The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1beta Activation

Published: November 27, 2018Intrinsic apoptosis resulting from BAX/BAK-mediated mitochondrial membrane damage is regarded as immunologically silent. We show here that in macrophages, BAX/BAK activation results in inhibitor of apoptosis (IAP) protein degradation to promote caspase-8-mediated activation of IL-1β. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1β maturation that requires potassium efflux. Remarkably, following BAX/BAK activation, the apoptotic executioner caspases, caspase-3 and -7, act upstream of both caspase-8 and NLRP3-induced IL-1β maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1β release. These findings highlight that innate immune cells undergoing BAX/BAK-mediated apoptosis have the capacity to generate pro-inflammatory signals and provide an explanation as to why IL-1β activation is often associated with cellular stress, such as during chemotherapy.James E. Vince, Dominic De Nardo, Wenqing Gao, Angelina J. Vince, Cathrine Hall, Kate McArthur, Daniel Simpson, Swarna Vijayaraj, Lisa M. Lindqvist, Philippe Bouillet, Mark A. Rizzacasa, Si Ming Man, John Silke, Seth L. Masters, Guillaume Lessene, David C.S. Huang, Daniel H.D. Gray, Benjamin T. Kile, Feng Shao, and Kate E. Lawlo

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Reproducibility in the absence of selective reporting : An illustration from large-scale brain asymmetry research

Altres ajuts: Max Planck Society (Germany).The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Tourniquet injury in a Papuan snakebite victim

We report a case of snake bite complicated by tourniquet induced ischaemic damage and rhabdomyolysis causing acute renal failure. The case highlights the dangers of tourniquet use and of sudden release. We outline measures which can be taken to minimize morbidity in such patients

The Utility of a Peer Review Application in Interdisciplinary Teamwork Arrangements

Project and challenge-based learning typically require students to navigate personal and professional relationships within a team, in order to collaboratively solve authentic problems. These collaborations are often interdisciplinary in nature - an arrangement that adds increased complexity to the team's functioning. This is due to distinctions in approaches, epistemologies, ethos or jargon. The ability to provide (and receive) appropriate and constructive feedback to peers, within the team, is a key skill that can enhance team functioning and ultimately, output. Furthermore, it is a competence that aids in lubricating social and work impediments that may be causing bottlenecks to creativity, or the manifestation of ideas. The aim of this study, set within three different interdisciplinary bachelor modules, is to determine to what extent the use of the 'Buddycheck' application for peer review, is appreciated by students and teachers. The application, hosted within the learning management system of the university, allows students to rank their peers' performance according to teacher-set criteria, as well as through flexible open-format feedback; in order to facilitate opportunities for enhanced communication and expectation alignment. We wish to ascertain to what degree team functioning is enhanced through the scaffolded communication opportunities, by highlighting and creating openings to discuss undesirable behaviours, through the feedback application. Preliminary results appear to favour this mode of feedback facilitation, albeit with certain caveats, detailed later. Since teamwork is universal in tertiary education, these insights may be helpful for educators attempting to further improve the evaluation of the process of their projects or challenges

Student motivation and disciplinary expertise in Challenge-Based Learning

Challenge-based learning (CBL) seeks to help students acquire skills necessary for collaborative real-world problem solving. It generally favours self-learning, in which students should seek out their own role in a problem-solving environment and choose their own set of skills to develop which are relevant to the challenge. However students from traditional degree programmes may enter with an expectation that their disciplinary expertise will count and be valued in the context of a project, but face a situation that the problem chosen by a group or the dynamics of a group render their expertise less relevant. In survey-based studies of two CBL modules, we explore the relationship between the roles students play and their levels of motivation. We find no evidence that the lack of a disciplinary role strongly affects student motivation. Rather the data suggests that if a CBL environment is properly framed around self-development and multiple potential learning goals students can relax any commitments or expectations related to their expertise, and take on different roles. This is good news for the CBL aims and goals. That said students do have a tendency to revert to disciplinary roles over the course of projects and are against their disciplinary roles being excluded when they are clearly relevant. Instructors can potentially avoid problems by having students evaluate their role choices against desired project outcomes

Multi-, inter- and transdisciplinarity in challenge-based engineering education

Challenge-based learning (CBL) offers students in engineering programmes an opportunity to develop communicative and collaborative skills, apply disciplinary knowledge and develop boundary-crossing competencies. Mono-disciplinary approaches to CBL are generally regarded too limited, but whether multi-disciplinary, interdisciplinary, or transdisciplinary approaches should be used is open to discussion. Often, these concepts are used interchangeably, but there are notable differences. In literature, knowledge integration is mostly mentioned to make a distinction, but because of difficulties in applying this concept to education, we focus on tangible differences in educational practices, related to learning objectives, assessment, and the design of challenges. The different forms of CBL are illustrated by three case-studies carried out at a research university in the Netherlands. We found similarities, but also some subtle differences between multi-, inter- and transdisciplinary approaches to CBL. Multidisciplinary CBL projects are relatively pre-structured, with an indication of the knowledge that is to be applied, deepened, or combined. Interdisciplinary CBL is more open-ended, with students made responsible for connecting their disciplinary backgrounds to the project and for integrating disciplinary perspectives. Transdisciplinary CBL focuses more on impact than on integrating disciplinary contributions. Challenges are open-ended from a content and stakeholder perspective, while structure emerges in the interactions between students, teachers and stakeholders. Which form of CBL can best be employed in a course or programme is dependent on the intended learning objectives. Educators should be aware of tradeoffs and of the specific teacher competences required to design and support these different forms of CBL