Axon Death Pathways Converge on Axed to Promote Axon Disassembly

Axons use a conserved program to actively drive their own destruction after injury. Axon degeneration is present in many neurological disorders and an axon death program could be a major pharmaceutical target to preserve neuronal function. This intrinsic signaling cascade activates pro-degenerative dSarm/Sarm1, rapidly depletes axonal stores of NAD+, and terminates in cytoskeletal breakdown. Conversely, loss of dSarm/Sarm1, maintenance of NAD+ levels or its biosynthetic enzyme Nmnat, result in long-term morphological perseveration of severed axons. Exactly how dSarm/Sarm1 and loss of NAD+ execute axon death remains poorly defined. We sought to uncover novel regulators of axon death and maintenance by performing a deficiency screen and a forward genetic mutagenesis screen in axotomized Drosophila wing sensory neurons. We identified a BTB domain protein enriched in neurons, we named Axundead (Axed), which is specifically required for axon death. Severed axons harboring loss of function mutations in axed, similar to dSarm mutants, remain preserved for 50 days post axotomy. Spontaneous neurodegeneration induced by activated dSarm or dNmnat depletion are both suppressed in axed mutants, but not in dSarm mutant alleles. Additionally, severed axed mutant axons also expressing activated dSarm or lacking Nmnat are preserved. These results indicate that dSarm acts upstream of dNmnat loss, and both events precede essential Axed function and axon destruction. Thus, the axon death pathway converges on Axed function

Impact of trailing edge overhang length on the loss characteristics of fully cooled transonic nozzle guide vanes

The trailing edge (TE) design of a cooled high-pressure (HP) nozzle guide vane (NGV) requires consideration of both cooling and aerodynamic performances. Two designs are in common use: the centered-ejection design, in which coolant is ejected through a slot in the TE with roughly symmetrical suction-side (SS) and pressure-side (PS) TE tips; and the SS-overhang design, in which the SS and PS TE tips are staggered. This second design has been favored in recent years because it has been presumed to be aerodynamically advantageous. In this article, we re-examine this assumption by studying a parametric design set between these two design extremes. We do this using extensive high-fidelity experimental measurements performed at engine-scaled conditions (matched Mach number, Reynolds number, and coolant-to-mainstream pressure ratio) on a full-annular cascade of real engine parts. To provide insight into the mechanisms affecting loss, we use complementary unsteady computational fluid dynamics (CFD) simulations. We analyze the changes in the flow structure, local loss coefficient distribution, wake mixing rate, average profile loss coefficient, and base pressures

“It sounds silly now, but it was important then”: Supporting the significance of a personal experience in psychotherapy

The article examines a previously undocumented practice whereby psychotherapy clients support the significance of their experience against the background of how it can otherwise be heard. This practice is the phrase “it sounds X, but Y” (e.g., “which sounds silly now, but was like important then”). We call this an SXB-contrast. We used conversation analysis to examine 21 instances of this phenomenon, identified in 12 audio-recorded individual psychotherapy sessions involving 10 clients and 8 therapists. Clients use SXB-contrasts to mark part of their talk as delicate, specifically by voicing an unsympathetic hearing of that talk whilst supporting its experiential significance. Evidence for our claims comes from clients’ use of SXB-contrasts in association with practices of speech delivery (e.g., laughter) and self-repair operations which also establish a part of their talk as delicate. Therapist responses provide additional supporting evidence. The study contributes to understanding how clients can use meta-talk to convey the meaning of their experiences in therapy whilst also making available their own emerging awareness of the multiple meanings of those experiences

Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila

Axons damaged by acute injury, toxic insults, or neurodegenerative diseases execute a poorly defined autodestruction signaling pathway leading to widespread fragmentation and functional loss. Here, we describe an approach to study Wallerian degeneration in the Drosophila L1 wing vein that allows for analysis of axon degenerative phenotypes with single-axon resolution in vivo. This method allows for the axotomy of specific subsets of axons followed by examination of progressive axonal degeneration and debris clearance alongside uninjured control axons. We developed new Flippase (FLP) reagents using proneural gene promoters to drive FLP expression very early in neural lineages. These tools allow for the production of mosaic clone populations with high efficiency in sensory neurons in the wing. We describe a collection of lines optimized for forward genetic mosaic screens using MARCM (mosaic analysis with a repressible cell marker; i.e., GFP-labeled, homozygous mutant) on all major autosomal arms ( approximately 95% of the fly genome). Finally, as a proof of principle we screened the X chromosome and identified a collection eight recessive and two dominant alleles of highwire, a ubiquitin E3 ligase required for axon degeneration. Similar unbiased forward genetic screens should help rapidly delineate axon death genes, thereby providing novel potential drug targets for therapeutic intervention to prevent axonal and synaptic loss

CHESHIRE (Reino Unido) (Inglaterra). Mapas generales (1794). 1:65000

Dedicatoria : "By Permission to His Royal Highness, George, Prince of Wales, Duke of Cornwall & Roshsay, and Earl of Chester &c. &c. This Survey of the County Palatine of Chester, is most humbly Dedicated, by His Royal Highnefs's most Devoted Servant P.P. Burdett"Título redactado a partir del contenido del documentoEscala gráfica de 6 millas [= 14,9 cm]. Coordenadas referidas al meridiano de Londres (O 3°23'30''--O 1°44'20''/N 53°39'20''--N 52°59'55''). Recuadro geográfico de 5' en 5'. Orientado con lis en rosa de ocho vientosOrografía a trazosTabla de signos convencionales para indicar ciudades, parroquias, molinos, límites entre "hundreds", etc.Dedicatoria enmarcada en cartela decorada con motivos vegetalesForma parte de la Colección MendozaInserta : "The Series of great triangles reduce to an Horizontal Plane" ; "A Plan of the City of Chester". Escala [ca. 1:6800], 600 yardas [= 8,1 cm

Sexual selection, automata and ethics in George Eliot's The Mill on the Floss and Olive Schreiner's Undine and From Man to Man

This paper brings together two related areas of debate in the latter half of the nineteenth century. The first concerns how the courtship plot of the nineteenth-century novel responded to, and helped to shape, scientific ideas of sexual competition and selection. In The Mill on the Floss (1860), George Eliot strikingly prefigures Darwin's later work on sexual selection, drawing from her own extensive knowledge of the wider debates within which evolutionary theory developed. Maggie Tulliver's characterisation allows Eliot to explore the ethical complexities raised by an increasingly powerful scientific naturalism, where biology is seen to be embedded within morality in newly specific ways. The second strand of the paper examines the extension of scientific method to human mind and motivation which constituted the new psychology. It argues that there are crucial continuities of long-established ethical and religious ideas within this increasingly naturalistic view of human mind and motivation. The contention that such ideas persist and are transformed, rather than simply jettisoned, is illustrated through the example of Thomas Henry Huxley's 1874 essay on automata. Turning finally to focus on Olive Schreiner's Undine (1929) and From Man to Man (1926), the paper explores the importance of these persistent ethical and religious ideas in two novels which remained unpublished during her lifetime. It argues that they produce both difficulty and opportunity for imagining love plots within the context of increasingly assertive biological and naturalistic accounts of human beings

Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration

Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here we identify a role for the Drosophila C2H2 zinc finger transcription factor Pebbled [Peb, Ras-responsive element binding protein 1 (RREB1) in mammals] in axon death. Loss of Peb in Drosophila glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. peb mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with dsarm mutants, linking peb/RREB1 to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and peb mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling

Photolytic and thermolytic decomposition products from iron pentacarbonyl adsorbed on Y zeolite

Zeolite supported iron systems obtained by photolysis and thermolysis of Fe(CO)5/Na---Y adducts are characterized via evaluation of the respective magnetic isotherms taken with a FONER magnetometer at T = 4.2 K. Thermolysis under fast heating in inert gas and under fluidized shallow bed conditions completes within a few minutes at not, vert, similar 500 K, and gives iron clusters of which at least 70 to 90 wt% is smaller than 1 nm. Prolonged photolysis at 290 K in the same fluidized bed conditions does not result in the formation of ‘naked’ iron(O) clusters, but gives a limited fraction of magnetically coupled Fex(CO)y entities. Photodimerization cannot be excluded to be the main reaction path

Ecosystem engineer morphological traits and taxon identity shape biodiversity across the euphotic-mesophotic transition

Funding was provided by a Leverhulme Trust Research Project grant (no. RPG-2018-113) to H.L.B., G.A.T. and I.D.W.S., an Engineering and Physical Sciences Research Council grant (no. EP/L017008/1) to G.A.T. and I.D.W.S., and a São Paulo Research Foundation (FAPESP) individual grant (no. 2016/14017-0) to G.H.P.F.The euphotic-mesophotic transition is characterized by dramatic changes in environmental conditions, which can significantly alter the functioning of ecosystem engineers and the structure of their associated communities. However, the drivers of biodiversity change across the euphotic-mesophotic transition remain unclear. Here, we investigated the mechanisms affecting the biodiversity-supporting potential of free-living red coralline algae-globally important habitat creators-towards mesophotic depths. Across a 73 m depth gradient, we observed a general decline in macrofaunal biodiversity (fauna abundance, taxon richness and alpha diversity), but an increase in beta-diversity (i.e. variation between assemblages) at the deepest site (86 m depth, where light levels were less than 1% surface irradiance). We identified a gradient in abundance decline rather than distinct ecological shifts, driven by a complex interaction between declining light availability, declining size of the coralline algal host individuals and a changing host taxonomy. However, despite abundance declines, high between-assemblage variability at deeper depths allowed biodiversity-supporting potential to be maintained, highlighting their importance as coastal refugia.PostprintPeer reviewe

Octahedral rotation-induced ferroelectricity in cation ordered perovskites

Increasing demands for electric field-tunable electric, magnetic, and orbital (EMO) materials has renewed interests in ferroelectricity and its coupling to EMO properties in complex perovskite oxides. The historic design strategy to achieve a spontaneous polarization involves the incorporation of second-order Jahn-Teller (SOJT) active cations. The challenge, however, is that this mechanism is limited to specific chemistries and the polar distortions that arise are largely decoupled from EMO properties, limiting their use as field-tunable multifunctional technology materials. Here we report the crystal-chemistry criteria which circumvents those restrictions and enables the rational design of new materials displaying octahedral rotation-induced ferroelectricity - an innovative route to realize electric polarization without the need for SOJT cations - from non-polar building blocks. The strategy exploits the centric octahedral rotation patterns, which strongly couple to EMO properties, and cation ordering commonly observed in non-polar $AB$O$_3$ perovskites. By uniting switchable electric polarizations to the connectivity of the transition-metal oxygen octahedra, electric-field control over materials properties is possible.Comment: Supplementary information available upon reques