Bunch length measurements using a transverse deflecting cavity on VELA

The VELA facility at Daresbury Laboratory in the UK includes a 5 MeV/c 2.5 cell S-band photoinjector gun. This gun operates in the "blow-out" regime with a sub-200 fs length drive laser: the resulting bunch length is determined by space-charge effects. We present measurements made with an S-band transverse deflecting cavity to characterise the bunch length as a function of charge, and as a function of the gun operating phase

Optimising the chick chorioallantoic membrane xenograft model of neuroblastoma for drug delivery

Background Neuroblastoma is a paediatric cancer that despite multimodal therapy still has a poor outcome for many patients with high risk tumours. Retinoic acid (RA) promotes differentiation of some neuroblastoma tumours and cell lines, and is successfully used clinically, supporting the view that differentiation therapy is a promising strategy for treatment of neuroblastoma. To improve treatment of a wider range of tumour types, development and testing of novel differentiation agents is essential. New pre-clinical models are therefore required to test therapies in a rapid cost effective way in order to identify the most useful agents. Methods As a proof of principle, differentiation upon ATRA treatment of two MYCN-amplified neuroblastoma cell lines, IMR32 and BE2C, was measured both in cell cultures and in tumours formed on the chick chorioallantoic membrane (CAM). Differentiation was assessed by 1) change in cell morphology, 2) reduction in cell proliferation using Ki67 staining and 3) changes in differentiation markers (STMN4 and ROBO2) and stem cell marker (KLF4). Results were compared to MLN8237, a classical Aurora Kinase A inhibitor. For the in vivo experiments, cells were implanted on the CAM at embryonic day 7 (E7), ATRA treatment was between E11 and E13 and tumours were analysed at E14. Results Treatment of IMR32 and BE2C cells in vitro with 10 μM ATRA resulted in a change in cell morphology, a 65% decrease in cell proliferation, upregulation of STMN4 and ROBO2 and downregulation of KLF4. ATRA proved more effective than MLN8237 in these assays. In vivo, 100 μM ATRA repetitive treatment at E11, E12 and E13 promoted a change in expression of differentiation markers and reduced proliferation by 43% (p < 0.05). 40 μM ATRA treatment at E11 and E13 reduced proliferation by 37% (p < 0.05) and also changed cell morphology within the tumour. Conclusion Differentiation of neuroblastoma tumours formed on the chick CAM can be analysed by changes in cell morphology, proliferation and gene expression. The well-described effects of ATRA on neuroblastoma differentiation were recapitulated within 3 days in the chick embryo model, which therefore offers a rapid, cost effective model compliant with the 3Rs to select promising drugs for further preclinical analysis

1Design of the Primary Prevention Parameters Evaluation (PREPARE) trial of implantablecardioverter defibrillators to reduce patient morbidity [NCT00279279]

BACKGROUND: Implantable Cardioverter Defibrillator (ICD) therapy has been proven to be beneficial and efficacious for the treatment of serious ventricular tachyarrhythmias in primary prevention patients. However, primary prevention patients appear to have a lower incidence of ventricular arrhythmias in comparison to secondary prevention patients and consequently likely experience a higher proportion of detections due to supraventricular arrhythmias. Recent trials have demonstrated that strategic and specific programming choices reduce the number of inappropriate shocks and that anti-tachycardia pacing (ATP) is an effective alternative to shock therapy for many sustained ventricular arrhythmias. METHODS: The Primary Prevention Parameters Evaluation (PREPARE) study is a multi-center cohort study, evaluating the efficacy of a pre-specified strategic profile of VT/VF detection and therapy settings in 700 primary prevention patients in an effort to safely reduce the number of shock therapies delivered. The patients, both with and without cardiac resynchronization therapy, are compared to a well-qualified set (n = 691) of historical controls derived from the MIRACLE ICD and EMPIRIC trials. This manuscript describes the design of the PREPARE study. The study results, to be presented separately, will characterize the efficacy of this programming set (PREPARE) compared with physician-tailored programming (MIRACLE ICD and EMPIRIC)

Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures

The implications of the United Nations Paris Agreement on climate change for globally significant biodiversity areas

Climate change is already affecting species and their distributions. Distributional range changes have occurred and are projected to intensify for many widespread plants and animals, creating associated risks to many ecosystems. Here, we estimate the climate change-related risks to the species in globally significant biodiversity conservation areas over a range of climate scenarios, assessing their value as climate refugia. In particular, we quantify the aggregated benefit of countries’ emission reduction pledges (Intended Nationally Determined Contributions and Nationally Determined Contributions under the Paris Agreement), and also of further constraining global warming to 2 °C above pre-industrial levels, against an unmitigated scenario of 4.5 °C warming. We also quantify the contribution that can be made by using smart spatial conservation planning to facilitate some levels of autonomous (i.e. natural) adaptation to climate change by dispersal. We find that without mitigation, on average 33% of each conservation area can act as climate refugium (or 18% if species are unable to disperse), whereas if warming is constrained to 2 °C, the average area of climate refuges doubles to 67% of each conservation area (or, without dispersal, more than doubles to 56% of each area). If the country pledges are fulfilled, an intermediate estimate of 47–52% (or 31–38%, without dispersal) is obtained. We conclude that the Nationally Determined Contributions alone have important but limited benefits for biodiversity conservation, with larger benefits accruing if warming is constrained to 2 °C. Greater benefits would result if warming was constrained to well below 2 °C as set out in the Paris Agreement

A methodology for the risk assessment of climate variability and change under uncertainty

Existing methods for the assessment of the potential impacts of climate change in productive activities and sectors are usually limited to point estimates that do not consider the inherent variability and uncertainty of climatic and socioeconomic variables. This is a major drawback given that only a limited and potentially misleading estimation of risk can be expected when ignoring such determinant factors. In this paper, a new methodology is introduced that is capable of integrating the agent's beliefs and expert judgment into the assessment of the potential impacts of climate change in a quantitative manner by means of an objective procedure. The goal is to produce tailor-made information to assist decision-making under uncertainty in a way that is consistent with the current state of knowledge and the available subjective "expert" information. Time-charts of the evolution of different risk measures, that can be relevant for assisting decision-making and planning, can be constructed using this new methodology. This methodology is illustrated with a case study of coffee production in Mexico. Time-dependent probabilistic scenarios for coffee production and income, conditional on the agent's beliefs and expert judgment, are developed for the average producer under uncertain future conditions. It is shown that variability in production and income, generated by introducing climate variability and uncertainty are important factors affecting decision-making and the assessment of economic viability that are frequently ignored. The concept of Value at Risk, commonly applied in financial risk management, is introduced as a means for estimating the maximum expected loss for a previously chosen confidence level. Results are tailor-made for agents that have incomplete information and different beliefs. In this case study, the costs of climate change for coffee production in Veracruz are estimated to have a present value representing from 3 to 14 times the current annual value of coffee production in the state. © 2011 The Author(s)

The Influence of Life History Milestones and Association Networks on Crop-Raiding Behavior in Male African Elephants

Factors that influence learning and the spread of behavior in wild animal populations are important for understanding species responses to changing environments and for species conservation. In populations of wildlife species that come into conflict with humans by raiding cultivated crops, simple models of exposure of individual animals to crops do not entirely explain the prevalence of crop raiding behavior. We investigated the influence of life history milestones using age and association patterns on the probability of being a crop raider among wild free ranging male African elephants; we focused on males because female elephants are not known to raid crops in our study population. We examined several features of an elephant association network; network density, community structure and association based on age similarity since they are known to influence the spread of behaviors in a population. We found that older males were more likely to be raiders than younger males, that males were more likely to be raiders when their closest associates were also raiders, and that males were more likely to be raiders when their second closest associates were raiders older than them. The male association network had sparse associations, a tendency for individuals similar in age and raiding status to associate, and a strong community structure. However, raiders were randomly distributed between communities. These features of the elephant association network may limit the spread of raiding behavior and likely determine the prevalence of raiding behavior in elephant populations. Our results suggest that social learning has a major influence on the acquisition of raiding behavior in younger males whereas life history factors are important drivers of raiding behavior in older males. Further, both life-history and network patterns may influence the acquisition and spread of complex behaviors in animal populations and provide insight on managing human-wildlife conflict

Pediatric meningiomas in The Netherlands 1974–2010: a descriptive epidemiological case study

The purpose of this study was to review the epidemiology and the clinical, radiological, pathological, and follow-up data of all surgically treated pediatric meningiomas during the last 35 years in The Netherlands. Patients were identified in the Pathological and Anatomical Nationwide Computerized Archive database, the nationwide network and registry of histopathology and cytopathology in The Netherlands. Pediatric patients of 18 years or younger at first operation in 1974-2009 with the diagnosis meningioma were included. Clinical records, follow-up data, radiological findings, operative reports, and pathological examinations were reviewed. In total, 72 patients (39 boys) were identified. The incidence of operated meningiomas in the Dutch pediatric population is 1:1,767,715 children per year. Median age at diagnosis was 13 years (range 0-18 years). Raised intracranial pressure and seizures were the most frequent signs at presentation. Thirteen (18 %) patients had neurofibromatosis type 2 (NF2). Fifty-three (74 %) patients had a meningioma World Health Organization grade I. Total resection was achieved in 35 of 64 patients. Fifteen patients received radiotherapy postoperatively. Mean follow-up was 4.8 years (range 0-27.8 years). Three patients died as a direct result of their meningioma within 3 years. Four patients with NF2 died as a result of multiple tumors. Nineteen patients had disease progression, requiring additional treatment. Meningiomas are extremely rare in the pediatric population; 25 % of all described meningiomas show biological aggressive behavior in terms of disease progression, requiring additional treatment. The 5-year survival is 83.9 %, suggesting that the biological behavior of pediatric menigiomas is more aggressive than that of its adult counterpart

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition