Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDAR synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice, and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a novel strategy for autism treatment.

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Highlights d FACS of NURR1::GFP dopaminergic (DA) precursors enriches DA neuron culture purity d SATB1 KO DA neurons show hallmarks of cellular senescence, including SASP d SATB1 is required to repress CDKN1A in DA neurons d Senescence induced by SATB1 reduction in vivo induces microglial activation

Understanding the influence of gene expression on the molecular mechanisms underpinning human phenotypic diversity is fundamental to being able to predict health outcomes and treat disease. We have carried out whole transcriptome expression analysis on a series of eight normal human postmortem eyes by RNA sequencing. Here we present data showing that ∼80% of the transcriptome is expressed in the posterior layers of the eye and that there is significant differential expression not only between the layers of the posterior part of the eye but also between locations of a tissue layer. These differences in expression also extend to alternative splicing and splicing factors. Differentially expressed genes are enriched for genes associated with psychiatric, immune and cardiovascular disorders. Enrichment categories for gene ontology included ion transport, synaptic transmission and visual and sensory perception. Lastly, allele-specific expression was found to be significant forCFH,C3 andCFB, which are known risk genes for age-related macular degeneration. These expression differences should be useful in determining the underlying biology of associations with common diseases of the human retina, retinal pigment epithelium and choroid and in guiding the analysis of the genomic regions involved in the control of normal gene expression.

We evaluated the type and amount of physical activity associated with risk of endometrial cancer. In this population-based case-control study, in-person interviews were completed among 832 incident endometrial cancer cases and 846 age-matched controls. Physical activity from exercise, household activities, and transportation was assessed in adolescence and adulthood, as was lifetime occupational activity. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence limits (95% CL). Women reporting exercise participation in both adolescence and adulthood were at nearly a 40% reduced risk (OR, 0.63; 95% CL, 0.42-0.95), compared with women reporting no exercise in either life period. Postmenopausal women who initiated exercise in adulthood were also at reduced risk (OR, 0.76; 95% CL, 0.56-1.02). Reductions in risk were also observed for common lifestyle activities, including household activity (both life periods) and walking for transportation (adulthood). Examination of the independent and combined effect of exercise and lifestyle activities revealed that women with less active lifestyles but who reported exercise were at 35% reduced risk (OR, 0.65; 95% CL, 0.41-1.02), whereas nonexercisers with more active lifestyles were at 40% to 45% reduced risk. These findings suggest that both lifestyle activities of lower intensity (e.g., walking and doing household chores) and intentional exercise can reduce endometrial cancer risk. (Cancer Epidemiol Biomarkers Prev 2005;14(4):779 -85)