THE DESIGN AND ANALYSIS OF EXPERIMENTS. By Oscar Kempthorne. New York, John Wiley and Sons, Inc., 1952. 631 pp. $8.50. This book by a teacher of statistics (as well as a consultant for \"experimenters\") is a comprehensive study of the philosophical background for the statistical design of experiment. It is necessary to have some facility with algebraic notation and manipulation to be able to use the volume intelligently. The problems are presented from the theoretical point of view, without such practical examples as would be helpful for those not acquainted with mathematics. The mathematical justification for the techniques is given. As a somewhat advanced treatment of the design and analysis of experiments, this volume will be interesting and helpful for many who approach statistics theoretically as well as practically. With emphasis on the \"why,\" and with description given broadly, the author relates the subject matter to the general theory of statistics and to the general problem of experimental inference. MARGARET J. ROBERTSON

The Design and Analysis of Experiments

In 1974 an article appeared in Science magazine with the dry-sounding title “Judgment Under Uncertainty: Heuristics and Biases” by a pair of psychologists who were not well known outside their discipline of decision theory. In it Amos Tversky and Daniel Kahneman introduced the world to Prospect Theory, which mapped out how humans actually behave when faced with decisions about gains and losses, in contrast to how economists assumed that people behave. Prospect Theory turned Economics on its head by demonstrating through a series of ingenious experiments that people are much more concerned with losses than they are with gains, and that framing a choice from one perspective or the other will result in decisions that are exactly the opposite of each other, even if the outcomes are monetarily the same. Prospect Theory led cognitive psychology in a new direction that began to uncover other human biases in thinking that are probably not learned but are part of our brain’s wiring.

Thinking fast and slow.

To understand biology at the system level, we must examine the structure and dynamics of cellular and organismal function, rather than the characteristics of isolated parts of a cell or organism. Properties of systems, such as robustness, emerge as central issues, and understanding these properties may have an impact on the future of medicine. However, many breakthroughs in experimental devices, advanced software, and analytical methods are required before the achievements of systems biology can live up to their much-touted potential.

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Systems biology: a brief overview.

This book explains the relationship of electrophysiology, nonlinear dynamics, and the computational properties of neurons, with each concept presented in terms of both neuroscience and mathematics and illustrated using geometrical intuition In order to model neuronal behavior or to interpret the results of modeling studies, neuroscientists must call upon methods of nonlinear dynamics This book offers an introduction to nonlinear dynamical systems theory for researchers and graduate students in neuroscience It also provides an overview of neuroscience for mathematicians who want to learn the basic facts of electrophysiology "Dynamical Systems in Neuroscience" presents a systematic study of the relationship of electrophysiology, nonlinear dynamics, and computational properties of neurons It emphasizes that information processing in the brain depends not only on the electrophysiological properties of neurons but also on their dynamical properties The book introduces dynamical systems starting with one- and two-dimensional Hodgkin-Huxley-type models and continuing to a description of bursting systems Each chapter proceeds from the simple to the complex, and provides sample problems at the end The book explains all necessary mathematical concepts using geometrical intuition; it includes many figures and few equations, making it especially suitable for non-mathematicians Each concept is presented in terms of both neuroscience and mathematics, providing a link between the two disciplines Nonlinear dynamical systems theory is at the core of computational neuroscience research, but it is not a standard part of the graduate neuroscience curriculum - or taught by math or physics department in a way that is suitable for students of biology This book offers neuroscience students and researchers a comprehensive account of concepts and methods increasingly used in computational neuroscience

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Dynamical Systems in Neuroscience

We propose that the crucial difference between human cognition and that of other species is the ability to participate with others in collaborative activities with shared goals and intentions: shared intentionality. Participation in such activities requires not only especially powerful forms of intention reading and cultural learning, but also a unique motivation to share psychological states with oth- ers and unique forms of cognitive representation for doing so. The result of participating in these activities is species-unique forms of cultural cognition and evolution, enabling everything from the creation and use of linguistic symbols to the construction of social norms and individual beliefs to the establishment of social institutions. In support of this proposal we argue and present evidence that great apes (and some children with autism) understand the basics of intentional action, but they still do not participate in activities involving joint intentions and attention (shared intentionality). Human children's skills of shared intentionality develop gradually during the first 14 months of life as two ontogenetic pathways intertwine: (1) the general ape line of understanding others as animate, goal-directed, and intentional agents; and (2) a species-unique motivation to share emotions, experience, and activities with other persons. The develop- mental outcome is children's ability to construct dialogic cognitive representations, which enable them to participate in earnest in the collectivity that is human cognition.

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Understanding and sharing intentions: The origins of cultural cognition

Conduction of Electrical Current to and Through the Human February 6th, 2017 PART A BASICS OF ELECTRICITY AND HOW IT INTERACTS WITH THE HUMAN BODY Electric shock is defined as a sudden violent response to electric current flow through any part of a person s body Electrocution is death caused by electric shock Primary electrical injury is tissue damage produced directly by electrical current or voltage Secondary injuries such as falls are common

Electric Current Flow in Excitable Cells

The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. In this article we introduce a mathematical model of the action potential of human ventricular cells that, while including a high level of electrophysiological detail, is computationally cost-effective enough to be applied in large-scale spatial simulations for the study of reentrant arrhythmias. The model is based on recent experimental data on most of the major ionic currents: the fast sodium, L-type calcium, transient outward, rapid and slow delayed rectifier, and inward rectifier currents. The model includes a basic calcium dynamics, allowing for the realistic modeling of calcium transients, calcium current inactivation, and the contraction staircase. We are able to reproduce human epicardial, endocardial, and M cell action potentials and show that differences can be explained by differences in the transient outward and slow delayed rectifier currents. Our model reproduces the experimentally observed data on action potential duration restitution, which is an important characteristic for reentrant arrhythmias. The conduction velocity restitution of our model is broader than in other models and agrees better with available data. Finally, we model the dynamics of spiral wave rotation in a two-dimensional sheet of human ventricular tissue and show that the spiral wave follows a complex meandering pattern and has a period of 265 ms. We conclude that the proposed model reproduces a variety of electrophysiological behaviors and provides a basis for studies of reentrant arrhythmias in human ventricular tissue.

/pdf/a-model-for-human-ventricular-tissue-3iwzhwqfm7.pdf

A model for human ventricular tissue

A modification of the Hodgkin—Huxley equations applicable to Purkinje fibre action and pacemaker potentials

Equations have been developed to describe cardiac action potentials and pacemaker activity. The model takes account of extensive developments in experimental work since the formulation of the M.N.T. (R. E. McAllister, D. Noble and R. W. Tsien, J. Physiol., Lond. 251, 1-59 (1975)) and B.R. (G. W. Beeler and H. Reuter, J. Physiol., Lond. 268, 177-210 (1977)) equations. The current mechanism i $\_{K2}$ has been replaced by the hyperpolarizing-activated current, i $\_f$ . Depletion and accumulation of potassium ions in the extracellular space are represented either by partial differential equations for diffusion in cylindrical or spherical preparations or, when such accuracy is not essential, by a three-compartment model in which the extracellular concentration in the intercellular space is uniform. The description of the delayed K current, i $\_K$ , remains based on the work of D. Noble and R. W. Tsien (J. Physiol., Lond. 200, 205-231 (1969a)). The instantaneous inward-rectifier, i $\_{K1}$ , is based on S. Hagiwara and K. Takahashi's equation (J. Membrane Biol. 18, 61-80 (1974)) and on the patch clamp studies of B. Sakmann and G. Trube (J. Physiol., Lond. 347, 641-658 (1984)) and of Y. Momose, G. Szabo and W. R. Giles (Biophys. J. 41, 311a (1983)). The equations successfully account for all the properties formerly attributed to i $\_{K2}$ , as well as giving more complete descriptions of i $\_{K1}$ and i $\_K$ . The sodium current equations are based on experimental data of T. J. Colatsky (J. Physiol., Lond. 305, 215-234 (1980)) and A. M. Brown, K. S. Lee and T. Powell (J. Physiol., Lond. 318, 479-500 (1981)). The equations correctly reproduce the range and magnitude of the sodium \`window' current. The second inward current is based in part on the data of H. Reuter and H. Scholz (J. Physiol., Lond. 264, 17-47 (1977)) and K. S. Lee and R. W. Tsien (Nature, Lond. 297, 498-501 (1982)) so far as the ion selectivity is concerned. However, the activation and inactivation gating kinetics have been greatly speeded up to reproduce the very much faster currents recorded in recent work. A major consequence of this change is that Ca current inactivation mostly occurs very early in the action potential plateau. The sodium-potassium exchange pump equations are based on data reported by D. C. Gadsby (Proc. natn. Acad. Sci. U.S.A. 77, 4035-4039 (1980)) and by D. A. Eisner and W. J. Lederer (J. Physiol., Lond. 303, 441-474 (1980)). The sodium-calcium exchange current is based on L. J. Mullins' equations (J. gen. Physiol. 70, 681-695 (1977)). Intracellular calcium sequestration is represented by simple equations for uptake into a reticulum store which then reprimes a release store. The repriming equations use the data of W. R. Gibbons & H. A. Fozzard (J. gen. Physiol. 65, 367-384 (1975b)). Following Fabiato & Fabiato's work (J. Physiol., Lond. 249, 469-495 (1975)), Ca release is assumed to be triggered by intracellular free calcium. The equations reproduce the essential features of intracellular free calcium transients as measured with aequorin. The explanatory range of the model entirely includes and greatly extends that of the M.N.T. equations. Despite the major changes made, the overall time-course of the conductance changes to potassium ions strongly resembles that of the M.N.T. model. There are however important differences in the time courses of Na and Ca conductance changes. The Na conductance now includes a component due to the hyperpolarizing-activated current, i $\_f$ , which slowly increases during the pacemaker depolarization. The Ca conductance changes are very much faster than in the M.N.T. model so that in action potentials longer than about 50 ms the primary contribution of the fast gated calcium channel to the plateau is due to a steady-state \`window' current or non-inactivated component. Slower calcium or Ca-activated currents, such as the Na-Ca exchange current, or Ca-gated currents, or a much slower Ca channel must then play the dynamic role previously attributed to the kinetics of a single type of calcium channel. This feature of the model in turn means that the repolarization process should be related to the inotropic state, as indicated by experimental work. The model successfully reproduces intracellular sodium concentration changes produced by variations in [Na] $\_o$ , or Na-K pump block. The sodium dependence of the overshoot potential is well reproduced despite the fact that steady state intracellular Na is proportional to extracellular Na, as in the experimental results of D. Ellis J. Physiol., Lond. 274, 211-240 (1977)). The model reproduces the responses to current pulses applied during the plateau and pacemaker phases. In particular, a substantial net decrease in conductance is predicted during the pacemaker depolarization despite the fact that the controlling process is an increase in conductance for the hyperpolarizing-activated current. The immediate effects of changing extracellular [K] are reproduced, including: (i) the shortening of action potential duration and suppression of pacemaker activity at high [K]; (ii) the increased automaticity at moderately low [K]; and (iii) the depolarization to the plateau range with premature depolarizations and low voltage oscillations at very low [K]. The ionic currents attributed to changes in Na-K pump activity are well reproduced. It is shown that the apparent K $\_m$ for K activation of the pump depends strongly on the size of the restricted extracellular space. With a 30% space (as in canine Purkinje fibres) the apparent K $\_m$ is close to the assumed real value of 1 mM. When the extracellular space is reduced to below 5%, the apparent K $\_m$ increases by up to an order of magnitude. A substantial part of the pump is then not available for inhibition by low [K] $\_b$ . These results can explain the apparent discrepancies in the literature concerning the K $\_m$ for pump activation.

A Model of Cardiac Electrical Activity Incorporating Ionic Pumps and Concentration Changes

Successful physiological analysis requires an understanding of the functional interactions between the key components of cells, organs, and systems, as well as how these interactions change in disease states. This information resides neither in the genome nor even in the individual proteins that genes code for. It lies at the level of protein interactions within the context of subcellular, cellular, tissue, organ, and system structures. There is therefore no alternative to copying nature and computing these interactions to determine the logic of healthy and diseased states. The rapid growth in biological databases; models of cells, tissues, and organs; and the development of powerful computing hardware and algorithms have made it possible to explore functionality in a quantitative manner all the way from the level of genes to the physiological function of whole organs and regulatory systems. This review illustrates this development in the case of the heart. Systems physiology of the 21st century is set to become highly quantitative and, therefore, one of the most computer-intensive disciplines.

https://science.sciencemag.org/content/sci/295/5560/1678.full.pdf

Denis Noble

Papers

Electric Current Flow in Excitable Cells

A model for human ventricular tissue

A modification of the Hodgkin—Huxley equations applicable to Purkinje fibre action and pacemaker potentials

A Model of Cardiac Electrical Activity Incorporating Ionic Pumps and Concentration Changes

Modeling the heart--from genes to cells to the whole organ.