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

Conceptually driven and visually rich tasks in texts and teaching practice: the case of infinite series

The study we report here examines parts of what Chevallard calls the institutional dimension of the students’ learning experience of a relatively under-researched, yet crucial, concept in Analysis, the concept of infinite series. In particular, we examine how the concept is introduced to students in texts and in teaching practice. To this purpose, we employ Duval's Theory of Registers of Semiotic Representation towards the analysis of 22 texts used in Canada and UK post-compulsory courses. We also draw on interviews with in-service teachers and university lecturers in order to discuss briefly teaching practice and some of their teaching suggestions. Our analysis of the texts highlights that the presentation of the concept is largely a-historical, with few graphical representations, few opportunities to work across different registers (algebraic, graphical, verbal), few applications or intra-mathematical references to the concept's significance and few conceptually driven tasks that go beyond practising with the application of convergence tests and prepare students for the complex topics in which the concept of series is implicated. Our preliminary analysis of the teacher interviews suggests that pedagogical practice often reflects the tendencies in the texts. Furthermore, the interviews with the university lecturers point at the pedagogical potential of: illustrative examples and evocative visual representations in teaching; and, student engagement with systematic guesswork and writing explanatory accounts of their choices and applications of convergence tests

Insegnare nell'era INVALSI

Il forum ha come scopo fare il punto sulle problematiche che condizionano i processi di apprendimento/insegnamento nello scenario delineato dall'introduzione delle prove INVALS

WebGIS as boundary tools between scientific geoinformation and disaster risk reduction action in volcanic areas

As the amount of spatial data is growing, there is increased interest in developing tools to explore, visualize and interpret them, with the final aim of informing decision making efficiently. Within the European MIAVITA project, we examined this issue in the case of volcanic areas, where existing geospatial databases are particularly complex due to the number of threats to be considered, including volcanic (e.g. lava flows, ash fall) and non-volcanic hazards, such as landslides or tsunamis. We involved a group of hazard and risk analysts and managers, civil security officers, GIS analysts and system developers to design a Web-based geographical information system (WebGIS). We tested the system at the Mount Cameroon volcano, taking advantage of a complex hazard and risk geographical database. This study enabled identifying key requirements for such tools in volcanic areas, such as the need to manage user privileges differently according to their profile and the status of the volcano. This work also highlights that, in addition to the development of large geoinformation clearinghouses, there is a need for site-specific information systems focused on working procedures of users, in order to fill the last gap between data producers and users

Prognostic value of18 f-choline pet/ct in patients with metastatic castration-resistant prostate cancer treated with radium-223

We aimed to investigate the role of positron emission computed tomography (PET/CT) with F-18-choline for predicting the outcome of metastatic castration-resistant prostate cancer (mCRPC) submitted to treatment with Radium-223 (Ra-223-therapy). Clinical records of 20 mCRPC patients submitted to PET/CT with F-18-choline before Ra-223-therapy were retrospectively evaluated. The following PET-derived parameters were calculated: number of lesions, maximum and mean standardized uptake values (SUVmax, SUVmean), lean body mass corrected SUV peak (SULpeak), metabolic tumor volume (MATV), and total lesion activity (TLA). After Ra-223-therapy, all patients underwent regular follow-up until death. The predictive power of clinical and PET-derived parameters on overall survival (OS) was assessed by Kaplan-Meier analysis and the Cox proportional hazard method. All the patients showed F-18-choline-avid lesions at baseline PET/CT. Among the enrolled subjects, eleven (55%) completed all the six scheduled cycles of Ra-223-therapy; seven (35%) were responders according to imaging and biochemical parameters. Mean OS was 12.7 +/- 1.4 months: by Kaplan-Meier analysis, number of lesions, PSA level and TLA were significantly correlated with OS. In multivariate Cox analysis, TLA remained the only significant predictor of survival (p = 0.003; hazard ratio = 7.6, 95% confidence interval = 1.9-29.5 months). F-18-choline PET may be useful for patients' stratification before Ra-223-therapy. In particular, high metabolically active tumor burden (i.e., TLA) was predictive of poor outcome

Systematic review and discussion of production control systems that emerged between 1999 and 2018

There exists a large literature on well-known Production Control Systems (PCS) such as Kanban, Constant Work-In-Process (CONWIP), Material Requirements Planning (MRP) and Paired Cell Overlapping Loops of Cards with Authorisation (POLCA). However, there are also many new systems that have emerged in the last 20 years. These systems are less well known, and no systematic review exists. Through a systematic literature review, 13 PCS’s were identified, such as COBACABANA, REDUTEX, BK-CONWIP and B-CONWIP. For each system, we describe its characteristics, how they work and in what productive environments it proves useful. A cross-comparison of the 13 systems was then conducted using seven variables: primary control variable (WIP or throughput), degree of centralisation, material flow (productive environment), whether it was introduced as card-based, types of authorizations, number of articles published and type of articles published (theoretical or empirical). Most new PCS’s (7 out of 13) show characteristics that are similar to Kanban, CONWIP and POLCA: they are decentralised, card-based and use WIP as primary control variable. This may be a result of the strong influence of Lean Manufacturing paradigms Meanwhile, there is a general lack of empirical studies, being 11 PCS’s developed from mathematical simulations

LISA test mass charging process due to cosmic ray nuclei and electrons

none10noolar energetic particles and galactic cosmic rays with energies larger than 100 MeV cause progressive charging of the LISA experiment test masses. Consequently, Coulomb forces occur between the test masses and the surrounding conducting surfaces generating spurious signals that might be mistaken for gravitational wave signals. We have parametrized the energy spectra of galactic cosmic-ray nuclei and electrons near the LISA orbit in order to evaluate their role in the test-mass charging relative to the most abundant proton component. This work has been carried out using the FLUKA Monte Carlo program.openC. GRIMANI; H. VOCCA; G. BAGNI; L. MARCONI; R. STANGA; F. VETRANO; A. VICERÉ; P. AMICO; L. GAMMAITONI; F. MARCHESONIGrimani, Catia; H., Vocca; G., Bagni; L., Marconi; R., Stanga; Vetrano, Flavio; Vicere', Andrea; P., Amico; L., Gammaitoni; F., Marcheson

Cost of noninfectious comorbidities in patients with HIV

OBJECTIVES: We hypothesized that the increased prevalence of noninfectious comorbidities (NICMs) observed among HIV-infected patients may result in increased direct costs of medical care compared to the general population. Our objective was to provide estimates of and describe factors contributing to direct costs for medical care among HIV-infected patients, focusing on NICM care expenditure. METHODS: A case-control study analyzing direct medical care costs in 2009. Antiretroviral therapy (ART)-experienced HIV-infected patients (cases) were compared to age, sex, and race-matched adults from the general population, included in the CINECA ARNO database (controls). NICMs evaluated included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. Medical care cost information evaluated included pharmacy, outpatient, and inpatient hospital expenditures. Linear regression models were constructed to evaluate predictors of total care cost for the controls and cases. RESULTS: There were 2854 cases and 8562 controls. Mean age was 46 years and 37% were women. We analyzed data from 29,275 drug prescription records. Positive predictors of health care cost in the overall population: HIV infection (β = 2878; confidence interval (CI) = 2001-3755); polypathology (β = 8911; CI = 8356-9466); age (β = 62; CI = 45-79); and ART exposure (β = 18,773; CI = 17,873-19,672). Predictors of health care cost among cases: Center for Disease Control group C (β = 1548; CI = 330-2766); polypathology (β = 11,081; CI = 9447-12,716); age < 50 years (β = 1903; CI = 542-3264); protease inhibitor exposure (per month of use; β = 69; CI = 53-85); CD4 count < 200 cells/mm3 (β = 5438; CI = 3082-7795); and ART drug change (per change; β = 911; CI = 716-1106). CONCLUSION: Total cost of medical care is higher in cases than controls. Lower medical costs associated with higher CD4 strata are offset by increases in the care costs needed for advancing age, particularly for NICMs