The analysis of Bcr-Abl—Nox signalling in chronic myeloid leukaemia

Chronic Myeloid Leukaemia (CML) is a myeloproliferative disorder characterised by increased proliferation of haematopoietic stem cells. CML results following generation of the chimeric protein Bcr-Abl, a constitutively active tyrosine kinase which induces oncogenesis in part by promoting increased cell survival and proliferation. Since the development of Bcr-Abl-specific tyrosine kinase inhibitors (TKIs) there has been a substantial improvement in the clinical treatment of CML. Unfortunately, residual disease and the development of TKI resistance has become an ever growing concern, resulting in the need for a greater understanding of the disease in order to develop new treatment strategies. Interestingly, constitutive expression of the Bcr-Abl in CML is known to produce elevated levels of Reactive Oxygen Species (ROS) which are known to influence a variety of cellular processes. Previous studies have demonstrated that NADPH oxidase (Nox) activity contributes to intracellular-ROS levels in Bcr-Abl-positive cells, enhancing survival signalling. The objective of this study was to elucidate how Nox protein activity was influenced downstream of Bcr-Abl while examining how Nox-derived ROS influenced CML disease phenotype to identify the potential in targeting these proteins to improve CML treatment. These studies demonstrated that inhibition of Bcr-Abl signalling, led to a significant reduction in ROS levels which was concurrent with the GSK-3dependent, post-translational down-regulation of the small membrane-bound protein p22phox, an essential component of the Nox complex. siRNA knockdown of p22phox identified it to have a significant role in cellular proliferation and cell viability, demonstrating the importance of Nox protein activity in CML disease phenotype. Furthermore, removal of p22phox was demonstrated to make cells significantly more susceptible to Bcr-Abl-specific TKI treatment, while pharmacological silencing of Nox activity in combination with TKIs was demonstrated to produce substantial, synergistic increases in cell death through augmentation of apoptosis, demonstrating the therapeutic potential of targeting Nox proteins in combination with Bcr-Abl inhibition.

The UK 9/11 evacuation study: Analysis of survivors’ recognition and response phase in WTC1

The September 11th 2001 impact on the World Trade Centre (WTC) resulted in one of the most significant evacuations of a high-rise building in modern times. The UK High-rise Evacuation Evaluation Database (HEED) study aimed to capture and collate the experiences and behaviours of WTC evacuees in a database, which would facilitate and encourage future research, which in turn would influence the design construction and use of safer built environments. A data elicitation tool designed for the purpose comprised a pre-interview questionnaire followed by a one-to-one interview protocol consisting of free-flow narratives and semi-structured interviews of WTC evacuees. This paper, which is one in a series dealing with issues relating to the successful evacuations of towers 1 and 2, focuses on cue recognition and response patterns within WTC1. Results are presented by vertical floor clusters and include information regarding cues experienced, activities prior and subsequent to occupants first becoming aware that something was wrong, perceived personal risk, time taken to respond and the inter-relationships between them. The results indicate differences in occupant activities across the floor clusters and suggest that these differences can be explained in terms of the perception of risk and the nature and extent of cues received by the participants.

Analysis of the footprint in school age of 8-10 years old

Biomechanical problems in children, is an important subject currently, existing controversy in different areas, for example, the majority of children have a flattened footprint, or the hypermobility joint is linked to a musculoskeletal pain. The objective of the study was to determine what kind of footprint is most frequent in school-age children (8-10 years) in the area of Plasencia. This was taken as a sign 50 children, of whom 28 were males and 22 females. All the subjects in the study underwent an assessment of footprint planted in static as well as an exploration of different parameters through inspection in a standing position (formula digital, rearfoot). The results show that excavated footprint is present in a 72% cases of the population, 16% was belonging to an excavated footprint in which we find a higher percentage of weight related.For the digital formula we find that the most common is the Egyptian foot by 40% of the cases and that the prevalence in the rearfoot, is a normal hindfoot. In relation with the hypermobility joint, we check that it is more common in girls and that none of them presents an association to musculoskeletal pain. As a future line we could establish a more comprehensive study with new techniques and valuingchild’s statics and dynamics, to have a more accurate study of the different variables in the sample population studied.

Analysis about the society of 'Pa Negre' (Agustí Villaronga, 2010)

This article has developed with the intention of analyzing how the stereotypes, prejudices and lies can influence the education of the children. Formation, that usually comes from family and teachers, who sometimes move for extremist ideologies. There exist multiple fictions in which we observe these social archetypes, but it is the case of the movie Pa negre (Agustí Villaronga, 2010), where the principal personage evolves psychologically, because of that its eyes observe and the ideas that the people transmit him on its family, in the rural environments, where the tradition of the rumors coexists.

The Effects of Social Class and Ethnicity on Gender Differences in GCSE Attainment: A Secondary Analysis of the Youth Cohort Study of England and Wales 1997-2001

This article is based upon a secondary analysis of the Youth Cohort Study of England and Wales 1998 and examines the effects of social class and ethnicity on gender differences in GCSE attainment for those who left school in 1997 (n = 14,662). The article shows that both social class and ethnicity exert a far greater influence on the GCSE performance of boys and girls than gender. Moreover, the article also shows that an interaction effect is present between social class and gender and also between ethnicity and gender in relation to their impact upon GCSE attainment. More specifically, the findings suggest that a strong correlation exists such that the lower the overall levels of educational attainment for any group (whether that group is defined in terms of social class or ethnicity), the higher the gender differences that exist between those within that group.

Analysis of the admissions tests for teacher training in Spain and Finland: knowledge or competences

One of the most decisive factors in the quality of education and academic performance of students is quality, preparation and dedication of the teachers. The exquisite system of selecting candidates for teacher training programs is one of the fundamentals of success of the Finnish Education System. The responsibility of choosing the best students to convert them into teachers is a challenge that involves a significant reform of university admission. Achieving this goal involves the choice of strategies and educational tools in accordance to the complexity of the demands presented by the teaching profession in the digital age. This study describes, analyzes and compares the admission tests in the University of Spain (PAU) and Finland (VAKAVA), for those who wish to become professional educators, in order to understand the possible influence of these tests to select the most suitable candidates to develop into future teaching professionals. The results showed that in Spain, the entrance test to universities is developed in a general way for all the students that aspire to any field of knowledge, while in Finland, the test is specific and particular for students aspiring to the field of education. The results of this study can guide and encourage the necessary changes that have to be done in the admission tests to Spanish university in general and to teacher education faculties in particular.

Analysis of the reading and comprehension control in scientific texts in high school students

Students' learning process can be negatively affected when their reading and comprehension control is not appropriated. This research focuses on the analysis of how a group of students from high school evaluate their reading comprehension in manipulated scientific texts. An analysis tool was designed to determine the students' degree of comprehension control when reading a scientific short text with an added contradiction. The results have revealed that the students from 1st and 3rd ESO do not properly self-evaluated their reading comprehension. A different behavior has been observed in 1st Bachillerato, where appropriate evaluation and regulation seem to be more frequent. Moreover, no significant differences have been found regarding the type of text, year or gender. Finally, as identified by previous research, the correlations between the students' comprehension control and their school marks have shown to have a weak relationship and inversely proportional to the students' age.

Comparative proteome analysis of triclabendazole response in the liver fluke, Fasciola hepatica.

Control of Fasciola hepatica infections of livestock in the absence of vaccines depends largely on the chemical triclabendazole (TCBZ) because it is effective against immature and adult parasites. Overdependence on a single drug and improper application is considered a significant factor in increasing global reports of fluke resistant to TCBZ. The mode(s) of action and biological target(s) of TCBZ are not confirmed, delaying detection and the monitoring of early TCBZ resistance. In this study, to further understand liver fluke response to TCBZ, the soluble proteomes of TCBZ-resistant and TCBZ-susceptible isolates of F. hepatica were compared with and without in vitro exposure to the metabolically active form of the parent drug triclabendazole sulphoxide (TCBZ-SO), via two-dimensional gel electrophoresis (2-DE). Gel image analysis revealed proteins displaying altered synthesis patterns and responses both between isolates and under TCBZ-SO exposure. These proteins were identified by mass spectrometry supported by a F. hepatica expressed sequence tag (EST) data set. The TCBZ responding proteins were grouped into three categories; structural proteins, energy metabolism proteins, and “stress” response proteins. This single proteomic investigation supported the reductionist experiments from many laboratories that collectively suggest TCBZ has a range of effects on liver fluke metabolism. Proteomics highlighted differences in the innate proteome profile of different fluke isolates that may influence future therapy and diagnostics design. Two of the TCBZ responding proteins, a glutathione transferase and a fatty acid binding protein, were cloned, produced as recombinants, and both found to bind TCBZ-SO at physiologically relevant concentrations, which may indicate a role in TCBZ metabolism and resistance.

Stress correlation between instrumentation and simulation analysis of the die for high pressure die casting

A strain gauge instrumentation trial on a high pressure die casting ‘HPDC’ die was compared to a corresponding simulation model using Magmasoft® casting simulation software at two strain gauge rosette locations. The strains were measured during the casting cycle, from which the von Mises stress was determined and then compared to the simulation model. The von Mises stress from the simulation model correlated well with the findings from the instrumentation trial, showing a difference of 5.5%, ~ 10 MPa for one strain gauge rosette located in an area of low stress gradient. The second rosette was in a region of steep stress gradient, which resulted in a difference of up to 40%, ~40 MPa between the simulation and instrumentation results. Factors such as additional loading from die closure force or metal injection pressure which are not modelled by Magmasoft® were seen to have very little influence on the stress in the die, less than 7%.

Obesity associated severe asthma represents a distinct clinical phenotype - Analysis of the British Thoracic Society Difficult Asthma Registry patient cohort according to body mass index

BACKGROUND: Obesity has emerged as a risk factor for the development of asthma and it may also influence asthma control and airways inflammation. However, the role of obesity in severe asthma remains unclear. OBJECTIVE: To explore the association between obesity (defined by BMI) and severe asthma. METHODS: Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics and healthcare utilisation between three body mass index (BMI) categories (normal weight: 18.5 -24.99, overweight: 25 -29.99, obese: =30) in a well characterised group of severe asthmatic adults. RESULTS: The study population consisted of 666 severe asthmatics with a median BMI of 29.8 (interquartile range 22.5 -34.0). The obese group exhibited greater asthma medication requirements in terms of maintenance corticosteroid therapy (48.9% versus 40.4% and 34.5% in the overweight and normal weight groups, respectively), steroid burst therapy and short-acting ß2-agonist (SABA) use per day. Significant differences were seen with gastro-oesophageal reflux disease (GORD) (53.9% versus 48.1% and 39.7% in the overweight and normal weight groups, respectively) and proton pump inhibitor (PPI) use. Bone density scores were higher in the obese group, whilst pulmonary function testing revealed a reduced FVC and raised Kco. Serum IgE levels decreased with increasing BMI and the obese group were more likely to report eczema, but less likely to have a history of nasal polyps. CONCLUSIONS: Severe asthmatics display particular characteristics according to BMI that support the view that obesity associated severe asthma may represent a distinct clinical phenotype.1Royal Brompton Hospital, London, UK;2Department of Computing, Imperial College, UK3Airways Disease, National Heart & Lung Institute, Imperial College, UK;4Centre for infection and immunity, Queen's University of Belfast, UK;5University of Leicester, UK;6The University of Manchester and University Hospital of South Manchester, UK;7Birmingham Heartlands Hospital, University of Birmingham, UK;8Gartnavel General Hospital, University of Glasgow, UK;9Glasgow Royal Infirmary, Glasgow, UKCorrespondence: Dr Andrew N. Menzies-Gow, Royal Brompton Hospital, Fulham Road, London SW3 6HP.

Income, deprivation, and economic strain. An analysis of the European community household panel

This paper is concerned with the relationship between household income and life-style deprivation, and their combined impact on households' perceptions of economic strain. It takes as a point of departure findings from a number of European countries showing that the relationship between income and deprivation is weaker than widely assumed and that relative income poverty lines may perform poorly in terms of identifying the most deprived households. It proceeds to examine how far these conclusions about income and deprivation can be generalized to the countries included in the first wave of the European Community Household Panel. Results show that five distinct dimensions of deprivation emerge from an overall European analysis and that these are consistent across individual countries. While a good deal of similarity is observed in the income-deprivation relationship, countries differ in the strength of relationship between income and what is termed 'current liferstyle deprivation' with the relationship being generally weakest in the richer countries. The implications of these findings for the use of relative income poverty lines are developed. Extending this analysis to an assessment of how income and deprivation combine to influence perceptions of economic strain, we show that within-nation reference group processes operating in a uniform manner across countries can account for the bulk of the variation in strain. Cross-national differences can be accounted for by corresponding variation in income and deprivation levels.

Review and quantitative meta-analysis of diet suggests the Eurasian otter (Lutra lutra) is likely to be a poor bioindicator

The Eurasian otter (Lutra lutra L.) is a top predator in aquatic systems and plays an important role in ecosystem functioning. However, it has undergone dramatic declines throughout Europe as a result of environmental degradation. We examine the putative role of the otter as a bioindicator in Ireland which remains a stronghold for the species and affords a unique opportunity to examine variation in its ecological niche. We describe diet, using spraint contents, along rivers during 2010 and conduct a review and quantitative meta-analysis of the results of a further 21 studies. We aimed to assess variation in otter diet in relation to river productivity, a proxy for natural nutrification and anthropogenic eutrophication, and availability of salmonid prey (Salmo trutta and Salmo salar), to test the hypothesis that otter diet is related to environmental quality. Otter diet did not vary with levels of productivity or availability of salmonids whilst Compositional Analysis suggested there was no selection of salmonid over non-salmonid fish. There was a distinct niche separation between riverine and lacustrine systems, the latter being dominated by Atlantic eel (Anguilla anguilla). Otters are opportunistic and may take insects, freshwater mussels, birds, mammals and even fruit. Otters living along coasts have a greatest niche breath than those in freshwater systems which encompasses a wide variety of intertidal prey though pelagic fish are rarely taken. It is concluded that the ability of the otter to feed on a wide diversity of prey taxa and the strong influence of habitat type, renders it a poor bioindicator of environmental water quality. It seems likely that the plasticity of the habitat and dietary niche of otters, and the extent of suitable habitat, may have sustained populations in Ireland despite intensification of agriculture during the 20th century.

A New Analysis of Mars "Special Regions": Findings of the Second MEPAG Special Regions Science Analysis Group (SR-SAG2)

A committee of the Mars Exploration Program Analysis Group (MEPAG) has reviewed and updated the description of Special Regions on Mars as places where terrestrial organisms might replicate (per the COSPAR Planetary Protection Policy). This review and update was conducted by an international team (SR-SAG2) drawn from both the biological science and Mars exploration communities, focused on understanding when and where Special Regions could occur. The study applied recently available data about martian environments and about terrestrial organisms, building on a previous analysis of Mars Special Regions (2006) undertaken by a similar team. Since then, a new body of highly relevant information has been generated from the Mars Reconnaissance Orbiter (launched in 2005) and Phoenix (2007) and data from Mars Express and the twin Mars Exploration Rovers (all 2003). Results have also been gleaned from the Mars Science Laboratory (launched in 2011). In addition to Mars data, there is a considerable body of new data regarding the known environmental limits to life on Earth—including the potential for terrestrial microbial life to survive and replicate under martian environmental conditions. The SR-SAG2 analysis has included an examination of new Mars models relevant to natural environmental variation in water activity and temperature; a review and reconsideration of the current parameters used to define Special Regions; and updated maps and descriptions of the martian environments recommended for treatment as “Uncertain” or “Special” as natural features or those potentially formed by the influence of future landed spacecraft. Significant changes in our knowledge of the capabilities of terrestrial organisms and the existence of possibly habitable martian environments have led to a new appreciation of where Mars Special Regions may be identified and protected. The SR-SAG also considered the impact of Special Regions on potential future human missions to Mars, both as locations of potential resources and as places that should not be inadvertently contaminated by human activity. Key Words: Martian environments—Mars astrobiology—Extreme environment microbiology—Planetary protection—Exploration resources. Astrobiology 14, 887–968.

Genome-wide gene pathway analysis of psychotic illness symptom dimensions based on a new schizophrenia-specific model of the OPCRIT

Empirically derived phenotypic measurements have the potential to enhance gene-finding efforts in schizophrenia. Previous research based on factor analyses of symptoms has typically included schizoaffective cases. Deriving factor loadings from analysis of only narrowly defined schizophrenia cases could yield more sensitive factor scores for gene pathway and gene ontology analyses. Using an Irish family sample, this study 1) factor analyzed clinician-rated Operational Criteria Checklist items in cases with schizophrenia only, 2) scored the full sample based on these factor loadings, and 3) implemented genome-wide association, gene-based, and gene-pathway analysis of these SCZ-based symptom factors (final N= 507). Three factors emerged from the analysis of the schizophrenia cases: a manic, a depressive, and a positive symptom factor. In gene-based analyses of these factors, multiple genes had q<. 0.01. Of particular interest are findings for PTPRG and WBP1L, both of which were previously implicated by the Psychiatric Genomics Consortium study of SCZ; results from this study suggest that variants in these genes might also act as modifiers of SCZ symptoms. Gene pathway analyses of the first factor indicated over-representation of glutamatergic transmission, GABA-A receptor, and cyclic GMP pathways. Results suggest that these pathways may have differential influence on affective symptom presentation in schizophrenia.

The artist biopic: a historical analysis of narrative cinema, 1934-2010

The thesis provides an historical overview of the artist biopic that has emerged as a distinct sub-genre of the biopic as a whole, totalling some ninety films from Europe and America alone since the first talking artist biopic in 1934. Their making usually reflects a determination on the part of the director or star to see the artist as an alter-ego. Many of them were adaptations of successful literary works, which tempted financial backers by having a ready-made audience based on a pre-established reputation. The sub-genre’s development is explored via the grouping of films with associated themes and the use of case studies. These examples can then be used as models for exploring similar sets of data from other countries and time periods. The specific topics chosen for discussion include the representation of a single painter, for example, Vincent Van Gogh, to see how the treatment of an artist varies across several countries and over seventy years. British artist biopics are analysed as a case study in relation to the idea of them posing as a national stereotype. Topics within sex and gender studies are highlighted in analysis of the representation of the female artist and the queer artist as well as artists who have lived together as couples. A number of well-known gallery artists have become directors of artist biopics and their films are considered to see what particular insights a professional working artist can bring to the portrayal of artistic genius and creation. In the concluding part of the thesis it is argued that the artist biopic overall has survived the bad press which some individual productions have received and can even be said to have matured under the influence of directors producing a quality product for the art house, festival and avant-garde distribution circuits. As a genre it has proved extremely adaptable and has reflected the changing attitudes towards art and artists within the wider community. It has both encouraged renewed interest in the work of established national artists and also raised the profile of those relatively obscure such as Séraphine de Senlis and Pirosmani.