Elisa Fontanesi

Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm-aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act.

Down Syndrome (DS) is characterized by a wide spectrum of clinical signs, which include segmental premature aging of central nervous and immune systems.Although it is well established that the causative defect of DS is the trisomy of chromosome 21, the molecular bases of its phenotype are still largely unknown.We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 DS persons, using their relatives (mothers and unaffected siblings) as controls.This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors.Although differentially methylated regions (DMRs) displayed a genome-wide distribution, they were enriched on chromosome 21.DMRs mapped in genes involved in developmental functions, including embryonic development (HOXA family) and haematological (RUNX1 and EBF4) and neuronal (NCAM1) development.Moreover, genes involved in the regulation of chromatin structure (PRMD8, KDM2B, TET1) showed altered methylation.The data also showed that several pathways are affected in DS, including PI3K-Akt signaling.In conclusion, we identified an epigenetic signature of DS that sustains a link between developmental defects and disease phenotype, including segmental premature aging.www.impactaging.

Aging is characterized by a profound remodeling of the epigenetic architecture in terms of DNA methylation patterns. To date the most effective tool to study genome wide DNA methylation changes is Infinium HumanMethylation450 BeadChip (Infinium 450k). Despite the wealth of tools for Infinium 450k analysis, the identification of the most biologically relevant DNA methylation changes is still challenging. Here we propose an analytical pipeline to select differentially methylated regions (DMRs), tailored on microarray architecture, which is highly effective in highlighting biologically relevant results. The pipeline groups microarray probes on the basis of their localization respect to CpG islands and genic sequences and, depending on probes density, identifies DMRs through a single-probe or a region-centric approach that considers the concomitant variation of multiple adjacent CpG probes. We successfully applied this analytical pipeline on 3 independent Infinium 450k datasets that investigated age-associated changes in blood DNA methylation. We provide a consensus list of genes that systematically vary in DNA methylation levels from 0 to 100 years and that have a potentially relevant role in the aging process.

Natural epigenetic diversity has been suggested as a key mechanism in microevolutionary processes due to its capability to create phenotypic variability within individuals and populations. It constitutes an important reservoir of variation potentially useful for rapid adaptation in response to environmental stimuli. The analysis of population epigenetic structure represents a possible tool to study human adaptation and to identify external factors that are able to naturally shape human DNA methylation variability. The aim of this study is to investigate the dynamics that create epigenetic diversity between and within different human groups. To this end, we first used publicly available epigenome-wide data to explore population-specific DNA methylation changes that occur at macro-geographic scales. Results from this analysis suggest that nutrients, UVA exposure and pathogens load might represent the main environmental factors able to shape DNA methylation profiles. Then, we evaluated DNA methylation of candidate genes (KRTCAP3, MAD1L1, and BRSK2), emerged from the previous analysis, in individuals belonging to different populations from Morocco, Nigeria, Philippines, China, and Italy, but living in the same Italian city. DNA methylation of the BRSK2 gene is significantly different between Moroccans and Nigerians (pairwise t-test: CpG 6 P-value = 5.2*10 (-) (3); CpG 9 P-value = 2.6*10 (-) (3); CpG 10 P-value = 3.1*10 (-) (3); CpG 11 P-value = 2.8*10 (-) (3)). Comprehensively, these results suggest that DNA methylation diversity is a source of variability in human groups at macro and microgeographical scales and that population demographic and adaptive histories, as well as the individual ancestry, actually influence DNA methylation profiles.

The series of upgrades to the Large Hadron Collider, culminating in the High Luminosity Large Hadron Collider, will enable a significant expansion of the physics program of the CMS experiment. However, the accelerator upgrades will also make the experimental conditions more challenging, with implications for detector operations, triggering, and data analysis. The luminosity of the proton-proton collisions is expected to exceed $2-3\times10^{34}$~cm$^{-2}$s$^{-1}$ for Run 3 (starting in 2022), and it will be at least $5\times10^{34}$~cm$^{-2}$s$^{-1}$ when the High Luminosity Large Hadron Collider is completed for Run 4. These conditions will affect muon triggering, identification, and measurement, which are critical capabilities of the experiment. To address these challenges, additional muon detectors are being installed in the CMS endcaps, based on Gas Electron Multiplier technology. For this purpose, 161 large triple-Gas Electron Multiplier detectors have been constructed and tested. Installation of these devices began in 2019 with the GE1/1 station and will be followed by two additional stations, GE2/1 and ME0, to be installed in 2023 and 2026, respectively. The assembly and quality control of the GE1/1 detectors were distributed across several production sites around the world. We motivate and discuss the quality control procedures that were developed to standardize the performance of the detectors, and we present the final results of the production. Out of 161 detectors produced, 156 detectors passed all tests, and 144 detectors are now installed in the CMS experiment. The various visual inspections, gas tightness tests, intrinsic noise rate characterizations, and effective gas gain and response uniformity tests allowed the project to achieve this high success rate.

Little is known about the impact of space (geography/ancestry) and time (age of the individuals) on DNA methylation variability in humans. We investigated DNA methylation of the imprinted IGF2/H19 locus in: i) a cohort of individuals homogeneous for age and gender (males with restricted age range: 30-50 years) belonging to four Italian districts representative of the major genetic clines, informative for the geographical dimension; ii) a cohort of monozygotic (MZ) and dizygotic (DZ) twins of different ages (age-range: 22-97 years), informative for the temporal dimension. DNA methylation of the analyzed regions displayed high levels of inter-individual variability that could not be ascribed to any geographical cline. In MZ twins we identified two IGF2/H19 regions where the intra-couple variations significantly increased after the age of 60 years. The analysis of twins' individual life histories suggests that the within twin pairs difference is likely the result of the aging process itself, as sharing a common environment for long periods had no effect on DNA methylation divergence. On the whole, the data here reported suggest that: i) aging more than population genetics is responsible for the inter-individual variability in DNA methylation patterns in humans; ii) DNA methylation variability appears to be highly region-specific.

Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm- aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act. Keywords: Inflammation, aging, centenarians, cell senescence, immunosenescence, immunological stimuli, pro-inflammatory mediators, markers, inflamm-aging, longevity

Triple-GEM detector technology was recently selected by CMS for a part of the upgrade of its forward muon detector system as GEM detectors provide a stable operation in the high radiation environment expected during the future High-Luminosity phase of the Large Hadron Collider (HL-LHC). In a first step, GEM chambers (detectors) will be installed in the innermost muon endcap station in the $1.6<\left|\eta\right|<2.2$ pseudo-rapidity region, mainly to control level-1 muon trigger rates after the second LHC Long Shutdown. These new chambers will add redundancy to the muon system in the $\eta$-region where the background rates are high, and the bending of the muon trajectories due to the CMS magnetic field is small. A novel construction technique for such chambers has been developed in such a way where foils are mounted onto a single stack and then uniformly stretched mechanically, avoiding the use of spacers and glue inside the active gas volume. We describe the layout, the stretching mechanism and the overall assembly technique of such GEM chambers.

The high-luminosity phase of the Large Hadron Collider (HL-LHC) will result in ten times higher particle background than measured during the first phase of LHC operation. In order to fully exploit the highly-demanding operating conditions during HL-LHC, the Compact Muon Solenoid (CMS) Collaboration will use Gas Electron Multiplier (GEM) detector technology. The technology will be integrated into the innermost region of the forward muon spectrometer of CMS as an additional muon station called GE1∕1. The primary purpose of this auxiliary station is to help in muon reconstruction and to control level-1 muon trigger rates in the pseudo-rapidity region 1.6≤|η|≤2.2. The new station will contain trapezoidal-shaped GEM detectors called GE1∕1 chambers. The design of these chambers is finalized, and the installation is in progress during the Long Shutdown phase two (LS-2) that started in 2019. Several full-size prototypes were built and operated successfully in various test beams at CERN. We describe performance measurements such as gain, efficiency, and time resolution of these prototype chambers, developed after years of R&D, and summarize their behavior in different gas compositions as a function of the applied voltage.

IDEA (Innovative Detector for Electron–positron Accelerators) is a detector concept designed for a future leptonic collider operating as a Higgs factory. It is based on innovative detector technologies developed over years of R&D. In September 2018, prototypes of the proposed sub-detectors have been tested for the first time on a beam line at CERN. The preliminary results from this test of a full slice of the IDEA detector and standalone measurements of dual read-out calorimeter prototypes are presented.

Gas Electron Multiplier (GEM) technology, in particular triple-GEM, was selected for the upgrade of the CMS endcap muon system following several years of intense effort on R&D. The triple-GEM chambers (GE1/1) are being installed at station 1 during the second long shutdown with the goal of reducing the Level-1 muon trigger rate and improving the tracking performance in the harsh radiation environment foreseen in the future LHC operation [1]. A first installation of a demonstrator system started at the beginning of 2017: 10 triple-GEM detectors were installed in the CMS muon system with the aim of gaining operational experience and demonstrating the integration of the GE1/1 system into the trigger. In this context, a dedicated Detector Control System (DCS) has been developed, to control and monitor the detectors installed and integrating them into the CMS operation. This paper presents the slice test DCS, describing in detail the different parts of the system and their implementation.

The CMS muon system in the region with 2.03<|η|<2.82 is characterized by a very harsh radiation environment which can generate hit rates up to 144 kHz/cm2 and an integrated charge of 8 C/cm2 over ten years of operation. In order to increase the detector performance and acceptance for physics events including muons, a new muon station (ME0) has been proposed for installation in that region. The technology proposed is Triple—Gas Electron Multiplier (Triple-GEM), which has already been qualified for the operation in the CMS muon system. However, an additional set of studies focused on the discharge probability is necessary for the ME0 station, because of the large radiation environment mentioned above. A test was carried out in 2017 at the Cern High energy AcceleRator Mixed (CHARM) facility, with the aim of giving an estimation of the discharge probability of Triple-GEM detectors in a very intense radiation field environment, similar to the one of the CMS muon system. A dedicated standalone Geant4 simulation was performed simultaneously, to evaluate the behavior expected in the detector exposed to the CHARM field. The geometry of the detector has been carefully reproduced, as well as the background field present in the facility. This paper presents the results obtained from the Geant4 simulation, in terms of sensitivity of the detector to the CHARM environment, together with the analysis of the energy deposited in the gaps and of the processes developed inside the detector. The discharge probability test performed at CHARM will be presented, with a complete discussion of the results obtained, which turn out to be consistent with measurements performed by other groups.

Aging | doi:10.18632/aging.100915. Maria Giulia Bacalini, Alessio Boattini, Davide Gentilini, Enrico Giampieri, Chiara Pirazzini, Cristina Giuliani, Elisa Fontanesi, Daniel Remondini, Miriam Capri, Alberto Del Rio, Donata Luiselli, Giovanni Vitale, Daniela Mari, Gastone Castellani, Anna Maria Di Blasio, Stefano Salvioli, Claudio Franceschi, Paolo Garagnani

Abstract A temperature monitoring system based on fibre Bragg grating (FBG) fibre optic sensors has been developed for the gas electron multiplier (GEM) chambers of the Compact Muon Solenoid (CMS) detector. The monitoring system was tested in prototype chambers undergoing a general test of the various technological solutions adopted for their construction. The test lasted about two years and was conducted with the chambers being installed in the CMS detector and operated during regular experimental running. In this paper, we present test results that address the choice of materials and procedures for the production and installation of the FBG temperature monitoring system in the final GEM chambers.

We present analytical calculations, Finite Element Analysis modelling, and physical measurements of the interstrip capacitances for different potential strip geometries and dimensions of the readout boards for the GE2/1 triple-Gas Electron Multiplier detector in the CMS muon system upgrade. The main goal of the study is to find configurations that minimize the interstrip capacitances and consequently maximize the signal-to-noise ratio for the detector. We find agreement at the 1.5–4.8% level between the two methods of calculations and on the average at the 17% level between calculations and measurements. A configuration with halved strip lengths and doubled strip widths results in a measured 27–29% reduction over the original configuration while leaving the total number of strips unchanged. We have now adopted this design modification for all eight module types of the GE2/1 detector and will produce the final detector with this new strip design.

Persons affected by Down Syndrome show a heterogeneous phenotype that includes developmental defects and cognitive and haematological disorders. Premature accelerated aging and the consequent development of age associated diseases like Alzheimer Disease (AD) seem to be the cause of higher mortality late in life of DS persons. Down Syndrome is caused by the complete or partial trisomy of chromosome 21, but it is not clear if the molecular alterations of the disease are triggered by the specific functions of a limited number of genes on chromosome 21 or by the disruption of genetic homeostasis due the presence of a trisomic chromosome. As epigenomic studies can help to shed light on this issue, here we used the Infinium HumanMethilation450 BeadChip to analyse blood DNA methylation patterns of 29 persons affected by Down syndrome (DSP), using their healthy siblings (DSS) and mothers (DSM) as controls. In this way we obtained a family-based model that allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. We showed that defects in DNA methylation map in genes involved in developmental, neurological and haematological pathways. These genes are enriched on chromosome 21 but localize also in the rest of the genome, suggesting that the trisomy of specific genes on chromosome 21 induces a cascade of events that engages many genes on other chromosomes and results in a global alteration of genomic function. We also analysed the methylation status of three target regions localized at the promoter (Ribo) and at the 5’ sequences of 18S and 28S regions of the rDNA, identifying differently methylated CpG sites. In conclusion, we identified an epigenetic signature of Down Syndrome in blood cells that sustains a link between developmental defects and disease phenotype, including segmental premature aging.

The CMS experiment at the Large Hadron Collider (LHC) features a sophisticated two-level triggering system composed of the Level 1 (L1) trigger, instrumented by custom-design hardware boards, and the High Level Trigger (HLT), a software based trigger exploiting a complete event information and full detector resolution. The CMS L1 trigger relies on separate calorimeter and muon trigger systems that provide jet, e/$\gamma$, $\tau$, and muon candidates along with calculations of energy sums to the global trigger (GT), where selections are based on the candidate kinematics. During Run 2, the L1 trigger hardware was entirely upgraded to handle proton-proton collisions at a center-of-mass energy of 13~TeV with a peak instantaneous luminosity of $2.2 \times 10^{34}$~$\textrm{cm}^{-2}\textrm{s}^{-1}$, more than double the design luminosity of the machine. In view of Run 3 of the LHC, an optimized selection at both the L1 trigger and HLT is crucial to achieving the ambitious CMS physics program. A wide range of measurements and searches will profit from the new features and strategies implemented in the trigger system. Dedicated variables and non-standard trigger techniques to target long-lived particles searches and identify unconventional physics signatures have been developed. Moreover, the implementation of new kinematic computations in the L1 GT will improve b physics measurements and resonance searches. This talk will present these new features and their expected performance measured on benchmark physics signals.

The measurement of the Higgs self-interaction is an important test of the Standard Model (SM) electroweak symmetry breaking sector. Sensitivity to the Higgs self-coupling for m$_{H}$ = 125 GeV is evaluated through the measurement of the non-resonant di-Higgs production final states in proton-proton collisions at a future hadron collider with a center-of-mass energy of 100 TeV. The parton-level generation of the signal and the backgrounds is performed by using MadGraph5$\_$aMC@NLO; then, the Delphes framework is used for a fast parametrization of the FCC-hh detector response. The considered decay channels are $HH \to VVb\bar{b}$, where $V=Z,W$. For the non-resonant SM signal in an ideal detector parametrization, a precision of O(10%-20%) on the SM cross-section can be estimated in the $b\bar{b}ZZ(4l)$ and $b\bar{b}WW(l\nu jj)$, respectively, corresponding to a precision of O(14%-40%) on the Higgs trilinear coupling.

Prospects for the study of Higgs boson pair (HH) production in the HH → b b4l (l = e, µ) channel are studied in the context of the High Luminosity LHC.The analysis is performed using a parametric simulation of the Phase-2 CMS detector response provided by the Delphes software and assuming an average of 200 proton-proton collisions per bunch crossing at a center-of-mass energy of 14 TeV.Assuming a projected integrated luminosity of 3000 fb -1 , the expected significance for the nonresonant standard model (SM) HH signal is 0.37 σ ; a 95% confidence level (CL) upper limit on its cross section is set to 6.6 times the SM prediction.The statistical combination of five decay channels (b bb b, b bττ, b bγγ, b bWW, b bZZ) results in an expected significance for the SM HH signal of 2.6 σ and an expected 68% and 95% CL intervals for the self-coupling modifier κ λ = λ HHH /λ SM HHH of [0.35, 1.9] and [-0.18, 3.6], respectively.

CERN-ACC-2018-004517 March 2019Higgs and Electro-weak symmetry breaking at the FCC-hhL. Borgonovi∗, S. Braibant∗, B. Di Micco†, E. Fontanesi∗, P. Harris‡, C. Helsens§, D. Jamin§,M.L. Mangano§, G. Ortona¶, M. Selvaggi1)§, A. Sznajder‖, M. Testa¶, M. Verducci¶On behalf of the FCC-hh Collaboration∗Universita di Bologna, Italy,†Universita degli Studi Roma Tre, Italy,‡Massachusetts Institute of Technology (MIT), Cambridge, USA,§European Organization for Nuclear Research (CERN), Geneva, Switzerland,¶Laboratoire Leprince-Ringuet, Ecole Polytechnique (LLR), Palaiseau, France,‖Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, BrazilAbstractThe future circular hadron-hadron collider FCC-hh is expected to produce collisions at thecenter of mass energy of√s=100 TeV and to deliver an integrated luminosity of 30 ab−1.The Higgs-self coupling will be measured with a 5% precision via double Higgs production.Tens of billions of Higgs bosons will be produced at the FCC-hh. Such large statisticswill allow for a wide range of possibilities in the realm of precision Higgs measurements.Several Higgs couplings will be measured to a percent level precision, including the secondgeneration muon yukawa coupling. The Higgs to invisible branching fraction will be probedto a level of few 10−4and the rate of longitudinally polarized vector bosons produced invector boson scattering will be measured with 2% precision.

The discussion of this thesis is dedicated to the precision measurements of the Higgs (H) boson properties, spanning from the study of the H boson decaying into four leptons with the CMS experiment at the Large Hadron Collider (LHC) to the future investigation of the H boson sector at large lepton colliders. The H → ZZ* → 4l (l=e,μ) decay channel offers an optimal way to study the H boson profile, playing a central role since the time of the discovery. Properties of the H boson are measured exploiting the total amount of data produced in proton-proton collisions at the LHC during Run 2. The dataset collected by the CMS experiment at a center-of-mass energy of 13 TeV corresponds to an integrated luminosity of 137 fb−1. The inclusive signal strength modifier and the signal strength modifiers for the main H boson production modes are reported. In addition, results within the framework of the Simplified Template Cross Sections are produced to explore the different H boson production mechanisms in specific kinematic regions of the phase space. The inclusive fiducial cross section for the H → 4l process is presented and the differential cross sections as a function of the transverse momentum and rapidity of the four-lepton system, the transverse momentum of the leading jet, and the jet multiplicity are shown. All results are found to be in agreement with the SM predictions. Along the way, the perspectives offered by future colliders in the exploration of the Higgs sector and an overview of the different projects of future machines and experiments are also presented. A large focus is reserved for the ongoing development of the design of a detector proposal called IDEA (Innovative Detector for Electron-positron Accelerators), specifically intended for the future H boson factory colliders.

The Phase-II high luminosity upgrade to the Large Hadron Collider (LHC) is planned for 2023, significantly increasing the collision rate and therefore the background rate, particularly in the high $\eta$ region. To improve both the tracking and triggering of muons, the Compact Muon Solenoid (CMS) Collaboration plans to install triple-layer Gas Electron Multiplier (GEM) detectors in the CMS muon endcaps. Demonstrator GEM detectors were installed in CMS during 2017 to gain operational experience and perform a preliminary investigation of detector performance. We present the results of triple-GEM detector performance studies performed in situ during normal CMS and LHC operations in 2018. The distribution of cluster size and the efficiency to reconstruct high $p_T$ muons in proton--proton collisions are presented as well as the measurement of the environmental background rate to produce hits in the GEM detector.

Abstract In 2018, a system of large-size triple-GEM demonstrator chambers was installed in the CMS experiment at CERN's Large Hadron Collider (LHC). The demonstrator's design mimicks that of the final detector, installed for Run-3. A successful Monte Carlo (MC) simulation of the collision-induced background hit rate in this system in proton-proton collisions at 13 TeV is presented. The MC predictions are compared to CMS measurements recorded at an instantaneous luminosity of 1.5 ×10 34 cm -2 s -1 . The simulation framework uses a combination of the FLUKA and GEANT4 packages. FLUKA simulates the radiation environment around the GE1/1 chambers. The particle flux by FLUKA covers energy spectra ranging from 10 -11 to 10 4 MeV for neutrons, 10 -3 to 10 4 MeV for γ's, 10 -2 to 10 4 MeV for e ± , and 10 -1 to 10 4 MeV for charged hadrons. GEANT4 provides an estimate of the detector response (sensitivity) based on an accurate description of the detector geometry, the material composition, and the interaction of particles with the detector layers. The detector hit rate, as obtained from the simulation using FLUKA and GEANT4, is estimated as a function of the perpendicular distance from the beam line and agrees with data within the assigned uncertainties in the range 13.7-14.5%. This simulation framework can be used to obtain a reliable estimate of the background rates expected at the High Luminosity LHC.