Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP.

We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P ( www.ebi.ac.uk/gene2phenotype ) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance

Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32

Hearing loss is often caused by death of the mechanosensory hair cells of the inner ear. Hair cells are susceptible to death caused by aging, noise trauma, and ototoxic drugs, including the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Ototoxic drugs result in permanent hearing loss for over 500 000 Americans annually. We showed previously that induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. In order to begin to translate these findings into a clinical therapy aimed at inhibiting ototoxic drug-induced hearing loss, we have now examined a pharmacological HSP inducer, celastrol. Celastrol induced upregulation of HSPs in utricles, and it provided significant protection against aminoglycoside-induced hair cell death in vitro and in vivo. Moreover, celastrol inhibited hearing loss in mice receiving systemic aminoglycoside treatment. Our data indicate that the major heat shock transcription factor HSF-1 is not required for celastrol-mediated protection. HSP32 (also called heme oxygenase-1, HO-1) is the primary mediator of the protective effect of celastrol. HSP32/HO-1 inhibits pro-apoptotic c-Jun N-terminal kinase (JNK) activation and hair cell death. Taken together, our data indicate that celastrol inhibits aminoglycoside ototoxicity via HSP32/HO-1 induction

EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders

BACKGROUND: Genomic variant prioritisation is one of the most significant bottlenecks to mainstream genomic testing in healthcare. Tools to improve precision while ensuring high recall are critical to successful mainstream clinical genomic testing, in particular for whole genome sequencing where millions of variants must be considered for each patient. METHODS: We developed EyeG2P, a publicly available database and web application using the Ensembl Variant Effect Predictor. EyeG2P is tailored for efficient variant prioritisation for individuals with inherited ophthalmic conditions. We assessed the sensitivity of EyeG2P in 1234 individuals with a broad range of eye conditions who had previously received a confirmed molecular diagnosis through routine genomic diagnostic approaches. For a prospective cohort of 83 individuals, we assessed the precision of EyeG2P in comparison with routine diagnostic approaches. For 10 additional individuals, we assessed the utility of EyeG2P for whole genome analysis. RESULTS: EyeG2P had 99.5% sensitivity for genomic variants previously identified as clinically relevant through routine diagnostic analysis (n=1234 individuals). Prospectively, EyeG2P enabled a significant increase in precision (35% on average) in comparison with routine testing strategies (p<0.001). We demonstrate that incorporation of EyeG2P into whole genome sequencing analysis strategies can reduce the number of variants for analysis to six variants, on average, while maintaining high diagnostic yield. CONCLUSION: Automated filtering of genomic variants through EyeG2P can increase the efficiency of diagnostic testing for individuals with a broad range of inherited ophthalmic disorders

Dense gas in nearby galaxies XVI. The nuclear starburst environment in NGC4945

A multi-line millimeter-wave study of the nearby starburst galaxy NGC 4945 has been carried out using the Swedish-ESO Submillimeter Telescope (SEST). The study covers the frequency range from 82 GHz to 354 GHz and includes 80 transitions of 19 molecules. 1.3 mm continuum data of the nuclear source are also presented. A large number of molecular species indicate the presence of a prominent high density interstellar gas component characterized by $n_{\rm H_2}\sim10^5$ cm$^{-3}$. Abundances of molecular species are calculated and compared with abundances observed toward the starburst galaxies NGC 253 and M 82 and galactic sources. Apparent is an `overabundance' of HNC in the nuclear environment of NGC 4945. While the HNC/HCN $J$=1--0 line intensity ratio is $\sim$0.5, the HNC/HCN abundance ratio is $\sim$1. While HCN is subthermally excited ($T_{\rm ex}\sim$8 K), CN is even less excited ($T_{\rm ex}\sim$3--4 K), indicating that it arises from a less dense gas component and that its $N$=2--1 line can be optically thin even though its $N$=1--0 emission is moderately optically thick. Overall, fractional abundances of NGC 4945 suggest that the starburst has reached a stage of evolution that is intermediate between those observed in NGC 253 and M 82. Carbon, nitrogen, oxygen and sulfur isotope ratios are also determined. Within the limits of uncertainty, carbon and oxygen isotope ratios appear to be the same in the nuclear regions of NGC 4945 and NGC 253. High $^{18}$O/$^{17}$O, low $^{16}$O/$^{18}$O and $^{14}$N/$^{15}$N and perhaps also low $^{32}$S/$^{34}$S ratios appear to be characteristic properties of a starburst environment in which massive stars have had sufficient time to affect the isotopic composition of the surrounding interstellar medium.Comment: 26 pages, 16 figures, accepted bt A&

A CH3CN and HCO+ survey towards southern methanol masers associated with star formation

We present the initial results of a 3-mm spectral line survey towards 83 methanol maser selected massive star-forming regions. Here we report observations of the J=5-4 and 6-5 rotational transitions of methyl cyanide (CH3CN) and the J=1-0 transition of HCO+and H13CO+. CH3CN emission is detected in 58 sources (70 %) of our sample). We estimate the temperature and column density for 37 of these using the rotational diagram method. The temperatures we derive range from 28-166 K, and are lower than previously reported temperatures, derived from higher J transitions. We find that CH3CN is brighter and more commonly detected towards ultra-compact HII (UCHII) regions than towards isolated maser sources. Detection of CH3CN towards isolated maser sources strongly suggests that these objects are internally heated and that CH3CN is excited prior to the UCHII phase of massive star-formation. HCO+ is detected towards 82 sources (99 % of our sample), many of which exhibit asymmetric line profiles compared to H13CO+. Skewed profiles are indicative of inward or outward motions, however, we find approximately equal numbers of red and blue-skewed profiles among all classes. Column densities are derived from an analysis of the HCO+ and H13CO+ line profiles. 80 sources have mid-infrared counterparts: 68 seen in emission and 12 seen in absorption as `dark clouds'. Seven of the twelve dark clouds exhibit asymmetric HCO+ profiles, six of which are skewed to the blue, indicating infalling motions. CH3CN is also common in dark clouds, where it has a 90 % detection rate.Comment: 29 pages, 16 figures. Accepted for publication in MNRAS. For associated online figures please see http://www.phys.unsw.edu.au/~crp/papers/cpurcell_2005_online.pd

A realist evaluation of the role of communities of practice in changing healthcare practice

<p>Abstract</p> <p>Background</p> <p>Healthcare organisations seeking to manage knowledge and improve organisational performance are increasingly investing in communities of practice (CoPs). Such investments are being made in the absence of empirical evidence demonstrating the impact of CoPs in improving the delivery of healthcare. A realist evaluation is proposed to address this knowledge gap. Underpinned by the principle that outcomes are determined by the context in which an intervention is implemented, a realist evaluation is well suited to understand the role of CoPs in improving healthcare practice. By applying a realist approach, this study will explore the following questions: What outcomes do CoPs achieve in healthcare? Do these outcomes translate into improved practice in healthcare? What are the contexts and mechanisms by which CoPs improve healthcare?</p> <p>Methods</p> <p>The realist evaluation will be conducted by developing, testing, and refining theories on how, why, and when CoPs improve healthcare practice. When collecting data, context will be defined as the setting in which the CoP operates; mechanisms will be the factors and resources that the community offers to influence a change in behaviour or action; and outcomes will be defined as a change in behaviour or work practice that occurs as a result of accessing resources provided by the CoP.</p> <p>Discussion</p> <p>Realist evaluation is being used increasingly to study social interventions where context plays an important role in determining outcomes. This study further enhances the value of realist evaluations by incorporating a social network analysis component to quantify the structural context associated with CoPs. By identifying key mechanisms and contexts that optimise the effectiveness of CoPs, this study will contribute to creating a framework that will guide future establishment and evaluation of CoPs in healthcare.</p

Culture, government, and spatiality: re-assessing the 'Foucault effect' in cultural-policy studies

This article critically discusses the reconceptualization of culture and governmentality in recent Australian ‘cultural–policy studies’. It argues that the further development of this conceptualization requires a more careful consideration of the complex relations between culture, power and the different spatialities of social practices. The assumptions of this literature regarding social-democratic public institutions and the nation-state are critically addressed in the light of contemporary processes of globalization. It is argued that the use made of Foucault in this paradigm privileges a model of disciplinary power which is dependent on a particular spatialization of social subjects and technologies of the self. As a result, an uncritical application of this model to all cultural practices supports a far too coherent image of practices of ‘government’ in producing sought-after subject-effects. It is suggested that the different articulations of spatio-temporal presence and absence in cultural technologies require a less totalizing understanding of the forms of power exercised through governmental practices

The MPI Facial Expression Database — A Validated Database of Emotional and Conversational Facial Expressions

The ability to communicate is one of the core aspects of human life. For this, we use not only verbal but also nonverbal signals of remarkable complexity. Among the latter, facial expressions belong to the most important information channels. Despite the large variety of facial expressions we use in daily life, research on facial expressions has so far mostly focused on the emotional aspect. Consequently, most databases of facial expressions available to the research community also include only emotional expressions, neglecting the largely unexplored aspect of conversational expressions. To fill this gap, we present the MPI facial expression database, which contains a large variety of natural emotional and conversational expressions. The database contains 55 different facial expressions performed by 19 German participants. Expressions were elicited with the help of a method-acting protocol, which guarantees both well-defined and natural facial expressions. The method-acting protocol was based on every-day scenarios, which are used to define the necessary context information for each expression. All facial expressions are available in three repetitions, in two intensities, as well as from three different camera angles. A detailed frame annotation is provided, from which a dynamic and a static version of the database have been created. In addition to describing the database in detail, we also present the results of an experiment with two conditions that serve to validate the context scenarios as well as the naturalness and recognizability of the video sequences. Our results provide clear evidence that conversational expressions can be recognized surprisingly well from visual information alone. The MPI facial expression database will enable researchers from different research fields (including the perceptual and cognitive sciences, but also affective computing, as well as computer vision) to investigate the processing of a wider range of natural facial expressions

Ensembl 2014

Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training