Protein interacting with C kinase 1 suppresses invasion and anchorage independent growth of astrocytic tumour cells

Astrocytic tumors are the most common form of primary brain tumor. Astrocytic tumor cells infiltrate the surrounding CNS tissue, allowing them to evade removal upon surgical resection of the primary tumor. Dynamic changes to the actin cytoskeleton are crucial to cancer cell invasion, but the specific mechanisms that underlie the particularly invasive phenotype of astrocytic tumor cells are unclear. Protein interacting with C kinase 1 (PICK1) is a PDZ and BAR domain–containing protein that inhibits actin-related protein 2/3 (Arp2/3)-dependent actin polymerization and is involved in regulating the trafficking of a number of cell-surface receptors. Here we report that, in contrast to other cancers, PICK1 expression is down-regulated in grade IV astrocytic tumor cell lines and also in clinical cases of the disease in which grade IV tumors have progressed from lower-grade tumors. Exogenous expression of PICK1 in the grade IV astrocytic cell line U251 reduces their capacity for anchorage-independent growth, two-dimensional migration, and invasion through a three-dimensional matrix, strongly suggesting that low PICK1 expression plays an important role in astrocytic tumorigenesis. We propose that PICK1 negatively regulates neoplastic infiltration of astrocytic tumors and that manipulation of PICK1 is an attractive possibility for therapeutic intervention

DETI Inspire Engagement Report 2020-2021

From September 2020 to December 2021, DETI Inspire has delivered an impressive array of outputs and engagement activities. In two years, the team have directly engaged 6,832 children and 216 teachers from 73 schools and community groups in the West of England, with an estimated 97,550 children reached altogether through dissemination efforts. Along the way, children have been able to have conversations with real-life engineers through (online) Q&A sessions, card games and skill shares. 455 engineers have so far shared their experiences, as well as at least 17 industry partners and three charities.42% of total direct engagements (N=3,415) came directly through in-person BoxED sessions, all four developed and launched by DETI Inspire in 2021: The West in Minecraft (N=2,047, 60%), Engineering Curiosity (N=357, 10%), WeCount (N=319, 9%), and We Make Our Future (N=692, 20%). 42% (10) of all the schools engaged in BoxED sessions (total = 24) came from areas within the most deprived 20% of the country, and 17% (4) came from the most deprived 30%.The last 20 months has seen the programme: pair female junior engineers with senior female mentors (page 13); establish a network of 102 engineers from diverse backgrounds (page 13); distribute 132 Engineering Curiosity card packs to schools and community groups and launch 40 Tik-Tok videos to accompany them (p 16); host a Sustainable Solutions Summit to 16-18-year-olds (page 26); champion sustainable engineering at COP26 (page 28); beam in engineers to 3,500 children during the height of the pandemic (p39); and reach over 250,000 people through social media (p 35). For a full list of highlights, and for details of DETI Inspire’s engagements, see Table 1.Despite another year of uncertainty, with rules around in-person events frequently changing, the DETI Inspire programme has excelled under the circumstances. Adapting to the changing rules and guidance, the team managed to engage in-person when they could – enriching children and young people’s cultural experiences, limited by the pandemic – and offer well attended online events when they could not. For instance, from two online events alone, DETI Inspire reached 9,000 children and young people.DETI Inspire will continue to deliver BoxED activities to schools across the West of England Combined Authority (WECA), with a full calendar of bookings right up until June. The programme will also support this year’s Leaders Award (p 42), Great Science Share (p51), and take part in the long-awaited return of Bristol’s Storytale Festival (p 511), among other activities. DETI Inspire is excelling in promoting engineering for sustainability among children, young people and adults from diverse backgrounds, not only in WECA, but also nationally and across Europe

The antagonistic modulation of Arp2/3 activity by N-WASP/WAVE2 and PICK1 defines dynamic changes in astrocyte morphology

Astrocytes exhibit a complex, branched morphology, allowing them to functionally interact with numerous blood vessels, neighboring glial processes and neuronal elements, including synapses. They also respond to central nervous system (CNS) injury by a process known as astrogliosis, which involves morphological changes, including cell body hypertrophy and thickening of major processes. Following severe injury, astrocytes exhibit drastically reduced morphological complexity and collectively form a glial scar. The mechanistic details behind these morphological changes are unknown. Here, we investigate the regulation of the actin-nucleating Arp2/3 complex in controlling dynamic changes in astrocyte morphology. In contrast to other cell types, Arp2/3 inhibition drives the rapid expansion of astrocyte cell bodies and major processes. This intervention results in a reduced morphological complexity of astrocytes in both dissociated culture and in brain slices. We show that this expansion requires functional myosin II downstream of ROCK and RhoA. Knockdown of the Arp2/3 subunit Arp3 or the Arp2/3 activator N-WASP by siRNA also results in cell body expansion and reduced morphological complexity, whereas depleting WAVE2 specifically reduces the branching complexity of astrocyte processes. By contrast, knockdown of the Arp2/3 inhibitor PICK1 increases astrocyte branching complexity. Furthermore, astrocyte expansion induced by ischemic conditions is delayed by PICK1 knockdown or N-WASP overexpression. Our findings identify a new morphological outcome for Arp2/3 activation in restricting rather than promoting outwards movement of the plasma membrane in astrocytes. The Arp2/3 regulators PICK1, and N-WASP and WAVE2 function antagonistically to control the complexity of astrocyte branched morphology, and this mechanism underlies the morphological changes seen in astrocytes during their response to pathological insult

We make our future: Final project report

We Make Our Future is a planetarium show developed by the Inspire Sustainability team at UWE Bristol and outreach experts Explorer Dome. The show celebrates the ingenuity of human engineering, and our potential to tackle huge problems such as the Climate and Ecological Emergency. This Ingenious grant had two aims; one was to train diverse engineers in storytelling and presentation skills, and the other was to increase the diversity of backgrounds and jobs showcased to children within the sustainability solutions show. Overall, 29 diverse engineers took part in storytelling training; 68% were female, 36% were from a Black, Asian or Ethnic Minority background, and 53% worked in industry. After training, 63% said they were ‘quite confident’ to engage with young people, correlating with improvements in average Engineering Outreach Self-Efficacy scores from 6.03 to 7.25 out of 10. Four engineers went on to take part in filming for the We Make Our Future show. The films were then shown in 77 viewings of the show to 2065 children aged between 8 to 15 years old. All 17 schools taking part were in deprived areas, with 43% of children eligible for Free School Meals. Survey responses from children (N=911) indicated 93% enjoyed the show and 83% stated they had learnt something new about engineering. The children showed a high interest in green jobs, with 86% stating they had found out how engineering can help the world and 77% interested in finding out more about solutions to save the planet from climate change. School teachers (N=41) rated the children’s enjoyment of the show as M=4.62 (out of 5) and thought the show would inspire children to take action on sustainability issues (M=4.44). The teachers rated children’s knowledge of engineering, and this improved from 54% before the show to 76% after the show. Teachers also indicated their personal experience of the show, with 100% indicating they enjoyed the show and would recommend it to others. The project successfully raised awareness about how engineering can help people and planet, and inspired children to take action in their local area or in their future careers. Working with diverse engineers showcased relatable people and career pathways to young people from deprived backgrounds. The project introduced engineering as a relevant and attainable aspiration for thousands of young people, highlighting how the engineering design process can initiate change in our society and tackle climate change

DETI Inspire Final Report

Inspiring a future generation of engineers has never been more important, as we seek urgent solutions to the Climate Crisis. The West of England is leading the way developing sustainability solutions with academia and industry collaborating to reach Net Zero by 2030. These green jobs are vital to our regional economy as well as the future security of our world. The DETI Inspire programme aims to catalyse green career accessibility and progression through enhanced STEM outreach, connected to the cutting-edge DETI industrial test cases. The programme has developed the Digital Trailblazers (secondary schools) and Curiosity Connections (primary schools) networks in the West of England and we are at the heart of innovative school and industry regional collaborative projects, with national partners for further reach. Using curriculum-linked engineering outreach and careers support, we are renowned for connecting children with real-life, diverse engineering role models to widen participation and aspirations for green STEM careers. Encouraging diversity and inclusivity, DETI Inspire has engaged children in primary and secondary education across the West of England, with a focus on disadvantaged areas. From September 2020 to December 2022, DETI Inspire delivered a wide range of outputs and engagement activities. In two years, the team directly engaged over 20,206 children, 469 teachers, and 218 schools, with over 117,000 additional children reached through indirect dissemination efforts. Along the way, children have been able to have conversations with real-life engineers through Q&A sessions, card games and skill shares. 483 engineers have so far been part of the outreach, as well as at least 17 industry partners and three charities. Of those direct engagements, 5,787 young people have received at least one in-person, presented BoxED workshop with their school (The West in Minecraft, We Make Our Future, Engineering Curiosity, WeCount). Of those 5,787, 29% (N=1,699) of the young people have been from schools in the two lowest IMD bands; i.e. areas representing the most deprived 20% of the country.1,473 student feedback responses have been collected during the presenter-led workshops.From these responses, 58% of students engaged are female, versus 42% male. When asked to describe their level of interest in engineering before and after the session, ‘Very Interested’ in engineering responses increased 39% from before the session to after and ‘Interested’ increased by 11%. ‘Neutral’, ‘Of Little Interest’ and ‘Not Interested’ all decreased.DETI Inspire will continue to deliver activities to schools across the West of England Combined Authority (WECA). We will provide much needed coordination for digital engineering and green career progression through our Diversity Demonstrator with support from STEM Ambassadors. We will champion green jobs and STEM careers to ensure the development of this vital industry for the West of England, enabling our region to work towards our goal of Net Zero 2030