A Framework for Analysis and Expansion of Public Charging Infrastructure under Fast Penetration of Electric Vehicles

The improvement commercial competitiveness of private electric vehicles supported by the European policy for the decarbonisation of transport and with the consumers awareness-raising about CO2 emissions and climate change, are driving the increase of electric vehicles on the roads. Therefore, public charging networks are facing the challenge of supply electricity to a fast increasing number of electric cars. The objective of this paper is to establish an assessment framework for analysis and monitor of existing charging networks. The developed methodology comprises modelling the charging infrastructure electricity profile, analysing the data by using machine learning models such as functional k-means clustering and defining a novel congestion metric. The described framework has been tested against Irish public charging network historical datasets. The analyses reveal a lack of reliability of the communication network infrastructure, frequent congestion events for commercial and shopping areas in specific clusters of charge points and the presence of power peaks caused by the high number of simultaneous charging events. Several recommendations for future network expansion have been highlighted

Increased platelet adhesion and thrombus formation in a mouse model of Alzheimer's disease

Vascular dysfunctions and Alzheimer's disease show significant similarities and overlaps. Cardiovascular risk factors (hypercholesterolemia, hypertension, obesity, atherosclerosis and diabetes) increase the risk of vascular dementia and Alzheimer's disease. Conversely, Alzheimer's patients have considerably increased predisposition of ischemic and hemorrhagic strokes. Platelets are major players in haemostasis and thrombosis and are involved in inflammation. We have investigated morphology and function of platelets in 3xTg-AD animals, a consolidate murine model for Alzheimer's disease. Platelets from aged 3xTg-AD mice are normal in number and glycoprotein expression, but adhere more avidly on matrices such as fibrillar collagen, von Willebrand factor, fibrinogen and amyloid peptides compared to platelets from age-matching wild type mice. 3xTg-AD washed platelets adherent to collagen also show increased phosphorylation of selected signaling proteins, including tyrosine kinase Pyk2, PI3 kinase effector Akt, p38MAP kinase and myosin light chain kinase, and increased ability to form thrombi under shear. In contrast, aggregation and integrin αIIbβ3 activation induced by several agonists in 3xTg-AD mice are similar to wild type platelets. These results demonstrated that Alzheimer's mutations result in a significant hyper-activated state of circulating platelets, evident with the progression of the disease

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Search for space charge effects in the ICARUS T600 LAr-TPC

Space charge in Liquid Argon Time Projection Chamber is due to the accumu- lation of positive ions, produced by ionizing tracks crossing the detector, which slowly flow toward the cathode. As a consequence, electric field distortions may arise, thus hindering the possibility to produce faithful 3D images of the ionizing events. The presence of space charge becomes relevant for large TPCs operating at surface or at shallow depths, where cosmic ray flux is high. These effects could interest the next phase of the ICARUS T600 detector, which will be deployed at shallow depths as a Far Detector for Short Baseline Neutrino experiment at FNAL dedicated to sterile neutrino searches. In 2001, the first ICARUS T600 module (T300) operated at surface in Pavia (Italy), recording cosmic ray data. In this work, a sample of cosmic muon tracks from the 2001 run was analyzed and results on space charge effects in LAr-TPCs are shown

Effects of electric and magnetic fields on the event reconstruction in the ICARUS T600 detector

In recent years, a number of anomalies in neutrino oscillation scenario were observed, that point out to possible non-standard oscillations which could imply the existence of a fourth (or more) sterile neutrino. Its existence, or absence, calls for a definitive clarification with new data. In particular, the Short Baseline Neutrino program at FNAL, will exploit three Liquid Argon Time Projection Chamber (LAr TPC) detectors along the Booster Neutrino Beamline. Each detector has different mass and a different position: the near detector SBND is the smallest, the intermediate detector MicroBooNE is the medium sized while the biggest one is the far detector, the ICARUS T600. This Ph.D. thesis is focused on the ICARUS T600 detector, the largest LAr TPC ever built, which concluded successfully the operation at LNGS in Italy. Here it was exposed at underground conditions to the CNGS beam to study oscillations. After the CNGS shut down, the detector continued taking data with cosmic rays until it was de-commissioned and transported to CERN, where it is now under refurbishment, before moving to FNAL. In a LAr TPC, when a charged particle crosses the detector, ionizing electrons are drifted towards the wire anode planes, where they are collected providing two spatial coordinates of the track; arrays of PMTs detect scintillation light, providing the measurement of the absolute time of occurrence that, combined with the knowledge of the drift velocity, permits the determination of the third coordinate of the track, that along the drift direction. The goal of the ICARUS reconstruction procedure is to extract, in an accurate way, all the physical information contained in the wire and PMT output signals, to build a complete 3D spatial and calorimetric picture of the event. To have this faithful event reconstruction, it is mandatory to determine wire and drift coordinates accurately and so it is essential to understand everything that could distort the information. The uniformity of electric field is essential in order to ensure a uniform drift velocity and thus the proportionality between drift time and drift coordinate. Electric field distortions may arise by a local accumulation, along the drift path, of positive ions, which are drifted towards the cathode more slowly than the electrons. This accumulation is emphasised by high interaction rate, given for example by high cosmic ray flux. This problem, called space charge, could be present at FNAL, where the ICARUS detector will be placed at shallow depths. In order to understand the influence of this effect in track reconstruction, a data sample is analysed, collected when the detector was at surface condition for a test run in Pavia. In the thesis are described the parameters used to study space charge effects in the ICARUS detector and the obtained results are illustrated. As stated before, the drift coordinate precision is derived by the electrons drifted towards the wire planes and it is affected by several factors, such as the diffusion. To evaluate the diffusion parameter, a dedicated run with different electric field values was performed collecting cosmic rays at the end of LNGS run. The analysis of these data samples is pointed out, considering the dependence of the width of the signal registered by the TPC. The ICARUS Collaboration is also involved in a long time project, called DUNE (Deep Underground Neutrino Experiment): it will be a long baseline experiment, with modular kiloton LAr-TPCs, to be built in the next 20 years. The T600 could be used as Near Detector, once provided with a magnetic field for particle momentum measurements and charged particle identification. The presence of a magnetic field introduces new parameters and possibilities for the reconstruction procedure. In this framework, an algorithm is developed, in order to discriminate between electron neutrino and electron antineutrino, considering their interaction products.In recent years, a number of anomalies in neutrino oscillation scenario were observed, that point out to possible non-standard oscillations which could imply the existence of a fourth (or more) sterile neutrino. Its existence, or absence, calls for a definitive clarification with new data. In particular, the Short Baseline Neutrino program at FNAL, will exploit three Liquid Argon Time Projection Chamber (LAr TPC) detectors along the Booster Neutrino Beamline. Each detector has different mass and a different position: the near detector SBND is the smallest, the intermediate detector MicroBooNE is the medium sized while the biggest one is the far detector, the ICARUS T600. This Ph.D. thesis is focused on the ICARUS T600 detector, the largest LAr TPC ever built, which concluded successfully the operation at LNGS in Italy. Here it was exposed at underground conditions to the CNGS beam to study oscillations. After the CNGS shut down, the detector continued taking data with cosmic rays until it was de-commissioned and transported to CERN, where it is now under refurbishment, before moving to FNAL. In a LAr TPC, when a charged particle crosses the detector, ionizing electrons are drifted towards the wire anode planes, where they are collected providing two spatial coordinates of the track; arrays of PMTs detect scintillation light, providing the measurement of the absolute time of occurrence that, combined with the knowledge of the drift velocity, permits the determination of the third coordinate of the track, that along the drift direction. The goal of the ICARUS reconstruction procedure is to extract, in an accurate way, all the physical information contained in the wire and PMT output signals, to build a complete 3D spatial and calorimetric picture of the event. To have this faithful event reconstruction, it is mandatory to determine wire and drift coordinates accurately and so it is essential to understand everything that could distort the information. The uniformity of electric field is essential in order to ensure a uniform drift velocity and thus the proportionality between drift time and drift coordinate. Electric field distortions may arise by a local accumulation, along the drift path, of positive ions, which are drifted towards the cathode more slowly than the electrons. This accumulation is emphasised by high interaction rate, given for example by high cosmic ray flux. This problem, called space charge, could be present at FNAL, where the ICARUS detector will be placed at shallow depths. In order to understand the influence of this effect in track reconstruction, a data sample is analysed, collected when the detector was at surface condition for a test run in Pavia. In the thesis are described the parameters used to study space charge effects in the ICARUS detector and the obtained results are illustrated. As stated before, the drift coordinate precision is derived by the electrons drifted towards the wire planes and it is affected by several factors, such as the diffusion. To evaluate the diffusion parameter, a dedicated run with different electric field values was performed collecting cosmic rays at the end of LNGS run. The analysis of these data samples is pointed out, considering the dependence of the width of the signal registered by the TPC. The ICARUS Collaboration is also involved in a long time project, called DUNE (Deep Underground Neutrino Experiment): it will be a long baseline experiment, with modular kiloton LAr-TPCs, to be built in the next 20 years. The T600 could be used as Near Detector, once provided with a magnetic field for particle momentum measurements and charged particle identification. The presence of a magnetic field introduces new parameters and possibilities for the reconstruction procedure. In this framework, an algorithm is developed, in order to discriminate between electron neutrino and electron antineutrino, considering their interaction products

Search for space charge effects in the ICARUS T600 LAr-TPC

Space charge in Liquid Argon Time Projection Chamber is due to the accumu- lation of positive ions, produced by ionizing tracks crossing the detector, which slowly flow toward the cathode. As a consequence, electric field distortions may arise, thus hindering the possibility to produce faithful 3D images of the ionizing events. The presence of space charge becomes relevant for large TPCs operating at surface or at shallow depths, where cosmic ray flux is high. These effects could interest the next phase of the ICARUS T600 detector, which will be deployed at shallow depths as a Far Detector for Short Baseline Neutrino experiment at FNAL dedicated to sterile neutrino searches. In 2001, the first ICARUS T600 module (T300) operated at surface in Pavia (Italy), recording cosmic ray data. In this work, a sample of cosmic muon tracks from the 2001 run was analyzed and results on space charge effects in LAr-TPCs are shown

Characterization of SiPM arrays in different series and parallel configurations

A number of innovative experiments dedicated to neutrino and rare-event physics use liquefied noble-gases both as a target and as a detector. These media have the remarkable property to efficiently produce scintillation photons after the passage of ionizing particles. Scintillation light, which is used for triggering and timing purposes, is traditionally detected by large area Photo-Multiplier Tubes (PMTs) working at cryogenic temperature. Silicon Photo-Multiplier (SiPM) arrays are gradually substituting PMTs in many applications, especially where low voltages are required and magnetic field is present. One of the problems of this devices is the small active area. For this reason we built several prototype arrays made by different SiPM models with a common readout: the basic unit is a device with an active area of (1.2×1.2)cm2 . A fast signal leading edge is crucial to realize devices to be used for triggering and timing. To this purpose we studied different series/parallel electrical configurations to obtain the best timing performance, by operating our custom arrays both at room and cryogenic temperatures

Molecular mechanisms of platelet activation and aggregation induced by breast cancer cells

Tumor cell-induced platelet aggregation represents a critical process both for successful metastatic spread of the tumor and for the development of thrombotic complications in cancer patients. To get further insights into this process, we investigated and compared the molecular mechanisms of platelet aggregation induced by two different breast cancer cell lines (MDA-MB-231 and MCF7) and a colorectal cancer cell line (Caco-2). All the three types of cancer cells were able to induce comparable platelet aggregation, which, however, was observed exclusively in the presence of CaCl2 and autologous plasma. Aggregation was supported both by fibrinogen binding to integrin αIIbβ3 as well as by fibrin formation, and was completely prevented by the serine protease inhibitor PPACK. Platelet aggregation was preceded by generation of low amounts of thrombin, possibly through tumor cells-expressed tissue factor, and was supported by platelet activation, as revealed by stimulation of phospholipase C, intracellular Ca2+ increase and activation of Rap1b GTPase. Pharmacological inhibition of phospholipase C, but not of phosphatidylinositol 3-kinase or Src family kinases prevented tumor cell-induced platelet aggregation. Tumor cells also induced dense granule secretion and the stimulation of the P2Y12 receptor by released ADP was found to be necessary for complete platelet aggregation. By contrast, prevention of thromboxane A2 synthesis by aspirin did not alter the ability of all the cancer cell lines analyzed to induce platelet aggregation. These results indicate that tumor cell-induced platelet aggregation is not related to type of the cancer cells or to their metastatic potential, and is triggered by platelet activation and secretion driven by the generation of small amount of thrombin from plasma and supported by the positive feedback signaling through secreted ADP

Novel pharmacological inhibitors demonstrate the role of the tyrosine kinase Pyk2 in adhesion and aggregation of human platelets

Pyk2 is a Ca(2+)-regulated kinase predominantly expressed in neuronal and in haematopoietic cells. Previous studies on Pyk2-null mice have demonstrated that Pyk2 plays a crucial role in platelet activation and thrombus formation, thus representing a possible target for antithrombotic therapy. Very limited information is available about the role of Pyk2 in human platelets, mainly because of the lack of specific pharmacological inhibitors. In this work, we have tested two novel Pyk2 inhibitors, PF-4594755 and PF-4520440, to validate their specificity and to investigate their ability to modulate platelet activation. Both molecules were able to efficiently block Pyk2 activity in human and mouse platelets stimulated with thrombin or with the Ca(2+)-ionophore. In wild-type murine platelets, PF-4594755 and PF-4520440 reduced thrombin-induced aggregation to the level observed in Pyk2 knockout platelets, but did not affect aggregation induced by GPVI stimulation. Importantly, neither compounds affected the residual thrombin-induced aggregation of Pyk2-null platelets, thus excluding possible off-target effects. In human platelets, PF-4594755 and PF-4520440 significantly reduced aggregation stimulated by thrombin, but not by the GPVI agonist convulxin. Both inhibitors reduced platelet adhesion on fibrinogen and prevented Akt phosphorylation in adherent cells, indicating that Pyk2 regulates PI3K and cell spreading downstream of integrins in human platelets. Finally, the Pyk2 inhibitors significantly inhibited thrombus formation upon blood perfusion on immobilized collagen under arterial flow rate. These results demonstrate that PF-4594755 and PF-4520440 are specific inhibitors of Pyk2 in intact platelets and allowed to reliably document that this kinase plays a relevant role in human platelet activation