Introduction

This chapter: ■ explains what is meant by a complex emergency and the different phases of an emergency ■ discusses the impact of complex emergencies, explaining who is affected ■ provides basic information about malaria parasites, malaria transmission and populations at risk, and why malaria is signifi cant in emergency situations ■ sets out the key steps of an effective emergency response

Calcium-regulated exocytosis of dense-core vesicles requires the activation of ADP-ribosylation factor (ARF)6 by ARF nucleotide binding site opener at the plasma membrane

The ADP ribosylation factor (ARF) GTP binding proteins are believed to mediate cytoskeletal remodeling and vesicular trafficking along the secretory pathway. Here we show that ARF6 is specifically associated with dense-core secretory granules in neuroendocrine PC12 cells. Stimulation with a secretagogue triggers the recruitment of secretory granules to the cell periphery and the concomitant activation of ARF6 by the plasma membrane-associated guanine nucleotide exchange factor, ARF nucleotide binding site opener (ARNO). Expression of the constitutively inactive ARF6(T27N) mutant inhibits secretagogue-dependent exocytosis from PC12 cells. Using a mutant of ARF6 specifically impaired for PLD1 stimulation, we find that ARF6 is functionally linked to phospholipase D (PLD)1 in the exocytotic machinery. Finally, we show that ARNO, ARF6, and PLD1 colocalize at sites of exocytosis, and we demonstrate direct interaction between ARF6 and PLD1 in stimulated cells. Together, these results provide the first direct evidence that ARF6 plays a role in calcium-regulated exocytosis in neuroendocrine cells, and suggest that ARF6-stimulated PLD1 activation at the plasma membrane and consequent changes in membrane phospholipid composition are critical for formation of the exocytotic fusion pore

Practice and Philosophy of Climate Model Tuning Across Six U.S. Modeling Centers

Model calibration (or tuning) is a necessary part of developing and testing coupled ocean-atmosphere climatemodels regardless of their main scientific purpose. There is an increasing recognition that this process needs to become more transparent for both users of climate model output and other developers. Knowing how and why climate models are tuned and which targets are used is essential to avoiding possible misattributions of skillful predictions to data accommodation and vice versa. This paper describes the approach and practice of model tuning for the six major U.S. climate modeling centers. While details differ among groups in terms of scientific missions, tuning targets and tunable parameters, there is a core commonality of approaches. However, practices differ significantly on some key aspects, in particular, in the use of initialized forecast analyses as a tool, the explicit use of the historical transient record, and the use of the present day radiative imbalance vs. the implied balance in the pre-industrial as a target

Evaluation of large-Eddy simulations via observations of nocturnal marine stratocumulus

Data from the first research flight (RF01) of the second Dynamics and Chemistry of Marine Stratocumulus (DYCOMS-II) field study are used to evaluate the fidelity with which large-eddy simulations (LESs) can represent the turbulent structure of stratocumulus-topped boundary layers. The initial data and forcings for this case placed it in an interesting part of parameter space, near the boundary where cloud-top mixing is thought to render the cloud layer unstable on the one hand, or tending toward a decoupled structure on the other hand. The basis of this evaluation consists of sixteen 4-h simulations from 10 modeling centers over grids whose vertical spacing was 5 m at the cloud-top interface and whose horizontal spacing was 35 m. Extensive sensitivity studies of both the configuration of the case and the numerical setup also enhanced the analysis. Overall it was found that (i) if efforts are made to reduce spurious mixing at cloud top, either by refining the vertical grid or limiting the effects of the subgrid model in this region, then the observed turbulent and thermodynamic structure of the layer can be reproduced with some fidelity; (ii) the base, or native configuration of most simulations greatly overestimated mixing at cloud top, tending toward a decoupled layer in which cloud liquid water path and turbulent intensities were grossly underestimated; (iii) the sensitivity of the simulations to the representation of mixing at cloud top is, to a certain extent, amplified by particulars of this case. Overall the results suggest that the use of LESs to map out the behavior of the stratocumulus-topped boundary layer in this interesting region of parameter space requires a more compelling representation of processes at cloud top. In the absence of significant leaps in the understanding of subgrid-scale (SGS) physics, such a representation can only be achieved by a significant refinement in resolution—a refinement that, while conceivable given existing resources, is probably still beyond the reach of most centers

Phospholipid Scramblase-1 controls efficient neurotransmission and synaptic vesicle retrieval at cerebellar synapses

Phospholipids (PLs) are asymmetrically distributed at the plasma membrane. This asymmetric lipid distribution is transiently altered during calcium-regulated exocytosis, but the impact of this transient remodeling on presynaptic function is currently unknown. As phospholipid scramblase 1 (PLSCR1) randomizes PL distribution between the two leaflets of the plasma membrane in response to calcium activation, we set out to determine its role in neurotransmission. We report here that PLSCR1 is expressed in cerebellar granule cells (GrCs) and that PLSCR1-dependent phosphatidylserine egress occurred at synapses in response to neuron stimulation. Synaptic transmission is impaired at GrC Plscr1 -/- synapses, and both PS egress and synaptic vesicle (SV) endocytosis are inhibited in Plscr1 -/- cultured neurons from male and female mice, demonstrating that PLSCR1 controls PL asymmetry remodeling and SV retrieval following neurotransmitter release. Altogether, our data reveal a novel key role for PLSCR1 in SV recycling and provide the first evidence that PL scrambling at the plasma membrane is a prerequisite for optimal presynaptic performance. </p

The art and science of climate model tuning

PublishedThis is the final version of the article. Available from American Meteorological Society via the DOI in this record.We survey the rationale and diversity of approaches for tuning, a fundamental aspect of climate modeling which should be more systematically documented and taken into account in multi-model analysis. The process of parameter estimation targeting a chosen set of observations is an essential aspect of numerical modeling. This process is usually named tuning in the climate modeling community. In climate models, the variety and complexity of physical processes involved, and their interplay through a wide range of spatial and temporal scales, must be summarized in a series of approximate sub-models. Most sub-models depend on uncertain parameters. Tuning consists of adjusting the values of these parameters to bring the solution as a whole into line with aspects of the observed climate. Tuning is an essential aspect of climate modeling with its own scientific issues, which is probably not advertised enough outside the community of model developers. Optimization of climate models raises important questions about whether tuning methods a priori constrain the model results in unintended ways that would affect our confidence in climate projections. Here we present the definition and rationale behind model tuning, review specific methodological aspects, and survey the diversity of tuning approaches used in current climate models. We also discuss the challenges and opportunities in applying so-called ‘objective‘ methods in climate model tuning. We discuss how tuning methodologies may affect fundamental results of climate models, such as climate sensitivity. The article concludes with a series of recommendations to make the process of climate model tuning more transparent.The authors would like to thank the World Climate Research Program and its Working Group on Coupled Modeling for initiating and helping organize the workshop on model tuning in October 2014 in Garmisch-Partenkirchen, Germany. Work at LLNL was performed under the auspices the U.S. Department of Energy by Lawrence Livermore National Laboratory under contract No. DE-AC52-07NA27344. The National Center for Atmospheric Research is sup- ported by the U.S. National Science Foundation. The contribution of Yun Qian was supported by the U.S. Department of Energy’s Office of Science as part of the Earth System Modeling Program. The Pacific Northwest National Laboratory is operated for DOE by Battelle Memorial Institute under contract DE-AC05-76RL0183

Phospholipid Scramblase-1-Induced Lipid Reorganization Regulates Compensatory Endocytosis in Neuroendocrine Cells

Calcium-regulated exocytosis in neuroendocrine cells and neurons is accompanied by the redistribution of phosphatidylserine (PS) to the extracellular space, leading to a disruption of plasma membrane asymmetry. How and why outward translocation of PS occurs during secretion are currently unknown. Immunogold labeling on plasma membrane sheets coupled with hierarchical clustering analysis demonstrate that PS translocation occurs at the vicinity of the secretory granule fusion sites. We found that altering the function of the phospholipid scramblase-1 (PLSCR-1) by expressing a PLSCR-1 calcium-insensitive mutant or by using chromaffin cells from PLSCR-1−/−mice prevents outward translocation of PS in cells stimulated for exocytosis. Remarkably, whereas transmitter release was not affected, secretory granule membrane recapture after exocytosis was impaired, indicating that PLSCR-1 is required for compensatory endocytosis but not for exocytosis. Our results provide the first evidence for a role of specific lipid reorganization and calcium-dependent PLSCR-1 activity in neuroendocrine compensatory endocytosis