Peptide binding to HLA-DP proteins at pH 5.0 and pH 7.0:a quantitative molecular docking study

Background: HLA-DPs are class II MHC proteins mediating immune responses to many diseases. Peptides bind MHC class II proteins in the acidic environment within endosomes. Acidic pH markedly elevates association rate constants but dissociation rates are almost unchanged in the pH range 5.0 - 7.0. This pH-driven effect can be explained by the protonation/deprotonation states of Histidine, whose imidazole has a pKa of 6.0. At pH 5.0, imidazole ring is protonated, making Histidine positively charged and very hydrophilic, while at pH 7.0 imidazole is unprotonated, making Histidine less hydrophilic. We develop here a method to predict peptide binding to the four most frequent HLA-DP proteins: DP1, DP41, DP42 and DP5, using a molecular docking protocol. Dockings to virtual combinatorial peptide libraries were performed at pH 5.0 and pH 7.0. Results: The X-ray structure of the peptide - HLA-DP2 protein complex was used as a starting template to model by homology the structure of the four DP proteins. The resulting models were used to produce virtual combinatorial peptide libraries constructed using the single amino acid substitution (SAAS) principle. Peptides were docked into the DP binding site using AutoDock at pH 5.0 and pH 7.0. The resulting scores were normalized and used to generate Docking Score-based Quantitative Matrices (DS-QMs). The predictive ability of these QMs was tested using an external test set of 484 known DP binders. They were also compared to existing servers for DP binding prediction. The models derived at pH 5.0 predict better than those derived at pH 7.0 and showed significantly improved predictions for three of the four DP proteins, when compared to the existing servers. They are able to recognize 50% of the known binders in the top 5% of predicted peptides. Conclusions: The higher predictive ability of DS-QMs derived at pH 5.0 may be rationalised by the additional hydrogen bond formed between the backbone carbonyl oxygen belonging to the peptide position before p1 (p-1) and the protonated ε-nitrogen of His 79β. Additionally, protonated His residues are well accepted at most of the peptide binding core positions which is in a good agreement with the overall negatively charged peptide binding site of most MHC proteins. © 2012 Patronov et al.; licensee BioMed Central Ltd.

Consumer responses to really new products: examining the impacts of learning strategies and presentation formats on product comprehension and attitude formation

Mental simulations and analogies have been identified as powerful learning tools for RNPs. Furthermore, visuals in advertising have recently been conceptualized as meaningful sources of information as opposed to peripheral cues and thus may help consumers learn about RNPs. The study of visual attention may also contribute to understanding the links between conceptual and perceptual analyses when learning for a RNP. Two conceptual models are developed. the first model consists of causal relationships between the attributes of advertising stimuli for RNPs and consumer responses, as well as mediating influences. The second model focuses on the role of visual attention in product comprehension as a response to advertising stimuli. Two experiments are conducted: a Web-Experiment and an eye-tracking experiment. The first experiment (858 subjects) examines the effect of learning strategies (mental simulation vs. analogy vs. no analogy/no mental simulation) and presentation formats (words vs. pictures) on individual responses. The mediating role of emotions is assessed. The second experiment investigates the effect of learning strategies and presentation formats on product comprehension, along with the role of attention (17 subjects). The findings from experiment 1 indicate that learning strategies and presentation formats can either enhance or undermine the effect of advertising stimuli on individual responses. Moreover, the nature of the product (i.e. hedonic vs. utilitarian vs. hybrid) should be considered when designing communications for RNPs. The mediating role of emotions is verified. Experiment 2 suggests that an increase in attention to the message may either reflect enhanced comprehension or confusion.

The SEC’s retail investor 2.0: Interactive data and the rise of calculative accountability

The Securities and Exchange Commission (SEC) in the United States mandated a new digital reporting system for US companies in late 2008. The new generation of information provision has been dubbed by Chairman Cox, ‘interactive data’ (SEC, 2006a). Despite the promise of its name, we find that in the development of the project retail investors are invoked as calculative actors rather than engaged in dialogue. Similarly, the potential for the underlying technology to be applied in ways to encourage new forms of accountability appears to be forfeited in the interests of enrolling company filers. We theorise the activities of the SEC and in particular its chairman at the time, Christopher Cox, over a three year period, both prior to and following the ‘credit crisis’. We argue that individuals and institutions play a central role in advancing the socio-technical project that is constituted by interactive data. We adopt insights from ANT (Callon, 1986; Latour, 1987, 2005b) and governmentality (Miller, 2008; Miller and Rose, 2008) to show how regulators and the proponents of the technology have acted as spokespersons for the interactive data technology and the retail investor. We examine the way in which calculative accountability has been privileged in the SEC’s construction of the retail investor as concerned with atomised, quantitative data (Kamuf, 2007; Roberts, 2009; Tsoukas, 1997). We find that the possibilities for the democratising effects of digital information on the Internet has not been realised in the interactive data project and that it contains risks for the very investors the SEC claims to seek to protect.

5-Hydroxytryptamine induced excitation and inhibition in the subthalamic nucleus:action at 5-HT2C, 5-HT4 and 5-HT1A receptors

Extracellular single-unit recordings in mouse brain slices were used to determine the effect of exogenously applied 5-HT on STN neurones. Recordings were made from 74 STN cells which fired action potentials at a regular rate of 7.19 ± 0.5 Hz. In 61 cells (82%), 5-HT application increased STN neurone firing rate (10 μM, 180 ± 16.8%, n = 35) with an estimated EC 50 of 5.4 μM. The non-specific 5-HT2 receptor agonist α-methyl 5-HT (1-10 μM) mimicked 5-HT induced excitations (15 cells). These excitations were significantly reduced by pre-perfusion with the specific 5-HT2C receptor antagonist RS102221 (500 nM, 9 cells) and the 5HT4 antagonist GR113808 (500 nM, 7 cells). In 6 cells (8%) 5-HT induced biphasic responses where excitation was followed by inhibition, while in 7 cells (9%) inhibition of firing rate was observed alone. Inhibitory responses were reduced by the 5-HT1A antagonist WAY100135 (1 μM, 4 cells). No inhibitory responses were observed following α-methyl 5-HT applications. Both the excitations and inhibitions were unaffected by picrotoxin (50 μM, n = 5) and CNQX (10 μM, n = 5) indicative of direct postsynaptic effects. Thus, in STN neurones, 5-HT elicits two distinct effects, at times on the same neurone, the first being an excitation which is mediated by 5-HT 2C and 5-HT4 receptors and the second an inhibition which is mediated by 5-HT1A receptors. © 2005 Elsevier Ltd. All rights reserved.

Information processing and the UK weekend effect:Do investors cut their losses on Mondays?

This paper complements earlier work by the author that shows that the pattern of information arrivals into the UK stock market may explain the behaviour of returns. It is argued that delays or other systematic behaviour in the processing of this information could compound the impact of information arrival patterns. It is found, however, that this does not happen, and so it is the arrival and not the processing of news that is most important. © 2004 Taylor & Francis Ltd.

A note on information seasonality and the disappearance of the weekend effect in the UK stock market

The weekend effect in UK stock prices has disappeared in the 1990s. Beneath the surface however there remain systematic day-of-the-week effects only visible when returns are partitioned by the direction of the market. A systematic pattern of market-wide news arrivals into the UK stock market is discovered and found to provide an explanation for these day-of-the-week effects.

Phakometric measurement of ocular surface radii of curvature, axial separations and alignment in relaxed and accommodated human eyes

Measurements (autokeratometry, A-scan ultrasonography and video ophthalmophakometry) of ocular surface radii, axial separations and alignment were made in the horizontal meridian of nine emmetropes (aged 20-38 years) with relaxed (cycloplegia) and active accommodation (mean ± 95% confidence interval: 3.7 ± 1.1 D). The anterior chamber depth (-1.5 ± 0.3 D) and both crystalline lens surfaces (front 3.1 ± 0.8 D; rear 2.1 ± 0.6 D) contributed to dioptric vergence changes that accompany accommodation. Accommodation did not alter ocular surface alignment. Ocular misalignment in relaxed eyes is mainly because of eye rotation (5.7 ± 1.6° temporally) with small amounts of lens tilt (0.2 ± 0.8° temporally) and decentration (0.1 ± 0.1 mm nasally) but these results must be viewed with caution as we did not account for corneal asymmetry. Comparison of calculated and empirically derived coefficients (upon which ocular surface alignment calculations depend) revealed that negligible inherent errors arose from neglect of ocular surface asphericity, lens gradient refractive index properties, surface astigmatism, effects of pupil size and centration, assumed eye rotation axis position and use of linear equations for analysing Purkinje image shifts. © 2004 The College of Optometrists.

Information management and the holistic, process-oriented enterprise

This research examines the role of the information management process within a process-oriented enterprise, Xerox Ltd. The research approach is based on a post-positive paradigm and has resulted in thirty-five idiographic statements. The three major outcomes are: 1. The process-oriented holistic enterprise is an organisation that requires a long-term management commitment to its development. It depends on the careful management of people, tasks, information and technology. A complex integration of business processes is required and this can be managed through the use of consistent documentation techniques, clarity in the definition of process responsibilities and management attention to the global metrics and the centralisation of the management of the process model are critical to its success. 2. The role of the information management process within the context of a process-oriented enterprise is to provide flexible and cost-effective applications, technological, and process support to the business. This is best achieved through a centralisation of the management of information management and of the process model. A business-led approach combined with the consolidation of applications, information, process, and data architectures is central to providing effective business and process-focused support. 3. In a process oriented holistic enterprise, process and information management are inextricably linked. The model of process management depends heavily on information management, whilst the model of information management is totally focused around supporting and creating the process model. The two models are mutually creating - one cannot exist without the other. There is a duality concept of process and information management.

Investigating the supply and demand relationship in a profession: the English and Welsh schools of librarianship and information Studies and the Higher Education Library and Information Services employment sector in England and Wales.

Concern has been expressed in the professional literature - borne out by professional experience and observation - that the supply and demand relationship existing between the 13 English and Welsh Library and Information Studies (LIS) Schools (as providers of `First Professional' staff) and the Higher Education Library and Information Services (HE LIS) sector of England and Wales (as one group of employers of such staff) is unsatisfactory and needs attention. An appropriate methodology to investigate this problem was devised. A basic content analysis of Schools' curricular and recruitment material intended for public consumption was undertaken to establish an overview of the LIS initial professional education system in England and Wales, and to identify and analyse any covert messages imparted to readers. This was followed by a mix of Main Questionnaires and Semi-Structured Interviews with appropriate populations. The investigation revealed some serious areas of dissatisfaction by the HE LIS Chiefs with the role and function of the Schools. Considerable divergence of views emerged on the state of the working relationships between the two sectors and on the Schools' successes in meeting the needs of the HE LIS sector and on CPD provision. There were, however, areas of substantial and consistent agreement between the two sectors. The main implications of the findings were that those areas encompassing divergence of views were worrying and needed addressing by both sides. Possible ways forward included recommendations on improving the image of the profession purveyed by the Schools; the forming of closer and more effective inter-sectoral relationships; recognising fully the importance of `practicum' and increasing and sustaining the network of `practicum' providers.

Properties of intention:component structure and consequences for behavior, information processing and resistance

Three studies tested the impact of properties of behavioral intention on intention-behavior consistency, information processing, and resistance. Principal components analysis showed that properties of intention formed distinct factors. Study 1 demonstrated that temporal stability, but not the other intention attributes, moderated intention-behavior consistency. Study 2 found that greater stability of intention was associated with improved memory performance. In Study 3, participants were confronted with a rating scale manipulation designed to alter their intention scores. Findings showed that stable intentions were able to withstand attack. Overall, the present research findings suggest that different properties of intention are not simply manifestations of a single underlying construct ("intention strength"), and that temporal stability exhibits superior resistance and impact compared to other intention attributes. © 2013 Wiley Periodicals, Inc.

Alignment of information systems and organisation structure:developing an executive information systems with a cybernetic method

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Quinols as novel therapeutic agents. 2.1 4-(1-arylsulfonylindol- 2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents

A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones1 with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol- 2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI50 value of 16 nM and a mean LC50 value of 2.24 μM in the NCI 60-cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.