Towards the spatial resolution of metalloprotein charge states by detailed modeling of XFEL crystallographic diffraction.

Oxidation states of individual metal atoms within a metalloprotein can be assigned by examining X-ray absorption edges, which shift to higher energy for progressively more positive valence numbers. Indeed, X-ray crystallography is well suited for such a measurement, owing to its ability to spatially resolve the scattering contributions of individual metal atoms that have distinct electronic environments contributing to protein function. However, as the magnitude of the shift is quite small, about +2 eV per valence state for iron, it has only been possible to measure the effect when performed with monochromated X-ray sources at synchrotron facilities with energy resolutions in the range 2-3 × 10-4 (ΔE/E). This paper tests whether X-ray free-electron laser (XFEL) pulses, which have a broader bandpass (ΔE/E = 3 × 10-3) when used without a monochromator, might also be useful for such studies. The program nanoBragg is used to simulate serial femtosecond crystallography (SFX) diffraction images with sufficient granularity to model the XFEL spectrum, the crystal mosaicity and the wavelength-dependent anomalous scattering factors contributed by two differently charged iron centers in the 110-amino-acid protein, ferredoxin. Bayesian methods are then used to deduce, from the simulated data, the most likely X-ray absorption curves for each metal atom in the protein, which agree well with the curves chosen for the simulation. The data analysis relies critically on the ability to measure the incident spectrum for each pulse, and also on the nanoBragg simulator to predict the size, shape and intensity profile of Bragg spots based on an underlying physical model that includes the absorption curves, which are then modified to produce the best agreement with the simulated data. This inference methodology potentially enables the use of SFX diffraction for the study of metalloenzyme mechanisms and, in general, offers a more detailed approach to Bragg spot data reduction

Experiment requirements: Vitamin D metabolites and bone demineralization, Spacelab 2, experiment no. 1

As a contribution toward an understanding of the molecular basis of bone loss, mineral imbalance, and increasing fecal calcium under conditions of prolonged space flight, the blood levels of biologically active vitamin D metabolites of flight crew members will be quantitatively measured. Prior to the mission, the refinement of existing and the development of new techniques for the assay of all vitamin D metabolites will provide an arsenal of methods suitable for a wide range of metabolite levels. In terms of practical application, the analysis of human and animal plasma samples, Spacelab crew plasma samples, and flight hardware are envisioned

Everyday Mobile Belonging: Theorising Higher Education Student Mobilities

This book presents a framework for a new kind of thinking about student mobilities and belonging, which foregrounds the everyday and rhythmic dimensions of students' experiences

Learning the rules of the ‘student game’: Transforming the ‘student habitus’ through [im]mobility

In recent years, a growing body of literature has emerged concerning the mobilities of students, specifically relating to the interactions between local and non-local students, which can accentuate unequal access to education; social interactions and learner outcomes. Central to much of this literature is a sense that being mobile in institutional choice is the most appropriate and expected approach to successful university life. Conversely, local students, disadvantaged by their age, history, external commitments and immobility, are thought to be unlikely to share the same ‘student experiences’ as their traditional counterparts, leading to feelings of alienation within the student community. This paper will seek to problematise this binary by examining the experiences of a group of local and non-local students studying at the University of Portsmouth using Bourdieu’s reading of habitus and capital. This is useful as it provides a more critical insight into how students’ [dis]advantaged learner identities are [re]produced through their everyday sociability. Moreover, these findings extend previous discussions of first year transitions by questioning the influence of accommodation upon the formation of identities and the initial experiences of ‘being’, or ‘becoming’ students. This paper also seeks to extend previous theoretical tendencies that privilege identity formation through mobility rather than stasis

The atmospheric effects of stratospheric aircraft: A current consensus

In the early 1970's, a fleet of supersonic aircraft flying in the lower stratosphere was proposed. A large fleet was never built for economic, political, and environmental reasons. Technological improvements may make it economically feasible to develop supersonic aircraft for current markets. Some key results of earlier scientific programs designed to assess the impact of aircraft emissions on stratospheric ozone are reviewed, and factors that must be considered to assess the environmental impact of aircraft exhaust are discussed. These include the amount of nitrogen oxides injected in the stratosphere, horizontal transport, and stratosphere/troposphere assessment models are presented. Areas in which improvements in scientific understanding and model representation must be made to reduce the uncertainty in model calculations are identified

Predicting Ares I Reaction Control System Performance by Utilizing Analysis Anchored with Development Test Data

The Ares I launch vehicle is an integral part of NASA s Constellation Program, providing a foundation for a new era of space access. The Ares I is designed to lift the Orion Crew Module and will enable humans to return to the Moon as well as explore Mars.1 The Ares I is comprised of two inline stages: a Space Shuttle-derived five-segment Solid Rocket Booster (SRB) First Stage (FS) and an Upper Stage (US) powered by a Saturn V-derived J-2X engine. A dedicated Roll Control System (RoCS) located on the connecting interstage provides roll control prior to FS separation. Induced yaw and pitch moments are handled by the SRB nozzle vectoring. The FS SRB operates for approximately two minutes after which the US separates from the vehicle and the US Reaction Control System (ReCS) continues to provide reaction control for the remainder of the mission. A representation of the Ares I launch vehicle in the stacked configuration and including the Orion Crew Exploration Vehicle (CEV) is shown in Figure 1. Each Reaction Control System (RCS) design incorporates a Gaseous Helium (GHe) pressurization system combined with a monopropellant Hydrazine (N2H4) propulsion system. Both systems have two diametrically opposed thruster modules. This architecture provides one failure tolerance for function and prevention of catastrophic hazards such as inadvertent thruster firing, bulk propellant leakage, and over-pressurization. The pressurization system on the RoCS includes two ambient pressure-referenced regulators on parallel strings in order to attain the required system level single Fault Tolerant (FT) design for function while the ReCS utilizes a blow-down approach. A single burst disk and relief valve assembly is also included on the RoCS to ensure single failure tolerance for must-not-occur catastrophic hazards. The Reaction Control Systems are designed to support simultaneously firing multiple thrusters as require

The novel MAPT mutation K298E:mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons

Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem

Highlighting when animals expend excessive energy for travel using dynamic body acceleration

Travel represents a major cost for many animals so there should be selection pressure for it to be efficient – at minimum cost. However, animals sometimes exceed minimum travel costs for reasons that must be correspondingly important. We use Dynamic Body Acceleration (DBA), an acceleration-based metric, as a proxy for movement-based power, in tandem with vertical velocity (rate of change in depth) in a shark (Rhincodon typus) to derive the minimum estimated power required to swim at defined vertical velocities. We show how subtraction of measured DBA from the estimated minimum power for any given vertical velocity provides a “proxy for power above minimum” metric (PPAmin), highlighting when these animals travel above minimum power. We suggest that the adoption of this metric across species has value in identifying where and when animals are subject to compelling conditions that lead them to deviate from ostensibly judicious energy expenditure

Highly efficient synthesis of the tricyclic core of Taxol by cascade metathesis

An efficient enantioselective synthesis of the ABC tricyclic core of the anticancer drug Taxol is reported. The key step of this synthesis is a cascade metathesis reaction, which leads in one operation to the required tricycle if appropriate fine-tuning of the dienyne precursor is performed

‘Trying to pin down jelly’ - exploring intuitive processes in quality assessment for meta-ethnography

Background: Studies that systematically search for and synthesise qualitative research are becoming more evident in health care, and they can make an important contribution to patient care. However, there is still no agreement as to whether, or how we should appraise studies for inclusion. We aimed to explore the intuitive processes that determined the ‘quality’ of qualitative research for inclusion in qualitative research syntheses. We were particularly interested to explore the way that knowledge was constructed. Methods: We used qualitative methods to explore the process of quality appraisal within a team of seven qualitative researchers funded to undertake a meta-ethnography of chronic non-malignant musculoskeletal pain. Team discussions took place monthly between October 2010 and June 2012 and were recorded and transcribed. Data was coded and organised using constant comparative method. The development of our conceptual analysis was both iterative and collaborative. The strength of this team approach to quality came from open and honest discussion, where team members felt free to agree, disagree, or change their position within the safety of the group. Results: We suggest two core facets of quality for inclusion in meta-ethnography - (1) Conceptual clarity; how clearly has the author articulated a concept that facilitates theoretical insight. (2) Interpretive rigour; fundamentally, can the interpretation ‘be trusted?’ Our findings showed that three important categories help the reader to judge interpretive rigour: (ii) What is the context of the interpretation? (ii) How inductive is the interpretation? (iii) Has the researcher challenged their interpretation? Conclusions: We highlight that methods alone do not determine the quality of research for inclusion into a meta-ethnography. The strength of a concept and its capacity to facilitate theoretical insight is integral to meta-ethnography, and arguably to the quality of research. However, we suggest that to be judged ‘good enough’ there also needs to be some assurance that qualitative findings are more than simply anecdotal. Although our conceptual model was developed specifically for meta-ethnography, it may be transferable to other research methodologies