Anning a spectrum of high and low frequencies [4,5]. T cells have a fundamental role in clinical medicine, especially in cancer therapeutics. As an example, clinical outcomes following stem cell transplantation (SCT) are closely associated with T-cell reconstitution, both from the standpoint of infection control and control of malignancy [6,7]. T-cell reconstitution over time following SCT may be considered as a dynamical system, where T-cell clonal expansion can be modelled as a function of time using ordinary differential equations, specifically the logistic equation. This suggests that successive states of evolution of T-cell repertoire complexity when plotted as a function of time may be described mathematically as a deterministic process [8,9]. Talmapimod biological activity Support for determinism shaping the T-cell repertoire in humans comes from the observation of fractal self-similar PD168393 web organization with respect to TCR gene segment usage [10]. Fractal geometry is observed in structures demonstrating organizational selfsimilarity across scales of magnitude, in other words structures look similar (not identical) no matter what magnification they are observed at. This structural motif is widely observed in nature, e.g. in the branching patterns of trees and in the vascular and neuronal networks in animals [11?4]. However, while mathematical fractal constructs may be self-similar over an infinite number of scales; in nature, the scales of magnitude demonstrating self-similar organization are limited. Mathematically, logarithmic transformation of simple numeric data is used to identify this scale invariance, because this makes values across different scales comparable. Self-similarity in fractals is evident if the logarithm of magnitude of a parameter (y) maintains a relatively stable ratio to the logarithm of a scaling factor value (x), a ratio termed fractal dimension (FD) [15]. FD takes on non-integer values between the classical Euclidean dimensional values of one, two and three used to define the dimensions of a line, square and a cube. Fractal geometry has been used to describe molecular folding of DNA, and the nucleotide distribution in the genome [16?9]. In such instances, FD explains the complex structural organization of natural objects. Evaluating T-cell clonal frequencies, when unique clonotypes bearing specific TCR b J, V ?J and VDJ ?NI are plotted in order of frequency, a power law distribution is observed over approximately 3? orders of magnitude. This proportionality of clonal frequency distribution across scales of magnitude (number of gene segmentsused to define clonality in this instance) means that there are a small number of high-frequency clones, and a proportionally larger number of clones in each of the lower frequency ranks in an individual’s T-cell repertoire [10,20]. The observed determinism of the TCR repertoire poses the question as to whether this may originate in the organization of the TCR locus, and whether this may also be described mathematically. Using fractal geometry, one may consider the TCR loci similarly, such that when the linear germ-line DNA of the TCR V, D and J segments is rearranged, this process lends geometric complexity to the rearranged locus compared to its native state, in other words, changes its FD. Another feature of the TCR gene segment distribution arguing against the stochastic nature of TCR gene rearrangement is the periodic nature of their location on the gene locus. Repetitive or cyclic phenomenon too may.Anning a spectrum of high and low frequencies [4,5]. T cells have a fundamental role in clinical medicine, especially in cancer therapeutics. As an example, clinical outcomes following stem cell transplantation (SCT) are closely associated with T-cell reconstitution, both from the standpoint of infection control and control of malignancy [6,7]. T-cell reconstitution over time following SCT may be considered as a dynamical system, where T-cell clonal expansion can be modelled as a function of time using ordinary differential equations, specifically the logistic equation. This suggests that successive states of evolution of T-cell repertoire complexity when plotted as a function of time may be described mathematically as a deterministic process [8,9]. Support for determinism shaping the T-cell repertoire in humans comes from the observation of fractal self-similar organization with respect to TCR gene segment usage [10]. Fractal geometry is observed in structures demonstrating organizational selfsimilarity across scales of magnitude, in other words structures look similar (not identical) no matter what magnification they are observed at. This structural motif is widely observed in nature, e.g. in the branching patterns of trees and in the vascular and neuronal networks in animals [11?4]. However, while mathematical fractal constructs may be self-similar over an infinite number of scales; in nature, the scales of magnitude demonstrating self-similar organization are limited. Mathematically, logarithmic transformation of simple numeric data is used to identify this scale invariance, because this makes values across different scales comparable. Self-similarity in fractals is evident if the logarithm of magnitude of a parameter (y) maintains a relatively stable ratio to the logarithm of a scaling factor value (x), a ratio termed fractal dimension (FD) [15]. FD takes on non-integer values between the classical Euclidean dimensional values of one, two and three used to define the dimensions of a line, square and a cube. Fractal geometry has been used to describe molecular folding of DNA, and the nucleotide distribution in the genome [16?9]. In such instances, FD explains the complex structural organization of natural objects. Evaluating T-cell clonal frequencies, when unique clonotypes bearing specific TCR b J, V ?J and VDJ ?NI are plotted in order of frequency, a power law distribution is observed over approximately 3? orders of magnitude. This proportionality of clonal frequency distribution across scales of magnitude (number of gene segmentsused to define clonality in this instance) means that there are a small number of high-frequency clones, and a proportionally larger number of clones in each of the lower frequency ranks in an individual’s T-cell repertoire [10,20]. The observed determinism of the TCR repertoire poses the question as to whether this may originate in the organization of the TCR locus, and whether this may also be described mathematically. Using fractal geometry, one may consider the TCR loci similarly, such that when the linear germ-line DNA of the TCR V, D and J segments is rearranged, this process lends geometric complexity to the rearranged locus compared to its native state, in other words, changes its FD. Another feature of the TCR gene segment distribution arguing against the stochastic nature of TCR gene rearrangement is the periodic nature of their location on the gene locus. Repetitive or cyclic phenomenon too may.

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