Molecular mechanism of activation-triggered subunit exchange in Ca(2+)/calmodulin-dependent protein kinase II.

Activation triggers the exchange of subunits in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.

The Neolithic of El Niño cave (Ayna, Albacete) in the Sierra del Segura context

Since its excavation in the summer of 1973, El Niño cave has been considered a key site to understand the process of production economy and pottery technology introduction in South-eastern Iberian Peninsula, and especially to approach how such process could have affected people already settled in the Segura mountains. However, data from El Niño cave was very fragmentary, due to the lack of a broad study of Neolithic occupations of the site. In this paper, we present the analysis of pottery, lithic industry and faunal remains, as well as the existing dates from the site´s Holocene levels. The review of different evidence from the site allows suggesting that El Niño cave would have probably acted as a hunting and shepherding station, being a logistical site of larger places. However, limitations due to the fact that we are dealing with a 40- year-old excavation, prevent specifying how the process of Neolithic introduction in the Segura Mountains occurred.

Correlation between anxiety and academic self-concept in interpreter trainees

This paper focuses on two basic issues: the anxiety-generating nature of the interpreting task and the relevance of interpreter trainees’ academic self-concept. The first has already been acknowledged, although not extensively researched, in several papers, and the second has only been mentioned briefly in interpreting literature. This study seeks to examine the relationship between the anxiety and academic self-concept constructs among interpreter trainees. An adapted version of the Foreign Language Anxiety Scale (Horwitz et al., 1986), the Academic Autoconcept Scale (Schmidt, Messoulam & Molina, 2008) and a background information questionnaire were used to collect data. Students’ t-Test analysis results indicated that female students reported experiencing significantly higher levels of anxiety than male students. No significant gender difference in self-concept levels was found. Correlation analysis results suggested, on the one hand, that younger would-be interpreters suffered from higher anxiety levels and students with higher marks tended to have lower anxiety levels; and, on the other hand, that younger students had lower self-concept levels and higher-ability students held higher self-concept levels. In addition, the results revealed that students with higher anxiety levels tended to have lower self-concept levels. Based on these findings, recommendations for interpreting pedagogy are discussed.

The role of the National Audit Office in Private Finance Initiative endurance

The Private Finance Initiative (PFI) has become one of the UK’s most contentious public policies. Despite New Labour’s advocacy of PFI as a means of achieving better value for money, criticisms of PFI have centred on key issues such as a lack of cost effectiveness, exaggerated pricing of risk transfers, excessive private sector profits, inflexibility and cumbersome administrative arrangements. Nevertheless, PFI has persisted as a key
infrastructure procurement method in the UK and has been supported as such by successive governments, as well as influencing policy in the Republic of Ireland and other European Nations. This paper explores this paradoxical outcome in relation to the role played in the UK by the National Audit Office (NAO). Under pressure to justify its support for PFI, the Blair government sought support for its policies by encouraging the NAO to investigate issues relating to PFI as well as specific PFI projects. It would have been expected that in fulfilling its role as independent auditor, the NAO would have examined whether PFI projects could have been delivered more efficiently, effectively or economically through other means. Yet, in line with earlier research, we find evidence that the NAO failed to comprehensively assess
key issues such as the value for money of PFI projects, and in so doing effectively acted as a legitimator of PFI policy. Using concepts relating to legitimacy theory and the idea of framing, our paper looks into 67 NAO private finance reports published between 1997 and 2011, with the goal of identifying the preferences, values and ideology underpinning the
NAO’s view on PFI during this period. Our analysis suggests that the NAO sought to legitimise existing PFI practices via a selective framing of problems and questions. Utilising a longitudinal approach, our analysis further suggests that this patterns of selective framing persisted over an extended time period during which fundamental parameters of the policy (such as contract length, to name one of the most important issues) were rarely addressed.
Overall the NAO’ supportive stance toward PFI seems to have relied on 1) a focused on positive aspects of PFI, such as on time delivery or lessons learned, and 2) positive comments on aspects of PFI that were criticised elsewhere, such as the lack of flexibility of underlying contractual arrangements. Our paper highlights the possibility that, rather than providing for a critical assessment of existing policies, national auditing bodies can
contribute to the creation of legitimatory environments. In terms of accounting research we would suggests that the objectivity and independence of accounting watchdogs should not be taken for granted, and that instead a critical investigation of the biases which can characterise these bodies can contribute to a deeper understanding of the nature of lobbying networks in the modern state.

How can we use systematic reviews to inform clinical practice?

Aims/purpose: Systematic reviews provide the highest quality evidence and inform clinical practice. For patient benefit, it is imperative that nurses keep abreast of evidence-based practice. This presentation highlights where to find systematic reviews and how the information presented can be used to inform care.
Presentation description: Clinical research is increasing at an incredible rate. In the clinical trials database alone, more than 2000 new studies are registered/month and this does not include qualitative studies that do not require registration. Keeping abreast of current evidence can not only be a time consuming process, but can be problematic when studies produce conflicting results. Systematic reviews can be useful for summarizing the increasing amount of knowledge that is gained from scientific papers. In addition, combining individual studies in a meta-analysis increases statistical power, resulting in more precise effect estimates. This presentation draws upon a few systematic reviews relevant to ICU nursing practice, highlights their findings and demonstrates how the information can be used to inform translation of evidence into practice. Additionally, although these reviews include steps to minimize bias, nurses should be aware of some of the biases that may reduce confidence in the findings.
Conclusion: Systematic reviews can be useful tools for informing evidence based practice, although careful interpretation is necessary for understanding their relevance to local practice.

Statin use and breast cancer survival: a nationwide cohort study in Scotland

Background: Preclinical evidence suggests that statins could delay cancer progression. Previous epidemiological findings have been inconsistent and some have been limited by small sample sizes, as well as certain time-related biases. This study aimed to investigate whether breast cancer patients who were exposed to statins had reduced breast cancer-specific mortality. Methods: We conducted a retrospective cohort study of 15,140 newly diagnosed invasive breast cancer patients diagnosed from 2009 to 2012 within the Scottish Cancer Registry. Dispensed medication usage was obtained from linkages to the Scottish Prescribing Information System and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Using time-dependent Cox regression models, hazard ratios (HR) and 95 % confidence intervals (CI) were calculated for the association between post-diagnostic exposure to statins (including simvastatin) and breast cancer-specific mortality. Adjustments were made for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of aspirin. Results: A total of 1,190 breast cancer-specific deaths occurred up to January 2015. Overall, after adjustment for potential confounders, there was no evidence of an association between statin use and breast cancer-specific death (adjusted HR 0.93, 95 % CI 0.77, 1.12). No significant associations were observed in dose–response analyses or in analysis of all-cause mortality. For simvastatin use specifically, a weak non-significant reduction in breast cancer-specific mortality was observed compared to non-users (adjusted HR 0.89, 95 % CI 0.73, 1.08). Statin use before diagnosis was weakly associated with a reduction in breast cancer-specific mortality (adjusted HR 0.85, 95 % CI 0.74, 0.98). Conclusion: Overall, we found little evidence of a protective association between post-diagnostic statin use and cancer-specific mortality in a large nation-wide cohort of breast cancer patients. These findings will help inform the decision whether to conduct randomised controlled trials of statins as an adjuvant treatment in breast cancer.

An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors.

Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation.

Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM).

Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene).

Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications.

We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.

National Diet and Nutrition Survey: assessment of dietary sodium in adults (19 to 64 years) in England, 2014

There is an established relationship between salt intake and risk of high blood pressure (BP). High blood pressure (hypertension) is a risk factor for cardiovascular disease (CVD) and scientific evidence shows that a high salt intake can contribute to the development of elevated blood pressure. The Scientific Advisory Committee on Nutrition (SACN) recommend a target reduction in the average salt intake of the population to no more than 6g per day. This figure has been adopted by the UK government as the recommended maximum salt intake for adults and children aged 11 years and over. Following publication of the SACN report in 2003, the government began a programme of reformulation work with the food industry aimed at reducing the salt content of processed food products. Voluntary salt reduction targets were first set in 2006, and subsequently in 2009, 2011 and 2014, for a range of food categories that contribute the most to the population’s salt intakes. Population representative urinary sodium data were collected in England in 2005-06, 2008 (UK), 2011 and 2014. In the latest survey assessment, estimated salt intake of adults aged 19 to 64 years in England was assessed from 24-hour urinary sodium excretion of 689 adults, selected to be representative of this section of the population. Estimated salt intake was calculated using the equation 17.1mmol of sodium = 1g of salt and assumes all sodium was derived from salt. The data were validated as representing daily intake by checking completeness of the urine collections by the para-amino benzoic acid (PABA) method. Urine samples were collected over five months (May to September) in 2014, concurrently with a similar survey in Scotland. This report presents the results for the latest survey assessment (2014) and a new analysis of the trend in estimated salt intake over time. The trend analysis is based on data for urinary sodium excretion from this survey and previous sodium surveys (including data from the National Diet and Nutrition Survey Rolling Programme (NDNS RP) Years 1 to 5) carried out in England over the last ten years, between 2005-06 and 2014. This data has been adjusted to take account of biases resulting from differences between surveys in laboratory analytical methods used for sodium. The analysis provides a revised assessment of the trend in estimated salt intake over time. The trend analysis in this report supersedes the trend analysis published in the report of the 2011 England urinary sodium survey.

Transient simulations for present and last interglacials using a comprehensive coupled climate model CCSM3 (Community Climate System Model 3.0), links to model result files in NetCDF format

Transient simulations are widely used in studying the past climate as they provide better comparison with any exisiting proxy data. However, multi-millennial transient simulations using coupled climate models are usually computationally very expensive. As a result several acceleration techniques are implemented when using numerical simulations to recreate past climate. In this study, we compare the results from transient simulations of the present and the last interglacial with and without acceleration of the orbital forcing, using the comprehensive coupled climate model CCSM3 (Community Climate System Model 3). Our study shows that in low-latitude regions, the simulation of long-term variations in interglacial surface climate is not significantly affected by the use of the acceleration technique (with an acceleration factor of 10) and hence, large-scale model-data comparison of surface variables is not hampered. However, in high-latitude regions where the surface climate has a direct connection to the deep ocean, e.g. in the Southern Ocean or the Nordic Seas, acceleration-induced biases in sea-surface temperature evolution may occur with potential influence on the dynamics of the overlying atmosphere. The data provided here are from both accelerated and non-accelerated runs as decadal mean values.

Mandevillian Intelligence: From Individual Vice to Collective Virtue

Abstract Mandevillian intelligence is a specific form of collective intelligence in which individual cognitive vices (i.e., shortcomings, limitations, constraints and biases) are seen to play a positive functional role in yielding collective forms of cognitive success. In this talk, I will introduce the concept of mandevillian intelligence and review a number of strands of empirical research that help to shed light on the phenomenon. I will also attempt to highlight the value of the concept of mandevillian intelligence from a philosophical, scientific and engineering perspective. Inasmuch as we accept the notion of mandevillian intelligence, then it seems that the cognitive and epistemic value of a specific social or technological intervention will vary according to whether our attention is focused at the individual or collective level of analysis. This has a number of important implications for how we think about the cognitive impacts of a number of Web-based technologies (e.g., personalized search mechanisms). It also forces us to take seriously the idea that the exploitation (or even the accentuation!) of individual cognitive shortcomings could, in some situations, provide a productive route to collective forms of cognitive and epistemic success. Speaker Biography Dr Paul Smart Paul Smart is a senior research fellow in the Web and Internet Science research group at the University of Southampton in the UK. He is a Fellow of the British Computer Society, a professional member of the Association of Computing Machinery, and a member of the Cognitive Science Society. Paul’s research interests span a number of disciplines, including philosophy, cognitive science, social science, and computer science. His primary area of research interest relates to the social and cognitive implications of Web and Internet technologies. Paul received his bachelors degree in Psychology from the University of Nottingham. He also holds a PhD in Experimental Psychology from the University of Sussex.

Looking a Gift Horse in the Mouth: Decision-Making about Acquisitions at Community Historical Organizations

Thesis (Master's)--University of Washington, 2016-06

A Parameter Estimation and Identifiability Analysis Methodology Applied to a Street Canyon Air Pollution Model

Mathematical models are increasingly used in environmental science thus increasing the importance of uncertainty and sensitivity analyses. In the present study, an iterative parameter estimation and identifiability analysis methodology is applied to an atmospheric model – the Operational Street Pollution Model (OSPMr). To assess the predictive validity of the model, the data is split into an estimation and a prediction data set using two data splitting approaches and data preparation techniques (clustering and outlier detection) are analysed. The sensitivity analysis, being part of the identifiability analysis, showed that some model parameters were significantly more sensitive than others. The application of the determined optimal parameter values was shown to succesfully equilibrate the model biases among the individual streets and species. It was as well shown that the frequentist approach applied for the uncertainty calculations underestimated the parameter uncertainties. The model parameter uncertainty was qualitatively assessed to be significant, and reduction strategies were identified.

Combinative Aspects of Leadership Style and Emotional Intelligence

Purpose – The purpose of this paper is to examine whether the leader’s emotional intelligence influences the leader’s preferences for different ways of combining leadership behaviors (i.e. combinative aspects of leadership style). Design/methodology/approach – The authors used a hybrid design to collect the data to avoid common-method biases. The authors described a high-stress workplace in a vignette and asked participants to rank four styles of combining a task-oriented leadership (i.e. Pressure) statement and a socio-emotional leadership (i.e. Support) statement. The authors then asked participants to complete a Likert-scale based questionnaire on emotional intelligence. Findings – The authors found that leaders who prefer to provide Support immediately before Pressure have higher levels of emotional intelligence than do leaders who prefer the three other combinative styles. Leaders who prefer to provide Pressure and Support separately (i.e. provide Pressure 30 minutes after Support) have the lowest levels of emotional intelligence. Research limitations/implications – A key implicit assumption in the work is that leaders do not want to evoke negative emotions in followers. The authors did not take into account factors that influence leadership style which participating managers would be likely to encounter on a daily basis such as the relationship with the follower, the follower’s level of performance and work experience, the gender of the leader and the gender of the follower, the hierarchical levels of the leader and follower, and the followers’ preferred combinative style. The nature of the sample and the use of a hypothetical scenario are other limitations of the study. Practical implications – Providing leadership behaviors that are regarded as effective is necessary but not enough because the emotional impact of leadership behaviors appears to also depend on how the behaviors are configured. Originality/value – This is the first study to show that the emotional intelligence of leaders is related to their preferences for the manner in which they combine task and social leadership statements. Furthermore, two-factor theories of leadership propose that the effects of task and social leadership are additive. However, the findings show that the effects are interactive.

Quantifying Selection Bias from Birth History Estimates of Child Mortality

Thesis (Master's)--University of Washington, 2016-08