Genomic Analysis of Drosophila Neuronal Remodeling: A Role for the RNA-Binding Protein Boule as a Negative Regulator of Axon Pruning

Drosophila mushroom body (MB) {gamma} neurons undergo axon pruning during metamorphosis through a process of localized degeneration of specific axon branches. Developmental axon degeneration is initiated by the steroid hormone ecdysone, acting through a nuclear receptor complex composed of USP (ultraspiracle) and EcRB1 (ecdysone receptor B1) to regulate gene expression in MB {gamma} neurons. To identify ecdysone-dependent gene expression changes in MB {gamma} neurons at the onset of axon pruning, we use laser capture microdissection to isolate wild-type and mutant MB neurons in which EcR (ecdysone receptor) activity is genetically blocked, and analyze expression changes by microarray. We identify several molecular pathways that are regulated in MB neurons by ecdysone. The most striking observation is the upregulation of genes involved in the UPS (ubiquitin–proteasome system), which is cell autonomously required for {gamma} neuron pruning. In addition, we characterize the function of Boule, an evolutionarily conserved RNA-binding protein previously implicated in spermatogenesis in flies and vertebrates. boule expression is downregulated by ecdysone in MB neurons at the onset of pruning, and forced expression of Boule in MB {gamma} neurons is sufficient to inhibit axon pruning. This activity is dependent on the RNA-binding domain of Boule and a conserved DAZ (deleted in azoospermia) domain implicated in interactions with other RNA-binding proteins. However, loss of Boule does not result in obvious defects in axon pruning or morphogenesis of MB neurons, suggesting that it acts redundantly with other ecdyonse-regulated genes. We propose a novel function for Boule in the CNS as a negative regulator of developmental axon pruning

Spatiotemporal Changes in Nuclear Strain Measured by Traction Force Microscopy

The knowledge of how cells interact with and sense their surroundings is missing the key components of time dependency and how substrate stiffness affects amount and rate of strain. This new knowledge of cell-substrate interaction can be applied further to research regarding chromatin spatiotemporal dynamics to better understand gene accessibility for transcription. Studying how the cell functions on a deeper level will provide understanding of cellular morphological changes and proliferation. This study uses the methods of optical microscopy and traction force microscopy (TFM) to image substrate deformation as well as analyze its strain profile to find where forces are interacting with the substrate the most. A 60X objective on a confocal microscope was used to image the cell membrane, nucleus, and fluorescent beads in PDMS gels of varying stiffness on which the cells were placed. Based on how the nucleus deforms as well as how the beads move due to cell-substrate interaction, a strain profile of the gel along with traction force analysis can be determined to quantify how the cell is interacting with its substrate. The results are that as the cell is trypsinized after spreading along the substrate, the focal adhesions made by the cell will disconnect, causing the beads to spread out locally around the cell. It was also found that as substrate stiffness increases, the rate of cell spreading increases. From these findings, it can be concluded that the cell responds more positively in environments of higher stiffness and spreads at a faster rate

Challenges in the care of familial hypercholesterolemia: a community care perspective

Familial hyperchoelsterolaemia (FH) remains under-diagnosed and under-treated in the community setting. Earlier evidence suggested prevalence of 1:500 worldwide but newer evidence suggests it is more common. Less than 15% of FH patients are ever diagnosed with children and young adults rarely tested despite having most to gain given their lifetime exposure. Increasing awareness among primary care teams is critical to improve detection profile for FH. Cascade testing in the community setting needs a sustainable approach to be developed to facilitate family tracing of index cases. The use of the Dutch Lipid Clinic Network Criteria score to facilitate a phenotypic diagnosis is the preferred approach adopted in Australia and eliminates the need to undertake genetic testing for all suspected FH cases

Cues and knowledge structures used by mental-health professionals when making risk assessments

Background: Research into mental-health risks has tended to focus on epidemiological approaches and to consider pieces of evidence in isolation. Less is known about the particular factors and their patterns of occurrence that influence clinicians’ risk judgements in practice. Aims: To identify the cues used by clinicians to make risk judgements and to explore how these combine within clinicians’ psychological representations of suicide, self-harm, self-neglect, and harm to others. Method: Content analysis was applied to semi-structured interviews conducted with 46 practitioners from various mental-health disciplines, using mind maps to represent the hierarchical relationships of data and concepts. Results: Strong consensus between experts meant their knowledge could be integrated into a single hierarchical structure for each risk. This revealed contrasting emphases between data and concepts underpinning risks, including: reflection and forethought for suicide; motivation for self-harm; situation and context for harm to others; and current presentation for self-neglect. Conclusions: Analysis of experts’ risk-assessment knowledge identified influential cues and their relationships to risks. It can inform development of valid risk-screening decision support systems that combine actuarial evidence with clinical expertise

Theoretical studies of the historical development of the accounting discipline: a review and evidence

Many existing studies of the development of accounting thought have either been atheoretical or have adopted Kuhn's model of scientific growth. The limitations of this 35-year-old model are discussed. Four different general neo-Kuhnian models of scholarly knowledge development are reviewed and compared with reference to an analytical matrix. The models are found to be mutually consistent, with each focusing on a different aspect of development. A composite model is proposed. Based on a hand-crafted database, author co-citation analysis is used to map empirically the entire literature structure of the accounting discipline during two consecutive time periods, 1972–81 and 1982–90. The changing structure of the accounting literature is interpreted using the proposed composite model of scholarly knowledge development

Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer’s: A 1-year randomized controlled trial

Background Our goal was to investigate the role of physical exercise to protect brain health as we age, including the potential to mitigate Alzheimer’s-related pathology. We assessed the effect of 52 weeks of a supervised aerobic exercise program on amyloid accumulation, cognitive performance, and brain volume in cognitively normal older adults with elevated and sub-threshold levels of cerebral amyloid as measured by amyloid PET imaging. Methods and findings This 52-week randomized controlled trial compared the effects of 150 minutes per week of aerobic exercise vs. education control intervention. A total of 117 underactive older adults (mean age 72.9 [7.7]) without evidence of cognitive impairment, with elevated (n = 79) or subthreshold (n = 38) levels of cerebral amyloid were randomized, and 110 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. We conducted 18F-AV45 PET imaging of cerebral amyloid and anatomical MRI for whole brain and hippocampal volume at baseline and Week 52 follow-up to index brain health. Neuropsychological tests were conducted at baseline, Week 26, and Week 52 to assess executive function, verbal memory, and visuospatial cognitive domains. Cardiorespiratory fitness testing was performed at baseline and Week 52 to assess response to exercise. The aerobic exercise group significantly improved cardiorespiratory fitness (11% vs. 1% in the control group) but there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control. Conclusions Aerobic exercise was not associated with reduced amyloid accumulation in cognitively normal older adults with cerebral amyloid. In spite of strong systemic cardiorespiratory effects of the intervention, the observed lack of cognitive or brain structure benefits suggests brain benefits of exercise reported in other studies are likely to be related to non-amyloid effects

A continental-scale validation of ecosystem service models

Faced with environmental degradation, governments worldwide are developing policies to safeguard ecosystem services (ES). Many ES models exist to support these policies, but they are generally poorly validated, especially at large scales, which undermines their credibility. To address this gap, we describe a study of multiple models of five ES, which we validate at an unprecedented scale against 1675 data points across sub-Saharan Africa. We find that potential ES (biophysical supply of carbon and water) are reasonably well predicted by the existing models. These potential ES models can also be used as inputs to new models for realised ES (use of charcoal, firewood, grazing resources and water), by adding information on human population density. We find that increasing model complexity can improve estimates of both potential and realised ES, suggesting that developing more detailed models of ES will be beneficial. Furthermore, in 85% of cases, human population density alone was as good or a better predictor of realised ES than ES models, suggesting that it is demand, rather than supply that is predominantly determining current patterns of ES use. Our study demonstrates the feasibility of ES model validation, even in data-deficient locations such as sub-Saharan Africa. Our work also shows the clear need for more work on the demand side of ES models, and the importance of model validation in providing a stronger base to support policies which seek to achieve sustainable development in support of human well-being

VERTICO VI: Cold-gas asymmetries in Virgo cluster galaxies

We analyze cold-gas distributions in Virgo cluster galaxies using resolved CO(2-1) (tracing molecular hydrogen, H2) and HI observations from the Virgo Environment Traced In CO (VERTICO) and the VLA Imaging of Virgo in Atomic Gas (VIVA) surveys. From a theoretical perspective, it is expected that environmental processes in clusters will have a stronger influence on diffuse atomic gas compared to the relatively dense molecular gas component, and that these environmental perturbations can compress the cold interstellar medium in cluster galaxies leading to elevated star formation. In this work we observationally test these predictions for star-forming satellite galaxies within the Virgo cluster. We divide our Virgo galaxy sample into HI-normal, HI-tailed, and HI-truncated classes and show, unsurprisingly, that the HI-tailed galaxies have the largest quantitative HI asymmetries. We also compare to a control sample of non-cluster galaxies and find that Virgo galaxies, on average, have HI asymmetries that are 40 +/- 10 per cent larger than the control. There is less separation between control, HI-normal, HI-tailed, and HI-truncated galaxies in terms of H2 asymmetries, and on average, Virgo galaxies have H2 asymmetries that are only marginally (20 +/- 10 per cent) larger than the control sample. We find a weak correlation between HI and H2 asymmetries over our entire sample, but a stronger correlation for those specific galaxies being strongly impacted by environmental perturbations. Finally, we divide the discs of the HI-tailed Virgo galaxies into a leading half and trailing half according to the observed tail direction. We find evidence for excess molecular gas mass on the leading halves of the disc. This excess molecular gas on the leading half is accompanied by an excess in star formation rate such that the depletion time is, on average, unchanged.Comment: 15 pages, 8 figures, 1 table, accepted for publication in A&

All-sky search for periodic gravitational waves in LIGO S4 data

We report on an all-sky search with the LIGO detectors for periodic gravitational waves in the frequency range 50-1000 Hz and with the frequency's time derivative in the range -1.0E-8 Hz/s to zero. Data from the fourth LIGO science run (S4) have been used in this search. Three different semi-coherent methods of transforming and summing strain power from Short Fourier Transforms (SFTs) of the calibrated data have been used. The first, known as "StackSlide", averages normalized power from each SFT. A "weighted Hough" scheme is also developed and used, and which also allows for a multi-interferometer search. The third method, known as "PowerFlux", is a variant of the StackSlide method in which the power is weighted before summing. In both the weighted Hough and PowerFlux methods, the weights are chosen according to the noise and detector antenna-pattern to maximize the signal-to-noise ratio. The respective advantages and disadvantages of these methods are discussed. Observing no evidence of periodic gravitational radiation, we report upper limits; we interpret these as limits on this radiation from isolated rotating neutron stars. The best population-based upper limit with 95% confidence on the gravitational-wave strain amplitude, found for simulated sources distributed isotropically across the sky and with isotropically distributed spin-axes, is 4.28E-24 (near 140 Hz). Strict upper limits are also obtained for small patches on the sky for best-case and worst-case inclinations of the spin axes.Comment: 39 pages, 41 figures An error was found in the computation of the C parameter defined in equation 44 which led to its overestimate by 2^(1/4). The correct values for the multi-interferometer, H1 and L1 analyses are 9.2, 9.7, and 9.3, respectively. Figure 32 has been updated accordingly. None of the upper limits presented in the paper were affecte

Search for gravitational waves from binary inspirals in S3 and S4 LIGO data

We report on a search for gravitational waves from the coalescence of compact binaries during the third and fourth LIGO science runs. The search focused on gravitational waves generated during the inspiral phase of the binary evolution. In our analysis, we considered three categories of compact binary systems, ordered by mass: (i) primordial black hole binaries with masses in the range 0.35 M(sun) < m1, m2 < 1.0 M(sun), (ii) binary neutron stars with masses in the range 1.0 M(sun) < m1, m2 < 3.0 M(sun), and (iii) binary black holes with masses in the range 3.0 M(sun)< m1, m2 < m_(max) with the additional constraint m1+ m2 < m_(max), where m_(max) was set to 40.0 M(sun) and 80.0 M(sun) in the third and fourth science runs, respectively. Although the detectors could probe to distances as far as tens of Mpc, no gravitational-wave signals were identified in the 1364 hours of data we analyzed. Assuming a binary population with a Gaussian distribution around 0.75-0.75 M(sun), 1.4-1.4 M(sun), and 5.0-5.0 M(sun), we derived 90%-confidence upper limit rates of 4.9 yr^(-1) L10^(-1) for primordial black hole binaries, 1.2 yr^(-1) L10^(-1) for binary neutron stars, and 0.5 yr^(-1) L10^(-1) for stellar mass binary black holes, where L10 is 10^(10) times the blue light luminosity of the Sun.Comment: 12 pages, 11 figure