Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection

Pseudomonas elastase (LasB), a metalloprotease virulence factor, is known to play a pivotal role in pseudomonal infection. LasB is secreted at the site of infection, where it exerts a proteolytic action that spans from broad tissue destruction to subtle action on components of the host immune system. The former enhances invasiveness by liberating nutrients for continued growth, while the latter exerts an immunomodulatory effect, manipulating the normal immune response. In addition to the extracellular effects of secreted LasB, it also acts within the bacterial cell to trigger the intracellular pathway that initiates growth as a bacterial bio?lm. The key role of LasB in pseudomonal virulence makes it a potential target for the development of an inhibitor as an antimicrobial agent. The concept of inhibition of virulence is a recently established antimicrobial strategy, and such agents have been termed “second-generation” antibiotics. This approach holds promise in that it seeks to attenuate virulence processes without bactericidal action and, hence, without selection pressure for the emergence of resistant strains. A potent inhibitor of LasB,N-mercaptoacetyl-Phe-Tyr-amide (Ki 41 nM) has been developed, and its ability to block these virulence processes has been assessed. It has been demonstrated that thes compound can completely block the action of LasB on protein targets that are instrumental in bio?lm formation and immunomodulation. The novel LasB inhibitor has also been employed in bacterial-cell-based assays, to reduce the growth of pseudomonal bio?lms, and to eradicate bio?lm completely when used in combination with conventional antibiotics.

A Computer Music Retrospective

A composer who has worked in the field of computer music for the last 25 years reflects on how technological developments during that time have affected his work in computer music, instrumental music and hybrid combinations of the two. The compositional trajectories traced here often run parallel to opportunities afforded by the evolution of computer technology suitable for the generation of digital audio.

Photometric observations of the Type Ia SN 2002er in UGC 10743

Extensive light and colour curves for the Type Ia supernova (SN Ia) SN 2002er are presented as part of the European Supernova Collaboration. We have collected UBVRI photometry from 11 different telescopes covering the phases from 7 d before until 619 d after maximum light. Corrections for the different instrumental systems and the non-thermal spectrum of the supernova (S-corrections) have been applied. With the densely sampled light curves we can make detailed comparisons to other well-observed objects. SN 2002er most closely resembles SN 1996X after maximum, but clearly shows a different colour evolution before peak light and a stronger shoulder in V and R bands compared to other well-observed SNe Ia. In particular, the rise time appears to be longer than what is expected from the rise time versus decline rate relation. We use several methods to determine the reddening towards SN 2002er based on the colour evolution at near peak and at late phases. The uvoir (bolometric) light curve shows great similarity with SN 1996X, but also indications of a higher luminosity, longer rise time and a more pronounced shoulder 25 d past maximum. The interpretation of the light curves was carried out with two independent light curve codes. Both find that given the luminosity of SN 2002er the Ni-56 mass exceeds 0.6 M-circle dot with preferred values near 0.7 M-circle dot. Uncertainties in the exact distance to SN 2002er are the most serious limitation of this measurement. The light-curve modelling also indicates a high level of mixing of the nickel in the explosion of SN 2002er.

Exoplanets or Dynamic Atmospheres? The Radial Velocity and Line Shape Variations of 51 Pegasi and tau Bootis

The stars 51 Pegasi and tau Bootis show radial velocity variations that have been interpreted as resulting from companions with roughly Jovian mass and orbital periods of a few days. Gray and Gray & Hatzes reported that the radial velocity signal of 51 Peg is synchronous with variations in the shape of the line lambda 6253 Fe I; thus, they argue that the velocity signal arises not from a companion of planetary mass but from dynamic processes in the atmosphere of the star, possibly nonradial pulsations. Here we seek confirming evidence for line shape or strength variations in both 51 Peg and tau Boo, using R = 50,000 observations taken with the Advanced Fiber Optic Echelle. Because of our relatively low spectral resolution, we compare our observations with Gray's line bisector data by fitting observed line profiles to an expansion in terms of orthogonal (Hermite) functions. To obtain an accurate comparison, we model the emergent line profiles from rotating and pulsating stars, taking the instrumental point-spread function into account. We describe this modeling process in detail. We find no evidence for line profile or strength variations at the radial velocity period in either 51 Peg or in tau Boo. For 51 Peg, our upper limit for line shape variations with 4.23 day periodicity is small enough to exclude with 10 sigma confidence the bisector curvature signal reported by Gray & Hatzes; the bisector span and relative line depth signals reported by Gray are also not seen, but in this case with marginal (2 sigma ) confidence. We cannot, however, exclude pulsations as the source of 51 Peg's radial velocity variation because our models imply that line shape variations associated with pulsations should be much smaller than those computed by Gray & Hatzes; these smaller signals are below the detection limits both for Gray & Hatzes's data and for our own. tau Boo's large radial velocity amplitude and v sin i make it easier to test for pulsations in this star. Again we find no evidence for periodic line shape changes, at a level that rules out pulsations as the source of the radial velocity variability. We conclude that the planet hypothesis remains the most likely explanation for the existing data.

Veblen's Placebo: A historical perspective on administrative evil

Thorstein Veblen was a turn of the 20th century American economist concerned with the implications of financial capitalists directing the means of production. Veblen proposed that the rationality of "material science" as practiced by the "production engineers" is fundamentally different from the rationality of market capitalism. If this claim is valid, our previous contentions regarding accounting, as a facilitating technology, for administrative evil warrant reconsideration. Veblen's position provides a historical perspective on one dimension of administrative evil that is generally unquestionably accepted, especially within accounting. That is, technology, such as accounting and the related information systems, is amoral, and it is only through ideologically instigated applications that any moral value accrues. We discuss administrative evil and the role of instrumental rationality generally, and accounting specifically, in creating it. Veblen's characterization of financial capitalism and production engineers and his arguments for the primacy of economic efficiency versus "pecuniary gain" provide a basis for evaluating the legitimating action. We consider how Veblen's work relates to notions of instrumental rationality and then undertake a critical assessment of the ideas. Some of Veblen's ideas, while utopian, might be seen as an elixir for the detrimental influences of financial capital; however, at best, they provide a placebo for the ills of administrative evil and, as such, do not provide an amoral basis for legitimating the associated accounting systems.

Toenail trace element status and risk of Barrett's oesophagus and oesophageal adenocarcinoma. Results from the FINBAR study

Trace elements have been cited as both inhibitory and causative agents of cancer but importantly exposure to them is potentially modifiable. Our study aimed to examine toenail trace element status and risk of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Toenail clippings from each hallux were obtained from 638 participants of the FINBAR (Factors Influencing the Barrett's Adenocarcinoma Relationship) study comprising 221 healthy controls, 98 reflux oesophagitis, 182 BO and 137 OAC cases. The concentrations of eight toenail trace elements were determined using instrumental neutron activation analysis. Using multivariable adjusted logistic regression analysis, odds ratios (OR) and 95% confidence intervals (CIs) were calculated within tertiles of trace element concentrations. A twofold increased risk of BO was observed, but not OAC, among individuals in the highest tertile of toenail zinc status OR 2.21 (95% CI, 1.11-4.40). A higher toenail selenium status was not associated with risk of OAC OR 0.94 (95% CI, 0.44-2.04) or BO OR 0.89 (95% CI, 0.37-2.12). A borderline significant increased risk of BO was detected with a higher toenail cobalt concentration, OR 1.97 (95% CI, 1.01-3.85). No association was found between toenail levels of chromium, cerium, mercury and OAC or BO risk. This is the first case-control study to investigate a variety of trace elements in relation to OAC and BO risk. Despite antioxidant and proapoptotic properties, no associations were found with selenium. Higher concentrations of toenail zinc and cobalt were associated with an increased BO risk, but not OAC. These findings need confirmation in prospective analysis.

Semiotics, Presence and the Sublime in the Work of Alvin Lucier

Alvin Lucier, in his uncompromising exploration into the artistic potential of acoustic phenomena, has developed a body of work that remains highly original and hugely influential across many disciplines. His seminal works such as I am sitting in a room and Music for Solo Performer foreshadowed ways of approaching sound that are in common use among electro-acoustic composers, installation artists, as well as in commercial products. Lucier, despite his far reaching influence, is and has always been a composer, and his explorations of acoustics have been singularly focused on the development of a rich body of music. In this article, I investigate Lucier’s unique approach and attitude towards acoustics and aspire to enumerate important aesthetic developments he has made in creating music through the exploration of acoustic phenomena. In particular, this article seeks to investigate the role of semiotics in Lucier’s work, commenting on the pre-linguistic nature of Lucier’s approach to acoustic phenomenon. Here as well, an exploration of Lucier’s musical materials takes place, focusing on his instrumental compositions, specifically Diamonds for One, Two or Three Orchestras, where instruments are used as catalysts to generate in real-time acoustic phenomenon which interact to produce a rich yet intimate world of sound. Finally, Lucier’s approach to semiotics and real-time generation of music is viewed through a sublime aesthetic provoking questions regarding issues of presence and the now.

Assessing the determinants of public confidence in the police: A case study of a post-conflict community in Northern Ireland

Drawing upon original survey research this article seeks to identify the generative processes that influence perceptions of the police in the context of an inner-city neighbourhood in Northern Ireland that has been affected by increases in crime and disorder in the aftermath of the peace process. Conceptually we draw upon recent research from England and Wales that outlines confidence in the police in terms of instrumental and expressive dimensions. We apply this framework and consider whether it provides a useful template for understanding the post-conflict dynamics of police-community relations in our study area. Contrary to much received wisdom our analysis suggests that instrumental concerns about crime and illegal activity are a more influential predictor of attitudes to the police than expressive concerns with disorder and anti-social behaviour. Consequently our discussion points to the variance in local and national survey data and questions the degree to which the latter can usefully inform our understanding of trends and developments in discrete micro-spaces. Our conclusion outlines the potential policy implications for state policing practice in deprived urban spaces.

Using Noise Techniques to Destabilize Composition and Improvisation

A description of the uses of computer-generated noise in my instrumental scores and guided improvisations.

Denial, Silence and the Politics of the Past: Unpicking the Opposition to Truth Recovery in Northern Ireland

There has been considerable and protracted debate on whether a formal truth recovery process should be established in Northern Ireland. Some of the strongest opposition to the creation of such a body has been from unionist political elites and the security forces. Based on qualitative fieldwork, this article argues that the dynamics of denial and silence have been instrumental in shaping their concerns. It explores how questions of memory, identity and denial have created a ‘myth of blamelessness’ in unionist discourse that is at odds with the reasons for a truth process being established. It also examines how three interlocking manifestations of silence – ‘silence as passivity,’ ‘silence as loyalty’ and ‘silence as pragmatism’ – have furthered unionists’ opposition to dealing with the past. This article argues that making peace with the past requires an active deconstruction of these practices.

Pharmaceutical applications of dynamic mechanical thermal analysis

The successful development of polymeric drug delivery and biomedical devices requires a comprehensive understanding of the viscoleastic properties of polymers as these have been shown to directly affect clinical efficacy. Dynamic mechanical thermal analysis (DMTA) is an accessible and versatile analytical technique in which an oscillating stress or strain is applied to a sample as a function of oscillatory frequency and temperature. Through cyclic application of a non-destructive stress or strain, a comprehensive understanding of the viscoelastic properties of polymers may be obtained. In this review, we provide a concise overview of the theory of DMTA and the basic instrumental/operating principles. Moreover, the application of DMTA for the characterization of solid pharmaceutical and biomedical systems has been discussed in detail. In particular we have described the potential of DMTA to measure and understand relaxation transitions and miscibility in binary and higher-order systems and describe the more recent applications of the technique for this purpose. © 2011 Elsevier B.V.

Risk-informed decision-making in the presence of epistemic uncertainty

An important issue in risk analysis is the distinction between epistemic and aleatory uncertainties. In this paper, the use of distinct representation formats for aleatory and epistemic uncertainties is advocated, the latter being modelled by sets of possible values. Modern uncertainty theories based on convex sets of probabilities are known to be instrumental for hybrid representations where aleatory and epistemic components of uncertainty remain distinct. Simple uncertainty representation techniques based on fuzzy intervals and p-boxes are used in practice. This paper outlines a risk analysis methodology from elicitation of knowledge about parameters to decision. It proposes an elicitation methodology where the chosen representation format depends on the nature and the amount of available information. Uncertainty propagation methods then blend Monte Carlo simulation and interval analysis techniques. Nevertheless, results provided by these techniques, often in terms of probability intervals, may be too complex to interpret for a decision-maker and we, therefore, propose to compute a unique indicator of the likelihood of risk, called confidence index. It explicitly accounts for the decisionmaker’s attitude in the face of ambiguity. This step takes place at the end of the risk analysis process, when no further collection of evidence is possible that might reduce the ambiguity due to epistemic uncertainty. This last feature stands in contrast with the Bayesian methodology, where epistemic uncertainties on input parameters are modelled by single subjective probabilities at the beginning of the risk analysis process.

Possibilistic Information Fusion Using Maximal Coherent Subsets

When multiple sources provide information about the same unknown quantity, their fusion into a synthetic interpretable message is often a tedious problem, especially when sources are conicting. In this paper, we propose to use possibility theory and the notion of maximal coherent subsets, often used in logic-based representations, to build a fuzzy belief structure that will be instrumental both for extracting useful information about various features of the information conveyed by the sources and for compressing this information into a unique possibility distribution. Extensions and properties of the basic fusion rule are also studied.

Characterizing Pb mobilization from upland soils to streams using (206)Pb/(207)Pb isotopic ratios

Anthropogenically deposited lead (Pb) binds efficiently to soil organic matter, which can be mobilized through hydrologically mediated mechanisms, with implications for ecological and potable quality of receiving waters. Lead isotopic ((206)Pb/(207)Pb) ratios change down peat profiles as a consequence of long-term temporal variation in depositional sources, each with distinctive isotopic signatures. This study characterizes differential Pb transport mechanisms from deposition to streams at two small catchments with contrasting soil types in upland Wales, U.K., by determining Pb concentrations and (206)Pb/(207)Pb ratios from soil core profiles, interstitial pore waters, and stream water. Hydrological characteristics of soils are instrumental in determining the location in soil profiles of exported Pb and hence concentration and (206)Pb/(207)Pb ratios in surface waters. The highest Pb concentrations from near-surface soils are mobilized, concomitant with high dissolved organic carbon (DOC) exports, from hydrologically responsive peat soils with preferential shallow subsurface flows, leading to increased Pb concentrations in stream water and isotopic signatures more closely resembling recently deposited Pb. In more minerogenic soils, percolation of water allows Pb, bound to DOC, to be retained in mineral horizons and combined with other groundwater sources, resulting in Pb being transported from throughout the profile with a more geogenic isotopic signature. This study shows that (206)Pb/(207)Pb ratios can enhance our understanding of the provenances and transport mechanisms of Pb and potentially organic matter within upland soils.

Constrained adoptive parenthood and family transition: Adopters' experience of unplanned birth family contact in adolescence

Adoption policy in the UK emphasizes its role in providing secure, permanent relationships to children in care who are unable to live with their birth families. Adoptive parents are crucial in providing this life-long, stable experience of family for these vulnerable children. This paper explores the experience of adoptive parenthood in the context of changes to adoptive kinship relationships brought about by new, unplanned contact with birth family during their child's middle adolescence. This contact was initiated via informal social networks and/or social media, with older birth siblings instrumental in negotiating renewed relationships. The contact precipitated a transition in adoptive family life resulting in emotional challenges and changes in parent/child relationships, which were experienced as additional to the normative transitions expected during adolescence. Parental concern as a dominant theme was founded in the child and birth sibling's stage of adolescence, coupled with constraints on adoptive parenthood imposed by the use of social media, by perceived professional attitudes and by parental social cognitions about the importance of birth ties. Adoptive parents' accounts are interpreted with reference to family life-cycle theory and implications are suggested for professional support of adoptive kinship relationships.