Electronic systems for intelligent particle tracking in the High Energy Physics field

This Ph.D thesis describes the development of a novel readout ASIC for hybrid pixel detector with intelligent particle tracking capabilities in High Energy Physics (HEP) application, called Macro Pixel ASIC (MPA). The concept of intelligent tracking is introduced for the upgrade of the particle tracking system of the Compact Muon Solenoid (CMS) experiment of the Large Hadron Collider (LHC) at CERN: this detector must be capable of selecting at front--end level the interesting particle and of providing them continuously to the back-end. This new functionality is required to cope with the improved performances of the LHC when, in about ten years' time, a major upgrade will lead to the High Luminosity scenario (HL-LHC). The high complexity of the digital logic for particle selection and the very low power requirement of 95% in particle selection and a data reduction from 200 Tb/s/cm2 to 1 Tb/s/cm2. A prototype, called MPA-Light, has been designed, produced and tested. According to the measurements, the prototype respects all the specications. The same device has been used for multi-chip assembly with a pixelated sensor. The assembly characterization with radioactive sources conrms the result obtained on the bare chip

Clonal tracking of Glioma progression

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glioblastoma models driven by different mutations converge to the proneural subtype

Abstract The need of reliable syngeneic animal models for gliomas has been addressed in the last decades by reproducing genetic alterations typical of human glioblastoma in the mouse. Since different alterations underlie different molecular glioblastoma subtypes it is commonly expected that tumors induced by specific alterations represent models of the corresponding subtypes. We tested this assumption by a multilevel analysis ranging from a detailed histopathological analysis to a genome-wide expression profiling by microarray and RNA-seq on gliomas induced by two distinct molecular alterations: the overstimulation of the PDGF- and the EGF- pathways. These alterations are landmarks of proneural and classical glioblastoma subtypes respectively. However, our results consistently showed a strong similarity between the two glioma models. The expression profiles of both models converged toward a signature typical of oligodendrocyte progenitor cells, regardless the wide differentiative potential of the cell of origin. A classification based on similarity with human gliomas profiles revealed that both models belong to the proneural subtype. Our results highlight that reproducing a molecular alteration specific of a glioblastoma subtype not necessarily generates a tumor model recapitulating such subtype

Investigating the Paracrine Role of Perinatal Derivatives: Human Amniotic Fluid Stem Cell-Extracellular Vesicles Show Promising Transient Potential for Cardiomyocyte Renewal

Cardiomyocyte renewal represents an unmet clinical need for cardiac regeneration. Stem cell paracrine therapy has attracted increasing attention to resurge rescue mechanisms within the heart. We previously characterized the paracrine effects that human amniotic fluid-derived stem cells (hAFSC) can exert to provide cardioprotection and enhance cardiac repair in preclinical models of myocardial ischemia and cardiotoxicity. Here, we analyze whether hAFSC secretome formulations, namely, hAFSC conditioned medium (hAFSC-CM) over extracellular vesicles (hAFSC-EVs) separated from it, can induce cardiomyocyte renewal. c-KIT+ hAFSC were obtained by leftover samples of II trimester prenatal amniocentesis (fetal hAFSC) and from clinical waste III trimester amniotic fluid during scheduled C-section procedures (perinatal hAFSC). hAFSC were primed under 1% O2 to enrich hAFSC-CM and EVs with cardioactive factors. Neonatal mouse ventricular cardiomyocytes (mNVCM) were isolated from cardiac tissue of R26pFUCCI2 mice with cell cycle fluorescent tagging by mutually exclusive nuclear signal. mNVCM were stimulated by fetal versus perinatal hAFSC-CM and hAFSC-EVs to identify the most promising formulation for in vivo assessment in a R26pFUCCI2 neonatal mouse model of myocardial infarction (MI) via intraperitoneal delivery. While the perinatal hAFSC secretome did not provide any significant cardiogenic effect, fetal hAFSC-EVs significantly sustained mNVCM transition from S to M phase by 2-fold, while triggering cytokinesis by 4.5-fold over vehicle-treated cells. Treated mNVCM showed disorganized expression of cardiac alpha-actinin, suggesting cytoskeletal re-arrangements prior to cell renewal, with a 40% significant downregulation of Cofilin-2 and a positive trend of polymerized F-Actin. Fetal hAFSC-EVs increased cardiomyocyte cell cycle progression by 1.8-fold in the 4-day-old neonatal left ventricle myocardium short term after MI; however, such effect was lost at the later stage. Fetal hAFSC-EVs were enriched with a short isoform of Agrin, a mediator of neonatal heart regeneration acting by YAP-related signaling; yet in vitro application of YAP inhibitor verteporfin partially affected EV paracrine stimulation on mNVCM. EVs secreted by developmentally juvenile fetal hAFSC can support cardiomyocyte renewal to some extension, via intercellular conveyance of candidates possibly involving Agrin in combination with other factors. These perinatal derivative promising cardiogenic effects need further investigation to define their specific mechanism of action and enhance their potential translation into therapeutic opportunity

Pix-ESL: a SystemC framework for architectural modelling of readout systems in HEP

The high cost of prototyping at advanced technology nodes, as well as the complexity of future detectors, necessitate the use of a system design technique widely used in industry: design space exploration through high-level architecture studies to establish precise and optimal requirements. This work presents Pix-ESL: a programmable SystemC framework for simulating the readout chain from the front-end chips to the detector back-end. The model is transaction accurate, comprises an event generator and connects with real-world physics events, and provides metrics such as readout efficiency, latency, and average queue occupancy. This contribution outlines the framework's structure as well as a case study based on Velopix2

Readout architecture for the Pixel-Strip module of the CMS Outer Tracker Phase-2 upgrade

The Outer Tracker upgrade of the Compact Muon Solenoid (CMS) experiment at CERN introduces new challenges for the front-end readout electronics. In particular, the capability of identifying particles with high transverse momentum using modules with double sensor layers requires high speed real time interconnects between readout ASICs. The Pixel-Strip module combines a pixelated silicon layer with a silicon-strip layer. Consequently, it needs two different readout ASICs, namely the Short Strip ASIC (SSA) for the strip sensor and the Macro Pixel ASIC (MPA) for the pixelated sensor. The architecture proposed in this paper allows for a total data flow between readout ASICs of $\sim$100\,Gbps and reduces the output data flow from 1.3\,Tbps to 30\,Gbps per module while limiting the total power density to below 100\,mW/cm$^2$. In addition a system-level simulation framework of all the front-end readout ASICs is developed in order to verify the data processing algorithm and the hardware implementation allowing multichip verification with performance evaluation. Finally, power consumption and efficiency performance are estimated and reported for the described readout architecture

System Level simulation framework for the ASICs development of a novel particle physics detector

The simulation of the passage of particles through matter using Monte Carlo methods is broadly used in the development of particle detectors for high energy physics experiments. To develop the readout electronics for the Compact Muon Solenoid (CMS) experiment at CERN, and to assist the design of the on-detector ASICs, a simulation framework was build capable to link the physics Monte Carlo simulations platforms with an industry standard EDA simulation tools. This contribution focuses on the implementation of the simulation framework based on the System Verilog language and the Universal Verification Methodology (UVM). The simulation results that guided the development of the ASICs and the choice of the final architecture are presented

Noninvasive Monitoring of Glioma Growth in the Mouse

Malignant gliomas are the most common and deadly primary malignant brain tumors. In vivo orthotopic models could doubtless represent an appropriate tool to test novel treatment for gliomas. However, methods commonly used to monitor the growth of glioma inside the mouse brain are time consuming and invasive. We tested the reliability of a minimally invasive procedure, based on a secreted luciferase (Gaussia luciferase), to frequently monitor the changes of glioma size. Gluc activity was evaluated from blood samples collected from the tail tip of mice twice a week, allowing to make a growth curve for the tumors. We validated the correlation between Gluc activity and tumor size by analysing the tumor after brain dissection. We found that this method is reliable for monitoring human glioma transplanted in immunodeficient mice, but it has strong limitation in immunocompetent models, where an immune response against the luciferase is developed during the first weeks after transplant