Ligand Specificity Modulated by Prolyl Imide Bond Cis/Trans Isomerization in the Itk SH2 Domain: A Quantitative NMR Study

The Src homology 2 (SH2) domain of interleukin-2 tyrosine kinase (Itk) binds two separate ligands:  a phosphotyrosine-containing peptide and the Itk Src homology 3 (SH3) domain. Binding specificity for these ligands is regulated via cis/trans isomerization of the Asn 286−Pro 287 imide bond in the Itk SH2 domain. In this study, we develop a novel method of analyzing chemical shift perturbation and cross-peak volumes to measure the affinities of both ligands for each SH2 conformer. We find that the cis imide bond containing SH2 conformer exhibits a 3.5-fold higher affinity for the Itk SH3 domain compared with binding of the trans conformer to the same ligand, while the trans conformer binds phosphopeptide with a 4-fold greater affinity than the cis-containing SH2 conformer. In addition to furthering the understanding of this system, the method presented here will be of general application in quantitatively determining the specificities of conformationally heterogeneous systems that use a molecular switch to regulate binding between multiple distinct ligands

Group descent algorithms for nonconvex penalized linear and logistic regression models with grouped predictors

Penalized regression is an attractive framework for variable selection problems. Often, variables possess a grouping structure, and the relevant selection problem is that of selecting groups, not individual variables. The group lasso has been proposed as a way of extending the ideas of the lasso to the problem of group selection. Nonconvex penalties such as SCAD and MCP have been proposed and shown to have several advantages over the lasso; these penalties may also be extended to the group selection problem, giving rise to group SCAD and group MCP methods. Here, we describe algorithms for fitting these models stably and efficiently. In addition, we present simulation results and real data examples comparing and contrasting the statistical properties of these methods

Investigating the timecourse of accessing conversational implicatures during incremental sentence interpretation

Many contextual inferences in utterance interpretation are explained as following from the nature of conversation and the assumption that participants are rational. Recent psycholinguistic research has focussed on certain of these ‘Gricean’ inferences and have revealed that comprehenders can access them in online interpretation. However there have been mixed results as to the time-course of access. Some results show that Gricean inferences can be accessed very rapidly, as rapidly as any other contextually specified information (Sedivy, 2003; Grodner, Klein, Carbery, & Tanenhaus, 2010); while other studies looking at the same kind of inference suggest that access to Gricean inferences are delayed relative to other aspects of semantic interpretation (Huang & Snedeker, 2009; in press). While previous timecourse research has focussed on Gricean inferences that support the online assignment of reference to definite expressions, the study reported here examines the timecourse of access to scalar implicatures, which enrich the meaning of an utterance beyond the semantic interpretation. Even if access to Gricean inference in support of reference assignment may be rapid, it is still unknown whether genuinely enriching scalar implicatures are delayed. Our results indicate that scalar implicatures are accessed as rapidly as other contextual inferences. The implications of our results are discussed in reference to the architecture of language comprehension

Birmingham’s Eastside story: making steps towards sustainability?

Sustainability has come to play a dominant discursive role in the UK planning system, particularly relating to urban regeneration. The purpose of this paper is to evaluate the role that sustainability plays in a major regeneration programme, known as Eastside, currently underway in Birmingham, the UK. That this £6 billion redevelopment is now widely talked about by such key players as Birmingham City Council and the Regional Development Agency, Advantage West Midlands, as having a central sustainability agenda points to the growing importance of the ideal of sustainability in planning and regeneration agendas. In this paper, we investigate in detail how and why sustainability has become part of the planning discourse for Eastside and critically evaluate what impact, if any, this is having on public policy decision-making

Exploring the existential/universal ambiguity in singular donkey sentences

Although widely discussed in the semantics literature, donkey sentences have been the subject of very little experimental study. In this paper, we present experimental work that is aimed at addressing somewhat open questions around donkey sentences with determiners other than ‘every’ and their susceptibility to both Universal and Existential readings. Our experiments test donkey sentences with ‘every’, ‘no’, ‘some’ and ‘more than two’. By using both verification and act-out tasks, we are able to show that Universal readings are available for donkey sentences with existential determiners (specifically, ‘more than two’), as well as Existential readings. However, our studies fail to show that sentences with ‘no’ have a Universal reading, and they also provide some evidence against the idea that ‘no’ sentences have dual readings

Thinking about Later Life: Insights from the Capability Approach

A major criticism of mainstream gerontological frameworks is the inability of such frameworks to appreciate and incorporate issues of diversity and difference in engaging with experiences of aging. Given the prevailing socially structured nature of inequalities, such differences matter greatly in shaping experiences, as well as social constructions, of aging. I argue that Amartya Sen’s capability approach (2009) potentially offers gerontological scholars a broad conceptual framework that places at its core consideration of human beings (their values) and centrality of human diversity. As well as identifying these key features of the capability approach, I discuss and demonstrate their relevance to thinking about old age and aging. I maintain that in the context of complex and emerging identities in later life that shape and are shaped by shifting people-place and people-people relationships, Sen’s capability approach offers significant possibilities for gerontological research

Genomics of Mature and Immature Olfactory Sensory Neurons

The continuous replacement of neurons in the olfactory epithelium provides an advantageous model for investigating neuronal differentiation and maturation. By calculating the relative enrichment of every mRNA detected in samples of mature mouse olfactory sensory neurons (OSNs), immature OSNs, and the residual population of neighboring cell types, and then comparing these ratios against the known expression patterns of \u3e300 genes, enrichment criteria that accurately predicted the OSN expression patterns of nearly all genes were determined. We identified 847 immature OSN-specific and 691 mature OSN-specific genes. The control of gene expression by chromatin modification and transcription factors, and neurite growth, protein transport, RNA processing, cholesterol biosynthesis, and apoptosis via death domain receptors, were overrepresented biological processes in immature OSNs. Ion transport (ion channels), presynaptic functions, and cilia-specific processes were overrepresented in mature OSNs. Processes overrepresented among the genes expressed by all OSNs were protein and ion transport, ER overload response, protein catabolism, and the electron transport chain. To more accurately represent gradations in mRNA abundance and identify all genes expressed in each cell type, classification methods were used to produce probabilities of expression in each cell type for every gene. These probabilities, which identified 9,300 genes expressed in OSNs, were 96% accurate at identifying genes expressed in OSNs and 86% accurate at discriminating genes specific to mature and immature OSNs. This OSN gene database not only predicts the genes responsible for the major biological processes active in OSNs, but also identifies thousands of never before studied genes that support OSN phenotypes

Quantile regression with group lasso for classification

Applications of regression models for binary response are very common and models specific to these problems are widely used. Quantile regression for binary response data has recently attracted attention and regularized quantile regression methods have been proposed for high dimensional problems. When the predictors have a natural group structure, such as in the case of categorical predictors converted into dummy variables, then a group lasso penalty is used in regularized methods. In this paper, we present a Bayesian Gibbs sampling procedure to estimate the parameters of a quantile regression model under a group lasso penalty for classification problems with a binary response. Simulated and real data show a good performance of the proposed method in comparison to mean-based approaches and to quantile-based approaches which do not exploit the group structure of the predictors

Developing a utility index for the Aberrant Behavior Checklist (ABC-C) for fragile X syndrome

Purpose This study aimed to develop a utility index (the ABC-UI) from the Aberrant Behavior Checklist-Community (ABC-C), for use in quantifying the benefit of emerging treatments for fragile X syndrome (FXS). Methods The ABC-C is a proxy-completed assessment of behaviour and is a widely used measure in FXS. A subset of ABC-C items across seven dimensions was identified to include in health state descriptions. This item reduction process was based on item performance, factor analysis and Rasch analysis performed on an observational study dataset, and consultation with five clinical experts and a methodological expert. Dimensions were combined into health states using an orthogonal design and valued using time trade-off (TTO), with lead-time TTO methods used where TTO indicated a state valued as worse than dead. Preference weights were estimated using mean, individual level, ordinary least squares and random-effects maximum likelihood estimation [RE (MLE)] regression models. Results A representative sample of the UK general public (n = 349; mean age 35.8 years, 58.2 % female) each valued 12 health states. Mean observed values ranged from 0.92 to 0.16 for best to worst health states. The RE (MLE) model performed best based on number of significant coefficients and mean absolute error of 0.018. Mean utilities predicted by the model covered a similar range to that observed. Conclusions The ABC-UI estimates a wide range of utilities from patient-level FXS ABC-C data, allowing estimation of FXS health-related quality of life impact for economic evaluation from an established FXS clinical trial instrument