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A theoretical framework for TTO valuations and a taxonomy of TTO approaches: results from a pilot study
Actions of Agonists, Fipronil and Ivermectin on the Predominant In Vivo Splice and Edit Variant (RDLbd, I/V) of the Drosophila GABA Receptor Expressed in Xenopus laevis Oocytes
Ionotropic GABA receptors are the targets for several classes of insecticides. One of the most widely-studied insect GABA receptors is RDL (resistance to dieldrin), originally isolated from Drosophila melanogaster. RDL undergoes alternative splicing and RNA editing, which influence the potency of GABA. Most work has focussed on minority isoforms. Here, we report the first characterisation of the predominant native splice variant and RNA edit, combining functional characterisation with molecular modelling of the agonist-binding region. The relative order of agonist potency is GABA> muscimol> TACA> β-alanine. The I/V edit does not alter the potency of GABA compared to RDLbd. Docking calculations suggest that these agonists bind and activate RDLbdI/V through a similar binding mode. TACA and β-alanine are predicted to bind with lower affinity than GABA, potentially explaining their lower potency, whereas the lower potency of muscimol and isoguvacine cannot be explained structurally from the docking calculations. The A301S (resistance to dieldrin) mutation reduced the potency of antagonists picrotoxin, fipronil and pyrafluprole but the I/V edit had no measurable effect. Ivermectin suppressed responses to GABA of RDLbdI/V, RDLbd and RDLbdI/VA301S. The dieldrin resistant variant also showed reduced sensitivity to Ivermectin. This study of a highly abundant insect GABA receptor isoform will help the design of new insecticides
Mechanisms of Action, Resistance and Toxicity of Insecticides Targeting GABA Receptors
Background: γ-Aminobutyric acid (GABA) receptors play a central role in fast inhibitory neurotransmission in insects. Several classes of insecticides targeting insect GABA-gated chloride channels have been developed. The important resistant to dieldrin GABA receptor subunit (RDL) has been used to investigate insecticide sites of action using radioligands, electrophysiology and site-directed mutagenesis. Although this important subunit readily forms robust functional homomeric receptors when expressed, alternative splicing and RNA A-to-I editing can generate diverse forms of the receptor. /
Methods: We have reviewed studies on native and recombinant insect GABA-gated chloride channels, their interactions with ligands acting at orthosteric and allosteric sites and their interactions with insecticides. Since some GABA receptor modulators act on L-glutamate-gated chloride channels, some comparisons are included. /
Results: The actions on GABA-gated chloride channels of polychlorocycloalkanes, cyclodienes, macrocyclic lactones, phenylpyrazoles, isoxazolines, and metadiamides are described and the mechanisms of action of members of these insecticide classes are addressed. Mutations that lead to resistance are discussed as they can be important in developing field diagnostic tests. Toxicity issues relating to insecticides targeting GABA-gated chloride channels are also addressed. /
An overview of all major insecticide classes targeting insect GABA-gated chloride channels has enhanced our understanding of these important receptors and their insecticide binding sites. However, the subunit composition of native GABA receptors remains unknown and studies to clarify this are needed. Also, the precise sites of action of the recently introduced isoxazolines and meta-diamides will be of interest to pursue
Using XML and XSLT for flexible elicitation of mental-health risk knowledge
Current tools for assessing risks associated with mental-health problems require assessors to make high-level judgements based on clinical experience. This paper describes how new technologies can enhance qualitative research methods to identify lower-level cues underlying these judgements, which can be collected by people without a specialist mental-health background.
Methods and evolving results: Content analysis of interviews with 46 multidisciplinary mental-health experts exposed the cues and their interrelationships, which were represented by a mind map using software that stores maps as XML. All 46 mind maps were integrated into a single XML knowledge structure and analysed by a Lisp program to generate quantitative information about the numbers of experts associated with each part of it. The knowledge was refined by the experts, using software developed in Flash to record their collective views within the XML itself. These views specified how the XML should be transformed by XSLT, a technology for rendering XML, which resulted in a validated hierarchical knowledge structure associating patient cues with risks.
Conclusions: Changing knowledge elicitation requirements were accommodated by flexible transformations of XML data using XSLT, which also facilitated generation of multiple data-gathering tools suiting different assessment circumstances and levels of mental-health knowledge
Critical Ultrasonics Near the Superfluid Transition : Finite Size Effects
The suppression of order parameter fluctuations at the boundaries causes the
ultrasonic attenuation near the superfluid transition to be lowered below the
bulk value. We calculate explicitly the first deviation from the bulk value for
temperatures above the lambda point. This deviation is significantly larger
than for static quantities like the thermodynamic specific heat or other
transport properties like the thermal conductivity. This makes ultrasonics a
very effective probe for finite size effects.Comment: 10 pages (LaTeX), 1 figure (PostScript
Inorganic nitrogen and glucose additions alter the short-term formation efficiency of mineral associated organic matter carbon
Carbon within mineral associated organic matter (MAOM) is an important persistent form of soil organic carbon (SOC). However, processes driving the retention of new labile C in MAOM are not fully understood. We investigated the effects of glucose and ammonium nitrate (AN) addition on the short-term (72 h) retention of applied 13C-glucose within MAOM. We found an interactive effect of AN addition with the glucose addition rate. Higher rates of glucose addition resulted in proportionally less glucose-C retained, indicating lower MAOM-C formation efficiency. Addition of AN only altered the proportional retention of glucose where glucose was applied at the lowest rate. In this instance glucose-13C recovery increased with AN addition. However, after 72 h there was no treatment difference in total MAOM-C, indicating that any changes in formation efficiency as a result of AN and glucose additions, did not result in differences in total MAOM-C in the short-term. Whether and how this affects the medium and longer-term dynamics of MAOM-C requires further investigation
'Surely the most natural scenario in the world’: Representations of ‘Family’ in BBC Pre-school Television
Historically, the majority of work on British children’s television has adopted either an institutional or an audience focus, with the texts themselves often overlooked. This neglect has meant that questions of representation in British children’s television – including issues such as family, gender, class or ethnicity - have been infrequently analysed in the UK context. In this article, we adopt a primarily qualitative methodology and analyse the various textual manifestations of ‘family’, group, or community as represented in a selected number of BBC pre-school programmes. In doing so, we question the (limited amount of) international work that has examined representations of the family in children’s television, and argue that nuclear family structures do not predominate in this sphere
Evolving Spatially Aggregated Features from Satellite Imagery for Regional Modeling
Satellite imagery and remote sensing provide explanatory variables at
relatively high resolutions for modeling geospatial phenomena, yet regional
summaries are often desirable for analysis and actionable insight. In this
paper, we propose a novel method of inducing spatial aggregations as a
component of the machine learning process, yielding regional model features
whose construction is driven by model prediction performance rather than prior
assumptions. Our results demonstrate that Genetic Programming is particularly
well suited to this type of feature construction because it can automatically
synthesize appropriate aggregations, as well as better incorporate them into
predictive models compared to other regression methods we tested. In our
experiments we consider a specific problem instance and real-world dataset
relevant to predicting snow properties in high-mountain Asia
MicroRNA regulation of the paired-box transcription factor Pax3 confers robustness to developmental timing of myogenesis
Commitment of progenitors in the dermomyotome to myoblast fate is the first step in establishing the body musculature. Pax3 is a crucial transcription factor, important for skeletal muscle development and expressed in myogenic progenitors in the dermomyotome of developing somites and in migratory muscle progenitors that populate the limb buds. Down-regulation of Pax3 is essential to ignite the myogenic program, including up-regulation of myogenic regulators, Myf-5 and MyoD. MicroRNAs (miRNAs) confer robustness to developmental timing by posttranscriptional repression of genetic programs that are related to previous developmental stages or to alternative cell fates. Here we demonstrate that the muscle-specific miRNAs miR-1 and miR-206 directly target Pax3. Antagomir-mediated inhibition of miR-1/miR-206 led to delayed myogenic differentiation in developing somites, as shown by transient loss of myogenin expression. This correlated with increased Pax3 and was phenocopied using Pax3-specific target protectors. Loss of myogenin after antagomir injection was rescued by Pax3 knockdown using a splice morpholino, suggesting that miR-1/miR-206 control somite myogenesis primarily through interactions with Pax3. Our studies reveal an important role for miR-1/miR-206 in providing precision to the timing of somite myogenesis. We propose that posttranscriptional control of Pax3 downstream of miR-1/miR-206 is required to stabilize myoblast commitment and subsequent differentiation. Given that mutually exclusive expression of miRNAs and their targets is a prevailing theme in development, our findings suggest that miRNA may provide a general mechanism for the unequivocal commitment underlying stem cell differentiation
Quantum Fluctuations of Coulomb Potential as a Source of Flicker Noise. The Influence of External Electric Field
Fluctuations of the electromagnetic field produced by quantized matter in
external electric field are investigated. A general expression for the power
spectrum of fluctuations is derived within the long-range expansion. It is
found that in the whole measured frequency band, the power spectrum of
fluctuations exhibits an inverse frequency dependence. A general argument is
given showing that for all practically relevant values of the electric field,
the power spectrum of induced fluctuations is proportional to the field
strength squared. As an illustration, the power spectrum is calculated
explicitly using the kinetic model with the relaxation-type collision term.
Finally, it is shown that the magnitude of fluctuations produced by a sample
generally has a Gaussian distribution around its mean value, and its dependence
on the sample geometry is determined. In particular, it is demonstrated that
for geometrically similar samples, the power spectrum is inversely proportional
to the sample volume. Application of the obtained results to the problem of
flicker noise is discussed.Comment: 14 pages, 3 figure
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