Hedgehog signaling is required for the differentiation of ES cells into neurectoderm

AbstractMouse embryonic stem cells can differentiate in vitro into cells of the nervous system, neurons and glia. This differentiation mimics stages observed in vivo, including the generation of primitive ectoderm and neurectoderm in embryoid body culture. We demonstrate here that embryonic stem cell lines mutant for components of the Hedgehog signaling cascade are deficient at generating neurectoderm-containing embryoid bodies. The embryoid bodies derived from mutant cells are also unable to respond to retinoic acid treatment by producing nestin-positive neural stem cells, a response observed in cultures of heterozygous cells, and contain cores apparently arrested at the primitive ectoderm stage. The mutant cultures are also deficient in their capacity to differentiate into mature neurons and glia. These data are consistent with a role for Hedgehog signaling in generating neurectoderm capable of producing the appropriate neuronal and glial progenitors in ES cell culture

Shaping social innovation in local communities: The contribution of intermediaries

Participatory social innovation projects often involve the coming together of design researchers, community development groups, and community members to develop (often technological) solutions to social problems or challenges. "Intermediaries" are specific individuals and organisations who contribute to these projects by translating intentions, values and experiences between design researchers and communities. Previous research has not yet critically examined the role of intermediaries in such projects. This paper does so in a project carried out in rural areas of Europe, which sought to test and develop a technology to support the creation of FM community radio stations in isolated areas. We present the project as a biography of infrastructures to provide an account of intermediaries' interactions during the project's unfolding. We find that how intermediaries shape the social base and ends of the project, and the interpretation of the technology involved, is influenced by their position, goals, and relationships in the process

Co-designing convivial tools to support participation in community radio

Connectivity made possible by the diffusion of digital technologies has offered new possibilities for the public to interact with media, including radio. However, interactions are often framed by globally managed platforms, owned by companies with values based on maximizing profit, rather than prioritising Illich’s forms of conviviality. In this article, we draw on experiences from the Grassroot Wavelengths project that introduces an innovative peer-to-peer platform to support the creation and management of community radio stations. We offer insight into the practices of participation in community media, where the users influence decisions concerning the technology, the content, the actors and the organization policy of the radio station, through a participatory design approach. These collaborations between researchers and users, together with a focus on the development of relational assets in local contexts, are fundamental in an attempt to design a platform that fosters conviviality and offers an alternative way to consider participation in community media

Feasibility of ActivABLES to promote home-based exercise and physical activity of community-dwelling stroke survivors with support from caregivers : A mixed methods study

BackgroundTechnical applications can promote home-based exercise and physical activity of community-dwelling stroke survivors. Caregivers are often able and willing to assist with home-based exercise and physical activity but lack the knowledge and resources to do so. ActivABLES was established to promote home-based exercise and physical activity among community-dwelling stroke survivors, with support from their caregivers. The aim of our study is to investigate the feasibility of ActivABLES in terms of acceptability, demand, implementation and practicality.MethodsA convergent design of mixed methods research in which quantitative results were combined with personal experiences of a four-week use of ActivABLES by community-dwelling stroke survivors with support from their caregivers. Data collection before, during and after the four-week period included the Berg Balance Scale (BBS), Activities-Specific Balance Confidence Scale (ABC), Timed-Up-and-Go (TUG) and Five Times Sit to Stand Test (5xSST) and data from motion detectors. Semi-structured interviews were conducted with stroke survivors and caregivers after the four-week period. Descriptive statistics were used for quantitative data. Qualitative data was analysed with direct content analysis. Themes were identified related to the domains of feasibility: acceptability, demand, implementation and practicality. Data was integrated by examining any (dis)congruence in the quantitative and qualitative findings.ResultsTen stroke survivors aged 55-79years participated with their informal caregivers. Functional improvements were shown in BBS (+2.5), ABC (+0.9), TUG (-4.2) and 5xSST (-2.7). More physical activity was detected with motion detectors (stand up/sit down +2, number of steps +227, standing +0.3h, hours sitting/lying -0.3h). The qualitative interviews identified themes for each feasibility domain: (i) acceptability: appreciation, functional improvements, self-initiated activities and expressed potential for future stroke survivors; (2) demand: reported use, interest in further use and need for follow-up; (3) implementation: importance of feedback, variety of exercises and progression of exercises and (4) practicality: need for support and technical problems. The quantitative and qualitative findings converged well with each other and supported the feasibility of ActivABLES.ConclusionsActivABLES is feasible and can be a good asset for stroke survivors with slight or moderate disability to use in their homes. Further studies are needed with larger samples.Peer reviewe

Making civic initiatives last: Ecosystems, technologies, approaches and challenges

Civic initiatives aim to create impact, often beyond the initial (design) activity or process. HCI practice and research has turned toward exploring methods, technologies, processes, to work toward lasting initiatives that can continue effectively beyond the project or grant timeline. Nonetheless, there is a growing need to create a forum where researchers and practitioners can share their approaches so as to shed light on opportunities and challenges of supporting lasting civic initiatives moving forward. This workshop aims to bring together researchers and practitioners interested in how to make civic initiatives have lasting impact: either by supporting and sustaining such initiatives or by focusing on how their outcomes increase people’s capacity to act on their ideas and wishes

Developing ActivABLES for community-dwelling stroke survivors using the Medical Research Council framework for complex interventions.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBackground: Novel technical solutions are called for to promote home-based exercise among community-dwelling stroke survivors supported by their caregivers. Lack of resources and knowledge about how to accomplish it, has been demonstrated. The objective of this study is to describe in detail the development of ActivABLES, a technical intervention to promote home-based exercise and physical activity engagement of community-dwelling stroke survivors with support from their caregivers. Methods: The technical development process of ActivABLES was guided by the Medical Research Council (MRC) framework for development and evaluation of complex interventions as well as by principles of human-centred design and co-design. The main steps included: (1) Synthesis of evidence supporting the inclusion of balance exercises, mobility and walking exercises and exercises for the upper arm; (2) Implementation of initial user studies with qualitative data collection from individual interviews with stroke survivors, and focus group interviews with caregivers and health professionals; (3) Preliminary testing of eight prototypes with seven stroke survivors and their caregivers. Results: After the preliminary testing of eight prototypes, four prototypes were not further developed whereas four prototypes were modified further. In addition, two new prototypes were developed, leaving six prototypes for further modification: 1) ActivFOAM for balance exercises, 2) WalkingSTARR to facilitate walking, 3) ActivBALL for hand exercises, 4) ActivSTICKS for upper arm exercises, and 5) ActivLAMP and 6) ActivTREE which both give visual feedback on progress of daily exercise and physical activities. ActivFOAM, ActivBALL and ActivSTICKS are all connected to a tablet where exercise instructions are given. All the exercise prototypes can be connected to ActivLAMP and ActivTREE to give feedback on how much exercise the user has done. Settings can be individualised and recommended daily time and/or repetition can easily be changed as the user progresses to higher activity levels. Conclusions: The development process of ActivABLES was guided by the principles of human-centred design, with iterative testing of future users, and by the MRC framework of complex intervention, with a repeated process of development and testing. This process resulted in six prototypes which are available for feasibility testing among a small group of community-dwelling stroke survivors. Keywords: Home-based exercise; Stroke survivors; Technical intervention.NordForsk ActivABLES project Icelandic Physiotherapy Association Icelandic Ministry of Welfar

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)