An Extended Empirical Saddlepoint Approximation for Intractable Likelihoods

The challenges posed by complex stochastic models used in computational ecology, biology and genetics have stimulated the development of approximate approaches to statistical inference. Here we focus on Synthetic Likelihood (SL), a procedure that reduces the observed and simulated data to a set of summary statistics, and quantifies the discrepancy between them through a synthetic likelihood function. SL requires little tuning, but it relies on the approximate normality of the summary statistics. We relax this assumption by proposing a novel, more flexible, density estimator: the Extended Empirical Saddlepoint approximation. In addition to proving the consistency of SL, under either the new or the Gaussian density estimator, we illustrate the method using two examples. One of these is a complex individual-based forest model for which SL offers one of the few practical possibilities for statistical inference. The examples show that the new density estimator is able to capture large departures from normality, while being scalable to high dimensions, and this in turn leads to more accurate parameter estimates, relative to the Gaussian alternative. The new density estimator is implemented by the esaddle R package, which can be found on the Comprehensive R Archive Network (CRAN)

Explanation Retrieval in Semantic Networks : Understanding Spreading Activation based Recommendations

Spreading Activation is a well-known semantic search technique to determine the relevance of nodes in a semantic network. When used for decision support, meaningful explanations of semantic search results are crucial for the user’s acceptance and trust. Usually, explanations are generated based on the original network. Indeed, the data accumulated during the spreading activation process contains semantically extremely valuable information. Therefore, our approach exploits the so-called spread graph, a specific data structure that comprises the spreading progress data. In this paper, we present a three-step explanation retrieval method based on spread graphs. We show how to retrieve the most relevant parts of a network by minimization and extraction techniques and formulate meaningful explanations. The evaluation of the approach is then performed with a prototypical decision support system for automotive safety analyses

Role of VANGL1 as an effector of R-RAS

The WNT pathway plays a key role in development and disease. In addition to the better studied ß-catenin dependent pathway, WNT ligands can also activate the separate ‘non-canonical’ or Planar Cell Polarity (PCP) pathway. Perturbations in the PCP pathway contribute to the pathogenesis of a variety of diseases including cardiac and neural tube defects, and to the invasiveness of cancer cells. R-RAS subgroup GTPases share many of the properties of classical RAS GTPases including the ability to behave as oncogenes. However, they also have distinct functions of their own and how signalling and biological specificity is achieved is not fully understood. Using a proteomic approach to identify novel R-RAS subgroup effectors led to the identification of VANGL1, a WNT/PCP protein, demonstrated to be a novel R-RAS interacting protein. In this thesis, I have shown that VANGL1 functions as an effector of R-RAS and TC21. Using proteomic approaches, multiple VANGL1 interacting proteins have been identified and R-RAS, as well as selected Frizzled (FZD) receptors and the tyrosine kinase ROR2 can modulate at least some of these VANGL1 interactions. Furthermore, VANGL1 leads to the protein degradation of PRICKLE by a mechanism that remains to be determined, and R-RAS GTPases are able to inhibit this effect. Using RBD pulldown assays, I was able to show that WNT ligands and ROR2 can lead to the activation of R-RAS, and that R-RAS and TC21 are key mediators of RHO activation by WNT5a. Finally, I demonstrated that R-RAS/TC21 and VANGL1 are critically required for directed migration. The identification of R-RAS activation by WNT ligands and its interaction with VANGL1 provides an exciting new link between the R-RAS subgroup of the RAS family and the WNT/PCP pathway

The Ultraviolet Emission Properties of Five Low-Redshift Active Galactic Nuclei at High Signal to Noise and Spectral Resolution

We analyze the ultraviolet (UV) emission line and continuum properties of five low-redshift active galactic nuclei (four luminous quasars: PKS~0405$-$123, H1821+643, PG~0953+414, and 3C273, and one bright Seyfert 1 galaxy: Mrk~205). The HST spectra have higher signal-to-noise ratios (typically $\sim 60$ per resolution element) and spectral resolution ($R = 1300$) than all previously- published UV spectra used to study the emission characteristics of active galactic nuclei. We include in the analysis ground-based optical spectra covering \hb\ and the narrow [O III] $\lambda\lambda$4959,5007 doublet. The following new results are obtained: \lyb/\lya=0.03$-$0.12 for the four quasars, which is the first accurate measurement of the long-predicted \lyb\ intensity in QSOs. The cores of \lya\ and C~IV are symmetric to an accuracy of better than 2.5% within about 2000 km s$^{-1}$ of the line peak. This high degree of symmetry of \lya\ argues against models in which the broad line cloud velocity field has a significant radial component. The observed smoothness of the \lya\ and C~IV line profiles requires at least $\sim 10^4$ individual clouds if bulk velocity is the only line-broadening mechanism. The overall similarity of the \lya\ and C IV $\lambda$1549 profiles rules out models for the broad line region (BLR) with a radial distribution of virialized....Comment: 39 pages (+ 6 pages of tables + 16 of figures), AST 93/2

Production of Polarized Vector Mesons off Nuclei

Using the light-cone QCD dipole formalism we investigate manifestations of color transparency (CT) and coherence length (CL) effects in electroproduction of longitudinally (L) and transversally (T) polarized vector mesons. Motivated by forthcoming data from the HERMES experiment we predict both the A and Q^2 dependence of the L/T- ratios, for rho^0 mesons produced coherently and incoherently off nuclei. For an incoherent reaction the CT and CL effects add up and result in a monotonic A dependence of the L/T-ratio at different values of Q^2. On the contrary, for a coherent process the contraction of the CL with Q^2 causes an effect opposite to that of CT and we expect quite a nontrivial A dependence, especially at Q^2 >> m_V^2.Comment: Revtex 24 pages and 14 figure

Human 3D Airway Tissue Models for Real-Time Microscopy: Visualizing Respiratory Virus Spreading

Our knowledge about respiratory virus spreading is mostly based on monolayer cultures that hardly reflect the complex organization of the airway epithelium. Thus, there is a strong demand for biologically relevant models. One possibility to study virus spreading at the cellular level is real-time imaging. In an attempt to visualize virus spreading under somewhat more physiological conditions, Calu-3 cells and human primary fibroblasts were co-cultured submerged or as air-liquid interface (ALI). An influenza A virus (IAV) replicating well in cell culture, and carrying a red fluorescent protein (RFP) reporter gene was used for real-time imaging. Our three-dimensional (3D) models exhibited important characteristics of native airway epithelium including a basement membrane, tight junctions and, in ALI models, strong mucus production. In submerged models, first fluorescence signals appeared between 9 and 12 h post infection (hpi) with a low multiplicity of infection of 0.01. Virus spreading further proceeded in the immediate vicinity of infected cells. In ALI models, RFP was found at 22 hpi and later. Consequently, the progression of infection was delayed, in contrast to the submerged model. With these features, we believe that our 3D airway models can deliver new insights in the spreading of IAV and other respiratory viruses

M87: A Misaligned BL LAC?

The nuclear region of M87 was observed with the Faint Object Spectrograph (FOS) on the Hubble Space Telescope (HST) at 6 epochs, spanning 18 months, after the HST image quality was improved with the deployment of the corrective optics (COSTAR) in December 1993. From the FOS target acquisition data, we have established that the flux from the optical nucleus of M87 varies by a factor ~2 on time scales of ~2.5 months and by as much as 25% over 3 weeks, and remains unchanged (<= 2.5%) on time scales of ~1 day. The changes occur in an unresolved central region <= 5 pc in diameter, with the physical size of the emitting region limited by the observed time scales to a few hundred gravitational radii. The featureless continuum spectrum becomes bluer as it brightens while emission lines remain unchanged. This variability combined with the observations of the continuum spectral shape, strong relativistic boosting and the detection of significant superluminal motions in the jet, strongly suggest that M87 belongs to the class of BL Lac objects but is viewed at an angle too large to reveal the classical BL Lac properties.Comment: 12 pages, 3 Postscript figure

The association between green space and cause-specific mortality in urban New Zealand: an ecological analysis of green space utility

&lt;b&gt;Background:&lt;/b&gt; There is mounting international evidence that exposure to green environments is associated with health benefits, including lower mortality rates. Consequently, it has been suggested that the uneven distribution of such environments may contribute to health inequalities. Possible causative mechanisms behind the green space and health relationship include the provision of physical activity opportunities, facilitation of social contact and the restorative effects of nature. In the New Zealand context we investigated whether there was a socioeconomic gradient in green space exposure and whether green space exposure was associated with cause-specific mortality (cardiovascular disease and lung cancer). We subsequently asked what is the mechanism(s) by which green space availability may influence mortality outcomes, by contrasting health associations for different types of green space. &lt;b&gt;Methods:&lt;/b&gt; This was an observational study on a population of 1,546,405 living in 1009 small urban areas in New Zealand. A neighbourhood-level classification was developed to distinguish between usable (i.e., visitable) and non-usable green space (i.e., visible but not visitable) in the urban areas. Negative binomial regression models were fitted to examine the association between quartiles of area-level green space availability and risk of mortality from cardiovascular disease (n = 9,484; 1996 - 2005) and from lung cancer (n = 2,603; 1996 - 2005), after control for age, sex, socio-economic deprivation, smoking, air pollution and population density. &lt;b&gt;Results:&lt;/b&gt; Deprived neighbourhoods were relatively disadvantaged in total green space availability (11% less total green space for a one standard deviation increase in NZDep2001 deprivation score, p &#60; 0.001), but had marginally more usable green space (2% more for a one standard deviation increase in deprivation score, p = 0.002). No significant associations between usable or total green space and mortality were observed after adjustment for confounders. &lt;b&gt;Conclusion&lt;/b&gt; Contrary to expectations we found no evidence that green space influenced cardiovascular disease mortality in New Zealand, suggesting that green space and health relationships may vary according to national, societal or environmental context. Hence we were unable to infer the mechanism in the relationship. Our inability to adjust for individual-level factors with a significant influence on cardiovascular disease and lung cancer mortality risk (e.g., diet and alcohol consumption) will have limited the ability of the analyses to detect green space effects, if present. Additionally, green space variation may have lesser relevance for health in New Zealand because green space is generally more abundant and there is less social and spatial variation in its availability than found in other contexts

VLT and ACS observations of RDCS J1252.9-2927: dynamical structure and galaxy populations in a massive cluster at z=1.237

We present results from an extensive spectroscopic survey, carried out with VLT FORS, and from an extensive multiwavelength imaging data set from the HST Advanced Camera for Surveys and ground based facilities, of the cluster of galaxies RDCS J1252.9-2927. We have spectroscopically confirmed 38 cluster members in the redshift range 1.22 < z < 1.25. A cluster median redshift of z=1.237 and a rest-frame velocity dispersion of 747^{+74}_{-84} km/s are obtained. Using the 38 confirmed redshifts, we were able to resolve, for the first time at z > 1, kinematic structure. The velocity distribution, which is not Gaussian at the 95% confidence level, is consistent with two groups that are also responsible for the projected east-west elongation of the cluster. The groups are composed of 26 and 12 galaxies with velocity dispersions of 486^{+47}_{-85} km/s and 426^{+57}_{-105} km/s, respectively. The elongation is also seen in the intracluster gas and the dark matter distribution. This leads us to conclude that RDCS J1252.9-2927 has not yet reached a final virial state. We extend the analysis of the color-magnitude diagram of spectroscopic members to more than 1 Mpc from the cluster center. The scatter and slope of non-[OII]-emitting cluster members in the near-IR red sequence is similar to that seen in clusters at lower redshift. Furthermore, most of the galaxies with luminosities greater than ~ K_s*+1.5 do not show any [OII], indicating that these more luminous, redder galaxies have stopped forming stars earlier than the fainter, bluer galaxies. Our observations provide detailed dynamical and spectrophotometric information on galaxies in this exceptional high-redshift cluster, delivering an in-depth view of structure formation at this epoch only 5 Gyr after the Big Bang.Comment: 29 pages. 16 figures. ApJ accepted. Tables 2,3 and 5, figure 1 and the full figure 5 will be available in the paper and electronic editions from ApJ. v2: minor corrections to the abstract and text to match the Journal's versio