Henningsenproctor0984

Mix23 is critical for the efficient import of proteins into the mitochondrial matrix, particularly if the function of the translocase of the inner membrane 23 is compromised such as in temperature-sensitive mutants of Tim17. Our observations identify Mix23 as a novel regulator or stabilizer of the mitochondrial protein import machinery that is specifically up-regulated upon mitoprotein-induced stress conditions.Most proteins in the secretory pathway are glycosylated. However, the role of glycans in membrane trafficking is still unclear. Here, we discovered that transmembrane secretory cargos, such as interleukin 2 receptor α subunit or Tac, transferrin receptor, and cluster of differentiation 8a, unexpectedly displayed substantial Golgi localization when their O-glycosylation was compromised. By quantitatively measuring their Golgi residence times, we found that the observed Golgi localization of O-glycan-deficient cargos is due to their slow Golgi export. Using a superresolution microscopy method that we previously developed, we revealed that O-glycan-deficient Tac chimeras localize at the interior of the trans-Golgi cisternae. O-Glycans were observed to be both necessary and sufficient for the efficient Golgi export of Tac chimeras. Citarinostat price By sequentially introducing O-glycosylation sites to ST6GAL1, we demonstrated that O-glycan's effect on Golgi export is probably additive. Finally, the finding that N-glycosylated GFP substantially reduces the Golgi residence time of a Tac chimera suggests that N-glycans might have a similar effect. Therefore, both O- and N-glycans might function as a generic Golgi export signal at the trans-Golgi to promote the constitutive exocytic trafficking.Mutations in the skeletal muscle ryanodine receptor gene (RYR1) can cause susceptibility to malignant hyperthermia (MH), a potentially lethal genetic condition triggered by volatile anesthetics. MH is associated with hypermetabolism, which has directed research interest into oxidative phosphorylation and muscle bioenergetics. The most common cause of MH in the United Kingdom is the c.7300G>A RYR1 variant, which is present in ∼16% of MH families. Our study focuses on the MH susceptible G2435R-RYR1 knock-in mouse model, which is the murine equivalent of the human c.7300G>A genotype. Using a combination of transcriptomics, protein expression, and functional analysis, we investigated adult muscle fiber bioenergetics in this mouse model. RNA-Seq data showed reduced expression of genes associated with mitochondria and fatty acid oxidation in RYR1 mutants when compared with WT controls. Mitochondrial function was assessed by measuring oxygen consumption rates in permeabilized muscle fibers. Comparisons between WT and homozygous G2435R-RYR1 mitochondria showed a significant increase in complex I-facilitated oxidative phosphorylation in mutant muscle. Furthermore, we observed a gene-dose-specific increase in reactive oxygen species production in G2435R-RYR1 muscle fibers. Collectively, these findings provide evidence of metabolic defects in G2435R-RYR1 knock-in mouse muscle under basal conditions. Differences in metabolic profile could be the result of differential gene expression in metabolic pathways, in conjunction with mitochondrial damage accumulated from chronic exposure to increased oxidative stress.Through statistical learning (SL), cognitive systems may discover the underlying regularities in the environment. Testing human adults (n = 35, 21 females), we document, in the context of a classical visual SL task, divergent rhythmic EEG activity in the interstimulus delay periods within patterns versus between patterns (i.e., pattern transitions). Our findings reveal increased oscillatory activity in the beta band (∼20 Hz) at triplet transitions that indexes learning it emerges with increased pattern repetitions; and importantly, it is highly correlated with behavioral learning outcomes. These findings hold the promise of converging on an online measure of learning regularities and provide important theoretical insights regarding the mechanisms of SL and prediction.SIGNIFICANCE STATEMENT Statistical learning has become a major theoretical construct in cognitive science, providing the primary means by which organisms learn about regularities in the environment. As such, it is a critical building block for basic and higher-order cognitive functions. Here we identify, for the first time, a spectral neural index in the time window before stimulus presentation, which evolves with increased pattern exposure, and is predictive of learning performance. The manifestation of learning that is revealed, not in stimulus processing but in the blank interval between stimuli, makes a direct link between the fields of statistical learning on the one hand and either prediction or consolidation on the other hand, suggesting a possible mechanistic account of visual statistical learning.The hippocampal formation encodes maps of space and a key question in neuroscience is whether its spatial coding principles also provide a universal metric for the organization of nonspatial, conceptual information. Previous work demonstrated directional coding during navigation through a continuous stimulus feature space as well as mapping of distances in a feature space that was relevant for concept learning. Here we provide the first unambiguous evidence for a hippocampal representation of the actual concept space, by showing that the hippocampal distance signal selectively reflects the mapping of specifically conceptually relevant rather than of all feature dimensions. During fMRI scanning of 32 human participants (21 females), we presented everyday objects, which had beforehand been associated with specific values on three continuous feature dimensions. Crucially, only two dimensions were relevant to prior concept learning. We find that hippocampal responses to the objects reflect their relative distances in a space defined along conceptually relevant dimensions compared with distances in a space defined along all feature dimensions. These findings suggest that the hippocampus supports knowledge acquisition by dynamically encoding information in a space spanned along dimensions that are relevant in relation to define concepts.SIGNIFICANCE STATEMENT How are neural representations of conceptual knowledge organized, such that humans are able to infer never experienced relations or categorize new exemplars? Map-like representations as supported by the hippocampal formation to encode physical space during navigation have been suggested as a suitable format. Here we provide the first evidence for a hippocampal representation of a conceptual space compared with a general feature-based space.