Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

© 2015 Elsevier Inc. The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes. Pasciuto etal. show that dual dysregulation of APP and ADAM10, during a critical period of postnatal development, leads to overproduction of sAPPα. Modulation of ADAM10 activity re-establishes physiological sAPPα levels and ultimately ameliorates FXS molecular, synaptic, and behavioral deficits.Stichting Alzheimer Onderzoek -Fondation Recherche Maladie Alzheimer (SAO-FMA), Vlaams Instituut voor Biotechnologie (VIB), KU Leuven (Opening the Future), European Research Projects on Neurodevelopmental Disorders NEURON ERA-NET, Associazione Italiana Sindrome X Fragile, Compagnia San Paolo, and Fondation Jerome Lejeune to C.B., a European Research Council Grant ERC-2010-AG_268675 to B.D.S.; a Methusalem grant of the KU Leuven/Flemish Government to B.D.S. and C.D. B.D.S. is supported by the Bax-Vanluffelen Chair for Alzheimer’s Disease. C.B. and B.D.S. are supported by ‘‘Opening the Future’’ of the Leuven Universiteit Fonds (LUF). Deutsche Forschungsgemeinschaft (DFG) (MU 1457/8-1; 1457/9-1)Peer Reviewe

Design of the cooling system of the Mu2e electromagnetic calorimeter at Fermi National Accelerator Laboratory

Nella tesi si discute del sistema di raffreddamento dell'elettronica del calorimetro dell'esperimento Mu2e. Sono presentate le soluzioni tecniche analizzate per il raffreddamento delle schede di front-end, delle interface board e dei waveform digitizer. In particolare è sviluppato il progetto di un crate allocato sulla superficie esterna del disco del calorimetro. Oltre che sorreggere le schede, è anche parte integrante del sistema di raffreddamento. Si discute inoltre del sistema di distribuzione del fluido refrigerante per il calorimetro. Sono successivamente sviluppate le soluzioni manifatturiere per la realizzazione dei crate e dei componenti necessari per la refrigerazione dell'elettronica. Infine sono presentate le principali prove sperimentali che verranno eseguite per la validazione delle simulazioni analitiche effettuate. In this Thesis, the cooling of the electronics of the Mu2e calorimeter has been discussed. The analysed technical solutions for the cooling of the front-end boards, the waveform digitizers boards and the interface boards have been presented. The project of the crate has been showed in detail. It is placed in the outer surface of the calorimeter disk and it is a mechanical support for the boards and also part of the thermal circuit. The distributing system of the refrigerant fluid for the whole calorimeter has been analysed too. Then the manufacturing solutions of the crates and the components for the thermal path have been developed. At the end, the main experimental tests have been presented. They are going to be realized in the next months

Autonomous Satellite Operations Via Secure Virtual Mission Operations Center

The science community is interested in improving their ability to respond to rapidly evolving, transient phenomena via autonomous rapid reconfiguration, which derives from the ability to assemble separate but collaborating sensors and data forecasting systems to meet a broad range of research and application needs. Current satellite systems typically require human intervention to respond to triggers from dissimilar sensor systems. Additionally, satellite ground services often need to be coordinated days or weeks in advance. Finally, the boundaries between the various sensor systems that make up such a Sensor Web are defined by such things as link delay and connectivity, data and error rate asymmetry, data reliability, quality of service provisions, and trust, complicating autonomous operations. Over the past ten years, researchers from the NASA Glenn Research Center (GRC), General Dynamics, Surrey Satellite Technology Limited (SSTL), Cisco, Universal Space Networks (USN), the U.S. Geological Survey (USGS), the Naval Research Laboratory, the DoD Operationally Responsive Space (ORS) Office, and others have worked collaboratively to develop a virtual mission operations capability. Called VMOC (Virtual Mission Operations Center), this new capability allows cross-system queuing of dissimilar mission unique systems through the use of a common security scheme and published application programming interfaces (APIs). Collaborative VMOC demonstrations over the last several years have supported the standardization of spacecraft to ground interfaces needed to reduce costs, maximize space effects to the user, and allow the generation of new tactics, techniques and procedures that lead to responsive space employment

Doing it Well: Education to Promote Satisfaction with Sexual Intimacy for People with Spinal Cord Injury

Physical and psychosocial effects of a spinal cord injury may lead to concerns and difficulty with sexual satisfaction, exploration, and arousal as well as diminished confidence with participation in intimate relationships (Craig Hospital, 2012). Current research indicates a decreased level of satisfaction with participation in sexual intimacy for adults with spinal cord injury (Fisher et al., 2002). Occupational therapists have a key role in the rehabilitation of individuals with spinal cord injury, and sexuality is an area of occupation which falls within our scope of practice (AOTA, 2008). Therefore it is necessary that occupational therapists are assertive in addressing the needs of this population through patient education in order to promote participation in this meaningful activity of daily living. A systematic review was conducted to explore the literature addressing the efficacy of patient education in order to promote satisfaction with participation in sexual intimacy for adults with spinal cord injury. Following a database search including CINHAL, PubMed, Medline and OTSearch, seventeen articles were reviewed pertaining to sexuality after spinal cord injury. These included only peer reviewed articles written in English within the past 15 years involving adults (18 years and older) with spinal cord injury (Level S4 and above). All articles were critiqued using Law & MacDermid (2008) critical review forms. Findings indicate a need for further research to identify the needs of adults living with SCI in the area of sexuality and intimacy, especially within the occupational therapy literature. More specifically, themes emerged including satisfaction with sexual intimacy pre and post injury, experiences with sexual education following injury, the unmet needs of women and recommendations for rehabilitation programs. The findings will allow for a more holistic and effective approach to sexual rehabilitation programs for this population, as there is a recurrent theme of dissatisfaction with current practices across disciplines. References: American Occupational Therapy Association. (2008). Occupational therapy practice framework: Domain and process (2nd ed.). American Journal of Occupational Therapy, 62, 625-683. Craig Hospital. (2012). Sexual function for men after spinal cord injury. Englewood, Colorado. Fisher, T., Laud, P., Byfield, M., Brown, T., Hayat, M., & Fiedler, I. (2002). Sexual Health After Spinal Cord Injury: A Longitudinal Study. Archives of Physical Medicine and Rehabilitation, 83, 1043 - 1051

Bringing People to Good Food and Good Food to People: Enhancing food access through transportation and land use policies

This report examined links between transportation and food access in South Los Angeles and recommends ways to increase access to healthy food through transportation and land use programs and policies. The report is the product of Food Access and Transportation in South Los Angeles project, a collaboration between the Community Redevelopment Agency of the City of Los Angeles (CRA/LA), the Urban & Environmental Policy Institute at Occidental College (UEPI), and Esperanza Community Housing Corporation (Esperanza). The recommendations were developed through research of best practices and policies throughout the country; surveys of food retail stores and mobile food vendors in the project area; mapping of food retail locations and transportation routes in the project area; and the experiences of the project partners in working on food access issues in low-income communities in Los Angeles

PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites.

Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility