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Sea-ice diatoms are known to accumulate in large aggregates in and under sea ice and in melt ponds. There is recent evidence from the Arctic that such aggregates can contribute substantially to particle export when sinking from the ice. The role and regulation of microbial aggregation in the highly seasonal, nutrient- and light-limited Arctic sea-ice ecosystem is not well understood. To elucidate the mechanisms controlling the formation and export of algal aggregates from sea ice, we investigated samples taken in late summer 2011 and 2012, during two cruises to the Eurasian Basin of the Central Arctic Ocean. Spherical aggregates densely packed with pennate diatoms, as well as filamentous aggregates formed by Melosira arctica showed sign of different stages of degradation and physiological stoichiometries, with carbon to chlorophyll a ratios ranging from 110 to 66700, and carbon to nitrogen molar ratios of 8-35 and 9-40, respectively. Sub-ice algal aggregate densities ranged between 1 and 17 aggregates m(-2), maintaining an estimated net primary production of 0.4-40 mg C m(-2) d(-1), and accounted for 3-80% of total phototrophic biomass and up to 94% of local net primary production. A potential factor controlling the buoyancy of the aggregates was light intensity, regulating photosynthetic oxygen production and the amount of gas bubbles trapped within the mucous matrix, even at low ambient nutrient concentrations. Our data-set was used to evaluate the distribution and importance of Arctic algal aggregates as carbon source for pelagic and benthic communities.

Sea-ice ecosystems are among the most extensive of Earth’s habitats; yet its autotrophic and heterotrophic activities remain poorly constrained. We employed the in situ aquatic eddy-covariance (AEC) O2 flux method and laboratory incubation techniques (H14CO3−, [3H] thymidine and [3H] leucine) to assess productivity in Arctic sea-ice using different methods, in conditions ranging from land-fast ice during winter, to pack ice within the central Arctic Ocean during summer. Laboratory tracer measurements resolved rates of bacterial C demand of 0.003–0.166 mmol C m−2 day−1 and primary productivity rates of 0.008–0.125 mmol C m−2 day−1 for the different ice floes. Pack ice in the central Arctic Ocean was overall net autotrophic (0.002–0.063 mmol C m−2 day−1), whereas winter land-fast ice was net heterotrophic (− 0.155 mmol C m−2 day−1). AEC measurements resolved an uptake of O2 by the bottom-ice environment, from ~ − 2 mmol O2 m−2 day−1 under winter land-fast ice to~ − 6 mmol O2 m−2 day−1 under summer pack ice. Flux of O2-deplete meltwater and changes in water flow velocity masked potential biological-mediated activity. AEC estimates of primary productivity were only possible at one study location. Here, productivity rates of 1.3 ± 0.9 mmol O2 m−2 day−1, much larger than concurrent laboratory tracer estimates (0.03 mmol C m−2 day−1), indicate that ice algal production and its importance within the marine Arctic could be underestimated using traditional approaches. Given careful flux interpretation and with further development, the AEC technique represents a promising new tool for assessing oxygen dynamics and sea-ice productivity in ice-covered regions.

Anoxic mineralization of organic matter releases dissolved inorganic carbon and produces reduced mineralization products. The reoxidation of these reduced compounds is essential for biogeochemical cycling in sediments and is mainly performed by chemoautotrophic microbes, which synthesize new organic carbon by dark CO₂ fixation. At present however, the biogeochemical importance of chemoautotrophy in high-latitude sediments is largely unknown. Here, we determine the seasonal variation in sedimentary chemoautotrophic production in Kobbefjord (SW Greenland). Intact sediment cores from the fjord were incubated, and dark CO₂ fixation was quantified by combining bacterial phospholipid-derived fatty acid analysis with 13C stable isotope probing (PLFA-SIP). Our results reveal a distinct seasonal cycle in chemoautotrophic activity, which increases after the spring bloom and shows lowest activity in the late winter when the fjord is covered by sea ice. The depth distribution of chemoautotrophic activity also varied seasonally, likely due to seasonal variation in the bioturbation activity of sediment infauna. Although chemoautotrophy rates (0.4 ± 0.2 mmol C m−2 d−1) were in the low range for coastal sediments, they are comparable to those from intertidal sandflats and brackish tropical lagoons, and scale with the sulfide production through sulfate reduction in the fjord. Chemoautotrophic production in these fjord sediments thus appears to be mainly driven by sulfide oxidation and can re-fix 4% of the CO₂ produced by mineralization.

Climate change is expected to have a pronounced effect on biogeochemical cycling in Arctic fjords, but current insight on the biogeochemical functioning of these systems is limited. Here, we present seasonal data on primary production, export of particulate organic carbon (POC), and the coupling to benthic biogeochemistry in Kobbefjord (SW Greenland). Primary production and associated POC export from the photic zone showed marked seasonality, with annual integrated values of 7.2 and 19.9 mol C m−2 yr−1, respectively. This discrepancy, the isotopic signature, and C:N ratio of the sedimentating material suggested substantial import of marine POC from outside the fjord. At least 52% of the POC export reached the sediment, but the seasonality in pelagic productivity was not reflected in the sediment biogeochemistry, showing only moderate variation. Benthic mineralization and burial of organic carbon amounted to 3.2 and 5.3 mol C m−2 yr−1, respectively. Sulfate reduction was the most prominent mineralization pathway, accounting for 69% of the benthic mineralization, while denitrification accounted for 2%. Overall, the carbon mineralization and burial in Kobbefjord were significantly higher than previously observed in other more northerly Arctic fjords. Data compilation from Arctic fjords suggests proportional increases in surface production, POC export, benthic mineralization and burial of organic material with increasing duration of the ice-free period. Thus, the projected decline in ice coverage in higher Arctic Greenlandic fjords will, as a first approximation, entail proportional increases in productivity, mineralization, and burial of organic carbon in the fjords, which will thus become similar to present-day southerly systems.

Surface topography across the marginal zone of the Greenland Ice Sheet is constantly evolving in response to changing weather, season, climate, and ice dynamics. However, current digital elevation models (DEMs) for the ice sheet are usually based on data from a multi-year period, thus obscuring these changes over time. Here we present four 500 m resolution summer DEMs (PRODEMs) of the Greenland Ice Sheet marginal zone for 2019 through 2022. The PRODEMs cover the marginal zone from the ice edge to 50 km inland, hence capturing all Greenland outlet glaciers. Each PRODEM is based on data fusion of CryoSat-2 radar altimetry and ICESat-2 laser altimetry using regionally varying kriging of elevation anomalies relative to ArcticDEM. The PRODEMs are validated using leave-one-out cross-validation, and PRODEM19 is further validated against an external data set, showcasing their ability to correctly represent surface elevations within the associated spatially varying prediction uncertainties. We observe a general lowering of surface elevations during the 4-year PRODEM period, but the spatial pattern of change is highly complex and with annual changes superimposed. The PRODEMs enable detailed studies of the marginal ice sheet elevation changes. With their high spatio-temporal resolution, the PRODEMs will be of value to a wide range of researchers and users studying ice sheet dynamics and monitoring how the ice sheet responds to changing environmental conditions. PRODEMs from summer 2019 through 2022 are available at https://doi.org/10.22008/FK2/52WWHG (Winstrup, 2024), and we plan to annually update the product henceforth.

BackgroundCurrently, there are no reliable biomarkers for predicting treatment response in chronic inflammatory diseases (CIDs).ObjectiveTo determine whether serum microfibrillar-associated protein 4 (MFAP4) levels can predict the treatment response to biological therapy in patients with CIDs.MethodsThe BELIEVE study was originally designed as a prospective, multi-center cohort study of 233 patients with either rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, Crohn’s disease, or ulcerative colitis, initiating treatment with a biologic agent (or switching to another). Clinical assessment and blood sample collection were performed at baseline and 14–16 weeks after treatment initiation. The primary analyses included participants with available blood samples at baseline; missing data were handled as non-responders. The patients were stratified into the upper tertile of serum MFAP4 (High MFAP4) versus a combined category of middle and lower tertiles (Other MFAP4). The primary outcome was the proportion of patients with clinical response to biologic therapy after 14–16 weeks.Results211 patients were included in the primary analysis population. The mean age was 43.7 (SD: 14.8) years, and 120 (59%) were female. Positive treatment response was observed in 41 (59%) and 69 (49%) for High MFAP4 and Other MFAP4, respectively. When adjusting for pre-specified variables (CID, age, sex, smoking status, and BMI), the adjusted OR was 2.28 (95% CI: 1.07 to 4.85) for a positive treatment outcome in the High MFAP4 group.ConclusionA high MFAP4 status before initiating biological treatment is associated with a positive clinical response, when adjusting for confounding factors.

Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6–20.0) and 6% (95% CI 5.1–7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis.

Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects. To exploit these properties of TF, a covalent complex between FVIIa and the soluble ectodomain of TF (sTF) was engineered by introduction of a nonperturbing cystine bridge (FVIIa Q64C-sTF G109C) in the interface. Upon coexpression, FVIIa Q64C and sTF G109C spontaneously assembled into a covalent complex with functional properties similar to the noncovalent wild-type complex. Additional introduction of a FVIIa-M306D mutation to uncouple the sTF-mediated allosteric stimulation of FVIIa provided a final complex with FVIIa-like activity in solution, while exhibiting a two to three orders-of-magnitude increase in activity relative to FVIIa upon exposure to a procoagulant membrane. In a mouse model of hemophilia A, the complex normalized hemostasis upon vascular injury at a dose of 0.3 nmol/kg compared with 300 nmol/kg for FVIIa.

Glucagon Receptor Knockout Mice Display Increased Insulin Sensitivity and Impaired β-Cell Function Heidi Sørensen 1 , Maria Sörhede Winzell 2 , Christian L. Brand 1 , Keld Fosgerau 1 , Richard W. Gelling 3 , Erica Nishimura 1 and Bo Ahren 2 1 Diabetes Research Unit, Novo Nordisk, Måløv, Denmark 2 Department of Clinical Sciences, Section of Medicine, Lund University, Lund, Sweden 3 Department of Medicine, University of Washington, Seattle, Washington Address correspondence and reprint requests to Heidi Sørensen, Diabetes Research Unit, Novo Nordisk Park, 2760 Måløv, Denmark. E-mail: hesn{at}novonordisk.com Abstract In previous studies, glucagon receptor knockout mice (Gcgr −/− ) display reduced blood glucose and increased glucose tolerance, with hyperglucagonemia and increased levels of glucagon-like peptide (GLP)-1. However, the role of glucagon receptor signaling for the regulation of islet function and insulin sensitivity is unknown. We therefore explored β-cell function and insulin sensitivity in Gcgr −/− and wild-type mice. The steady-state glucose infusion rate during hyperinsulinemic-euglycemic clamp was elevated in Gcgr −/− mice, indicating enhanced insulin sensitivity. Furthermore, the acute insulin response (AIR) to intravenous glucose was higher in Gcgr −/− mice. The augmented AIR to glucose was blunted by the GLP-1 receptor antagonist, exendin-3. In contrast, AIR to intravenous administration of other secretagogues was either not affected (carbachol) or significantly reduced (arginine, cholecystokinin octapeptide) in Gcgr −/− mice. In islets isolated from Gcgr −/− mice, the insulin responses to glucose and several insulin secretagogues were all significantly blunted compared with wild-type mice. Furthermore, glucose oxidation was reduced in islets from Gcgr −/− mice. In conclusion, the present study shows that glucagon signaling is required for normal β-cell function and that insulin action is improved when disrupting the signal. In vivo, augmented GLP-1 levels compensate for the impaired β-cell function in Gcgr −/− mice. AIR, acute insulin response CCK-8, cholecystokinin octapeptide GIP, glucose-dependent insulinotropic polypeptide GIR, glucose infusion rate GLP, glucagon-like peptide GSIS, glucose-stimulated insulin secretion HGP, hepatic glucose production IVGTT, intravenous glucose tolerance test Footnotes B.A. has served on an advisory panel for Novantis, Novo Nordisk. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 29, 2006. Received March 7, 2006. DIABETES

IntroductionChronic inflammatory diseases (CIDs) are frequently treated with biological medications, specifically tumour necrosis factor inhibitors (TNFi)). These medications inhibit the pro-inflammatory molecule TNF alpha, which has been strongly implicated in the aetiology of these diseases. Up to one-third of patients do not, however, respond to biologics, and lifestyle factors are assumed to affect treatment outcomes. Little is known about the effects of dietary lifestyle as a prognostic factor that may enable personalised medicine. The primary outcome of this multidisciplinary collaborative study will be to identify dietary lifestyle factors that support optimal treatment outcomes.Methods and analysisThis prospective cohort study will enrol 320 patients with CID who are prescribed a TNFi between June 2017 and March 2019. Included among the patients with CID will be patients with inflammatory bowel disease (Crohn’s disease and ulcerative colitis), rheumatic disorders (rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis), inflammatory skin diseases (psoriasis, hidradenitis suppurativa) and non-infectious uveitis. At baseline (pretreatment), patient characteristics will be assessed using patient-reported outcome measures, clinical assessments of disease activity, quality of life and lifestyle, in addition to registry data on comorbidity and concomitant medication(s). In accordance with current Danish standards, follow-up will be conducted 14–16 weeks after treatment initiation. For each disease, evaluation of successful treatment response will be based on established primary and secondary endpoints, including disease-specific core outcome sets. The major outcome of the analyses will be to detect variability in treatment effectiveness between patients with different lifestyle characteristics.Ethics and disseminationThe principle goal of this project is to improve the quality of life of patients suffering from CID by providing evidence to support dietary and other lifestyle recommendations that may improve clinical outcomes. The study is approved by the Ethics Committee (S-20160124) and the Danish Data Protecting Agency (2008-58-035). Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences.Trial registration numberNCT03173144; Pre-results.