Asymmetric localisation of Miranda and its cargo proteins during neuroblast division requires the anaphase-promoting complex/cyclosome

Asymmetric cell divisions generate cell fate diversity during both invertebrate and vertebrate development. Drosophila neural progenitors or neuroblasts (NBs) each divide asymmetrically to produce a larger neuroblast and a smaller ganglion mother cell (GMC). The asymmetric localisation of neural cell fate determinants and their adapter proteins to the neuroblast cortex during mitosis facilitates their preferential segregation to the GMC upon cytokinesis. In this study we report a novel role for the anaphase-promoting complex/cyclosome (APC/C) during this process. Attenuation of APC/C activity disrupts the asymmetric localisation of the adapter protein Miranda and its associated cargo proteins Staufen, Prospero and Brat, but not other components of the asymmetric division machinery. We demonstrate that Miranda is ubiquitylated via its C-terminal domain; removal of this domain disrupts Miranda localisation and replacement of this domain with a ubiquitin moiety restores normal asymmetric Miranda localisation. Our results demonstrate that APC/C activity and ubiquitylation of Miranda are required for the asymmetric localisation of Miranda and its cargo proteins to the NB cortex

TarO : a target optimisation system for structural biology

This work was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) Structural Proteomics of Rational Targets (SPoRT) initiative, (Grant BBS/B/14434). Funding to pay the Open Access publication charges for this article was provided by BBSRC.TarO (http://www.compbio.dundee.ac.uk/taro) offers a single point of reference for key bioinformatics analyses relevant to selecting proteins or domains for study by structural biology techniques. The protein sequence is analysed by 17 algorithms and compared to 8 databases. TarO gathers putative homologues, including orthologues, and then obtains predictions of properties for these sequences including crystallisation propensity, protein disorder and post-translational modifications. Analyses are run on a high-performance computing cluster, the results integrated, stored in a database and accessed through a web-based user interface. Output is in tabulated format and in the form of an annotated multiple sequence alignment (MSA) that may be edited interactively in the program Jalview. TarO also simplifies the gathering of additional annotations via the Distributed Annotation System, both from the MSA in Jalview and through links to Dasty2. Routes to other information gateways are included, for example to relevant pages from UniProt, COG and the Conserved Domains Database. Open access to TarO is available from a guest account with private accounts for academic use available on request. Future development of TarO will include further analysis steps and integration with the Protein Information Management System (PIMS), a sister project in the BBSRC Structural Proteomics of Rational Targets initiative.Publisher PDFPeer reviewe

Altered visual processing in a rodent model of Attention-Deficit Hyperactivity Disorder

A central component of Attention-Deficit Hyperactivity Disorder (ADHD) is increased distractibility, which is linked to the superior colliculus (SC) in a range of species, including humans. Furthermore, there is now mounting evidence of altered collicular functioning in ADHD and it is proposed that a hyper-responsive SC could mediate the main symptoms of ADHD, including distractibility. In the present study we have provided a systematic characterization of the SC in the most commonly used and well-validated animal model of ADHD, the spontaneously hypertensive rat (SHR). We examined collicular-dependent orienting behavior, local field potential (LFP) and multiunit responses to visual stimuli in the anesthetized rat and morphological measures in the SHR in comparison to the Wistar Kyoto (WKY) and Wistar (WIS). We found that SHRs remain responsive to a repeated visual stimulus for more presentations than control strains and have a longer response duration. In addition, LFP and multiunit activity within the visually responsive superficial layers of the SC showed the SHR to have a hyper-responsive SC relative to control strains, which could not be explained by altered functioning of the retinocollicular pathway. Finally, examination of collicular volume, neuron and glia densities and glia:neuron ratio revealed that the SHR had a reduced ratio relative to the WKY which could explain the increased responsiveness. In conclusion, this study demonstrates strain-specific changes in the functioning and structure of the SC in the SHR, providing convergent evidence that the SC might be dysfunctional in ADHD

Integrated modelling of cost-effective siting and operation of flow-control infrastructure for river ecosystem conservation

Wetland and floodplain ecosystems along many regulated rivers are highly stressed, primarily due to a lack of environmental flows of appropriate magnitude, frequency, duration, and timing to support ecological functions. In the absence of increased environmental flows, the ecological health of river ecosystems can be enhanced by the operation of existing and new flow-control infrastructure (weirs and regulators) to return more natural environmental flow regimes to specific areas. However, determining the optimal investment and operation strategies over time is a complex task due to several factors including the multiple environmental values attached to wetlands, spatial and temporal heterogeneity and dependencies, nonlinearity, and time-dependent decisions. This makes for a very large number of decision variables over a long planning horizon. The focus of this paper is the development of a nonlinear integer programming model that accommodates these complexities. The mathematical objective aims to return the natural flow regime of key components of river ecosystems in terms of flood timing, flood duration, and interflood period. We applied a 2-stage recursive heuristic using tabu search to solve the model and tested it on the entire South Australian River Murray floodplain. We conclude that modern meta-heuristics can be used to solve the very complex nonlinear problems with spatial and temporal dependencies typical of environmental flow allocation in regulated river ecosystems. The model has been used to inform the investment in, and operation of, flow-control infrastructure in the South Australian River Murray.<br /

Nicotine enhances an auditory Event-Related Potential component which is inversely related to habituation

Nicotine is a psychoactive substance that is commonly consumed in the context of music. However, the reason why music and nicotine are coconsumed is uncertain. One possibility is that nicotine affects cognitive processes relevant to aspects of music appreciation in a beneficial way. Here we investigated this possibility using Event-Related Potentials (ERPs). Participants underwent a simple decision-making task (to maintain attentional focus), responses to which were signaled by auditory stimuli. Unlike most previous research looking at the effects of nicotine on auditory processing, we used tones of different pitch, a fundamental element of music. In addition, unlike most other studies, we tested non-smoking subjects to avoid withdrawal-related complications. We found that nicotine (4.0 mg, administered as gum) increased P2 amplitude in the frontal region. Since a decrease in P2 amplitude and latency is related to habituation processes, and an enhanced ability to disengage from irrelevant stimuli, our findings suggest that nicotine may cause a reduction in habituation, resulting in non-smokers being less able to adapt to repeated stimuli. A corollary of that decrease in adaptation may be that nicotine extends the temporal window during which a listener is able and willing to engage with a piece of music

Characterisation of the muon beams for the Muon Ionisation Cooling Experiment

A novel single-particle technique to measure emittance has been developed and used to characterise seventeen different muon beams for the Muon Ionisation Cooling Experiment (MICE). The muon beams, whose mean momenta vary from 171 to 281 MeV/c, have emittances of approximately 1.2–2.3 π mm-rad horizontally and 0.6–1.0 π mm-rad vertically, a horizontal dispersion of 90–190 mm and momentum spreads of about 25 MeV/c. There is reasonable agreement between the measured parameters of the beams and the results of simulations. The beams are found to meet the requirements of MICE

MICE: The muon ionization cooling experiment. Step I: First measurement of emittance with particle physics detectors

Copyright @ 2011 APSThe Muon Ionization Cooling Experiment (MICE) is a strategic R&D project intended to demonstrate the only practical solution to providing high brilliance beams necessary for a neutrino factory or muon collider. MICE is under development at the Rutherford Appleton Laboratory (RAL) in the United Kingdom. It comprises a dedicated beamline to generate a range of input muon emittances and momenta, with time-of-flight and Cherenkov detectors to ensure a pure muon beam. The emittance of the incoming beam will be measured in the upstream magnetic spectrometer with a scintillating fiber tracker. A cooling cell will then follow, alternating energy loss in Liquid Hydrogen (LH2) absorbers to RF cavity acceleration. A second spectrometer, identical to the first, and a second muon identification system will measure the outgoing emittance. In the 2010 run at RAL the muon beamline and most detectors were fully commissioned and a first measurement of the emittance of the muon beam with particle physics (time-of-flight) detectors was performed. The analysis of these data was recently completed and is discussed in this paper. Future steps for MICE, where beam emittance and emittance reduction (cooling) are to be measured with greater accuracy, are also presented.This work was supported by NSF grant PHY-0842798