329 research outputs found
Yield of array-CGH analysis in Tunisian children with autism spectrum disorder
Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic underpinnings. Microarray-based comparative genomic hybridization (aCGH) technology has been proposed as a first-level test in the genetic diagnosis of ASD and of neurodevelopmental disorders in general. Methods: We performed aCGH on 98 Tunisian children (83 boys and 15 girls) diagnosed with ASD according to DSM-IV criteria. Results: âPathogenicâ or âlikely pathogenicâ copy number variants (CNVs) were detected in 11 (11.2%) patients, CNVs of âuncertain clinical significanceâ in 26 (26.5%), âlikely benignâ or âbenignâ CNVs were found in 37 (37.8%) and 24 (24.5%) patients, respectively. Gene set enrichment analysis involving genes spanning rare âpathogenic,â âlikely pathogenic,â or âuncertain clinical significanceâ CNVs, as well as SFARI database âautism genesâ in common CNVs, detected eight neuronal Gene Ontology classes among the top 10 most significant, including synapse, neuron differentiation, synaptic signaling, neurogenesis, and others. Similar results were obtained performing g: Profiler analysis. Neither transcriptional regulation nor immune pathways reached significance. Conclusions: aCGH confirms its sizable diagnostic yield in a novel sample of autistic children from North Africa. Recruitment of additional families is under way, to verify whether genetic contributions to ASD in the Tunisian population, differently from other ethnic groups, may involve primarily neuronal genes, more than transcriptional regulation and immune-related pathways
Quantifying ultrasonic mouse vocalizations using acoustic analysis in a supervised statistical machine learning framework
Examination of rodent vocalizations in experimental conditions can yield valuable insights into how disease manifests and progresses over time. It can also be used as an index of social interest, motivation, emotional development or motor function depending on the animal model under investigation. Most mouse communication is produced in ultrasonic frequencies beyond human hearing. These ultrasonic vocalizations (USV) are typically described and evaluated using expert defined classification of the spectrographic appearance or simplistic acoustic metrics resulting in nine call types. In this study, we aimed to replicate the standard expert-defined call types of communicative vocal behavior in mice by using acoustic analysis to characterize USVs and a principled supervised learning setup. We used four feature selection algorithms to select parsimonious subsets with maximum predictive accuracy, which are then presented into support vector machines (SVM) and random forests (RF). We assessed the resulting models using 10-fold cross-validation with 100 repetitions for statistical confidence and found that a parsimonious subset of 8 acoustic measures presented to RF led to 85% correct out-of-sample classification, replicating the experts' labels. Acoustic measures can be used by labs to describe USVs and compare data between groups, and provide insight into vocal-behavioral patterns of mice by automating the process on matching the experts' call types
Early motor signs of attention-deficit hyperactivity disorder: a systematic review
ADHD is a common neurodevelopmental disorder with onset of symptoms typically in early childhood. First signs of the disorder, including language delay, motor delay and temperament characteristics, may be evident as early as infancy. The present review describes published evidence about early motor signs of either children with later symptoms of ADHD or a later diagnosis of the disorder. Nine published cohort studies were included after a systematic search of related terms in PubMed and PsycInfo databases. Study eligibility criteria included: (1) report on early motor function or any motor-related signs; (2) the presence of a participantsâ assessment by/at 12 months of age; (3) report of a later presence of ADHD symptoms. The limited number of reports included suggests an association between mild early neurological markers and later developmental coordination disorder and motor overflow movements. Unfortunately, due to their small sample sizes and focus on group reports rather than individuals, they have limited power to find strong associations. Early motor indicators of ADHD, if present, appear to be non-specific, and therefore not yet useful in clinical screening. Spontaneous motility seems to be a promising measure for early ADHD detection, although further studies with large cohorts are recommended to determine its clinical role in children at risk for ADHD
Nonadiabatic Superconductivity and Vertex Corrections in Uncorrelated Systems
We investigate the issue of the nonadiabatic superconductivity in
uncorrelated systems. A local approximation is employed coherently with the
weak dependence on the involved momenta. Our results show that nonadiabatic
vertex corrections are never negligible, but lead to a strong suppression of
with respect to the conventional theory. This feature is understood in
terms of the momentum-frequency dependence of the vertex function. In contrast
to strongly correlated systems, where the small -selection probes the
positive part of vertex function, vertex corrections in uncorrelated systems
are essentially negative resulting in an effective reduction of the
superconducting pairing. Our analysis shows that vertex corrections in
nonadiabatic regime can be never disregarded independently of the degree of
electronic correlation in the system.Comment: 4 pages, 3 eps fig
Diagnostic yield and clinical impact of chromosomal microarray analysis in autism spectrum disorder
Background: Autism spectrum disorder (ASD) is characterized by high heritability estimates and recurrence rates; its genetic underpinnings are very heterogeneous and include variable combinations of common and rare variants. Array-comparative genomic hybridization (aCGH) offers significant sensitivity for the identification of copy number variants (CNVs), which can act as susceptibility or causal factors for ASD. Methods: The aim of this study was to evaluate both diagnostic yield and clinical impact of aCGH in 329 ASD patients of Italian descent. Results: Pathogenic/likely pathogenic CNVs were identified in 50/329 (15.2%) patients, whereas 89/329 (27.1%) carry variants of uncertain significance. The 10 most enriched gene sets identified by Gene Ontology Enrichment Analysis are primarily involved in neuronal function and synaptic connectivity. In 13/50 (26.0%) patients with pathogenic/likely pathogenic CNVs, the outcome of array-CGH led to the request of 25 additional medical exams which would not have otherwise been prescribed, mainly including brain MRI, EEG, EKG, and/or cardiac ultrasound. A positive outcome was obtained in 12/25 (48.0%) of these additional tests. Conclusions: This study confirms the satisfactory diagnostic yield of aCGH, underscoring its potential for better, more in-depth care of children with autism when genetic results are analyzed also with a focus on patient management
Nonadiabatic Pauli susceptibility in fullerene compounds
Pauli paramagnetic susceptibility is unaffected by the electron-phonon
interaction in the Migdal-Eliashberg context. Fullerene compounds however do
not fulfill the adiabatic assumption of Migdal's theorem and nonadiabatic
effects are expected to be relevant in these materials. In this paper we
investigate the Pauli spin susceptibility in nonadiabatic regime by following a
conserving approach based on Ward's identity. We find that a sizable
renormalization of due to electron-phonon coupling appears when
nonadiabatic effects are taken into account. The intrinsic dependence of
on the electron-phonon interaction gives rise to a finite and negative isotope
effect which could be experimentally detected in fullerides. In addition, we
find an enhancement of the spin susceptibility with temperature increasing, in
agreement with the temperature dependence of observed in fullerene
compounds. The role of electronic correlation is also discussed.Comment: Revtex, 10 pages, 8 figures include
Isotope Effect in the Presence of Magnetic and Nonmagnetic Impurities
The effect of impurities on the isotope coefficient is studied theoretically
in the framework of Abrikosov-Gor'kov approach generalized to account for both
potential and spin-flip scattering in anisotropic superconductors. An
expression for the isotope coefficient as a function of the critical
temperature is obtained for a superconductor with an arbitrary contribution of
spin-flip processes to the total scattering rate and an arbitrary degree of
anisotropy of the superconducting order parameter, ranging from isotropic
s-wave to d-wave and including anisotropic s-wave and mixed (s+d)-wave as
particular cases. It is found that both magnetic and nonmagnetic impurities
enhance the isotope coefficient, the enhancement due to magnetic impurities
being generally greater than that due to nonmagnetic impurities. From the
analysis of the experimental results on La-Sr-Cu-M-O high temperature
superconductor, it is concluded that the symmetry of the pairing state in this
system differs from a pure d-wave.Comment: 4 pages, 3 figure
Dysfunctional dopaminergic neurotransmission in asocial BTBR mice
Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by pronounced social and communication deficits and stereotyped behaviours. Recent psychosocial and neuroimaging studies have highlighted reward-processing deficits and reduced dopamine (DA) mesolimbic circuit reactivity in ASD patients. However, the neurobiological and molecular determinants of these deficits remain undetermined. Mouse models recapitulating ASD-like phenotypes could help generate hypotheses about the origin and neurophysiological underpinnings of clinically relevant traits. Here we used functional magnetic resonance imaging (fMRI), behavioural and molecular readouts to probe dopamine neurotransmission responsivity in BTBR T+ Itpr3tf/J mice (BTBR), an inbred mouse line widely used to model ASD-like symptoms owing to its robust social and communication deficits, and high level of repetitive stereotyped behaviours. C57BL/6J (B6) mice were used as normosocial reference comparators. DA reuptake inhibition with GBR 12909 produced significant striatal DA release in both strains, but failed to elicit fMRI activation in widespread forebrain areas of BTBR mice, including mesolimbic reward and striatal terminals. In addition, BTBR mice exhibited no appreciable motor responses to GBR 12909. DA D1 receptor-dependent behavioural and signalling responses were found to be unaltered in BTBR mice, whereas dramatic reductions in pre- and postsynaptic DA D2 and adenosine A2A receptor function was observed in these animals. Overall these results document profoundly compromised DA D2-mediated neurotransmission in BTBR mice, a finding that is likely to have a role in the distinctive social and behavioural deficits exhibited by these mice. Our results call for a deeper investigation of the role of dopaminergic dysfunction in mouse lines exhibiting ASD-like phenotypes, and possibly in ASD patient populations
Poor screening and nonadiabatic superconductivity in correlated systems
In this paper we investigate the role of the electronic correlation on the
hole doping dependence of electron-phonon and superconducting properties of
cuprates. We introduce a simple analytical expression for the one-particle
Green's function in the presence of electronic correlation and we evaluate the
reduction of the screening properties as the electronic correlation increases
by approaching half-filling. The poor screening properties play an important
role within the context of the nonadiabatic theory of superconductivity. We
show that a consistent inclusion of the reduced screening properties in the
nonadiabatic theory can account in a natural way for the - phase
diagram of cuprates. Experimental evidences are also discussed.Comment: 12 Pages, 6 Figures, Accepted on Physical Review
Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development
Background: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. Methods: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. Results: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. Conclusions: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work
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