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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 10 August 2010, Vol.107(32), pp.14315-20
    Description: Mitochondrial networks in cardiac myocytes under oxidative stress show collective (cluster) behavior through synchronization of their inner membrane potentials (DeltaPsi(m)). However, it is unclear whether the oscillation frequency and coupling strength between individual mitochondria affect the size of the cluster and vice versa. We used the wavelet transform and developed advanced signal processing tools that allowed us to capture individual mitochondrial DeltaPsi(m) oscillations in cardiac myocytes and examine their dynamic spatio-temporal properties. Heterogeneous frequency behavior prompted us to sort mitochondria according to their frequencies. Signal analysis of the mitochondrial network showed an inverse relationship between cluster size and cluster frequency as well as between cluster amplitude and cluster size. High cross-correlation coefficients between neighboring mitochondria clustered longitudinally along the myocyte striations, indicated anisotropic communication between mitochondria. Isochronal mapping of the onset of myocyte-wide DeltaPsi(m) depolarization further exemplified heterogeneous DeltaPsi(m) among mitochondria. Taken together, the results suggest that frequency and amplitude modulation of clusters of synchronized mitochondria arises by means of strong changes in local coupling between neighboring mitochondria.
    Keywords: Biological Clocks ; Mitochondria -- Physiology ; Myocytes, Cardiac -- Cytology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Biophysical Journal, 21 April 2015, Vol.108(8), pp.1922-1933
    Description: Oscillatory behavior of mitochondrial inner membrane potential (ΔΨ ) is commonly observed in cells subjected to oxidative or metabolic stress. In cardiac myocytes, the activation of inner membrane pores by reactive oxygen species (ROS) is a major factor mediating intermitochondrial coupling, and ROS-induced ROS release has been shown to underlie propagated waves of ΔΨ depolarization as well as synchronized limit cycle oscillations of ΔΨ in the network. The functional impact of ΔΨ instability on cardiac electrophysiology, Ca handling, and even cell survival, is strongly affected by the extent of such intermitochondrial coupling. Here, we employ a recently developed wavelet-based analytical approach to examine how different substrates affect mitochondrial coupling in cardiac cells, and we also determine the oscillatory coupling properties of mitochondria in ventricular cells in intact perfused hearts. The results show that the frequency of ΔΨ oscillations varies inversely with the size of the oscillating mitochondrial cluster, and depends on the strength of local intermitochondrial coupling. Time-varying coupling constants could be quantitatively determined by applying a stochastic phase model based on extension of the well-known Kuramoto model for networks of coupled oscillators. Cluster size-frequency relationships varied with different substrates, as did mitochondrial coupling constants, which were significantly larger for glucose (7.78 × 10 ± 0.98 × 10 s ) and pyruvate (7.49 × 10 ± 1.65 × 10 s ) than lactate (4.83 × 10 ± 1.25 × 10 s ) or -hydroxybutyrate (4.11 × 10 ± 0.62 × 10 s ). The findings indicate that mitochondrial spatiotemporal coupling and oscillatory behavior is influenced by substrate selection, perhaps through differing effects on ROS/redox balance. In particular, glucose-perfusion generates strong intermitochondrial coupling and temporal oscillatory stability. Pathological changes in specific catabolic pathways, which are known to occur during the progression of cardiovascular disease, could therefore contribute to altered sensitivity of the mitochondrial network to oxidative stress and emergent ΔΨ instability, ultimately scaling to produce organ level dysfunction.
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
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  • 3
    In: Concepts in Magnetic Resonance Part A, May 2015, Vol.44(3), pp.150-159
    Description: The diffusion of spin‐bearing particles around simple geometrical objects like cylinders and spheres abides by the form of the diffusion propagator that specifies the probability of a particle to diffuse from one position to another within a specific time span. While diffusion propagators for diffusion inside a cylinder or sphere are well‐analyzed, diffusion propagators for hindered diffusion around these open geometries are rarely discussed in MR literature. Knowledge of such diffusion propagators for hindered diffusion allows quantifying the influence of diffusion processes on the MR signal around single vessels or blood residues and ultra‐small iron‐oxide particles, respectively, when there is no outer boundary present. In this work, analytical expressions for the diffusion propagator for hindered diffusion in one, two and three dimensions as well as the resulting correlation functions for diffusion in a dipole field around cylinders and spheres are derived. © 2015 Wiley Periodicals, Inc. Concepts Magn Reson Part A 44A: 150–159, 2015.
    Keywords: Diffusion Propagator ; Half Space ; Cylinder ; Sphere ; Correlation Function
    ISSN: 1546-6086
    E-ISSN: 1552-5023
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  • 4
    In: Annals of Neurology, March 2018, Vol.83(3), pp.588-598
    Description: To visualize and quantify differences of microstructural nerve damage in distal symmetric diabetic neuropathy (DPN) between type 1 diabetes (T1D) and type 2 diabetes (T2D), and to detect correlations between neuropathic symptoms and serological risk factors. Three-tesla magnetic resonance neurography of the sciatic nerve was performed in 120 patients (T1D, n = 35; T2D, n = 85) with either DPN (n = 84) or no DPN (n = 36). Results were subsequently correlated with clinical, serological, and electrophysiological patient data. T2-weighted (T2w)-hyperintense lesions correlated negatively with tibial compound motor action potential (r = -0.58, p 〈 0.0001) and peroneal nerve conduction (r = 0.51, p = 0.0002), and positively with neuropathy disability score (NDS; r = -0.54, p 〈 0.0001), neuropathy symptom score (NSS; r = 0.52, p 〈 0.0001), and HbA1c level (r = 0.23, p = 0.014). T2w-hypointense lesions correlated positively with NDS (r = 0.28, p = 0.002), NSS (r = 0.36, p 〈 0.0001), and serum triglycerides (r = 0.34, p = 0.0003), and negatively with serum high-density lipoprotein (HDL; r = -0.48, p 〈 0.0001). For DPN in T1D, elevated values of T2w-hyperintense lesions (19.67 ± 4.13% vs 12.49 ± 1.23%, p = 0.027) and HbA1c (8.74 ± 0.29% vs 7.11 ± 0.16%, p 〈 0.0001) were found when compared to T2D. For DPN in T2D, elevated T2w-hypointense lesions (23.41 ± 2.69mm vs 11.43 ± 1.74mm , p = 0.046) and triglycerides (220.70 ± 23.70mg/dl vs 106.60 ± 14.51mg/dl, p 〈 0.0001), and lower serum HDL (51.29 ± 3.02mg/dl vs 70.79 ± 4.65mg/dl, p 〈 0.0001) were found when compared to T1D. The predominant type of nerve lesion in DPN differs between T1D and T2D. Correlations found between lesion type and serological parameters indicate that predominant nerve lesions in T1D are associated with poor glycemic control and loss of nerve conduction, whereas predominant lesions in T2D are associated with changes in lipid metabolism. These findings may be helpful for future studies on the underlying pathophysiological pathways and possible treatments for DPN in T1D and T2D. Ann Neurol 2018;83:588-598.
    Keywords: Magnetic Resonance Spectroscopy ; Diabetes Mellitus, Type 1 -- Pathology ; Diabetes Mellitus, Type 2 -- Pathology ; Diabetic Neuropathies -- Pathology;
    ISSN: 0364-5134
    E-ISSN: 1531-8249
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  • 5
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(11), p.e0141894
    Description: Since changes in lung microstructure are important indicators for (early stage) lung pathology, there is a need for quantifiable information of diagnostically challenging cases in a clinical setting, e.g. to evaluate early emphysematous changes in peripheral lung tissue. Considering alveoli as spherical air-spaces surrounded by a thin film of lung tissue allows deriving an expression for Carr-Purcell-Meiboom-Gill transverse relaxation rates R2 with a dependence on inter-echo time, local air-tissue volume fraction, diffusion coefficient and alveolar diameter, within a weak field approximation. The model relaxation rate exhibits the same hyperbolic tangent dependency as seen in the Luz-Meiboom model and limiting cases agree with Brooks et al. and Jensen et al. In addition, the model is tested against experimental data for passively deflated rat lungs: the resulting mean alveolar radius of RA = 31.46 ± 13.15 μm is very close to the literature value (∼34 μm). Also, modeled radii obtained from relaxometer measurements of ageing hydrogel foam (that mimics peripheral lung tissue) are in good agreement with those obtained from μCT images of the same foam (mean relative error: 0.06 ± 0.01). The model's ability to determine the alveolar radius and/or air volume fraction will be useful in quantifying peripheral lung microstructure.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: Nature, 03 December 2015, Vol.528(7580), pp.93-8
    Description: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
    Keywords: Astrocytoma -- Pathology ; Brain Neoplasms -- Pathology ; Gap Junctions -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 7
    Language: English
    In: Kurz, Felix T., Miguel A. Aon, Brian O'Rourke, and Antonis A. Armoundas. 2014. “Cardiac mitochondria exhibit dynamic functional clustering.” Frontiers in Physiology 5 (1): 329. doi:10.3389/fphys.2014.00329. http://dx.doi.org/10.3389/fphys.2014.00329.
    Description: Multi-oscillatory behavior of mitochondrial inner membrane potential ΔΨm in self-organized cardiac mitochondrial networks can be triggered by metabolic or oxidative stress. Spatio-temporal analyses of cardiac mitochondrial networks have shown that mitochondria are heterogeneously organized in synchronously oscillating clusters in which the mean cluster frequency and size are inversely correlated, thus suggesting a modulation of cluster frequency through local inter-mitochondrial coupling. In this study, we propose a method to examine the mitochondrial network's topology through quantification of its dynamic local clustering coefficients. Individual mitochondrial ΔΨm oscillation signals were identified for each cardiac myocyte and cross-correlated with all network mitochondria using previously described methods (Kurz et al., 2010a). Time-varying inter-mitochondrial connectivity, defined for mitochondria in the whole network whose signals are at least 90% correlated at any given time point, allowed considering functional local clustering coefficients. It is shown that mitochondrial clustering in isolated cardiac myocytes changes dynamically and is significantly higher than for random mitochondrial networks that are constructed using the Erdös–Rényi model based on the same sets of vertices. The network's time-averaged clustering coefficient for cardiac myocytes was found to be 0.500 ± 0.051 (N = 9) vs. 0.061 ± 0.020 for random networks, respectively. Our results demonstrate that cardiac mitochondria constitute a network with dynamically connected constituents whose topological organization is prone to clustering. Cluster partitioning in networks of coupled oscillators has been observed in scale-free and chaotic systems and is therefore in good agreement with previous models of cardiac mitochondrial networks.
    Keywords: Mitochondrial Clustering ; Mitochondrial Oscillator ; Functional Connectivity ; Wavelets ; Cardiac Myocyte
    ISSN: 1664-042X
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  • 8
    Language: English
    In: Magnetic Resonance Imaging, November 2015, Vol.33(9), pp.1126-1145
    Description: In this work, the time evolution of the free induction decay caused by the local dipole field of a spherical magnetic perturber is analyzed. The complicated treatment of the diffusion process is replaced by the strong-collision-approximation that allows a determination of the free induction decay in dependence of the underlying microscopic tissue parameters such as diffusion coefficient, sphere radius and susceptibility difference. The interplay between susceptibility- and diffusion-mediated effects yields several dephasing regimes of which, so far, only the classical regimes of motional narrowing and static dephasing for dominant and negligible diffusion, respectively, were extensively examined. Due to the asymmetric form of the dipole field for spherical objects, the free induction decay exhibits a complex component in contradiction to the cylindrical case, where the symmetric local dipole field only causes a purely real induction decay. Knowledge of the shape of the corresponding frequency distribution is necessary for the evaluation of more sophisticated pulse sequences and a detailed understanding of the off-resonance distribution allows improved quantification of transverse relaxation.
    Keywords: Susceptibility Effects ; Dipole Field ; Frequency Density of States ; Line Broadening ; Lung Tissue ; Medicine
    ISSN: 0730-725X
    E-ISSN: 1873-5894
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  • 9
    Language: English
    In: SpringerPlus, 2015, Vol.4, pp.390
    Description: The cylindrical Bessel differential equation and the spherical Bessel differential equation in the interval [Formula: see text] with Neumann boundary conditions are considered. The eigenfunctions are linear combinations of the Bessel function [Formula: see text] or linear combinations of the spherical Bessel functions [Formula: see text]. The orthogonality relations with analytical expressions for the normalization constant are given. Explicit expressions for the Lommel integrals in terms of Lommel functions are derived. The cross product zeros [Formula: see text] and [Formula: see text] are considered in the complex plane for real as well as complex values of the index [Formula: see text] and approximations for the exceptional zero [Formula: see text] are obtained. A numerical scheme based on the discretization of the two-dimensional and three-dimensional Laplace operator with Neumann boundary conditions is presented. Explicit representations of the radial part of the Laplace operator in form of a tridiagonal matrix allow the simple computation of the cross product zeros.
    Keywords: Bessel Function ; Integral ; Linear Combination
    ISSN: 2193-1801
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  • 10
    Language: English
    In: Advances in experimental medicine and biology, 2017, Vol.982, pp.1-24
    Description: The spatio-temporal organization of mitochondria in cardiac myocytes facilitates myocyte-wide, cluster-bound, mitochondrial inner membrane potential oscillatory depolarizations, commonly triggered by metabolic or oxidative stressors. Local intermitochondrial coupling can be mediated by reactive oxygen species (ROS) that activate inner membrane pores to initiate a ROS-induced-ROS-release process that produces synchronized limit cycle oscillations of mitochondrial clusters within the whole mitochondrial network. The network's dynamic organization, structure and function can be assessed by quantifying dynamic local coupling constants and dynamic functional clustering coefficients, both providing information about the network's response to external stimuli. In addition to its special organization, the mitochondrial network of cardiac myocytes exhibits substrate-sensitive coupling constants and clustering coefficients. The myocyte's ability to form functional clusters of synchronously oscillating mitochondria is sensitive to conditions such as substrate availability (e.g., glucose, pyruvate, β-hydroxybutyrate), antioxidant status, respiratory chain activity, or history of oxidative challenge (e.g., ischemia-reperfusion). This underscores the relevance of quantitative methods to characterize the network's functional status as a way to assess the myocyte's resilience to pathological stressors.
    Keywords: Cardiac Myocyte ; Mitochondrial Clustering ; Mitochondrial Coupling ; Mitochondrial Oscillator ; Wavelets ; Energy Metabolism ; Signal Transduction ; Adenosine Triphosphate -- Metabolism ; Mitochondria, Heart -- Metabolism ; Myocytes, Cardiac -- Metabolism
    ISSN: 0065-2598
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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