NEMO-Bohai 1.0 : a high-resolution ocean and sea ice modelling system for the Bohai Sea, China

Severe ice conditions in the Bohai Sea could cause serious harm to maritime traffic, offshore oil exploitation, aquaculture, and other economic activities in the surrounding regions. In addition to providing sea ice forecasts for disaster prevention and risk mitigation, sea ice numerical models could help explain the sea ice variability within the context of climate change in marine ecosystems, such as spotted seals, which are the only ice-dependent animal that breeds in Chinese waters. Here, we developed NEMO-Bohai, an ocean-ice coupled model based on the Nucleus for European Modelling of the Ocean (NEMO) model version 4.0 and Sea Ice Modelling Integrated Initiative (SI3) (NEMO4.0-SI3) for the Bohai Sea. This study will present the scientific design and technical choices of the parameterizations for the NEMO-Bohai model. The model was calibrated and evaluated with in situ and satellite observations of the ocean and sea ice. The model simulations agree with the observations with respect to sea surface height (SSH), temperature (SST), salinity (SSS), currents, and temperature and salinity stratification. The seasonal variation of the sea ice area is well simulated by the model compared to the satellite remote sensing data for the period of 1996-2017. Overall agreement is found for the occurrence dates of the annual maximum sea ice area. The simulated sea ice thickness and volume are in general agreement with the observations with slight overestimations. NEMO-Bohai can simulate seasonal sea ice evolution and long-term interannual variations. Hence, NEMO-Bohai is a valuable tool for long-term ocean and ice simulations and climate change studies.Peer reviewe

Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease

Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.Peer reviewe

Trend correlations for coastal eutrophication and its main local and whole-sea drivers – Application to the Baltic Sea

Coastal eutrophication is a major environmental issue worldwide. In the Baltic Sea, eutrophication affects both the coastal waters and the open sea. Various policy frameworks aim to hinder its progress but eutrophicationrelevant water quality variables, such as chlorophyll-a concentrations, still exhibit opposite temporal trends in various Baltic Sea marine and coastal waters. In this study, we investigate the temporal-trend linkages of measured water quality variables and their various anthropogenic, climatic and hydrospheric drivers over the period 1990-2020 with focus on the Swedish coastal waters and related marine basins in the Baltic Sea. We find that it is necessary to distinguish more and less isolated coastal waters, based on their water exchanges with the open sea, to capture different coastal eutrophication dynamics. In less isolated coastal waters, eutrophication is primarily related to nitrogen concentrations, while it is more related to phosphorus concentrations in more isolated coastal waters. In the open sea, trends in eutrophication conditions correlate best with trends in climatic and hydrospheric drivers, like wind speed and water salinity, respectively. In the coastal waters, driver signals are more mixed, with considerable influences from anthropogenic land-based nutrient loads and sea ice cover duration. Summer chlorophyll-a concentration in the open sea stands out as a main change driver of summer chlorophyll-a concentration in less isolated coastal waters. Overall, coastal waters are a melting pot of driver influences over various scales, from local land-based drivers to large-scale total catchment and open sea conditions. The latter in turn depend on long-term integration of pathway-dependent influences from the various coastal parts of the Baltic Sea and their land-based nutrient load drivers, combined with overarching climate conditions and internal feedback loops. As such, our results challenge any unidirectional local source-to-sea paradigm and emphasize a need for concerted local land-catchment and whole-sea measures for robust coastal eutrophication management. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Peer reviewe

Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2

The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)→Akt→mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease

Subpolar Southern Ocean response to changes in the surface momentum, heat, and freshwater fluxes under 2xCO2

The Antarctic subpolar Southern Ocean (sSO) has fundamental climate importance. Antarctic Bottom Water (AABW) originates in the sSO and supplies the lower limb of the meridional overturning circulation (MOC), occupying 36% of ocean volume. Climate models struggle to represent continental shelf processes that form AABW. We explore sources of persistent model biases by examining response of the sSO to perturbations in surface forcing in a global ocean–sea ice model (ACCESS-OM2) that forms AABW both on shelf and in open ocean. The sSO response to individual and combined perturbations of surface heat, freshwater, and momentum fluxes follows the WCRP CMIP6 FAFMIP-protocol. Wind perturbation (i.e., a poleward shift and intensification of the westerlies) is dominant, enhancing AABW formation and accelerating the global MOC. This occurs through upwelling of warm waters and inhibition of sea ice growth during winter, which triggers large open water polynya (OWP) events with associated deep convection. These events occur in the Weddell and Ross Seas and their variability is associated with availability of heat at midocean depths. These OWPs cease when the heat reservoir is depleted. Effects of surface warming and freshening only partially compensate changes from increasing winds on ocean stratification and depletion of AABW formation. These results indicate that overly convective models, such ACCESS-OM2, can respond to CO2-perturbed scenarios by forming too much AABW in OWP, which might not hold in models without OWPs. This might contribute to the large intermodel spread thermosteric sea level projections, being relevant to the interpretation of future projections by current climate models.Peer reviewe

A beta 2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

beta 2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta(2)-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the beta 2-integrin (TTT/AAA-beta 2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-beta 2-integrin KI dendritic cells, which leads to a failure of MRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of beta 2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of beta 2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function

Red-cell ICAM-4 is a ligand for the monocyte/macrophage integrinCD11c/CD18 : characterization of the binding sites on ICAM-4

Intercellular adhesion molecule-4 (ICAM-4) is a unique member of the ICAM family due to its specific expression on erythroid cells and ability to interact with several types of integrins expressed on blood and endothelial cells. The first reported receptors for ICAM-4 were CD11a/CD18 and CD11b/CD18. In contrast to these two, the cellular ligands and the functional role of the third beta2-integrin, CD11c/CD18, have not been well defined. Here we show that ICAM-4 functions as a ligand for the monocyte/macrophage specific CD11c/CD18. Deletion of the individual immunoglobulin domains of ICAM-4 demonstrated that both its domains contain binding sites for CD11c/CD18. Analysis of a panel of ICAM-4 point mutants identified residues that affected binding to the integrin. By molecular modeling the important residues were predicted to cluster in two distinct but spatially close regions of the first domain with an extension to the second domain spatially distant from the other residues. We also identified two peptides derived from sequences of ICAM-4 that are capable of modulating the binding to CD11c/CD18. CD11c/CD18 is expressed on macrophages in spleen and bone marrow. Inhibition of erythrophagocytosis by anti-ICAM-4 and anti-integrin antibodies suggests a role for these interactions in removal of senescent red cells

The Clinical Frailty Scale is a useful tool for predicting postoperative complications following elective colon cancer surgery at the age of 80 years and above: A prospective, multicentre observational study

Aim Identification of the risks of postoperative complications may be challenging in older patients with heterogeneous physical and cognitive status. The aim of this multicentre, observational study was to identify variables that affect the outcomes of colon cancer surgery and, especially, to find tools to quantify the risks related to surgery. Method Patients aged >= 80 years with electively operated Stage I-III colon cancer were recruited. The prospectively collected data included comorbidities, results of the onco-geriatric screening tool (G8), Clinical Frailty Scale (CFS), Charlson Comorbidity Index (CCI) and Mini Nutritional Assessment-Short Form (MNA-SF), and operative and postoperative outcomes. Results A total of 161 patients (mean 84.5 years, range 80-97, 60% female) were included. History of cerebral stroke (64% vs. 37%, p = 0.02), albumin level 31-34 g/l compared with >= 35 g/l (57% vs. 32%, p = 0.007), CFS 3-4 and 5-9 compared with CFS 1-2 (49% and 47% vs. 16%, respectively) and American Society of Anesthesiologists score >3 (77% vs. 28%, P = 0.006) were related to a higher risk of complications. In multivariate logistic regression analysis CFS >= 3 (OR 6.06, 95% CI 1.88-19.5, p = 0.003) and albumin level 31-34 g/l (OR 3.88, 1.61-9.38, p = 0.003) were significantly associated with postoperative complications. Severe complications were more common in patients with chronic obstructive pulmonary disease (43% vs. 13%, p = 0.047), renal failure (25% vs. 12%, p = 0.021), albumin level 31-34 g/l (26% vs. 8%, p = 0.014) and CCI >6 (23% vs. 10%, p = 0.034). Conclusion Surgery on physically and cognitively fit aged colon cancer patients with CFS 1-2 can lead to excellent operative outcomes similar to those of younger patients. The CFS could be a useful screening tool for predicting postoperative complications.Peer reviewe

Plasma osteopontin concentrations in preeclampsia - is there an association with endothelial injury?

Background: It has been previously reported that plasma osteopontin (OPN) concentrations are increased in cardiovascular disorders. The goal of the present study was to determine plasma OPN concentrations in healthy pregnant women and preeclamptic patients, and to investigate their relationship to the clinical characteristics of the study subjects and to markers of inflammation [C-reactive protein (CRP)], endothelial activation [von Willebrand factor antigen (VWF: Ag)] or endothelial injury (fibronectin), oxidative stress [malondialdehyde (MDA)] and trophoblast debris (cell-free fetal DNA). Methods: Forty-four patients with preeclampsia and 44 healthy pregnant women matched for age and gestational age were involved in this case-control study. Plasma OPN concentrations were measured with ELISA. Serum CRP concentrations were determined with an autoanalyzer using the manufacturer's reagents. Plasma VWF: Ag was quantified by ELISA, while plasma fibronectin concentrations were measured by nephelometry. Plasma MDA concentrations were estimated by the thiobarbituric acid-based colorimetric assay. The amount of cell-free fetal DNA in maternal plasma was determined by quantitative real-time PCR analysis of the sex-determining region Y (SRY) gene. For statistical analyses, non-parametric methods were applied. Results: Serum levels of CRP, as well as plasma concentrations of VWF: Ag, fibronectin, MDA and cell-free fetal DNA were significantly higher in preeclamptic patients than in healthy pregnant women. There was no significant difference in plasma OPN concentrations between controls and the preeclamptic group. However, preeclamptic patients with plasma fibronectin concentrations in the upper quartile had significantly higher plasma OPN concentrations than those below the 75th percentile, as well as healthy pregnant women [median (interquartile range): 9.38 (8.10-11.99) vs. 7.54 (6.31-9.40) and 7.40 (6.51-8.80) ng/mL, respectively, p < 0.05 for both]. Furthermore, in preeclamptic patients, plasma OPN concentrations showed a significant positive linear association with plasma fibronectin (Spearman R = 0.38, standardized regression coefficient (beta) = 0.41, p < 0.05 for both). Conclusions: Plasma OPN concentrations are increased in preeclamptic patients with extensive endothelial injury. However, further studies are warranted to explore the relationship between OPN and endothelial damage. Clin Chem Lab Med 2010;48: 181-7