Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

Designing a web-application to support home-based care of childhood CKD stages 3-5: Qualitative study of family and professional preferences

Background: There is a lack of online, evidence-based information and resources to support home-based care of childhood CKD stages 3-5. Methods. Qualitative interviews were undertaken with parents, patients and professionals to explore their views on content of the proposed online parent information and support (OPIS) web-application. Data were analysed using Framework Analysis, guided by the concept of Self-efficacy. Results: 32 parents, 26 patients and 12 professionals were interviewed. All groups wanted an application that explains, demonstrates, and enables parental clinical care-giving, with condition-specific, continously available, reliable, accessible material and a closed communication system to enable contact between families living with CKD. Professionals advocated a regularly updated application to empower parents to make informed health-care decisions. To address these requirements, key web-application components were defined as: (i) Clinical care-giving support (information on treatment regimens, video-learning tools, condition-specific cartoons/puzzles, and a question and answer area) and (ii) Psychosocial support for care-giving (social-networking, case studies, managing stress, and enhancing families' health-care experiences). Conclusions: Developing a web-application that meets parents' information and support needs will maximise its utility, thereby augmenting parents' self-efficacy for CKD caregiving, and optimising outcomes. Self-efficacy theory provides a schema for how parents' self-efficacy beliefs about management of their child's CKD could potentially be promoted by OPIS. © 2014 Swallow et al.; licensee BioMed Central Ltd

Local and global Fokker-Planck neoclassical calculations showing flow and bootstrap current modification in a pedestal

In transport barriers, particularly H-mode edge pedestals, radial scale lengths can become comparable to the ion orbit width, causing neoclassical physics to become radially nonlocal. In this work, the resulting changes to neoclassical flow and current are examined both analytically and numerically. Steep density gradients are considered, with scale lengths comparable to the poloidal ion gyroradius, together with strong radial electric fields sufficient to electrostatically confine the ions. Attention is restricted to relatively weak ion temperature gradients (but permitting arbitrary electron temperature gradients), since in this limit a delta-f (small departures from a Maxwellian distribution) rather than full-f approach is justified. This assumption is in fact consistent with measured inter-ELM H-Mode edge pedestal density and ion temperature profiles in many present experiments, and is expected to be increasingly valid in future lower collisionality experiments. In the numerical analysis, the distribution function and Rosenbluth potentials are solved for simultaneously, allowing use of the exact field term in the linearized Fokker-Planck collision operator. In the pedestal, the parallel and poloidal flows are found to deviate strongly from the best available conventional neoclassical prediction, with large poloidal variation of a different form than in the local theory. These predicted effects may be observable experimentally. In the local limit, the Sauter bootstrap current formulae appear accurate at low collisionality, but they can overestimate the bootstrap current near the plateau regime. In the pedestal ordering, ion contributions to the bootstrap and Pfirsch-Schluter currents are also modified

Detectability of Terrestrial Planets in Multi-Planet Systems: Preliminary Report

We ask if Earth-like planets (terrestrial mass and habitable-zone orbit) can be detected in multi-planet systems, using astrometric and radial velocity observations. We report here the preliminary results of double-blind calculations designed to answer this question.Comment: 10 pages, 0 figure

Emerging communities of child-healthcare practice in the management of long-term conditions such as chronic kidney disease: Qualitative study of parents' accounts

Background: Parents of children and young people with long-term conditions who need to deliver clinical care to their child at home with remote support from hospital-based professionals, often search the internet for care-giving information. However, there is little evidence that the information available online was developed and evaluated with parents or that it acknowledges the communities of practice that exist as parents and healthcare professionals share responsibility for condition management. Methods. The data reported here are part of a wider study that developed and tested a condition-specific, online parent information and support application with children and young people with chronic-kidney disease, parents and professionals. Semi-structured interviews were conducted with 19 fathers and 24 mothers who had recently tested the novel application. Data were analysed using Framework Analysis and the Communities of Practice concept. Results: Evolving communities of child-healthcare practice were identified comprising three components and several sub components: (1) Experiencing (parents making sense of clinical tasks) through Normalising care, Normalising illness, Acceptance & action, Gaining strength from the affected child and Building relationships to formalise a routine; (2) Doing (Parents executing tasks according to their individual skills) illustrated by Developing coping strategies, Importance of parents' efficacy of care and Fear of the child's health failing; and (3) Belonging/Becoming (Parents defining task and group members' worth and creating a personal identity within the community) consisting of Information sharing, Negotiation with health professionals and Achieving expertise in care. Parents also recalled factors affecting the development of their respective communities of healthcare practice; these included Service transition, Poor parent social life, Psycho-social affects, Family chronic illness, Difficulty in learning new procedures, Shielding and avoidance, and Language and cultural barriers. Health care professionals will benefit from using the communities of child-healthcare practice model when they support parents of children with chronic kidney disease. Conclusions: Understanding some of the factors that may influence the development of communities of child-healthcare practice will help professionals to tailor information and support for parents learning to manage their child's healthcare. Our results are potentially transferrable to professionals managing the care of children and young people with other long-term conditions. © 2014 Carolan et al.; licensee BioMed Central Ltd

Implicit and explicit body representations

Several forms of perception require that sensory information be referenced to representations of the size and shape of the body. This requirement is especially acute in somatosensation in which the main receptor surface (i.e., the skin) is itself coextensive with the body. In this paper I will review recent research investigating the body representations underlying somatosensory information processing, including abilities such as tactile localisation, tactile size perception, and position sense. These representations show remarkably large and stereotyped distortions of represented body size and shape. Intriguingly, these distortions appear to mirror distortions characteristic of somatosensory maps, though in attenuated form. In contrast, when asked to make overt judgments about perceived body form, participants are generally quite accurate. This pattern of results suggests that higher-level somatosensory processing relies on a class of implicit body representation, distinct from the conscious body image. I discuss the implications of these results for understanding the nature of body representation and the factors which influence it

Assessing stationarity in web analytics: A study of bounce rates

Evidence-based methods for evaluating marketing interventions such as A/B testing have become standard practice. However, the pitfalls associated with the misuse of this decision-making instrument are not well understood by managers and analytics professionals. In this study, we assess the impact of stationarity on the validity of samples from conditioned time series, which are abundant in web metrics. Such a prominent metric is the bounce rate, which is prevalent in assessing engagement with web content as well as the performance of marketing touchpoints. In this study, we show how to control for stationarity using an algorithmic transformation to calculate the optimum sampling period. This distance is based on a novel stationary ergodic process that considers that a stationary series presents reversible symmetric features and is calculated using a dynamic time warping algorithm in a self-correlation procedure. This study contributes to the expert and intelligent systems literature by demonstrating a robust method for sub-sampling time-series data, which are critical in decision making

An Ultra-High-Resolution Survey of the Interstellar ^7Li-to-^6Li Isotope Ratio in the Solar Neighborhood

In an effort to probe the extent of variations in the interstellar ^7Li/^6Li ratio seen previously, ultra-high-resolution (R ~ 360,000), high signal-to-noise spectra of stars in the Perseus OB2 and Scorpius OB2 Associations were obtained. These measurements confirm our earlier findings of an interstellar ^7Li/^6Li ratio of about 2 toward o Per, the value predicted from models of Galactic cosmic ray spallation reactions. Observations of other nearby stars yield limits consistent with the isotopic ratio ~ 12 seen in carbonaceous chondrite meteorites. If this ratio originally represented the gas toward o Per, then to decrease the original isotope ratio to its current value an order of magnitude increase in the Li abundance is expected, but is not seen. The elemental K/Li ratio is not unusual, although Li and K are formed via different nucleosynthetic pathways. Several proposals to account for the low ^7Li/^6Li ratio were considered, but none seems satisfactory. Analysis of the Li and K abundances from our survey highlighted two sight lines where depletion effects are prevalent. There is evidence for enhanced depletion toward X Per, since both abundances are lower by a factor of 4 when compared to other sight lines. Moreover, a smaller Li/H abundance is observed toward 20 Aql, but the K/H abundance is normal, suggesting enhanced Li depletion (relative to K) in this direction. Our results suggest that the ^7Li/^6Li ratio has not changed significantly during the last 4.5 billion years and that a ratio ~ 12 represents most gas in the solar neighborhood. In addition, there appears to be a constant stellar contribution of ^7Li, indicating that one or two processes dominate its production in the Galaxy.Comment: 54 pages, accepted for publication in the Astrophysical Journa

Photoionization of ultracold and Bose-Einstein condensed Rb atoms

Photoionization of a cold atomic sample offers intriguing possibilities to observe collective effects at extremely low temperatures. Irradiation of a rubidium condensate and of cold rubidium atoms within a magneto-optical trap with laser pulses ionizing through 1-photon and 2-photon absorption processes has been performed. Losses and modifications in the density profile of the remaining trapped cold cloud or the remaining condensate sample have been examined as function of the ionizing laser parameters. Ionization cross-sections were measured for atoms in a MOT, while in magnetic traps losses larger than those expected for ionization process were measured.Comment: 9 pages, 7 figure