Nanoplankton : the dominant vector for carbon export across the Atlantic Southern Ocean in spring

DATA AND MATERIAL AVAILABILITY : The data used in this manuscript are available in the Zenodo data repository: 10.5281/zenodo.7820428. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.SUPPLEMENTARY MATERIAL : Supplementary Text; Figs. S1 to S4; Tables S1 and S2.Across the Southern Ocean, large (≥20 μm) diatoms are generally assumed to be the primary vector for carbon export, although this assumption derives mainly from summertime observations. Here, we investigated carbon production and export potential during the Atlantic Southern Ocean’s spring bloom from size-fractionated measurements of net primary production (NPP), nitrogen (nitrate, ammonium, urea) and iron (labile inorganic iron, organically complexed iron) uptake, and a high-resolution characterization of phytoplankton community composition. The nanoplankton-sized (2.7 to 20 μm) diatom, Chaetoceros spp., dominated the biomass, NPP, and nitrate uptake across the basin (40°S to 56°S), which we attribute to their low iron requirement, rapid response to increased light, and ability to escape grazing when aggregated into chains. We estimate that the spring Chaetoceros bloom accounted for >25% of annual export production across the Atlantic Southern Ocean, a finding consistent with recent observations from other regions highlighting the central role of the phytoplankton “middle class” in carbon export.The South African National Research Foundation, South African National Antarctic Programme, University of Cape Town Science Faculty Fellowship, University of Cape Town Vice-Chancellor Doctoral Research Scholarship, University of Cape Town Vice-Chancellor Future Leaders 2030 Award, European Union’s Horizon 2020 Research and Innovation Programme No. 844733, Academy of Finland, and Funds from an Anonymous Charitable Donor Trust as part of Whales and Climate Change Program.https://www.science.org/journal/sciadvhj2024GeneticsSDG-14:Life below wate

Coronin 1C harbours a second actin-binding site that confers co-operative binding to F-actin

Dynamic rearrangement of actin filament networks is critical for cell motility, phagocytosis and endocytosis. Coronins facilitate these processes, in part, by their ability to bind F-actin (filamentous actin). We previously identified a conserved surface-exposed arginine (Arg30) in the β-propeller of Coronin 1B required for F-actin binding in vitro and in vivo. However, whether this finding translates to other coronins has not been well defined. Using quantitative actin-binding assays, we show that mutating the equivalent residue abolishes F-actin binding in Coronin 1A, but not Coronin 1C. By mutagenesis and biochemical competition, we have identified a second actin-binding site in the unique region of Coronin 1C. Interestingly, leading-edge localization of Coronin 1C in fibroblasts requires the conserved site in the β-propeller, but not the site in the unique region. Furthermore, in contrast with Coronin 1A and Coronin 1B, Coronin 1C displays highly co-operative binding to actin filaments. In the present study, we highlight a novel mode of coronin regulation, which has implications for how coronins orchestrate cytoskeletal dynamics

Epidemiology, clinical features and management of autoimmune hepatitis in Switzerland: a retrospective and prospective cohort study

BACKGROUND AND AIMS: The Swiss Autoimmune Hepatitis Cohort Study is a nationwide registry, initiated in 2017, that collects retrospective and prospective clinical data and biological samples from patients of all ages with autoimmune hepatitis treated at Swiss hepatology centres. Here, we report the analysis of the first 5 years of registry data. RESULTS: A total of 291 patients with autoimmune hepatitis have been enrolled, 30 of whom were diagnosed before 18 years of age and composed the paediatric cohort. Paediatric cohort: median age at diagnosis 12.5 years (range 1–17, interquartile range (IQR) 8–15), 16 (53%) girls, 6 (32%) with type 2 autoimmune hepatitis, 8 (27%) with autoimmune sclerosing cholangitis, 1 with primary biliary cholangitis variant syndrome, 4 (15%) with inflammatory bowel disease and 10 (41%) with advanced liver fibrosis at diagnosis. Adult cohort: median age at diagnosis 54 years (range 42–64, IQR 18–81), 185 (71%) women, 51 (20%) with primary biliary cholangitis variant syndrome, 22 (8%) with primary sclerosing cholangitis variant syndrome, 9 (4%) with inflammatory bowel disease and 66 (32%) with advanced liver fibrosis at diagnosis. The median follow-up time for the entire cohort was 5.2 years (IQR 3–9.3 years). Treatment in children: 29 (97%) children were initially treated with corticosteroids, 28 of whom received combination treatment with azathioprine. Budesonide was used in four children, all in combination with azathioprine. Mycophenolate mofetil was used in five children, all of whom had previously received corticosteroids and thiopurine. Treatment in adults (data available for 228 patients): 219 (96%) were treated with corticosteroids, mostly in combination with azathioprine. Predniso(lo)ne was the corticosteroid used in three-quarters of patients; the other patients received budesonide. A total of 78 (33%) patients received mycophenolate mofetil, 62 of whom had previously been treated with azathioprine. Complete biochemical response was achieved in 13 of 19 (68%) children and 137 of 182 (75%) adults with available follow-up data. All children were alive at the last follow-up, and none had undergone liver transplantation. Five (2%) adults underwent liver transplantation, two of whom had a fulminant presentation. Four (2%) adults with autoimmune hepatitis died (two from liver-associated causes). CONCLUSION: Patients with autoimmune hepatitis in Switzerland had clinical features similar to those in other cohorts. The proportion of patients diagnosed with primary biliary cholangitis variant syndrome was higher than expected. Autoimmune hepatitis was managed according to guidelines, except for the use of budesonide in a small proportion of paediatric patients. The outcomes were excellent, but the findings must be confirmed over a longer follow-up period

The identification of short linear motif-mediated interfaces within the human interactome

Motivation: Eukaryotic proteins are highly modular, containing multiple interaction interfaces that mediate binding to a network of regulators and effectors. Recent advances in high-throughput proteomics have rapidly expanded the number of known protein–protein interactions (PPIs); however, the molecular basis for the majority of these interactions remains to be elucidated. There has been a growing appreciation of the importance of a subset of these PPIs, namely those mediated by short linear motifs (SLiMs), particularly the canonical and ubiquitous SH2, SH3 and PDZ domain-binding motifs. However, these motif classes represent only a small fraction of known SLiMs and outside these examples little effort has been made, either bioinformatically or experimentally, to discover the full complement of motif instances

Study design for development of novel safety biomarkers of drug-induced liver injury by the translational safety biomarker pipeline (TransBioLine) consortium: a study protocol for a nested case–control study

A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative’s TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case–control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application

Nemitin, a Novel Map8/Map1s Interacting Protein with Wd40 Repeats

In neurons, a highly regulated microtubule cytoskeleton is essential for many cellular functions. These include axonal transport, regional specialization and synaptic function. Given the critical roles of microtubule-associated proteins (MAPs) in maintaining and regulating microtubule stability and dynamics, we sought to understand how this regulation is achieved. Here, we identify a novel LisH/WD40 repeat protein, tentatively named nemitin (neuronal enriched MAP interacting protein), as a potential regulator of MAP8-associated microtubule function. Based on expression at both the mRNA and protein levels, nemitin is enriched in the nervous system. Its protein expression is detected as early as embryonic day 11 and continues through adulthood. Interestingly, when expressed in non-neuronal cells, nemitin displays a diffuse pattern with puncta, although at the ultrastructural level it localizes along the microtubule network in vivo in sciatic nerves. These results suggest that the association of nemitin to microtubules may require an intermediary protein. Indeed, co-expression of nemitin with microtubule-associated protein 8 (MAP8) results in nemitin losing its diffuse pattern, instead decorating microtubules uniformly along with MAP8. Together, these results imply that nemitin may play an important role in regulating the neuronal cytoskeleton through an interaction with MAP8

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition

Nomenclature, Diagnosis and Management of Drug-induced Autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarizes the major topics discussed at a joint International Conference held between Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and often resolve spontaneously after stopping the culprit drug whereas patients with AIH mostly need long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements such as Khat and Tinospora cordifolia have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow a precise diagnosis and similarly, there is no single feature which is diagnostic of AIH. A management algorithm is proposed. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterization of this condition

The LRRK2 signalling system

The LRRK2 gene is a major contributor to genetic risk for Parkinson's disease and understanding the biology of the leucine-rich repeat kinase 2 (LRRK2, the protein product of this gene) is an important goal in Parkinson's research. LRRK2 is a multi-domain, multi-activity enzyme and has been implicated in a wide range of signalling events within the cell. Because of the complexities of the signal transduction pathways in which LRRK2 is involved, it has been challenging to generate a clear idea as to how mutations and disease associated variants in this gene are altered in disease. Understanding the events in which LRRK2 is involved at a systems level is therefore critical to fully understand the biology and pathobiology of this protein and is the subject of this review

Prognostic scores for ursodeoxycholic acid-treated patients predict graft loss and mortality in recurrent primary biliary cholangitis after liver transplantation

\ua9 2024 The AuthorsBackground & Aims: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. Methods: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2–62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. Results: During a median follow-up of 8.7 years [IQR 4.3–12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. Conclusion: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. Impact and implications: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis