REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia

The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.

The psychological impact of diagnostic food challenges to confirm the resolution of peanut or tree nut allergy

Background - Twenty percent of children outgrow peanut allergy and 10% outgrow tree nut allergy. Resolution can be confirmed by a food challenge. Little is known about the psychosocial impact of the challenge. We aimed to investigate effects of a food challenge on anxiety, stress and quality of life (QoL) in children and their mothers on the day of a food challenge to peanuts or nuts, and in the months following the challenge. Methods - One hundred and three families participated. Forty children undergoing food challenges to access resolution of allergy, and their mothers, completed validated questionnaires to measure generic and food specific quality of life, stress and anxiety prior to challenge, on the day of investigation and 3–6 months later. Sixty-three children with no clinical indication to challenge (i.e. in the opinion of the allergist had persistent allergy) acted as comparison group completing questionnaires 3–6 months apart. Results - Mothers reported raised anxiety on the day of challenge (P = 0.007), but children were less anxious. The children (P = 0.01) and mothers (P = 0.01) had improved food-related, but not general, QoL 3–6 months following challenge. Children reported lower anxiety levels following the challenge (P = 0.02), but anxiety remained unchanged in mothers. The improvements in maternal and children's QoL and anxiety levels were irrespective of the challenge outcome and despite co-existing food allergies in 50% of children. Conclusions - Mothers experienced increased anxiety on the day of food challenge, unlike the children, perhaps reflecting the differences in their perceived risks. Food challenges are associated with improved food-related QoL in the following months even in those with a positive challenge.

Optical coherence tomography confirmed resolution of macular edema in a diabetic patient after hemodialysis

Purpose: The authors report the first case, to their knowledge, of resolution of diffuse macular edema after hemodialysis, which has been confirmed by optical coherence tomography. Methods: A 53-year-old white woman with type 2 diabetes developed worsening macular edema and was examined in the ophthalmology clinic and scheduled for macular grid laser photocoagulation. The laser, however, was deferred for 4 weeks because she had also developed end-stage renal failure and required hemodialysis. Results: When she was reviewed in the ophthalmology clinic 4 weeks later for laser therapy, it was found that her macular edema had resolved, vision had improved, and laser was unnecessary. Review at 6 months showed that the macular edema remains resolved. Conclusion: Ophthalmologists should be aware that hemodialysis may reduce macular edema in such patients. Copyright © by Ophthalmic Communications Society Inc.

Towards requirements aware systems:run-time resolution of design-time assumptions

In earlier work we proposed the idea of requirements-aware systems that could introspect about the extent to which their goals were being satisfied at runtime. When combined with requirements monitoring and self adaptive capabilities, requirements awareness should help optimize goal satisfaction even in the presence of changing run-time context. In this paper we describe initial progress towards the realization of requirements-aware systems with REAssuRE. REAssuRE focuses on explicit representation of assumptions made at design time. When such assumptions are shown not to hold, REAssuRE can trigger system adaptations to alternative goal realization strategies.

Run-time resolution of uncertainty

Requirements awareness should help optimize requirements satisfaction when factors that were uncertain at design time are resolved at runtime. We use the notion of claims to model assumptions that cannot be verified with confidence at design time. By monitoring claims at runtime, their veracity can be tested. If falsified, the effect of claim negation can be propagated to the system's goal model and an alternative means of goal realization selected automatically, allowing the dynamic adaptation of the system to the prevailing environmental context. © 2011 IEEE.

Matrix-assisted diffusion-ordered spectroscopy:application of surfactant solutions to the resolution of isomer spectra

The component spectra of a mixture of isomers with nearly identical diffusion coefficients cannot normally be distinguished in a standard diffusion-ordered spectroscopy (DOSY) experiment but can often be easily resolved using matrix-assisted DOSY, in which diffusion behaviour is manipulated by the addition of a co-solute such as a surfactant. Relatively little is currently known about the conditions required for such a separation, for example, how the choice between normal and reverse micelles affects separation or how the isomer structures themselves affect the resolution. The aim of this study was to explore the application of sodium dodecyl sulfate (SDS) normal micelles in aqueous solution and sodium 1,4-bis(2-ethylhexyl)sulfosuccinate (AOT) aggregates in chloroform, at a range of concentrations, to the diffusion resolution of some simple model sets of isomers such as monomethoxyphenols and short chain alcohols. It is shown that SDS micelles offer better resolution where these isomers differ in the position of a hydroxyl group, whereas AOT aggregates are more effective for isomers differing in the position of a methyl group. For both the normal SDS micelles and the less well-defined AOT aggregates, differences in the resolution of the isomers can in part be rationalised in terms of differing degrees of hydrophobicity, amphiphilicity and steric effects. Copyright © 2012 John Wiley & Sons, Ltd.

MicroRNA-155 promotes resolution of hypoxia-inducible factor 1α activity during prolonged hypoxia

The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1a (but not HIF-2a) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxiainducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1a mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1a in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1a mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1a stabilization and activity. Based on these data and a mathematical model of HIF-1a suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1a activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1a-dependent transcription. © 2011, American Society for Microbiology.

Odour pollution problems within the district of the Wrekin council

This thesis is concerned with various aspects of Air Pollution due to smell, the impact it has on communities exposed to it, the means by which it may be controlled and the manner in which a local authority may investigate the problems it causes. The approach is a practical one drawing on examples occurring within a Local Authority's experience and for that reason the research is anecdotal and is not a comprehensive treatise on the full range of options available. Odour Pollution is not yet a well organised discipline and might be considered esoteric as it is necessary to incorporate elements of science and the humanities. It has been necessary to range widely across a number of aspects of the subject so that discussion is often restricted but many references have been included to enable a reader to pursue a particular point in greater depth. In a `fuzzy' subject there is often a yawning gap separating theory and practice, thus case studies have been used to illustrate the interplay of various disciplines in resolution of a problem. The essence of any science is observation and measurement. Observation has been made of the spread of odour pollution through a community and also of relevant meterological data so that a mathematical model could be constructed and its predictions checked. It has been used to explore the results of some options for odour control. Measurements of odour perception and human behaviour seldom have the precision and accuracy of the physical sciences. However methods of social research enabled individual perception of odour pollution to be quantified and an insight gained into reaction of a community exposed to it. Odours have four attributes that can be measured and together provide a complete description of its perception. No objective techniques of measurement have yet been developed but in this thesis simple, structured procedures of subjective assessment have been improvised and their use enabled the functioning of the components of an odour control system to be assessed. Such data enabled the action of the system to be communicated using terms that are understood by a non specialist audience.

Sales manager problem resolution styles:measure development and an examination of their salesperson-related consequences

Personal selling and sales management play a critical role in the short and long term success of the firm, and have thus received substantial academic interest since the 1970s. Sales research has examined the role of the sales manager in some depth, defining a number of key technical and interpersonal roles which sales managers have in influencing sales force effectiveness. However, one aspect of sales management which appears to remain unexplored is that of their resolution of salesperson-related problems. This study represents the first attempt to address this gap by reporting on the conceptual and empirical development of an instrument designed to measure sales managers' problem resolution styles. A comprehensive literature review and qualitative research study identified three key constructs relating to sales managers' problem resolution styles. The three constructs identified were termed; sales manager willingness to respond, sales manager caring, and sales manager aggressiveness. Building on this, existing literature was used to develop a conceptual model of salesperson-specific consequences of the three problem resolution style constructs. The quantitative phase of the study consisted of a mail survey of UK salespeople, achieving a total sample of 140 fully usable responses. Rigorous statistical assessment of the sales manager problem resolution style measures was undertaken, and construct validity examined. Following this, the conceptual model was tested using latent variable path analysis. The results for the model were encouraging overall, and also with regard to the individual hypotheses. Sales manager problem resolution styles were found individually to have significant impacts on the salesperson-specific variables of role ambiguity, emotional exhaustion, job satisfaction, organisational commitment and organisational citizenship behaviours. The findings, theoretical and managerial implications, limitations and directions for future research are discussed.

Spatial aspects of MRSA epidemiology:A case study using stochastic simulation, kernel estimation and SaTScan

The identification of disease clusters in space or space-time is of vital importance for public health policy and action. In the case of methicillin-resistant Staphylococcus aureus (MRSA), it is particularly important to distinguish between community and health care-associated infections, and to identify reservoirs of infection. 832 cases of MRSA in the West Midlands (UK) were tested for clustering and evidence of community transmission, after being geo-located to the centroids of UK unit postcodes (postal areas roughly equivalent to Zip+4 zip code areas). An age-stratified analysis was also carried out at the coarser spatial resolution of UK Census Output Areas. Stochastic simulation and kernel density estimation were combined to identify significant local clusters of MRSA (p<0.025), which were supported by SaTScan spatial and spatio-temporal scan. In order to investigate local sampling effort, a spatial 'random labelling' approach was used, with MRSA as cases and MSSA (methicillin-sensitive S. aureus) as controls. Heavy sampling in general was a response to MRSA outbreaks, which in turn appeared to be associated with medical care environments. The significance of clusters identified by kernel estimation was independently supported by information on the locations and client groups of nursing homes, and by preliminary molecular typing of isolates. In the absence of occupational/ lifestyle data on patients, the assumption was made that an individual's location and consequent risk is adequately represented by their residential postcode. The problems of this assumption are discussed, with recommendations for future data collection.

Sonically induced narrowing of the NMR spectra of solids and other novel NMR techniques

A typical liquid state NMR spectrum is composed of a number of discrete absorptions which can be readily interpreted to yield detailed information about the chemical environment of the nuclei found within the sample. The same cannot be said about the spectra of solid samples. For these the absorptions are typically broad, featureless and yield little information directly. This situation may be further exacerbated by the characteristically long T1 values of nuclei bound within a solid lattice which, consequently, require long inter-sequence delays that necessitate lengthy experiments. This work attempts to address both of these inherent problems. Classically, the resolution of the broad-line spectra of solids into discrete resonances has been achieved by imparting to the sample coherent rotation about specific axes in relation to the polarising magnetic field, as implemented in the magic-angle spinning (MAS) [1], dynamic angle spinning (DAS) [2] and double rotation (DOR) [3] NMR experiments. Recently, an alternative method, sonically induced narrowing of the NMR spectra of solids (SINNMR) [4], has been reported which yields the same well resolved solid-state spectra as the classic solid-state NMR experiments, but which achieves the resolution of the broad-line spectra through the promotion of incoherent motion in a suspension of solid particles. The first part of this work examines SINNMR and, in particular, concentrates on ultrasonically induced evaluation, a phenomenon which is thought to be essential to the incoherent averaging mechanism. The second part of this work extends the principle of incoherent motion, implicit in SINNMR, to a new genre of particulate systems, air fluidized beds, and examines the feasibility of such systems to provide well resolved solid state NMR spectra. Samples of trisodium phosphate dodecahydrate and of aluminium granules are examined using the new method with partially resolved spectra being reported in the case of the latter.

Automated mapping of environmental variables from a SEIS or SISE perspective

The INTAMAP FP6 project has developed an interoperable framework for real-time automatic mapping of critical environmental variables by extending spatial statistical methods and employing open, web-based, data exchange protocols and visualisation tools. This paper will give an overview of the underlying problem, of the project, and discuss which problems it has solved and which open problems seem to be most relevant to deal with next. The interpolation problem that INTAMAP solves is the generic problem of spatial interpolation of environmental variables without user interaction, based on measurements of e.g. PM10, rainfall or gamma dose rate, at arbitrary locations or over a regular grid covering the area of interest. It deals with problems of varying spatial resolution of measurements, the interpolation of averages over larger areas, and with providing information on the interpolation error to the end-user. In addition, monitoring network optimisation is addressed in a non-automatic context.

Privatization : problems of implementation in Egypt

This study aims to investigate to what extent the views of the managers of the enterprises to be privatized are a barrier to smooth implementation of privatization as opposed to other problems. Accordingly, the research tackles two main issues: Identification and analysis of the major problems encountered in the implementation of the Egyptian privatization programme and at which level these problems exist while proposing different approaches to tackle them; and views of public sector top and middle-level managers regarding the main issues of privatization. The study relies upon a literature survey, interviews with stakeholders, a survey of managers' attitudes and several illustrative case studies. A model of "good practice" for the smooth and effective implementation of privatization has been designed. Practice in Egypt has then been studied and compared with the "good practice" model. Lack of strictness and firmness in implementing the announced privatization programme has been found to be a characteristic of Egyptian practice. This is partly attributable to the inadequacy of the programme and partly to the different obstacles to implementation. The main obstacles are doubtful desirability of privatization on the part of the managers at different implementation levels, resistance of stakeholders, in adequately of the legal framework governing privatization, redundant labour, lack of an efficient monitoring system allowing for accountability, inefficient marketing of privatization, ineffective communication, insufficient information at different levels and problems related to valuation and selling procedures. A large part of the thesis is concerned with SOE (State Owned Enterprise) managers' attitudes on and understanding of the privatization (appraised through surveys). Although most managers have stated their acceptance of privatization, many of their responses show that they do not accept selling SOEs. They understand privatization to include enterprise reform and restructuring, changing procedures and giving more authority to company executives, but not necessarily as selling SOEs. The majority of managers still see many issues that have to be addressed for smooth implementation of privatization e.g. insufficiency of information, incompleteness of legal framework, restructuring and labour problems. The main contribution to knowledge of this thesis is the study of problems of implementing privatization in developing countries especially managers' resistance to privatization as a major change, partly because of the threat it poses and partly because of the lack of understanding of privatization and implications of operating private businesses. A programme of persuading managers and offsetting the unfavourable effects is recommended as an outcome of the study. Five different phrases and words for the national Index to theses are: Egypt, privatization, implementation of privatization, problems of implementing privatization and managers' attitudes towards privatization.