The importance of behaviour as an aesthetic feature

In this study we measured aesthetics of interactive objects (IOs), which are three-dimensional physical artefacts. By means of an Arduino Mini board fitted with a motion sensor to detect the ‎objects being picked up, IOs can exhibit autonomous behaviour when ‎handled. These stimuli therefore activate more than one sense at the time, in compound stimulation. The main aim of this research was to test the hypotheses that behaviour is an aesthetic feature. Corollary aims were to investigate whether aesthetic preference for distinctive objects' structures emerges in compound stimulation to investigate whether aesthetic preference for distinctive objects' structures emerges in compound stimulation; secondly, to explore whether there exists aesthetic preference for distinctive objects’ behaviours; and lastly, to test whether there exists aesthetic preference for specific combinations of objects' structures and behaviours. The following variables were manipulated: 1) IOs’ contour (rounded vs. angular); 2) IOs’ size (small vs. large); 3) IOs’ surface texture (rough vs. smooth); and 4) IOs’ behaviour (Lighting, Sounding, Vibrating, and Quiescent). Results show that behaviour influenced aesthetics preference more than any other characteristic; Vibrating IOs were preferred over Lighting and Sounding IOs, supporting the importance of haptic processing in aesthetics. Results did not confirm the size and smoothness effects previously reported in vision and touch, respectively; this suggests that, for some stimulation, the aesthetics preference that emerges in isolated conditions may be different in compound stimulation. Results corroborate the smooth curvature effect. It is concluded that for Interactive Objects behaviour can be considered an aesthetic primitive

Exploring the aesthetics of tangible interaction : experiments on the perception of hybrid objects

We report the results of an extended empirical two-stage study on the aesthetics of hybrid objects that combine form and behaviour. By combining two shapes (spheres and cubes); two sizes (7.5cm and 15cm); two materials (fabric and plastic); and four behaviours (emitting light, emitting sound, vibrating or displaying no behaviour) we created 32 objects that differ for a single feature. In a between-participants study, 175 participants assessed and described the 32 objects. From this, seven dimensions were identified: pleasant; interesting; comfortable; playful; relaxing; special and surprising. In a second between-participants experiment 486 participants rated each object on the seven dimensions from the first study. Overall Spheres, Fabric, and Vibration were the preferred features, but for some of the dimensions specific combinations of features were rated more positively. This paper contribution is twofold: it provides a first study on the aesthetic of tangible interaction as a combination of form and behaviour outlining a potential instrument to measure it; and it provides empirical evidence of the value of experimenting with different forms (spheres) and material (fabric) even if they are difficult to create as they generate the strongest aesthetic effects

Head and neck osteosarcoma—the ongoing challenge about reconstruction and dental rehabilitation

Head and Neck osteosarcoma is an uncommon disease. Hitherto, the treatment is surgical resection and survival is influenced by the presence of free margins. However, the dimension of the resection may represent a hurdle for an adequate Quality of Life (QOL). Maxillofacial district is a narrow space where the function, esthetics and patient’s relational skills fit together like the gears of a clock. The functional results depend on the type of reconstruction and prosthetic rehabilitation that are both important to guarantee a good aesthetic result and finally increase the patient’s self-esteem. This study aims to report our experience about head and neck (HN) osteosarcoma focusing the attention on reconstructive and dental-rehabilitative problems. It is a retrospective study all patients were surgically treated in our department. Subjects with histological diagnosis of HN osteosarcoma, treated between 2005 and 2017 were included. The demographic characteristics, surgical treatment, eventually secondary reconstruction and prosthetic rehabilitation, performed in the same department, have been collected. The QOL was assessed through the EORTC QLQ-H&N35 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35) questionnaire. Fifteen patients were enrolled, eight received a free flap microsurgical reconstruction. Dental rehabilitation was performed in five cases and a mobile prosthesis was always delivered. Eighteen implants were inserted in fibula bones for three patients; highly porous implants were use

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels

Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing developmen

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile

Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact. Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the “episignature” associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression. Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches

De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.This work was supported by: UK Medical Research Council Project Grants [MR/M00046X/1], [MR/R026440/1] and Project grant from National Institute of Health Research Biomedical Research Centre at Addenbrooke's Hospital (to E.R.), Fondazione Bambino Gesù (Vite Coraggiose) and Italian Ministry of Health (CCR-2017-23669081) (to M.T.), National Institute for Health Research (NIHR) for the Cambridge Biomedical Research Centre and NIHR BioResource (Grant Number RG65966) (to F.L.R.), and a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 216370/Z/19/Z) (to J.E.). CIMR was supported by a Wellcome Trust Strategic Award [100140] and Equipment Grant [093026]. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support

Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?

Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott–Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients’ cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions

De novo missense variants in FBXW11 cause diverse developmental phenotypes including brain, eye and digit anomalies

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include b-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw

The THESEUS space mission concept: science case, design and expected performances

THESEUS is a space mission concept aimed at exploiting Gamma-Ray Bursts for investigating the early Universe and at providing a substantial advancement of multi-messenger and time-domain astrophysics. These goals will be achieved through a unique combination of instruments allowing GRB and X-ray transient detection over a broad field of view (more than 1sr) with 0.5¿1 arcmin localization, an energy band extending from several MeV down to 0.3¿keV and high sensitivity to transient sources in the soft X-ray domain, as well as on-board prompt (few minutes) follow-up with a 0.7¿m class IR telescope with both imaging and spectroscopic capabilities. THESEUS will be perfectly suited for addressing the main open issues in cosmology such as, e.g., star formation rate and metallicity evolution of the inter-stellar and intra-galactic medium up to redshift 10, signatures of Pop III stars, sources and physics of re-ionization, and the faint end of the galaxy luminosity function. In addition, it will provide unprecedented capability to monitor the X-ray variable sky, thus detecting, localizing, and identifying the electromagnetic counterparts to sources of gravitational radiation, which may be routinely detected in the late ¿20s/early ¿30s by next generation facilities like aLIGO/ aVirgo, eLISA, KAGRA, and Einstein Telescope. THESEUS will also provide powerful synergies with the next generation of multi-wavelength observatories (e.g., LSST, ELT, SKA, CTA, ATHENA).© 2018 COSPARS.E. acknowledges the financial support from contracts ASI-INAF 1/009/10/0, NARO15 ASI-INAF 1/037/12/0 and ASI 2015-046-R.0. R.H. acknowledges GACR grant 13-33324S. S.V. research leading to these results has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 606176. D.S. was supported by the Czech grant 1601116S GA CR. Maria Giovanna Dainotti acknowledges funding from the European Union through the Marie Curie Action FP7-PEOPLE-2013-IOF, under grant agreement No. 626267 (>Cosmological Candles>)