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Repeats mimic pathogen-associated patterns across a vast evolutionary landscape.

An emerging hallmark of many human diseases is transcription of typically silenced repetitive DNA containing pathogen-associated molecular patterns (PAMPs). These PAMPs engage the innate immune system via pattern recognition receptors (PRRs)-a phenomenon known as viral mimicry. We propose a statistical physics framework to quantify viral mimicry by measuring "selective forces" that enrich PAMPs compared to a genome-wide reference distribution. We validate our predictions by identifying repeats that bind different PRRs and show potential viral mimics in different repeat families across eukaryotic genomes, suggesting shared mechanisms drive emergence and retention. We propose two non-exclusive evolutionary hypotheses. The first "repeat-centric" hypothesis posits PAMPs are integral to the repeat life cycle and are therefore enriched as they mediate repeat expansion. The second "organism-centric" hypothesis proposes viral mimicry functions as a cell-intrinsic feedback mechanism for sensing and reacting to transcriptional dysregulation, which provides a selective pressure to maintain PAMPs in genomes.

Humans

ODS_BOOTSTRAP: assessing the statistical reliability of physical maps by bootstrap resampling.

In the program ODS_BOOTSTRAP we provide a methodology for quickly ordering clones in a genomic library into a physical map and for applying a statistical tool known as the bootstrap to assess the statistical reliability of a clonal ordering. Each clone is assigned a binary fingerprint by one of a variety of experimental approaches to physical mapping. For example, the binary fingerprints might be generated by hybridizing a panel of m probes to a library of n clones. The resulting n x m binary data matrix, X, is input to ODS_BOOTSTRAP, which utilizes the similarity in binary fingerprints of clones to construct a physical map. Under this particular implementation of bootstrap resampling, the m probes (or columns of the data matrix) are sampled randomly with replacement in the computer to generate a new n x m data matrix, X*, from which a second physical map is constructed. The resampling process is repeated 100 or more times to generate 100 or more X* matrices. The resulting 100 or more physical maps are compared with the original physical map based on the original data matrix X by counting how often links in the original physical map reappear. Three confidence statistics are introduced for each link in a physical map. The statistic C1 is defined as the percentage of time two neighboring clones on the original map reappear as neighbors under resampling. The statistic C2 is defined as the percentage of time that two neighboring clones i and j on the original map reappear as neighbors or that a clone with an identical binary fingerprint to clone i reappears as a neighbor to clone j. The statistic C3 is defined as the percentage of time that two neighboring clones on the original map reappear in the same contig under resampling.

Algorithms

Physician knowledge and utilization of physical therapy procedures.

The purpose of this study was to assess physician knowledge and utilization of physical therapy procedures. We sent a questionnaire to 600 physicians in three medical specialties (neurology, orthopedic surgery, and physical medicine and rehabilitation), in four geographic regions of the United States. The usable return was 41 percent. Overall knowledge, technical knowledge, and professional knowledge scores were compared by medical specialty, region of the country, years in practice, and three measures of utilization using analysis of variance, student's t, and chi-square statistics. Physical medicine and rehabilitation specialists and physicians in practice 10 years or more had the most knowledge of physical therapy procedures. Respondents preferred a prescriptive relationship when referring patients to physical therapists, and they most often selected "technical" procedures traditionally associated with the profession rather than "professional" procedures when referring patients to physical therapy. Those practicing medicine in their specialty 10 years or more were more conservative in their referral preferences than those in practice less than 10 years. The implications for educational intervention concerning the professional role of the physical therapist are briefly discussed.

Attitude of Health Personnel

Analysis of cell locomotion. Contact guidance of human polymorphonuclear leukocytes.

The methods of statistical physics have been applied to the analysis of cell movement. Human polymorphonuclear leukocytes were exposed to different surfaces possessing parallel oriented physical structures (scratched glass surface, machine drilled aluminum surface, optical grid and stretched polyethylene foil) and cell migration was observed using time-lapse photography. We demonstrate that in cell migration along physical structures, referred to as contact guidance, two subgroups can be distinguished: 1) The nematic type where the cell size is large in relation to the grid distance of the undulate surface. 2) The smectic type where the cell size is small in relation to the grid distance of the substrate. Nematic contact guidance is characterized by an anisotropic random walk. In all substrates investigated the diffusion process parallel to the lines was faster than the diffusion process perpendicular to them. The angular dependent diffusion coefficient was described by an ellipse. Deviation from a circle defined an apolar order parameter, whose value was about 0.3. The amount of information which the cells collected from, the undulate surface was very low, between 0.1 and 0.2 bits. We demonstrate that cells do not recognize all the details of their surroundings and that their migration can be compared to the "groping around" of a short sighted man. The blurred environment can be described by a mean field whose strength is proportional to the apolar order parameter. It is argued that the anisotropic surface tension is the basic source for nematic contact guidance. Smectic contact guidance is characterized by an anisotropic random walk and is quantified by a density order parameter which is 0.28 in the case of the scratched glass surface of a Neubauer counting chamber. The information which the cells collect from their environment is very low (0.03 bits). The lines seen by the cell can be described by a mean field whose strength is proportional to the density oder parameter. Finally, we demonstrate that the locomotion of granulocytes is governed by an internal clock and internal programs. After migrating for a certain time (32 s) in a particular direction, a new direction of locomotion is determined by an internal program. The cell decides basically between left or right, thereby preferring a turn angle such that the cell migrates either parallel or perpendicular to the lines. The angles are nearly equally probable but the cell moves, in the case of nematic guidance, with different velocities in the + or - direction. The cell also has directional memories with characteristic times of 32 s and greater than 100 s.

Cell Movement

Quantitative assessment of the microstructure of rat behavior: I, f(d), the extension of the scaling hypothesis.

Previous studies demonstrated that drug effects on the movement sequences of rats in unconditioned motor activity paradigms can be quantified by scaling measures that describe the average relationship between a variable of interest and an experimental parameter. However, rats engage in a wide variety of geometrically distinct movements that can be influenced differentially by drugs. In this investigation, the extended scaling approach is presented to capture quantitatively the relative contributions of geometrically distinct movement sequences to the overall path structure. The calculation of the spectrum of local spatial scaling exponents, f(d), is based on ensemble methods used in statistical physics. Results of the f(d) analysis confirm that the amount of motor activity is not correlated with the geometrical structure of movement sequences. Changes in the average spatial scaling exponent, d, correspond to shifting the entire f(d) function, and indicate overall changes in path structure. With the extended scaling approach, straight movement sequences are assessed independently from highly circumscribed movements. Thus, the f(d) function identifies drug effects on particular ranges of movement sequences as defined by the geometrical structure of movements. More generally, the f(d) function quantifies the relationship between microscopically recorded variables, in this paradigm consecutive (x,y) locations, and the macroscopic behavioral patterns that constitute the animal's response topography.

Animals

Neuronal models of cognitive functions.

Understanding the neural bases of cognition has become a scientifically tractable problem, and neurally plausible models are proposed to establish a causal link between biological structure and cognitive function. To this end, levels of organization have to be defined within the functional architecture of neuronal systems. Transitions from any one of these interacting levels to the next are viewed in an evolutionary perspective. They are assumed to involve: (1) the production of multiple transient variations and (2) the selection of some of them by higher levels via the interaction with the outside world. The time-scale of these "evolutions" is expected to differ from one level to the other. In the course of development and in the adult this internal evolution is epigenetic and does not require alteration of the structure of the genome. A selective stabilization (and elimination) of synaptic connections by spontaneous and/or evoked activity in developing neuronal networks is postulated to contribute to the shaping of the adult connectivity within an envelope of genetically encoded forms. At a higher level, models of mental representations, as states of activity of defined populations of neurons, are discussed in terms of statistical physics, and their storage is viewed as a process of selection among variable and transient pre-representations. Theoretical models illustrate that cognitive functions such as short-term memory and handling of temporal sequences may be constrained by "microscopic" physical parameters. Finally, speculations are offered about plausible neuronal models and selectionist implementations of intentions.

Animals

Ca2+ imaging in single living cells: theoretical and practical issues.

The measurement of intracellular calcium ion concentrations [( Ca2+]i) in single living cells using quantitative fluorescence microscopy draws from a diverse set of disciplines, including cellular biology, optical physics, statistics and computer science. Over the last few years, we have devised and built a number of systems for measuring [Ca2+]i with Fura-2, and have applied them in the exploration of a wide range of biological processes controlled by Ca2+. In this report we discuss these systems and their advantages and limitations. We also describe the theoretical and practical problems associated with using Fura-2 to measure [Ca2+]i, and the solutions that we, and others, have developed to overcome them. The approaches described should provide useful guidance for others interested in imaging [Ca2+] distribution in living cells. The factors that limit current methods are discussed, and areas for future development are highlighted.

Animals

A simple tension-displacement model for hemoglobin cooperativity.

Based on the Perutz view of hemoglobin cooperativity and the methodology of statistical physics, a molecular model for heme-heme interactions is proposed. The motion of the iron atom with respect to the heme plane is assumed to be the important feature of the oxygenation step, and results in an expression for hemoglobin saturation as an explicit function of the internal tension of the hemoglobin molecule. Closure of the equation is obtained with the assumption of linearity between the internal tension and the displacement of the iron atom above the heme plane. All model parameters are physically realizable and are characteristic of the hemoglobin molecule. Finally, the model is capable of discriminating between positive and negative cooperativity.

Binding Sites

Application of the one- and two-dimensional Ising models to studies of cooperativity between ion channels.

The Ising model of statistical physics provides a framework for studying systems of protomers in which nearest neighbors interact with each other. In this article, the Ising model is applied to the study of cooperative phenomena between ligand-gated ion channels. Expressions for the mean open channel probability, rho o, and the variance, sigma 2, are derived from the grand partition function. In the one-dimensional Ising model, interactions between neighboring open channels give rise to a sigmoidal rho o versus concentration curve and a nonquadratic relationship between sigma 2 and rho o. Positive cooperativity increases the slope at the midpoint of the rho o versus concentration curve, shifts the apparent binding affinity to lower concentrations, and increases the variance for a given rho o. Negative cooperativity has the opposite effects. Strong negative cooperativity results in a bimodal sigma 2 versus rho o curve. The slope of the rho o versus concentration curve increases linearly with the number of binding sites on a protomer, but the sigma 2 versus rho o relationship is independent of the number of ligand binding sites. Thus, the sigma 2 versus rho o curve provides unambiguous information about channel interactions. In the two-dimensional Ising model, rho o and sigma 2 are calculated numerically from a series expansion of the grand partition function appropriate for weak interactions. Virtually all of the features exhibited by the one-dimensional model are qualitatively present in the two-dimensional model. These models are also applicable to voltage-gated ion channels.

Animals

Biophysical models of protein denaturation. II. Effects of denaturants and of pH.

In order to broaden the scope and increase the utility of differential scanning calorimetry, a theoretical model of calorimetric thermograms is presently proposed which facilitates their biophysical interpretation and accounts explicitly for their modifications induced by denaturing agents and/or pH. The model rests mainly on statistical-physical considerations, the denaturation-linked increase of the number of binding sites for denaturants (including H+) serving as the conceptual basis for thermogram modelling. Denaturants were envisioned as contributing indirectly to thermal denaturation by forming complexes preferentially with unfolded protein molecules, shifting thus the equilibrium towards the denatured phase. After postulating the probability of complex formation, mean numbers of the relevant molecular species were computed by ensemble averaging. Finally, an eight-parameter expression has been derived defining protein heat capacity as a function of both temperature and denaturant concentration (or pH), each of the eight parameters having a distinct biophysical meaning. The model has been tested by applying it to the prediction of the pH-dependence of thermograms. Four proteins have been considered (lysozyme, myoglobin, apomyoglobin, and ribonuclease A), each represented by a series of three to four published thermograms recorded under different pH conditions. Model equations, fitted simultaneously to all thermograms in a pH series, reproduced correctly experimental tracings. Parameter values obtained as best-fit requirements (particularly those representing the number of binding sites unmasked by denaturation and the free energy of ion binding) were in close agreement with empirical, mainly potentiometric, data from literature. The empirically established pH-independence of the total enthalpy of denaturation, the phenomenon of cold denaturation, the pH-dependence of the Gibbs free energy of denaturation, of the melting temperature and of the temperature of cold denaturation, were all correctly predicted by the model. Combined effects of multiple denaturants, including the effects of pH in the presence of denaturants other than protons, are also predictable by the model.

Calorimetry

Tooth eruption: the phase transition theory on biological formation of an orderly structure.

The mechanism of the formation of an orderly structure from random elements in organ development was clarified by studying the maturation of the dental arch in the human mandible. First, an application of methods established in statistical physics to a system of organ development was made possible, and then, the mathematical procedures for quantitative study of the structure and development of the dental arch were established in relation to radiographic data. The experimental results demonstrate that a parallel arrangement of the longitudinal axes of the lateral teeth is formed co-operatively in the dental arch. As formulation of the results to mathematical relations, the regulatory process was expressed by a non-linear Langevin equation of order parameter denoting an angle between longitudinal axes of the individual teeth. It follows that the orderly structure evolves with a change in thermodynamic potential; that is, the establishment of order in a phase transition. We propose the concept that organ differentiation is a phase transition in a dissipative system, with the decrease of gene activity substituted for temperature.

Adolescent

A program for the application of the radial distribution function to cluster analysis in cell biology.

The radial distribution function g(r) is one measure of spatial pattern commonly used in statistical physics to analyze the structure of liquids and has been used in several cellular systems. The graphs of the radial distribution function present three different functional forms. The first form indicates a random distribution; in the second form the graph is characteristic of the cluster distribution; and the third type is characteristic of substantial order. The Funct-G program uses the coordinates (x,y) of each point on m photographs to calculate the radial distribution function g(r) and produce a histogram to analyze graphically this function and to define the distribution model.

Cell Biology

Estimation of the parameters of a binary Markov random field on a graph with application to fibre type distributions in a muscle cross-section.

Methods are discussed for the estimation of the parameters of a binary Markov random field (BMRF) defined on a graph. The standard method is maximum pseudo-likelihood (MPL) estimation. Maximum likelihood (ML) estimation has been hampered in the past by the intractability of the likelihood function. Recently Markov chain Monte Carlo (MCMC) methods have been introduced for ML estimation. In this paper a new method for Monte Carlo maximum likelihood is described. It is used for the estimation of the parameters of a simple model (the Ising model of statistical physics). As an application the distribution of fibre types in a cross-section of human muscle is analysed.

Animals

[The Ising model for the description of allosteric kinetics of polymeric enzymes].

A new class of models for the description of the complex allosteric kinetics of oligomeric enzymes has been offered. Its regulation can be realized at the expense of two types of the cooperative interactions. First, the cooperative interaction of the neighboring enzyme protomers is examined on the basis of one-dimensional Ising model; second, subunits that compose the protomer are described by analogy with the model of indirect cooperation of Monod--Wyman--Changeux. The methods of statistical physics open approach to the unification of the models of allosteric regulation in the modern biochemistry. A detailed analysis of the one-ligand model of the polymeric enzymes was performed and possible ways of its generalization were shown.

Allosteric Regulation

Cell movement analysis in a necrotactic assay.

The methods of statistical physics have been applied to analysis of cell movement. Human leukocytes (granulocytes) were observed using time-lapse photography. The paths of the migrating cells were determined. The chemokinetic response at 35 degrees C is described by the diffusion constant (D = 233 micron2/min) and the track velocity (25 micron/min). A time-dependent chemotactic gradient is created by killing an erythrocyte by an intense laser flash. The chemotactic response at 35 degrees C is described by the degree of polar orientation (P1 = 0.85), the track velocity 24 micron/min, and the drift velocity towards the necrotactic source (v parallel = 20 micron/min). The track velocity as well the drift velocity show a broad distribution. The half-width of the velocity distribution. The half-width of the velocity distribution is approximately 5 micron/min. Cell movement can be described by elementary moving states. The characteristic time of the internal clock of the migrating cell is approximately 0.5 min. We found that the information transfer from the necrotactic gradient to the migrating cell is 1 bit per change in directed movement. A migrating cell cannot be stimulated within a period of approximately 10 s after the last decision to adapt a new moving direction.

Biophysical Phenomena

Analysis of cell movement.

The methods of statistical physics have been applied to the analysis of cell movement. Human leukocytes (granulocytes) were observed using time-lapse photography. The center of gravity of a cell, variations of cell shape, and cell orientation were investigated. This analytical description leads to a better understanding of cell movement. Stationary motion of a cell is described by the anisotropy of the cell shape. The cell displacement can be characterized by three different types of movement: The persistent mode where the cell moves away from an arbitrary chosen origin with its track velocity. The diffusion mode where the cells become dispersed in space by a random walk process. The drift mode where the cell moves with a drift velocity, v parallel, in a concentration gradient of chemoattractant molecules. The chemokinetic response is described by the diffusion constant D (= 240 microns2/min) and the track velocity vc (= 30 microns/min). The chemotactic response is described by the degree of orientation P1 (= 0.8), which is identical with the McCutcheon index and the chemotropism index. Cell movement can be described by elementary moving states, and the life time of such a moving state is 0.5 min. The survival probability of the moving state is determined by an internal program. It is not described by a stochastic process. The angular change in moving direction is also programmed, as the square root of the mean square angular change is +/- 50 degrees. The plus and minus direction are equally probable in a chemokinetic response. However, in a chemotactic assay the plus and minus directions are not equally probably. We found that the information transfer from the chemotactic gradient to the migrating cell is 1 bit per change in moving direction. A disturbance in this information transfer leads to an order-disorder transition. Furthermore, we found that the migrating cell exhibits a directional memory of 75 s.

Biophysical Phenomena