RATIONALE:TRPM2 (transient receptor potential melastatin-2) expressed in endothelial cells (ECs) is a cation channel mediating Ca entry in response to intracellular generation of adenosine ...diphosphoribose—the TRPM2 ligand.
OBJECTIVE:Because polymorphonuclear neutrophils (PMN) interaction with ECs generates reactive oxygen species, we addressed the possible role of TRPM2 expressed in ECs in the mechanism of transendothelial migration of PMNs.
METHODS AND RESULTS:We observed defective PMN transmigration in response to lipopolysaccharide challenge in adult mice in which the EC expressed TRPM2 is conditionally deleted (Trpm2). PMN interaction with ECs induced the entry of Ca in ECs via the EC-expressed TRPM2. Prevention of generation of adenosine diphosphoribose in ECs significantly reduced Ca entry in response to PMN activation of TRPM2 in ECs. PMNs isolated from gp91phox mice significantly reduced Ca entry in ECs via TRPM2 as compared with wild-type PMNs and failed to induce PMN transmigration. Overexpression of the adenosine diphosphoribose insensitive TRPM2 mutant channel (C1008→A) in ECs suppressed the Ca entry response. Further, the forced expression of TRPM2 mutant channel (C1008→A) or silencing of poly ADP-ribose polymerase in ECs of mice prevented PMN transmigration.
CONCLUSIONS:Thus, endotoxin-induced transmigration of PMNs was secondary to TRPM2-activated Ca signaling and VE-cadherin phosphorylation resulting in the disassembly of adherens junctions and opening of the paracellular pathways. These results suggest blocking TRPM2 activation in ECs is a potentially important means of therapeutically modifying PMN-mediated vascular inflammation.
Nowadays, finite element method is the most accurate approach to study an electrical machine. However, its use in an optimization process remains often unsuitable because it can still require ...prohibitive calculation times. An analytical approach would then be more adapted but it should be as accurate as possible. In the case of an analytical model of a squirrel cage induction machine, currents induced in the rotor bars constitute quantities that are difficult to obtain. The equivalent electrical circuit to use should be well adapted and each of its elements has to be accurately estimated. In this article, an equivalent circuit based on bar lumped parameters is proposed and their identification is detailed. The proposed approach is validated through the comparisons of simulation results with the ones obtained by classical FEA in the case of two examples of squirrel cage induction machines with distributed and concentrated armature windings.
Oxidative stress through the production of oxygen metabolites such as hydrogen peroxide (H2O2) increases vascular endothelial permeability. H2O2 stimulates ADP-ribose formation, which in turn opens ...transient receptor potential melastatin (TRPM)2 channels. Here, in endothelial cells, we demonstrate transcript and protein expression of TRPM2, a Ca-permeable, nonselective cation channel. We further show the importance of TRPM2 expression in signaling of increased endothelial permeability by oxidative stress. Exposure of endothelial cell monolayers to sublytic concentrations of H2O2 induced a cationic current measured by patch-clamp recording and Ca entry detected by intracellular fura-2 fluorescence. H2O2 in a concentration-dependent manner also decreased trans-monolayer transendothelial electrical resistance for 3 hours (with maximal effect seen at 300 μmol/L H2O2), indicating opening of interendothelial junctions. The cationic current, Ca entry, and transendothelial electrical resistance decrease elicited by H2O2 were inhibited by siRNA depleting TRPM2 or antibody blocking of TRPM2. H2O2 responses were attenuated by overexpression of the dominant-negative splice variant of TRPM2 or inhibition of ADP-ribose formation. Overexpression of the full-length TRPM2 enhanced H2O2-mediated Ca entry, cationic current, and the transendothelial electrical resistance decrease. Thus, TRPM2 mediates H2O2-induced increase in endothelial permeability through the activation of Ca entry via TRPM2. TRPM2 represents a novel therapeutic target directed against oxidant-induced endothelial barrier disruption.
Summary
The transient receptor potential (melastatin) 2 (TRPM2), is an oxidant-activated non-selective cation channel that is widely expressed in mammalian tissues including the vascular endothelium. ...Oxidative stress, through the generation of oxygen meta-bolites including H
2
O
2
, stimulates intracellular ADP-ribose formation which, in turn, opens TRPM2 channels. These channels act as an endogenous redox sensor for mediating oxidative stress/ROS-induced Ca
2+
entry and the subsequent specific Ca
2+
-dependent cellular reactions such as endothelial hyper-permeability and apoptosis. This review summarizes recent findings on the mechanism by which oxidants induce TRPM2 activation, the role of these channels in the signalling vascular endothelial dysfunctions, and the modulation of oxidant-induced TRPM2 activation by PKCα and phospho-tyrosine phosphates L1.
Background Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes ...with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. Methods We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. Results In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. Conclusions Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors. Keywords: Prolactin receptor PRLR, Antibody drug conjugate, Pyrrolobenzodiazepine dimer, Combination therapy, Poly (ADP-ribose) polymerase I
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although many empirical rules have been established for correctly choosing the number of stator and rotor slots so as to limit the audible magnetic noise level radiated by induction machines, these ...rules never take into account the stator natural frequencies or the fact that the motor is run at variable speed. In this paper, we present a fast simulation tool for the variable-speed magnetic noise emitted by induction machines, based on fully analytical models. On the basis of these models, we derive and experimentally validate an analytical expression for magnetic vibrations due to slotting reluctance harmonics, confirming the prime importance of slot combination in magnetic noise radiation. We ran simulations on a 700-W squirrel-cage motor in order to quantify the noise emitted by all possible combinations of slot numbers in two- and three-pole pairs, including odd slot numbers. We thus obtained a database that efficiently replaces the old empirical rules for slot combination numbers and helps in designing quiet induction motors. Similar databases can be built for other power ranges.
This paper presents a method to characterize the main magnetic force waves occurring in a sinusoidally fed induction machine. Three main force types are identified: slotting force waves, winding ...force waves, and saturation force waves. Slotting force waves are characterized in terms of number of nodes, velocity, propagation direction, and magnitude. On the ground of the expression of these forces magnitude, a method to cancel a given magnetic force wave by properly choosing the rotor slot or stator slot opening width is presented. This new method is validated with both simulations and experiments. Contrary to the common design rule that advices to decrease rotor and stator slot openings width in order to reduce magnetic noise, it is shown that a wider slot opening can lower the global noise level when properly chosen.
Induction motor design requires making numerous tradeoffs, especially when including electromagnetic noise criterion besides usual criteria like efficiency and cost. Moreover, adding the noise ...objective significantly increases computational time as it must be evaluated at variable speed in order to take into account resonance effects. In that case, the application of multiobjective optimization algorithms can be hard for their computational cost as for the difficulty to interpret multidimensional results in both design variables and objectives spaces. This paper first describes a fast analytical model of a variable-speed induction machine which calculates both motor performances and sound power level of electromagnetic origin. This model is then coupled to Nondominating Sorting Genetic Algorithm (NSGA-II) in order to perform global constrained optimizations with respect to several objectives (e.g., noise level, efficiency and material cost). As induction machine design involves both continuous and discrete variables, a modified NSGA-II algorithm handling mixed variables is detailed. Finally, some optimization results are presented and analyzed by the aid of several visualization tools.
In order to optimize the design of an enclosed induction machine of railway traction, a multi-physical model is developed taking into account electromagnetic, mechanical and thermal-flow phenomena. ...The electromagnetic model is based on analytical formulations and allows calculating the losses. The thermal-flow modeling is based on an equivalent thermal circuit which has the feature to consider the flow structure inside the machine. In this way, a numerical study has been carried out to evaluate this internal flow structure depending on the rotational speed. The results of the multi-physical model are confronted with experimental results.
RATIONALE:Oxidants generated by activated endothelial cells are known to induce apoptosis, a pathogenic feature of vascular injury and inflammation from multiple pathogeneses. The melastatin-family ...transient receptor potential 2 (TRPM2) channel is an oxidant-sensitive Ca permeable channel implicated in mediating apoptosis; however, the mechanisms of gating of the supranormal Ca influx required for initiating of apoptosis are not understood.
OBJECTIVE:Here, we addressed the role of TRPM2 and its interaction with the short splice variant TRPM2 short variant (TRPM2-S) in mediating the Ca entry burst required for induction of endothelial cell apoptosis.
METHODS AND RESULTS:We observed that TRPM2-S was basally associated with TRPM2 in the endothelial plasmalemma, and this interaction functioned to suppress TRPM2-dependent Ca gating constitutively. Reactive oxygen species production in endothelial cells or directly applying reactive oxygen species induced protein kinase C-α activation and phosphorylation of TRPM2 at Ser 39. This in turn stimulated a large entry of Ca and activated the apoptosis pathway. A similar TRPM2-dependent endothelial apoptosis mechanism was seen in intact vessels. The protein kinase C-α–activated phosphoswitch opened the TRPM2 channel to allow large Ca influx by releasing TRPM2-S inhibition of TRPM2, which in turn activated caspase-3 and cleaved the caspase substrate poly(ADP-ribose) polymerase.
CONCLUSIONS:Here, we describe a fundamental mechanism by which activation of the trp superfamily TRPM2 channel induces apoptosis of endothelial cells. The signaling mechanism involves reactive oxygen species–induced protein kinase C-α activation resulting in phosphorylation of TRPM2-S that allows enhanced TRPM2-mediated gating of Ca and activation of the apoptosis program. Strategies aimed at preventing the uncoupling of TRPM2-S from TRPM2 and subsequent Ca gating during oxidative stress may mitigate endothelial apoptosis and its consequences in mediating vascular injury and inflammation.
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