EU project UPGRADE (No 724036) - measurements of a Jeep Renegade prototype vehicle by JRC

Within Work Package 5 of the H2020 project UPGRADE (High efficient Particulate free Gasoline Engines) http://www.upgrade-project.eu/, JRC tested a demonstrator vehicle specifically developed by Centro Ricerche Fiat (CRF) in WLTP conditions. The results showed that: 1. All pollutants were below the EURO 6 limits. 2. Particle number emissions were two orders of magnitude below the limit of 6*10^11/km. PN10 were in average 13% higher than PN23. 3. CO2 emissions were on average 165.3 g/km.JRC.C.4-Sustainable Transpor

Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons

The phosphorylation of Amyloid Precursor Protein (APP) at Thr668 plays a key role in APP metabolism that is highly relevant to AD. The c-Jun-N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (Cdk5) can all be responsible for this phosphorylation. These kinases are activated by excitotoxic stimuli fundamental hallmarks of AD. The exposure of cortical neurons to a high dose of NMDA (100 μM) for 30'-45' led to an increase of P-APP Thr668. During NMDA stimulation APP hyperphosphorylation has to be assigned to GSK-3β activity, since addition of L803-mts, a substrate competitive inhibitor of GSK-3β reduced APP phosphorylation induced by NMDA. On the contrary, inhibition of JNK and Cdk5 with D-JNKI1 and Roscovitine respectively did not prevent NMDA-induced P-APP increase. These data show a tight connection, in excitotoxic conditions, between APP metabolism and the GSK-3β signaling pathway

Assessment of on-road emissions of refuse collection vehicles

One of the most challenging issues for building sustainable cities is the improvement of municipal solid waste (MSW) management, which requires a substantial effort to reduce its production and improve its collection, transport and treatment systems. Modern (Euro VI) heavy-duty vehicles have significantly lower emissions compared to older vehicles. However, there are still concerns regarding the emissions of refuse collection vehicles in cities, because they use engines designed for long haulage trucks and consequently not optimised for low speed stop and start driving. The very low average speeds and the frequent stops represent difficult conditions to cope with from the emission reduction perspective. In fact, for short periods, where the exhaust gas temperature is low for the aftertreatment devices (cold start, some city conditions), the emissions are relatively high. In an effort to provide insight on the optimal future planning and renewal of the Milan waste collection vehicle fleet, the Joint Research Centre (JRC) of the European Commission (EC), in collaboration with the Azienda Milanese Servizi Ambientali (AMSA), initiated an on-road emission testing campaign. The aim of this extensive experimental study, performed both under real and laboratory controlled operating conditions was to identify the actual emission levels of the waste collection vehicles, comparing two different engine technologies (diesel and natural gas fuelled engines) and assess the environmental efficiency of the different engines solutions. For this purpose, we tested a Diesel Euro VI step C and a Compressed Natural Gas (CNG) Euro VI step C refuse collection heavy-duty vehicle both in the laboratory and on the road using a cycle similar to the in-service conformity (ISC) trips for this type of vehicles (N3). The vehicles were also tested using actual refuse collection cycles. The idea was to directly compared the two vehicles’ engine technology to evaluate the performance and the pollutant emissions under realistic and controlled operating conditions in order to support a fleet renewal initiative in the city of Milan. Particle and gaseous pollutants were measured using a Portable Emissions Measurement System (PEMS). Additionally, in the laboratory we used laboratory grade gaseous, particle number and FTIR (Fourier-transform infrared spectroscopy) systems to measure the emissions and check the proper operation of the PEMS. The present work summarizes the results of the aforementioned experimental activity lead on two vehicles (one Diesel and one Compressed Natural Gas), which were tested in three different phases using a portable emission measurement system. The first phase included a similar In-Service Conformity test (ISC_LIKE) and a city simulation cycle (CITY_SIM), the second part involved real world operation in the city of Milan, whilst a third phase was dedicated to the comparison lab test in confined conditions. This report will address only the road comparison, while the laboratory tests and the relative comparison together with the real world findings will be object of a future report. Focusing on CITY_MILAN cycle, which is the most representative of the real in-use conditions, THC calculated emission factors were two orders of magnitude lower in Diesel engine (0.79 mg/kWh) than in CNG (73.49 mg/kWh), even if we have to consider a different limit for CNG engines. Continuing with the analysis of “Urban” routes, CNG truck showed NOX emission nearly 4 times higher than the Diesel (755.31 mg/kWh vs 157.10 mg/kWh), exceeding the reference limits. The CNG engine PN levels were 3 times higher than in Diesel one. Including also the regeneration events in the Diesel vehicle, the emissions increased the PN significantly, but it still remained below the limit of 6×10^11 particle/kWh. In the metropolitan cycle (CITY_MILAN) CNG truck has a CO emission reduction of -85 % compared to the Diesel one, with respectively 40.92 and 320.30 mg/kWh. Nevertheless, CO emissions of both tested vehicles appear to be at very low levels, abundantly below the reference limits (4000 mg/kWh). This trends did not vary significantly among the different routes. In general, Diesel technology presented important advantages with regards to the NOX, PN, CO2 emissions as compared to the CNG engine, while the CNG vehicle provided a better CO emission behaviour. This trade off needs to be carefully analysed prior to decide if a fleet should be shifted towards either technology, mainly because is based only to a limited comparison between the two considered vehicles. Therefore, the conclusions drawn in this report are only valid for the tested vehicles and they cannot be extrapolated or generalised for a larger fleet of vehicles.JRC.C.4 - Sustainable Transpor

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

Chronic BACE-1 Inhibitor Administration in TASTPM Mice (APP KM670/671NL and PSEN1 M146V Mutation): An EEG Study

Objective: In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer's disease (AD) amyloid neuropathology as compared to wild type (WT) mice. Methods: Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. Results: Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). Conclusions: The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers

Detection of prion seeding activity in the olfactory mucosa of patients with Fatal Familial Insomnia

Fatal Familial Insomnia (FFI) is a genetic prion disease caused by a point mutation in the prion protein gene (PRNP) characterized by prominent thalamic atrophy, diffuse astrogliosis and moderate deposition of PrP Sc in the brain. Here, for the first time, we demonstrate that the olfactory mucosa (OM) of patients with FFI contains trace amount of PrP Sc detectable by PMCA and RT-QuIC. Quantitative PMCA analysis estimated a PrP Sc concentration of about 1 \uc3\u97 10-14g/ml. In contrast, PrP Sc was not detected in OM samples from healthy controls and patients affected by other neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and frontotemporal dementia. These results indicate that the detection limit of these assays is in the order of a single PrP Sc oligomer/molecule with a specificity of 100%

The Efficacy of Tetracyclines in Peripheral and Intracerebral Prion Infection

We have previously shown that tetracyclines interact with and reverse the protease resistance of pathological prion protein extracted from scrapie-infected animals and patients with all forms of Creutzfeldt-Jakob disease, lowering the prion titre and prolonging survival of cerebrally infected animals. To investigate the effectiveness of these drugs as anti-prion agents Syrian hamsters were inoculated intramuscularly or subcutaneously with 263K scrapie strain at a 10−4 dilution. Tetracyclines were injected intramuscularly or intraperitoneally at the dose of 10 mg/kg. A single intramuscular dose of doxycycline one hour after infection in the same site of inoculation prolonged median survival by 64%. Intraperitoneal doses of tetracyclines every two days for 40 or 44 days increased survival time by 25% (doxycycline), 32% (tetracycline); and 81% (minocycline) after intramuscular infection, and 35% (doxycycline) after subcutaneous infection. To extend the therapeutic potential of tetracyclines, we investigated the efficacy of direct infusion of tetracyclines in advanced infection. Since intracerebroventricular infusion of tetracycline solutions can cause overt acute toxicity in animals, we entrapped the drugs in liposomes. Animals were inoculated intracerebrally with a 10−4 dilution of the 263K scrapie strain. A single intracerebroventricular infusion of 25 µg/ 20 µl of doxycycline or minocycline entrapped in liposomes was administered 60 days after inoculation, when 50% of animals showed initial symptoms of the disease. Median survival increased of 8.1% with doxycycline and 10% with minocycline. These data suggest that tetracyclines might have therapeutic potential for humans

European market surveillance of motor vehicles

This report presents the results for the work conducted by the JRC as European Commission contribution to the first year of market surveillance and regarding emissions from motor vehicles. The document is structured in three main chapters: the requirements and methodologies for their verification (Part A), the test results and compliance outcome for the activities conducted by the Commission (Part B) and an overview of the main findings (Part C). Part A focuses on the requirements to be fulfilled by the vehicles and provides the main elements, further details being available in the regulatory texts. For some requirements, the verification cannot be made using the type approval procedure (e.g. durability, OBD). In such a case, ad-hoc procedures are proposed and are likely to be revised on a yearly basis making use of the experience gained. Part B presents the emissions test results and compliance findings for the individual vehicles analysed by the JRC during the last year. Part C is a summary of the findings and a tentative to draw recommendations from the lessons learnt, with a view to identifying the most critical items (e.g. which requirements have the highest risk not to be fulfilled) and to improving the efficiency of the whole process.JRC.C.4 - Sustainable Transpor