Deer Park

The score to a musical setting of a text by J. K. Randall.

Dynamics of relativistic transparency and optical shuttering in expanding overdense plasmas

Overdense plasmas are usually opaque to laser light. However, when the light is of sufficient intensity to drive electrons in the plasma to near light speeds, the plasma becomes transparent. This process—known as relativistic transparency—takes just a tenth of a picosecond. Yet all studies of relativistic transparency so far have been restricted to measurements collected over timescales much longer than this, limiting our understanding of the dynamics of this process. Here we present time-resolved electric field measurements (with a temporal resolution of ~ 50 fs) of the light, initially reflected from, and subsequently transmitted through, an expanding overdense plasma. Our result provides insight into the dynamics of the transparent-overdense regime of relativistic plasmas, which should be useful in the development of laser-driven particle accelerators, X-ray sources and techniques for controlling the shape and contrast of intense laser pulses.

Influence of a Single Grain Boundary on Domain Wall Motion in Ferroelectrics

Epitaxial tetragonal 425 and 611 nm thick Pb(ZrTi)O (PZT) films are deposited by pulsed laser deposition on SrRuO-coated (100) SrTiO 24° tilt angle bicrystal substrates to create a single PZT grain boundary with a well-defined orientation. On either side of the bicrystal boundary, the films show square hysteresis loops and have dielectric permittivities of 456 and 576, with loss tangents of 0.010 and 0.015, respectively. Using piezoresponse force microscopy (PFM), a decrease in the nonlinear piezoelectric response is observed in the vicinity (720-820 nm) of the grain boundary. This region represents the width over which the extrinsic contributions to the piezoelectric response (e.g., those associated with the domain density/configuration and/or the domain wall mobility) are influenced by the presence of the grain boundary. Transmission electron microscope (TEM) images collected near and far from the grain boundary indicate a strong preference for (101)/(1-01) type domain walls at the grain boundary, whereas (011)/(01-1) and (101)/(1-01) are observed away from this region. It is proposed that the elastic strain field at the grain boundary interacts with the ferro-electric/elastic domain structure, stabilizing (101)/(1-01) rather than (011)/(01-1) type domain walls, which inhibits domain wall motion under applied field and decreases non-linearity. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Does vicarious traumatisation affect oncology nurses?:A literature review

It is widely documented that nurses experience work-related stress [Quine, L., 1998. Effects of stress in an NHS trust: a study. Nursing Standard 13 (3), 36-41; Charnley, E., 1999. Occupational stress in the newly qualified staff nurse. Nursing Standard 13 (29), 32-37; McGrath, A., Reid, N., Boore, J., 2003. Occupational stress in nursing. International Journal of Nursing Studies 40, 555-565; McVicar, A., 2003. Workplace stress in nursing: a literature review. Journal of Advanced Nursing 44 (6), 633-642; Bruneau, B., Ellison, G., 2004. Palliative care stress in a UK community hospital: evaluation of a stress-reduction programme. International Journal of Palliative Nursing 10 (6), 296-304; Jenkins, R., Elliott, P., 2004. Stressors, burnout and social support: nurses in acute mental health settings. Journal of Advanced Nursing 48 (6), 622-631], with cancer nursing being identified as a particularly stressful occupation [Hinds, P.S., Sanders, C.B., Srivastava, D.K., Hickey, S., Jayawardene, D., Milligan, M., Olsen, M.S., Puckett, P., Quargnenti, A., Randall, E.A., Tyc, V., 1998. Testing the stress-response sequence model in paediatric oncology nursing. Journal of Advanced Nursing 28 (5), 1146-1157; Barnard, D., Street, A., Love, A.W., 2006. Relationships between stressors, work supports and burnout among cancer nurses. Cancer Nursing 29 (4), 338-345]. Terminologies used to capture this stress are burnout [Pines, A.M., and Aronson, E., 1988. Career Burnout: Causes and Cures. Free Press, New York], compassion stress [Figley, C.R., 1995. Compassion Fatigue. Brunner/Mazel, New York], emotional contagion [Miller, K.I., Stiff, J.B., Ellis, B.H., 1988. Communication and empathy as precursors to burnout among human service workers. Communication Monographs 55 (9), 336-341] or simply the cost of caring (Figley, 1995). However, in the mental health field such as psychology and counselling, there is terminology used to captivate this impact, vicarious traumatisation. Vicarious traumatisation is a process through which the therapist's inner experience is negatively transformed through empathic engagement with client's traumatic material [Pearlman, L.A., Saakvitne, K.W., 1995a. Treating therapists with vicarious traumatization and secondary traumatic stress disorders. In: Figley, C.R. (Ed.), Compassion Fatigue: Coping with Secondary Traumatic Stress Disorder in Those Who Treat the Traumatized. Brunner/Mazel, New York, pp. 150-177]. Trauma not only affects individuals who are primarily present, but also those with whom they discuss their experience. If an individual has been traumatised as a result of a cancer diagnosis and shares this impact with oncology nurses, there could be a risk of vicarious traumatisation in this population. However, although Thompson [2003. Vicarious traumatisation: do we adequately support traumatised staff? The Journal of Cognitive Rehabilitation 24-25] suggests that vicarious traumatisation is a broad term used for workers from any profession, it has not yet been empirically determined if oncology nurses experience vicarious traumatisation. This purpose of this paper is to introduce the concept of vicarious traumatisation and argue that it should be explored in oncology nursing. The review will highlight that empirical research in vicarious traumatisation is largely limited to the mental health professions, with a strong recommendation for the need to empirically determine whether this concept exists in oncology nursing.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Generation of replication-proficient influenza virus NS1 point mutants with interferon-hyperinducer phenotype

The NS1 protein of influenza A viruses is the dedicated viral interferon (IFN)-antagonist. Viruses lacking NS1 protein expression cannot multiply in normal cells but are viable in cells deficient in their ability to produce or respond to IFN. Here we report an unbiased mutagenesis approach to identify positions in the influenza A NS1 protein that modulate the IFN response upon infection. A random library of virus ribonucleoproteins containing circa 40 000 point mutants in NS1 were transferred to infectious virus and amplified in MDCK cells unable to respond to interferon. Viruses that activated the interferon (IFN) response were subsequently selected by their ability to induce expression of green-fluorescent protein (GFP) following infection of A549 cells bearing an IFN promoter-dependent GFP gene. Using this approach we isolated individual mutant viruses that replicate to high titers in IFN-compromised cells but, compared to wild type viruses, induced higher levels of IFN in IFN-competent cells and had a reduced capacity to counteract exogenous IFN. Most of these viruses contained not previously reported NS1 mutations within either the RNA-binding domain, the effector domain or the linker region between them. These results indicate that subtle alterations in NS1 can reduce its effectiveness as an IFN antagonist without affecting the intrinsic capacity of the virus to multiply. The general approach reported here may facilitate the generation of replication-proficient, IFN-inducing virus mutants, that potentially could be developed as attenuated vaccines against a variety of viruses.

An unbiased genetic screen reveals the polygenic nature of the influenza virus anti-interferon response

UNLABELLED: Influenza A viruses counteract the cellular innate immune response at several steps, including blocking RIG I-dependent activation of interferon (IFN) transcription, interferon (IFN)-dependent upregulation of IFN-stimulated genes (ISGs), and the activity of various ISG products; the multifunctional NS1 protein is responsible for most of these activities. To determine the importance of other viral genes in the interplay between the virus and the host IFN response, we characterized populations and selected mutants of wild-type viruses selected by passage through non-IFN-responsive cells. We reasoned that, by allowing replication to occur in the absence of the selection pressure exerted by IFN, the virus could mutate at positions that would normally be restricted and could thus find new optimal sequence solutions. Deep sequencing of selected virus populations and individual virus mutants indicated that nonsynonymous mutations occurred at many phylogenetically conserved positions in nearly all virus genes. Most individual mutants selected for further characterization induced IFN and ISGs and were unable to counteract the effects of exogenous IFN, yet only one contained a mutation in NS1. The relevance of these mutations for the virus phenotype was verified by reverse genetics. Of note, several virus mutants expressing intact NS1 proteins exhibited alterations in the M1/M2 proteins and accumulated large amounts of deleted genomic RNAs but nonetheless replicated to high titers. This suggests that the overproduction of IFN inducers by these viruses can override NS1-mediated IFN modulation. Altogether, the results suggest that influenza viruses replicating in IFN-competent cells have tuned their complete genomes to evade the cellular innate immune system and that serial replication in non-IFN-responsive cells allows the virus to relax from these constraints and find a new genome consensus within its sequence space.

IMPORTANCE: In natural virus infections, the production of interferons leads to an antiviral state in cells that effectively limits virus replication. The interferon response places considerable selection pressure on viruses, and they have evolved a variety of ways to evade it. Although the influenza virus NS1 protein is a powerful interferon antagonist, the contributions of other viral genes to interferon evasion have not been well characterized. Here, we examined the effects of alleviating the selection pressure exerted by interferon by serially passaging influenza viruses in cells unable to respond to interferon. Viruses that grew to high titers had mutations at many normally conserved positions in nearly all genes and were not restricted to the NS1 gene. Our results demonstrate that influenza viruses have fine-tuned their entire genomes to evade the interferon response, and by removing interferon-mediated constraints, viruses can mutate at genome positions normally restricted by the interferon response.

Improving allied health professionals' research implementation behaviours for children with cerebral palsy: protocol for a before-after study

BACKGROUND: Cerebral palsy is a permanent disorder of posture and movement caused by disturbances in the developing brain. It affects approximately 1 in every 500 children in developed countries and is the most common form of childhood physical disability. People with cerebral palsy may also have problems with speech, vision and hearing, intellectual difficulties and epilepsy. Health and therapy services are frequently required throughout life, and this care should be effective and evidence informed; however, accessing and adopting new research findings into day-to-day clinical practice is often delayed.

METHODS/DESIGN: This 3-year study employs a before and after design to evaluate if a multi-strategy intervention can improve research implementation among allied health professionals (AHPs) who work with children and young people with cerebral palsy and to establish if children's health outcomes can be improved by routine clinical assessment. The intervention comprises (1) knowledge brokering with AHPs, (2) access to an online research evidence library, (3) provision of negotiated evidence-based training and education, and (4) routine use of evidence-based measures with children and young people aged 3-18 years with cerebral palsy. The study is being implemented in four organisations, with a fifth organisation acting as a comparison site, across four Australian states. Effectiveness will be assessed using questionnaires completed by AHPs at baseline, 6, 12 and 24 months, and by monitoring the extent of use of evidence-based measures. Children's health outcomes will be evaluated by longitudinal analyses.

DISCUSSION: Government, policy makers and service providers all seek evidence-based information to support decision-making about how to distribute scarce resources, and families are seeking information to support intervention choices. This study will provide knowledge about what constitutes an efficient, evidence-informed service and which allied health interventions are implemented for children with cerebral palsy.

TRIAL REGISTRATION: Trial is not a controlled healthcare intervention and is not registered.