Methylome Profiling in Fabry Disease in Clinical Practice: A Proof of Concept

Anderson–Fabry disease (FD) is an X-linked disease caused by a functional deficit of the α-galactosidase A enzyme. FD diagnosis relies on the clinical manifestations and research of GLA gene mutations. However, because of the lack of a clear genotype/phenotype correlation, FD diagnosis can be challenging. Recently, several studies have highlighted the importance of investigating DNA methylation patterns for confirming the correct diagnosis of different rare Mendelian diseases, but to date, no such studies have been reported for FD. Thus, in the present investigation, we analyzed for the first time the genome-wide methylation profile of a well-characterized cohort of patients with Fabry disease. We profiled the methylation status of about 850,000 CpG sites in 5 FD patients, all carrying the same mutation in the GLA gene (exon 6 c.901C>G) and presenting comparable low levels of α-Gal A activity. We found that, although the whole methylome profile did not discriminate the FD group from the unaffected one, several genes were significantly differentially methylated in Fabry patients. Thus, we provide here a proof of concept, to be tested in patients with different mutations and in a larger cohort, that the methylation state of specific genes can potentially identify Fabry patients and possibly predict organ involvement and disease evolution.     

Assessing T-Cell Immunity in Kidney Transplant Recipients with Absent Antibody Production after a 3rd Dose of the mRNA-1273 Vaccine

The vulnerable population of kidney transplant recipients (KTRs) are low responders to COVID-19 vaccines, so specific immune surveillance is needed. The interferon-gamma (IFN-γ) release assay (IGRA) is effective in assessing T cell-mediated immunity. We assessed SARS-CoV-2-directed T cell responses in KTRs with absent antibody production after a third dose of the mRNA-1273 vaccine, using two different IGRAs. A cohort of 57 KTRs, who were actively followed up, received a third dose of the mRNA-1273 vaccine. After the evaluation of humoral immunity to SARS-CoV-2, 14 seronegative patients were tested with two commercial IGRAs (SD Biosensor and Euroimmun). Out of 14 patients, one and three samples were positive by IGRAs with Euroimmun and SD Biosensor, respectively. The overall agreement between the two assays was 85.7% (κ = 0.444). In addition, multivariate linear regression analysis showed no statistically significant association between the IFN-γ concentration, and the independent variables analyzed (age, gender, years since transplant, total lymphocytes cells/mcl, CD3+ cells/mcl, CD3+ CD4+ cells/mcl, CD3+ CD8+ cells/mcl, CD19+ cells/mcl, CD3-CD16+CD56+ cells/mcl) (p > 0.01). In a vulnerable setting, assessing cellular immune response to complement the humoral response may be advantageous. Since the two commercial IGRAs showed a good agreement on negative samples, the three discordant samples highlight the need for further investigations.     

Modelling and predicting the effect of social distancing and travel restrictions on COVID-19 spreading

To date, the only effective means to respond to the spreading of the COVID-19 pandemic are non-pharmaceutical interventions (NPIs), which entail policies to reduce social activity and mobility restrictions. Quantifying their effect is difficult, but it is key to reducing their social and economic consequences. Here, we introduce a meta-population model based on temporal networks, calibrated on the COVID-19 outbreak data in Italy and applied to evaluate the outcomes of these two types of NPIs. Our approach combines the advantages of granular spatial modelling of meta-population models with the ability to realistically describe social contacts via activity-driven networks. We focus on disentangling the impact of these two different types of NPIs: those aiming at reducing individuals’ social activity, for instance through lockdowns, and those that enforce mobility restrictions. We provide a valuable framework to assess the effectiveness of different NPIs, varying with respect to their timing and severity. Results suggest that the effects of mobility restrictions largely depend on the possibility of implementing timely NPIs in the early phases of the outbreak, whereas activity reduction policies should be prioritized afterwards.     

Prediction of air and steam leak rate through cracked reinforced concrete panels

The leak rate prediction of air and steam through a cracked concrete wall is an extremely important issue in assessing the safety of a nuclear reactor containment building. Such a problem requires a multidisciplinary approach involving both the non-linear analysis of the structure, and the thermodynamics aspects related to the flow of a gas through a conduit. In the present paper, some of the available leak rate evaluation formulae are reviewed, and an application to the prediction of the leak rate of either dry air or air+steam mixture through a cracked concrete panel is presented. Finally, in order to validate the numerical procedure herein adopted and to give some indication on the relative merit of the different leak rate formulae considered, the results of the numerical application are compared against leak rate values measured during an experimental test carried out at the ISMES laboratory.     

Intramuscular fatty acid composition of “Galician Mountain” foals breed: Effect of sex,slaughtered age and livestock production system

The effects of sex, slaughtered age (9 vs. 12 months) and livestock production system (freedom extensive system vs. semi extensive system) of “Galician Mountain” foals breed on the fatty acid composition were studied. The sex and slaughtered age of the animals had no statistical significance in the intramuscular fatty acids. Furthermore, the livestock production system showed differences in the fatty acid profiles from the Longissimus dorsi. The feeding system showed significant differences in PUFA content (P < 0.001) higher in freedom extensive production system that semi extensive system, whereas MUFA content was significantly (P < 0.001) higher in semi extensive system. This major PUFA content in freedom extensive production showed a significant (r = 0.70, P < 0.01) correlation with C18:3n− 3 content and can be attributed to their eaten only pasture until slaughtered. The higher MUFA contents (P < 0.001) observed for semi extensive production system foals were very significant (r = 0.98, p < 0.01) correlated with C18:1cis−9 content and less significant (r = 0.81, P < 0.01) correlated with C16:1cis−9 content. In addition, the data reinforced the evidence that foals from extensive production system on wood pasture have a higher nutritional quality (mainly due to the higher levels of n−3 PUFA) when compared to concentrate-fed foals, as a result of the beneficial effects of grass on meat fatty acid profiles.     

A new approach to the cheap LQ regulator exploiting the geometric properties of the Hamiltonian system

The cheap LQ regulator is reinterpreted as an output nulling problem which is a basic problem of the geometric control theory. In fact, solving the LQ regulator problem is equivalent to keep the output of the related Hamiltonian system identically zero. The solution lies on a controlled invariant subspace whose dimension is characterized in terms of the minimal conditioned invariant of the original system, and the optimal feedback gain is computed as the friend matrix of the resolving subspace. This study yields a new computational framework for the cheap LQ regulator, relying only on the very basic and simple tools of the geometric approach, namely the algorithms for controlled and conditioned invariant subspaces and invariant zeros.     

Lapis lazuli provenance study by means of micro-PIXE

In this paper we report about the micro-PIXE characterisation of lapis lazuli, for a provenance study of this semi-precious stone, used for glyptic as early as 7000 years ago. The final aim is to find markers permitting to identify the origin of the raw material coming from three quarries in regions of historical importance: Afghanistan, Pamir Mountains and Siberia. This may help to reconstruct trade routes, especially for ancient objects for which written testimonies are scanty or absent at all.Due to the heterogeneity of lapis lazuli we concentrate our attention on single phases instead of the whole stone; in particular we focused on two of the main phases: lazurite, responsible for the blue colour, and diopside, the most frequent accessory mineral. This study was preceded and completed by means of microanalysis with Scanning Electron Microscopy (SEM-EDX) and Cold-Cathodoluminescence (cold-CL) analysis.Despite the limited number of analysed samples, results are sufficient to exclude/suggest a few features as provenance markers, partly confirming what has been previously published in literature.     

Postviral gastroparesis: presentation, treatment, and outcome

We describe the clinical features and long-term outcome of 11 children who had persistent gastroparesis after an acute viral illness, eight of whom tested positive for rotavirus. Gastric emptying was delayed in the 10 children evaluated with scintigraphy. Antroduodenal manometry confirmed postprandial antral hypomotility in 10 subjects. All children recovered within 6 to 24 months.     

Necessary conditions for positive realizability of continuous-time linear systems

This paper deals with the positive realization problem. The problem is to find, from a given transfer function, a state equation in which state variables and the output take nonnegative values whenever initial states and inputs are nonnegative. Necessary conditions are investigated and a new one is given, together with some related results.