Replication functional models

In this essay, I argue for a new perspective on units of evolutionary transition. I analyze the process of reproduction, which leads to a conception of units of evolution as reproducers. These units resolve to more familiar ideas of replicators or interactors at levels of spatial organization when explicit spatial and functional models are imposed on abstract reproducers. I also sketch a heuristically promising program of reductionistic research that flows from the new perspective. 

DNA replication at the ARS origin in yeast. This sequence corresponds to a binding site for the yeast transcription factor ABF1. Studies with eukaryotic viral origins of replication have suggested that some of the proteins involved in RNA synthesis (also called transcription factors, see Chapter 24) have dual functions in transcription and initiation of DNA replication. Current models suggest that transcription factors may be necessary to recruit replication proteins to the origin. 

The formation of the encapsulating membranes is discussed by Turk-MacLeod et al. the operative strictures of thermodynamics in these processes and in the functional role of cell membranes are elaborated. The competition between vesicles that encapsulate RNA and those incapable of doing so, considered as model protocells, and its relation to the evolutionary fitness of replicator functions, is considered at length in terms of the driving forces of thermodynamics. It is noted that membrane stabilization is a key objective in this competition but this results also in a reduction of permeability, thus diminishing the ability of the protocell to use nutrients. Further evolution of the membrane and its constituents is necessary to overcome this restriction in function. In this respect it is of interest that model protocell membranes composed of particular mixtures of amphiphiles have superior... 

Complexity Part 1—Developing a Functional Model for the Simplest Self-Replicator... 

Kemp s Acid Enzyme-Cleft and Self-Replication Models 347 5.2.1 Enzyme-Cleft Models with Convergent Functional Croups... 

A protease-specific model has also been reported in which a replication-defective adenovirus encoding an NS3 protease-SEAP fusion protein is injected into mouse tail veins, resulting in expression of the fusion protein in the liver [82, 83]. Protease activity can be detected both by measuring activity of liberated SEAP or by protease-induced liver damage. Protease activity was found to be reduced by administration of protease inhibitors. This model can be used to show that candidate inhibitors have adequate pharmacokinetic properties in mice to function in the intended target organ, but it is not a true disease model. 

Implicit in the functioning of the Watson-Crick DNA model is the idea that the strands of a DNA molecule must separate and new daughter strands must be synthesized in response to the sequence of bases in the mother strand. This is called semiconservative replication. Still, conservative replication, in which both strands of a daughter molecule are newly synthesized, could not be ruled out by consideration of the structure of DNA alone. 

For example, with the crystal structure of the aspartyl protease from human immundeficiency virus (HIV-1) in 1989 came the opportunity to design molecules to block this important enzyme that acts as a molecular scissors. HIV is the virus responsible for AIDS. Essential to viral replication, the HIV protease cuts long strands composed of many proteins into the functional proteins found in mature virus particles. This proteolysis occurs at the very end of the HIV replication cycle (Figure 7-1). The three-dimensional structural information derived from the x-ray crystal structure, combined with computer modeling techniques, allowed chemists to design potent, selective inhibitors of the protease enzyme (Figure... 

Laskey, R. A. and Madine, M. A. A rotary pumping model for helicase function of MCM proteins at a distance from replication forks. EMBO Rep 2003, 4, 26-30. 

The use of animals for pharmacological and toxicological studies has yielded invaluable information for drug development. However, many drug candidates failed in Phase I and II clinical trials because the animal models were insufficient to represent human systems and functions for some drugs. Efficacy and acceptable toxicities derived from animal models were not replicated in humans (Exhibit 5.8). In recent years, the direction in development of drugs has shifted toward the use of ex vivo, in vitro assays and even in silico methods. Nevertheless, some tests must stiU be confirmed in animals. 

In the text which follows we shall examine in numerical detail the decision levels and detection limits for the Fenval-erate calibration data set ( set-B ) provided by D. Kurtz (17). In order to calculate said detection limits it was necessary to assign and fit models both to the variance as a function of concentration and the response (i.e., calibration curve) as a function of concentration. No simple model (2, 3 parameter) was found that was consistent with the empirical calibration curve and the replication error, so several alternative simple functions were used to illustrate the approach for calibration curve detection limits. A more appropriate treatment would require a new design including real blanks and Fenvalerate standards spanning the region from zero to a few times the detection limit. Detailed calculations are given in the Appendix and summarized in Table V. 

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