Surface Tension of Seawater

New measurements and a reference correlation for the surface tension of seawater at atmospheric pressure are presented in this paper. Surface tension of seawater was measured across a salinity range of 20 ⩽ S ⩽ 131 g/kg and a temperature range of 1 ⩽ t ⩽ 92 °C at atmospheric pressure using the Wilhelmy plate method. The uncertainty within measurements varied from 0.18 to 0.37 mN/m with the average uncertainty being 0.22 mN/m. The experimental procedures were validated with tests conducted on ACS reagent grade water and aqueous sodium chloride solutions. Literature data and present measurements were evaluated and a reference correlation was developed expressing surface tension of seawater as a function of temperature and salinity. The average absolute percentage deviation between measurements and the correlation was 0.19% while the maximum deviation was 0.60%.Center for Clean Water and Clean Energy at MIT and KFUPM (Project R13-CW-10

α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas

Abstract Background Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGFβ signaling. Methods To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to α-PD-1, α-TGFβ or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses. Results We show that α-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. α-TGFβ monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. α-PD-1 synergizes with α-TGFβ, increasing CR rates to 60% (CCK168) and 20% (CCK169). α-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas α-TGFβ antibody administration attenuates these effects. We show that α-TGFβ acts in part through suppressing immunosuppressive Tregs induced by α-PD-1, that limit the anti-tumor activity of α-PD-1 monotherapy. Additionally, in vitro and in vivo, α-TGFβ acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery. Conclusions We show that α-PD-1 not only initiates a tumor rejection program, but can induce a competing TGFβ-driven immuno-suppressive program. We identify new opportunities for α-PD-1/α-TGFβ combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of α-TGFβ/α-PD-1 combination therapy (NCT02947165).https://deepblue.lib.umich.edu/bitstream/2027.42/148212/1/40425_2018_Article_493.pd

Global CO2 fluxes inferred from surface air-sample measurements and from TCCON retrievals of the CO2 total column

We present the first estimate of the global distribution of CO2surface fluxes from 14 stations of the Total Carbon Column Observing Network (TCCON). The evaluation of this inversion is based on 1) comparison with the fluxes from a classical inversion of surface air-sample-measurements, and 2) comparison of CO2mixing ratios calculated from the inverted fluxes with independent aircraft measurements made during the two years analyzed here, 2009 and 2010. The former test shows similar seasonal cycles in the northern hemisphere and consistent regional carbon budgets between inversions from the two datasets, even though the TCCON inversion appears to be less precise than the classical inversion. The latter test confirms that the TCCON inversion has improved the quality (i.e., reduced the uncertainty) of the surface fluxes compared to the assumed or prior fluxes. The consistency between the surface-air-sample-based and the TCCON-based inversions despite remaining flaws in transport models opens the possibility of increased accuracy and robustness of flux inversions based on the combination of both data sources and confirms the usefulness of space-borne monitoring of the CO2 column.It was co-funded by the European Commission under the EU Seventh Research Framework Programme (grants agreements 218793, MACC, and 212196, COCOS

History of chemically and radiatively important atmospheric gases from the Advanced Global Atmospheric Gases Experiment (AGAGE)

We present the organization, instrumentation, datasets, data interpretation, modeling, and accomplishments of the multinational global atmospheric measurement program AGAGE (Advanced Global Atmospheric Gases Experiment). AGAGE is distinguished by its capability to measure globally, at high frequency, and at multiple sites all the important species in the Montreal Protocol and all the important non-carbon-dioxide (non-CO₂) gases assessed by the Intergovernmental Panel on Climate Change (CO₂ is also measured at several sites). The scientific objectives of AGAGE are important in furthering our understanding of global chemical and climatic phenomena. They are the following: (1) to accurately measure the temporal and spatial distributions of anthropogenic gases that contribute the majority of reactive halogen to the stratosphere and/or are strong infrared absorbers (chlorocarbons, chlorofluorocarbons – CFCs, bromocarbons, hydrochlorofluorocarbons – HCFCs, hydrofluorocarbons – HFCs and polyfluorinated compounds (perfluorocarbons – PFCs), nitrogen trifluoride – NF₃, sulfuryl fluoride – SO₂F₂, and sulfur hexafluoride – SF₆) and use these measurements to determine the global rates of their emission and/or destruction (i.e., lifetimes); (2) to accurately measure the global distributions and temporal behaviors and determine the sources and sinks of non-CO₂ biogenic–anthropogenic gases important to climate change and/or ozone depletion (methane – CH₄, nitrous oxide – N₂O, carbon monoxide – CO, molecular hydrogen – H₂, methyl chloride – CH₃Cl, and methyl bromide – CH₃Br); (3) to identify new long-lived greenhouse and ozone-depleting gases (e.g., SO₂F₂, NF₃, heavy PFCs (C₄F₁₀, C₅F₁₂, C₆F₁₄, C₇F₁₆, and C₈F₁₈) and hydrofluoroolefins (HFOs; e.g., CH₂  =  CFCF₃) have been identified in AGAGE), initiate the real-time monitoring of these new gases, and reconstruct their past histories from AGAGE, air archive, and firn air measurements; (4) to determine the average concentrations and trends of tropospheric hydroxyl radicals (OH) from the rates of destruction of atmospheric trichloroethane (CH₃CCl₃), HFCs, and HCFCs and estimates of their emissions; (5) to determine from atmospheric observations and estimates of their destruction rates the magnitudes and distributions by region of surface sources and sinks of all measured gases; (6) to provide accurate data on the global accumulation of many of these trace gases that are used to test the synoptic-, regional-, and global-scale circulations predicted by three-dimensional models; and (7) to provide global and regional measurements of methane, carbon monoxide, and molecular hydrogen and estimates of hydroxyl levels to test primary atmospheric oxidation pathways at midlatitudes and the tropics. Network Information and Data Repository: <a href="http://agage.mit.edu/data" target="_blank">http://agage.mit.edu/data</a> or <a href="http://cdiac.ess-dive.lbl.gov/ndps/alegage.html" target="_blank">http://cdiac.ess-dive.lbl.gov/ndps/alegage.html</a> (<a href="https://doi.org/10.3334/CDIAC/atg.db1001" target="_blank">https://doi.org/10.3334/CDIAC/atg.db1001</a>)

CTLA-4 Activation of Phosphatidylinositol 3-Kinase (PI 3-K) and Protein Kinase B (PKB/AKT) Sustains T-Cell Anergy without Cell Death

The balance of T-cell proliferation, anergy and apoptosis is central to immune function. In this regard, co-receptor CTLA-4 is needed for the induction of anergy and tolerance. One central question concerns the mechanism by which CTLA-4 can induce T-cell non-responsiveness without a concurrent induction of antigen induced cell death (AICD). In this study, we show that CTLA-4 activation of the phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. CTLA-4 ligation induced PI 3K activation as evidenced by the phosphorylation of PKB/AKT that in turn inactivated GSK-3. The level of activation was similar to that observed with CD28. CTLA-4 induced PI 3K and AKT activation also led to phosphorylation of the pro-apoptotic factor BAD as well as the up-regulation of BcL-XL. In keeping with this, CD3/CTLA-4 co-ligation prevented apoptosis under the same conditions where T-cell non-responsiveness was induced. This effect was PI 3K and PKB/AKT dependent since inhibition of these enzymes under conditions of anti-CD3/CTLA-4 co-ligation resulted in cell death. Our findings therefore define a mechanism by which CTLA-4 can induce anergy (and possibly peripheral tolerance) by preventing the induction of cell death

A Role for Rebinding in Rapid and Reliable T Cell Responses to Antigen

Experimental work has shown that T cells of the immune system rapidly and specifically respond to antigenic molecules presented on the surface of antigen-presenting-cells and are able to discriminate between potential stimuli based on the kinetic parameters of the T cell receptor-antigen bond. These antigenic molecules are presented among thousands of chemically similar endogenous peptides, raising the question of how T cells can reliably make a decision to respond to certain antigens but not others within minutes of encountering an antigen presenting cell. In this theoretical study, we investigate the role of localized rebinding between a T cell receptor and an antigen. We show that by allowing the signaling state of individual receptors to persist during brief unbinding events, T cells are able to discriminate antigens based on both their unbinding and rebinding rates. We demonstrate that T cell receptor coreceptors, but not receptor clustering, are important in promoting localized rebinding, and show that requiring rebinding for productive signaling reduces signals from a high concentration of endogenous pMHC. In developing our main results, we use a relatively simple model based on kinetic proofreading. However, we additionally show that all our results are recapitulated when we use a detailed T cell receptor signaling model. We discuss our results in the context of existing models and recent experimental work and propose new experiments to test our findings

Regulation of Glucose Homeostasis by KSR1 and MARK2

Protein scaffolds control the intensity and duration of signaling and dictate the specificity of signaling through MAP kinase pathways. KSR1 is a molecular scaffold of the Raf/MEK/ERK MAP kinase cascade that regulates the intensity and duration of ERK activation. Relative to wild-type mice, ksr1-/- mice are modestly glucose intolerant, but show a normal response to exogenous insulin. However, ksr1-/- mice also demonstrate a three-fold increase in serum insulin levels in response to a glucose challenge, suggesting a role for KSR1 in insulin secretion. The kinase MARK2 is closely related to C-TAK1, a known regulator of KSR1. Mice lacking MARK2 have an increased rate of glucose disposal in response to exogenous insulin, increased glucose tolerance, and are resistant to diet-induced obesity. mark2-/-ksr1-/- (DKO) mice were compared to wild type, mark2-/-, and ksr1-/- mice for their ability to regulate glucose homeostasis. Here we show that disruption of KSR1 in mark2-/- mice reverses the increased sensitivity to exogenous insulin resulting from MARK2 deletion. DKO mice respond to exogenous insulin similarly to wild type and ksr1-/- mice. These data suggest a model whereby MARK2 negatively regulates insulin sensitivity in peripheral tissue through inhibition of KSR1. Consistent with this model, we found that MARK2 binds and phosphorylates KSR1 on Ser392. Phosphorylation of Ser392 is a critical regulator of KSR1 stability, subcellular location, and ERK activation. These data reveal an unexpected role for the molecular scaffold KSR1 in insulin-regulated glucose metabolism