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<jats:title>Abstract</jats:title><jats:p>Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer’s disease, and is often also associated with motor disorders<jats:sup>1</jats:sup>. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins<jats:sup>2</jats:sup>. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes<jats:sup>3,4</jats:sup>. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD–FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD–FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7–99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.</jats:p>

<jats:title>Abstract</jats:title><jats:p>The transfer of photosynthetically produced organic carbon from surface to mesopelagic waters draws carbon dioxide from the atmosphere<jats:sup>1</jats:sup>. However, current observation-based estimates disagree on the strength of this biological carbon pump (BCP)<jats:sup>2</jats:sup>. Earth system models (ESMs) also exhibit a large spread of BCP estimates, indicating limited representations of the known carbon export pathways<jats:sup>3</jats:sup>. Here we use several decades of hydrographic observations to produce a top-down estimate of the strength of the BCP with an inverse biogeochemical model that implicitly accounts for all known export pathways. Our estimate of total organic carbon (TOC) export at 73.4 m (model euphotic zone depth) is 15.00 ± 1.12 Pg C year<jats:sup>−1</jats:sup>, with only two-thirds reaching 100 m depth owing to rapid remineralization of organic matter in the upper water column. Partitioned by sequestration time below the euphotic zone, <jats:italic>τ</jats:italic>, the globally integrated organic carbon production rate with <jats:italic>τ</jats:italic> &gt; 3 months is 11.09 ± 1.02 Pg C year<jats:sup>−1</jats:sup>, dropping to 8.25 ± 0.30 Pg C year<jats:sup>−1</jats:sup> for <jats:italic>τ</jats:italic> &gt; 1 year, with 81% contributed by the non-advective-diffusive vertical flux owing to sinking particles and vertically migrating zooplankton. Nevertheless, export of organic carbon by mixing and other fluid transport of dissolved matter and suspended particles remains regionally important for meeting the respiratory carbon demand. Furthermore, the temperature dependence of the sequestration efficiency inferred from our inversion suggests that future global warming may intensify the recycling of organic matter in the upper ocean, potentially weakening the BCP.</jats:p>

<jats:title>Abstract</jats:title><jats:p>In vitro-transcribed (IVT) mRNAs are modalities that can combat human disease, exemplified by their use as vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IVT mRNAs are transfected into target cells, where they are translated into recombinant protein, and the biological activity or immunogenicity of the encoded protein exerts an intended therapeutic effect<jats:sup>1,2</jats:sup>. Modified ribonucleotides are commonly incorporated into therapeutic IVT mRNAs to decrease their innate immunogenicity<jats:sup>3–5</jats:sup>, but their effects on mRNA translation fidelity have not been fully explored. Here we demonstrate that incorporation of <jats:italic>N</jats:italic><jats:sup>1</jats:sup>-methylpseudouridine into mRNA results in +1 ribosomal frameshifting in vitro and that cellular immunity in mice and humans to +1 frameshifted products from BNT162b2 vaccine mRNA translation occurs after vaccination. The +1 ribosome frameshifting observed is probably a consequence of <jats:italic>N</jats:italic><jats:sup>1</jats:sup>-methylpseudouridine-induced ribosome stalling during IVT mRNA translation, with frameshifting occurring at ribosome slippery sequences. However, we demonstrate that synonymous targeting of such slippery sequences provides an effective strategy to reduce the production of frameshifted products. Overall, these data increase our understanding of how modified ribonucleotides affect the fidelity of mRNA translation, and although there are no adverse outcomes reported from mistranslation of mRNA-based SARS-CoV-2 vaccines in humans, these data highlight potential off-target effects for future mRNA-based therapeutics and demonstrate the requirement for sequence optimization.</jats:p>