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Antarctic ice shelves are losing mass at increasing rates, yet the ice‐ocean interactions that cause significant ice loss are not well understood. A new approach of high‐resolution phase‐change simulations is used to model vertical ice melting into a stratified ocean. The ocean dynamics show complicated interplay between a turbulent buoyant meltwater plume and double‐diffusive layers, while the ice actively melts and changes topography. At room temperatures, the double‐diffusive layer thickness is closely linked to ice scalloping. At lower, more realistic ocean temperatures, the meltwater plume becomes prominent with a laminar‐to‐turbulent transition imprinting an indent on the melting ice. The double‐diffusive layer thickness is consistent with scaling prediction, while the real‐world application demonstrates reasonably good matching of the scaling prediction for some Antarctic regions. Our study is a key first step toward the future use of high‐resolution phase‐change fluid dynamics simulations to better understand Antarctic ice shelves in a changing climate. Plain Language Summary: Future climate scenarios and sea level rise are closely tied to the accelerating loss of Antarctic ice shelves, which lose significant mass by melting into the surrounding ocean. However, the extent of ice shelf mass loss in a changing climate is currently not well understood, with lack of knowledge on the fine‐scale ice‐ocean interactions presenting a key restriction on the accuracy of climate predictions. Here, we use a new suite of numerical computer simulations to model an ice face melting into the ocean. In particular, our simulations allow the ice face to melt back and change shape, which previous numerical simulations could not attempt. We see interesting ocean dynamics known as "double‐diffusive layers" that occur because temperature and salinity both affect the water density. In addition, we also see a buoyant meltwater plume evolve next to the ice face. Both the double‐diffusive layers and meltwater plume can influence the ice melting and shape. Our results are a first step in using these new phase‐change simulations to model ice‐ocean interactions, and will help to better understand the Antarctic response to a changing climate. Key Points: High‐resolution phase‐change simulations are used to examine a vertical ice face melting into a stratified ocean at low temperaturesA distinct laminar‐to‐turbulent transition occurs in the meltwater plume as it rises, accompanied by an indent in the ice at the transitionDouble‐diffusive layers adjacent to the turbulent plume are consistent with scaling predictions and are relevant to the ocean application [ABSTRACT FROM AUTHOR]

Anti- c mAb CSL311 inhibits human nasal polyp pathophysiology in a humanized mouse xenograft model We found that treatment with CSL311 for 1 week resulted in an immediate reduction in NP volume measured externally, which was not observed with positive control prednisolone treatment. CSL311 mAb treatment reduces (A) volume of nasal polyp measured externally every week, (B) granulocytes and plasma B-cell populations, (C) mast cell numbers, (D) mucous gland numbers and mucus production and (E) fibroblast numbers in xenografted nasal polyps compared with isotype control mAb treatment. To understand how CSL311 treatment inhibited NP growth, we examined the immune cell profiles in the xenografted NPs collected at the end of the 5-week engraftment. [Extracted from the article]

Interleukin-3 (IL-3) is a member of the beta common family of cytokines that regulate multiple functions of myeloid cells. The IL-3 receptor-specific alpha subunit (IL3Rα) is overexpressed on stem cells/progenitor cells of patients with acute myeloid leukaemia, where elevated receptor expression correlates clinically with a reduced patient survival rate. The monoclonal antibody (MAb) CSL362 is a humanized MAb derived from the murine MAb 7G3, originally identified for its ability to specifically recognize the human IL-3 receptor and for blocking the signalling of IL-3 in myeloid and endothelial cells. In order to elucidate the molecular mechanism of CSL362 antagonism, a preliminary structure of human IL3Rα in complex with the MAb CSL362 has been determined. [ABSTRACT FROM AUTHOR]

Macrophage colony stimulating factor (M-CSF) or CSF-1 controls the development of the macrophage lineage through its receptor tyrosine kinase, c-Fms. cAMP has been shown to influence proliferation and differentiation in many cell types, including macrophages. In addition, modulation of cellular ERK activity often occurs when cAMP levels are raised. We have shown previously that agents that increase cellular cAMP inhibited CSF-1-dependent proliferation in murine bone marrow-derived macrophages (BMM) which was associated with an enhanced extracellular signal-regulated kinase (ERK) activity. We report here that increasing cAMP levels, by addition of either 8-bromo cAMP (8BrcAMP) or prostaglandin E1 (PGE1), can induce macrophage differentiation in M1 myeloid cells engineered to express the CSF-1 receptor (M1/WT cells) and can potentiate CSF-1-induced differentiation in the same cells. The enhanced CSF-1-dependent differentiation induced by raising cAMP levels correlated with enhanced ERK activity. Thus, elevated cAMP can promote either CSF-1-induced differentiation or inhibit CSF-1-induced proliferation depending on the cellular context. The mitogen-activated protein kinase/extracellular signal-related protein kinase kinase (MEK) inhibitor, PD98059, inhibited both the cAMP- and the CSF-1R-dependent macrophage differentiation of M1/WT cells suggesting that ERK activity might be important for differentiation in the M1/WT cells. Surprisingly, addition of 8BrcAMP or PGE1 to either CSF-1-treated M1/WT or BMM cells suppressed the CSF-1R-dependent tyrosine phosphorylation of cellular substrates, including that of the CSF-1R itself. It appears that there are at least two CSF-1-dependent pathway(s), one MEK/ERK dependent pathway and another controlling the bulk of the tyrosine phosphorylation, and that cAMP can modulate signalling through both of these pathways. [ABSTRACT FROM AUTHOR]

Initiation of an effective immune response requires dose interactions between innate and adaptive immunity. Recent advances in the field of cytokine biology have led to an increased understanding of how myeloid cell-derived factors regulate the immune system to protect the host from infections and prevent tumor development. In this review, we focus on the function of interleukin (IL)-23, a new member of the IL-12 family of regulatory cytokines produced by activated macrophages and dendritic cells. We propose that IL-12 and IL-23 promote two distinct immunological pathways that have separate but complementary functions. IL-12 is required for antimicrobial responses to intracellular pathogens, whereas IL-23 is likely to be important for the recruitment and activation of a range of inflammatory cells that is required for the induction of chronic inflammation and granuloma formation. These two cytokines work in concert to regulate cellular immune responses critical for host defense and tumor suppression. [ABSTRACT FROM AUTHOR]

Objectives: Plasmacytoid dendritic cells (pDCs), through the production of type 1 interferons (IFNs) and other cytokines, are major contributors to systemic lupus erythematosus (SLE) pathogenesis. IL‐3 promotes pDC survival, but its role in SLE is not well characterised. This study investigated serum IL‐3 and IFN levels, and a whole blood 'IL‐3 gene signature', in human SLE. Methods: Serum cytokine levels were measured by ELISA in n = 42 SLE patients, and n = 44 healthy donors. IL‐3‐regulated genes were determined by RNASeq of healthy donor whole blood cells (WBCs) stimulated in vitro with IL‐3 for 6 or 24 h. Whole blood cell RNASeq analysis was undertaken in a separate cohort of n = 31 SLE patients, and n = 28 healthy donors. Results: Serum IL‐3 levels correlated with IFNα (r = 0.612, 95% CI 0.455–0.733, P < 0.001) and type III IFN (r = 0.585, 95% CI 0.406–0.720, P < 0.0001). IL‐3 stimulation of WBC in vitro altered 794 genes (−1 ≥ logFC ≥ 1, FDR < 0.05), of which 35 overlapped with genes differentially expressed between SLE and healthy donors. These 35 genes were expressed in 27/31 SLE donors, revealing the presence of an 'IL‐3 gene signature'. There was strong correlation between the IL‐3 signature and an IFN signature, as determined by hierarchical clustering of the 500 most variable genes in SLE donors (r = 0.939, 95% CI 0.898–0.964, P < 0.0001). Conclusion: A dual IL‐3/IFN gene signature is a feature of SLE. An association between IL‐3 and IFN raises the possibility that dual blockade of IL‐3 and IFN may be especially useful for SLE patients with this dual cytokine gene signature. [ABSTRACT FROM AUTHOR]

Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus, responses to available treatments are unpredictable. Here, we developed a new stratification scheme for patients with SLE, based on the computational analysis of patients' whole‐blood transcriptomes. Methods: We applied machine learning approaches to RNA‐sequencing (RNA‐seq) data sets to stratify patients with SLE into four distinct clusters based on their gene expression profiles. A meta‐analysis on three recently published whole‐blood RNA‐seq data sets was carried out, and an additional similar data set of 30 patients with SLE and 29 healthy donors was incorporated in this study; a total of 161 patients with SLE and 57 healthy donors were analysed. Results: Examination of SLE clusters, as opposed to unstratified SLE patients, revealed underappreciated differences in the pattern of expression of disease‐related genes relative to clinical presentation. Moreover, gene signatures correlated with flare activity were successfully identified. Conclusion: Given that SLE disease heterogeneity is a key challenge hindering the design of optimal clinical trials and the adequate management of patients, our approach opens a new possible avenue addressing this limitation via a greater understanding of SLE heterogeneity in humans. Stratification of patients based on gene expression signatures may be a valuable strategy allowing the identification of separate molecular mechanisms underpinning disease in SLE. Further, this approach may have a use in understanding the variability in responsiveness to therapeutics, thereby improving the design of clinical trials and advancing personalised therapy. [ABSTRACT FROM AUTHOR]