The role of Arkadia2C and the BMP signalling pathway in motor neuron development

Motor neurons elongate axons over great distances during development, with some extending from the spinal cord to the distal limb, but little is known about extracellular signals that control this growth. The TGF-β superfamily includes two major classes of ligands: Nodallike and BMP. BMP signalling is essential for neuromuscular synaptic growth and plasticity in Drosophila; however, a similar role for the pathway in mammalian motor neurons has not been described. It has previously been shown that the E3-RING ubiquitin ligase Arkadia enhances signalling through the Nodal branch of TGF-β signalling. A second Arkadia locus was previously found to contain two isoforms; the C-terminal isoform (Arkadia2C) contains domains critical for Arkadia’s activity. This project addresses the in vivo function of Arkadia2C in mice. Arkadia2C was found to be expressed specifically in the nervous system throughout embryonic development and adulthood. In a neuronal context Arkadia2C enhances signalling through the Smad1/5/8 branch of the TGF-β pathway in a RING domain-dependent manner. Mice null for Arkadia2C display motor neuron disease-like symptoms including weak motor control and difficulties breathing and eating, leading to postnatal mortality in the majority of mice. A subset of Arkadia2C null embryonic innervation defects was analysed; the majority of the motor axons of the dorsal forelimb fail to form synapses with their target muscles while the phrenic nerve exhibits shorter terminal branches. Postnatally, a failure to maintain neuromuscular junctions was observed leading to atrophy of several muscles. Active BMP signalling was observed in the neurons that innervate the limb and diaphragm and genetic reduction of BMP signalling in asymptomatic Arkadia2C heterozygous mice caused the appearance of the same muscle innervation defects observed in the null individuals. Together, these findings suggest that Arkadia2C’s enhancement of the BMP signalling pathway is critical for the growth and connectivity of certain motor neurons

Co-production of ethanol and squalene using a Saccharomyces cerevisiae ERG1 (squalene epoxidase) mutant and agro-industrial feedstock

Background: Genetically customised Saccharomyces cerevisiae that can produce ethanol and additional bio-based chemicals from sustainable agro-industrial feedstocks (for example, residual plant biomass) are of major interest to the biofuel industry. We investigated the microbial biorefinery concept of ethanol and squalene co-production using S. cerevisiae (strain YUG37- ERG1 ) wherein ERG1 (squalene epoxidase) transcription is under the control of a doxycycline-repressible tet0 7 -CYC1 promoter. The production of ethanol and squalene by YUG37- ERG1 grown using agriculturally sourced grass juice supplemented with doxycycline was assessed. Results: Use of the tet0 7 -CYC1 promoter permitted regulation of ERG1 expression and squalene accumulation in YUG37- ERG1, allowing us to circumvent the lethal growth phenotype seen when ERG1 is disrupted completely. In experiments using grass juice feedstock supplemented with 0 to 50 μ g doxycycline mL − 1 , YUG37- ERG1 fermented ethanol (22.5 [±0.5] mg mL − 1 ) and accumulated the highest squalene content (7.89 ± 0.25 mg g − 1 dry biomass) and yield (18.0 ± 4.18 mg squalene L − 1 ) with supplements of 5.0 and 0.025 μ g doxycycline mL − 1 , respectively. Grass juice was found to be rich in water-soluble carbohydrates (61.1 [±3.6] mg sugars mL − 1 ) and provided excellent feedstock for growth and fermentation studies using YUG37- ERG1 . Conclusion: Residual plant biomass components from crop production and rotation systems represent possible substrates for microbial fermentation of biofuels and bio-based compounds. This study is the first to utilise S. cerevisiae for the co-production of ethanol and squalene from grass juice. Our findings underscore the value of the biorefinery approach and demonstrate the potential to integrate microbial bioprocess engineering with existing agriculture

Can manipulation of differentiation conditions eliminate proliferative cells from a population of ES cell-derived forebrain cells?

There is preliminary evidence that implantation of primary fetal striatal cells provides functional benefit in patients with Huntington’s disease, a neurodegenerative condition resulting in loss of medium-sized spiny neurons (MSN) of the striatum. Scarcity of primary fetal tissue means it is important to identify a renewable source of cells from which to derive donor MSNs. Embryonic stem (ES) cells, which predominantly default to telencephalic-like precursors in chemically defined medium (CDM), offer a potentially inexhaustible supply of cells capable of generating the desired neurons. Using an ES cell line, with the forebrain marker FoxG1 tagged to the LacZ reporter, we assessed effects of known developmental factors on the yield of forebrain-like precursor cells in CDM suspension culture. Addition of FGF2, but not DKK1, increased the proportion of FoxG1- expressing cells at day 8 of neural induction. Oct4 was expressed at day 8, but was undetectable by day 16. Differentiation of day 16 precursors generated GABA-expressing neurons, with few DARPP32 positive MSNs. Transplantation of day 8 precursor cells into quinolinic acid-lesioned striata resulted in generation of teratomas. However, transplantation of day 16 precursors yielded grafts expressing neuronal markers including NeuN, calbindin and parvalbumin, but no DARPP32 6 weeks post-transplantation. Manipulation of fate of ES cells requires optimization of both concentration and timing of addition of factors to culture systems to generate the desired phenotypes. Furthermore, we highlight the value of increasing the precursor phase of ES cell suspension culture when directing differentiation toward forebrain fate, so as to dramatically reduce the risk of teratoma formation

Molecular regulation of striatal development: a review

The central nervous system is composed of the brain and the spinal cord. The brain is a complex organ that processes and coordinates activities of the body in bilaterian, higher-order animals. The development of the brain mirrors its complex function as it requires intricate genetic signalling at specific times, and deviations from this can lead to brain malformations such as anencephaly. Research into how the CNS is specified and patterned has been studied extensively in chick, fish, frog, and mice, but findings from the latter will be emphasised here as higher-order mammals show most similarity to the human brain. Specifically, we will focus on the embryonic development of an important forebrain structure, the striatum (also known as the dorsal striatum or neostriatum). Over the past decade, research on striatal development in mice has led to an influx of new information about the genes involved, but the precise orchestration between the genes, signalling molecules, and transcription factors remains unanswered. We aim to summarise what is known to date about the tightly controlled network of interacting genes that control striatal development. This paper will discuss early telencephalon patterning and dorsal ventral patterning with specific reference to the genes involved in striatal development

The effects of Positive Youth Development interventions on substance use, violence and inequalities: systematic review of theories of change, processes and outcomes

BackgroundPositive Youth Development (PYD) delivered outside school aims to enable young people to develop positive assets such as relationships and confidence, rather than to merely address risk. Existing reviews of PYD effects on substance use or violence are old and unsystematic.ObjectivesTo systematically review evidence to answer the following questions: what theories of change inform PYD interventions addressing substance use and violence? What characteristics of participants and contexts are identified as barriers to and facilitators of implementation and receipt in process evaluations of PYD? What is the effectiveness and cost-effectiveness of PYD in reducing substance use and violence? What characteristics of participants and contexts appear to moderate, or are necessary and sufficient for, PYD effectiveness?Data sourcesA total of 21 bibliographic databases; 35 websites and contacting authors.Review methodsWe included reports published in English since 1985 and reporting on theories of change, as well as process, outcome and economic evaluations of PYD targeting 11- to 18-year-olds and addressing substance use or violence. References were screened on title/abstract and, where appropriate, on full report. Data extraction and quality assessment used Critical Appraisal Skills Programme, Evidence for Policy and Practice Information and Co-ordinating Centre and Cochrane tools. Theories of change and process evaluations were qualitatively metasynthesised. Outcome evaluations were synthesised narratively and meta-analytically.Results32,394 unique references were identified and 48 were included. A total of 16 reports described theories, 13 (10 studies) evaluated processes and 25 (10 studies) evaluated outcomes.Theories of changePYD interventions aim to offer opportunities for young people to develop positive ‘assets’ such as skills and confidence. These are theorised to promote and be promoted by young people’s ‘intentional self-regulation’, which involves reflecting on behaviour; determining goals; using existing resources to pursue these; and redirecting effort when thwarted. This enables ‘developmental regulation’, namely individuals capitalising on other opportunities to promote personal development. Positive assets thus accrued reduce health risks by reducing the impact on individuals of environmental risk or by ameliorating the impact of such risks. The literature offers limited insights beyond these general ideas.Process evaluationsCommunity engagement ensured that programmes were accessible and appealing. Staff capacity and continuity were crucial factors but often challenging when programmes could not offer full-time jobs. Tensions arose between a desire to empower participants to choose activities and a requirement for them to undertake a breadth of activities.Outcome evaluationsMeta-analyses of all combined outcomes and of short-term alcohol use, illicit drug use and smoking found no significant effects. There were small, statistically significant, short-term effects for an omnibus measure of substance use and for violence. We could not undertake metaregression to assess sociodemographic moderators but narrative synthesis suggested no clear pattern of effects by sex. We found no economic evaluations.LimitationsInsufficient studies precluded qualitative comparative analyses.ConclusionsHow PYD might promote health is currently undertheorised. Implementation can be challenging. We found little evidence that current PYD interventions delivered outside school reduce substance use or violence. However, these may not constitute a test of the effectiveness of the PYD model, as some included interventions that, although meeting our inclusion criteria, were not exemplars of PYD.Future workFurther evaluations should assess interventions employing PYD theory of change.Study registrationThis study is registered as PROSPERO CRD42013005439.FundingThe National Institute for Health Research Public Health Research programme.</jats:sec

Farmers Markets and the Local Food System: The Case of Gettysburg, Pennsylvania

In order to examine and obtain a better understanding of the local food system within Adams County, Pennsylvania, this study explores the characteristics and perspectives of the customers and vendors at the farmers markets in Gettysburg, Pennsylvania. Survey findings from the Gettysburg Farmers Market and the three Adams County Farmers Markets include customer demographic information, perspectives and shopping behavior as well as vendor product information, farm size and location and preference for market management. Introductory background information on the Farm Bill and the influence of agricultural practices on the environment, human health and nutrition and the relationship between farmers markets and the local economy are offered in order to emphasize the value of a well-managed local food system. Conclusions provide evidence that lower income and lower education levels are not sufficiently represented at all the markets and food stamp programs are being underutilized. This study suggests employing additional marketing to target underrepresented demographic groups, public transportation to potentially inaccessible market locations and increased advertisement and encouragement of food stamp programs at all markets in order to expand the customer base and increase access to healthy, local foods for less advantaged citizens. The results from this study are intended to offer evidence that will promote and facilitate market management, strengthen customer/vendor relationships and encourage better ties between the local community and local food systems at the farmers markets within Gettysburg in Adams County, Pennsylvania

Concert recording 2017-04-12b

[Track 1]. Angel Falls / Lewis Songer -- [Track 2]. Grand Canyon Octet. Andante appassionato [Track 3]. Lento-allegro molto / Eric Ewazen -- [Track 4]. Quipperies / Lowell Shaw -- [Track 5]. Birdland / Josef Zawinul arranged by Kummerlander

Factors influencing the provision of end-of-life care for adolescents and young adults with advanced cancer: a scoping review

Background There is international recognition that cancer in young people is on the rise and that improvements in outcomes for young people lag well behind advances achieved for both children and older adults over the past 30 years. Cancer is the third leading cause of death in adolescents and young adults; however, little is known about how the end of life unfolds for those who die of the progressive disease. Objective This scoping review sought to locate and describe literature relating to end of life care for adolescents and young adults with cancer