Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline

Adult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover, spermatogonia very rarely form tumors, so-called spermatocytic tumors (SpT). In line with the previous identification of FGFR3 and HRAS selfish mutations in a subset of cases, candidate gene screening of 29 SpTs identified an oncogenic NRAS mutation in two cases. To gain insights in the etiology of SpT and into properties of the male germline, we performed whole-genome sequencing of five tumors (4/5 with matched normal tissue). The acquired single nucleotide variant load was extremely low (~0.2 per Mb), with an average of 6 (2±9) no

Cerebral malaria: Gamma-interferon redux

There are two theories that seek to explain the pathogenesis of cerebral malaria, the mechanical obstruction hypothesis and the immunopathology hypothesis. Evidence consistent with both ideas has accumulated from studies of the human disease and experimental models. Thus, some combination of these concepts seems necessary to explain the very complex pattern of changes seen in cerebral malaria. The interactions between malaria parasites, erythrocytes, the cerebral microvascular endothelium, brain parenchymal cells, platelets and microparticles need to be considered. One factor that seems able to knit together much of this complexity is the cytokine interferon-gamma (IFN-?). In this review we consider findings from the clinical disease, in vitro models and the murine counterpart of human cerebral malaria in order to evaluate the roles played by IFN-? in the pathogenesis of this often fatal and debilitating condition. © 2014 Hunt, Ball, Hansen, Khaw, Guo, Bakmiwewa, Mitchell, Combes and Grau

Quantitative analyses and modelling to support achievement of the 2020 goals for nine neglected tropical diseases

Quantitative analysis and mathematical models are useful tools in informing strategies to control or eliminate disease. Currently, there is an urgent need to develop these tools to inform policy to achieve the 2020 goals for neglected tropical diseases (NTDs). In this paper we give an overview of a collection of novel model-based analyses which aim to address key questions on the dynamics of transmission and control of nine NTDs: Chagas disease, visceral leishmaniasis, human African trypanosomiasis, leprosy, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. Several common themes resonate throughout these analyses, including: the importance of epidemiological setting on the success of interventions; targeting groups who are at highest risk of infection or re-infection; and reaching populations who are not accessing interventions and may act as a reservoir for infection,. The results also highlight the challenge of maintaining elimination 'as a public health problem' when true elimination is not reached. The models elucidate the factors that may be contributing most to persistence of disease and discuss the requirements for eventually achieving true elimination, if that is possible. Overall this collection presents new analyses to inform current control initiatives. These papers form a base from which further development of the models and more rigorous validation against a variety of datasets can help to give more detailed advice. At the moment, the models' predictions are being considered as the world prepares for a final push towards control or elimination of neglected tropical diseases by 2020

Perivascular macrophages create an intravascular niche for CD8 + T cell localisation prior to the onset of fatal experimental cerebral malaria

Objectives: The immunologic events that build up to the fatal neurological stage of experimental cerebral malaria (ECM) are incompletely understood. Here, we dissect immune cell behaviour occurring in the central nervous system (CNS) when Plasmodium berghei ANKA (PbA)-infected mice show only minor clinical signs. Methods: A 2-photon intravital microscopy (2P-IVM) brain imaging model was used to study the spatiotemporal context of early immunological events in situ during ECM. Results: Early in the disease course, antigen-specific CD8+ T cells came in contact and arrested on the endothelium of post-capillary venules. CD8+ T cells typically adhered adjacent to, or were in the near vicinity of, perivascular macrophages (PVMs) that line post-capillary venules. Closer examination revealed that CD8+ T cells crawled along the inner vessel wall towards PVMs that lay on the abluminal side of large post-capillary venules. 'Activity hotspots' in large post-capillary venules were characterised by T-cell localisation, activated morphology and clustering of PVM, increased abutting of post-capillary venules by PVM and augmented monocyte accumulation. In the later stages of infection, when mice exhibited neurological signs, intravascular CD8+ T cells increased in number and changed their behaviour, actively crawling along the endothelium and displaying frequent, short-term interactions with the inner vessel wall at hotspots. Conclusion: Our study suggests an active interaction between PVM and CD8+ T cells occurs across the blood-brain barrier (BBB) in early ECM, which may be the initiating event in the inflammatory cascade leading to BBB alteration and neuropathology

Evaluation plan

The overall objectives of TeleFOT are to assess the impacts of aftermarket and nomadic devices used in vehicles for driver support and to raise the awareness of the functions and potential that these devices offer. This report starts from the scientific and technological objectives that will make these overall objectives more concrete. They are 1. Build, mobilise and integrate European test communities for long term testing and assessment of driver support functions through aftermarket and nomadic devices 2. Create a methodological framework for executing the tests and analysing the data 3. Study aftermarket and nomadic devices in different technical contexts 4. Study different levels of impacts on drivers and society 5. Focus on functions and services for safe, efficient and economical travel 6. Investigate the contents of functions provided for cooperative driver support 7. Develop effective procedures of enhancing awareness and take-up of driver support ICT systems among the public 8. Focus also on aspects in the use of aftermarket and nomadic devices that may decrease safety TeleFOT is supposed adopt the approach of Field Operational Test (FOT). When going into the actual work in TeleFOT, as laid out in the DoW, it was seen as a useful step to make use of the structure of the deliverable D2.2.1 Testing and Evaluation strategy I, based on the FESTA FOT Chain (from the FESTA Handbook). This was done in order to identify what findings in the TeleFOT project (so far) has a unique and from the FESTA Handbook deviating approach. The intention has been to highlight these deviations (or improvements) in order to widen the potential use of the FOT methodology in the future. This IP-level deliverable is therefore focused on what constitutes the unique features of TeleFOT that could have an impact also on a more general level. This is especially important as new FOTs are planned in the area “cooperative driving”. Most of the TeleFOT deliverables until today have been consulted including the first series of deliverables addressing the Data Analysis Plans for all the impact areas to be covered by TeleFOT; they are Efficiency, Environment, Mobility, Safety and User Uptake. It is concluded that the first of the overall objectives has been met to quite a high degree, even if there still are some important steps that must be finished. The second overall objective is not yet addressed in a systematic way. However, there are WPs in the TeleFOT DoW that are supposed to cover these aspects in the last part of the project

Neural changes following cognitive behaviour therapy for psychosis: A longitudinal study

A growing body of evidence demonstrates that persistent positive symptoms, particularly delusions, can be improved by cognitive behaviour therapy for psychosis. Heightened perception and processing of threat are believed to constitute the genesis of delusions. The present study aimed to examine functional brain changes following cognitive behaviour therapy for psychosis. The study involved 56 outpatients with one or more persistent positive distressing symptoms of schizophrenia. Twenty-eight patients receiving cognitive behaviour therapy for psychosis for 6–8 months in addition to their usual treatment were matched with 28 patients receiving treatment as usual. Patients’ symptoms were assessed by a rater blind to treatment group, and they underwent functional magnetic resonance imaging during an affect processing task at baseline and end of treatment follow-up. The two groups were comparable at baseline in terms of clinical and demographic parameters and neural and behavioural responses to facial and control stimuli. The cognitive behaviour therapy for psychosis with treatment-as-usual group (22 subjects) showed significant clinical improvement compared with the treatment-as-usual group (16 subjects), which showed no change at follow-up. The cognitive behaviour therapy for psychosis with treatment-as-usual group, but not the treatment-as-usual group, showed decreased activation of the inferior frontal, insula, thalamus, putamen and occipital areas to fearful and angry expressions at treatment follow-up compared with baseline. Reduction of functional magnetic resonance imaging response during angry expressions correlated directly with symptom improvement. This study provides the first evidence that cognitive behaviour therapy for psychosis attenuates brain responses to threatening stimuli and suggests that cognitive behaviour therapy for psychosis may mediate symptom reduction by promoting processing of threats in a less distressing way

TeleFOT, field operational tests of aftermarket nomadic devices in vehicles, early results

This paper presents the European Large Scale Collaborative Project TeleFOT, describing its status and its first results. The paper is structured into two main sections: The first paragraph briefly introduces the justification and core elements of TeleFOT, showing the scope and primary objectives of the project. Significant research and development in Europe in recent years have been focusing on Intelligent Transport Systems (ITS), since they are contributing to a change in mobility. The number of devices supporting transportation is increasing. In particular, the market penetration of aftermarket nomadic devices as personal navigation devices (PND) or smart phones is growing exponentially according to the market trends, but no scientific evidence of impacts directly related to the use of aftermarket and nomadic devices in vehicle exist yet. Therefore there is a need to test via Field Operational Tests (FOT) the impacts of driver support functions on the driving task, including future interactive traffic services that will become part of driving environment systems. The second paragraph of this paper illustrates the Field Operational Tests to be conducted in TeleFOT and progress reached so far in the project. These include (but are not limited to) large scale test sites in 8 member states, FOT framework creation, benchmarking, piloting and data analysis planning

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Photoelectron spectroscopy of manganese-based Heusler alloys

Ultraviolet-photoemission spectroscopy has been employed to investigate the valence-band electronic structures of the magnetic alloys Co2MnSn, Cu2MnAl, and Pd2MnSn.The valence band of Co2MnSn extends to approximately 5 eV below the Fermi level with a high density of states immediately below the Fermi edge. Cu2MnAl and Pd2MnSn have valence-band widths of 6 and 7 eV, respectively, with the highest density of states lying some 3 eV below the Fermi level in each case. Photoemission measurements in the region of the Mn 3p threshold indicate that Mn 3d character extends across the full width of the valence band for all three alloys. For Pd2MnSn, additional photoemission measurements in the region of the Pd 4d Cooper minimum confirm this conclusion. Modulations in photocurrent resulting from Mn 3p-to-3d resonances across the valence band of Co2MnSn are most intense towards the bottom of the band. This is discussed in terms of possible variations in initial-state hybridization. The experimental photoemission spectra are compared with calculated spectra derived from theoretical band structures. Although there are some differences in shape, the bandwidths of the calculated spectra agree very well with the experimental results

Direct evidence of a prey depletion "halo" surrounding a pelagic predator colony

Colonially breeding birds and mammals form some of the largest gatherings of apex predators in the natural world and have provided model systems for studying mechanisms of population regulation in animals. According to one influential hypothesis, intense competition for food among large numbers of spatially constrained foragers should result in a zone of prey depletion surrounding such colonies, ultimately limiting their size. However, while indirect and theoretical support for this phenomenon, known as "Ashmole's halo," has steadily accumulated, direct evidence remains exceptionally scarce. Using a combination of vesselbased surveys and Global Positioning System tracking, we show that pelagic seabirds breeding at the tropical island that first inspired Ashmole's hypothesis do indeed deplete their primary prey species (flying fish; Exocoetidae spp.) over a considerable area, with reduced prey density detectable >150 km from the colony. The observed prey gradient was mirrored by an opposing trend in seabird foraging effort, could not be explained by confounding environmental variability, and can be approximated using a mechanistic consumption-dispersion model, incorporating realistic rates of seabird predation and random prey dispersal. Our results provide a rare view of the resource footprint of a pelagic seabird colony and reveal how aggregations of these central-place foraging, marine top predators profoundly influence the oceans that surround them