Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>Cultivated oat (<jats:italic>Avena sativa</jats:italic> L.) is an allohexaploid (AACCDD, 2<jats:italic>n</jats:italic> = 6<jats:italic>x</jats:italic> = 42) thought to have been domesticated more than 3,000 years ago while growing as a weed in wheat, emmer and barley fields in Anatolia<jats:sup>1,2</jats:sup>. Oat has a low carbon footprint, substantial health benefits and the potential to replace animal-based food products. However, the lack of a fully annotated reference genome has hampered efforts to deconvolute its complex evolutionary history and functional gene dynamics. Here we present a high-quality reference genome of <jats:italic>A</jats:italic>. <jats:italic>sativa</jats:italic> and close relatives of its diploid (<jats:italic>Avena longiglumis</jats:italic>, AA, 2<jats:italic>n</jats:italic> = 14) and tetraploid (<jats:italic>Avena insularis</jats:italic>, CCDD, 2<jats:italic>n</jats:italic> = 4<jats:italic>x</jats:italic> = 28) progenitors. We reveal the mosaic structure of the oat genome, trace large-scale genomic reorganizations in the polyploidization history of oat and illustrate a breeding barrier associated with the genome architecture of oat. We showcase detailed analyses of gene families implicated in human health and nutrition, which adds to the evidence supporting oat safety in gluten-free diets, and we perform mapping-by-sequencing of an agronomic trait related to water-use efficiency. This resource for the <jats:italic>Avena</jats:italic> genus will help to leverage knowledge from other cereal genomes, improve understanding of basic oat biology and accelerate genomics-assisted breeding and reanalysis of quantitative trait studies.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together<jats:sup>1–3</jats:sup>. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents—which normally mediate touch sensation as well as allodynia in intact nerve territories after injury<jats:sup>4–7</jats:sup>—did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Oestradiol establishes neural sex differences in many vertebrates<jats:sup>1–3</jats:sup> and modulates mood, behaviour and energy balance in adulthood<jats:sup>4–8</jats:sup>. In the canonical pathway, oestradiol exerts its effects through the transcription factor oestrogen receptor-α (ERα)<jats:sup>9</jats:sup>. Although ERα has been extensively characterized in breast cancer, the neuronal targets of ERα, and their involvement in brain sex differences, remain largely unknown. Here we generate a comprehensive map of genomic ERα-binding sites in a sexually dimorphic neural circuit that mediates social behaviours. We conclude that ERα orchestrates sexual differentiation of the mouse brain through two mechanisms: establishing two male-biased neuron types and activating a sustained male-biased gene expression program. Collectively, our findings reveal that sex differences in gene expression are defined by hormonal activation of neuronal steroid receptors. The molecular targets we identify may underlie the effects of oestradiol on brain development, behaviour and disease.</jats:p>

<jats:title>Abstract</jats:title><jats:p>T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age<jats:sup>1–10</jats:sup>. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice<jats:sup>11–18</jats:sup>; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved<jats:sup>1,12,16,17,19–27</jats:sup>. Here we combine scRNA-seq and a new CRISPR–Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Missense driver mutations in cancer are concentrated in a few hotspots<jats:sup>1</jats:sup>. Various mechanisms have been proposed to explain this skew, including biased mutational processes<jats:sup>2</jats:sup>, phenotypic differences<jats:sup>3–6</jats:sup> and immunoediting of neoantigens<jats:sup>7,8</jats:sup>; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical ‘free fitness’ framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on <jats:italic>TP53</jats:italic>, the most mutated gene in cancer<jats:sup>1</jats:sup>, we present an inference of mutant p53 concentration and demonstrate that <jats:italic>TP53</jats:italic> hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The Cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of <jats:italic>TP53</jats:italic> variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on <jats:italic>TP53</jats:italic> mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.</jats:p>