Publications
Moving beyond P values: data analysis with estimation graphics.
For at least 77 years, the limitations of null-hypothesis significance testing (NHST) have been discussed, without agreement on a suitable alternative. Estimation methods that estimate effect sizes and their uncertainty have great potential to shift the current data-analysis culture away from dichotomous thinking and toward quantitative reasoning. Although NHST limits the analyst to the ill-conceived question of “Does it?”, estimation instead draws the analyst’s attention to the question of “How much?”—the very topic that defines quantitative research. Here we describe the estimation graphic, a plot that displays an experimental dataset’s complete statistical information. We also introduce software that makes high-quality estimation graphics available to all.
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Altered steady state and activity-dependent de novo protein expression in fragile X syndrome.
Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.
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Turning up translation in fragile X syndrome.
Fragile X syndrome (FXS) is the most prevalent inherited form of intellectual disability and autism. FXS is usually caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene, which encodes fragile X mental retardation protein (FMRP), an RNA-binding protein that is thought to repress the translation of specific messenger RNAs (mRNAs). Precise translational control is especially critical in neurons because rapid synthesis of proteins from preexisting mRNAs underlies many forms of synaptic plasticity, which is altered in animal models of FXS. Progress has been made in identifying RNAs that FMRP binds, but its functional targets and modes of translational control remain elusive, especially during development. On page 709 of this issue, Greenblatt and Spradling use Drosophila melanogaster oocytes to demonstrate that FMRP increases the translation of multiple long mRNAs, many of which are implicated in intellectual disability and autism.
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Ancient Anxiety Pathways Influence Drosophila Defense Behaviors.
Anxiety helps us anticipate and assess potential danger in ambiguous situations; however, the anxiety disorders are the most prevalent class of psychiatric illness. Emotional states are shared between humans and other animals, as observed by behavioral manifestations, physiological responses, and gene conservation. Anxiety research makes wide use of three rodent behavioral assays-elevated plus maze, open field, and light/dark box-that present a choice between sheltered and exposed regions. Exposure avoidance in anxiety-related defense behaviors was confirmed to be a correlate of rodent anxiety by treatment with known anxiety-altering agents and is now used to characterize anxiety systems. Modeling anxiety with a small neurogenetic animal would further aid the elucidation of its neuronal and molecular bases. Drosophila neurogenetics research has elucidated the mechanisms of fundamental behaviors and implicated genes that are often orthologous across species. In an enclosed arena, flies stay close to the walls during spontaneous locomotion, a behavior proposed to be related to anxiety. We tested this hypothesis with manipulations of the GABA receptor, serotonin signaling, and stress. The effects of these interventions were strikingly concordant with rodent anxiety, verifying that these behaviors report on an anxiety-like state. Application of this method was able to identify several new fly anxiety genes. The presence of conserved neurogenetic pathways in the insect brain identifies Drosophila as an attractive genetic model for the study of anxiety and anxiety-related disorders, complementing existing rodent systems.