Plos Biol
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A focus on novel, confirmatory, and statistically significant results leads to substantial bias in the scientific literature. One type of bias, known as "p-hacking," occurs when researchers collect or select data or statistical analyses until nonsignificant results become significant. ⋯ We then illustrate how one can test for p-hacking when performing a meta-analysis and show that, while p-hacking is probably common, its effect seems to be weak relative to the real effect sizes being measured. This result suggests that p-hacking probably does not drastically alter scientific consensuses drawn from meta-analyses.
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Understanding how pain is processed in the brain has been an enduring puzzle, because there doesn't appear to be a single "pain cortex" that directly codes the subjective perception of pain. An emerging concept is that, instead, pain might emerge from the coordinated activity of an integrated brain network. In support of this view, Woo and colleagues present evidence that distinct brain networks support the subjective changes in pain that result from nociceptive input and self-directed cognitive modulation. This evidence for the sensitivity of distinct neural subsystems to different aspects of pain opens up the way to more formal computational network theories of pain.
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Central to research funding are grant proposals that researchers send in to potential funders for review, in the hope of approval. A survey of policies at major research funders found that there is room for more transparency in the process of grant review, which would strengthen the case for the efficiency of public spending on research. ⋯ The present article adds to this discussion by providing further context from the literature, along with considerations on the effect size of the proposed measures. The article then explores the option of opening to the public key components of the process, makes the case for pilot projects in this area, and sketches out the potential that such measures might have to transform the research landscape in those areas in which they are implemented.
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Diseases of protein folding arise because of the inability of an altered peptide sequence to properly engage protein homeostasis components that direct protein folding and function. To identify global principles of misfolding disease pathology we examined the impact of the local folding environment in alpha-1-antitrypsin deficiency (AATD), Niemann-Pick type C1 disease (NPC1), Alzheimer's disease (AD), and cystic fibrosis (CF). ⋯ We show that down-regulation of this maladaptive stress response (MSR), through silencing of HSF1, the master regulator of the HSR, restores cellular protein folding and improves the disease phenotype. We propose that restoration of a more physiological proteostatic environment will strongly impact the management and progression of loss-of-function and gain-of-toxic-function phenotypes common in human disease.
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Postsynaptic scaffolding proteins regulate coordinated neurotransmission by anchoring and clustering receptors and adhesion molecules. Gephyrin is the major instructive molecule at inhibitory synapses, where it clusters glycine as well as major subsets of GABA type A receptors (GABAARs). Here, we identified palmitoylation of gephyrin as an important mechanism of strengthening GABAergic synaptic transmission, which is regulated by GABAAR activity. ⋯ Furthermore, gephyrin pamitoylation potentiated GABAergic synaptic transmission, as evidenced by an increased amplitude of miniature inhibitory postsynaptic currents. Consistently, inhibiting gephyrin palmitoylation either pharmacologically or by expression of palmitoylation-deficient gephyrin reduced the gephyrin cluster size. In aggregate, our study reveals that palmitoylation of gephyrin by DHHC-12 contributes to dynamic and functional modulation of GABAergic synapses.