Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors

The Fantastic Voyage: an arts-led approach to 3D virtual reality visualization of clinical stroke data

Stroke survivors directly link stroke education with their ability to access appropriate treatments and reduce their risk of future strokes. However, with such a diverse population a universal mode of delivering education must be sought. This paper places the artist at the heart of educating patients and carers about their disease by developing a technical process of delivering 3D CT patient stroke data on the Virtual Reality (VR) platform Oculus Rift DK2. VR has already been proven as an efficacious rehabilitation tool for this population but its use in education has not yet been established. This work is being piloted in a new collaboration between the Art & Design Faculty at the University of New South Wales, Australia and the Stroke Rehabilitation Service at St Vincent's Hospital in Sydney. Importantly, this paper places the artist's at the center of the process -- from developing the concept, to prototyping and creating the final visual aesthetic. The different stages of the technical design process are also described in this paper. These provide an early framework for working with VR in a clinical context. The practicalities and pitfalls of navigating vascular datasets in immersive real-time 3D on VR are discussed at the end of this paper. Several recommendations for the future development of this process and its scalability for clinical use are made