Mutations in the Arabidopsis Peroxisomal ABC Transporter COMATOSE Allow Differentiation between Multiple Functions In Planta: Insights from an Allelic Series

COMATOSE (CTS), the Arabidopsis homologue of human Adrenoleukodystrophy protein (ALDP), is required for import of substrates for peroxisomal β-oxidation. A new allelic series and a homology model based on the bacterial ABC transporter, Sav1866, provide novel insights into structure-function relations of ABC subfamily D proteins. In contrast to ALDP, where the majority of mutations result in protein absence from the peroxisomal membrane, all CTS mutants produced stable protein. Mutation of conserved residues in the Walker A and B motifs in CTS nucleotide-binding domain (NBD) 1 resulted in a null phenotype but had little effect in NBD2, indicating that the NBDs are functionally distinct in vivo. Two alleles containing mutations in NBD1 outside the Walker motifs (E617K and C631Y) exhibited resistance to auxin precursors 2,4-dichlorophenoxybutyric acid (2,4-DB) and indole butyric acid (IBA) but were wild type in all other tests. The homology model predicted that the transmission interfaces are domain-swapped in CTS, and the differential effects of mutations in the conserved "EAA motif" of coupling helix 2 supported this prediction, consistent with distinct roles for each NBD. Our findings demonstrate that CTS functions can be separated by mutagenesis and the structural model provides a framework for interpretation of phenotypic data

The European Marine Observation and Data Network (EMODnet): Visions and roles of the gateway to marine data in Europe

Marine data are needed for many purposes: for acquiring a better scientific understanding of the marine environment, but also, increasingly, as marine knowledge for decision making as well as developing products and services supporting economic growth. Data must be of sufficient quality to meet the specific users' needs. It must also be accessible in a timely manner. And yet, despite being critical, this timely access to known-quality data proves challenging. Europe's marine data have traditionally been collected by a myriad of entities with the result that much of our data are scattered throughout unconnected databases and repositories. Even when data are available, they are often not compatible, making the sharing of the information and data aggregation particularly challenging. In this paper, we present how the European Marine Observation and Data network (EMODnet) has developed over the last decade to tackle these issues. Today, EMODnet is comprised of more than 150 organizations which gather marine data, metadata, and data products and make them more easily accessible for a wider range of users. EMODnet currently consists of seven sub-portals: bathymetry, geology, physics, chemistry, biology, seabed habitats, and human activities. In addition, Sea-basin Checkpoints have been established to assess the observation capacity in the North Sea, Mediterranean, Atlantic, Baltic, Artic, and Black Sea. The Checkpoints identify whether the observation infrastructure in Europe meets the needs of users by undertaking a number of challenges. To complement this, a Data Ingestion Service has been set up to tackle the problem of the wealth of marine data that remain unavailable, by reaching out to data holders, explaining the benefits of sharing their data and offering a support service to assist them in releasing their data and making them available through EMODnet. The EMODnet Central Portal (www.emodnet.eu) provides a single point of access to these services, which are free to access and use. The strategic vision of EMODnet in the next decade is also presented, together with key focal areas toward a more user-oriented service, including EMODnet for business, internationalization for global users, and stakeholder engagement to connect the diverse communities across the marine knowledge value chain

Pancreatic β-cell signaling: toward better understanding of diabetes and its treatment

Pancreatic β-cells play a central role in the maintenance glucose homeostasis by secreting insulin, a key hormone that regulates blood glucose levels. Dysfunction of the β-cells and/or a decrease in the β-cell mass are associated closely with the pathogenesis and pathophysiology of diabetes mellitus, a major metabolic disease that is rapidly increasing worldwide. Clarification of the mechanisms of insulin secretion and β-cell fate provides a basis for the understanding of diabetes and its better treatment. In this review, we discuss cell signaling critical for the insulin secretory function based on our recent studies

Diving into the vertical dimension of elasmobranch movement ecology

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements

Diving into the vertical dimension of elasmobranch movement ecology

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements

The genesis of gold mineralisation hosted by orogenic belts: A lead isotope investigation of Irish gold deposits

Lead isotope analyses have been performed on 109 gold and 23 sulphide samples from 34 Irish gold occurrences, including 27 placers, and used to shed light on the sources of mineralising fluids and metals associated with gold mineralisation hosted by orogenic belts. The Pb isotope ratios of lode and placer gold range from 206Pb/204Pb=17.287-18.679, 207Pb/204Pb=15.382-15.661, and 208Pb/204Pb=37.517-38.635, consistent with the Pb isotopic data on previously reported Irish sulphide mineralisation. There is no evidence that gold mineralisation is associated with distinctive source regions, and it appears to have been derived from similar sources to those responsible for the widespread sulphide mineralisation in Ireland. It is inferred that the principal controls on the Au mineralisation are structural and not related to the distribution of Au in their source rocks. The range of Pb isotope ratios favours the interaction of multiple source reservoirs predominantly during the Caledonian Orogeny (c. 475-380Ma). Underlying basement was the primary control on two key sources of Pb. Gold occurrences located to the south-east of the Iapetus Suture are characterised by Pb compositions that derive predominantly from the Late Proterozoic crustal basement or overlying Lower Palaeozoic sediments, whilst those located north-west of the Iapetus Suture are characterised by less radiogenic Pb signatures derived predominantly from Late Proterozoic or older crustal basement. A third source, relatively enriched in radiogenic Pb, also played a role in the formation of a number of Irish gold occurrences, and may have been associated with syn- to post-orogenic intrusives. Magmatic processes may therefore have played an important role in the formation of some orogenic gold occurrences

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript