Physical and dynamical characterisation of low Delta-V NEA (190491) 2000 FJ10

We investigated the physical properties and dynamical evolution of Near Earth Asteroid (NEA) (190491) 2000 FJ10 in order to assess the suitability of this accessible NEA as a space mission target. Photometry and colour determination were carried out with the 1.54 m Kuiper Telescope and the 10 m Southern African Large Telescope during the object's recent favourable apparition in 2011-12. During the earlier 2008 apparition, a spectrum of the object in the 6000-9000 Angstrom region was obtained with the 4.2 m William Herschel Telescope. Interpretation of the observational results was aided by numerical simulations of 1000 dynamical clones of 2000 FJ10 up to 10^6 yr in the past and in the future. The asteroid's spectrum and colours determined by our observations suggest a taxonomic classification within the S-complex although other classifications (V, D, E, M, P) cannot be ruled out. On this evidence, it is unlikely to be a primitive, relatively unaltered remnant from the early history of the solar system and thus a low priority target for robotic sample return. Our photometry placed a lower bound of 2 hrs to the asteroid's rotation period. Its absolute magnitude was estimated to be 21.54+-0.1 which, for a typical S-complex albedo, translates into a diameter of 130+-20 m. Our dynamical simulations show that it has likely been an Amor for the past 10^5 yr. Although currently not Earth-crossing, it will likely become so during the period 50 - 100 kyr in the future. It may have arrived from the inner or central Main Belt > 1 Myr ago as a former member of a low-inclination S-class asteroid family. Its relatively slow rotation and large size make it a suitable destination for a human mission. We show that ballistic Earth-190491-Earth transfer trajectories with Delta-V < 2 km s^-1 at the asteroid exist between 2052 and 2061.Comment: 2 Tables, 11 Figures, accepted for publication in Astronomy & Astrophysic

The isolated muscle fibre as a model of disuse atrophy: characterization using PhAct, a method to quantify f-actin

Research into muscle atrophy and hypertrophy is hampered by limitations of the available experimental models. Interpretation of in vivo experiments is confounded by the complexity of the environment while in vitro models are subject to the marked disparities between cultured myotubes and the mature myofibres of living tissues. Here we develop a method (PhAct) based on ex vivo maintenance of the isolated myofibre as a model of disuse atrophy, using standard microscopy equipment and widely available analysis software, to measure f-actin content per myofibre and per nucleus over two weeks of ex vivo maintenance. We characterize the 35% per week atrophy of the isolated myofibre in terms of early changes in gene expression and investigate the effects on loss of muscle mass of modulatory agents, including Myostatin and Follistatin. By tracing the incorporation of a nucleotide analogue we show that the observed atrophy is not associated with loss or replacement of myonuclei. Such a completely controlled investigation can be conducted with the myofibres of a single muscle. With this novel method we can identify those features and mechanisms of atrophy and hypertrophy that are intrinsic to the muscle fibre from those that include activities of other tissues and systemic agents

Spatial distribution of micrometre‐scale porosity and permeability across the damage zone of a reverse‐reactivated normal fault in a tight sandstone : Insights from the Otway Basin, SE Australia

This research forms part of a PhD project supported by the Australian Research Council [Discovery Project DP160101158] and through an Australian Government Research Training Program Scholarship. Dave Healy acknowledges the support of the Natural Environment Research Council (NERC, UK) through the award NE/N003063/1 ‘Quantifying the Anisotropy of Permeability in Stressed Rock’. This study was also funded by scholarships from the Petroleum Exploration Society of Australia and the Australian Petroleum Production and Exploration Association. We thank Gordon Holm for preparing thin sections and Colin Taylor for carrying out particle size measurements and mercury injection capillary pressure analyses. Aoife McFadden and David Kelsey from Adelaide Microscopy, Braden Morgan, and Sophie Harland are acknowledged for their assistance with laboratory work. Field assistants James Hall, Rowan Hansberry, and Lachlan Furness are also gratefully acknowledged for their assistance with sample collection. Discussions with Ian Duddy on the mineralogy of the Eumeralla Formation are also greatly appreciated. This forms TRaX record 416.Peer reviewedPublisher PD

Atmospheric oxygen tension slows myoblast proliferation via mitochondrial activation

Mitochondrial activity inhibits proliferation and is required for differentiation of myoblasts. Myoblast proliferation is also inhibited by the ~20% oxygen level used in standard tissue culture. We hypothesize that mitochondrial activity would be greater at hyperoxia (20% O(2)) relative to more physiological oxygen (5% O(2)).Murine primary myoblasts from isolated myofibres and conditionally immortalized H-2K myoblasts were cultured at 5% and 20% oxygen. Proliferation, assayed by cell counts, EdU labeling, and CFSE dilution, was slower at 20% oxygen. Expression of MyoD in primary myoblasts was delayed at 20% oxygen, but myogenicity, as measured by fusion index, was slightly higher. FACS-based measurement of mitochondrial activity indicators and luminometric measurement of ATP levels revealed that mitochondria exhibited greater membrane potential and higher levels of Reactive Oxygen Species (ROS) at 20% oxygen with concomitant elevation of intracellular ATP. Mitochondrial mass was unaffected. Low concentrations of CCCP, a respiratory chain uncoupler, and Oligomycin A, an ATP synthase inhibitor, each increased the rate of myoblast proliferation. ROS were investigated as a potential mechanism of mitochondrial retrograde signaling, but scavenging of ROS levels by N-acetyl-cysteine (NAC) or α-Phenyl-N-tert-butylnitrone (PBN) did not rescue the suppressed rate of cell division in hyperoxic conditions, suggesting other pathways. Primary myoblasts from older mice showed a slower proliferation than those from younger adult mice at 20% oxygen but no difference at 5% oxygen.These results implicate mitochondrial regulation as a mechanistic explanation for myoblast response to oxygen tension. The rescue of proliferation rate in myoblasts of aged mice by 5% oxygen suggests a major artefactual component to age-related decline of satellite cell proliferation in standard tissue culture at 20% oxygen. It lends weight to the idea that these age-related changes result at least in part from environmental factors rather than characteristics intrinsic to the satellite cell

A realist review of the causes of, and current interventions to address ‘missingness’ in health care

Background: This protocol describes a realist review exploring the problem of “missingness” in healthcare, defined as the repeated tendency not to take up offers of care that has a negative impact on the person and their life chances. More specifically, the review looks at the phenomenon of patients missing multiple appointments in primary care in the UK – at the causal factors that influence how patients come to be “missing” in this way, and what interventions might support uptake and “presence” in healthcare. Background research informing this project suggests that a high rate of missed appointments predicted high premature death rates, and patients were more likely to have multiple long-term health conditions and experience significant socioeconomic disadvantage. Most research in this field focuses on population- or service-level characteristics of patients who miss appointments, often making no distinction between causes of single missed appointments and of multiple missed appointments. There have therefore been no interventions for ‘missingness’, accounting for the complex life circumstances or common mechanisms that cause people to repeatedly miss appointments. Methods: We use a realist review approach to explore what causes missingness - and what might prevent or address it - for whom, and in what circumstances. The review uses an iterative approach of database searching, citation-tracking and sourcing grey literature, with selected articles providing insight into the causal dynamics underpinning missed appointments and the interventions designed to address them. Discussion: The findings of this review will be combined with the findings of a qualitative empirical study and the contributions of a Stakeholder Advisory Group (STAG) to inform the development of a programme theory that seeks to explain how missingness occurs, whom it affects and under what circumstances. This will be used to develop a complex intervention to address multiple missed appointments in primary care. PROSPERO registration: CRD4202234600

Motivated proteins: a web application for studying small three-dimensional protein motifs

&lt;b&gt;BACKGROUND:&lt;/b&gt; Small loop-shaped motifs are common constituents of the three-dimensional structure of proteins. Typically they comprise between three and seven amino acid residues, and are defined by a combination of dihedral angles and hydrogen bonding partners. The most abundant of these are alphabeta-motifs, asx-motifs, asx-turns, beta-bulges, beta-bulge loops, beta-turns, nests, niches, Schellmann loops, ST-motifs, ST-staples and ST-turns.We have constructed a database of such motifs from a range of high-quality protein structures and built a web application as a visual interface to this. &lt;b&gt;DESCRIPTION:&lt;/b&gt; The web application, Motivated Proteins, provides access to these 12 motifs (with 48 sub-categories) in a database of over 400 representative proteins. Queries can be made for specific categories or sub-categories of motif, motifs in the vicinity of ligands, motifs which include part of an enzyme active site, overlapping motifs, or motifs which include a particular amino acid sequence. Individual proteins can be specified, or, where appropriate, motifs for all proteins listed. The results of queries are presented in textual form as an (X)HTML table, and may be saved as parsable plain text or XML. Motifs can be viewed and manipulated either individually or in the context of the protein in the Jmol applet structural viewer. Cartoons of the motifs imposed on a linear representation of protein secondary structure are also provided. Summary information for the motifs is available, as are histograms of amino acid distribution, and graphs of dihedral angles at individual positions in the motifs. &lt;b&gt;CONCLUSION:&lt;/b&gt; Motivated Proteins is a publicly and freely accessible web application that enables protein scientists to study small three-dimensional motifs without requiring knowledge of either Structured Query Language or the underlying database schem

Evaluation of expression and function of the H+/myo-inositol transporter HMIT;

BACKGROUND: The phosphoinositide (PIns) signalling pathway regulates a series of neuronal processes, such as neurotransmitter release, that are thought to be altered in mood disorders. Furthermore, mood-stabilising drugs have been shown to inhibit key enzymes that regulate PIns production and alter neuronal growth cone morphology in an inositol-reversible manner. Here, we describe analyses of expression and function of the recently identified H+/myo-inositol transporter (HMIT) investigated as a potential regulator of PIns signalling. RESULTS: We show that HMIT is primarily a neuronal transporter widely expressed in the rat and human brain, with particularly high levels in the hippocampus and cortex, as shown by immunohistochemistry. The transporter is localised at the Golgi apparatus in primary cultured neurones. No HMIT-mediated electrophysiological responses were detected in rat brain neurones or slices; in addition, inositol transport and homeostasis were unaffected in HMIT targeted null-mutant mice. CONCLUSION: Together, these data do not support a role for HMIT as a neuronal plasma membrane inositol transporter, as previously proposed. However, we observed that HMIT can transport inositol triphosphate, indicating unanticipated intracellular functions for this transporter that may be relevant to mood control

Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials