Mesoscale perturbations control inter-ocean exchange south of Africa

The quantification of inter-ocean leakage from the South Indian to the South Atlantic Ocean is an important measure for the role of the Agulhas system in the global thermohaline circulation. To explore the specific role of mesoscale variability (such as Agulhas rings and Mozambique eddies) in this process a high-resolution model (based on NEMO-ORCA) for the Agulhas region has been set up. It is nested into a global coarse-resolution model. The high-resolution nest captures all salient features of the greater Agulhas region, including the upstream perturbations of the Agulhas Current and Natal Pulses along the African coast. A comparison of the inter-ocean exchange in the high-resolution nest with its coarse resolution counterpart reveals that the latter significantly over-estimates the amount of water flowing into the Atlantic Ocean, demonstrating the need to explicitly simulate the mesoscale features. A sensitivity experiment that excludes the upstream perturbations revealed no difference in the amount of inter-ocean exchange. However, the realistic representation of Agulhas rings and their drift path into the South Atlantic depends on the simulation of those upstream perturbations

The Ocean Circulation in Thermohaline Coordinates

The thermohaline streamfunction is presented. The thermohaline streamfunction is the integral of transport in temperature–salinity space and represents the net pathway of oceanic water parcels in that space. The thermohaline streamfunction is proposed as a diagnostic to understand the global oceanic circulation and its role in the global movement of heat and freshwater. The coordinate system used filters out adiabatic fluctuations. Physical pathways and ventilation time scales are naturally diagnosed, as are the roles of the mean flow and turbulent fluctuations. Because potential density is a function of temperature and salinity, the framework is naturally isopycnal and is ideal for the diagnosis of water-mass transformations and advective diapycnal heat and freshwater transports. Crucially, the thermohaline streamfunction is computationally and practically trivial to implement as a diagnostic for ocean models. Here, the thermohaline streamfunction is computed using the output of an equilibrated intermediate complexity climate model. It describes a global cell, a warm tropical cell, and a bottom water cell. The streamfunction computed from eddy-induced advection is equivalent in magnitude to that from the total advection, demonstrating the leading-order importance of parameterized eddy fluxes in oceanic heat and freshwater transports. The global cell, being clockwise in thermohaline space, tends to advect both heat and salt toward denser (poleward) water masses in symmetry with the atmosphere’s poleward transport of moisture. A reprojection of the global cell from thermohaline to geographical coordinates reveals a thermohaline circulation reminiscent of the schematized “global conveyor.

Indian Ocean sources of Agulhas leakage

We examine the mean pathways, transit timescales, and transformation of waters flowing from the Pacific and the marginal seas through the Indian Ocean (IO) on their way toward the South Atlantic within a high-resolution ocean/sea-ice model. The model fields are analyzed from a Lagrangian perspective where water volumes are tracked as they enter the IO. The IO contributes 12.6 Sv to Agulhas leakage, which within the model is 14.1 ± 2.2 Sv, the rest originates from the South Atlantic. The Indonesian Through-flow constitutes about half of the IO contribution, is surface bound, cools and salinificates as it leaves the basin within 10–30 years. Waters entering the IO south of Australia are at intermediate depths and maintain their temperature-salinity properties as they exit the basin within 15–35 years. Of these waters, the contribution from Tasman leakage is 1.4 Sv. The rest stem from recirculation from the frontal regions of the Southern Ocean. The marginal seas export 1.0 Sv into the Atlantic within 15–40 years, and the waters cool and freshen on-route. However, the model's simulation of waters from the Gulfs of Aden and Oman are too light and hence overly influenced by upper ocean circulations. In the Cape Basin, Agulhas leakage is well mixed. On-route, temperature-salinity transformations occur predominantly in the Arabian Sea and within the greater Agulhas Current region. Overall, the IO exports at least 7.9 Sv from the Pacific to the Atlantic, thereby quantifying the strength of the upper cell of the global conveyor belt

Quantitative estimate of the paleo-Agulhas leakage

The Indian-Atlantic water exchange south of Africa (Agulhas leakage) is a key component of the global ocean circulation. No quantitative estimation of the paleo-Agulhas leakage exists. We quantify the variability in interocean exchange over the past 640,000 years, using planktic foraminiferal assemblage data from two marine sediment records to define an Agulhas leakage efficiency index. We confirm the validity of our new approach with a numerical ocean model that realistically simulates the modern Agulhas leakage changes. Our results suggest that, during the past several glacial-interglacial cycles, the Agulhas leakage varied by ~10 sverdrup and more during major climatic transitions. This lends strong credence to the hypothesis that modifications in the leakage played a key role in changing the overturning circulation to full strength mode. Our results are instrumental for validating and quantifying the contribution of the Indian-Atlantic water leakage to the global climate changes

Agulhas Leakage Predominantly Responds to the Southern Hemisphere Westerlies

The Agulhas Current plays a crucial role in the thermohaline circulation through its leakage into the South Atlantic. Under both past and present climates, the trade winds and westerlies could have the ability to modulate the amount of Indian-Atlantic inflow. Compelling arguments have been put forward suggesting that trade winds alone have little impact on the magnitude of Agulhas leakage. Here, employing three ocean models for robust analysis – a global coarse resolution, a regional eddy-permitting and a nested high-resolution eddy-resolving configuration – and systematically altering the position and intensity of the westerly wind belt in a series of sensitivity experiments, it is shown that the westerlies, in particular their intensity, control the leakage. Leakage responds proportionally to the westerlies intensity up to a certain point. Beyond this, through the adjustment of the large-scale circulation, energetic interactions occur between the Agulhas Return Current and the Antarctic Circumpolar Current that result in a state where leakage no longer increases. This adjustment takes place within 1 to 2 decades. Contrary to previous assertions, our results further show that an equatorward (poleward) shift in westerlies increases (decreases) leakage. This occurs due to the redistribution of momentum input by the winds. It is concluded that the reported present-day leakage increase could therefore reflect an unadjusted oceanic response mainly to the strengthening westerlies over the last few decades

Characterization of Notch1 Antibodies That Inhibit Signaling of Both Normal and Mutated Notch1 Receptors

Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target.Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD), and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR). The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50) values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL). In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell-penetrating gamma-secretase inhibitors.Antibodies that compete with Notch1 ligand binding or that bind to the negative regulatory region can act as potent inhibitors of Notch1 signaling. These antibodies may have clinical utility for conditions in which inhibition of signaling by wild-type Notch1 is desired, but are likely to be of limited value for treatment of T-ALLs associated with aberrant Notch1 activation

Hermeneutics and Nature

This paper contributes to the on-going research into the ways in which the humanities transformed the natural sciences in the late Eighteenth and early Nineteenth Centuries. By investigating the relationship between hermeneutics -- as developed by Herder -- and natural history, it shows how the methods used for the study of literary and artistic works played a crucial role in the emergence of key natural-scientific fields, including geography and ecology

Atlantic Equatorial Undercurrent and associated cold tongue variability

The Atlantic Equatorial Undercurrent (EUC) is studied using a simulation for the period 1990–2002 with a high-resolution ocean general circulation model. Simulated transports of the EUC that supplies the annual mean upwelling in the central and eastern equatorial Atlantic are in good agreement with new transport estimates derived from ship observations, i.e., 19.9 and 14.0 Sv at 35°W and 23°W, respectively. Although the observations are not conclusive concerning the seasonal cycle of EUC transports, the simulated seasonal cycles fit largely in the observed range. The analysis of the EUC variability associated with interannual boreal summer variability of the equatorial cold tongue showed that cold tongue indices, defined either by near-surface temperature or steric height anomalies, are anticorrelated with thermocline EUC transport anomalies: A strong EUC corresponds to low near-surface temperatures and steric heights. The importance of equatorial waves for the cold tongue region is shown: Surface layer transport anomalies at 23°W and 10°W are significantly correlated with both near-surface temperature and steric height anomalies in the equatorial and coastal upwelling regions, indicating an associated eastward phase propagation along the equator toward the African coast where the signal bifurcates into two poleward branches along the coast and is reflected into a westward propagating wave

Calcium Influx Rescues Adenylate Cyclase-Hemolysin from Rapid Cell Membrane Removal and Enables Phagocyte Permeabilization by Toxin Pores

Bordetella adenylate cyclase toxin-hemolysin (CyaA) penetrates the cytoplasmic membrane of phagocytes and employs two distinct conformers to exert its multiple activities. One conformer forms cation-selective pores that permeabilize phagocyte membrane for efflux of cytosolic potassium. The other conformer conducts extracellular calcium ions across cytoplasmic membrane of cells, relocates into lipid rafts, translocates the adenylate cyclase enzyme (AC) domain into cells and converts cytosolic ATP to cAMP. We show that the calcium-conducting activity of CyaA controls the path and kinetics of endocytic removal of toxin pores from phagocyte membrane. The enzymatically inactive but calcium-conducting CyaA-AC− toxoid was endocytosed via a clathrin-dependent pathway. In contrast, a doubly mutated (E570K+E581P) toxoid, unable to conduct Ca2+ into cells, was rapidly internalized by membrane macropinocytosis, unless rescued by Ca2+ influx promoted in trans by ionomycin or intact toxoid. Moreover, a fully pore-forming CyaA-ΔAC hemolysin failed to permeabilize phagocytes, unless endocytic removal of its pores from cell membrane was decelerated through Ca2+ influx promoted by molecules locked in a Ca2+-conducting conformation by the 3D1 antibody. Inhibition of endocytosis also enabled the native B. pertussis-produced CyaA to induce lysis of J774A.1 macrophages at concentrations starting from 100 ng/ml. Hence, by mediating calcium influx into cells, the translocating conformer of CyaA controls the removal of bystander toxin pores from phagocyte membrane. This triggers a positive feedback loop of exacerbated cell permeabilization, where the efflux of cellular potassium yields further decreased toxin pore removal from cell membrane and this further enhances cell permeabilization and potassium efflux

The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms