Genetic and functional characterisation of the autosomal dominant form of Hyper IgE Syndrome

Background: Autosomal dominant Hyper IgE Syndrome (AD-HIES) is a rare primary immunodeficiency characterized by high serum IgE levels, eosinophilia, and skin and lung infections. Additional features of AD-HIES include characteristic facial appearance, scoliosis, retained primary teeth, and joint hyperextensibility. Recently, AD-HIES has been associated with heterozygous dominant negative mutations in the signal transducer and activator of transcription 3 (STAT3) which plays a key role in the signal transduction of a broad range of cytokines, and is crucial for IL-6-mediated regulation of Th17 cells. Objective: We aimed to characterize patients with the clinical diagnosis of ADHIES, to identify STAT3 mutations, and to assess the frequency and functional consequences of these mutations. Furthermore, we studied STAT3-dependent signalling pathways in patients with an AD-HIES phenotype but no STAT3 mutation. Methods: We sequenced STAT3 in 153 patients with a strong clinical suspicion of AD-HIES and further components of the IL-6 signalling pathway in patients found to be STAT3 wild type. The impact of the mutations on immune cell function was assessed by measurement of cytokine release by immune cells, T cell phenotyping and STAT1 phosphorylation assays. Results: About 60% of the AD-HIES patients revealed mutations in STAT3. All mutations found were heterozygous, clustered mainly in the DNA-binding or the SH2 domain and exerted dominant-negative effects. Functional analysis of mutations affecting different domains of STAT3 revealed that some mutations might have a less severe impact on functionality of STAT3, About 40% of our cohort of patients presenting with AD-HIES phenotype harboured wild type STAT3 and may carry mutations in other genes of either the same or closely related signalling pathways. Nevertheless, we ruled out mutations affecting the IL-6 pathway iIn five Sardinian patients with wild type STAT3. Impact of findings: The results lead to a better characterization of heterozygous STAT3 mutations and of the pathogenesis of AD-HIES

Stress concentration targeted reinforcement using multi-material based 3D printing

Topological engineering (3D printing into complex geometry) has emerged as a pragmatic approach to develop high specific strength (high strength and low density) lightweight structures. These complex lightweight structures fail at high-stress concentration regions, which can be, replaced with soft/tough material using 3D printing. It can improve mechanical properties such as strength, toughness and energy absorption etc. Here, we have developed stress concentration targeted multi-material schwarzite structures by 3D printing technique. The soft (Thermoplastic Polyurethane) material is reinforced at high-stress concentration regions of hard (Polylactic acid) schwarzite structures to enhance the specific yield strength and resilience. The mechanical properties and responses of these structures were then assessed via uniaxial compression tests. The multi-materials 3D printed composite structure shows improved mechanical properties compared to single materials architecture. The specific resilience of composites demonstrates remarkable enhancements, with percentage increases of 204.70 %, 596.50 %, and 1530.99 % observed when compared to hard primitives, and similarly impressive improvements of 182.45 %, 311.64 %, and 477.75 % observed in comparison to hard gyroids. The obtained experimental findings were comprehensively examined and validated with molecular dynamics (MD) simulations. The promising characteristics of these lightweight multi-material-based Schwarzites structures can be utilized in various fields such as energy harvesting devices, protective, safety gears, and aerospace components

Boron Nitride Nanotube Peapod under Ultrasonic Velocity Impacts: A Fully Atomistic Molecular Dynamics Investigation

In this work, we investigated the mechanical response and fracture dynamics of boron nitride nanotubes (BNNTs)-peapods under ultrasonic velocity impacts (from 1 km/s to 6 km/s) against a solid target. BNNT-peapods are BNNTs containing an encapsulated linear arrangement of C60 molecules. We carried out fully atomistic reactive (ReaxFF) molecular dynamics simulations. We have considered the case of horizontal and vertical shootings. Depending on the velocity values we observed tube bending, tube fracture, and C60 ejection. One interesting result was tube unzipping with the formation of bilayer nanoribbons 'incrusted' with C60 molecules.Comment: 1