Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>Nitrogen dioxide (NO<jats:sub>2</jats:sub>) is an important contributor to air pollution and can adversely affect human health<jats:sup>1–9</jats:sup>. A decrease in NO<jats:sub>2</jats:sub> concentrations has been reported as a result of lockdown measures to reduce the spread of COVID-19<jats:sup>10–20</jats:sup>. Questions remain, however, regarding the relationship of satellite-derived atmospheric column NO<jats:sub>2</jats:sub> data with health-relevant ambient ground-level concentrations, and the representativeness of limited ground-based monitoring data for global assessment. Here we derive spatially resolved, global ground-level NO<jats:sub>2</jats:sub> concentrations from NO<jats:sub>2</jats:sub> column densities observed by the TROPOMI satellite instrument at sufficiently fine resolution (approximately one kilometre) to allow assessment of individual cities during COVID-19 lockdowns in 2020 compared to 2019. We apply these estimates to quantify NO<jats:sub>2</jats:sub> changes in more than 200 cities, including 65 cities without available ground monitoring, largely in lower-income regions. Mean country-level population-weighted NO<jats:sub>2</jats:sub> concentrations are 29% ± 3% lower in countries with strict lockdown conditions than in those without. Relative to long-term trends, NO<jats:sub>2</jats:sub> decreases during COVID-19 lockdowns exceed recent Ozone Monitoring Instrument (OMI)-derived year-to-year decreases from emission controls, comparable to 15 ± 4 years of reductions globally. Our case studies indicate that the sensitivity of NO<jats:sub>2</jats:sub> to lockdowns varies by country and emissions sector, demonstrating the critical need for spatially resolved observational information provided by these satellite-derived surface concentration estimates.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Transatlantic exploration took place centuries before the crossing of Columbus. Physical evidence for early European presence in the Americas can be found in Newfoundland, Canada<jats:sup>1,2</jats:sup>. However, it has thus far not been possible to determine when this activity took place<jats:sup>3–5</jats:sup>. Here we provide evidence that the Vikings were present in Newfoundland in <jats:sc>ad</jats:sc> 1021. We overcome the imprecision of previous age estimates by making use of the cosmic-ray-induced upsurge in atmospheric radiocarbon concentrations in <jats:sc>ad</jats:sc> 993 (ref. <jats:sup>6</jats:sup>). Our new date lays down a marker for European cognisance of the Americas, and represents the first known point at which humans encircled the globe. It also provides a definitive tie point for future research into the initial consequences of transatlantic activity, such as the transference of knowledge, and the potential exchange of genetic information, biota and pathologies<jats:sup>7,8</jats:sup>.</jats:p>

<jats:title>Abstract</jats:title><jats:p>During neurogenesis, mitotic progenitor cells lining the ventricles of the embryonic mouse brain undergo their final rounds of cell division, giving rise to a wide spectrum of postmitotic neurons and glia<jats:sup>1,2</jats:sup>. The link between developmental lineage and cell-type diversity remains an open question. Here we used massively parallel tagging of progenitors to track clonal relationships and transcriptomic signatures during mouse forebrain development. We quantified clonal divergence and convergence across all major cell classes postnatally, and found diverse types of GABAergic neuron that share a common lineage. Divergence of GABAergic clones occurred during embryogenesis upon cell-cycle exit, suggesting that differentiation into subtypes is initiated as a lineage-dependent process at the progenitor cell level.</jats:p>

<jats:title>Abstract</jats:title><jats:p>The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans<jats:sup>1</jats:sup>. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 μg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (<jats:italic>n</jats:italic> = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden<jats:sup>1</jats:sup>. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method<jats:sup>2</jats:sup>. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.</jats:p>

<jats:title>Abstract</jats:title><jats:p>The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling<jats:sup>1</jats:sup> and is altered in over 20% of cancers<jats:sup>2,3</jats:sup>. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)<jats:sup>+</jats:sup> forkhead box A1 (FOXA1)<jats:sup>+</jats:sup> prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts <jats:italic>cis</jats:italic>-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the <jats:italic>AR</jats:italic>, <jats:italic>FOXA1</jats:italic> and <jats:italic>MYC</jats:italic> oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.</jats:p>