Effect of inter layer cold work on 2024 aluminium alloy produced by wire directed energy deposition

Aluminium copper magnesium alloys are widely used in the aerospace sector. Wire-based Directed Energy Deposition could replace conventional manufacturing routes to build large and semi-complex components for this industry if high mechanical performance can be achieved in the deposit. The scope of this study was to assess the effect of inter-pass rolling on a 2024 aluminium alloy wire-based DED built structure and to investigate the impact of cold work during the deposition process on the microstructure and mechanical performances. The 2024 aluminium alloy was deposited using two variants of gas metal arc process, and the effects of the deposition process, cold work and heat treatment were studied using macro and microstructural observations, hardness measurement and tensile tests. The material response to inter-pass rolling and the formation of rolling defects was found to depend on the deposition process variant and bead geometry. While a significant strengthening of the deposit was observed with one process, only a drastic reduction of defects was observed with the second. It was also found that the application of cold work and heat treatment led to lowering of anisotropy and higher ductility when compared with heat-treated deposit without any inter-pass rolling

UNC-108/RAB-2 and its effector RIC-19 are involved in dense core vesicle maturation in Caenorhabditis elegans

Uncoordinated movement in Rab2 mutants is caused by impaired retention of cargo on dense core vesicles, not by defective synaptic vesicle release. (Also see the companion article by Edwards et al. in this issue.

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrix-dependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression

Maturation of active zone assembly by Drosophila Bruchpilot

Synaptic vesicles fuse at active zone (AZ) membranes where Ca2+ channels are clustered and that are typically decorated by electron-dense projections. Recently, mutants of the Drosophila melanogaster ERC/CAST family protein Bruchpilot (BRP) were shown to lack dense projections (T-bars) and to suffer from Ca2+ channel–clustering defects. In this study, we used high resolution light microscopy, electron microscopy, and intravital imaging to analyze the function of BRP in AZ assembly. Consistent with truncated BRP variants forming shortened T-bars, we identify BRP as a direct T-bar component at the AZ center with its N terminus closer to the AZ membrane than its C terminus. In contrast, Drosophila Liprin-α, another AZ-organizing protein, precedes BRP during the assembly of newly forming AZs by several hours and surrounds the AZ center in few discrete punctae. BRP seems responsible for effectively clustering Ca2+ channels beneath the T-bar density late in a protracted AZ formation process, potentially through a direct molecular interaction with intracellular Ca2+ channel domains

Dissociating neural signatures of mental state retrodiction and classification based on facial expressions

Posed facial expressions of actors have often been used as stimuli to induce mental state inferences, in order to investigate “Theory of Mind” processes. However, such stimuli make it difficult to determine whether perceivers are using a basic or more elaborated mentalizing strategy. The current study used as stimuli covert recordings of target individuals who viewed various emotional expressions, which caused them to spontaneously mimic these expressions. Perceivers subsequently judged these subtle emotional expressions of the targets: In one condition (“classification”) participants were instructed to classify the target’s expression (i.e., match it to a sample) and in another condition (“retrodicting”) participants were instructed to retrodict (i.e., infer which emotional expression the target was viewing). When instructed to classify, participants showed more prevalent activations in event-related brain potentials (ERPs) at earlier and mid-latency ERP components N170, P200 and P300-600. By contrast, when instructed to retrodict participants showed enhanced late frontal and rontotemporal ERPs (N800-1000), with more sustained activity over the right than the left hemisphere. These findings reveal different cortical processes involved when retrodicting about a facial expression compared to merely classifying it, despite comparable performance on the behavioural tas

Analysis and suppression of mutant sel-12 in Caenorhabditis elegans

sel-12 and hop-1 are two C. elegans genes which are structurally and functionally homologous to the human presenilins, PS1 and PS2. Mutations in the human presenilins contribute to the majority of familial Alzheimer's disease cases. Work in C. elegans also revealed that presenilins are involved in Notch signaling as a reduction of sel-12 presenilin activity is able to suppress the phenotype associated with lin-12/Notch gain-of-function mutations. Several lines of evidence suggest that presenilins are an active protease that mediate the transmembrane cleavage event that releases the LIN-12/Notch intra-cellular domain from the membrane. This step is crucial for nuclear Notch signaling. As a consequence, loss of all presenilin activity, in a sel-12; hop-1 double mutant, causes phenotypes associated with the complete absence of all Notch signaling in C. elegans. Loss of sel-12 function in C. elegans leads to a highly penetrant egg-laying defect (Egl) which resembles the Egl defect present in lin-12 hypomorphic alleles. The inability of sel-12 mutant animals to lay eggs is shown here to be caused by two defects: (i) a cell specification defect which results in a blockage of the vulva-uterine connection and (ii) a sex-muscle patterning defect leading to morphologically abnormal and misattached vulva-muscles. In order to find new molecules that are able to influence presenilin mediated signaling we screened for extragenic suppressors of the sel-12 Egl defect. In several screens four spr genes (suppressor of presenilin) were identified, which are able to suppress both sel-12 defects in the egg-laying system. The spr genes are not able to influence LIN-12/Notch signaling directly but require the activity of the second C. elegans presenilin hop-1 for sel-12 suppression. Molecular analysis of SPR-5 revealed that it belongs to a conserved family of FAD containing polyamine-oxidase like proteins. The human homologue is found to be an integral component of the CoREST transcriptional co-repressor complex. Further analysis of the other spr genes revealed that SPR-1 is the C. elegans homolog of the human CoREST protein, which is also a component of the CoREST complex. Based on the physical interaction of SPR-5 and SPR-1 presented here, it is likely that a CoREST like complex also exists in C. elegans. Mutations in this complex lead to a stage specific de-repression of hop-1 expression which is then able to substitute for sel-12 presenilin activity during development of the egg-laying system. The two remaining suppressors, spr-3 and spr-4, encode nuclear C2H2 zinc finger proteins that have been shown to up-regulate hop-1 transcription in a similar way and thus may be involved in nuclear targeting of the C elegans CoREST complex. sel-12 is also highly expressed in neurons, which suggests that it may also be required for neuronal function. Experiments presented here show that sel-12 is, for example, involved in the function and morphology of the AIY interneurons, which control the thermotaxis behaviour in C. elegans