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The developmental role of histone H3K9 methylation (H3K9me), which typifies heterochromatin, remains unclear. In Caenorhabditis elegans, loss of H3K9me leads to a highly divergent upregulation of genes with tissue and developmental-stage specificity. During development H3K9me is lost from differentiated cell type-specific genes and gained at genes expressed in earlier developmental stages or other tissues. The continuous deposition of H3K9me2 by the SETDB1 homolog MET-2 after terminal differentiation is necessary to maintain repression. In differentiated tissues, H3K9me ensures silencing by restricting the activity of a defined set of transcription factors at promoters and enhancers. Increased chromatin accessibility following the loss of H3K9me is neither sufficient nor necessary to drive transcription. Increased ATAC-seq signal and gene expression correlate at a subset of loci positioned away from the nuclear envelope, while derepressed genes at the nuclear periphery remain poorly accessible despite being transcribed. In conclusion, H3K9me deposition can confer tissue-specific gene expression and maintain the integrity of terminally differentiated muscle by restricting transcription factor activity., Nature Cell Biology, 23, ISSN:1465-7392, ISSN:1476-4679

Background Empathy has long been considered a multidimensional construct, encompassing cognitive, affective and behavioral domains. Deficits in empathic competences in early childhood contribute to psychopathology, and have been variably implicated in several clinical conditions, such as autism spectrum disorders (ASD) and conduct disorders. Aim To identify and describe empirically validated questionnaires assessing empathy in children and adolescents and to provide a summary of related theoretical perspectives on empathy definitional issues. Methods A systematic review of the literature was conducted. Three bibliographic databases were searched. A total of 47 studies were selected for final analysis and 16 distinct measures were identified and described. Results Questionable to excellent levels of internal consistency were observed, while few studies assessed test-retest reliability. Although construct definitions only partially overlapped, affective and cognitive domains of empathy were the commonest internal factors that were often separately evaluated. New facets of the construct (i.e., somatic empathy and sympathy) and specific clinical populations (i.e., ASD) could be specifically addressed through more recent instruments. Conclusion The combination of different assessment methods is recommended in order to foresee further improvements in this field and try to overcome the problem of limited convergence with more objective measures.

The paper outlines the fraught relationship between Alessandro Tassoni, founder of the ‘eroicomico’, and the comic poetry of the first half of the 16th century, dwelling in particular on the possible influence that Francesco Berni, the father of ‘burlesco’, may have had on Tassoni’s production. The analysis of Tassoni’s self-exegetic writings (declarations and prefaces) allows us to distinguish poetic pronouncements from actual textual realisations, as regards to Tassoni’s satirical poetry, a genre in which the lesson of the 16th-century masters (Berni for first) is substantial., Il contributo affronta la complessa questione del rapporto tra Alessandro Tassoni, fondatore del genere eroicomico, e la tradizione burlesca della prima metà del Cinquecento, soffermandosi in particolare sulla possibile influenza che Francesco Berni, capostipite della poesia burlesca, può avere avuto sulla produzione tassoniana. L’analisi degli scritti autoesegetici di Tassoni (dichiarazioni e prefazioni) consente di distinguere i pronunciamenti di poetica dalle effettive realizzazioni testuali, soprattutto per quanto concerne la poesia satirica e burlesca di Tassoni, un genere dove la lezione dei maestri cinquecenteschi (Berni in primis) appare consi-derevole.

Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.

Microduplications involving the MYT1L gene have mostly been described in series of patients with isolated schizophrenia. However, few reports have been published, and the phenotype has still not been well characterized. We sought to further characterize the phenotypic spectrum of this condition by describing the clinical features of patients with a pure 2p25.3 microduplication that included all or part of MYT1L. Through a French national collaboration and a literature review, we assessed a large cohort of patients (n = 43) with pure 2p25.3 microduplications identified by chromosomal microarray analysis. For each case, we recorded clinical data, the microduplication size, and the inheritance pattern. The clinical features were variable and included developmental and speech delays (33%), autism spectrum disorder (23%), mild-to-moderate intellectual disability (21%), schizophrenia (21%), or behavioral disorders (16%). Eleven patients did not have an obvious neuropsychiatric disorder. The microduplications ranged from 62.4 kb to 3.8 Mb in size and led to either duplication of all or part of MYT1L. There were seven cases of intragenic duplication. The inheritance pattern was available for 18 patients: the microduplication was inherited in 13 cases, and all but one of the parents had a normal phenotype. Our comprehensive review and expansion of the phenotypic spectrum associated with 2p25.3 microduplications involving MYT1L (previously linked to schizophrenia) should help clinicians to better assess, counsel and manage affected individuals. MYT1L microduplications are characterized by a spectrum of neuropsychiatric phenotypes with incomplete penetrance and variable expressivity, which are probably due to as-yet unknown genetic and nongenetic modifiers.

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with training of multiple supervised classifiers, to predict severity on the basis of screened features. Feature importance analysis from tree-based models allowed to identify a handful of 16 variants with highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with good accuracy (ACC=81.88%; ROC_AUC=96%; MCC=61.55%). Principal Component Analysis (PCA) and clustering of patients on important variants orthogonally identified two groups of individuals with a higher fraction of severe cases. Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response, such as JAK-STAT, Cytokine, Interleukin, and C-type lectin receptor signaling. It also identified additional processes cross-talking with immune pathways, such as GPCR signalling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, confirming their link with COVID-19 severity outcome. Taken together, our analysis suggests that curated genetic information can be effectively integrated along with other patient clinical covariates to forecast COVID-19 disease severity and dissect the underlying host genetic mechanisms for personalized medicine treatments.

Generally, tire deflation results in a decrease in both handling performance and tire lifetime, and in fuel consumption increment. Therefore, the real-time knowledge of the pressure is important. Direct approaches via pressure sensors mounted on the rim of each tire are not practical, due to technical and economic reasons. Cost-effective solutions with real-time estimation of tire pressure are generally less accurate and reliable than direct ones. Dynamical estimators based on a suspension model need road surface topology information to compute disturbances on the suspension system as an input, which is typically unknown. This paper proposes an innovative approach to estimate tire pressure indirectly, without actual road surface roughness information. A vertical suspension dynamic model is used to build several unscented Kalman filters, parametrised around different road surface topologies. These estimators are combined following the Interacting Multiple Model approach, which gives an acceptable estimation of tire stiffness through a weighted average obtained from a probabilistic model. A known linear static relationship between the tire stiffness and inflation pressure is utilized to indirectly estimate the tire inflation pressure. A Monte Carlo analysis has been performed on a wide range of driving scenarios and vehicle manoeuvres. The results of the estimation have been compared to those of a single unscented Kalman filter, in order to validate the effectiveness of the proposed solution and to highlight the improved performances in monitoring tire pressure.

This paper presents a test rig developed for the experimental investigations on a vibration isolation system, based on the use of magnetorheological elastomers (MRE). These intelligent materials allow to adapt their stiffness to the needs of the isolation as the material stiffness depends on the intensity of the magnetic field in which it is immersed; it is possible to modify the material stiffness, quickly and reversibly, by means of coils. The paper describes an isolation system, based on MRE pads, and the test rig developed for the experimental tests. The rig allows to experimentally study the effectiveness of different control algorithms adopted to adjust the material stiffness, considering that the stiffness of the MRE pads can only be increased by activating the material.