Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis

Nesprins-1 and -2 are highly expressed in skeletal and cardiac muscle and together with SUN (Sad1p/UNC84)-domain containing proteins and lamin A/C form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) bridging complex at the nuclear envelope (NE). Mutations in nesprin-1/2 have previously been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). In this study, three novel rare variants (R8272Q, S8381C and N8406K) in the C-terminus of the SYNE1 gene (nesprin-1) were identified in seven DCM patients by mutation screening. Expression of these mutants caused nuclear morphology defects and reduced lamin A/C and SUN2 staining at the NE. GST pull-down indicated that nesprin-1/lamin/SUN interactions were disrupted. Nesprin-1 mutations were also associated with augmented activation of the ERK pathway in vitro and in hearts in vivo. During C2C12 muscle cell differentiation, nesprin-1 levels are increased concomitantly with kinesin light chain (KLC-1/2) and immunoprecipitation and GST pull-down showed that these proteins interacted via a recently identified LEWD domain in the C-terminus of nesprin-1. Expression of nesprin-1 mutants in C2C12 cells caused defects in myoblast differentiation and fusion associated with dysregulation of myogenic transcription factors and disruption of the nesprin-1 and KLC-1/2 interaction at the outer nuclear membrane. Expression of nesprin-1α2 WT and mutants in zebrafish embryos caused heart developmental and conduction defects that varied in severity. These findings support a role for nesprin-1 in myogenesis and muscle disease, and uncover a novel mechanism whereby disruption of the LINC complex may contribute to the pathogenesis of DCM

Explainable AI-based identification of contributing factors to the mood state change in children and adolescents with pre-existing psychiatric disorders in the context of COVID-19-related lockdowns in Greece

The COVID-19 pandemic and its accompanying restrictions have significantly impacted people’s lives globally. There is an increasing interest in examining the influence of this unprecedented situation on our mental well-being, with less attention towards the impact of the elongation of COVID-19-related measures on youth with a pre-existing psychiatric/developmental disorder. The majority of studies focus on individuals, such as students, adults, and youths, among others, with little attention being given to the elongation of COVID-19-related measures and their impact on a special group of individuals, such as children and adolescents with diagnosed developmental and psychiatric disorders. In addition, most of these studies adopt statistical methodologies to identify pair-wise relationships among factors, an approach that limits the ability to understand and interpret the impact of various factors. In response, this study aims to adopt an explainable machine learning approach to identify factors that explain the deterioration or amelioration of mood state in a youth clinical sample. The purpose of this study is to identify and interpret the impact of the greatest contributing features of mood state changes on the prediction output via an explainable machine learning pipeline. Among all the machine learning classifiers, the Random Forest model achieved the highest effectiveness, with 76% best AUC-ROC Score and 13 features. The explainability analysis showed that stress or positive changes derived from the imposing restrictions and COVID-19 pandemic are the top two factors that could affect mood state

Parental Stress Scale: Psychometric Properties in Parents of Preschool Children with Developmental Language Disorder

Parents of children with developmental disabilities experience more stress compared to those of typically developing children; therefore, measuring parental stress may help clinicians to address it. The Parental Stress Scale (PSS) is a self-rceport measure in the public domain that assesses stress related to child rearing. The present study tested the psychometric properties of the Greek version of the PSS in 204 parents (mean age: 39.4 ± 5.7, 124 mothers and 80 fathers) of kindergarten children diagnosed with Developmental Language Disorder (DLD) after a clinical assessment. Confirmatory factor analysis (CFA) was used to confirm the original four-factor structure. The results showed that the original four-factor structure (parental rewards, parental stressors, lack of control and parental satisfaction) is valid in this specific Greek population. The reliability was high (ω = 0.78) and there were weak correlations (r = −0.372, r = −0.337, r = −0.236), yet of statistical significance (p < 0.001), with similar psychological constructs (quality of life, emotional functioning and worries). Our data confirmed that the PSS is a reliable and valid tool to measure parental stress in parents of children with DLD. Greek clinicians (mental health professionals, speech-language pathologists) can evaluate parental stress and design early interventions targeting specific stress aspects, along with core language interventions for the children

Sensitised near-infrared luminescence from lanthanide(III) centres using Re(I) and Pt(II) diimine complexes as energy donors in d-f dinuclear complexes based on 2,3-bis(2-pyridyl)pyrazine.

The luminescent transition metal complexes [Re(CO)(3)Cl(bppz)] and [Pt(CC-C(6)H(4)CF(3))(2)(bppz)] [bppz = 2,3-bis(2-pyridyl)pyrazine], in which one of the diimine binding sites of the potentially bridging ligand bppz is vacant, have been used as 'complex ligands' to make heterodinuclear d-f complexes by attachment of a {Ln(dik)(3)} fragment (dik = a 1,3-diketonate) at the vacant site. When Ln = Pr, Nd, Er or Yb the lanthanide centre has low-energy f-f excited states capable of accepting energy from the (3)MLCT excited state of the Pt(II) or Re(I) centre, quenching the (3)MLCT luminescence and affording sensitised lanthanide(III)-based luminescence in the near-IR region. UV/Vis and luminescence spectroscopic titrations allowed measurement of (i) the association constants for binding of the {Ln(dik)(3)} fragment at the vacant diimine site of [Re(CO)(3)Cl(bppz)] or [Pt(CC-C(6)H(4)CF(3))(2)(bppz)], and (ii) the degree of quenching of the (3)MLCT luminescence according to the nature of the Ln(III) centre. In all cases Nd(III) was found to be the most effective of the series at quenching the (3)MLCT luminescence of the d-block component because the high density of f-f excited states of the appropriate energy make it a particularly effective energy-acceptor

Health-Related Quality of Life and Behavioral Difficulties in Greek Preschool Children with Developmental Language Disorder

Developmental language disorder (DLD) has a great impact on language skills as well as on a wide range of functioning areas, such as social and school functioning. In the present study, we aim to explore the Health-Related Quality of Life (HRQoL) of preschool children with DLD, compared to children with no language difficulties, using a self and proxy report method. A total of 230 parents of preschool children with DLD and 146 parents of children without language difficulties completed the Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Generic Core Module and the Strengths and Difficulties Questionnaire (SDQ). Additionally, 71 children with DLD and 55 peers without DLD completed the self-reported PedsQLTM module. The parents of kindergarten children (5–6 years old) with DLD reported that their kids experience worse social and school functioning compared to the control group. In addition, the children with DLD self-reported lower physical and social functioning. The parents of children with DLD reported that their children experience higher hyperactivity/inattention problems than the parents of the control group. Kindergarten children with DLD have a poorer HRQoL compared to their peers, as perceived by themselves and their parents. Moreover, children with DLD present with higher hyperactivity and inattention symptoms. Health professionals working with children who have DLD need to consider not only the language difficulties but also the children’s wellbeing and symptoms of hyperactivity and inattention

CCDC 626879: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures