Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

A collision in 2009 as the origin of the debris trail of asteroid P/2010A2

The peculiar object P/2010A2 was discovered in January 2010 and given a cometary designation because of the presence of a trail of material, although there was no central condensation or coma. The appearance of this object, in an asteroidal orbit (small eccentricity and inclination) in the inner main asteroid belt attracted attention as a potential new member of the recently recognized class of main-belt comets. If confirmed, this new object would expand the range in heliocentric distance over which main-belt comets are found. Here we report observations of P/2010A2 by the Rosetta spacecraft. We conclude that the trail arose from a single event, rather than a period of cometary activity, in agreement with independent results. The trail is made up of relatively large particles of millimetre to centimetre size that remain close to the parent asteroid. The shape of the trail can be explained by an initial impact ejecting large clumps of debris that disintegrated and dispersed almost immediately. We determine that this was an asteroid collision that occurred around 10 February 2009.

Intersectional Discrimination in EU Law - a critical reflection

This chapter introduces the concept of intersectionality in its relevance for anti-discrimination law. It illustrates the use (or non-use) of this concept by the Court of Justice, and provides examples of case law ignoring intersectional inequalities. Finally, it proposes to re-frame and re-focus EU anti-discrimination law around nodes of inequalities as a way to better address intersectional inequalities.

Detection Limits of Organic Compounds Achievable with Intense, Short-Pulse Lasers

Many organic molecules have strong absorption bands which can be accessed by ultraviolet short pulse lasers to produce efficient ionization. This resonant multiphoton ionization scheme has already been exploited as an ionization source in time-of-flight mass spectrometers used for environmental trace analysis. In the present work we quantify the ultimate potential of this technique by measuring absolute ion yields produced from the interaction of 267 nm femtosecond laser pulses with the organic molecules indole and toluene, and gases Xe, N2 and O2. Using multiphoton ionization cross sections extracted from these results, we show that the laser pulse parameters required for real-time detection of aromatic molecules at concentrations of one part per trillion in air and a limit of detection of a few attomoles are achievable with presently available commercial laser systems. The potential applications for the analysis of human breath, blood and tissue samples are discussed.

Proton irradiation of DNA nucleosides in the gas phase

The four DNA nucleosides guanosine, adenosine, cytidine and thymidine have been produced in the gas phase by a laser thermal desorption source, and irradiated by a beam of protons with 5 keV kinetic energy. The molecular ions as well as energetic neutrals formed have been analyzed by mass spectrometry in order to shed light on the ionization and fragmentation processes triggered by proton collision. A range of 8-20 eV has been estimated for the binding energy of the electron captured by the proton. Glycosidic bond cleavage between the base and sugar has been observed with a high probability for all nucleosides, resulting in predominantly intact base ions for guanosine, adenosine, and cytidine but not for thymidine where intact sugar ions are dominant. This behavior is influenced by the ionization energies of the nucleobases (G < A < C < T), which seems to determine the localization of the charge following the initial ionization. This charge transfer process can also be inferred from the production of protonated base ions, which have a similar dependence on the base ionization potential. Other dissociation pathways have also been identified, including further fragmentation of the base and sugar moieties for thymidine and guanosine, respectively, and partial breakup of the sugar ring without glycosidic bond cleavage mainly for adenosine and cytidine. These results show that charge localization following ionization by proton irradiation is important in determining dissociation pathways of isolated nucleosides, which could in turn influence direct radiation damage in DNA.

Ultrafast charge dynamics in an amino acid induced by attosecond pulses

In the past few years, attosecond techniques have been implemented for the investigation of ultrafast dynamics in molecules. The generation of isolated attosecond pulses characterized by a relatively high photon flux has opened up new possibilities in the study of molecular dynamics. In this paper, we report on experimental and theoretical results of ultrafast charge dynamics in a biochemically relevant molecule, namely, the amino acid phenylalanine. The data represent the first experimental demonstration of the generation and observation of a charge migration process in a complexmolecule, where electron dynamics precede nuclear motion. The application of attosecond technology to the investigation of electron dynamics in biologically relevant molecules represents a multidisciplinary work, which can open new research frontiers: those in which few-femtosecond and even subfemtosecond electron processes determine the fate of biomolecules. It can also open new perspectives for the development of new technologies, for example, in molecular electronics, where electron processes on an ultrafast temporal scale are essential to trigger and control the electron current on the scale of the molecule.

Ultrafast Non-Radiative Decay of Gas-Phase Nucleosides

The ultrafast photo-physical properties of DNA are crucial in providing a stable basis for life. Although the DNA bases efficiently absorb ultraviolet (UV) radiation, this energy can be dissipated to the surrounding environment by the rapid conversion of electronic energy to vibrational energy within about a picosecond. The intrinsic nature of this internal conversion process has previously been demonstrated through gas phase experiments on the bases, supported by theoretical calculations. De-excitation rates appear to be accelerated when individual bases are hydrogen bonded to solvent molecules or their complementary Watson-Crick pair. In this paper, the first gas-phase measurements of electronic relaxation in DNA nucleosides following UV excitation are reported. Using a pump-probe ionization scheme, the lifetimes for internal conversion to the ground state following excitation at 267 nm are found to be reduced by around a factor of two for adenosine, cytidine and thymidine compared with the isolated bases. These results are discussed in terms of a recent proposition that a charge transfer state provides an additional internal conversion pathway mediated by proton transfer through a sugar to base hydrogen bond.

Supervised Aggregative Feature Extraction for Big Data Time Series Regression

In many applications, and especially those where batch processes are involved, a target scalar output of interest is often dependent on one or more time series of data. With the exponential growth in data logging in modern industries such time series are increasingly available for statistical modeling in soft sensing applications. In order to exploit time series data for predictive modelling, it is necessary to summarise the information they contain as a set of features to use as model regressors. Typically this is done in an unsupervised fashion using simple techniques such as computing statistical moments, principal components or wavelet decompositions, often leading to significant information loss and hence suboptimal predictive models. In this paper, a functional learning paradigm is exploited in a supervised fashion to derive continuous, smooth estimates of time series data (yielding aggregated local information), while simultaneously estimating a continuous shape function yielding optimal predictions. The proposed Supervised Aggregative Feature Extraction (SAFE) methodology can be extended to support nonlinear predictive models by embedding the functional learning framework in a Reproducing Kernel Hilbert Spaces setting. SAFE has a number of attractive features including closed form solution and the ability to explicitly incorporate first and second order derivative information. Using simulation studies and a practical semiconductor manufacturing case study we highlight the strengths of the new methodology with respect to standard unsupervised feature extraction approaches.

Rural communities and wind farms: a contingent valuation investigation

Using the contingent valuation method, this study investigates the preferences of local people for a wind farm that is planned in the Province of Rome. We estimate the reductions in their bimonthly electrical bills over a period of time that respondents are willing to accept as compensation for the installation of the wind farm. Our results suggest that respondents who perceive that the wind farm generates substantial negative impacts on landscape beauty ask higher reductions than others, while respondents who believe that the wind farm produces economic benefits for local communities ask lower reductions than others. Finally, we find that the demand for compensative measures is influenced particularly by socio-economic factors such as age and education.

How many bad apples are in a bunch? An experimental investigation of perceived pesticide residue risks

Subjective risks of having contaminated apples elicited via the Exchangeability Method (EM) are examined in this study. In particular, as the experimental design allows us to investigate the validity of elicited risk measures, we examine the magnitude of differences between valid and invalid observations. In addition, using an econometric model, we also explore the effect of consumers’ socioeconomic status and attitudes toward food safety on subjects’ perceptions of pesticide residues in apples. Results suggest first, that consumers do not expect an increase in the number of apples containing only one pesticide residue, but, rather, in the number of those apples with traces of multiple residues. Second, we find that valid subjective risk measures do not significantly diverge from invalid ones, indicative of little effect of internal validity on the actual magnitude of subjective risks. Finally, we show that subjective risks depend on age, education, a subject’s ties to the apple industry, and consumer association membership.