Atrial fibrillation (AF) is the most common cardiac rhythm disorder, often occurring in the setting of atrial distension and elevated myocardialstretch. While various mechano-electrochemical signal ...transduction pathways have been linked to AF development and progression, the underlying molecular mechanisms remain poorly understood, hampering AF therapies. In this review, we describe different aspects of stretch-induced electro-anatomical remodeling as seen in animal models and in patients with AF. Specifically, we focus on cellular and molecular mechanisms that are responsible for mechano-electrochemical signal transduction and the development of ectopic beats triggering AF from pulmonary veins, the most common source of paroxysmal AF. Furthermore, we describe structural changes caused by stretch occurring before and shortly after the onset of AF as well as during AF progression, contributing to longstanding forms of AF. We also propose mechanical stretch as a new dimension to the concept “AF begets AF”, in addition to underlying diseases. Finally, we discuss the mechanisms of these electro-anatomical alterations in a search for potential therapeutic strategies and the development of novel antiarrhythmic drugs targeted at the components of mechano-electrochemical signal transduction not only in cardiac myocytes, but also in cardiac non-myocyte cells.
•Atrial fibrillation (AF) often occurs in the setting of atrial distension and elevated myocardial stretch.•Stretch triggers AF by promoting ectopic automaticity, electro-anatomical remodeling, and impaired contractile function.•Chronically, these suppress atrial contractility leading to dilation and further stretch,promoting longstanding AF.•Targeting downstream stretch pathways may prevent AF progression and decrease the risk of associated complications.•Non-invasive assessment of atrial structure and function can predict and stratify arrhythmia risk in vulnerable patients.
The Advanced Fuels Campaign performed a series of irradiation tests of minor actinide-bearing mixed oxide fuel (MA-MOX), the so-called AFC-2C&D experiments, to investigate the transmutation of ...long-lived transuranic actinide isotopes contained in spent nuclear fuel via fast reactor technology at burnups exceeding 10 % fission of initial metallic atoms. This manuscript reports the test results derived from one of the five MA-MOX rodlets taken to higher burnup in the AFC-2D irradiation. This includes both non-destructive investigations, such as gamma and neutron spectrometry, and destructive investigations, such as fission gas release, ceramography, and chemical burnup analysis. In addition, the microstructure of the fuel was investigated using advanced electron microscopy techniques including electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM). It was observed with EBSD that the pellet had subdivision of the grains and the TEM observed migration of cladding material into the 5 metal precipitates in the fuel which could have been from the higher than desired oxygen/metal ratio. The TEM also showed an enrichment of Cr in fuel clad chemical interaction (FCCI) layer.
Caveolae are tiny invaginations in the sarcolemma that buffer extra membrane and contribute to mechanical regulation of cellular function. While the role of caveolae in membrane mechanosensation has ...been studied predominantly in non-cardiomyocyte cells, caveolae contribution to cardiac mechanotransduction remains elusive. Here, we studied the role of caveolae in the regulation of Ca2+ signaling in atrial cardiomyocytes. In Langendorff-perfused mouse hearts, atrial pressure/volume overload stretched atrial myocytes and decreased caveolae density. In isolated cells, caveolae were disrupted through hypotonic challenge that induced a temporal (<10 min) augmentation of Ca2+ transients and caused a rise in Ca2+ spark activity. Similar changes in Ca2+ signaling were observed after chemical (methyl-β-cyclodextrin) and genetic ablation of caveolae in cardiac-specific conditional caveolin-3 knock-out mice. Acute disruption of caveolae, both mechanical and chemical, led to the elevation of cAMP level in the cell interior, and cAMP-mediated augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at Ser2030 and Ser2808). Caveolae-mediated stimulatory effects on Ca2+ signaling were abolished via inhibition of cAMP production by adenyl cyclase antagonists MDL12330 and SQ22536, or reduction of PKA activity by H-89. A compartmentalized mathematical model of mouse atrial myocytes linked the observed changes to a microdomain-specific decrease in phosphodiesterase activity, which disrupted cAMP signaling and augmented PKA activity. Our findings add a new dimension to cardiac mechanobiology and highlight caveolae-associated cAMP/PKA-mediated phosphorylation of Ca2+ handling proteins as a novel component of mechano-chemical feedback in atrial myocytes.Caveolae are tiny invaginations in the sarcolemma that buffer extra membrane and contribute to mechanical regulation of cellular function. While the role of caveolae in membrane mechanosensation has been studied predominantly in non-cardiomyocyte cells, caveolae contribution to cardiac mechanotransduction remains elusive. Here, we studied the role of caveolae in the regulation of Ca2+ signaling in atrial cardiomyocytes. In Langendorff-perfused mouse hearts, atrial pressure/volume overload stretched atrial myocytes and decreased caveolae density. In isolated cells, caveolae were disrupted through hypotonic challenge that induced a temporal (<10 min) augmentation of Ca2+ transients and caused a rise in Ca2+ spark activity. Similar changes in Ca2+ signaling were observed after chemical (methyl-β-cyclodextrin) and genetic ablation of caveolae in cardiac-specific conditional caveolin-3 knock-out mice. Acute disruption of caveolae, both mechanical and chemical, led to the elevation of cAMP level in the cell interior, and cAMP-mediated augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at Ser2030 and Ser2808). Caveolae-mediated stimulatory effects on Ca2+ signaling were abolished via inhibition of cAMP production by adenyl cyclase antagonists MDL12330 and SQ22536, or reduction of PKA activity by H-89. A compartmentalized mathematical model of mouse atrial myocytes linked the observed changes to a microdomain-specific decrease in phosphodiesterase activity, which disrupted cAMP signaling and augmented PKA activity. Our findings add a new dimension to cardiac mechanobiology and highlight caveolae-associated cAMP/PKA-mediated phosphorylation of Ca2+ handling proteins as a novel component of mechano-chemical feedback in atrial myocytes.
•Post-irradiation examination of nonfertile metallic fuels (no uranium) tests are presented here for a series of compositions with and without minor actinides.•Precision gamma scanning and fission ...gas release results are similar to other historical metal fuel experiments in fast reactors.
This work was part of a program begun in 2001 to develop advanced nuclear fuels, originally as carriers for plutonium and minor actinides (neptunium, curium, and americium) taken from spent commercial light-water reactors (LWR) so that the plutonium and minor actinides could be ‘burned’ or transmuted in an accelerator or a fast nuclear reactor. A central part of these experiment programs has been the development of advanced fast reactor fuels, because a fast reactor was considered the most efficient vehicle to transmute the actinide waste products, and metallic fuels is a central focus of these tests. An experiment design was developed in which a thermal test reactor, the Advanced Test Reactor (ATR), was used to test small fuel pin prototypes, by creating areas in the core shielded by cadmium filters to produce a largely epithermal and fast neutron spectrum environment in which the pins could be irradiated. The results of non-fertile metallic fuel (no uranium) tests are presented here.
Pu-Am-Np-Zr fuels were irradiated to fission densities up to 33 × 1020 fission/cm3 and Pu-239 depletions of up to 39%. The depletions were created by roughly 2/3 by fission and 1/3 by transmutation neutron capture. Up to five fuel ‘rodlets’ were irradiated in three sealed capsules stacked axially in the core, and the peak cladding temperatures ranged from 300°C to 500°C, depending on axial location as those near the core centerline are operating hotter and to higher fission densities. Several post-irradiation examinations (precision gamma scanning and fission gas release) were similar to other historical metal fuel experiments in fast reactors. However, optical metallography indicated that two of the rodlets had breached. The exact reasons are unclear. Due to the design of this irradiation experiment a rodlet breach could have increased the temperature in others in the same capsule by contaminating the thermal gap helium with heavier and less conductive fission product gases. Some of those rodlets showed high amounts of fuel/cladding chemical interaction (FCCI).
Transmission electron microscopy characterization of irradiated U-7 wt%Mo dispersion fuel were performed on various U-Mo fuel samples to understand the effect of irradiation parameters (fission ...density, fission rate, and temperature) on the self-organized fission-gas-bubble superlattice that forms in the irradiated U-Mo fuel. The bubble superlattice was seen to form a face centered cubic structure coherent with the host U-7 wt%Mo body-centered cubic structure. At a fission density between 3.0 and 4.5 x 10 super(21) fiss/cm super(3), the superlattice bubbles appear to have reached a saturation size with additional fission gas associated with increasing bumup predominately accumulating along grain boundaries. At a fission density of ~4.5 x 10 super(21) fiss/cm super(3), the U-7 wt%Mo microstructure starts to undergo grain subdivision and can no longer support the ordered bubble superlattice. The sub-divided fuel grains are less than 500 nm in diameter with what appears to be micron-size fission-gas bubbles present on the grain boundaries. Solid fission products typically decorate the inside surface of the micron-sized fission-gas bubbles. Residual superlattice bubbles are seen in areas where fuel grains remain micron sized. Potential mechanisms of the formation and collapse of the bubble superlattice are discussed.
•Tensile stress in the fuel increased from 2 MPa to 100 MPa at shutdown.•This may explain pillowing of several test fuel plates irradiated to very high burnup.•Implications for safe use of monolithic ...fuel in research reactors are discussed.•Effect of burnup and power on shutdown-induced tensile stress explored.
Post-irradiation examination of RERTR-12 miniplates showed that in-reactor pillowing occurred in at least 4 plates, rendering performance of these plates unacceptable. To address in-reactor failures, efforts are underway to define the mechanisms responsible for in-reactor pillowing, and to suggest improvements to the fuel plate design and operational conditions. To achieve these objectives, the mechanical response of monolithic fuel to fission and thermally induced stresses was modeled using a commercial finite element analysis code. Calculations of stresses and deformations in monolithic miniplates during irradiation and after the shutdown revealed that the tensile stress generated in the fuel increased from 2 MPa to 100 MPa at shutdown. The increase in tensile stress at shutdown possibly explains in-reactor pillowing of several RERTR-12 miniplates irradiated to the peak local burnup of up to 1.11 × 1022 fissions/cm3. This paper presents the modeling approach and calculation results, and compares results with post-irradiation examinations and mechanical testing of irradiated fuel. The implications for the safe use of the monolithic fuel in research reactors are discussed, including the influence of fuel burnup and power on the magnitude of the shutdown-induced tensile stress.
The fuel development program for research and test reactors calls for improved knowledge on the effect of microstructure on fuel performance in reactors. This paper summarizes the recent TEM ...microstructural characterization of an irradiated U–7Mo/Al–5Si dispersion fuel plate (R3R050) in the Advanced Test Reactor (ATR) at Idaho National Laboratory (INL) to 5.2×1021fissions/cm3. While a large fraction of the fuel grains is decorated with large bubbles, there is no evidence showing interlinking of these bubbles at the specified fission density. The attachment of solid fission product precipitates to the bubbles is likely the result of fission product diffusion into these bubbles. The process of fission gas bubble superlattice collapse appears through bubble coalescence. The results are compared with the previous TEM work on the dispersion fuels irradiated to lower fission density from the same fuel plate.
An experiment was performed in the Experimental Breeder Rector-II (EBR-II) in the 1990s to show that metallic fast reactor fuel could be used in reactors with a single, once-through core. To prove ...the long duration, high burnup, high neutron exposure capability an experiment where the fuel pin was designed with a very large fission gas plenum and very low fuel smeared density (SD). The experiment, X496, operated to only 8.3 at.% burnup because the EBR-II reactor was scheduled for shut-down at that time. Many of the examinations of the fuel pins only funded recently with the resurgence of reactor designs using very high-burnup fuel. The results showed that, despite the low smeared density of 59% the fuel swelled radially to contact the cladding, fission gas release appeared to be slightly higher than demonstrated in conventional 75%SD fuel tests and axial growth was about the same as 75% SD fuel. There were axial positions in some of the fuel pins which showed evidence of fuel restructuring and an absence of fission products with low melting points and gaseous precursors (Cs and Rb). A model to investigate whether these areas may have overheated due to a loss of bond sodium indicates that it is a possible explanation for the fuel restructuring and something to be considered for fuel performance modeling of low SD fuel.
To address the low thermal conductivity of the ZrO2-based inert matrix fuel and the instability in water of the MgO-based inert matrix fuel, the dual-phase MgO-ZrO2 ceramics are proposed as a matrix ...for light water reactor fuel for actinide transmutation and Pu burning. It is envisioned that in a dual-phase system MgO will act as efficient heat conductor while ZrO2 will provide protection from the coolant attack. This paper describes results of fabrication, characterization and hydration testing of MgO-ZrO2 ceramics containing 30-70 wt% of MgO.
The pressure effect on crystal structures, lattice vibrations, and electrical transport properties of PdS2 and NiSe2 were studied under high pressures of up to ~50 GPa using Raman spectroscopy and ...electrical resistivity measurements. PdS2 undergoes semiconductor-to-metal transition at a pressure of ~7 GPa without a structural phase transition. Structural transition to the pyrite-type phase occurs at a pressure of ~16 GPa. Superconductivity emerges in the pyrite-type phase of PdS2 with a well-defined dome-shaped dependence of critical temperature of superconductivity on pressure, with a maximum value of 8.0 K at 37.4 GPa. Although this behavior is similar to that in isostructural PdSe2, correlation with anomalous anion bond softening at critical temperature is not observed in PdS2 in contrast to PdSe2. Conversely, the anion bond instability is observed by the softening of the Se22− internal vibrational Raman mode in pyrite NiSe2 under pressure. Despite the persisting structural instability due to destabilization of Se22− dimers, NiSe2 remains a normal nonsuperconducting metal.
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