Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.

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A common feature of severe Plasmodium falciparum infection is the increased systemic release of proinflammatory cytokines that contributes to the pathogenesis of malaria. Using human blood, we found that blood stage schizonts or soluble schizont extracts activated plasmacytoid dendritic cells (PDCs) to up-regulate CD86 expression and produce IFN-α. IFN-α production was also detected in malaria-infected patients, but the levels of circulating PDCs were markedly reduced, possibly because of schizont-stimulated up-regulation of CCR7, which is critical for PDC migration. The schizont-stimulated PDCs elicited a poor T cell response, but promoted γδ T cell proliferation and IFN-γ production. The schizont immune stimulatory effects could be reproduced using murine DCs and required the Toll-like receptor 9 (TLR9)-MyD88 signaling pathway. Although the only known TLR9 ligand is CpG motifs in pathogen DNA, the activity of the soluble schizont extract was far greater than that of schizont DNA, and it was heat labile and precipitable with ammonium sulfate, unlike the activity of bacterial DNA. These results demonstrate that schizont extracts contain a novel and previously unknown ligand for TLR9 and suggest that the stimulatory effects of this ligand on PDCs may play a key role in immunoregulation and immunopathogenesis of human falciparum malaria.

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Memory T cells are heterogeneous in terms of their phenotype and functional properties. We investigated the molecular profiles of human CD8 naive central memory (TCM), effector memory (TEM), and effector memory RA (TEMRA) T cells using gene expression microarrays and phospho-protein-specific intracellular flow cytometry. We demonstrate that TCM have a gene expression and cytokine signaling signature that lies between that of naive and TEM or TEMRA cells, whereas TEM and TEMRA are closely related. Our data define the molecular basis for the different functional properties of central and effector memory subsets. We show that TEM and TEMRA cells strongly express genes with known importance in CD8 T cell effector function. In contrast, TCM are characterized by high basal and cytokine-induced STAT5 phosphorylation, reflecting their capacity for self-renewal. Altogether, our results distinguish TCM and TEM/TEMRA at the molecular level and are consistent with the concept that TCM represent memory stem cells.

Aberrant production of IgE antibodies can lead to allergic diseases. Normally, IgE(+) B cells rarely differentiate into memory B cells (Bmem) or long-lived plasma cells (LLPCs), as they only transiently participate in the germinal center (GC), but the mechanism behind this remains elusive. We found that membrane IgE (mIgE) autonomously triggered rapid plasma-cell differentiation and apoptosis independently of antigen or cellular context, predominantly through the mutually independent CD19-PI3K-Akt-IRF4 and BLNK-Jnk/p38 pathways, respectively, and we identified the ectodomains of mIgE as being responsible. Accordingly, deregulated GC IgE(+) B cell proliferation and prolonged IgE production with exaggerated anaphylaxis were observed in CD19- and BLNK-deficient mice. Our findings reveal an autonomous mIgE signaling mechanism that normally prevents IgE(+) Bmem and LLPC formation, providing insights into the molecular pathogenesis of allergic diseases.

EBV infection in humans induces CD8+ T cell memory to viral epitopes derived from both lytic and latent cycle Ags. We have analyzed the relationship between the phenotype and function of the memory pool of T cells specific for these Ags. Lytic epitope-specific populations were heterogeneous in terms of CD45RO/RA and CD28 expression, whereas latent epitope-specific populations were uniformly CD45RO+ and CD28+, consistent with the higher antigenic challenge from lytic epitopes driving some memory cells toward a CD45RA+, CD28− phenotype. However, both types of memory population showed immediate epitope-specific cytotoxicity and type 1 cytokine production in ex vivo assays. Cytotoxic function was not associated with preactivated T cells, as EBV-specific populations were negative for activation markers such as CD69 or CD38, nor could cytotoxic function be ascribed to CD27− or CD56+ subsets, as such cells were not detected in EBV-specific memory. Furthermore, cytotoxicity was not limited to CD45RA+ and/or CD28− fractions, but also was observed in CD45RO+, CD28+ populations in lytic and latent epitope-specific memory. Cytokine (IFN-γ, TNF-α) responses, measured by intracytoplasmic staining after peptide stimulation, also were detectable in CD45RO+ and RA+ subsets as well as CD28+ and CD28− subsets. Of other markers that were heterogeneous in both lytic and latent epitope populations, CCR7 gave the best discrimination of functionality; thus, CCR7+ cells consistently failed to give an IFN-γ or TNF-α response, whereas many CCR7− cells were responsive. Our data are consistent with effector functions having a broad distribution among phenotypically distinct subsets of “effector memory” cells that have lost the CCR7 marker.

SummaryBackgroundIntracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.MethodsIn a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.FindingsOf 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07).InterpretationIn this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects i...