ALBERT

Description: Large initial condition ensembles of a climate model simulation provide many different realizations of internal variability noise superimposed on an externally forced signal. They have been used to estimate signal emergence time at individual grid points, but are rarely employed to identify global fingerprints of human influence. Here we analyze 50- and 40-member ensembles performed with 2 climate models; each was run with combined human and natural forcings. We apply a pattern-based method to determine signal detection time td in individual ensemble members. Distributions of td are characterized by the median td{m} and range td{r}, computed for tropospheric and stratospheric temperatures over 1979 to 2018. Lower stratospheric cooling—primarily caused by ozone depletion—yields td{m} values between 1994 and 1996, depending on model ensemble, domain (global or hemispheric), and type of noise data. For greenhouse-gas–driven tropospheric warming, larger noise and slower recovery from the 1991 Pinatubo eruption lead to later signal detection (between 1997 and 2003). The stochastic uncertainty td{r} is greater for tropospheric warming (8 to 15 y) than for stratospheric cooling (1 to 3 y). In the ensemble generated by a high climate sensitivity model with low anthropogenic aerosol forcing, simulated tropospheric warming is larger than observed; detection times for tropospheric warming signals in satellite data are within td{r} ranges in 60% of all cases. The corresponding number is 88% for the second ensemble, which was produced by a model with even higher climate sensitivity but with large aerosol-induced cooling. Whether the latter result is physically plausible will require concerted efforts to reduce significant uncertainties in aerosol forcing.

Description: Although hydraulic fracturing has been used for natural gas production for the past couple of decades, there are significant uncertainties about the underlying mechanisms behind the production curves that are seen in the field. A discrete fracture network based reservoir-scale work flow is used to identify the relative effect of flow of gas in fractures and matrix diffusion on the production curve. With realistic three dimensional representations of fracture network geometry and aperture variability, simulated production decline curves qualitatively resemble observed production decline curves. The high initial peak of the production curve is controlled by advective fracture flow of free gas within the network and is sensitive to the fracture aperture variability. Matrix diffusion does not significantly affect the production decline curve in the first few years, but contributes to production after approximately 10 years. These results suggest that the initial flushing of gas-filled background fractures combined with highly heterogeneous flow paths to the production well are sufficient to explain observed initial production decline. These results also suggest that matrix diffusion may support reduced production over longer time frames. This article is protected by copyright. All rights reserved.

Description: Here we present the radiative and snowmelt impacts of dust deposition to snow cover using a 6-year energy balance record (2005–2010) at alpine and subalpine micrometeorological towers in the Senator Beck Basin Study Area (SBBSA) in southwestern Colorado, USA. These results follow from the measurements described in part I. We simulate the evolution of snow water equivalent at each station under scenarios of observed and dust-free conditions, and +2°C and +4°C melt-season temperature perturbations to these scenarios. Over the 6 years of record, daily mean dust radiative forcing ranged from 0 to 214 W m−2, with hourly peaks up to 409 W m−2. Mean springtime dust radiative forcings across the period ranged from 31 to 49 W m−2 at the alpine site and 45 to 75 W m−2 at the subalpine site, in turn shortening snow cover duration by 21 to 51 days. The dust-advanced loss of snow cover (days) is linearly related to total dust concentration at the end of snow cover, despite temporal variability in dust exposure and solar irradiance. Under clean snow conditions, the temperature increases shorten snow cover by 5–18 days, whereas in the presence of dust they only shorten snow duration by 0–6 days. Dust radiative forcing also causes faster and earlier peak snowmelt outflow with daily mean snowpack outflow doubling under the heaviest dust conditions. On average, snow cover at the towers is lost 2.5 days after peak outflow in dusty conditions, and 1–2 weeks after peak outflow in clean conditions.

Description: [1]  Accurate prediction of snowmelt runoff is critical in the US Intermountain West, where water demand is increasing and snow patterns are shifting. Here we show that errors in the National Weather Service Colorado Basin River Forecast Center's operational streamflow predictions are correlated with the interannual variability of dust radiative forcing in snow. With data from 2000 – 2010, we show that errors in snowmelt-period streamflow prediction for the southern Colorado Rockies are linearly related to melt-period dust radiative forcing in snow as inferred from NASA MODIS data, which ranged interannually from 20 to 80 W m -2 . Each 10 W m -2 change of melt-period dust forcing resulted in a corresponding change in runoff prediction bias of 10.0± 1.5% and a 1.5± 0.6 day shift in runoff center of mass. Accounting for bias introduced by dust forcing could improve streamflow prediction in regions prone to dust deposition in the snowpack.

Description: We use updated and improved satellite retrievals of the temperature of the mid- to upper troposphere (TMT) to address key questions about the size and significance of TMT trends, agreement with model-derived TMT values, and whether models and satellite data show similar vertical profiles of warming. A recent study claimed that TMT trends over 1979 and 2015 are three times larger in climate models than in satellite data, but did not correct for the contribution TMT trends receive from stratospheric cooling. Here we show that the average ratio of modeled and observed TMT trends is sensitive to both satellite data uncertainties and to model-data differences in stratospheric cooling. When the impact of lower stratospheric cooling on TMT is accounted for, and when the most recent versions of satellite datasets are used, the previously claimed ratio of three between simulated and observed near-global TMT trends is reduced to ≈ 1.7. Next, we assess the validity of the statement that satellite data show no significant tropospheric warming over the last 18 years. This claim is not supported by our analysis: in five out of six corrected satellite TMT records, significant global-scale tropospheric warming has occurred within the last 18 years. Finally, we address long-standing concerns regarding discrepancies in modeled and observed vertical profiles of warming in the tropical atmosphere. We show that amplification of tropical warming between the lower and mid- to upper troposphere is now in close agreement in the average of 37 climate models and in one updated satellite record.

Description: Background: Patients with myelodysplastic syndromes (MDS) display several abnormalities of T cell and NK cellular immunity. Tumor lysis by NK cells occurs through orchestrated control by inhibitory NK receptors (NKRs) and activating NKRs. Lenalidomide is an immunomodulatory (IMiD) drug structurally related to thalidomide, which has proven clinical efficacy for the treatment of low-risk MDS (List et al, NEJM2005; 352:549). Investigations in patients with multiple myeloma (MM) reported that thalidomide was associated with enhanced cytolytic function and increased NK cells in responding patients. We investigated the action of lenalidomide on NK function and activating NK receptor expression in patients with MDS. Methods: MDS patients were categorized according to WHO category, age, sex, IPSS, and cytogenetics. Peripheral blood cells (PBMCs) were isolated from patients and normal donors and NK receptor expression determined in paired healthy and patient PBMCs by 3-color flow cytometry. NK receptor expression was analyzed for CD158a (KIR2DL1, KIR2DS1), CD158b (KIR2DL2, KIR2DL3, KIR2DL3), KIR3DL1, KIR2DS4, NKG2A, NKG2D, NKp30, NKp44, and NKp46. Cytotoxicity assays were performed using 5-hour 51Cr-release assays. Results: Forty-eight MDS patients and 37 normal donors were analyzed, demonstrating that NK cytolytic function was reduced in the patient population (19% ± 21 S.D. vs. 44% ± 21) (p

Description: We have previously shown that selection for resistance to the anthracenes, doxorubicin or mitoxantrone, results in coselection for resistance to CD95-mediated apoptosis (Landowski et al: Blood89:1854, 1997). In the present study, we were interested in determining if the converse is also true; that is, does selection for CD95 resistance coselect for resistance to chemotherapeutic drugs. To address this question, we used two isogenic models of CD95-resistant versus CD95-sensitive cell lines: 8226/S myeloma cells selected for resistance to CD95-mediated apoptosis; and K562 cells expressing ectopic CD95. Repeated exposure of the CD95-sensitive human myeloma cell line, 8226/S, to agonistic anti-CD95 antibody resulted in a cell line devoid of CD95 receptor surface expression and completely resistant to CD95-mediated apoptosis. Multiple clonal populations derived from the CD95-resistant cell line showed no difference in sensitivity to doxorubicin, mitoxantrone, Ara-C, or etoposide, demonstrating that cross-resistance between Fas-mediated apoptosis and drug-induced apoptosis occurs only when cytotoxic drugs are used as the selecting agent. Using the inverse approach, we transfected the CD95-negative cell line, K562, with a CD95 expression vector. Clones expressing variable levels of cell-surface CD95 were isolated by limiting dilution, and analyzed for sensitivity to CD95-mediated apoptosis and response to chemotherapeutic drugs. We show that CD95 surface expression confers sensitivity to CD95-mediated apoptosis; however, it does not alter response to chemotherapeutic drugs. Similarly, doxorubicin-induced activation of caspases 3 and 8 was identical in the CD95-sensitive and CD95-resistant cell lines in both isogenic cell systems. In addition, prior treatment with the CD95 receptor-blocking antibody, ZB4, inhibited CD95-activated apoptosis in 8226/S cells, but had no effect on doxorubicin cytotoxicity. These results show that CD95 and chemotherapeutic drugs use common apoptotic effectors, but the point of convergence in these two pathways is downstream of CD95 receptor/ligand interaction.

Description: BACKGROUND: LGL leukemia is a neoplasm arising from either CD3+ T-cells or CD3− NK-cells. Autoimmune-mediated anemia, neutropenia, and rheumatoid arthritis occur frequently in these patients and immunosuppressive agents are used for these associated clinical syndromes. In our previous studies, we found that patients display a constitutively activated Ras and MAPK/ERK signaling cascade that may drive leukemia survival. A multicenter phase 2 clinical trial was initiated to treat LGL leukemia patients with the farnysltransferase-inhibitor R115777 (tipifarnib, Zarnestra®, Johnson & Johnson) that inhibits Ras and other farnesylated proteins. One of the goals of this study was to determine the shifts in cytokine production during therapy. We found that LGL cells treated with tipifarnib in vitro displayed a switch to Th2 (IL-4 and IL-10)-polarized differentiation. After tipifarnib treatment of LGL patients, antigen-activated T-cells produced greater amounts of Th2 (IL4/IL-10) cytokines but less Th1 (IFNγ/TNFα). In this study, we determined the mechanism governing tipifarnib-mediated Th2 polarization in T-cells. METHODS: PBMCs were isolated from 10 healthy donors and from seven patients with T-LGL leukemia before and after treatment with tipifarnib 300 mg twice daily for 21 days of a 28- day cycle. LGL leukemia patients had increased numbers of αβ T lymphocytes and evidence of clonality in association with either neutropenia or transfusion-dependent anemia. Th1 and Th2 cytokines were determined by intracellular staining and flow cytometry after activation with anti-CD3 plus anti-CD28. In some experiments, Th1 polarization was induced by IL-12; whereas, Th2 was induced by IL-4. Expression of T-bet and GATA-3 transcription factors that regulate Th1 and Th2 polarization, respectively, phosphorylated (active) MAPK (ERK1 and ERK2), and total MAPK were measured by Western blots. FTI2153, tipifarnib, and geranylgeranyl transferase inhibitor(GGTI)-2417 were used compared to DMSO control. RESULTS: PBMCs from patients with T-LGL leukemia displayed a dose and time-dependent increase in IL-4 and IL-10 production after drug treatment (average increase to 100% and 43%, respectively). A dose-dependent increase in these Th2 cytokines in T-cells from healthy donors showed that the farnesylated protein targeted by tipifarnib was not selectively expressed in LGL leukemia. Culture with IL-12 induced Th1 differentiation associated with ERK phosphorylation and increased T-bet expression. Pre-treatment with tipifarnib and FTI2153 but not GGTI2417 prior to IL-12 inhibited T-bet induction with no change in anti-CD3-induced MAPK leading to enhanced IL-4 signaling and greater Th2 polarization. CONCLUSIONS: Our data reveal unique, previously unreported effects of FTIs on cytokine signaling in T-cells by inhibiting the induction of T-bet and blocking Th1 differentiation. These results are critical to determine the mechanism of action of tipifarnib in LGL leukemia and suggest that FTIs may be useful for autoimmune or lymphocyte-mediated disorders associated with excessive Th1 cytokine production.

Description: Low-dose methotrexate (MTX) is used as an immunosuppressive agent for the treatment of rheumatoid arthritis (RA), Large Granular Lymphocyte (LGL) leukemia, Cutaneous T Cell Lymphoma (CTCL), autoimmune diseases, and prevention of GvHD during bone marrow transplants. The mechanism for immunosuppression is not clearly understood but most data suggests that apoptosis of activated lymphocytes plays a critical role. In this study, we wanted to define the MTX-sensitive population and to determine the apoptotic pathway activated by MTX. Using a clinically relevant dosage range (8 nM- 1 μM), MTX-mediated apoptosis was first examined in a T lymphoblastic leukemia cell line (CEM). The apoptotic pathway induced by MTX included phosphotidylinositol externalization and caspase-3 activation along with a slight increase in mitochondrial membrane depolarization. We next examined a series of tumor cell lines and normal cells for evidence of MTX-induced apoptosis. Using the same clinically relevant dosage range, we found that MTX-induced apoptosis was primarily observed in the four T cell leukemia cell lines including CEM, Jurkat, MT-2, and HUT78 and in normal PBMCs activated with mitogens and IL-2. Less MTX-induced apoptosis was observed in two myeloid leukemia cell lines including HL-60 and K562 and in a B cell leukemia cell line Raji, and the multiple myeloma cell line 8226. Unactivated PBMCs were resistant to MTX-mediated apoptosis. T cells that are clonally expanded in patients with T-LGL leukemia have a CD8+ cytotoxic phenotype, whereas other diseases that are treated with low-dose MTX, such as CTCL and RA, are characterized by the expansion of CD4+ T cells. We found that both freshly sorted CD4+ and CD8+ cells were MTX resistant. In contrast, PHA plus IL-2 treatment induced MTX sensitivity in T cell with both immunophenotypes. We also examined clinical samples from patients with LGL leukemia. We found that freshly isolated PBMCs from T-LGL leukemia patients were resistant to MTX. Clonal cells from the peripheral blood of LGL leukemia patients are in G0/G1 phase of the cell cycle. Interestingly, we found that PHA plus IL-2 treatment induced the cells to enter S-phase and to become MTX sensitive. These results suggest that only fully activated, proliferating T cells from patients with LGL leukemia undergo apoptosis in response to low-dose MTX. Because there was only minor depolarization of mitochondria after MTX treatment in both CEM cells and normal activated PBMCs, we wanted to examine upstream apoptotic events after MTX treatment. We found that caspase-8 cleavage and enzymatic activity was induced by MTX in both CD95 Type I (HUT78) and Type II (CEM and Jurkat) cells but that there was a differential requirement for caspase-8 activity for apoptosis. We found that caspase-8 activation was independent of the Fas receptor as shown by immunoprecipitation experiments and MTX apoptotic assays in the JM3A5 Fas-receptor mutant Jurkat cell line. Using a Jurkat cell line with a homozygous deletion of the FADD gene, we found that caspase-8 activation, caspase-3 activation, and apoptosis in response to MTX were dependent on the adaptor protein FADD. These findings have important implications for understanding the mechanism of MTX for immunosuppressive therapy.