Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>The hippocampal cognitive map supports navigation towards, or away from, salient locations in familiar environments<jats:sup>1</jats:sup>. Although much is known about how the hippocampus encodes location in world-centred coordinates, how it supports flexible navigation is less well understood. We recorded CA1 place cells while rats navigated to a goal on the honeycomb maze<jats:sup>2</jats:sup>. The maze tests navigation via direct and indirect paths to the goal and allows the directionality of place cells to be assessed at each choice point. Place fields showed strong directional polarization characterized by vector fields that converged to sinks distributed throughout the environment. The distribution of these ‘convergence sinks’ (ConSinks) was centred near the goal location and the population vector field converged on the goal, providing a strong navigational signal. Changing the goal location led to movement of ConSinks and vector fields towards the new goal. The honeycomb maze allows independent assessment of spatial representation and spatial action in place cell activity and shows how the latter relates to the former. The results suggest that the hippocampus creates a vector-based model to support flexible navigation, allowing animals to select optimal paths to destinations from any location in the environment.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Oocytes form before birth and remain viable for several decades before fertilization<jats:sup>1</jats:sup>. Although poor oocyte quality accounts for most female fertility problems, little is known about how oocytes maintain cellular fitness, or why their quality eventually declines with age<jats:sup>2</jats:sup>. Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilization and embryo survival<jats:sup>3–5</jats:sup>. Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain through elimination of complex I. Combining live-cell imaging and proteomics in human and <jats:italic>Xenopus</jats:italic> oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced electron transport chain. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report a physiological cell type without complex I in animals. Our findings also clarify why patients with complex-I-related hereditary mitochondrial diseases do not experience subfertility. Complex I suppression represents an evolutionarily conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Mutations of the <jats:italic>ADAR1</jats:italic> gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon (IFN) responses, including Aicardi–Goutières syndrome and bilateral striatal necrosis<jats:sup>1–3</jats:sup>. The IFN-inducible p150 isoform of ADAR1 contains a Zα domain that recognizes RNA with an alternative left-handed double-helix structure, termed Z-RNA<jats:sup>4,5</jats:sup>. Hemizygous <jats:italic>ADAR1</jats:italic> mutations in the Zα domain cause type I IFN-mediated pathologies in humans<jats:sup>2,3</jats:sup> and mice<jats:sup>6–8</jats:sup>; however, it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation. Here we show that Z-DNA-binding protein 1 (ZBP1), the only other protein in mammals known to harbour Zα domains<jats:sup>9</jats:sup>, promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Zα domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zα domain (<jats:italic>Adar1</jats:italic><jats:sup><jats:italic>mZα</jats:italic>/–</jats:sup> mice). <jats:italic>Adar1</jats:italic><jats:sup><jats:italic>mZα</jats:italic>/–</jats:sup> mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads, which represent a likely source of Z-RNAs activating ZBP1. Notably, ZBP1 promoted IFN activation and severe pathology in <jats:italic>Adar1</jats:italic><jats:sup><jats:italic>mZα</jats:italic>/–</jats:sup> mice in a manner independent of RIPK1, RIPK3, MLKL-mediated necroptosis and caspase-8-dependent apoptosis, suggesting a novel mechanism of action. Thus, ADAR1 prevents endogenous Z-RNA-dependent activation of pathogenic type I IFN responses by ZBP1, suggesting that ZBP1 could contribute to type I interferonopathies caused by <jats:italic>ADAR1</jats:italic> mutations.</jats:p>

<jats:title>Abstract</jats:title><jats:p>The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer<jats:sup>1–3</jats:sup>. However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time<jats:sup>4</jats:sup>. Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that <jats:italic>APOBEC3A</jats:italic> deletion diminished APOBEC3-associated mutational signatures. Deletion of both <jats:italic>APOBEC3A</jats:italic> and <jats:italic>APOBEC3B</jats:italic> further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of <jats:italic>APOBEC3B</jats:italic> increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures.</jats:p>