Duality and Complexity of Allergic Type Inflammatory Mechanisms in Determining the Outcome of Malaria Disease

One of the effector arms of the pathogenesis of severe forms of malaria disease is the development of uncontrolled or excessive inflammatory responses. A characteristic inflammatory response may arise from the propensity of some individuals to produce IgE antibodies against environmental antigens or against parasite components. We believe that an allergic inflammatory response which develops concomitantly with a malaria episode may drive the disease course toward severe forms. The role of the IgE–FcεRI complex in malaria severity in Plasmodium falciparum-hosting patients is unknown. Subsequently, except a very limited number of reports, study of effector cells that express this complex such as mast cells and basophils and that may contribute to malaria pathogenesis have been particularly neglected. A better understanding of this type of inflammatory response and its implication in malaria disease and how it impacts Plasmodium parasite development may provide additional tools to alleviate or to cure this deadly disease

Munc18-2/syntaxin3 complexes are spatially separated from syntaxin3-containing SNARE complexes

AbstractExocytosis of mast cell granules requires a vesicular- and plasma membrane-associated fusion machinery. We examined the distribution of SNARE membrane fusion and Munc18 accessory proteins in lipid rafts of RBL mast cells. SNAREs were found either excluded (syntaxin2), equally distributed between raft and non-raft fractions (syntaxin4, VAMP-8, VAMP-2), or selectively enriched in rafts (syntaxin3, SNAP-23). Syntaxin4-binding Munc18-3 was absent, whereas small amounts of the syntaxin3-interacting partner Munc18-2 consistently distributed into rafts. Cognate SNARE complexes of syntaxin3 with SNAP-23 and VAMP-8 were enriched in rafts, whereas Munc18-2/syntaxin3 complexes were excluded. This demonstrates a spatial separation between these two types of complexes and suggests that Munc18-2 acts in a step different from SNARE complex formation and fusion

The SNARE Machinery in Mast Cell Secretion

Mast cells are known as inflammatory cells which exert their functions in allergic and anaphylactic reactions by secretion of numerous inflammatory mediators. During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators – stored in granules – as well as in de novo synthesis of various mediators like cytokines and chemokines. Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis. In addition, several accessory regulators like Munc13, Munc18, Rab GTPases, secretory carrier membrane proteins, complexins, or synaptotagmins were found to be involved in membrane fusion. In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion

Modeling, simulation, and optimization of geothermal energy production from hot sedimentary aquifers

Geothermal district heating development has been gaining momentum in Europe with numerous deep geothermal installations and projects currently under development. With the increasing density of geothermal wells, questions related to the optimal and sustainable reservoir exploitation become more and more important. A quantitative understanding of the complex thermo-hydraulic interaction between tightly deployed geothermal wells in heterogeneous temperature and permeability fields is key for a maximum sustainable use of geothermal resources. Motivated by the geological settings of the Upper Jurassic aquifer in the Greater Munich region, we develop a computational model based on finite element analysis and gradient-free optimization to simulate groundwater flow and heat transport in hot sedimentary aquifers, and investigate numerically the optimal positioning and spacing of multi-well systems. Based on our numerical simulations, net energy production from deep geothermal reservoirs in sedimentary basins by smart geothermal multi-well arrangements provides significant amounts of energy to meet heat demand in highly urbanized regions. Our results show that taking into account heterogeneous permeability structures and variable reservoir temperature may drastically affect the results in the optimal configuration. We demonstrate that the proposed numerical framework is able to efficiently handle generic geometrical and geologocal configurations, and can be thus flexibly used in the context of multi-variable optimization problems. Hence, this numerical framework can be used to assess the extractable geothermal energy from heterogeneous deep geothermal reservoirs by the optimized deployment of smart multi-well systems

Modeling, simulation, and optimization of geothermal energy production from hot sedimentary aquifers

Geothermal district heating development has been gaining momentum in Europe with numerous deep geothermal installations and projects currently under development. With the increasing density of geothermal wells, questions related to the optimal and sustainable reservoir exploitation become more and more important. A quantitative understanding of the complex thermo-hydraulic interaction between tightly deployed geothermal wells in heterogeneous temperature and permeability fields is key for a maximum sustainable use of geothermal resources. Motivated by the geological settings of the Upper Jurassic aquifer in the Greater Munich region, we develop a computational model based on finite element analysis and gradient-free optimization to simulate groundwater flow and heat transport in hot sedimentary aquifers, and investigate numerically the optimal positioning and spacing of multi-well systems. Based on our numerical simulations, net energy production from deep geothermal reservoirs in sedimentary basins by smart geothermal multi-well arrangements provides significant amounts of energy to meet heat demand in highly urbanized regions. Our results show that taking into account heterogeneous permeability structures and variable reservoir temperature may drastically affect the results in the optimal configuration. We demonstrate that the proposed numerical framework is able to efficiently handle generic geometrical and geologocal configurations, and can be thus flexibly used in the context of multi-variable optimization problems. Hence, this numerical framework can be used to assess the extractable geothermal energy from heterogeneous deep geothermal reservoirs by the optimized deployment of smart multi-well systems

ParMooN - a modernized program package based on mapped finite elements

{\sc ParMooN} is a program package for the numerical solution of elliptic and parabolic partial differential equations. It inherits the distinct features of its predecessor {\sc MooNMD} \cite{JM04}: strict decoupling of geometry and finite element spaces, implementation of mapped finite elements as their definition can be found in textbooks, and a geometric multigrid preconditioner with the option to use different finite element spaces on different levels of the multigrid hierarchy. After having presented some thoughts about in-house research codes, this paper focuses on aspects of the parallelization for a distributed memory environment, which is the main novelty of {\sc ParMooN}. Numerical studies, performed on compute servers, assess the efficiency of the parallelized geometric multigrid preconditioner in comparison with some parallel solvers that are available in the library {\sc PETSc}. The results of these studies give a first indication whether the cumbersome implementation of the parallelized geometric multigrid method was worthwhile or not.Comment: partly supported by European Union (EU), Horizon 2020, Marie Sk{\l}odowska-Curie Innovative Training Networks (ITN-EID), MIMESIS, grant number 67571

Mast Cells as Cellular Sensors in Inflammation and Immunity

Mast cells are localized in tissues. Intense research on these cells over the years has demonstrated their role as effector cells in the maintenance of tissue integrity following injury produced by infectious agents, toxins, metabolic states, etc. After stimulation they release a sophisticated array of inflammatory mediators, cytokines, and growth factors to orchestrate an inflammatory response. These mediators can directly initiate tissue responses on resident cells, but they have also been shown to regulate other infiltrating immune cell functions. Research in recent years has revealed that the outcome of mast cell actions is not always detrimental for the host but can also limit disease development. In addition, mast cell functions highly depend on the physiological context in the organism. Depending on the genetic background, strength of the injurious event, the particular microenvironment, mast cells direct responses ranging from pro- to anti-inflammatory. It appears that they have evolved as cellular sensors to discern their environment in order to initiate an appropriate physiological response either aimed to favor inflammation for repair or at the contrary limit the inflammatory process to prevent further damage. Like every sophisticated machinery, its dysregulation leads to pathology. Given the broad distribution of mast cells in tissues this also explains their implication in many inflammatory diseases

Yessotoxin, a Marine Toxin, Exhibits AntiAllergic and Anti-Tumoural Activities Inhibiting Melanoma Tumour Growth in a Preclinical Model

Yessotoxins (YTXs) are a group of marine toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drugDr. Araceli Tobio Ageitos was supported by a postdoctoral fellowship from Fundación Juana de Vega, Spain. Dr. Iris Madera-Salcedo was supported by an International collaboration grant between ANR France (ANR-12-ISV3-0006-01) and Conacyt Mexico (Conacyt-ANR 188565). This research project has been supported by the Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX, and DHU Fire. This work was also supported by the COST Action BM1007 (Mast cells and basophils–targets for innovative therapies) of the European CommunityS