Therapeutic target-site variability in α1-antitrypsin characterized at high resolution

The intrinsic propensity of [alpha]1-antitrypsin to undergo conformational transitions from its metastable native state to hyperstable forms provides a motive force for its antiprotease function. However, aberrant conformational change can also occur via an intermolecular linkage that results in polymerization. This has both loss-of-function and gain-of-function effects that lead to deficiency of the protein in human circulation, emphysema and hepatic cirrhosis. One of the most promising therapeutic strategies being developed to treat this disease targets small molecules to an allosteric site in the [alpha]1-antitrypsin molecule. Partial filling of this site impedes polymerization without abolishing function. Drug development can be improved by optimizing data on the structure and dynamics of this site. A new 1.8 Å resolution structure of [alpha]1-antitrypsin demonstrates structural variability within this site, with associated fluctuations in its upper and lower entrance grooves and ligand-binding characteristics around the innermost stable enclosed hydrophobic recess. These data will allow a broader selection of chemotypes and derivatives to be tested in silico and in vitro when screening and developing compounds to modulate conformational change to block the pathological mechanism while preserving function

K2: A new method for the detection of galaxy clusters based on CFHTLS multicolor images

We have developed a new method, K2, optimized for the detection of galaxy clusters in multicolor images. Based on the Red Sequence approach, K2 detects clusters using simultaneous enhancements in both colors and position. The detection significance is robustly determined through extensive Monte-Carlo simulations and through comparison with available cluster catalogs based on two different optical methods, and also on X-ray data. K2 also provides quantitative estimates of the candidate clusters' richness and photometric redshifts. Initially K2 was applied to 161 sq deg of two color gri images of the CFHTLS-Wide data. Our simulations show that the false detection rate, at our selected threshold, is only ~1%, and that the cluster catalogs are ~80% complete up to a redshift of 0.6 for Fornax-like and richer clusters and to z ~0.3 for poorer clusters. Based on Terapix T05 release gri photometric catalogs, 35 clusters/sq deg are detected, with 1-2 Fornax-like or richer clusters every two square degrees. Catalogs containing data for 6144 galaxy clusters have been prepared, of which 239 are rich clusters. These clusters, especially the latter, are being searched for gravitational lenses -- one of our chief motivations for cluster detection in CFHTLS. The K2 method can be easily extended to use additional color information and thus improve overall cluster detection to higher redshifts. The complete set of K2 cluster catalogs, along with the supplementary catalogs for the member galaxies, are available on request from the authors.Comment: Accepted in ApJ. 25 pages, including 10 figures. Latex with emulateapj v03/07/0

In silico assessment of potential druggable pockets on the surface of α1-Antitrypsin conformers

The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α1-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a Kd in the µM–nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation

Temperament and parental child-rearing style: unique contributions to clinical anxiety disorders in childhood

Both temperament and parental child-rearing style are found to be associated with childhood anxiety disorders in population studies. This study investigates the contribution of not only temperament but also parental child-rearing to clinical childhood anxiety disorders. It also investigates whether the contribution of temperament is moderated by child-rearing style, as is suggested by some studies in the general population. Fifty children were included (25 with anxiety disorders and 25 non-clinical controls). Child-rearing and the child’s temperament were assessed by means of parental questionnaire (Child Rearing Practices Report (CRPR) (Block in The Child-Rearing Practices Report. Institute of Human Development. University of California, Berkely, 1965; The Child-Rearing Practices Report (CRPR): a set of Q items for the description of parental socialisation attitudes and values. Unpublished manuscript. Institute of Human Development. University of California, Berkely, 1981), EAS Temperament Survey for Children (Boer and Westenberg in J Pers Assess 62:537–551, 1994; Buss and Plomin in Temperament: early developing personality traits. Lawrence Erlbaum Associates, Inc, Hillsdale, 1984s). Analysis of variance showed that anxiety-disordered children scored significantly higher on the temperamental characteristics emotionality and shyness than non-clinical control children. Hierarchical logistic regression analyses showed that temperament (emotionality and shyness) and child-rearing style (more parental negative affect, and less encouraging independence of the child) both accounted for a unique proportion of the variance of anxiety disorders. Preliminary results suggest that child-rearing style did not moderate the association between children’s temperament and childhood anxiety disorders. The limited sample size might have been underpowered to assess this interaction

Strong Ultraviolet Pulse From a Newborn Type Ia Supernova

Type Ia supernovae are destructive explosions of carbon oxygen white dwarfs. Although they are used empirically to measure cosmological distances, the nature of their progenitors remains mysterious, One of the leading progenitor models, called the single degenerate channel, hypothesizes that a white dwarf accretes matter from a companion star and the resulting increase in its central pressure and temperature ignites thermonuclear explosion. Here we report observations of strong but declining ultraviolet emission from a Type Ia supernova within four days of its explosion. This emission is consistent with theoretical expectations of collision between material ejected by the supernova and a companion star, and therefore provides evidence that some Type Ia supernovae arise from the single degenerate channel.Comment: Accepted for publication on the 21 May 2015 issue of Natur

Women take care and men take charge’: The case of leadership and gender in the Public and Commercial Services Union

This article presents the findings of a case study that aimed to understand the specific leadership styles that are valued by women and men lay representatives in the Public and Commercial Services (PCS) union and to determine the gendered implications for increasing women’s leadership and representation in trade unions. Survey responses from PCS lay representatives (reps) show the majority of women and men agreed that the leadership style they value, and makes a good union leader, is post-heroic (communal) leadership. This approach is associated with leadership characteristics such as being helpful, sensitive, and kind and are generally practised by women. This contrasts with male union leaders who are associated with a traditional, heroic (agentic) leadership style characterised by confidence, self-reliance, and decisiveness. Although some differences exist that highlight gender issues, both women and men lay reps have positive attitudes towards increasing women’s representation and participation in union leadership

The zCOSMOS Redshift Survey: the role of environment and stellar mass in shaping the rise of the morphology-density relation from z~1

For more than two decades we have known that galaxy morphological segregation is present in the Local Universe. It is important to see how this relation evolves with cosmic time. To investigate how galaxy assembly took place with cosmic time, we explore the evolution of the morphology-density relation up to redshift z~1 using about 10000 galaxies drawn from the zCOSMOS Galaxy Redshift Survey. Taking advantage of accurate HST/ACS morphologies from the COSMOS survey, of the well-characterised zCOSMOS 3D environment, and of a large sample of galaxies with spectroscopic redshift, we want to study here the evolution of the morphology-density relation up to z~1 and its dependence on galaxy luminosity and stellar mass. The multi-wavelength coverage of the field also allows a first study of the galaxy morphological segregation dependence on colour. We further attempt to disentangle between processes that occurred early in the history of the Universe or late in the life of galaxies. The zCOSMOS field benefits of high-resolution imaging in the F814W filter from the Advanced Camera for Survey (ACS). We use standard morphology classifiers, optimised for being robust against band-shifting and surface brightness dimming, and a new, objective, and automated method to convert morphological parameters into early, spiral, and irregular types. We use about 10000 galaxies down to I_AB=22.5 with a spectroscopic sampling rate of 33% to characterise the environment of galaxies up to z~1 from the 100 kpc scales of galaxy groups up to the 100 Mpc scales of the cosmic web. ABRIDGEDComment: 23 pages, 12 figures, accepted for publication in Astronomy and Astrophysic

Bayesian Wavelet Shrinkage of the Haar-Fisz Transformed Wavelet Periodogram.

It is increasingly being realised that many real world time series are not stationary and exhibit evolving second-order autocovariance or spectral structure. This article introduces a Bayesian approach for modelling the evolving wavelet spectrum of a locally stationary wavelet time series. Our new method works by combining the advantages of a Haar-Fisz transformed spectrum with a simple, but powerful, Bayesian wavelet shrinkage method. Our new method produces excellent and stable spectral estimates and this is demonstrated via simulated data and on differenced infant electrocardiogram data. A major additional benefit of the Bayesian paradigm is that we obtain rigorous and useful credible intervals of the evolving spectral structure. We show how the Bayesian credible intervals provide extra insight into the infant electrocardiogram data

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself