358 research outputs found
Structure of plastically compacting granular packings
The developing structure in systems of compacting ductile grains were studied
experimentally in two and three dimensions. In both dimensions, the peaks of
the radial distribution function were reduced, broadened, and shifted compared
with those observed in hard disk- and sphere systems. The geometrical
three--grain configurations contributing to the second peak in the radial
distribution function showed few but interesting differences between the
initial and final stages of the two dimensional compaction. The evolution of
the average coordination number as function of packing fraction is compared
with other experimental and numerical results from the literature. We conclude
that compaction history is important for the evolution of the structure of
compacting granular systems.Comment: 12 pages, 12 figure
Coincidence isometries of a shifted square lattice
We consider the coincidence problem for the square lattice that is translated
by an arbitrary vector. General results are obtained about the set of
coincidence isometries and the coincidence site lattices of a shifted square
lattice by identifying the square lattice with the ring of Gaussian integers.
To illustrate them, we calculate the set of coincidence isometries, as well as
generating functions for the number of coincidence site lattices and
coincidence isometries, for specific examples.Comment: 10 pages, 1 figure; paper presented at Aperiodic 2009 (Liverpool
Thermal history modeling of the H chondrite parent body
The cooling histories of individual meteorites can be empirically
reconstructed by using ages from different radioisotopic chronometers with
distinct closure temperatures. For a group of meteorites derived from a single
parent body such data permit the reconstruction of the cooling history and
properties of that body. Particularly suited are H chondrites because precise
radiometric ages over a wide range of closure temperatures are available. A
thermal evolution model for the H chondrite parent body is constructed by using
all H chondrites for which at least three different radiometric ages are
available. Several key parameters determining the thermal evolution of the H
chondrite parent body and the unknown burial depths of the H chondrites are
varied until an optimal fit is obtained. The fit is performed by an 'evolution
algorithm'. Empirical data for eight samples are used for which radiometric
ages are available for at least three different closure temperatures. A set of
parameters for the H chondrite parent body is found that yields excellent
agreement (within error bounds) between the thermal evolution model and
empirical data of six of the examined eight chondrites. The new thermal model
constrains the radius and formation time of the H chondrite parent body
(possibly (6) Hebe), the initial burial depths of the individual H chondrites,
the average surface temperature of the body, the average initial porosity of
the material the body accreted from, and the initial 60Fe content of the H
chondrite parent body.Comment: 16 pages, 7 figure
The prismatic Sigma 3 (10-10) twin bounday in alpha-Al2O3 investigated by density functional theory and transmission electron microscopy
The microscopic structure of a prismatic twin
boundary in \aal2o3 is characterized theoretically by ab-initio
local-density-functional theory, and experimentally by spatial-resolution
electron energy-loss spectroscopy in a scanning transmission electron
microscope (STEM), measuring energy-loss near-edge structures (ELNES) of the
oxygen -ionization edge. Theoretically, two distinct microscopic variants
for this twin interface with low interface energies are derived and analysed.
Experimentally, it is demonstrated that the spatial and energetical resolutions
of present high-performance STEM instruments are insufficient to discriminate
the subtle differences of the two proposed interface variants. It is predicted
that for the currently developed next generation of analytical electron
microscopes the prismatic twin interface will provide a promising benchmark
case to demonstrate the achievement of ELNES with spatial resolution of
individual atom columns
Interventricular Differences in βâAdrenergic Responses in the Canine Heart: Role of Phosphodiesterases
Background
RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in βâadrenergic (βâAR) responsiveness is unknown. In this study, we examine whether βâAR response and signaling differ in right (RV) versus left (LV) ventricles.
Methods and Results
Sarcomere shortening, Ca2+ transients, ICa,L and IKs currents were recorded in isolated dog LV and RV midmyocytes. Intracellular [cAMP] and PKA activity were measured by live cell imaging using FRETâbased sensors. Isoproterenol increased sarcomere shortening â10âfold and Ca2+âtransient amplitude â2âfold in LV midmyocytes (LVMs) versus â25âfold and â3âfold in RVMs. FRET imaging using targeted Epac2camps sensors revealed no change in subsarcolemmal [cAMP], but a 2âfold higher βâAR stimulation of cytoplasmic [cAMP] in RVMs versus LVMs. Accordingly, βâAR regulation of ICa,L and IKs were similar between LVMs and RVMs, whereas cytoplasmic PKA activity was increased in RVMs. Both PDE3 and PDE4 contributed to the βâAR regulation of cytoplasmic [cAMP], and the difference between LVMs and RVMs was abolished by PDE3 inhibition and attenuated by PDE4 inhibition. Finally LV and RV intracavitary pressures were recorded in anesthetized beagle dogs. A bolus injection of isoproterenol increased RV dP/dtmaxâ5âfold versus 3âfold in LV.
Conclusion
Canine RV and LV differ in their βâAR response due to intrinsic differences in myocyte βâAR downstream signaling. Enhanced βâAR responsiveness of the RV results from higher cAMP elevation in the cytoplasm, due to a decreased degradation by PDE3 and PDE4 in the RV compared to the LV
Bestrophin1: A Gene that Causes Many Diseases
Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that lead to the gradual loss of vision in and around the macular area. There are no treatments for patients suffering from bestrophinopathies, and no measures can be taken to prevent visual deterioration in those who have inherited disease-causing mutations. Bestrophinopathies are caused by mutations in the Bestrophin1 gene (BEST1), a protein found exclusively in the retinal pigment epithelial (RPE) cells of the eye. Mutations in BEST1 affect the function of the RPE leading to the death of overlying retinal cells and subsequent vision loss. The pathogenic mechanisms arising from BEST1 mutations are still not fully understood, and it is not clear how mutations in BEST1 lead to diseases with distinct clinical features. This chapter discusses BEST1, the use of model systems to investigate the effects of mutations and the potential to investigate individual bestrophinopathies using induced pluripotent stem cells
Treatments targeting inotropy
Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.Peer reviewe
Treatments targeting inotropy
Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term
Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle
Activation of 5-HT4 receptors in failing ventricles elicits a cAMP-dependent positive inotropic response which is mainly limited by the cGMP-inhibitable phosphodiesterase (PDE) 3. However, PDE4 plays an additional role which is demasked by PDE3 inhibition. The objective of this study was to evaluate the effect of cGMP generated by particulate and soluble guanylyl cyclase (GC) on the 5-HT4-mediated inotropic response. Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats, exhibiting heart failure 6 weeks after surgery. Contractility was measured in left ventricular preparations. Cyclic GMP was measured by EIA. In ventricular preparations, ANP or BNP displayed no impact on 5-HT4-mediated inotropic response. However, CNP increased the 5-HT4-mediated inotropic response as well as the β1-adrenoceptor (β1-AR)-mediated response to a similar extent as PDE3 inhibition by cilostamide. Pretreatment with cilostamide eliminated the effect of CNP. Inhibition of nitric oxide (NO) synthase and soluble GC by l-NAME and ODQ, respectively, attenuated the 5-HT4-mediated inotropic response, whereas the NO donor Sin-1 increased this response. The effects were absent during PDE3 inhibition, suggesting cGMP-dependent inhibition of PDE3. However, in contrast to the effects on the 5-HT4 response, Sin-1 inhibited whereas l-NAME and ODQ enhanced the β1-AR-mediated inotropic response. cGMP generated both by particulate (NPR-B) and soluble GC increases the 5-HT4-mediated inotropic response in failing hearts, probably through inhibition of PDE3. β1-AR and 5-HT4 receptor signalling are subject to opposite regulatory control by cGMP generated by soluble GC in failing hearts. Thus, cGMP from different sources is functionally compartmented, giving differential regulation of different Gs-coupled receptors
Cell-to-cell variability in troponin I phosphorylation in a porcine model of pacing-induced heart failure
We tested the hypothesis that myocardial contractile protein phosphorylation and the Ca2+ sensitivity of force production are dysregulated in a porcine model of pacing-induced heart failure (HF). The level of protein kinase A (PKA)-dependent cardiac troponin I (TnI) phosphorylation was lower in the myocardium surrounding the pacing electrode (pacing site) of the failing left ventricle (LV) than in the controls. Immunohistochemical assays of the LV pacing site pointed to isolated clusters of cardiomyocytes exhibiting a reduced level of phosphorylated TnI. Flow cytometry on isolated and permeabilized cardiomyocytes revealed a significantly larger cell-to-cell variation in the level of TnI phosphorylation of the LV pacing site than in the opposite region in HF or in either region in the controls: the interquartile range (IQR) on the distribution histogram of relative TnI phosphorylation was wider at the pacing site (IQRÂ =Â 0.53) than that at the remote site of HF (IQRÂ =Â 0.42; PÂ =Â 0.0047) or that of the free wall of the control animals (IQRÂ =Â 0.36; PÂ =Â 0.0093). Additionally, the Ca2+ sensitivities of isometric force production were higher and appeared to be more variable in single permeabilized cardiomyocytes from the HF pacing site than in the healthy myocardium. In conclusion, the level of PKA-dependent TnI phosphorylation and the Ca2+ sensitivity of force production exhibited a high cell-to-cell variability at the LV pacing site, possibly explaining the abnormalities of the regional myocardial contractile function in a porcine model of pacing-induced HF
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