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The possibility that a deep mantle plume manifests Pliocene and Quaternary volcanism and potential elevated heat flux in West Antarctica has been studied for more than 30 years. Recent seismic images support the plume hypothesis as the cause of Marie Byrd Land (MBL) volcanism and geophysical structure. Mantle plumes may more than double the geothermal heat flux above nominal continental values. A dearth of in situ ice sheet basal data exists that samples the heat flux. Consequently, we examine a realistic distribution of heat flux associated with a possible late Cenozoic mantle plume in West Antarctica and explore its impact on thermal and melt conditions at the ice sheet base. We use a simple analytical mantle plume parameterization to produce geothermal heat flux at the base of the ice sheet. The three‐dimensional ice flow model includes an enthalpy framework and full‐Stokes stress balance. As both the putative plume location and extent are uncertain, we perform broadly scoped experiments to characterize the impact of the plume on geothermal heat flux and ice sheet basal conditions. The experiments show that mantle plumes have an important local impact on the ice sheet, with basal melting rates reaching several centimeters per year directly above the hotspot. In order to be consistent with observations of basal hydrology in MBL, the upper bound on the plume‐derived geothermal heat flux is 150 mW/m2. In contrast, the active lake system of the lower part of Whillans Ice Stream suggests a widespread anomalous mantle heat flux, linked to a rift source. Mantle plume in West Antarctica compatible with presence of the ice sheetPresence of local plume impacts thermal conditions locallyAdditional observations necessary to refine basal conditions and structure of the plume

The mechanisms causing widespread flow acceleration of Jakobshavn Isbræ, West Greenland, remain unclear despite an abundance of observations and modeling studies. Here we simulate the glacier's evolution from 1985 to 2016 using a three‐dimensional thermomechanical ice flow model. The model captures the timing and 90% of the observed changes by forcing the calving front. Basal drag in the trough is low, and lateral drag balances the ice stream's driving stress. The calving front position is the dominant control on changes of Jakobshavn Isbræ since the ice viscosity in the shear margins instantaneously drops in response to the stress perturbation caused by calving front retreat, which allows for widespread flow acceleration. Gradual shear margin warming contributes 5 to 10% to the total acceleration. Our simulations suggest that the glacier will contribute to eustatic sea level rise at a rate comparable to or higher than at present. Calving front migration is responsible for 90% of Jakobshavn Isbrae's accelerationThe acceleration is due to low basal drag in the trough and a viscosity feedback in the shear marginsThe glacier is likely to lose mass at a rate comparable to current for at least the next century

Large uncertainties in model parameterizations and input data sets make projections of future sea level rise contributions of outlet glaciers challenging. Here we introduce a novel technique for weighing large ensemble model simulations that uses information of key observables. The approach is robust to input errors and yields calibrated means and error estimates of a glacier's mass balance. We apply the technique to Jakobshavn Isbræ, using a model that includes a dynamic calving law, and closely reproduce the observed behavior from 1985 to 2018 by forcing the model with ocean temperatures only. Our calibrated projection suggests that the glacier will continue to retreat and contribute about 5.1 mm to eustatic sea level rise by 2100 under present‐day climatic forcing. Our analysis shows that the glacier's future evolution will strongly depend on the ambient oceanic setting. Projections of future sea level rise are important planning information for coastal communities and ecosystems. Large uncertainties in model parameterizations and input data sets make the projections of the contributions of outlet glaciers and ice sheets challenging. Jakobshavn Isbræ in West Greenland is the world's fastest glacier, which retreated for more than 20 km and contributed alone more than 0.1 mm per year to sea level rise after its floating ice tongue broke up at the turn of this millennium. We use a novel technique to calibrate model simulations of Jakobshavn Isbræ using a record of observations in order to (a) understand the causes triggering its recent retreat and (b) produce weighted estimates of the glacier's future contribution to sea level rise. Our analysis shows that the glacier behavior is largely controlled by the oceanic thermal forcing and that its future evolution will strongly depend on the sustained intrusion of warm waters in its fjord. We project that the glacier will contribute an average of 5.1 mm to global sea level rise until 2100 under present‐day climatic forcing. We present a novel approach to calibrate projections of outlet glaciers using observationsWe model Jakobshavn Isbræ's observed evolution and retreat driven by oceanic forcing onlyJakobshavn Isbræ will contribute 5.1 mm to eustatic sea level rise by 2100 under present‐day climate

Glacier‐front dynamics is an important control on Greenland's ice mass balance. Warmer ocean waters trigger ice‐front retreats of marine‐terminating glaciers, and the corresponding loss in resistive stress leads to glacier acceleration and thinning. Here we present an approach to quantify the sensitivity and vulnerability of marine‐terminating glaciers to ocean‐induced melt. We develop a plan view model of Store Gletscher that includes a level set‐based moving boundary capability, a parameterized ocean‐induced melt, and a calving law with complete and precise land and fjord topographies to model the response of the glacier to increased melt. We find that the glacier is stabilized by a sill at its terminus. The glacier is dislodged from the sill when ocean‐induced melt quadruples, at which point the glacier retreats irreversibly for 27 km into a reverse bed. The model suggests that ice‐ocean interactions are the triggering mechanism of glacier retreat, but the bed controls its magnitude. Store is remarkably stable due to the presence of a sill in the vicinity of its frontA quadrupling of ocean‐induced melt is required to dislodge the glacier from its stabilizing sillA temporary increase in melting at the front can trigger a dramatic retreat of the glacier

After weaning, piglets are often fed diets supplemented with high concentrations of zinc (Zn) to decrease post-weaning diarrhea. The aim of this study was to elucidate the regulation of Zn homeostasis within intestinal epithelial cells during excessive Zn exposure. High Zn concentrations elevated the intracellular Zn level in IPEC-J2 and Caco-2 cells which was influenced by differentiation status and time of exposure. With increasing Zn concentrations, mRNA and protein levels of metallothionein (MT) and zinc transporter 1 (ZnT1) were upregulated, whereas zinc transporter 4 (ZIP4) expression was downregulated. Metal-regulatory transcription factor-1 (MTF1) mRNA expression was upregulated at high Zn concentrations in IPEC-J2 cells, which corresponded to higher intracellular Zn concentrations. Based on these results, we suggest that intestinal epithelial cells adapt the expression of these genes to the amount of extracellular Zn available in order to maintain Zn homeostasis. Cell line-dependent differences in the regulation of Zn homeostasis were detected.

Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder of immune regulation caused by defects in lymphocyte cytotoxicity. Rapid differentiation of primary, genetic forms from secondary forms of hemophagocytic lymphohistiocytosis (HLH) is crucial for treatment decisions. We prospectively evaluated the performance of degranulation assays based on surface up-regulation of CD107a on natural killer (NK) cells and cytotoxic T lymphocytes in a cohort of 494 patients referred for evaluation for suspected HLH. Seventy-five of 77 patients (97%) with FHL3-5 and 11 of 13 patients (85%) with Griscelli syndrome type 2 or Chediak-Higashi syndrome had abnormal resting NK-cell degranulation. In contrast, NK-cell degranulation was normal in 14 of 16 patients (88%) with X-linked lymphoproliferative disease and in 8 of 14 patients (57%) with FHL2, who were identified by diminished intracellular SLAM-associated protein (SAP), X-linked inhibitor of apoptosis protein (XIAP), and perforin expression, respectively. Among 66 patients with a clinical diagnosis of secondary HLH, 13 of 59 (22%) had abnormal resting NK-cell degranulation, whereas 0 of 43 had abnormal degranulation using IL-2–activated NK cells. Active disease or immunosuppressive therapy did not impair the assay performance. Overall, resting NK-cell degranulation below 5% provided a 96% sensitivity for a genetic degranulation disorder and a specificity of 88%. Therefore, degranulation assays allow a rapid and reliable classification of patients, benefiting treatment decisions.

Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder of immune regulation caused by defects in lymphocyte cytotoxicity. Rapid differentiation of primary, genetic forms from secondary forms of hemophagocytic lymphohistiocytosis (HLH) is crucial for treatment decisions. We prospectively evaluated the performance of degranulation assays based on surface up-regulation of CD107a on natural killer (NK) cells and cytotoxic T lymphocytes in a cohort of 494 patients referred for evaluation for suspected HLH. Seventy-five of 77 patients (97%) with FHL3-5 and 11 of 13 patients (85%) with Griscelli syndrome type 2 or Chediak-Higashi syndrome had abnormal resting NK-cell degranulation. In contrast, NK-cell degranulation was normal in 14 of 16 patients (88%) with X-linked lymphoproliferative disease and in 8 of 14 patients (57%) with FHL2, who were identified by diminished intracellular SLAM-associated protein (SAP), X-linked inhibitor of apoptosis protein (XIAP), and perforin expression, respectively. Among 66 patients with a clinical diagnosis of secondary HLH, 13 of 59 (22%) had abnormal resting NK-cell degranulation, whereas 0 of 43 had abnormal degranulation using IL-2–activated NK cells. Active disease or immunosuppressive therapy did not impair the assay performance. Overall, resting NK-cell degranulation below 5% provided a 96% sensitivity for a genetic degranulation disorder and a specificity of 88%. Therefore, degranulation assays allow a rapid and reliable classification of patients, benefiting treatment decisions.

AbstractThe calcium ionophore A23187, which was used to i n c rease the intracellular calcium concentration ([Ca[2+]]), was analyzed for effects on bovine leukemia virus (BLV) expression in two BLV infected cell lines. To clarify the role of intracellular free calcium in this response, [Ca[2+]] was measured during ionophore treatment with the fluorescent calcium indicator Fura-2. Elevation of intracellular calcium under these conditions caused an enhancement of BLV gp51 and p24 synthesis as well as an activation of the BLV long terminal repeat (LTR) in a dosedependent manner. Furthermore, it was observed that elevated levels of intracellular calcium following A23187 stimulation lead to activation of NFκB . Based on inhibitor studies, we hypothesize that the effect of A23187 on BLV expression appears to be mediated by PKC.

Natural Killer (NK) cells show potent anti-leukemic activity in vitro and thus NK cells isolated using the CliniMACS® Cell Separation System are currently under clinical evaluation as part of a treatment for acute myeloid leukemia (AML). (Uharek L et al., 2003, Gentilini C et al., 2005; Koehl U et al., 2004, 2005; Passweg, JR et al., 2005, 2006; Miller J et al., 2005). Currently, the processing of highly purified, clinical-grade NK cells requires a two-step method using the CliniMACS Instrument: Depletion of CD3+ cells followed by enrichment of CD56+ cells (Iyengar R et al., 2003). This procedure shows excellent performance (reviewed in Passweg et al., 2005) with yields of 30–60%, purities of >85%, > 99.97%/3.5 log T cell depletion but is time consuming. Simpler one-step procedures have thus been tried to reduce the processing time (CD3 depletion, CD3/CD19 depletion, CD6 depletion, CD56 enrichment) but result in a more heterogeneous final cell product that usually contains less than 60% NK cells. NKp46 (CD335) has been demonstrated to be primarily expressed by NK cells and may thus be a suitable selection marker for one-step NK cell enrichment. We evaluated an NKp46 enrichment strategy using the autoMACS™ Pro Separator, NKp46-Biotin, and Anti-Biotin MicroBeads. We could enrich CD56+CD3- cells from peripheral blood mononuclear cells (PBMCs) to a purity of 90% with a yield of 40–60% and a >99.92%/3.1 log depletion of T cells (n = 2). These results encouraged the evaluation of this procedure on a clinical scale by using the CliniMACS Cell Separation System. Using the CliniMACS Plus Instrument, NK cells could be enriched to 73–87% purity (n = 3) from Buffy Coats derived from whole blood. T cells were efficiently depleted (>99.92%/3.0 log) to such a degree that NKp46-selected NK cell products may fulfil the release criteria for NK cell donor lymphocyte infusions (NK-DLI) in the context of haploidentical stem cell transplantation. While CD56+ CD3- NK cells are not activated by antibody binding during cell separation, magnetic labelling using anti-NKp46 antibodies may trigger NK cell activation. NKp46-mediated NK cell activation may be synergistically enhanced by the use of IL-2. Functional studies of NK cells isolated by different methods will be required to further evaluate their feasibility for use in NK-DLIs.

Killer cell immunoglobulin-like receptors (KIRs) are known to modulate the cytotoxic ability of human Natural Killer (NK) cells, as well as a subset of T cells. To date, only a very small number of publications have discussed the role of KIRs on T cells, e.g. CMV-specific CD4+CD28-KIR+ cytotoxic T cells (van Bergen, J., J Immunol. 2004), so we investigated whether CD56+CD3+ NKT cells might also have KIR-positive subsets. Whole human blood as well as magnetically sorted human CD56+CD3+ NKT cells were analyzed for their expression of various KIR molecules using a novel panel of fluorochrome-conjugated, anti-KIR monoclonal antibodies (CD158a/h (KIR2DL1/DS1), CD158b (KIR2DL2), CD158e (KIR3DL1), CD158i (KIR2DS4), KIR2D; Miltenyi Biotec). KIR-positive CD56+CD3+ NKT cells were identified in every donor tested. Donors possessing NK cells of a specific KIR phenotype also possessed CD56+CD3+ NKT cells with the same KIR phenotype. KIRs were also expressed in a clonal fashion on CD56+CD3+ NKT cells, similarly to NK cells. The investigated KIRs were also shown to be expressed on unseparated NK and CD56+CD3+ NKT cells from whole blood. In addition, the ratio between KIR expression on NK and CD56+CD3+ NKT cells was calculated for each donor analyzed. The results show that there is no correlation between the frequencies of KIR expression on NK cells with that of CD56+CD3+ NKT cells. For example, the expression of CD158a/h in one donor was found to be the highest of all CD56+CD3+ NKT cells analyzed, but the lowest of all NK cells by comparison to the other donors tested. For all KIR phenotypes analyzed, the frequency of KIR+ NK cells was higher than the frequency of KIR+ CD56+CD3+ NKT cells in all samples (range: 1.1 to 25.3-fold higher). Interestingly, the frequency of KIR+ NK cells versus KIR+ CD56+CD3+ NKT cells differs significantly between donors: in one donor the frequency of KIR expression is between 7.3 to 25.3-fold higher in NK cells for multiple KIR phenotypes, while this range is more narrow in other donors (2.0–5.4-fold higher). The frequencies of CD56+CD3+ NKT cell subsets staining positive for particular KIRs differ significantly between donors, e.g. for CD158b, the number of positive CD56+CD3+ NKT cells fall within a range of 4.8% to 43.3%. For CD56+CD3+ NKT cells sorted with MACS® Technology, a similarly wide-ranging distribution of CD158b (KIR2DL2) expression was found (0.85%–5.82%), though at a lower level. Further research will be required to explore these differences as they may point to different mechanisms of KIR regulation. The identification of KIR-positive CD56+CD3+ NKT cells may also provide an opportunity for their use for functional KIR studies instead of NK cell clones, as the cloning of CD56+CD3+ NKT cells may prove easier (i.e. using standard T cell cloning methods) than that of NK cells.

Natural Killer (NK) cells show potent anti-leukemic activity in vitro and thus NK cells isolated using the CliniMACS® Cell Separation System are currently under clinical evaluation as part of a treatment for acute myeloid leukemia (AML). (Uharek L et al., 2003, Gentilini C et al., 2005; Koehl U et al., 2004, 2005; Passweg, JR et al., 2005, 2006; Miller J et al., 2005). Currently, the processing of highly purified, clinical-grade NK cells requires a two-step method using the CliniMACS Instrument: Depletion of CD3+ cells followed by enrichment of CD56+ cells (Iyengar R et al., 2003). This procedure shows excellent performance (reviewed in Passweg et al., 2005) with yields of 30–60%, purities of >85%, > 99.97%/3.5 log T cell depletion but is time consuming. Simpler one-step procedures have thus been tried to reduce the processing time (CD3 depletion, CD3/CD19 depletion, CD6 depletion, CD56 enrichment) but result in a more heterogeneous final cell product that usually contains less than 60% NK cells. NKp46 (CD335) has been demonstrated to be primarily expressed by NK cells and may thus be a suitable selection marker for one-step NK cell enrichment. We evaluated an NKp46 enrichment strategy using the autoMACS™ Pro Separator, NKp46-Biotin, and Anti-Biotin MicroBeads. We could enrich CD56+CD3- cells from peripheral blood mononuclear cells (PBMCs) to a purity of 90% with a yield of 40–60% and a >99.92%/3.1 log depletion of T cells (n = 2). These results encouraged the evaluation of this procedure on a clinical scale by using the CliniMACS Cell Separation System. Using the CliniMACS Plus Instrument, NK cells could be enriched to 73–87% purity (n = 3) from Buffy Coats derived from whole blood. T cells were efficiently depleted (>99.92%/3.0 log) to such a degree that NKp46-selected NK cell products may fulfil the release criteria for NK cell donor lymphocyte infusions (NK-DLI) in the context of haploidentical stem cell transplantation. While CD56+ CD3- NK cells are not activated by antibody binding during cell separation, magnetic labelling using anti-NKp46 antibodies may trigger NK cell activation. NKp46-mediated NK cell activation may be synergistically enhanced by the use of IL-2. Functional studies of NK cells isolated by different methods will be required to further evaluate their feasibility for use in NK-DLIs.

Killer cell immunoglobulin-like receptors (KIRs) are known to modulate the cytotoxic ability of human Natural Killer (NK) cells, as well as a subset of T cells. To date, only a very small number of publications have discussed the role of KIRs on T cells, e.g. CMV-specific CD4+CD28-KIR+ cytotoxic T cells (van Bergen, J., J Immunol. 2004), so we investigated whether CD56+CD3+ NKT cells might also have KIR-positive subsets. Whole human blood as well as magnetically sorted human CD56+CD3+ NKT cells were analyzed for their expression of various KIR molecules using a novel panel of fluorochrome-conjugated, anti-KIR monoclonal antibodies (CD158a/h (KIR2DL1/DS1), CD158b (KIR2DL2), CD158e (KIR3DL1), CD158i (KIR2DS4), KIR2D; Miltenyi Biotec). KIR-positive CD56+CD3+ NKT cells were identified in every donor tested. Donors possessing NK cells of a specific KIR phenotype also possessed CD56+CD3+ NKT cells with the same KIR phenotype. KIRs were also expressed in a clonal fashion on CD56+CD3+ NKT cells, similarly to NK cells. The investigated KIRs were also shown to be expressed on unseparated NK and CD56+CD3+ NKT cells from whole blood. In addition, the ratio between KIR expression on NK and CD56+CD3+ NKT cells was calculated for each donor analyzed. The results show that there is no correlation between the frequencies of KIR expression on NK cells with that of CD56+CD3+ NKT cells. For example, the expression of CD158a/h in one donor was found to be the highest of all CD56+CD3+ NKT cells analyzed, but the lowest of all NK cells by comparison to the other donors tested. For all KIR phenotypes analyzed, the frequency of KIR+ NK cells was higher than the frequency of KIR+ CD56+CD3+ NKT cells in all samples (range: 1.1 to 25.3-fold higher). Interestingly, the frequency of KIR+ NK cells versus KIR+ CD56+CD3+ NKT cells differs significantly between donors: in one donor the frequency of KIR expression is between 7.3 to 25.3-fold higher in NK cells for multiple KIR phenotypes, while this range is more narrow in other donors (2.0–5.4-fold higher). The frequencies of CD56+CD3+ NKT cell subsets staining positive for particular KIRs differ significantly between donors, e.g. for CD158b, the number of positive CD56+CD3+ NKT cells fall within a range of 4.8% to 43.3%. For CD56+CD3+ NKT cells sorted with MACS® Technology, a similarly wide-ranging distribution of CD158b (KIR2DL2) expression was found (0.85%–5.82%), though at a lower level. Further research will be required to explore these differences as they may point to different mechanisms of KIR regulation. The identification of KIR-positive CD56+CD3+ NKT cells may also provide an opportunity for their use for functional KIR studies instead of NK cell clones, as the cloning of CD56+CD3+ NKT cells may prove easier (i.e. using standard T cell cloning methods) than that of NK cells.