Hybrid Angular- and Energy-Dispersive X-ray Diffraction Computed Tomography

X-ray diffraction is a material-specific technique, the results of which can be used as a material fingerprint to identify unknowns. In this paper we present an adaptation to a novel hybrid angular- and energy-dispersive X-ray diffraction technique, which, until now, has been limited in utility by sample thickness. Computed tomography techniques have been applied to spatially resolve the origin of the scattering signals and to reconstruct the diffraction pattern in each pixel. 2D cross-correlation has been used to compare the reconstructed data to a library of standards as a means of identifying the material present

Validation tools: can they indicate the information content of macromolecular crystal structures?

AbstractThe explosive increase in the number of published three-dimensionsal structures of macromolecules determined by X-ray analysis places a responsibility on experimentalists, referees and curators of databases to ensure correspondence between the structure parameters and data. Validation tools will evolve as more appropriate statistical techniques and new information, such as that from proteins analysed at atomic resolution, becomes available

The Swedish system for compensation of patient injuries

Since 1975 Sweden has had a patient insurance system to compensate patients for health-related injuries. The system was initially based on a voluntary patient insurance solution, but in 1997 it was replaced by the Patient Insurance Act. The current Act covers both physical and mental injuries. Although about 9,000–10,000 cases are processed in Sweden annually, compensation is paid in barely half of these cases. In the Swedish patient injury claim processing system, the Patient Claims Panel is the authority that plays an important role in ensuring fair and consistent application of the Act

Effects of study design and allocation on participant behaviour-ESDA: study protocol for a randomized controlled trial

Background: What study participants think about the nature of a study has been hypothesised to affect subsequent behaviour and to potentially bias study findings. In this trial we examine the impact of awareness of study design and allocation on participant drinking behaviour. Methods/Design: A three-arm parallel group randomised controlled trial design will be used. All recruitment, screening, randomisation, and follow-up will be conducted on-line among university students. Participants who indicate a hazardous level of alcohol consumption will be randomly assigned to one of three groups. Group A will be informed their drinking will be assessed at baseline and again in one month (as in a cohort study design). Group B will be told the study is an intervention trial and they are in the control group. Group C will be told the study is an intervention trial and they are in the intervention group. All will receive exactly the same brief educational material to read. After one month, alcohol intake for the past 4 weeks will be assessed. Discussion: The experimental manipulations address subtle and previously unexplored ways in which participant behaviour may be unwittingly influenced by standard practice in trials. Given the necessity of relying on self-reported outcome, it will not be possible to distinguish true behaviour change from reporting artefact. This does not matter in the present study, as any effects of awareness of study design or allocation involve bias that is not well understood. There has been little research on awareness effects, and our outcomes will provide an indication of the possible value of further studies of this type and inform hypothesis generation

Asymptotic and numerical analysis of a simple model for blade coating

Motivated by the industrial process of blade coating, the two-dimensional flow of a thin film of Newtonian fluid on a horizontal substrate moving parallel to itself with constant speed under a fixed blade of finite length in which the flows upstream and downstream of the blade are coupled via the flow under the blade is analysed. A combination of asymptotic and numerical methods is used to investigate the number and nature of the steady solutions that exist. Specially, it is found that in the presence of gravity there is always at least one, and (depending on the parameter values) possibly as many as three, steady solutions, and that when multiple solutions occur they are identical under and downstream of the blade, but differ upstream of it. The stability of these solutions is investigated, and their asymptotic behaviour in the limits of large and small flux and weak and strong gravity effects, respectively, determined

Gene conversion in human rearranged immunoglobulin genes

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V<sub>H</sub> segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V<sub>H</sub> replacements with no addition of untemplated nucleotides at the V<sub>H</sub>–V<sub>H</sub> joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V<sub>H</sub> replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion

Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling

Cells with higher levels of Myc proliferate more rapidly and supercompetitively eliminate neighboring cells. Nonetheless, tumor cells in aggressive breast cancers typically exhibit significant and stable heterogeneity in their Myc levels, which correlates with refractoriness to therapy and poor prognosis. This suggests that Myc heterogeneity confers some selective advantage on breast tumor growth and progression. To investigate this, we created a traceable MMTV-Wnt1-driven in vivo chimeric mammary tumor model comprising an admixture of low-Myc- and reversibly switchable high-Myc-expressing clones. We show that such tumors exhibit interclonal mutualism wherein cells with high-Myc expression facilitate tumor growth by promoting protumorigenic stroma yet concomitantly suppress Wnt expression, which renders them dependent for survival on paracrine Wnt provided by low-Myc-expressing clones. To identify any therapeutic vulnerabilities arising from such interdependency, we modeled Myc/Ras/p53/Wnt signaling cross talk as an executable network for low-Myc, for high-Myc clones, and for the 2 together. This executable mechanistic model replicated the observed interdependence of high-Myc and low-Myc clones and predicted a pharmacological vulnerability to coinhibition of COX2 and MEK. This was confirmed experimentally. Our study illustrates the power of executable models in elucidating mechanisms driving tumor heterogeneity and offers an innovative strategy for identifying combination therapies tailored to the oligoclonal landscape of heterogenous tumors

The use of gaze to study cognition: limitations, solutions, and applications to animal welfare

The study of gaze responses, typically using looking time paradigms, has become a popular approach to improving our understanding of cognitive processes in non-verbal individuals. Our interpretation of data derived from these paradigms, however, is constrained by how we conceptually and methodologically approach these problems. In this perspective paper, we outline the application of gaze studies in comparative cognitive and behavioral research and highlight current limitations in the interpretation of commonly used paradigms. Further, we propose potential solutions, including improvements to current experimental approaches, as well as broad-scale benefits of technology and collaboration. Finally, we outline the potential benefits of studying gaze responses from an animal welfare perspective. We advocate the implementation of these proposals across the field of animal behavior and cognition to aid experimental validity, and further advance our knowledge on a variety of cognitive processes and welfare outcomes

Changes over time in the "healthy soldier effect"

Background: Death rates in military populations outside of combat are often lower than those in the general population. This study considers how this "healthy soldier effect" changes over time.Methods: Standardized mortality ratios were used to compare changes in death rates relative to the Australian population in two large studies of Australian servicemen of the Korean War (n = 17,381) and the Vietnam War era (n = 83,908).Results: The healthy soldier effect was most consistently observed in deaths from circulatory diseases. A large deficit in these deaths in the initial follow-up period (10-20 years) was observed before rates tended to rise to the level seen in the general population. There was no healthy soldier effect in deaths from external causes in enlisted personnel, and these death rates were significantly higher than expected in the initial follow-up period among Korean War veterans and regular Army veterans of the Vietnam War. Those selected for national service during the Vietnam War exhibited the strongest healthy soldier effect of all cohorts assessed.Conclusions: Patterns of the healthy soldier effect over time varied markedly by study cohort and by cause of death studied. In a number of analyses, the healthy soldier effect was still apparent after more than 30 years of follow-up