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

Justice for Injured Workers: The Struggle Continues

This article briefly reviews the role that community legal clinics have played in the injured worker movement. It chronicles the erosion of the basic principles of workers\u27 compensation and the shift in emphasis from compensating workers to containing costs. It exposes the myth of a debt crisis in workers\u27 compensation and explores the effect of this shift on workers\u27 benefits, on workplace health and safety, and ultimately on the viability of a no-fault, publicly-administered workers\u27 compensation system. The article also outlines the threat to the existing system in the workers\u27 compensation proposals of the current government

Justice for Injured Workers: The Struggle Continues

This article briefly reviews the role that community legal clinics have played in the injured worker movement. It chronicles the erosion of the basic principles of workers\u27 compensation and the shift in emphasis from compensating workers to containing costs. It exposes the myth of a debt crisis in workers\u27 compensation and explores the effect of this shift on workers\u27 benefits, on workplace health and safety, and ultimately on the viability of a no-fault, publicly-administered workers\u27 compensation system. The article also outlines the threat to the existing system in the workers\u27 compensation proposals of the current government

Актуальні проблеми розвитку виноградства та виноробства

В статті розглянуто сучасні тенденції та проблеми розвитку виноградарства та виноробства України. Надано рекомендації щодо пріоритетних напрямків розвитку виноробних підприємств.The modern tendencies and development problems of Ukraine viticulture and winemaking industry are considered in the article. The regards priority areas recommendations of winemaking enterprises development are given

Palaeomagnetic field intensity variations suggest Mesoproterozoic inner-core nucleation

The Earth’s inner core grows by the freezing of liquid iron at its surface. The point in history at which this process initiated marks a step-change in the thermal evolution of the planet. Recent computational and experimental studies1,2,3,4,5 have presented radically differing estimates of the thermal conductivity of the Earth’s core, resulting in estimates of the timing of inner-core nucleation ranging from less than half a billion to nearly two billion years ago. Recent inner-core nucleation (high thermal conductivity) requires high outer-core temperatures in the early Earth that complicate models of thermal evolution. The nucleation of the core leads to a different convective regime6 and potentially different magnetic field structures that produce an observable signal in the palaeomagnetic record and allow the date of inner-core nucleation to be estimated directly. Previous studies searching for this signature have been hampered by the paucity of palaeomagnetic intensity measurements, by the lack of an effective means of assessing their reliability, and by shorter-timescale geomagnetic variations. Here we examine results from an expanded Precambrian database of palaeomagnetic intensity measurements7 selected using a new set of reliability criteria8. Our analysis provides intensity-based support for the dominant dipolarity of the time-averaged Precambrian field, a crucial requirement for palaeomagnetic reconstructions of continents. We also present firm evidence for the existence of very long-term variations in geomagnetic strength. The most prominent and robust transition in the record is an increase in both average field strength and variability that is observed to occur between a billion and 1.5 billion years ago. This observation is most readily explained by the nucleation of the inner core occurring during this interval9; the timing would tend to favour a modest value of core thermal conductivity and supports a simple thermal evolution model for the Earth

Thermodynamic Limits on Magnetodynamos in Rocky Exoplanets

To ascertain whether magnetic dynamos operate in rocky exoplanets more massive or hotter than the Earth, we developed a parametric model of a differentiated rocky planet and its thermal evolution. Our model reproduces the established properties of Earth's interior and magnetic field at the present time. When applied to Venus, assuming that planet lacks plate tectonics and has a dehydrated mantle with an elevated viscosity, the model shows that the dynamo shuts down or never operated. Our model predicts that at a fixed planet mass, dynamo history is sensitive to core size, but not to the initial inventory of long-lived, heat-producing radionuclides. It predicts that rocky planets larger than 2.5 Earth masses will not develop inner cores because the temperature-pressure slope of the iron solidus becomes flatter than that of the core adiabat. Instead, iron "snow" will condense near or at the top of these cores, and the net transfer of latent heat upwards will suppress convection and a dynamo. More massive planets can have anemic dynamos due to core cooling, but only if they have mobile lids (plate tectonics). The lifetime of these dynamos is shorter with increasing planet mass but longer with higher surface temperature. Massive Venus-like planets with stagnant lids and more viscous mantles will lack dynamos altogether. We identify two alternative sources of magnetic fields on rocky planets: eddy currents induced in the hot or molten upper layers of planets on very short period orbits, and dynamos in the ionic conducting layers of "ocean" planets with ~10% mass in an upper mantle of water (ice).Comment: Accepted to The Astrophysical Journa

The Origin and Evolution of Magnetic Fabrics in Mafic Sills

Studying extinct volcanoes where erosion has exposed dykes and sills provides direct access to the fossil remnants of magma movement, however, linking crystallized magma to emplacement dynamics is challenging. This study investigates how magma flow varies across the thickness of a thin (6 m thick) mafic sill. We use a high-resolution sampling regime to measure micro-scale variations in magnetic anisotropy, which is associated with the orientation of the magnetic particles present within the crystalline rock. Fieldwork was conducted on exposed sills of the British and Irish Palaeogene Igneous Province, Isle of Skye, Scotland. Here Jurassic sedimentary rocks have been intruded by a series of sills, of picrite to crinanite composition, from the Little Minch Sill Complex (c.60 Ma). Anisotropy of magnetic susceptibility (AMS) and anisotropy of anhysteretic remanent magnetization (AARM) signals have been used to separate a crinanite sill into distinct magnetic groupings. We identified two AMS groups (the upper and lower sill margins, and the central region) and four AARM groups (the lower margin, the middle region, a region just below the upper margin, and the upper margin). Both AMS and AARM signals originate from titanomagnetite of multi-domain or vortex-state to single-domain sized grains, respectively. The AMS and AARM fabrics are aligned with each other in the margin regions preserving a history of magma flow toward the North during initial emplacement. However, in the sill interior the magnetic fabrics are oblique to each other, thus reflecting multiple origins. We suggest the AMS fabrics have recorded magma flow during sill growth, and AARM fabrics have recorded melt percolation flow as the interstitial melt migrated upward through a solidifying crystal mush. We demonstrate that when AMS and AARM are used in combination they enable a detailed understanding of magma flow and solidification dynamics to be obtained, from initial emplacement to solidification. Overall, our detailed sampling and analysis indicates that magnetic fabrics can be highly variable over small distances, supporting the suggestion of horizontal flow restriction and propagation path migration within growing sills, and that previous reports of magma flow and solidification dynamics based on under-sampled bodies may require reconsideration

Full vector archaeomagnetic records from Anatolia between 2400 and 1350 BCE: Implications for geomagnetic field models and the dating of fires in antiquity

Anatolia, as one of the busiest crossroads of ancient civilizations, provides an ideal platform for archaeomagnetic studies. Previous results from the Middle East have suggested the occurrence of a strong peak in geomagnetic intensity at ∼1000 BCE associated with dramatic field strength variations that could require a radical rethinking of geodynamo theory. The behavior of the field in the centuries preceding this peak remains poorly constrained, however. Here we present the results of full-vector archaeomagnetic experiments performed on 18 sets of samples from three archaeological sites belonging to Assyrian Trade Colony and Hittite periods. Associated rock magnetic analyses showed that the major magnetic carrier is magnetite chemically stable up to 700 °C and the magnetic mineral assemblage is composed mostly of non-interacting PSD grains. The directional results are compared with existing data and with the most recent global geomagnetic field models pfm9k.1b and SHA.DIF.14k. The directions are in remarkably good agreement with SHA.DIF.14k which is based on archaeomagnetic and lava flow data. Together with our earlier results from Anatolia, we triple the existing database of directions for the 700 year long period 2200–1500 BCE, over a large region from Greece to Azerbaijan, and from Moldavia/Ukraine to Egypt. Three archaeointensity methods: thermal IZZI-Thellier, microwave Thellier and the multi-specimen protocol (MSP) produced virtual axial dipole moment estimates () that are somewhat higher than contemporaneous (regional and global) data and model predictions suggesting that the field was already substantially stronger than today more than 800 years prior to the reported peak. In addition to constraining geomagnetic variability, our data also allow us to assign relative dates to inferred fire events in the Assyrian Trade Colony Period sites. This allows us to conclude that the fire events at the largest site, Kültepe, were not all contemporaneous with one another and with the abandonment of the site as has been previously hypothesized

Role of the Cys loop and transmembrane domain in the allosteric modulation of α4β2 nicotinic acetylcholine receptors

​Allosteric modulators of pentameric ligand gated ion channels (pLGICs) are thought to act on elements of the pathways that couple agonist binding to channel gating. Using α4β2 nicotinic acetylcholine receptors (nAChRs) and the α4β2-selective positive modulators 17β-estradiol (βEST) and desformylflustrabromine (dFBr), we have identified pathways that link the binding sites for these modulators to the Cys loop, a region that is critical for channel gating in all pLGICs. Previous studies have shown that the binding site for potentiating βEST is in the C-terminal (post-M4 region) of the α4 subunit. Here, using homology modelling in combination with mutagenesis and electrophysiology, we identified the binding site for potentiating dFBr on the top-half of a cavity between the third (M3) and fourth transmembrane (M4) α-helices of the α4 subunit. We found that the binding sites for βEST and dFBr communicate with the Cys loop, through interactions between the last residue of post-M4 and F170 of the conserved FPF sequence of the Cys loop, and that these interactions affect potentiating efficacy. In addition, interactions between a residue in M3 (Y309) and F167, a residue adjacent to the Cys loop FPF motif, also affect dFBr potentiating efficacy. Thus, the Cys loop acts as a key control element in the allosteric transduction pathway for potentiating βEST and dFBr. Overall, we propose that positive allosteric modulators that bind the M3-M4 cavity or post-M4 region increase the efficacy of channel gating through interactions with the Cys loop