The homeobox transcription factor Even-skipped regulates acquisition of electrical properties in Drosophila neurons.

BACKGROUND: While developmental processes such as axon pathfinding and synapse formation have been characterized in detail, comparatively less is known of the intrinsic developmental mechanisms that regulate transcription of ion channel genes in embryonic neurons. Early decisions, including motoneuron axon targeting, are orchestrated by a cohort of transcription factors that act together in a combinatorial manner. These transcription factors include Even-skipped (Eve), islet and Lim3. The perdurance of these factors in late embryonic neurons is, however, indicative that they might also regulate additional aspects of neuron development, including the acquisition of electrical properties. RESULTS: To test the hypothesis that a combinatorial code transcription factor is also able to influence the acquisition of electrical properties in embryonic neurons we utilized the molecular genetics of Drosophila to manipulate the expression of Eve in identified motoneurons. We show that increasing expression of this transcription factor, in two Eve-positive motoneurons (aCC and RP2), is indeed sufficient to affect the electrical properties of these neurons in early first instar larvae. Specifically, we observed a decrease in both the fast K+ conductance (IKfast) and amplitude of quantal cholinergic synaptic input. We used charybdotoxin to pharmacologically separate the individual components of IKfast to show that increased Eve specifically down regulates the Slowpoke (a BK Ca2+-gated potassium channel), but not Shal, component of this current. Identification of target genes for Eve, using DNA adenine methyltransferase identification, revealed strong binding sites in slowpoke and nAcRalpha-96Aa (a nicotinic acetylcholine receptor subunit). Verification using real-time PCR shows that pan-neuronal expression of eve is sufficient to repress transcripts for both slo and nAcRalpha-96Aa. CONCLUSION: Taken together, our findings demonstrate, for the first time, that Eve is sufficient to regulate both voltage- and ligand-gated currents in motoneurons, extending its known repertoire of action beyond its already characterized role in axon guidance. Our data are also consistent with a common developmental program that utilizes a defined set of transcription factors to determine both morphological and functional neuronal properties

Integration of the trigger and data acquisition systems in ATLAS

During 2006 and the first half of 2007, the installation, integration and commissioning of trigger and data acquisition (TDAQ) equipment in the ATLAS experimental area have progressed. There have been a series of technical runs using the final components of the system already installed in the experimental area. Various tests have been run including ones where level 1 preselected simulated proton-proton events have been processed in a loop mode through the trigger and dataflow chains. The system included the readout buffers containing the events, event building, level 2 and event filter trigger algorithms. The scalability of the system with respect to the number of event building nodes used has been studied and quantities critical for the final system, such as trigger rates and event processing times, have been measured using different trigger algorithms as well as different TDAQ components. This paper presents the TDAQ architecture, the current status of the installation and commissioning and highlights the main test results that validate the system

SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.

The secretory pathway of eukaryotic cells packages cargo proteins into COPII-coated vesicles for transport from the endoplasmic reticulum (ER) to the Golgi. We now report that complete genetic deficiency for the COPII component SEC24A is compatible with normal survival and development in the mouse, despite the fundamental role of SEC24 in COPII vesicle formation and cargo recruitment. However, these animals exhibit markedly reduced plasma cholesterol, with mutations in Apoe and Ldlr epistatic to Sec24a, suggesting a receptor-mediated lipoprotein clearance mechanism. Consistent with these data, hepatic LDLR levels are up-regulated in SEC24A-deficient cells as a consequence of specific dependence of PCSK9, a negative regulator of LDLR, on SEC24A for efficient exit from the ER. Our findings also identify partial overlap in cargo selectivity between SEC24A and SEC24B, suggesting a previously unappreciated heterogeneity in the recruitment of secretory proteins to the COPII vesicles that extends to soluble as well as trans-membrane cargoes. DOI:http://dx.doi.org/10.7554/eLife.00444.001

Insights about Cannabis and Psychosis Using Video Games for Young People with a First Episode of Psychosis, Particularly Those from Black Racialized Communities: Protocol for a Mixed Methods Study

Background: Cannabis use disorder among young people with a first episode of psychosis contributes to relapse, hospitalization, and impaired functioning. However, few studies have examined what young people with early phase psychosis, particularly those from Black racialized communities, understand or appreciate about this relationship, even though they may be at risk. There are no formally tested knowledge translation strategies that disseminate these research findings for young people with emerging psychosis from Black racialized communities. Objective: This study aims to conceptualize what young people with early phase psychosis/cannabis use disorder understand about the relationship between cannabis and psychosis, focusing on people from racialized backgrounds. This study also aims to assess whether the knowledge translation product, the “Back to Reality Series,” increases awareness of the impact of cannabis use on psychosis from the perspectives of young people with emerging psychosis and cannabis use disorder from Black African and Caribbean communities. Methods: Qualitative analysis will reveal themes from qualitative interviews about cannabis and psychosis from the perspectives of young people with emerging psychosis and cannabis use disorder from Black African and Caribbean communities. Perceptions before and after exposure to the Back to Reality Series will be qualitatively analyzed. A control game will be used for comparison, and scores on a quiz after playing the Back to Reality Series will be quantitatively analyzed to establish whether the Back to Reality Series raises awareness of the effects of cannabis on psychosis. An advisory council involving young people from Black communities, family members, and clinicians will bring community perspectives to this research. Results: We began recruiting participants for this study in September 2021. We will complete data collection on demographic and clinical factors, qualitative interviews, and quantitative assessments of the Back to Reality Series. Conclusions: The voices of young people from racialized backgrounds will generate preliminary data to inform early psychosis programs, addressing cannabis use in this population. The findings may advance the use of a new knowledge translation product that deals with gaps in knowledge about cannabis use for people experiencing early phase psychosis, particularly those from racialized communities

Lower serum levels of IL-1β and IL-6 cytokines in adolescents with anorexia nervosa and their association with gut microbiota in a longitudinal study

Introduction Anorexia nervosa (AN) is an often chronic and debilitating psychiatric disease whose etiology is not completely understood. Recently, a potential role of inflammation has emerged in other psychiatric diseases, such as depression, PTSD and schizophrenia. The first results in adults with AN seemed to confirm a low-grade proinflammatory state until recent studies presented more differential findings. Studying adolescents with a shorter illness duration and fewer confounding factors might help elucidate the role of inflammation in the underlying pathophysiology of AN; however, the few available studies in adolescents remain ambiguous, and no longitudinal data are available in this age range. Results TNF-α serum levels were significantly elevated in patients with AN at admission, while IL-1β and IL-6 levels were lower at admission and discharge than in HC. After treatment, we also found significantly elevated levels of IL-6 Rα compared to HC, while IL-15 did not show significant changes. Exploratory analyses revealed positive associations of cytokine and genus-level changes between admission and discharge for IL-1β (Bacteroides) and IL-15 (Romboutsia), and negative associations for IL-15 (Anaerostipes) and TNF-α (uncultured Lachnospiraceae). Conclusion We confirmed a previous finding of elevated levels of TNF-α also in adolescents with AN; however, the reduced IL-1β and IL-6 levels differed from the mostly increased levels found in adults. A mixed pro- and anti-inflammatory state appears to be present in adolescents, potentially due to their shorter illness duration. The gut microbiota, with its regulatory function on cytokine production, might play a role in mediating these inflammatory processes in AN and could offer targets for new therapeutic approaches

Co-creation of Public Service Innovation - Something Old, Something New, Something Borrowed, Something Tech

This paper draws together ideas about co-creation, social innovation, social investment and individual and collective values that underpin the CoSIE project (https://cosie.turkuamk.fi/) and shows the relationship between these concepts and how they can support innovation in public services

Generation and Characterization of the Drosophila melanogaster paralytic Gene Knock-Out as a Model for Dravet Syndrome

From MDPI via Jisc Publications RouterHistory: accepted 2021-11-17, pub-electronic 2021-11-18Publication status: PublishedFunder: Generalitat Valenciana; Grant(s): PROMETEU/2018/135Funder: European Commission; Grant(s): ERDF of Comunitat Valenciana 2014–2020Funder: ApoyoDravet; Grant(s): N/ADravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the paralytic gene, the single Drosophila melanogaster gene encoding this type of protein, by homologous recombination. These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight, and walking tests. Moreover, they also manifested some cognitive alterations, such as anxiety and problems in learning. Electrophysiological analyses from larval motor neurons showed a decrease in cell capacitance and membrane excitability, while persistent sodium current increased. To detect alterations in metabolism, we performed an NMR metabolomic profiling of heads, which revealed higher levels in some amino acids, succinate, and lactate; and also an increase in the abundance of GABA, which is the main neurotransmitter implicated in Dravet syndrome. All these changes in the paralytic knock-out flies indicate that this is a good model for epilepsy and specifically for Dravet syndrome. This model could be a new tool to understand the pathophysiology of the disease and to find biomarkers, genetic modifiers and new treatments

Where Next for Co-Creating Public Services? Emerging Lessons and New Questions from CoSIE

Many models of innovation involve co-creation, which implies that people who use (or potentially use) public services work with providers to initiate, design, deliver and evaluate them (Voorberg et al. 2014, Torfing et al. 2019). The goal of the Co-Creation of Public Service Innovation in Europe project (CoSIE) is to contribute to democratic renewal and social inclusion through co-creating innovative public services by engaging diverse citizen groups and stakeholders in varied public services. CoSIE assumes that co-creation becomes innovative if it not only concerns the reduction of the public expenditure, but if it manages also to meet social needs, and to empower the beneficiaries of policies, by changing socio-political relations and redistributing socio-political responsibilities. More specifically, it aims to a) advance the active shaping of service priorities by end users and their informal support network and b) engage citizens, especially groups often called ’hard to reach’, in the collaborative design of public services. One way it does this is through the development of ten pilot cases, embedded in national contexts which strongly differ in socio-cultural, socio-political and socio-economical dimensions. The subsequent comparison permits an examination of the existence of common enabling or hindering factors. The CoSIE project builds on the idea that public sector innovations can be best achieved by creating collaborative partnerships between service providers (i.e. public sector agencies, third sector organisations, private companies) and citizens who benefit from services either directly or indirectly. Co-creation in CoSIE is an emerging, collaborative and power balancing activity that aims to enrich and enhance the value in public service offerings at any stage in the development of new service and during its implementation. It is manifested in a constructive exchange of different kinds of resources (ideas, competences, lived experience, etc.) that enhance the experienced value of public service. Individual and public value may be understood in terms of increased wellbeing, shared visions for the common good, policies, strategies, regulatory frameworks or new services. This paper draws together some of the ‘big ideas’ emerging from CoSIE in the form of a discussion paper aimed at European, national and regional policy-makers. The big ideas emerging from CoSIE can be grouped together as ideas associated with conceptualising co-creation, implementing co-creation and evidencing co-creation: Conceptualising co-creation • Strengths or asset-based approaches are key to co-creation • Co-creation is a moral endeavour Implementing co-creation • The role of technology in co-creation and innovation • The role of professionals in co-creating public services • Scaling up co-created innovations in public service reform Evidencing and evaluating co-creation in public service reform • Challenges for evaluators • Options for evaluating co-creation and strengths-based approache

Precision Analysis of Evolved Stars

Evolved stars dominate galactic spectra, enrich the galactic medium, expand to change their planetary systems, eject winds of a complex nature, produce spectacular nebulae and illuminate them, and transfer material between binary companions. While doing this, they fill the HR diagram with diagnostic loops that write the story of late stellar evolution. Evolved stars sometimes release unfathomable amounts of energy in neutrinos, light, kinetic flow, and gravitational waves. During these late-life times, stars evolve complexly, with expansion, convection, mixing, pulsation, mass loss. Some processes have virtually no spatial symmetries, and are poorly addressed with low-resolution measurements and analysis. Even a "simple" question as how to model mass loss resists solution. However, new methods offer increasingly diagnostic tools. Astrometry reveals populations and groupings. Pulsations/oscillations support study of stellar interiors. Optical/radio interferometry enable 2-3d imagery of atmospheres and shells. Bright stars with rich molecular spectra and velocity fields are a ripe opportunity for imaging with high spatial and spectral resolution, giving insight into the physics and modeling of later stellar evolution