Study of the Immune Correlates of Protection in Rhesus Macaques Vaccinated against Simian Immunodeficiency Virus

After more than thirty years since the Human Immunodeficiency Virus (HIV) was identified, only the RV144 phase III vaccine clinical trial provided evidence of protection from virus infection, with 31.2% of the patients protected at three years since the end of the immunisation phase. Statistical analyses support serum IgG antibody recognition of the V2 region of viral gp120 as a mechanism of protection from acquisition. One hypothesis is that antibodies to this region might block the interaction with the integrin $\alpha4\beta7$, which protrudes from the surface of mucosal CD4+ T cells and is thought to capture the virus and facilitate infection. However, that $\alpha4\beta7$ blocking might be a protective mechanism of RV144 vaccination has yet to be definitively demonstrated. In this thesis, I aimed to describe at the molecular level the immune mechanisms of protection in a rhesus macaque (Macaca mulatta) vaccinated in an RV144-like schedule and protected from Simian Immunodeficiency Virus (SIV) infection, with a particular focus on the humoral immune response of the animal. More specifically, vaccine-induced monoclonal antibodies (mAbs) directed against the V2 region of SIV were isolated and characterised. One of them, NCI09, has been identified as a potent inhibitor of SIV gp120 interaction with human $\alpha4\beta7$. Notably, NCI09 antigen recognition is negatively affected by the presence of ITS41, a mAb targeting a distant epitope on V2. Moreover, to experimentally prove this mechanism I performed the passive immunoprophylaxis of rhesus macaques using the anti-V2 mAb ITS09. Unfortunately, this mAb proved ineffective in providing protection both alone and in combination. Finally, a vaccination protocol based on the immunisation regimen of RV144, but modified to elicit stronger immune responses was tested. Surprisingly, the protocol failed to afford protection. However, in a parallel group immunised with the standard RV144 regimen, protection was observed and correlated with the intensity of the innate immune responses. These results provide insights into possible mechanisms of protection of RV144 vaccination against HIV. Furthermore, these findings suggest that there may be a degree of structural plasticity of the V2 region that may impact its interaction with $\alpha4\beta7$ and evasion mechanisms from a potentially protective humoral immune response

Possible future monoclonal antibody (mAb)-based therapy against arbovirus infections

More than 150 arboviruses belonging to different families are known to infect humans, causing endemic infections as well as epidemic outbreaks. Effective vaccines to limit the occurrence of some of these infections have been licensed, while for the others several new immunogens are under development mostly for their improvements concerning safety and effectiveness profiles. On the other hand, specific and effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. Neutralizing monoclonal antibodies (mAbs) have been demonstrated to be effective in the treatment of several infectious diseases as well as in preliminary in vitro and in vivo models of arbovirus-related infections. Given their specific antiviral activity as well-tolerated molecules with limited side effects, mAbs could represent a new therapeutic approach for the development of an effective treatment, as well as useful tools in the study of the host-virus interplay and in the development of more effective immunogens. However, before their use as candidate therapeutics, possible hurdles (e.g., Ab-dependent enhancement of infection, occurrence of viral escape variants) must be carefully evaluated. In this review are described the main arboviruses infecting humans and candidate mAbs to be possibly used in a future passive immunotherapy

COVID-19 lockdown impact on familial relationships and mental health in a large representative sample of Italian adults

Purpose: Benefits of national-level stay-at-home order imposed in Italy to prevent SARS-CoV-2 transmission need to be carefully weighed against its impact on citizens' health. In a country with a strong familial culture and where welfare relies on households, confinement drastically decreased support provided by elder relatives, which may have resulted in mental health worsening. Methods: A web-based cross-sectional study (LOST in Italy) was conducted on a representative sample of Italian adults during lockdown (27th of April-3rd of May 2020). We asked 3156 subjects to report on reduced help in housework and childcare from retired parents to assess the impact of confinement on mental health, through validated scales before and during lockdown. Results: Overall, 1484 (47.0%) subjects reported reduced housework help from parents, and 769 (64.0%, of the 1202 subjects with children) diminished babysitting support. Subjects reporting reduced housework help had worsened sleep quality (multivariate odds ratio, OR = 1.74, 95% confidence interval, CI 1.49-2.03) and quantity (OR = 1.50, 95% CI 1.28-1.76), depressive (OR = 1.32, 95% CI 1.14-1.53) and anxiety symptoms (OR = 1.53, 95% CI 1.32-1.78), compared to those reporting unreduced help. Worsening in sleep quality (OR = 2.32, 95% CI 1.76-3.05), and quantity (OR = 1.80, 95% CI 1.36-2.37), depressive (OR = 1.79, 95% CI 1.39-2.31) and anxiety symptoms (OR = 1.90, 95% CI 1.48-2.46) was also associated with reduced babysitting help. Mental health outcomes were worse in subjects with poorer housing and teleworking during lockdown. Conclusion: Confinement came along with reduced familial support from parents, negatively impacting household members' mental health. Our findings might inform evidence-based family and welfare policies to promote population health within and beyond pandemic times

Task 1 - Deliverable 7: Strong motion data base

Database dati accelerometriciProgetto DPC-INGV S6 “Data base dei dati accelerometrici Italiani relativi al periodo 1972-2004"Published5.2. TTC - Banche dati di sismologia strumentaleope

Genome-wide mapping of 8-oxo-7,8-dihydro-2'-deoxyguanosine reveals accumulation of oxidatively-generated damage at DNA replication origins within transcribed long genes of mammalian cells

8-Oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) is one of the major DNA modifications and a potent pre-mutagenic lesion prone to mispair with 2- deoxyadenosine (dA). Several thousand residues of 8-oxodG are constitutively generated in the genome of mammalian cells, but their genomic distribution has not yet been fully characterized. Here, by using OxiDIP-Seq, a highly sensitive methodology that uses immuno-precipitation with efficient anti– 8-oxodG antibodies combined with high-throughput sequencing, we report the genome-wide distribution of 8-oxodG in human non-tumorigenic epithelial breast cells (MCF10A), and mouse embryonic fibroblasts (MEFs). OxiDIP-Seq revealed sites of 8- oxodG accumulation overlapping with H2AX ChIPSeq signals within the gene body of transcribed long genes, particularly at the DNA replication origins contained therein. We propose that the presence of persistent single-stranded DNA, as a consequence of transcription-replication clashes at these sites, determines local vulnerability to DNA oxidation and/or its slow repair. This oxidatively-generated damage, likely in combination with other kinds of lesion, might contribute to the formation of DNA double strand breaks and activation of DNA damage response

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde