A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Background

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties by gene expression profile. Lamb et al first proposed the Connectivity Map [Lamb et al (2006), Science 313, 1929–1935] to make successful connections among small molecules, genes, and diseases using genomic signatures.

Results

Here we have built on the principles of the Connectivity Map to present a simpler and more robust method for the construction of reference gene-expression profiles and for the connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with two randomly generated gene signatures and three experimentally derived gene signatures (for HDAC inhibitors, estrogens, and immunosuppressive drugs, respectively). Our testing with this method indicates that it achieves a higher level of specificity and sensitivity and so advances the original method.

Conclusion

The method presented here not only offers more principled statistical procedures for testing connections, but more importantly it provides effective safeguard against false connections at the same time achieving increased sensitivity. With its robust performance, the method has potential use in the drug development pipeline for the early recognition of pharmacological and toxicological properties in chemicals and new drug candidates, and also more broadly in other 'omics sciences.

Advanced glycation end products in vitreous: Structural and functional implications for diabetic vitreopathy

PURPOSE. Advanced glycation end products (AGES) form irreversible cross- links with many macromolecules and have been shown to accumulate in tissues at an accelerated rate in diabetes. In the present study, AGE formation in vitreous was examined in patients of various ages and in patients with diabetes. Ex vivo investigations were performed on bovine vitreous incubated in glucose to determine AGE formation and cross-linking of vitreous collagen. METHODS. By means of an AGE-specific enzyme-linked immunosorbent assay (ELISA), AGE formation was investigated in vitreous samples obtained after pars plana vitrectomy in patients with and without diabetes. In addition, vitreous AGES were investigated in bovine vitreous collagen after incubation in high glucose, high glucose with aminoguanidine, or normal saline for as long as 8 weeks. AGEs and AGE cross-linking was subsequently determined by quantitative and qualitative assays. RESULTS. There was a significant correlation between AGEs and increasing age in patients without diabetes (r = 0.74). Furthermore, a comparison between age-matched diabetic and nondiabetic vitreous showed a significantly higher level of AGEs in the patients with diabetes (P < 0.005). Collagen purified from bovine vitreous incubated in 0.5 M glucose showed an increase in AGE formation when observed in dot blot analysis, immunogold labeling, and AGE ELISA. Furthermore, there was increased cross-linking of collagen in the glucose-incubated vitreous, when observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and protein separation. This cross-linking was effectively inhibited by coincubation with 10 mM aminoguanidine. CONCLUSIONS. This study suggests that AGEs may form in vitreous with increasing age. This process seems to be accelerated in the presence of diabetes and as a consequence of exposure to high glucose. Advanced glycation and AGE cross-linking of the vitreous collagen network may help to explain the vitreous abnormalities characteristic of diabetes.

On-line Emotion Recognition in a 3-D Activation-Valence-Time Continuum using Acoustic and Linguistic Cues

For many applications of emotion recognition, such as virtual agents, the system must select responses while the user is speaking. This requires reliable on-line recognition of the user’s affect. However most emotion recognition systems are based on turnwise processing. We present a novel approach to on-line emotion recognition from speech using Long Short-Term Memory Recurrent Neural Networks. Emotion is recognised frame-wise in a two-dimensional valence-activation continuum. In contrast to current state-of-the-art approaches, recognition is performed on low-level signal frames, similar to those used for speech recognition. No statistical functionals are applied to low-level feature contours. Framing at a higher level is therefore unnecessary and regression outputs can be produced in real-time for every low-level input frame. We also investigate the benefits of including linguistic features on the signal frame level obtained by a keyword spotter.

A Comparison of the Flow Structures and Losses Within Vaned and Vaneless Stators for Radial Turbines

This paper details the numerical analysis of different vaned and vaneless radial inflow turbine stators. Selected results are presented from a test program carried out to determine performance differences between the radial turbines with vaned stators and vaneless volutes under the same operating conditions. A commercial computational fluid dynamics code was used to develop numerical models of each of the turbine configurations, which were validated using the experimental results. From the numerical models, areas of loss generation in the different stators were identified and compared, and the stator losses were quantified. Predictions showed the vaneless turbine stators to incur lower losses than the corresponding vaned stator at matching operating conditions, in line with the trends in measured performance.. Flow conditions at rotor inlet were studied and validated with internal static pressure measurements so as to judge the levels of circumferential nonuniformity for each stator design. In each case, the vaneless volutes were found to deliver a higher level of uniformity in the rotor inlet pressure field. [DOI: 10.1115/1.2988493]

Re-engineering Sources of Law for Unaided Litigants

The better models of e-Gov posit high levels of informational communication between citizen and state. Unfortunately, in one area, that communication has traditionally been poor: that is, access to sources of law. There have been a number of reasons for this, but a primary one has been that law was historically mediated for the citizen by the legal profession. This situation is changing with ever increasing numbers of unrepresented litigants being involved at all levels of national court systems in each and every country as well as a generally higher level of intrusion of legislation into everyday home and business life. There have been attempts to improve access through internet based services, but these have improved communication (‘understanding of law’) to only a limited extent. It may be time, this article suggests, to consider re-engineering legal sources so that they better fit the needs of eGov.

What is Irish Standard English?

Standard English need not be a matter of prescriptivism or any attempt to ‘create’ a particular standard, but, rather, can be a matter of observation of actual linguistic behaviour. For Hudson (2000), standard English is the kind of English which is written in published work, which is spoken in situations where published writing is most influential – especially in university level education and so in post-university professions – and which is spoken ‘natively’ at home by the ‘professional class’, i.e. people who are most influenced by published writing. In the papers in Bex and Watts (eds, 1999), it is recurrently claimed that, when speaking English, what the ‘social group with highest degree of power, wealth or prestige’ or more neutrally ‘educated people’ or ‘socially admired people’ speak is the variety known as ‘standard English’. However, ‘standard English’ may also mean that shared aspect of English which makes global communication possible. This latter perspective allows for two meanings of ‘standard’: it may refer both to an idealised set of shared features, and also to different sets of national features, reflecting different demographic and political histories and language influences. The methodology adopted in the International Corpus of English (henceforth ICE – cf. Greenbaum, 1996) enables us to observe and investigate each set of features, showing what everybody shares and also what makes each national variety of English different.

Cultural threat and anti-immigrant prejudice: The case of Protestants in Northern Ireland

Using data from the 2002 and 2009 Northern Ireland Life and Times (NILT) surveys, we examine attitudes towards immigrant and ethnic minority groups in Northern Ireland. We suggest that Protestant and unionist communities experience a higher level of cultural threat than Catholic and nationalist communities on account of the ‘parity of esteem’ principle that has informed changes in the province since the Belfast Agreement of 1998. Our analyses confirm that, while there is evidence for some level of anti-immigrant sentiment across all groups, Protestants and unionists do indeed report relatively more negative attitudes towards a range of immigrant and ethnic target groups compared to Catholic, nationalist, or respondents who do not identify with either religious or political category. The analyses further suggest that their higher level of perceived cultural threat partially accounts for this difference. We suggest that cultural threat can be interpreted as a response to changes in Northern Ireland that have challenged the dominant status enjoyed by Protestants and unionists in the past.

Parallel Programming of General-Purpose Programs Using Task-Based Programming Models

The prevalence of multicore processors is bound to drive most kinds of software development towards parallel programming. To limit the difficulty and overhead of parallel software design and maintenance, it is crucial that parallel programming models allow an easy-to-understand, concise and dense representation of parallelism. Parallel programming models such as Cilk++ and Intel TBBs attempt to offer a better, higher-level abstraction for parallel programming than threads and locking synchronization. It is not straightforward, however, to express all patterns of parallelism in these models. Pipelines are an important parallel construct, although difficult to express in Cilk and TBBs in a straightfor- ward way, not without a verbose restructuring of the code. In this paper we demonstrate that pipeline parallelism can be easily and concisely expressed in a Cilk-like language, which we extend with input, output and input/output dependency types on procedure arguments, enforced at runtime by the scheduler. We evaluate our implementation on real applications and show that our Cilk-like scheduler, extended to track and enforce these dependencies has performance comparable to Cilk++.

The role of working memory capacity in multiple-cue probability learning

Multiple-cue probability learning (MCPL) involves learning to predict a criterion when outcome feedback is provided for multiple cues. A great deal of research suggests that working memory capacity (WMC) is involved in a wide range of tasks that draw on higher level cognitive processes. In three experiments, we examined the role of WMC in MCPL by introducing measures of working memory capacity, as well as other task manipulations. While individual differences in WMC positively predicted performance in some kinds of multiple-cue tasks, performance on other tasks was entirely unrelated to these differences. Performance on tasks that contained negative cues was correlated with working memory capacity, as well as measures of explicit knowledge obtained in the learning process. When the relevant cues predicted positively, however, WMC became irrelevant. The results are discussed in terms of controlled and automatic processes in learning and judgement. © 2011 The Experimental Psychology Society.

Urban housing and the role of 'underclass' processes: the case of Ireland

Rising levels of urban deprivation and a perception that poverty has become more concentrated in such areas and has taken on a qualitatively different character have provoked a variety of popular and academic responses. The potentially most fruitful set of hypotheses focuses on the unintended of weak labour force attachment and social isolation is perceived to lead to behaviour and orientations that contribute to a vicious circle of deprivation. In examining the value of this conceptual framework in the Irish case we proceed by measuring directly the social-psychological factors which ave hypothesized to mediate the 'underclass' process.

A significantly higher level of poverty is found in urban public-sector tenant households. This finding cannot be accounted for entirely by socio-demographic differences. It is the assessment of this net or residual effect that is crucial to an evaluation of vicious circle explanations. Controlling for the critical social-psychological factors we found that net effect was reduced by less than a quarter and concluded that the remaining effect is more plausibly attributed to the role of selection than to underclass processes. Analysis of the changing relationship between urban public-sector tenancy and poverty provides support for this interpretation.

For the main part the distinctiveness of social housing tenants is a consequence of the disadvantages they stiffer in relation to employment opportunities and living standards. Ultimately it is these problems that policy interventions, whatever the level at which they take place, must address.

Substituting home care for hospitalization:The role of a quick response service for the elderly

The purpose of the present study was to examine the role of a rapid access home-based service as a means for the elderly to avoid admission to an acute-care hospital. The setting for the study included emergency departments in three acute care hospitals and a home care program in a mid-size Canadian city. Multiple sources of information were obtained to evaluate the service. Hospital emergency department records and home care records were reviewed. Patients who participated in the service (n=96) and physicians and nurses (n =119) who had involvement with the service were surveyed appraising the service in terms of relevance, access, quality and coordination. Study results revealed that elderly women with multiple health problems who lived alone were the most frequent users of the service. The majority of the patients admitted to the service presented with problems of a functional nature that were the result of a fall or mobility problems. The results indicated that the service did avert hospital admissions and facilitated a process by which patients could avoid the intermediate step of hospitalization before placed in a higher level of care or returning to previous levels of functioning. Economic analysis indicated that the value of the service stemmed from the benefits to patients and caregivers rather than from cost savings offered to acute care hospitals.

Who's minding the shop?:the role of Canadian research ethics boards in the creation and uses of registries and biobanks

Abstract. Background. The amount of research utilizing health information has increased dramatically over the last ten years. Many institutions have extensive biobank holdings collected over a number of years for clinical and teaching purposes, but are uncertain as to the proper circumstances in which to permit research uses of these samples. Research Ethics Boards (REBs) in Canada and elsewhere in the world are grappling with these issues, but lack clear guidance regarding their role in the creation of and access to registries and biobanks. Methods. Chairs of 34 REBS and/or REB Administrators affiliated with Faculties of Medicine in Canadian universities were interviewed. Interviews consisted of structured questions dealing with diabetes-related scenarios, with open-ended responses and probing for rationales. The two scenarios involved the development of a diabetes registry using clinical encounter data across several physicians' practices, and the addition of biological samples to the registry to create a biobank. Results. There was a wide range of responses given for the questions raised in the scenarios, indicating a lack of clarity about the role of REBs in registries and biobanks. With respect to the creation of a registry, a minority of sites felt that consent was not required for the information to be entered into the registry. Whether patient consent was required for information to be entered into the registry and the duration for which the consent would be operative differed across sites. With respect to the creation of a biobank linked to the registry, a majority of sites viewed biobank information as qualitatively different from other types of personal health information. All respondents agreed that patient consent was needed for blood samples to be placed in the biobank but the duration of consent again varied. Conclusion. Participants were more attuned to issues surrounding biobanks as compared to registries and demonstrated a higher level of concern regarding biobanks. As registries and biobanks expand, there is a need for critical analysis of suitable roles for REBs and subsequent guidance on these topics. The authors conclude by recommending REB participation in the creation of registries and biobanks and the eventual drafting of comprehensive legislation.

The effects of climate change on ovine parasitic gastroenteritis determined using veterinary surveillance and meteorological data for Northern Ireland over the period 1999-2009

While the influence of temperature and moisture on the free-living stages of gastrointestinal nematodes have been described in detail, and evidence for global climate change is mounting, there have been only a few attempts to relate altered incidence or seasonal patterns of disease to climate change. Studies of this type have been completed for England Scotland and Wales, but not for Northern Ireland (NI). Here we present an analysis of veterinary diagnostic data that relates three categories of gastrointestinal nematode infection in sheep to historical meteorological data for NI. The infections are: trichostrongylosis/teladorsagiosis (Teladorsagia/Trichostrongylus), strongyloidosis and nematodirosis. This study aims to provide a baseline for future climate change analyses and to provide basic information for the development of nematode control programmes. After identifying and evaluating possible sources of bias, climate change was found to be the most likely explanation for the observed patterns of change in parasite epidemiology, although other hypotheses could not be refuted. Seasonal rates of diagnosis showed a uniform year-round distribution for Teladorsagia and Trichostrongylus infections, suggesting consistent levels of larval survival throughout the year and extension of the traditionally expected seasonal transmission windows. Nematodirosis showed a higher level of autumn than Spring infection, suggesting that suitable conditions for egg and larval development occurred after the Spring infection period. Differences between regions within the Province were shown for strongyloidosis, with peaks of infection falling in the period September-November. For all three-infection categories (trichostrongylosis/teladorsagiosis, strongyloidosis and nematodirosis), significant differences in the rates of diagnosis, and in the seasonality of disease, were identified between regions. (C) 2012 Elsevier B.V. All rights reserved.

Chemical Communication of Antibiotic Resistance by a Highly Resistant Subpopulation of Bacterial Cells

The overall antibiotic resistance of a bacterial population results from the combination of a wide range of susceptibilities displayed by subsets of bacterial cells. Bacterial heteroresistance to antibiotics has been documented for several opportunistic Gram-negative bacteria, but the mechanism of heteroresistance is unclear. We use Burkholderia cenocepacia as a model opportunistic bacterium to investigate the implications of heterogeneity in the response to the antimicrobial peptide polymyxin B (PmB) and also other bactericidal antibiotics. Here, we report that B. cenocepacia is heteroresistant to PmB. Population analysis profiling also identified B. cenocepacia subpopulations arising from a seemingly homogenous culture that are resistant to higher levels of polymyxin B than the rest of the cells in the culture, and can protect the more sensitive cells from killing, as well as sensitive bacteria from other species, such as Pseudomonas aeruginosa and Escherichia coli. Communication of resistance depended on upregulation of putrescine synthesis and YceI, a widely conserved low-molecular weight secreted protein. Deletion of genes for the synthesis of putrescine and YceI abrogate protection, while pharmacologic inhibition of putrescine synthesis reduced resistance to polymyxin B. Polyamines and YceI were also required for heteroresistance of B. cenocepacia to various bactericidal antibiotics. We propose that putrescine and YceI resemble "danger" infochemicals whose increased production by a bacterial subpopulation, becoming more resistant to bactericidal antibiotics, communicates higher level of resistance to more sensitive members of the population of the same or different species.

Development and Validation of a Compact Thermal Model for an Aircraft Compartment

The development of accurate structural/thermal numerical models of complex systems, such as aircraft fuselage barrels, is often limited and determined by the smallest scales that need to be modelled. The development of reduced order models of the smallest scales and consequently their integration with higher level models can be a way to minimise the bottle neck present, while still having efficient, robust and accurate numerical models. In this paper a methodology on how to develop compact thermal fluid models (CTFMs) for compartments where mixed convection regimes are present is demonstrated. Detailed numerical simulations (CFD) have been developed for an aircraft crown compartment and validated against experimental data obtained from a 1:1 scale compartment rig. The crown compartment is defined as the confined area between the upper fuselage and the passenger cabin in a single aisle commercial aircraft. CFD results were utilised to extract average quantities (temperature and heat fluxes) and characteristic parameters (heat transfer coefficients) to generate CTFMs. The CTFMs have then been compared with the results obtained from the detailed models showing average errors for temperature predictions lower than 5%. This error can be deemed acceptable when compared to the nominal experimental error associated with the thermocouple measurements.

The CTFMs methodology developed allows to generate accurate reduced order models where accuracy is restricted to the region of Boundary Conditions applied. This limitation arises from the sensitivity of the internal flow structures to the applied boundary condition set. CTFMs thus generated can be then integrated in complex numerical modelling of whole fuselage sections.

Further steps in the development of an exhaustive methodology would be the implementation of a logic ruled based approach to extract directly from the CFD simulations numbers and positions of the nodes for the CTFM.