Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer<jats:sup>1</jats:sup>. Here we use a systematic approach to study spatial genome integrity in situ and describe previously unidentified clonal relationships. We used spatially resolved transcriptomics<jats:sup>2</jats:sup> to infer spatial copy number variations in &gt;120,000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Food and water are rewarding in part because they satisfy our internal needs<jats:sup>1,2</jats:sup>. Dopaminergic neurons in the ventral tegmental area (VTA) are activated by gustatory rewards<jats:sup>3–5</jats:sup>, but how animals learn to associate these oral cues with the delayed physiological effects of ingestion is unknown. Here we show that individual dopaminergic neurons in the VTA respond to detection of nutrients or water at specific stages of ingestion. A major subset of dopaminergic neurons tracks changes in systemic hydration that occur tens of minutes after thirsty mice drink water, whereas different dopaminergic neurons respond to nutrients in the gastrointestinal tract. We show that information about fluid balance is transmitted to the VTA by a hypothalamic pathway and then re-routed to downstream circuits that track the oral, gastrointestinal and post-absorptive stages of ingestion. To investigate the function of these signals, we used a paradigm in which a fluid’s oral and post-absorptive effects can be independently manipulated and temporally separated. We show that mice rapidly learn to prefer one fluid over another based solely on its rehydrating ability and that this post-ingestive learning is prevented if dopaminergic neurons in the VTA are selectively silenced after consumption. These findings reveal that the midbrain dopamine system contains subsystems that track different modalities and stages of ingestion, on timescales from seconds to tens of minutes, and that this information is used to drive learning about the consequences of ingestion.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Working memory—the brain’s ability to internalize information and use it flexibly to guide behaviour—is an essential component of cognition. Although activity related to working memory has been observed in several brain regions<jats:sup>1–3</jats:sup>, how neural populations actually represent working memory<jats:sup>4–7</jats:sup> and the mechanisms by which this activity is maintained<jats:sup>8–12</jats:sup> remain unclear<jats:sup>13–15</jats:sup>. Here we describe the neural implementation of visual working memory in mice alternating between a delayed non-match-to-sample task and a simple discrimination task that does not require working memory but has identical stimulus, movement and reward statistics. Transient optogenetic inactivations revealed that distributed areas of the neocortex were required selectively for the maintenance of working memory. Population activity in visual area AM and premotor area M2 during the delay period was dominated by orderly low-dimensional dynamics<jats:sup>16,17</jats:sup> that were, however, independent of working memory. Instead, working memory representations were embedded in high-dimensional population activity, present in both cortical areas, persisted throughout the inter-stimulus delay period, and predicted behavioural responses during the working memory task. To test whether the distributed nature of working memory was dependent on reciprocal interactions between cortical regions<jats:sup>18–20</jats:sup>, we silenced one cortical area (AM or M2) while recording the feedback it received from the other. Transient inactivation of either area led to the selective disruption of inter-areal communication of working memory. Therefore, reciprocally interconnected cortical areas maintain bound high-dimensional representations of working memory.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance<jats:sup>1–3</jats:sup>. Teixobactin<jats:sup>4</jats:sup> represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan<jats:sup>5</jats:sup>. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin<jats:sup>4</jats:sup>. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.</jats:p>

<jats:title>Abstract</jats:title><jats:p>The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes<jats:sup>1</jats:sup>. Despite their therapeutic potential<jats:sup>2</jats:sup>, our map of these surface interactions remains incomplete<jats:sup>3,4</jats:sup>. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention.</jats:p>