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<jats:title>Abstract</jats:title><jats:p>The medial entorhinal cortex is part of a neural system for mapping the position of an individual within a physical environment<jats:sup>1</jats:sup>. Grid cells, a key component of this system, fire in a characteristic hexagonal pattern of locations<jats:sup>2</jats:sup>, and are organized in modules<jats:sup>3</jats:sup> that collectively form a population code for the animal’s allocentric position<jats:sup>1</jats:sup>. The invariance of the correlation structure of this population code across environments<jats:sup>4,5</jats:sup> and behavioural states<jats:sup>6,7</jats:sup>, independent of specific sensory inputs, has pointed to intrinsic, recurrently connected continuous attractor networks (CANs) as a possible substrate of the grid pattern<jats:sup>1,8–11</jats:sup>. However, whether grid cell networks show continuous attractor dynamics, and how they interface with inputs from the environment, has remained unclear owing to the small samples of cells obtained so far. Here, using simultaneous recordings from many hundreds of grid cells and subsequent topological data analysis, we show that the joint activity of grid cells from an individual module resides on a toroidal manifold, as expected in a two-dimensional CAN. Positions on the torus correspond to positions of the moving animal in the environment. Individual cells are preferentially active at singular positions on the torus. Their positions are maintained between environments and from wakefulness to sleep, as predicted by CAN models for grid cells but not by alternative feedforward models<jats:sup>12</jats:sup>. This demonstration of network dynamics on a toroidal manifold provides a population-level visualization of CAN dynamics in grid cells.</jats:p>

<jats:title>Abstract</jats:title><jats:p>The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics<jats:sup>1</jats:sup>. Here we show that particular lineages of methicillin-resistant <jats:italic>Staphylococcus aureus</jats:italic>—a notorious human pathogen—appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte <jats:italic>Trichophyton erinacei</jats:italic> produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant <jats:italic>S. aureus</jats:italic> isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of <jats:italic>S. aureus</jats:italic> to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen<jats:sup>1,2</jats:sup>. Since the outbreak of the ongoing COVID-19 pandemic, a key question has focused on which SARS-CoV-2-specific T cells stimulated during acute infection give rise to long-lived memory T cells<jats:sup>3</jats:sup>. Here, using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor sequencing, we longitudinally characterized individual SARS-CoV-2-specific CD8<jats:sup>+</jats:sup> T cells of patients with COVID-19 from acute infection to 1 year into recovery and found a distinct signature identifying long-lived memory CD8<jats:sup>+</jats:sup> T cells. SARS-CoV-2-specific memory CD8<jats:sup>+</jats:sup> T cells persisting 1 year after acute infection express CD45RA, IL-7 receptor-α and T cell factor 1, but they maintain low expression of CCR7, thus resembling CD45RA<jats:sup>+</jats:sup> effector memory T cells. Tracking individual clones of SARS-CoV-2-specific CD8<jats:sup>+</jats:sup> T cells, we reveal that an interferon signature marks clones that give rise to long-lived cells, whereas prolonged proliferation and mechanistic target of rapamycin signalling are associated with clonal disappearance from the blood. Collectively, we describe a transcriptional signature that marks long-lived, circulating human memory CD8<jats:sup>+</jats:sup> T cells following an acute viral infection.</jats:p>