Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>The Cretaceous–Palaeogene mass extinction around 66 million years ago was triggered by the Chicxulub asteroid impact on the present-day Yucatán Peninsula<jats:sup>1,2</jats:sup>. This event caused the highly selective extinction that eliminated about 76% of species<jats:sup>3,4</jats:sup>, including all non-avian dinosaurs, pterosaurs, ammonites, rudists and most marine reptiles. The timing of the impact and its aftermath have been studied mainly on millennial timescales, leaving the season of the impact unconstrained. Here, by studying fishes that died on the day the Mesozoic era ended, we demonstrate that the impact that caused the Cretaceous–Palaeogene mass extinction took place during boreal spring. Osteohistology together with stable isotope records of exceptionally preserved perichondral and dermal bones in acipenseriform fishes from the Tanis impact-induced seiche deposits<jats:sup>5</jats:sup> reveal annual cyclicity across the final years of the Cretaceous period. Annual life cycles, including seasonal timing and duration of reproduction, feeding, hibernation and aestivation, vary strongly across latest Cretaceous biotic clades. We postulate that the timing of the Chicxulub impact in boreal spring and austral autumn was a major influence on selective biotic survival across the Cretaceous–Palaeogene boundary.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Genome-wide association studies (GWAS) have identified thousands of genetic variants linked to the risk of human disease. However, GWAS have so far remained largely underpowered in relation to identifying associations in the rare and low-frequency allelic spectrum and have lacked the resolution to trace causal mechanisms to underlying genes<jats:sup>1</jats:sup>. Here we combined whole-exome sequencing in 392,814 UK Biobank participants with imputed genotypes from 260,405 FinnGen participants (653,219 total individuals) to conduct association meta-analyses for 744 disease endpoints across the protein-coding allelic frequency spectrum, bridging the gap between common and rare variant studies. We identified 975 associations, with more than one-third being previously unreported. We demonstrate population-level relevance for mutations previously ascribed to causing single-gene disorders, map GWAS associations to likely causal genes, explain disease mechanisms, and systematically relate disease associations to levels of 117 biomarkers and clinical-stage drug targets. Combining sequencing and genotyping in two population biobanks enabled us to benefit from increased power to detect and explain disease associations, validate findings through replication and propose medical actionability for rare genetic variants. Our study provides a compendium of protein-coding variant associations for future insights into disease biology and drug discovery.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Nonlinear, multiplication-like operations carried out by individual nerve cells greatly enhance the computational power of a neural system<jats:sup>1–3</jats:sup>, but our understanding of their biophysical implementation is scant. Here we pursue this problem in the <jats:italic>Drosophila melanogaster</jats:italic> ON motion vision circuit<jats:sup>4,5</jats:sup>, in which we record the membrane potentials of direction-selective T4 neurons and of their columnar input elements<jats:sup>6,7</jats:sup> in response to visual and pharmacological stimuli in vivo. Our electrophysiological measurements and conductance-based simulations provide evidence for a passive supralinear interaction between two distinct types of synapse on T4 dendrites. We show that this multiplication-like nonlinearity arises from the coincidence of cholinergic excitation and release from glutamatergic inhibition. The latter depends on the expression of the glutamate-gated chloride channel GluClα<jats:sup>8,9</jats:sup> in T4 neurons, which sharpens the directional tuning of the cells and shapes the optomotor behaviour of the animals. Interacting pairs of shunting inhibitory and excitatory synapses have long been postulated as an analogue approximation of a multiplication, which is integral to theories of motion detection<jats:sup>10,11</jats:sup>, sound localization<jats:sup>12</jats:sup> and sensorimotor control<jats:sup>13</jats:sup>.</jats:p>

<jats:title>Abstract</jats:title><jats:p>A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord<jats:sup>1</jats:sup>. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing<jats:sup>2–4</jats:sup>. Single nucleotide polymorphisms in <jats:italic>UNC13A</jats:italic> are among the strongest hits associated with FTD and ALS in human genome-wide association studies<jats:sup>5,6</jats:sup>, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in <jats:italic>UNC13A</jats:italic>. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in <jats:italic>UNC13A</jats:italic> mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase <jats:italic>UNC13A</jats:italic> cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (<jats:italic>UNC13A</jats:italic> genetic variants), and loss of TDP-43 function.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Variants of <jats:italic>UNC13A</jats:italic>, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia<jats:sup>1–3</jats:sup>, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43<jats:sup>4,5</jats:sup>. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in <jats:italic>UNC13A</jats:italic>, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic <jats:italic>UNC13A</jats:italic> polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which <jats:italic>UNC13A</jats:italic> variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.</jats:p>