Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice

Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.     

Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor

Numerous inherited retinal degenerations exist in animals and humans, in which photoreceptors inexplicably degenerate and disappear. In RCS rats with inherited retinal dystrophy, the mutant gene is expressed in the retinal pigment epithelial (RPE) cell, and leads to the loss of photoreceptor cells. Photoreceptors can be rescued from degeneration if they are juxtaposed to wild-type RPE cells in experimental chimaeras or by the transplantation of RPE cells from normal rats. In both cases, the rescue effect extends beyond the immediate boundaries of the normal RPE cells, suggesting trophic action of a diffusible factor(s) from the normal RPE cells. We considered that the fibroblast growth factors, aFGF and bFGF, might have such a trophic role as they are found in the retina and RPE cells; bFGF acts as a neurotrophic agent after axonal injury in several regions of the central nervous system, and bFGF induces retinal regeneration from developing RPE cells. Here we report that subretinal injection of bFGF results in extensive rescue of photoreceptors in RCS rats for at least two months after the injection, and that intravitreal injection of bFGF results in even more widespread rescue, across almost the entire retina. The findings demonstrate for the first time that bFGF can act as a survival-promoting neurotrophic factor in a hereditary neuronal degeneration of the central nervous system.     

Common variants on 8p12 and 1q24.2 confer risk of schizophrenia

Schizophrenia is a severe mental disorder affecting ～1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10(-10)) and 1q24.2 (rs10489202, P = 9.50 × 10(-9)). Our findings provide new insights into the pathogenesis of schizophrenia.     

Elastic turbulence in a polymer solution flow

Turbulence is a ubiquitous phenomenon that is not fully understood. It is known that the flow of a simple, newtonian fluid is likely to be turbulent when the Reynolds number is large (typically when the velocity is high, the viscosity is low and the size of the tank is large). In contrast, viscoelastic fluids such as solutions of flexible long-chain polymers have nonlinear mechanical properties and therefore may be expected to behave differently. Here we observe experimentally that the flow of a sufficiently elastic polymer solution can become irregular even at low velocity, high viscosity and in a small tank. The fluid motion is excited in a broad range of spatial and temporal scales, and we observe an increase in the flow resistance by a factor of about twenty. Although the Reynolds number may be arbitrarily low, the observed flow has all the main features of developed turbulence. A comparable state of turbulent flow for a newtonian fluid in a pipe would have a Reynolds number as high as 10(5) (refs 1, 2). The low Reynolds number or 'elastic' turbulence that we observe is accompanied by significant stretching of the polymer molecules, resulting in an increase in the elastic stresses of up to two orders of magnitude.     

Inventing Electric Potential

Investigations with electrometers in the 1770s led Volta to envision mobile charge in electrical conductors as a compressible fluid. A pressure-like condition in this fluid, which Volta described as the fluid’s “effort to push itself out” of its conducting container, was the causal agent that makes the fluid move. In this paper I discuss Volta’s use of analogy and imagery in model building, and compare with a successful contemporary conceptual approach to introducing ideas about electric potential in instruction. The concept that today is called “electric potential” was defined mathematically by Poisson in 1811. It was understood after about 1850 to predict the same results in conducting matter as Volta’s pressure-like concept—and to predict electrostatic effects in the exterior space where Volta’s concept had nothing to say. Complete quantification in addition to greater generality made the mathematical concept a superior research tool for scientists. However, its spreading use in instruction has marginalized approaches to model building based on the analogy and imagery resources that students bring into the classroom. Data from pre and post testing in high schools show greater conceptual and confidence gains using the new conceptual approach than using conventional instruction. This provides evidence for reviving Volta’s compressible fluid model as an intuitive foundation which can then be modified to include electrostatic distant action. Volta tried to modify his compressible fluid model to include distant action, using imagery borrowed from distant heating by a flame. This project remained incomplete, because he did not envision an external field mediating the heating. However, pursuing Volta’s strategy of model modification to completion now enables students taught with the new conceptual approach to add distant action to an initial compressible fluid model. I suggest that a partial correspondence to the evolving model sequence that works for beginning students can help illuminate Volta’s use of intermediate explanatory models.