The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators

The activation of CD4(+) T helper cells is strictly dependent on the presentation of antigenic peptides by MHC class II (MHC-II) molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Besides this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 (human T cell lymphotropic virus type 1) and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolutio

Typing of a polymorphic human gene conferring susceptibility to insulin-dependent diabetes mellitus by picosecond-resolved FRET on non-purified/non-amplified genomic DNA

This work concerns the identification of the alleles of the polymorphic DQB1 gene of the human leukocyte antigen system, conferring susceptibility to the development of insulin-dependent diabetes mellitus (IDDM) in non-PCR amplified DNA samples and, more importantly, in crude cell extracts. Our method is based on the time-resolved analysis of a F\uf6rster energy-transfer mechanism that occurs in a dual-labelled fluorescent probe specific for the IDDM-associated DQB1-0201 allele. Such an oligonucleotide probe is labelled, at the two ends, by a pair of chromophores that operate as donor and acceptor in a F\uf6rster resonant energy transfer. The donor fluorescence is quenched with an efficiency that is strongly dependent on the donor-to-acceptor distance, hence on the configuration of the probe after hybridization with the various DQB1 alleles. By time-correlated single-photon counting, performed with an excitation/detection system endowed with 30-ps resolution, we measure the time-resolved fluorescence decay of the donor and discriminate, by means of the decaytime value, the DNA bearing the 'susceptible' allele from the DNAs bearing any other sequence in the same region of the DQB1 gene. We could also distinguish the presence of the DQB1-0201 allele in a homozygous versus a heterozygous condition

Brain tissue properties differentiate between motor and limbic basal ganglia circuits

Despite advances in understanding basic organizational principles of the human basal ganglia, accurate in vivo assessment of their anatomical properties is essential to improve early diagnosis in disorders with corticosubcortical pathology and optimize target planning in deep brain stimulation. Main goal of this study was the detailed topological characterization of limbic, associative, and motor subdivisions of the subthalamic nucleus (STN) in relation to corresponding corticosubcortical circuits. To this aim, we used magnetic resonance imaging and investigated independently anatomical connectivity via white matter tracts next to brain tissue properties. On the basis of probabilistic diffusion tractography we identified STN subregions with predominantly motor, associative, and limbic connectivity. We then computed for each of the nonoverlapping STN subregions the covariance between local brain tissue properties and the rest of the brain using high-resolution maps of magnetization transfer (MT) saturation and longitudinal (R1) and transverse relaxation rate (R2*). The demonstrated spatial distribution pattern of covariance between brain tissue properties linked to myelin (R1 and MT) and iron (R2*) content clearly segregates between motor and limbic basal ganglia circuits. We interpret the demonstrated covariance pattern as evidence for shared tissue properties within a functional circuit, which is closely linked to its function. Our findings open new possibilities for investigation of changes in the established covariance pattern aiming at accurate diagnosis of basal ganglia disorders and prediction of treatment outcom

GIADA performance during Rosetta mission scientific operations at comet 67P

The Grain Impact Analyser and Dust Accumulator (GIADA) instrument onboard Rosetta studied the dust environment of comet 67P/Churyumov–Gerasimenko from 3.7 au inbound, through perihelion, to 3.8 au outbound, measuring the dust flow and the dynamic properties of individual particles. GIADA is composed of three subsystems: 1) Grain Detection System (GDS); 2) Impact Sensor (IS); and 3) Micro-Balances System (MBS). Monitoring the subsystems’ performance during operations is an important element for the correct calibration of scientific measurements. In this paper, we analyse the GIADA inflight calibration data obtained by internal calibration devices for the three subsystems during the period from 1 August 2014 to 31 October 2015. The calibration data testify a nominal behaviour of the instrument during these fifteen months of mission; the only exception is a minor loss of sensitivity for one of the two GDS receivers, attributed to dust contamination

The dust-to-ices ratio in comets and Kuiper belt objects

Comet 67P/Churyumov-Gerasimenko (67P hereinafter) is characterized by a dust transfer from the southern hemi-nucleus to the night-side northern dust deposits, which constrains the dust-to-ices mass ratio inside the nucleus to values a factor of 2 larger than that provided by the lost mass of gas and non-volatiles. This applies to all comets because the gas density in all night comae cannot prevent the dust fallback. Taking into account Grain Impact Analyser and Dust Accumulator (GIADA) data collected during the entire Rosetta mission, we update the average dust bulk density to ρD=785 +520/−115 $\rho {}{}_{\rm D} = 785_{-115}^{+520}$ kg m$^-3$ that, coupled to the 67P nucleus bulk density, confirms an average dust-to-ices mass ratio δ = 7.5 inside 67P. The improved dust densities are consistent with a mixture of (20 ± 8) per cent of ices, (4 ± 1) per cent of Fe sulphides, (22 ± 2) per cent of silicates and (54 ± 5) per cent of hydrocarbons, on average volume abundances. These values correspond to solar chemical abundances, as suggested by the elemental C/Fe ratio observed in 67P. The ice content in 67P matches that inferred in Kuiper belt objects, (20 ± 12) per cent on average volume abundance and suggests a water content in all trans-Neptunian objects lower than in CI chondrites. The 67P icy pebbles and the dust collected by GIADA have a microporosity of (49 ± 5) and (59 ± 8) per cent, respectively

Mucosal immune response after the booster dose of the BNT162b2 COVID-19 vaccine

Background: To date, only a few studies reported data regarding the development of mucosal immune response after the BNT162b2-booster vaccination. Methods: Samples of both serum and saliva of 50 healthcare workers were collected at the day of the booster dose (T3) and after two weeks (T4). Anti-S1-protein IgG and IgA antibody titres and the neutralizing antibodies against the Wuhan wild-type Receptor-Binding Domain in both serum and saliva were measured by quantitative and competitive ELISA, respectively. Data were compared with those recorded after the primary vaccination cycle (T2). Neutralizing antibodies against the variants of concern were measured in those individuals with anti-Wuhan neutralizing antibodies in their saliva. Findings: After eight months from the second dose, IgG decreased in both serum (T2GMC: 23,838.5 ng/ml; T3GMC: 1473.8 ng/ml) and saliva (T2GMC: 12.9 ng/ml; T3GMC: 0.3 ng/ml). Consistently, serum IgA decreased (T2GMC: 48.6 ng/ml; T3GMC: 6.4 ng/ml); however, salivary IgA showed a different behaviour and increased (T2GMC: 0.06 ng/ml; T3GMC: 0.41 ng/ml), indicating a delayed activation of mucosal immunity. The booster elicited higher titres of both IgG and IgA when compared with the primary cycle, in both serum (IgG T4GMC: 98,493.9 ng/ml; IgA T4GMC: 187.5 ng/ml) and saliva (IgG T4GMC: 21.9 ng/ml; IgA T4GMC: 0.65 ng/ml). Moreover, the booster re-established the neutralizing activity in the serum of all individuals, not only against the Wuhan wild-type antigen (N = 50; INH: 91.6%) but also against the variants (Delta INH: 91.3%; Delta Plus INH: 89.8%; Omicron BA.1 INH: 85.1%). By contrast, the salivary neutralizing activity was high against the Wuhan antigen in 72% of individuals (N = 36, INH: 62.2%), but decreased against the variants, especially against the Omicron BA.1 variant (Delta N = 27, INH: 43.1%; Delta Plus N = 24, INH: 35.2%; Omicron BA.1 N = 4; INH: 4.7%). This was suggestive for a different behaviour of systemic immunity observed in serum with respect to mucosal immunity described in saliva (Wald chi-square test, 3 df of interaction between variants and sample type = 308.2, p < 0.0001). Interpretation: The BNT162b2-booster vaccination elicits a strong systemic immune response but fails in activating an effective mucosal immunity against the Omicron BA.1 variant. Funding: This work was funded by the Department of Medicine and Surgery, University of Insubria, and supported by Fondazione Umberto Veronesi (COVID-19 Insieme per la ricerca di tutti, 2020), Italy