Elucidating the molecular basis of spindle assembly checkpoint signaling

The spindle assembly checkpoint (SAC) is a highly conserved eukaryotic surveillance mechanism that maintains genomic integrity by delaying mitotic progression until all chromosomes have become properly attached to the mitotic spindle via their kinetochores. Malfunction of this checkpoint leads to chromosome segregation errors and has been implicated in tumorigenesis. SAC protein localization to unattached kinetochores is considered to be required for checkpoint signaling. This study employs the model organism Schizosaccharomyces pombe to investigate the role of different checkpoint components and their interactions with each other during the SAC signaling cascade. We examined the link between Mad1 and Bub1 to explore the connection between upstream and downstream events during checkpoint signaling. We found that conserved motifs in Bub1 and Mad1 are essential for Mad1 localization to the kinetochore and checkpoint activity. Furthermore, we revealed a hitherto unknown additional function of Mad1 in creating the checkpoint signal. Bub1 seems to act upstream of Mad1, and certain motifs in one of the kinetochore proteins are required for kinetochore recruitment of the Bub3-Bub1 complex. Here we provide evidence that a subset of these motifs is sufficient for this recruitment and checkpoint activity. The ultimate effector of checkpoint signaling is the mitotic checkpoint complex. It was recently found that the composition of this complex is different from previously assumed. While early work suggested the presence of one Cdc20 molecule in the complex, latest results revealed that the mitotic checkpoint complex actually contains two Cdc20 molecules when bound to the APC/C. We observed the same situation in fission yeast and describe the role of conserved motifs within the checkpoint protein Mad3 in binding to those Cdc20 molecules. We furthermore indicate a function of the APC/C subunit Apc15 in the checkpoint that was unexpected based on work in other model organisms. Taken together, we added new facets to the picture of spindle assembly checkpoint signaling and highlight similarities and differences between organisms, which illustrate how conserved, yet versatile this signaling pathway is.Der „spindle assembly checkpoint“ (SAC) ist ein hoch konservierter, eukaryontischer Überwachungsmechanismus der die genomische Integrität aufrechterhält, indem er das Fortschreiten der Mitose so lange verhindert, bis die Mikrotubuli der mitotischen Spindel sich an alle Kinetochore angeheftet haben. Eine Fehlfunktion dieses Kontrollmechanismus führt zu Fehlern bei der Chromosomensegregation und kann zur Tumorentstehung beitragen. SAC-Proteine konzentrieren sich an unangehefteten Kinetochoren, was als Voraussetzung für die Entstehung des SAC-Signals gilt. Diese Studie verwendet den Modellorganismus Schizosaccharomyces pombe um die Rolle der einzelnen SAC-Proteine und deren Interaktionen während der SACSignalkaskade aufzudecken. Wir haben die Verbindung zwischen Mad1 und Bub1 untersucht, um die Verknüpfung zwischen frühen und späteren Vorgängen des SACSignalwegs zu verstehen. Dabei haben wir herausgefunden, dass konservierte Motive in Bub1 und Mad1 essentiell sind, um Mad1 an Kinetochore zu rekrutieren und ein SAC-Signal zu generieren. Zudem haben wir gezeigt, dass Mad1 eine zusätzliche und bisher unbekannte Funktion im SAC hat. Bub1 spielt früher als Mad1 eine Rolle in der SAC-Signalkaskade und bestimmte Motive in einem der Kinetochorproteine werden für die Rekrutierung des Bub3-Bub1 Komplexes an die Kinetochore benötigt. Wir zeigen, dass ein kleiner Teil dieser Motive bereits für die Rekrutierung und die Aktivität des Checkpoints ausreicht. Der letztendliche Effektor des Checkpoint-Signals ist der „mitotische Checkpoint Komplex“. Es wurde kürzlich gezeigt, dass die Zusammensetzung dieses Komplexes von bisherigen Annahmen abweicht. Während frühere Arbeiten darauf hinwiesen, dass ein Molekül des Cdc20 Proteins Teil des Komplexes ist, haben neueste Ergebnisse gezeigt, dass der Komplex tatsächlich zwei Cdc20 Moleküle enthält, wenn er an den APC/C gebunden ist. Wir beobachteten eine vergleichbare Situation in Spalthefe und beschreiben wie konservierte Motive im Checkpoint Protein Mad3 zur Bindung dieser Cdc20 Moleküle beitragen. Zudem zeigen wir, dass die APC/C Untereinheit Apc15 in S. pombe für Checkpoint-Aktivität benötigt wird, was basierend auf Arbeiten in anderen Organismen unerwartet war. Zusammenfassend konnten wir neue Aspekte des „spindle assembly checkpoint“ Signalwegs aufzeigen und haben sowohl Übereinstimmungen als auch Unterschiede zwischen Organismen gefunden, was verdeutlicht wie konserviert aber zugleich wandlungsfähig dieser Signalweg ist

P1_2 Using Trebuchets for Lunar Satellites

In this paper we investigated the possibility of launching a 10 kg satellite into lunar orbit from the surface of the Moon, using a trebuchet. We found that the mass of the counterweight required would be 330 tonnes. We also discussed how the kinetic energy required for the speed of the orbit and the gravitational energy needed to be overcome changed as a result of the orbital radius

P1_5 Martian muon decay

One of the first pieces of evidence for Einstein's theory of special relativity was the apparent detection of muons at the surface of earth. We consider the same effect but using a Martian atmosphere. We calculate that the time taken to traverse the Troposphere is $t_{actual} = 1.3\times 10^{-5}$s after allowing for relativity. Lastly, we find that the number of muon's detectable is $\sim0.26\%$

Implant-Based Reconstruction following Mastectomy in Patients Who Have Had a Previous Breast Augmentation:Lessons from the National Multicenter Implant Breast Reconstruction Evaluation Study

Background: Breast augmentation is the most commonly performed cosmetic procedure, and increasingly women in this group present with breast cancer or request risk-reducing surgery, but their optimal management is unclear. The authors explored the clinical and patient-reported outcomes of patients undergoing immediate implant-based breast reconstruction following previous augmentation and compared these with outcomes of patients who had not had cosmetic implants in the Implant Breast Reconstruction Evaluation (iBRA) Study.   Methods: Patients undergoing immediate implant-based breast reconstruction were prospectively recruited from breast and plastic surgical units across the United Kingdom. Demographic, operative, and oncologic data, and information regarding complications within 3 postoperative months were collected. Patient-reported outcomes at 18 months were assessed using the BREAST-Q. The clinical and patient-reported outcomes of patients undergoing immediate implant-based breast reconstruction with and without previous breast augmentation were compared.   Results: A total of 2108 women were included in the iBRA Study, of whom 49 had undergone a previous augmentation. Women in the augmentation group were younger (median age, 45 years versus 50 years; p = 0.01), had a lower body mass index (22.8 kg/m2 versus 24.9 kg/m2; p < 0.01), and had smaller tumors (15 mm versus 25 mm; p = 0.01) than patients without augmentation. No differences were seen in operative technique between the groups. Complications at 3 months were similar in both groups and there were no significant differences in patient-reported outcomes at 18 months.   Conclusions: The clinical and patient-reported outcomes of patients undergoing immediate implant-based breast reconstruction following previous augmentation are consistent with those observed in the wider iBRA Study cohort, supporting the safety of this approach

P1_8 Escaping the Moons of Mars using a Pogo Stick

The objective of this paper was to investigate the gravitational field strengths of the Martian Moons; Deimos and Phobos’ effect on a pogo stick and it’s rider. It was hypothesised that spring required to escape Deimos would be smaller due to the gravitational field strength being lower. This hypothesis was tested using Hooke’s Law and the Newtonian Laws of gravity to calculate the spring size needed to propel the pogo stick and its rider to a point where it was no longer under the effects of the respective moons gravitational pull. We found this value for the spring decompression to be 1.56 m on Deimos and 5.1 m on Phobos. These values confirmed the hypothesis we made and therefore it would be possible to use a pogo stick to escape the Martian Moons’ gravity

P1_7 Solar-Powered Superhero: What’s Superman’s Power Consumption?

In this paper, we assess the viability of Superman being powered by solar energy. We do this by calculating the energy that he would be able to absorb in a day - 3 × 107J - and comparing it to the energy that he requires to carry out certain superhuman activities. We find that he could leap the Empire State Building 75 times using the energy he acquires in a day, but he requires 3 days worth of energy to match the energy output of a train for one second

Understanding the experiences of military families

Why is it important to understand the authentic experience of military family life? Military family life is unique and challenging but it is not without reward. Research into the challenges is manifold, whereas adaptive behaviours attract less attention. To better inform those who seek to support the military family, a more balanced and nuanced understanding of experiences that may warrant mitigation or maximisation may lead to more empathic and insightful policy and intervention. This would not only benefit the family, but also the service person(s) through reduction in domestic stressors and a sense of holistic support. How has the research been undertaken? A Narrative Inquiry approach was employed to interview families of recent military veterans, inviting them to reflect on their experiences as a military family and capture the entire journey from enlistment to transition back to civilian life. No preconditions were set and they were invited to tell their story on their own terms, consistent with the methodology. A theoretical framework based on social constructivism, strengths-based approaches and family systems theory was employed to analyse the subsequent data. What are the main research findings? Many of the known challenges such as separation, accommodation, spousal employment, access to healthcare and childrens’ education were highlighted. However, there were many examples of positive growth for some or all and overall the stories were positive, suggesting that those interviewed had been able to contextualise their experiences and in most cases celebrate growth and resilience as a family. As Brockman et al (2015) note, “It is remarkable that the majority of military service members and their intimate partners and children show considerable resilience in the face of these significant challenges” Why do these findings matter? Policy, aided by research, is most often employed to deal with a problem. A more measured and comprehensive understanding of the military family experience that acknowledges the benefits as well as the difficulties and seeks to preserve the former whilst mitigating the latter could potentially lead to policy that was more effective and enduring. Ultimately, anything which enhances combat power in our Armed Forces is invaluable and for service personnel to feel confident that their family were being supported and could in turn then support them would act as what is referred to in the military as a ‘force multiplier’

Melatonin for the prevention of postoperative delirium in older adults:a protocol for a systematic review and meta-analysis

INTRODUCTION: Postoperative delirium (POD) is a major cause of morbidity, particularly in elderly patients. Melatonin has been suggested as a low-risk pharmacological intervention to help prevent POD. A previous systematic review found limited high-quality evidence to support the use of melatonin in the prevention of POD. Several further randomised studies have since been published. This systematic review aims to synthesise the evidence from randomised controlled trials (RCTs) examining the effect of melatonin on the prevention of POD in older adults. METHODS AND ANALYSIS: A systematic search of RCTs of melatonin (any dose and formulation) in POD will be run across Embase, Medline, CINAHL and PsychInfo. RCTs published from January 1990 until the end of February 2022 and reporting outcomes for melatonin use to prevent POD in patients will be included. Screening of search results and data extraction from included articles will be performed by two independent reviewers. The primary outcome will be incidence of POD in older adults undergoing surgery. Secondary outcomes are delirium duration and length of hospital stay. The review will also describe the dosage, timing and administration regimes of melatonin therapy and as well as the scales and definitions used to describe POD. A registry review of ongoing trials will be also be performed. For the meta-analysis, data will be pooled using a random effects model to generate a forest plot and obtain an odds ratio (OR) for the incidence of POD. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. ETHICS AND DISSEMINATION: No ethical approval is required. This review will be disseminated via peer-reviewed manuscript and conferences. The results will be used as the basis of work to optimise this intervention for future trials in surgical populations. PROSPERO REGISTRATION NUMBER: This review is registered with PROSPERO (CRD42021285019)