Summary Autism spectrum disorder is typical of the majority of neuropsychiatric syndromes in that it is defined by signs and symptoms, rather than by aetiology. Not surprisingly, the causes of this ...complex human condition are manifold and include a substantial genetic component. Recent developments in gene-hunting technologies and methods, and the resulting plethora of genetic findings, promise to open new avenues to understanding of disease pathophysiology and to contribute to improved clinical management. Despite remarkable genetic heterogeneity, evidence is emerging for converging pathophysiology in autism spectrum disorder, but how this notion of convergent pathways will translate into therapeutics remains to be established. Leveraging genetic findings through advances in model systems and integrative genomic approaches could lead to the development of new classes of therapies and a personalised approach to treatment.
Recent progress in the genomics of non-syndromic autism spectrum disorder (nsASD) highlights rare, large-effect, germline, heterozygous de novo coding mutations. This distinguishes nsASD from ...later-onset psychiatric disorders where gene discovery efforts have predominantly yielded common alleles of small effect. These differences point to distinctive opportunities for clarifying the neurobiology of nsASD and developing novel treatments. We argue that the path ahead also presents key challenges, including distinguishing human pathophysiology from the potentially pleiotropic neurobiology mediated by established risk genes. We present our view of some of the conceptual limitations of traditional studies of model organisms, suggest a strategy focused on investigating the convergence of multiple nsASD genes, and propose that the detailed characterization of the molecular and cellular landscapes of developing human brain is essential to illuminate disease mechanisms. Finally, we address how recent advances are leading to novel strategies for therapeutics that target various points along the path from genes to behavior.
Sestan and State propose that the distinctive genomic findings in autism spectrum disorder, the deepening understanding of developing human brain, and the identification of spatiotemporal convergence of large-effect risk genes will help clarify pathophysiological mechanisms and identify novel treatment approaches.
Recent progress in the identification of genes and genomic regions contributing to autism spectrum disorder (ASD) has had a broad impact on our understanding of the nature of genetic risk for a range ...of psychiatric disorders, on our understanding of ASD biology, and on defining the key challenges now facing the field in efforts to translate gene discovery into an actionable understanding of pathology. While these advances have not yet had a transformative impact on clinical practice, there is nonetheless cause for real optimism: reliable lists of risk genes are large and growing rapidly; the identified encoded proteins have already begun to point to a relatively small number of areas of biology, where parallel advances in neuroscience and functional genomics are yielding profound insights; there is strong evidence pointing to mid-fetal prefrontal cortical development as one nexus of vulnerability for some of the largest-effect ASD risk genes; and there are multiple plausible paths forward toward rational therapeutics development that, while admittedly challenging, constitute fundamental departures from what was possible prior to the era of successful gene discovery.
Recent advances in the genetics of autism spectrum disorders (ASDs) are offering new valuable insights into molecular and cellular mechanisms of pathology. At the same time, the emerging data ...challenge long-standing diagnostic conventions and the notion of phenotypic specificity. This review addresses the particular issues that attend gene discovery in neuropsychiatric and neurodevelopmental disorders and ASDs in particular, summarizes recent findings in human genetics broadly that are driving the reevaluation of the conventional wisdom regarding the allelic architecture of common psychiatric conditions, reviews selected discoveries in ASDs and their relevance to models of pathology, highlights the conceptual and practical issues raised by the observation of a convergence of ASD genetic risks with distinct psychiatric disorders, and considers the important interplay of studies of neurobiology and genetics in clarifying and extending our understanding of social disability syndromes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Investigations into the genetics of child psychiatric disorders have finally begun to shed light on molecular and cellular mechanisms of psychopathology. The first strains of success in this ...notoriously difficult area of inquiry are the result of an increasingly sophisticated appreciation of the allelic architecture of common neuropsychiatric and neurodevelopmental disorders, the consolidation of large patient cohorts now beginning to reach sufficient size to power reliable studies, the emergence of genomic tools enabling comprehensive investigations of rare as well as common genetic variation, and advances in developmental neuroscience that are fueling the rapid translation of genetic findings.
Recent findings in a range of scientific disciplines are challenging the conventional wisdom regarding the etiology, classification, and treatment of psychiatric disorders. This Review focuses on the ...current state of the psychiatric diagnostic nosology and recent progress in three areas: genomics, neuroimaging, and therapeutics development. The accelerating pace of novel and unexpected findings is transforming the understanding of mental illness and represents a hopeful sign that the approaches and models that have sustained the field for the past 40 years are yielding to a flood of new data and presaging the emergence of a new and more powerful scientific paradigm.
ABSTRACT
We use a 3D radiative non-ideal magnetohydrodynamic simulation to investigate the formation and evolution of a young protostellar disc from a magnetized pre-stellar core. The simulation ...covers the first ${\sim }10\, {\rm kyr}$ after protostar formation and shows a massive, weakly magnetized disc with radius that initially grows and then saturates at ${\sim }30\, {\rm au}$. The disc is gravitationally unstable with prominent large-amplitude spiral arms. We use our simulation results and a series of physical arguments to construct a predictive and quantitative physical picture of Class 0/I protostellar disc evolution from several aspects, including (i) the angular-momentum redistribution in the disc, self-regulated by gravitational instability to make most of the disc marginally unstable; (ii) the thermal profile of the disc, well-approximated by a balance between radiative cooling and accretion heating; and (iii) the magnetic-field strength and magnetic-braking rate inside the disc, regulated by non-ideal magnetic diffusion. Using these physical insights, we build a simple 1D semi-analytic model of disc evolution. We show that this 1D model, when coupled to a computationally inexpensive simulation for the evolution of the surrounding pseudo-disc, can be used reliably to predict disc evolution in the Class 0/I phase. The predicted long-term evolution of disc size, which saturates at ${\sim }30\, {\rm au}$ and eventually shrinks, is consistent with a recent observational survey of Class 0/I discs. Such hierarchical modelling of disc evolution circumvents the computational difficulty of tracing disc evolution through Class 0/I phase with direct, numerically converged simulations.
ABSTRACT
We investigate the formation and early evolution of a protostellar disc from a magnetized prestellar core using non-ideal magnetohydrodynamic (MHD) simulations including ambipolar diffusion ...and Ohmic dissipation. The dynamical contraction of the prestellar core ultimately leads to the formation of a first hydrostatic core, after ambipolar diffusion decouples the magnetic field from the predominantly neutral gas. The hydrostatic core accumulates angular momentum from the infalling material, evolving into a rotationally supported torus; this ‘first hydrostatic torus’ then forms an accreting protostar and a rotationally supported disc. The disc spreads out by gravitational instability, reaching ∼30 au in diameter at ∼3 kyr after protostar formation. The total mass and angular momentum of the protostar–disc system are determined mainly by accretion of gas from an infalling pseudo-disc, which has low specific angular momentum because of magnetic braking; their removal from the protostar–disc system by outflow and disc magnetic braking are negligible, in part because the magnetic field is poorly coupled there. The redistribution of angular momentum within the protostar–disc system is facilitated mainly by gravitational instability; this allows formation of relatively large discs even when the specific angular momentum of infalling material is low. We argue that such discs should remain marginally unstable as they grow (with Toomre Q ∼ 1–2), an idea that is broadly consistent with recent observational estimates for Class 0/I discs. We discuss the numerical convergence of our results, and show that properly treating the inner boundary condition is crucial for achieving convergence at an acceptable computational cost.
Layered transition-metal trichalcogenides with the chemical formula ABX3 have attracted recent interest as potential candidates for two-dimensional magnets. Using first-principles calculations within ...density functional theory, we investigate the magnetic ground states of monolayers of Mn- and Cr-based semiconducting trichalcogenides.We show that the second and third nearest-neighbor exchange interactions (J2 and J3) between magnetic ions, which have been largely overlooked in previous theoretical studies, are crucial in determining the magnetic ground state. Specifically, we find that monolayer CrSiTe3 is an antiferromagnet with a zigzag spin texture due to significant contribution from J3, whereas CrGeTe3 is a ferromagnet with a Curie temperature of 106 K. Monolayers of Mn compounds (MnPS3 and MnPSe3) always show antiferromagnetic N eel order. We identify the physical origin of various exchange interactions, and demonstrate that strain can be an effective knob for tuning the magnetic properties. Possible magnetic ordering in the bulk is also discussed. In conclusion, our study suggests that ABX3 can be a promising platform to explore two-dimensional magnetic phenomena.
The Emerging Biology of Autism Spectrum Disorders State, Matthew W.; Šestan, Nenad
Science (American Association for the Advancement of Science),
09/2012, Letnik:
337, Številka:
6100
Journal Article
Recenzirano
Odprti dostop
Expression patterns of the diverse genes disrupted in autism spectrum disorders in the developing brain give a fresh perspective on the underlying biology.
Autism spectrum disorders (ASD) are a ...genetically and phenotypically heterogeneous group of syndromes defined by fundamental impairments in social reciprocity and language development accompanied by highly restrictive interests and/or repetitive behaviors. Recent advances in genetics, genomics, developmental neurobiology, systems biology, monogenic neurodevelopment syndromes, and induced pluripotent stem cells (iPSC) are now offering remarkable insights into their etiologies and converging to provide a clear and immediate path forward from the bench to the bedside.
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