Phenformin inhibits tumor growth through a Complex I-independent redox/corepressor axis

The antidiabetic drug phenformin displays potent anticancer activity in different tumors but its mechanism of action remains elusive. Using Shh Medulloblastoma as model, we show here that at the clinically relevant concentrations phenformin elicits a significant therapeutic effect through a redox-dependent, but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerol-phosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between the corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Since ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy

Adapting digital networks and resources for autistic users:A toolkit for the third and public sector

Welcome to Adapting digital networks and resources for autistic users: a toolkit for the third and public sector.WHO IS THIS TOOLKIT FOR?This toolkit offers practical support to any third and public sector professional who wants to adapt their use of digital platforms. You don’t need to have design or programming skills to be able to use this toolkit. The recommendations offered in this toolkit don’t ask you to re-design digital platforms from scratch, but rather provide support on how to manage the content which populates your online platforms, and to provide appropriate level of guidance to users. For those who do have the skills to design digital platforms or have a team of designers at disposition, we offer a separate toolkit specific to these needs, which you can find at www.autisticadultsonline.com/toolkits. The tips offered in this guide are not just for platforms that are meant to be used exclusively with autistic users, but are applicable to any website, social media, and online group which may include autistic users.Autism is largely underdiagnosed, and if you are using digital platforms with a public audience, chances are there will be neurodivergent people accessing your platforms. The adjustments recommended in this toolkit will improve the user experience of your audience as a whole. Digital platforms are in constant evolution. Providing platform-specific instructions, for instance how to set up a Facebook group, would have condemned this toolkit to a short lifespan. Instead, we focused on concepts and approaches that can be applied to any platform you are working with (websites, social media platforms, online groups, forums, online courses).<br/

Adapting digital networks and resources for autistic users:A toolkit for the third and public sector

Welcome to Adapting digital networks and resources for autistic users: a toolkit for the third and public sector.WHO IS THIS TOOLKIT FOR?This toolkit offers practical support to any third and public sector professional who wants to adapt their use of digital platforms. You don’t need to have design or programming skills to be able to use this toolkit. The recommendations offered in this toolkit don’t ask you to re-design digital platforms from scratch, but rather provide support on how to manage the content which populates your online platforms, and to provide appropriate level of guidance to users. For those who do have the skills to design digital platforms or have a team of designers at disposition, we offer a separate toolkit specific to these needs, which you can find at www.autisticadultsonline.com/toolkits. The tips offered in this guide are not just for platforms that are meant to be used exclusively with autistic users, but are applicable to any website, social media, and online group which may include autistic users.Autism is largely underdiagnosed, and if you are using digital platforms with a public audience, chances are there will be neurodivergent people accessing your platforms. The adjustments recommended in this toolkit will improve the user experience of your audience as a whole. Digital platforms are in constant evolution. Providing platform-specific instructions, for instance how to set up a Facebook group, would have condemned this toolkit to a short lifespan. Instead, we focused on concepts and approaches that can be applied to any platform you are working with (websites, social media platforms, online groups, forums, online courses).<br/

Stepping Through Remixed : Exploring the Limits of Linear Video in a Participatory Mental Health Film

Participatory filmmaking offers opportunities to counterbalance stereotypes about mental health often endorsed by the mainstream media, by involving participants who have a lived experience of mental health problems in production. It is our experience, however, that the linear videos traditionally resulting from such processes can fail to fully accommodate and represent a plurality of participant voices and viewpoints and, as a consequence, may lead to oversimplified accounts of mental health. Interactive film, on the other hand, could open up a space of opportunities for participatory films that allow multiple voices and complex representations to coexist. In this paper, we explore this opportunity by reviewing Stepping Through, a linear film produced by five men with mental health problems in 2016 about isolation and recovery. Through a series of workshops, the film was deconstructed by its creators, who analysed which additional possibilities of both form and content that could be revealed if the Stepping Through was transformed into a non-linear interactive film. Our findings reveal several expressive needs that a non-linear interactive film could more easily accommodate and opportunities for making participatory filmmaking truly dialogic by allowing an active exchange with audiences that preserves, rather than streamlines, the tension between collective views and personal accounts

The energy sensor AMPK regulates Hedgehog signaling in human cells through a unique Gli1 metabolic checkpoint

Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs) and its aberrant activation is a leading cause of Medulloblastoma, the most frequent pediatric brain tumor. We show here that the energy sensor AMPK inhibits Hh signaling by phosphorylating a single residue of human Gli1 that is not conserved in other species.Studies with selective agonists and genetic deletion have revealed that AMPK activation inhibits canonical Hh signaling in human, but not in mouse cells. Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. Notably, we show that selective AMPK activation inhibits Gli1-driven proliferation and that this effect is linked to Ser408 phosphorylation, which represents a key metabolic checkpoint for Hh signaling.Collectively, this data unveil a novel mechanism of inhibition of Gli1 function, which is exclusive for human cells and may be exploited for the treatment of Medulloblastoma or other Gli1 driven tumors

Mice with reduced expression of the telomere-associated protein Ft1 develop p53-sensitive progeroid traits

Human AKTIP and mouse Ft1 are orthologous ubiquitin E2 variant proteins involved in telomere maintenance and DNA replication. AKTIP also interacts with A- and B-type lamins. These features suggest that Ft1 may be implicated in aging regulatory pathways. Here, we show that cells derived from hypomorph Ft1 mutant (Ft1kof/kof ) mice exhibit telomeric defects and that Ft1kof/kof animals develop progeroid traits, including impaired growth, skeletal and skin defects, abnormal heart tissue, and sterility. We also demonstrate a genetic interaction between Ft1 and p53. The analysis of mice carrying mutations in both Ft1 and p53 (Ft1kof/kof ; p53ko/ko and Ft1kof/kof ; p53+/ko ) showed that reduction in p53 rescues the progeroid traits of Ft1 mutants, suggesting that they are at least in part caused by a p53-dependent DNA damage response. Conversely, Ft1 reduction alters lymphomagenesis in p53 mutant mice. These results identify Ft1 as a new player in the aging process and open the way to the analysis of its interactions with other progeria genes using the mouse model

Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.

SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB

Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation

The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA‑approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH‑GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH‑regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen‑activated kinase kinase kinase&nbsp;1&nbsp;(MEKK1), the most upstream kinase of the mitogen‑activated protein kinase&nbsp;(MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH‑regulated transcription factor. Phosphorylation occurred at multiple residues in the C‑terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins&nbsp;14‑3‑3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy

Designing structural participation in an interactive film on mental health

The practice of interactive documentary can provide participatory opportunities thanks to its capacity for making space for audiences to leave their marks in a film. However, participants’ inclusion has often been limited to an a-posteriori contribution of materials rather than a structural involvement in the film design. What happens when we treat participants as authors and let them imagine and design their own interactive film? This paper explores how design processes from participatory filmmaking can be adapted to achieve this goal by presenting the design process that led to the production of an interactive participatory film on mental health, Stepping Through Interactive. Five participants with lived experience of mental health problems explored, designed, and produced a non-linear film form to effectively represent their personal accounts of mental health. We review the challenges faced and the strategies deployed in the design process in view of supporting similar forms of production in other contexts