter)

Scalar form factors and nuclear interactions

The scalar-isoscalar term in the two-pion exchange $NN$ potential is abnormally large and does not respect the hierarchy of effects predicted by chiral perturbation theory. We argue that this anomaly is associated with non-perturbative effects, which are also present in the $\pi N$ scalar form factor.Comment: Talk given at the 20EFB, Pisa, Italy, September 2007. 3 pages and 4 figure

HTR4 gene structure and altered expression in the developing lung

Background: Meta-analyses of genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) spanning the 5-hydroxytryptamine receptor 4 (5-HT4R) gene (HTR4) associated with lung function. The aims of this study were to i) investigate the expression profile of HTR4 in adult and fetal lung tissue and cultured airway cells, ii) further define HTR4 gene structure and iii) explore the potential functional implications of key SNPs using a bioinformatic approach

The Size Distribution of Kuiper Belt Objects

We describe analytical and numerical collisional evolution calculations for the size distribution of icy bodies in the Kuiper Belt. For a wide range of bulk properties, initial masses, and orbital parameters, our results yield power-law cumulative size distributions, N_C propto r^{-q}, with q_L = 3.5 for large bodies with radii of 10-100 km, and q_s = 2.5-3 for small bodies with radii lesss than 0.1-1 km. The transition between the two power laws occurs at a break radius of 1-30 km. The break radius is more sensitive to the initial mass in the Kuiper Belt and the amount of stirring by Neptune than the bulk properties of individual Kuiper Belt objects (KBOs). Comparisons with observations indicate that most models can explain the observed sky surface density of KBOs for red magnitudes, R = 22-27. For R 28, the model surface density is sensitive to the amount of stirring by Neptune, suggesting that the size distribution of icy planets in the outer solar system provides independent constraints on the formation of Neptune.Comment: 24 pages of text, 12 figures; to appear in the Astronomical Journal, October 200

Effects of anthropogenic emissions on the molecular composition of urban organic aerosols: An ultrahigh resolution mass spectrometry study

Identification of the organic composition of atmospheric aerosols is necessary to develop effective air pollution mitigation strategies. However, the majority of the organic aerosol mass is poorly characterized and its detailed analysis is a major analytical challenge. In this study, we applied state-of-the-art direct infusion nano-electrospray (nanoESI) ultrahigh resolution mass spectrometry (UHRMS) and liquid chromatography ESI Quadrupole Time-of-Flight (Q-TOF) MS for the analysis of the organic fraction of fine particulate matter (PM2.5) collected at an urban location in Cork, Ireland. Comprehensive mass spectral data evaluation methods (e.g., Kendrick Mass Defect and Van Krevelen) were used to identify compound classes and mass distributions of the detected species. Up to 850 elemental formulae were identified in negative mode nanoESI-UHR-MS. Nitrogen and/or sulphur containing organic species contributed up to 40% of the total identified formulae and exhibited strong diurnal variations suggesting the importance of night-time NO3 chemistry at the site. The presence of a large number of oxidised aromatic and nitroaromatic compounds in the samples indicated a strong anthropogenic influence, i.e., from traffic emissions and domestic solid fuel (DSF) burning. Most of the identified biogenic secondary organic aerosol (SOA) compounds are later-generation nitrogen- and sulphur-containing products, indicating that SOA composition is strongly affected by anthropogenic species such as NOx and SO2. Unsaturated and saturated C12–C20 fatty acids were found to be the most abundant homologs with a composition reflecting a primary marine origin. The results of this work demonstrate that the studied site is a very complex environment affected by a variety of anthropogenic activities and natural sources.Research at the University of Cambridge was supported by a Marie Curie Intra-European fellowship (project # 254319) and the European Research Council (ERC starting grant 279405).This is the accepted version. The final version is available from Elsevier at http://www.sciencedirect.com/science/article/pii/S1352231014001472

Planet Formation in the Outer Solar System

This paper reviews coagulation models for planet formation in the Kuiper Belt, emphasizing links to recent observations of our and other solar systems. At heliocentric distances of 35-50 AU, single annulus and multiannulus planetesimal accretion calculations produce several 1000 km or larger planets and many 50-500 km objects on timescales of 10-30 Myr in a Minimum Mass Solar Nebula. Planets form more rapidly in more massive nebulae. All models yield two power law cumulative size distributions, N_C propto r^{-q} with q = 3.0-3.5 for radii larger than 10 km and N_C propto r^{-2.5} for radii less than 1 km. These size distributions are consistent with observations of Kuiper Belt objects acquired during the past decade. Once large objects form at 35-50 AU, gravitational stirring leads to a collisional cascade where 0.1-10 km objects are ground to dust. The collisional cascade removes 80% to 90% of the initial mass in the nebula in roughly 1 Gyr. This dust production rate is comparable to rates inferred for alpha Lyr, beta Pic, and other extrasolar debris disk systems.Comment: invited review for PASP, March 2002. 33 pages of text and 12 figure

‘You're kinda passing a test’: A phenomenological study of women's experiences of breastfeeding

Background: Despite an increasing research base about what helps or hinders breastfeeding, there is a dramatic drop in breastfeeding prevalence within the first 6 weeks. Aim: To explore the experiences of breastfeeding women. Methods: This study used interpretive phenomenology to research the experiences of 22 women who had all breastfed their youngest baby for at least 11 days. Data were collected using in-depth interviews when the women's babies were between 3-6 months of age. Thematic analysis was used to analyse findings. Findings: The women described tensions and mixed messages regarding breastfeeding, and contradictions between public health messages promoting breastfeeding and the support received to continue breastfeeding. The women also described how these approaches and messages affected their breastfeeding experiences, and how they managed breastfeeding as a result. Conclusions: The findings from this study revealed a patriarchal healthcare support system for breastfeeding whereby the women felt under surveillance and expected to perform to a prescribed ideal, but also a lack of support for exclusive breastfeeding after the initial postnatal period. These findings have clear implications for practice and policy

Efficient Symmetry Reduction and the Use of State Symmetries for Symbolic Model Checking

One technique to reduce the state-space explosion problem in temporal logic model checking is symmetry reduction. The combination of symmetry reduction and symbolic model checking by using BDDs suffered a long time from the prohibitively large BDD for the orbit relation. Dynamic symmetry reduction calculates representatives of equivalence classes of states dynamically and thus avoids the construction of the orbit relation. In this paper, we present a new efficient model checking algorithm based on dynamic symmetry reduction. Our experiments show that the algorithm is very fast and allows the verification of larger systems. We additionally implemented the use of state symmetries for symbolic symmetry reduction. To our knowledge we are the first who investigated state symmetries in combination with BDD based symbolic model checking

Localization of gravity on a de Sitter thick braneworld without scalar fields

In this work we present a simple thick braneworld model that is generated by an intriguing interplay between a 5D cosmological constant with a de Sitter metric induced in the 3-brane without the inclusion of scalar fields. We show that 4D gravity is localized on this brane, provide analytic expressions for the massive Kaluza-Klein (KK) fluctuation modes and also show that the spectrum of metric excitations displays a mass gap. We finally present the corrections to Newton's law due to these massive modes. This model has no naked singularities along the fifth dimension despite the existence of a mass gap in the graviton spectrum as it happens in thick branes with 4D Poincare symmetry, providing a simple model with very good features: the curvature is completely smooth along the fifth dimension, it localizes 4D gravity and the spectrum of gravity fluctuations presents a mass gap, a fact that rules out the existence of phenomenologically dangerous ultralight KK excitations in the model. We finally present our solution as a limit of scalar thick branes.Comment: 11 pages in latex, no figures, title and abstract changed, a new section and some references adde

Using honey to heal diabetic foot ulcers

Diabetic ulcers seem to be arrested in the inflammatory/proliferative stage of the healing process, allowing infection and inflammation to preclude healing. Antibiotic-resistant bacteria have become a major cause of infections, including diabetic foot infections. It is proposed here that the modern developments of an ancient and traditional treatment for wounds, dressing them with honey, provide the solution to the problem of getting diabetic ulcers to move on from the arrested state of healing. Honeys selected to have a high level of antibacterial activity have been shown to be very effective against antibiotic-resistant strains of bacteria in laboratory and clinical studies. The potent anti-inflammatory action of honey is also likely to play an important part in overcoming the impediment to healing that inflammation causes in diabetic ulcers, as is the antioxidant activity of honey. The action of honey in promotion of tissue regeneration through stimulation of angiogenesis and the growth of fibroblasts and epithelial cells, and its insulin-mimetic effect, would also be of benefit in stimulating the healing of diabetic ulcers. The availability of honey-impregnated dressings which conveniently hold honey in place on ulcers has provided a means of rapidly debriding ulcers and removing the bacterial burden so that good healing rates can be achieved with neuropathic ulcers. With ischemic ulcers, where healing cannot occur because of lack of tissue viability, these honey dressings keep the ulcers clean and prevent infection occurring