Bardet-Biedl syndrome proteins control cilia length through regulation of actin polymerisation.

Primary cilia are cellular appendages important for signal transduction and sensing the environment. Bardet-Biedl syndrome proteins form a complex that is important for several cytoskeleton-related processes such as ciliogenesis, cell migration and division. However, the mechanisms by which BBS proteins may regulate the cytoskeleton remain unclear. We discovered that Bbs4 and Bbs6 deficient renal medullary cells display a characteristic behaviour comprising poor migration, adhesion and division with an inability to form lamellipodial and filopodial extensions. Moreover, fewer mutant cells were ciliated (48% ± 6 for wild-type cells vs 23% ± 7 for Bbs4 null cells; P-value < 0.0001) and their cilia were shorter (2.55&emsp14;μm ± 0.41 for wild-type cells vs 2.16&emsp14;μm ± 0.23 for Bbs4 null cells; P-value < 0.0001). Whilst the microtubular cytoskeleton and cortical actin were intact, actin stress fibre formation was severely disrupted, forming abnormal apical stress fibre aggregates. Furthermore, we observed over-abundant focal adhesions in Bbs4, Bbs6 and Bbs8-deficient cells. In view of these findings and the role of RhoA in regulation of actin filament polymerisation, we showed that RhoA-GTP levels were highly upregulated in the absence of Bbs proteins. Upon treatment of Bbs4-deficient cells with chemical inhibitors of RhoA, we were able to restore cilia length and number as well as the integrity of the actin cytoskeleton. Together these findings indicate that Bbs proteins play a central role in the regulation of the actin cytoskeleton and control cilia length through alteration of RhoA levels

Time-Delay Interferometry

Equal-arm interferometric detectors of gravitational radiation allow phase measurements many orders of magnitude below the intrinsic phase stability of the laser injecting light into their arms. This is because the noise in the laser light is common to both arms, experiencing exactly the same delay, and thus cancels when it is differenced at the photo detector. In this situation, much lower level secondary noises then set overall performance. If, however, the two arms have different lengths (as will necessarily be the case with space-borne interferometers), the laser noise experiences different delays in the two arms and will hence not directly cancel at the detector. In order to solve this problem, a technique involving heterodyne interferometry with unequal arm lengths and independent phase-difference readouts has been proposed. It relies on properly time-shifting and linearly combining independent Doppler measurements, and for this reason it has been called Time-Delay Interferometry (or TDI). This article provides an overview of the theory and mathematical foundations of TDI as it will be implemented by the forthcoming space-based interferometers such as the Laser Interferometer Space Antenna (LISA) mission. We have purposely left out from this first version of our ``Living Review'' article on TDI all the results of more practical and experimental nature, as well as all the aspects of TDI that the data analysts will need to account for when analyzing the LISA TDI data combinations. Our forthcoming ``second edition'' of this review paper will include these topics.Comment: 51 pages, 11 figures. To appear in: Living Reviews. Added conten

Dual-gated bilayer graphene hot electron bolometer

Detection of infrared light is central to diverse applications in security, medicine, astronomy, materials science, and biology. Often different materials and detection mechanisms are employed to optimize performance in different spectral ranges. Graphene is a unique material with strong, nearly frequency-independent light-matter interaction from far infrared to ultraviolet, with potential for broadband photonics applications. Moreover, graphene's small electron-phonon coupling suggests that hot-electron effects may be exploited at relatively high temperatures for fast and highly sensitive detectors in which light energy heats only the small-specific-heat electronic system. Here we demonstrate such a hot-electron bolometer using bilayer graphene that is dual-gated to create a tunable bandgap and electron-temperature-dependent conductivity. The measured large electron-phonon heat resistance is in good agreement with theoretical estimates in magnitude and temperature dependence, and enables our graphene bolometer operating at a temperature of 5 K to have a low noise equivalent power (33 fW/Hz1/2). We employ a pump-probe technique to directly measure the intrinsic speed of our device, >1 GHz at 10 K.Comment: 5 figure

Association, effects and validation of polymorphisms within the NCAPG - LCORL locus located on BTA6 with feed intake, gain, meat and carcass traits in beef cattle

<p>Abstract</p> <p>Background</p> <p>In a previously reported genome-wide association study based on a high-density bovine SNP genotyping array, 8 SNP were nominally associated (<it>P </it>≤ 0.003) with average daily gain (ADG) and 3 of these were also associated (<it>P </it>≤ 0.002) with average daily feed intake (ADFI) in a population of crossbred beef cattle. The SNP were clustered in a 570 kb region around 38 Mb on the draft sequence of bovine chromosome 6 (BTA6), an interval containing several positional and functional candidate genes including the bovine <it>LAP3, NCAPG</it>, and <it>LCORL </it>genes. The goal of the present study was to develop and examine additional markers in this region to optimize the ability to distinguish favorable alleles, with potential to identify functional variation.</p> <p>Results</p> <p>Animals from the original study were genotyped for 47 SNP within or near the gene boundaries of the three candidate genes. Sixteen markers in the <it>NCAPG-LCORL </it>locus displayed significant association with both ADFI and ADG even after stringent correction for multiple testing (P ≤ 005). These markers were evaluated for their effects on meat and carcass traits. The alleles associated with higher ADFI and ADG were also associated with higher hot carcass weight (HCW) and ribeye area (REA), and lower adjusted fat thickness (AFT). A reduced set of markers was genotyped on a separate, crossbred population including genetic contributions from 14 beef cattle breeds. Two of the markers located within the <it>LCORL </it>gene locus remained significant for ADG (P ≤ 0.04).</p> <p>Conclusions</p> <p>Several markers within the <it>NCAPG-LCORL </it>locus were significantly associated with feed intake and body weight gain phenotypes. These markers were also associated with HCW, REA and AFT suggesting that they are involved with lean growth and reduced fat deposition. Additionally, the two markers significant for ADG in the validation population of animals may be more robust for the prediction of ADG and possibly the correlated trait ADFI, across multiple breeds and populations of cattle.</p

Uses Genres and Media Ensembles : A Conceptual Roadmap for Research of Convergent Audiences

This chapter tackles one of the main methodological and conceptual challenges to current audience research: fragmentation of viewers’ practices of reception. The use of digital and networked media and the consequent multiplication of screens, distribution channels and content sources have further complicated the notion of “watching television” and, along with that, academic and applied audience research. The chapter reintroduces Maria Bakardjieva’s concept of uses genres and connects it with the concept of media ensemble, suggesting that for research on the domestic consumption of films and TV series, the application of these concepts in qualitative (ethnographic) research and in audience surveys comes with strong advantages. Firstly, the concepts help to identify distinct types of consumption practices linked with specific technological objects, with specific audiovisual content and with typical everyday situations, and they enable us to analyze consumption explicitly within the contexts of the spatiotemporal and social organization of everyday life. Secondly, in cases of small- and peripheral-market audiences, the concepts enable us to identify specifics in audiences’ practices linked with the characteristics of these markets (e.g., with localized and non-localized content, with domestic and global production, etc.). And thirdly, the concepts explicitly acknowledge power both involved in and shaping the analyzed practices by emphasizing the “generative process of technology,” i.e., the transformative role of users’ practices in shaping technological and economic systems

An Evaluation of Prediction Equations for the 6 Minute Walk Test in Healthy European Adults Aged 50-85 Years

This study compared actual 6 minute walk test (6MWT) performance with predicted 6MWT using previously validated equations and then determined whether allometric modelling offers a sounder alternative to estimating 6MWT in adults aged 50-80 years.We compared actual 6MWT performance against predicted 6MWT in 125 adults aged 50-85 years (62 male, 63 female). In a second sample of 246 adults aged 50-85 years (74 male, 172 female), a new prediction equation for 6MWT performance was developed using allometric modelling. This equation was then cross validated using the same sample that the other prediction equations were compared with.Significant relationships were evident between 6MWT actual and 6MWT predicted using all of the commonly available prediction equations (all P<0.05 or better) with the exception of the Alameri et al prediction equation (P>0.05). A series of paired t-tests indicated significant differences between 6MWT actual and 6MWT predicted for all available prediction equations (all P<0.05 or better) with the exception of the Iwama et al equation (P = .540). The Iwama et al equation also had similar bias (79.8m) and a coefficient of variation of over 15%. Using sample 2, a log-linear model significantly predicted 6MWT from the log of body mass and height and age (P = 0.001, adjusted R2 = .526), predicting 52.6% of the variance in actual 6MWT. When this allometric equation was applied to the original sample, the relationship between 6MWT actual and 6MWT predicted was in excess of values reported for the other previously validated prediction equations (r = .706, P = 0.001). There was a significant difference between actual 6MWT and 6MWT predicted using this new equation (P = 0.001) but the bias, standard deviation of differences and coefficient of variation were all less than for the other equations.Where actual assessment of the 6MWT is not possible, the allometrically derived equation presented in the current study, offers a viable alternative which has been cross validated and has the least SD of differences and smallest coefficient of variation compared to any of the previously validated equations for the 6MWT

Assessment of learning curves in complex surgical interventions: a consecutive case-series study

Background: Surgical interventions are complex, which complicates their rigorous assessment through randomised clinical trials. An important component of complexity relates to surgeon experience and the rate at which the required level of skill is achieved, known as the learning curve. There is considerable evidence that operator performance for surgical innovations will change with increasing experience. Such learning effects complicate evaluations; the start of the trial might be delayed, resulting in loss of surgeon equipoise or, if an assessment is undertaken before performance has stabilised, the true impact of the intervention may be distorted. Methods: Formal estimation of learning parameters is necessary to characterise the learning curve, model its evolution and adjust for its presence during assessment. Current methods are either descriptive or model the learning curve through three main features: the initial skill level, the learning rate and the final skill level achieved. We introduce a fourth characterising feature, the duration of the learning period, which provides an estimate of the point at which learning has stabilised. We propose a two-phase model to estimate formally all four learning curve features. Results: We demonstrate that the two-phase model can be used to estimate the end of the learning period by incorporating a parameter for estimating the duration of learning. This is achieved by breaking down the model into a phase describing the learning period and one describing cases after the final skill level is reached, with the break point representing the length of learning. We illustrate the method using cardiac surgery data. Conclusions: This modelling extension is useful as it provides a measure of the potential cost of learning an intervention and enables statisticians to accommodate cases undertaken during the learning phase and assess the intervention after the optimal skill level is reached. The limitations of the method and implications for the optimal timing of a definitive randomised controlled trial are also discussed

Forced vital capacity trajectories in patients with idiopathic pulmonary fibrosis: a secondary analysis of a multicentre, prospective, observational cohort

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease with a variable clinical trajectory. Decline in forced vital capacity (FVC) is the main indicator of progression; however, missingness prevents long-term analysis of patterns in lung function. We aimed to identify distinct clusters of lung function trajectory among patients with idiopathic pulmonary fibrosis using machine learning techniques. METHODS: We did a secondary analysis of longitudinal data on FVC collected from a cohort of patients with idiopathic pulmonary fibrosis from the PROFILE study; a multicentre, prospective, observational cohort study. We evaluated the imputation performance of conventional and machine learning techniques to impute missing data and then analysed the fully imputed dataset by unsupervised clustering using self-organising maps. We compared anthropometric features, genomic associations, serum biomarkers, and clinical outcomes between clusters. We also performed a replication of the analysis on data from a cohort of patients with idiopathic pulmonary fibrosis from an independent dataset, obtained from the Chicago Consortium. FINDINGS: 415 (71%) of 581 participants recruited into the PROFILE study were eligible for further analysis. An unsupervised machine learning algorithm had the lowest imputation error among tested methods, and self-organising maps identified four distinct clusters (1-4), which was confirmed by sensitivity analysis. Cluster 1 comprised 140 (34%) participants and was associated with a disease trajectory showing a linear decline in FVC over 3 years. Cluster 2 comprised 100 (24%) participants and was associated with a trajectory showing an initial improvement in FVC before subsequently decreasing. Cluster 3 comprised 113 (27%) participants and was associated with a trajectory showing an initial decline in FVC before subsequent stabilisation. Cluster 4 comprised 62 (15%) participants and was associated with a trajectory showing stable lung function. Median survival was shortest in cluster 1 (2·87 years [IQR 2·29-3·40]) and cluster 3 (2·23 years [1·75-3·84]), followed by cluster 2 (4·74 years [3·96-5·73]), and was longest in cluster 4 (5·56 years [5·18-6·62]). Baseline FEV1 to FVC ratio and concentrations of the biomarker SP-D were significantly higher in clusters 1 and 3. Similar lung function clusters with some shared anthropometric features were identified in the replication cohort. INTERPRETATION: Using a data-driven unsupervised approach, we identified four clusters of lung function trajectory with distinct clinical and biochemical features. Enriching or stratifying longitudinal spirometric data into clusters might optimise evaluation of intervention efficacy during clinical trials and patient management. FUNDING: National Institute for Health and Care Research, Medical Research Council, and GlaxoSmithKline

The formation of professional identity in medical students: considerations for educators

&lt;b&gt;Context&lt;/b&gt; Medical education is about more than acquiring an appropriate level of knowledge and developing relevant skills. To practice medicine students need to develop a professional identity – ways of being and relating in professional contexts.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Objectives&lt;/b&gt; This article conceptualises the processes underlying the formation and maintenance of medical students’ professional identity drawing on concepts from social psychology.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Implications&lt;/b&gt; A multi-dimensional model of identity and identity formation, along with the concepts of identity capital and multiple identities, are presented. The implications for educators are discussed.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; Identity formation is mainly social and relational in nature. Educators, and the wider medical society, need to utilise and maximise the opportunities that exist in the various relational settings students experience. Education in its broadest sense is about the transformation of the self into new ways of thinking and relating. Helping students form, and successfully integrate their professional selves into their multiple identities, is a fundamental of medical education