Reconstructing genotypes in trios from a Sardinian sample for fine mapping of SNPs in MYO1D-ASIC2 genes using the Knockoff filter: a candidate region for Multiple Sclerosis susceptibility

Introduction. Multiple Sclerosis (MS) is a progressive autoimmune disease that damages the myelin, the protective covering of the central nervous system (CNS). This damage leads to a wide range of physical and cognitive impairments. While the primary symptoms are neurological, MS can also affect multiple organs, creating both health and social challenges. MS is considered a complex trait disease, as it results from the interplay of various factors, including genetic, biological, and environmental influences, along with their interactions. Aim. Our work focuses on a fine mapping method, a statistical technique used to narrow down a selected region of chromosome 17 (30820506:32483270 bp). In fine mapping settings, typically a statistical method that takes advantage of the patterns of linkage disequilibrium (LD) between genetic variants to find the strongest significant signals among all the genetic variants in the considered window. The region under investigation is near the ASIC2 gene and has already been targeted for association of microRNA with MS, hence it is likely to contain associated variants. The study was conducted by using a sample of families from Sardinia, a genetically isolated population, with high prevalence of MS, making it suitable for this kind of investigation. Indeed, Sardinian MS prevalence is estimated to reach 330 per 100,000 inhabitants (95%CI: [321, 338]) compared to mainland Italy (176 per 100,000) and the Northern European one (100-190 per 1000). Methods. The employed sample consisted of 157 trios (father-mother-child for a total of 471), on which a multi-step analysis was applied to localise MS-associated variants at multiple resolutions using the knockoff filter method. A total of 2537 single nucleotide polymorphisms (SNPs) have been imputed and filtered according to standard quality controls, and haplotypes were reconstructed for subsequent analyses. The analysis continued with the augmentation of the genotype matrix, by creating knockoff variants, which have the same correlation structure as the original variants but are independent of the disease conditional on the observed genotypes. Afterwards, filter was applied by testing the conditional associations of genetic segments of decreasing width along the targeted window using a family-based association test (FBAT). Results. Scanning the imputed variants, two distinct regions of chromosome 17 exhibited a noteworthy effect on MS. The variant rs756787, at 3’UTR MYO1D, was found to be associated with an increased risk of MS (OR=1.57, 95%CI: [1.07, 2.29]), while rs56175840, in intronic region of ASIC2, was found associated with a decreased risk of MS (OR=0.17, 95%CI: [0.04, 0.74]). The alternative allele of variant rs756787 (involving CDK5R1 and the 3’UTR of MYO1D) had a false discovery rate (FDR) of 0.21. By studying pathways and LD-traits in GWAS catalogues, this study allowed us to prioritise the rs756787 variant which is also linked to neurodegeneration and EBV pathway. This comprehensive analysis enhances our understanding of the genetic architecture of MS, offering insights for further investigation on genetic MS susceptibility

Study of WH production through vector boson scattering and extraction of the relative sign of the W and Z couplings to the Higgs boson in proton-proton collisions at s=13TeV

A search for the production of a W boson and a Higgs boson through vector boson scattering (VBS) is presented, using CMS data from proton-proton collisions at s=13TeV collected from 2016 to 2018. The integrated luminosity of the data sample is 138fb−1. Selected events must be consistent with the presence of two jets originating from VBS, the leptonic decay of the W boson to an electron or muon, possibly also through an intermediate τ lepton, and a Higgs boson decaying into a pair of b quarks, reconstructed as either a single merged jet or two resolved jets. A measurement of the process as predicted by the standard model (SM) is performed alongside a study of beyond-the-SM (BSM) scenarios. The SM analysis sets an observed (expected) 95% confidence level upper limit of 14.3 (9.9) on the ratio of the measured VBS WH cross section to that expected by the SM. The BSM analysis, conducted within the so-called κ framework, excludes all scenarios with λWZ<0 that are consistent with current measurements, where λWZ=κW/κZ and κW and κZ are the HWW and HZZ coupling modifiers, respectively. The significance of the exclusion is beyond 5 standard deviations, and it is consistent with the SM expectation of λWZ=1

Chiroptical properties of plasmonic nanohole arrays.

Recent advances in chiral nanophotonics in man-made metasurfaces have highlighted the importance of chirality in enhancing light-matter interactions, manipulating light’s polarization states, detecting and analyzing chemical substances, and many more. A typical probe of chirality is circular dichroism CD in optical properties like absorption, reflection, and transmission. Through this work, two chiral plasmonic metasurfaces were analyzed to enhance the CD -in particular, absorption CD and hence increase the chiral sensitivity of the system. The metasurfaces are arranged in a square lattice within a metallic layer placed on a glass substrate. The first metasurface consists of elliptical nanohole arrays realized in different metals such as silver, gold, and aluminum. This plasmonic metasurface exhibits an intrinsic chiral effect due to reduced symmetry via the elliptical shape of the nanoholes and their rotation. The findings reveal that strong CD occurs in the absorption and transmission spectra at wavelengths where extraordinary optical transmission EOT is observed. This indicates a significant resonant coupling between light and surface plasmon polaritons SPPs at the metal/glass and metal/air interfaces. The elliptical shape of the nanoholes leads to splitting of absorption peaks at each SPP resonance, while tilting of the nanohole axis produces an imbalance between the fields originating from linear polarizations along the long and short axes; as a result, they sum up with a phase delay of -90 (LCP) or +90(RCP), ending up in a CD for tilted holes and explaining the strongly dispersive features of CD spectra. The study also explores how to optimize CD by varying parameters such as the diameters and tilt of the elliptical nanoholes, the thickness of the metallic layer, and the lattice constant. This optimization is crucial for designing metasurfaces with robust and tunable CD properties. The results indicate that silver (Ag) and gold (Au) metasurfaces are effective for CD resonances above 600~nm. At the same time, aluminum (Al) metasurface is suitable for strong CD resonances in the shorter wavelength range of the visible spectrum and near-UV. The UV region is particularly noteworthy as it encompasses the absorption spectrum of various chiral biomolecules. Promising applications for these elliptical plasmonic metasurfaces can be in sensing the chiral molecules and detecting and analyzing biological substances that exhibit chirality. The second metasurface is a gold metasurface with nanoholes deformed from circular to oval shape. The metasurface with circular holes supports a bound state in the continuum BIC at the lower energy side of the SPP. Upon deforming the circular holes to oval holes, this metasurface displays an extrinsic chiral response primarily dominated by a quasi-BIC with nearly maximal values of the absorption CD at small angles of incidence, which are found to be almost independent of the specific deformation of the holes in the metasurface. This suggests that the design can be flexible while still achieving strong chiral effects. The research also highlights the demonstration of a strong CD in emission, indicating that the enhanced chiral response is not limited to absorption but extends to emitted light. This broadens the potential applications of the findings in chiral light sources. The extrinsically chiral response arises from a symmetry-broken BIC, associated with significantly enhancing the local electric field. This insight provides a deeper understanding of the mechanisms behind chiral responses in plasmonic metasurfaces. Moreover, we theoretically investigated the chiral plasmonic BIC in the strong coupling regime, wherein we found evidence of plasmon-polariton BIC modes coupled to the resonance of the active medium

Cybersecurity of Decision Support Systems, in the Quantum Era

One of the technologies that has a leading role in Industry 4.0 and Health 4.0 is the Decision Support System (DSS), which automates various processes without human involvement. The decisions are based on collected data, containing sensitive information, that must be secured via cryptographic algorithms. Their effectiveness in encoding information is based on the difficulty of solving specific mathematical problems. While the research regarding quantum computers is steadily increasing, the common cryptographic algorithms cannot continue to provide high security, because their mathematical problems will be solved significantly faster, resulting in successful brute force attacks. In this chapter, the Industry 4.0 and Health 4.0 based environment of DSSs and their cybersecurity issues will be analysed. Moreover, their common security standards and cryptographic algorithms will be demonstrated. The impact of quantum computers will also be explored, as they seem to be ideal for the two 4.0 frameworks, due to the faster execution of functions like machine learning and big data. However, it is important to also highlight the danger to cybersecurity, due to this higher speed completion of more complex problems. Finally, the quantumresistant cryptographic algorithms, that have been suggested to counter this problem, will be presented

Covalent adduct Grob fragmentation underlies LSD1 demethylase-specific inhibitor mechanism of action and resistance

Chromatin modifiers often work in concert with transcription factors (TFs) and other complex members, where they can serve both enzymatic and scaffolding functions. Due to this, active site inhibitors targeting chromatin modifiers may perturb both enzymatic and nonenzymatic functions. For instance, the antiproliferative effects of active-site inhibitors targeting lysine-specific histone demethylase 1A (LSD1) are driven by disruption of a protein-protein interaction with growth factor independence 1B (GFI1B) rather than inhibition of demethylase activity. Recently, next-generation precision LSD1 covalent inhibitors have been developed, which selectively block LSD1 enzyme activity by forming a compact N-formyl flavin adenine dinucleotide (FAD) adduct that spares the GFI1B interaction. However, the mechanism accounting for N-formyl-FAD formation remains unclear. Here we clarify the mechanism of these demethylase-specific inhibitors of LSD1, demonstrating that the covalent inhibitor-FAD adduct undergoes a Grob fragmentation. Using inhibitor analogs and structural biology, we identify structure-activity relationships that promote this transformation. Furthermore, we unveil an unusual drug resistance mechanism whereby distal active-site mutations can promote inhibitor-adduct Grob fragmentation even for previous generation compounds. Our study uncovers the unique Grob fragmentation underlying the mechanism of action of precision LSD1 enzyme inhibitors, offering insight into their reactivity with broader implications for drug resistance

Gestione dei modelli Open H-BIM per l’interoperabilità dei dati

L'implementazione del protocollo open-BIM incontra difficoltà a causa della man-canza di un linguaggio unificato per gli elementi del progetto, che influisce sulla condivisione delle informazioni. L'applica-zione delle tecniche Scan2-openBIM con-sente di collegare le rappresentazioni digi-tali con le proprietà del Prezzario dei Lavori Pubblici, semplificando questo processo