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D C Samuels

Publications and source records attributed to D C Samuels.

13 recordsLinked to original sources
PubMed2006

Is selection required for the accumulation of somatic mitochondrial DNA mutations in post-mitotic cells?

Mitochondrial DNA (mtDNA) mutations accumulate in the skeletal muscle of patients with mtDNA disease, and also as part of healthy ageing. Simulations of human muscle fibres suggest that, over many decades, the continuous destruction and copying of mtDNA (relaxed replication) can lead to dramatic changes in the percentage level of mutant mtDNA in non-dividing cells through random genetic drift. This process should apply to both pathogenic and neutral mutations. To test this hypothesis we sequenced the entire mitochondrial genome for 20 muscle fibres from a healthy elderly 85-year-old individual, chosen because of the low frequency of cytochrome c oxidase negative fibres. Phenotypically neutral single base substitutions were detected in 15% of the healthy fibres, supporting the hypothesis that positive selection is not essential for the clonal expansion of mtDNA point mutations during human life. Treatments that enhance mtDNA replication, such as vigorous excercise, could amplify this process, with potentially detrimental long-term consequences.

Aged, 80 and over↗
PubMed2005

Mitochondrial DNA copy number threshold in mtDNA depletion myopathy.

The authors measured the absolute amount of mitochondrial DNA (mtDNA) within single muscle fibers from two patients with thymidine kinase 2 (TK2) deficiency and two healthy controls. TK2 deficient fibers containing more than 0.01 mtDNA/microm3 had residual cytochrome c oxidase (COX) activity. This defines the minimum amount of wild-type mtDNA molecules required to maintain COX activity in skeletal muscle and provides an explanation for the mosaic histochemical pattern seen in patients with mtDNA depletion syndrome.

Adult↗
PubMed2001

Quantum signature of superfluid turbulence.

Using a numerical simulation backed up by physical arguments, we predict that the pressure spectrum of superfluid turbulence has a k(-2) dependence on the wave number k, which represents a macroscopic quantum signature not to be found in the classical Kolmogorov theory of turbulence.

Journal Article↗
PubMed2001

Fractal dimension of superfluid turbulence.

Superfluid turbulence consists of a disordered tangle of quantized vortex filaments which interact with each other and with the normal fluid. We develop a kinematic model of normal-fluid turbulence to study superfluid vortex tangles at finite temperatures and show by numerical simulation that the system of filaments has a fractal dimension larger than one. We find that the fractal dimension is directly related to the vortex-line density and is independent of temperature over a wide range.

Journal Article↗
PubMed2001

Kelvin waves cascade in superfluid turbulence.

We study numerically the interaction of four initial superfluid vortex rings in the absence of any dissipation or friction. We find evidence for a cascade of Kelvin waves generated by individual vortex reconnection events which transfers energy to higher and higher wave numbers k. After the vortex reconnections occur, the energy spectrum scales as k(-1) and the curvature spectrum becomes flat. These effects highlight the importance of Kelvin waves and reconnections in the transfer of energy within a turbulent vortex tangle.

Journal Article↗
PubMed2001

Sound emission due to superfluid vortex reconnections.

By performing numerical simulations based on the Gross-Pitaevskii equation, we make direct quantitative measurements of the sound energy released due to superfluid vortex reconnections. We show that the energy radiated expressed in terms of the loss of vortex line length is a simple function of the reconnection angle. In addition, we study the temporal and spatial distribution of the radiation and show that energy is emitted in the form of a sound pulse with a wavelength of a few healing lengths.

Journal Article↗
PubMed2001

Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age.

Human tissues acquire somatic mitochondrial DNA (mtDNA) mutations with age. Very high levels of specific mtDNA mutations accumulate within individual cells, causing a defect of mitochondrial oxidative metabolism. This is a fundamental property of nondividing tissues, but it is not known how it comes about. To explore this problem, we developed a model of mtDNA replication within single human cells. Using this model, we show that relaxed replication of mtDNA alone can lead, through random genetic drift, to the clonal expansion of single mutant events during human life. Significant expansions primarily develop from mutations acquired during a critical period in childhood or early adult life.

Adult↗
PubMed2000

Triple vortex ring structure in superfluid helium II.

Superfluids such as helium II consist of two interpenetrating fluids: the normal fluid and the superfluid. The helium II vortex ring has generally been considered merely as a superfluid object, neglecting any associated motion of the normal fluid. We report a three-dimensional calculation of the coupled motion of the normal-fluid and superfluid components, which shows that the helium II vortex ring consists of a superfluid vortex ring accompanied by two coaxial normal-fluid vortex rings of opposite polarity. The three vortex rings form a coherent, dissipative structure.

Journal Article↗
PubMed2000

The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both?

The mammalian mitochondrial genome (mtDNA) is a small double-stranded DNA molecule that is exclusively transmitted down the maternal line. Pathogenic mtDNA mutations are usually heteroplasmic, with a mixture of mutant and wild-type mtDNA within the same organism. A woman harbouring one of these mutations transmits a variable amount of mutant mtDNA to each offspring. This can result in a healthy child or an infant with a devastating and fatal neurological disorder. Understanding the biological basis of this uncertainty is one of the principal challenges facing scientists and clinicians in the field of mitochondrial genetics.

Animals↗
PubMed1999

Relaxed replication of mtDNA: A model with implications for the expression of disease.

Heteroplasmic mtDNA defects are an important cause of human disease with clinical features that primarily involve nondividing (postmitotic) tissues. Within single cells the percentage level of mutated mtDNA must exceed a critical threshold level before the genetic defect is expressed. Although the level of mutated mtDNA may alter over time, the mechanism behind the change is not understood. It currently is not possible to directly measure the level of mutant mtDNA within living cells. We therefore developed a mathematical model of human mtDNA replication, based on a solid foundation of experimentally derived parameters, and studied the dynamics of intracellular heteroplasmy in postmitotic cells. Our simulations show that the level of intracellular heteroplasmy can vary greatly over a short period of time and that a high copy number of mtDNA molecules delays the time to fixation of an allele. We made the assumption that the optimal state for a cell is to contain 100% wild-type molecules. For cells that contain pathogenic mutations, the nonselective proliferation of mutant and wild-type mtDNA molecules further delays the fixation of both alleles, but this leads to a rapid increase in the mean percentage level of mutant mtDNA within a tissue. On its own, this mechanism will lead to the appearance of a critical threshold level of mutant mtDNA that must be exceeded before a cell expresses a biochemical defect. The hypothesis that we present is in accordance with the available data and may explain the late presentation and insidious progression of mtDNA diseases.

Alleles↗
PubMed1997

The axon as a metabolic compartment: protein degradation, transport, and maximum length of an axon.

We present a model that predicts the maximum axonal length from the apparent velocity of slow axonal transport and cytoskeletal protein half-life. The model assumes that in mature axons the apparent velocity of slow transport varies with position, but that the density of cytoskeletal proteins and protein degradation are uniform. The model predicts that the apparent transport velocity of cytoskeletal proteins if highest near the cell body and decreases linearly along the axon, and that when axons branch the apparent velocity of transport decreases across the branch point. The predictions of this model are shown to be consistent with experiments. These results explain the variation in these fundamental metabolic parameters in different axons and species.

Animals↗
PubMed1996

The origin of neuronal polarization: a model of axon formation.

During development, most neurons become polarized when one neurite, generally the longest, becomes the axon and the other neurites become dendrites. The physical mechanism responsible for such length-related differentiation has not been established. Here, we present a model of neuronal polarization based upon the existence of a "determinant chemical' whose concentration at the neurite tips influences the growth rate of the neurite. Over an extended parameter range the equations describing the formation, transport, and consumption of this chemical and the resulting neurite growth undergo a winner-take-all instability, yielding rapid growth of one neurite (the axon) and diminished growth of all others. The behaviour of this model agrees well with the results of axotomy experiments and experiments in which growth-modulating substances are applied to individual growth cones. Possible candidates for the determinant chemical are discussed, and further experiments are proposed to test the model.

Animals↗