We demonstrate that exercise enables hippocampal-dependent learning in conditions that are normally subthreshold for encoding and memory formation, and depends on hippocampal induction of brain-derived neurotrophic factor (BDNF) as a key mechanism. Using a weak training paradigm in an object location memory (OLM) task, we show that sedentary mice are unable to discriminate 24 h later between familiar and novel object locations. In contrast, 3 weeks of prior voluntary exercise enables strong discrimination in the spatial memory task. Cognitive benefits of exercise match those attained with post-training sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor previously shown to enable subthreshold learning. We demonstrate that the enabling effects of exercise and NaB on subthreshold OLM learning are dependent on hippocampal BDNF upregulation, and are blocked by hippocampal infusion of BDNF short-interfering RNA. Exercise and NaB increased bdnf transcripts I and IV, and the increases were associated with BDNF promoter acetylation on H4K8 but not H4K12. These data provide support for the concept that exercise engages epigenetic control mechanisms and serves as a natural stimulus that operates in part like NaB and potentially other HDAC inhibitors, placing the brain into a state of readiness for plasticity.

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Quantifying the importance of the key sites on haemagglutinin in determining the selection advantage of influenza virus: Using A/H3N2 as an example Dear Editor , Declaration of Competing Interest MHW is a shareholder of Beth Bioinformatics Co., Ltd, and BCYZ is a shareholder of Beth Bioinformatics Co., Ltd and Health View Bioanalytics Ltd. Declarations Ethics approval and consent to participate The ethical approval or individual consent was not applicable. Availability of data and materials All influenza viruses sequence data were collected via the influenza virus database (IVD) of the National center for Biotechnology Information (NCBI). Please see the online supporting information for details. Consent for publication Not applicable.

The discovery that endoplasmic reticulum (ER) luminal chaperones such as GRP78/BiP can escape to the cell surface upon ER stress where they regulate cell signaling, proliferation, apoptosis, and immunity represents a paradigm shift. Toward deciphering the mechanisms, we report here that, upon ER stress, IRE1α binds to and triggers tyrosine kinase SRC activation, leading to ASAP1 phosphorylation and Golgi accumulation of ASAP1 and Arf1-GTP, resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. At the cell surface, GRP78 binds to and acts in concert with a glycosylphosphatidylinositol-anchored protein, CD109, in blocking TGF-β signaling by promoting the routing of the TGF-β receptor to the caveolae, thereby disrupting its binding to and activation of Smad2. Collectively, we uncover a SRC-mediated signaling cascade that leads to the relocalization of ER chaperones to the cell surface and a mechanism whereby GRP78 counteracts the tumor-suppressor effect of TGF-β.

Background: Axonal transport deficits are part of Alzheimer disease (AD) pathobiology. Results: ␤-Amyloid (A␤) impairs BDNF-dependent retrograde signaling, which is rescued by increasing cellular UCH-L1 levels. Conclusion: In AD, A␤ impairs neurotrophin-mediated retrograde signaling by disrupting ubiquitin homeostasis. Significance: Elucidating the mechanism by which A␤ causes transport deficits that compromise synaptic plasticity and neuronal survival is crucial for discovering novel therapeutics to reverse cognitive deficits in AD.