Determination of Spontaneous Mutation Frequencies in Measles Virus under Nonselective Conditions

There is a paradox between the remarkable genetic stability of measles virus (MV) in the field and the high mutation rates implied by the frequency of the appearance of monoclonal antibody escape mutants generated when the virus is pressured to revert in vitro (S. J. Schrag, P. A. Rota, and W. J. Bellini, J. Virol. 73: 51-54, 1999). We established a highly sensitive assay to determine frequencies of various categories of mutations in large populations of wild-type and laboratory-adapted MVs using recombinant viruses containing an additional transcription unit (ATU) encoding enhanced green fluorescent protein (EGFP). Single and double mutations were made in the fluorophore of EGFP to ablate fluorescence. The frequencies of reversion mutants in the population were determined by measuring the appearance of fluorescence indicating a revertant virus. This allows mutation rates to be measured under nonselective conditions, as phenotypic reversion to fluorescence requires only either a single-or a double-nucleotide change and amino acid substitution, which does not affect the length of the nonessential reporter protein expressed from the ATU. Mutation rates in MV are the same for wild-type and laboratory-adapted viruses, and they are an order of magnitude lower than the previous measurement assessed under selective conditions. The actual mutation rate for MV is approximately 1.8 x 10(-6) per base per replication event. Copyright © 2013, American Society for Microbiology. All Rights Reserved.

Heterogeneity assumptions in the specification of bargaining models: a study of household level trade-offs between commuting time and salary

With many real world decisions being made in conjunction with other decision makers, or single agent decisions having an influence on other members of the decision maker's immediate entourage, there is strong interest in studying the relative weight assigned to different agents in such contexts. In the present paper, we focus on the case of one member of a two person household being asked to make choices affecting the travel time and salary of both members. We highlight the presence of significant heterogeneity across individuals not just in their underlying sensitivities, but also in the relative weight they assign to their partner, and show how this weight varies across attributes. This is in contrast to existing work which uses weights assigned to individual agents at the level of the overall utility rather than for individual attributes. We also show clear evidence of a risk of confounding between heterogeneity in marginal sensitivities and heterogeneity in the weights assigned to each member. We show how this can lead to misleading model results, and argue that this may also explain past results showing bargaining or weight parameters outside the usual [0,1] range in more traditional joint decision making contexts. In terms of substantive results, we find that male respondents place more weight on their partner's travel time, while female respondents place more weight on their partner's salary.

Alfvén Waves in the Solar Atmosphere: From Theory to Observations

Alfvén waves are considered to be viable transporters of the non-thermal energy required to heat the Sun's quiescent atmosphere. An abundance of recent observations, from state-of-the-art facilities, have reported the existence of Alfvén waves in a range of chromospheric and coronal structures. Here, we review the progress made in disentangling the characteristics of transverse kink and torsional linear magnetohydrodynamic (MHD) waves. We outline the simple, yet powerful theory describing their basic properties in (non-)uniform magnetic structures, which closely resemble the building blocks of the real solar atmosphere.

Interpretation of electrochemical measurements made during micro-scale abrasion-corrosion

This paper brings together and analyzes recent work based on the interpretation of the electrochemical measurements made on a modified micro-abrasion-corrosion tester used in several research programmes. These programmes investigated the role of abradant size, test solution pH in abrasion-corrosion of biomaterials, the abrasion-corrosion performance of sintered and thermally sprayed tungsten carbide surfaces under downhole drilling environments and the abrasion-corrosion of UNS S32205 duplex stainless steel. Various abrasion tests were conducted under two-body grooving, three-body rolling and mixed grooving-rolling abrasion conditions, with and without abrasives, on cast F75 cobalt-chromium-molybdenum (CoCrMo) alloy in simulated body fluids, 2205 in chloride containing solutions as well as sprayed and sintered tungsten carbide surfaces in simulated downhole fluids. Pre- and post-test inspections based on optical and scanning electron microscopy analysis are used to help interpret the electrochemical response and current noise measurements made in situ during micro-abrasion-corrosion tests. The complex wear and corrosion mechanisms and their dependence on the microstructure and surface composition as a function of the pH, abrasive concentration, size and type are detailed and linked to the electrochemical signals. The electrochemical versus mechanical processes are plotted for different test parameters and this new approach is used to interpret tribo-corrosion test data to give greater insights into different tribo-corrosion systems. Thus new approaches to interpreting in-situ electrochemical responses to surfaces under different abrasive wear rates, different abrasives and liquid environments (pH and NaCl levels) are made. This representation is directly related to the mechano-electrochemical processes on the surface and avoids quantification of numerous synergistic, antagonistic and additive terms associated with repeat experiments. (C) 2010 Elsevier Ltd. All rights reserved.

Predicting the past: Understanding the causes of bank distress in the Netherlands in the 1920s

Why do some banks fail in financial crises while others survive? This article answers this question by analysing the effect of the Dutch financial crisis of the 1920s on 142 banks, of which 33 failed. We find that choices of balance sheet composition and product market strategy made in the lead-up to the crisis had a significant impact on banks’ subsequent chances of experiencing distress. We document that high-risk banks – those operating highly-leveraged portfolios and attracting large quantities of deposits – were more likely to fail. Branching and international activities also increased banks’ default probabilities. We measure the effects of board interlocks, which have been characterized in the extant literature as contributing to the Dutch crisis. We find that boards mattered: failing banks had smaller boards, shared directors with smaller and very profitable banks and had a lower concentration of interlocking directorates in non-financial firms.

An international comparison of legal frameworks for supported and substitute decision-making in mental health services

There have been important recent developments in law, research, policy and practice relating to supporting people with decision-making impairments, in particular when a person’s wishes and preferences are unclear or inaccessible. A driver in this respect is the United Nations Convention on the Rights of Persons with Disabilities (CRPD); the implications of the CRPD for policy and professional practices are currently debated. This article reviews and compares four legal frameworks for supported and substitute decision-making for people whose decision-making ability is impaired. In particular, it explores how these frameworks may apply to people with mental health problems. The four jurisdictions are: Ontario, Canada; Victoria, Australia; England and Wales, United Kingdom (UK); and Northern Ireland, UK. Comparisons and contrasts are made in the key areas of: the legal framework for supported and substitute decision-making; the criteria for intervention; the assessment process; the safeguards; and issues in practice. Thus Ontario has developed a relatively comprehensive, progressive and influential legal framework over the past thirty years but there remain concerns about the standardisation of decision-making ability assessments and how the laws work together. In Australia, the Victorian Law Reform Commission (2012) has recommended that the six different types of substitute decision-making under the three laws in that jurisdiction, need to be simplified, and integrated into a spectrum that includes supported decision-making. In England and Wales the Mental Capacity Act 2005 has a complex interface with mental health law. In Northern Ireland it is proposed to introduce a new Mental Capacity (Health, Welfare and Finance) Bill that will provide a unified structure for all substitute decision-making. The discussion will consider the key strengths and limitations of the approaches in each jurisdiction and identify possible ways that further progress can be made in law, policy and practice.

Multiwavelength studies of MHD waves in the solar chromosphere: An Overview of recent results

The chromosphere is a thin layer of the solar atmosphere that bridges the relatively cool photosphere and the intensely heated transition region and corona. Compressible and incompressible waves propagating through the chromosphere can supply significant amounts of energy to the interface region and corona. In recent years an abundance of high-resolution observations from state-of-the-art facilities have provided new and exciting ways of disentangling the characteristics of oscillatory phenomena propagating through the dynamic chromosphere. Coupled with rapid advancements in magnetohydrodynamic wave theory, we are now in an ideal position to thoroughly investigate the role waves play in supplying energy to sustain chromospheric and coronal heating. Here, we review the recent progress made in characterising, categorising and interpreting oscillations manifesting in the solar chromosphere, with an impetus placed on their intrinsic energetics.

Autism and ABA: Best Practice in America and the Way Forward for Europe.

According to recent estimates, 1 in each 68 new-borns will be diagnosed with an Autism Spectrum Disorder (ASD) in the USA (Centers for Disease Control and Prevention, 2014), while 1 in every 29 children will be diagnosed with ASD in the UK (Dillenburger, Jordan, McKerr, & Keenan, 2015). Individuals diagnosed with ASD share a set of characteristics at varying levels of severity: impairments in social communication skills and presence of restricted interests and repetitive behaviours (American Psychiatric Association, 2013).Notwithstanding these figures, little effort has been placed in European countries’ policies for reaching an early diagnosis. This has a detrimental effect on future prognosis for children with ASD, since research has clearly shown that when evidence-based interventions are accessed early in life, they can lead to great improvements on the overall functioning of children with ASD, including significant gains in social communication and reduction of inappropriate behaviours (Dawson, Rogers, Munson, Smith, Winter, Greenson, Donaldson, & Varley, 2009).Additionally, when looking at the services available for children with ASD and their families in Europe, it seems that not much improvement has been made in the last decades. Traditional eclectic approaches and a wealth of non-scientific methods seem to be available and often recommended by public bodies, while state-funded evidence-based interventions are not offered as part of the education or health system. Given that there is a wealth of evidence on the effectiveness of interventions based on the science of ABA, it seems that specific action is required to correct the situation, respecting children’s right to effective treatment and inclusion.In the present paper, these issues are fully discussed and recommendations for best practice are offered.

Powder semiconductor photocatalysis in aqueous solution: An overview of kinetics-based reaction mechanisms

A brief, historical overview of 10 apparently different, although in some cases, upon inspection, closely related, popular proposed reaction mechanisms and their associated rate equations, is given and in which the rate expression for each mechanism is derived from basic principles, Appendix A. In Appendix B, each of the 5 main mechanisms are tested using datasets, comprising initial reaction rate vs. organic pollutant concentration, [P] and incident irradiance, ρ, data, reported previously for TiO2, where P is phenol, 4-chlorophenol and formic acid. The best of those tested, in terms of overall fit, simplicity, usefulness and versatility is the disrupted adsorption kinetic model proposed by Ollis. The usual basic assumptions made in constructing these mechanisms are reported and the main underlying concerns explored.

Capsulotomy worsens diabetic retinopathy in the Ins2Akitamice

Purpose: Cataract surgery increases the risk of developing diabetic retinopathy (DR) and accelerates the progression of pre-existing DR. Recent evidence suggests that cataract surgery elicits retinal pro-inflammatory gene expression, although the underlying pathogenic mechanisms remain ill-defined. In this study, we investigated the effect of capsulotomy on visual function, retinal immune cell activation and photoreceptor stress in the Ins2Akita mice, a mouse model of Type-1 diabetes. Methods: Male heterozygous Ins2Akita mice (2 months of hyperglycemia) and C57BL/6J age-matched siblings were used in this study. An incision (1mm) was made in the peripheral cornea and Capsulotomy was performed in the anterior lens capsule of the right eye. Control mice received corneal incision without capsulotomy in the right eye. The unoperated left eyes were used as internal controls. Forty days following surgery, retinal function was assessed by electroretinography (ERG). Neuronal retinal damage and microglial activation were assessed by imunohistochemistry. Results: The Ins2Akita mice receiving capsulotomy presented lower scotopic a-wave, b-wave and oscillatory potentials amplitudes compared to other experimental groups. Fundus images, SD-OCT and H&E staining did not show significant changes between different groups. Immunostaining of Iba-1 and CD68 revealed exacerbated microglial activation and giant cell immune cell infiltration in eyes receiving capsulotomy in Ins2Akita mice. This was accompanied by a disruption of cone photoreceptor outer segments and abnormal rhodopsin expression at the outer nuclear layer. Conclusions: Our results suggest that capsulotomy induces retinal microglial activation and worsens retinal neuropathy in diabetic eyes.

Diabetes in the young - a global view and worldwide estimates of numbers of children with type 1 diabetes

This paper describes the methodology, results and limitations of the 2013 International Diabetes Federation (IDF) Atlas (6th edition) estimates of the worldwide numbers of prevalent cases of type 1 diabetes in children (<15 years). The majority of relevant information in the published literature is in the form of incidence rates derived from registers of newly diagnosed cases. Studies were graded on quality criteria and, if no information was available in the published literature, extrapolation was used to assign a country the rate from an adjacent country with similar characteristics. Prevalence rates were then derived from these incidence rates and applied to United Nations 2012 Revision population estimates for 2013 for each country to obtain estimates of the number of prevalent cases. Data availability was highest for the countries in Europe (76%) and lowest for the countries in sub-Saharan Africa (8%). The prevalence estimates indicate that there are almost 500,000 children aged under 15 years with type 1 diabetes worldwide, the largest numbers being in Europe (129,000) and North America (108,700). Countries with the highest estimated numbers of new cases annually were the United States (13,000), India (10,900) and Brazil (5000). Compared with the prevalence estimates made in previous editions of the IDF Diabetes Atlas, the numbers have increased in most of the IDF Regions, often reflecting the incidence rate increases that have been well-documented in many countries. Monogenic diabetes is increasingly being recognised among those with clinical features of type 1 or type 2 diabetes as genetic studies become available, but population-based data on incidence and prevalence show wide variation due to lack of standardisation in the studies. Similarly, studies on type 2 diabetes in childhood suggest increased incidence and prevalence in many countries, especially in Indigenous peoples and ethnic minorities, but detailed population-based studies remain limited.

Long-Term Imprisonment in Northern Ireland:Psychological or Political Survival?

The chapter reviews the literature on the affects of long-term imprisonment with a focus on concepts of psychological survival, learned helplessness and institutionalization. It then discusses trends in imprisonment in Northern Ireland and the exceptionally high proportion of prisoners serving life sentences. Through interviews with prisoners and their relatives, a critique of the literature is made in terms of the failure to take account of cases of collective prisoner organization and strong political motivation.

Recycling of demolition waste in Merseyside

There have been considerable developments in Merseyside over the last fifteen years with regards to the commercialisation of recycled demolition aggregate. Liverpool is an urban region that at the time was undergoing regeneration. This required the demolition of old infrastructure. Subsequent reconstruction required new construction materials. A project started in 2001 to investigate the economics, practicalities and technicalities of using recycled demolition aggregates in concrete precast products. It was estimated that if all six demolition contractors around Liverpool worked round the clock (i.e. assuming there was enough feed material) they would still have found it difficult to maintain the required supplies for a single precast factory. Investment in equipment was therefore required to guarantee supply and improve the quality of the recycled demolition aggregate. The market forces and the incentives/drivers for construction companies to adopt sustainable practises have encouraged investment of several million pounds to be made in new recycling plants and has resulted in ‘urban quarries’. This paper describes the developments in recycling of construction and demolition waste over the last decade in Merseyside and shows that recycling is not only sustainable but also profitable.

Control energy consumption and system performance in vector control of voltage source converters

Power electronics plays an important role in the control and conversion of modern electric power systems. In particular, to integrate various renewable energies using DC transmissions and to provide more flexible power control in AC systems, significant efforts have been made in the modulation and control of power electronics devices. Pulse width modulation (PWM) is a well developed technology in the conversion between AC and DC power sources, especially for the purpose of harmonics reduction and energy optimization. As a fundamental decoupled control method, vector control with PI controllers has been widely used in power systems. However, significant power loss occurs during the operation of these devices, and the loss is often dissipated in the form of heat, leading to significant maintenance effort. Though much work has been done to improve the power electronics design, little has focused so far on the investigation of the controller design to reduce the controller energy consumption (leading to power loss in power electronics) while maintaining acceptable system performance. This paper aims to bridge the gap and investigates their correlations. It is shown a more thoughtful controller design can achieve better balance between energy consumption in power electronics control and system performance, which potentially leads to significant energy saving for integration of renewable power sources.

DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines

BACKGROUND: Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes.

METHODS: HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity Pathway Analysis.

RESULTS: Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed.

CONCLUSION: This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.