Mechanistic Explanations and Models in Molecular Systems Biology

Mechanistic models in molecular systems biology are generally mathematical models of the action of networks of biochemical reactions, involving metabolism, signal transduction, and/or gene expression. They can be either simulated numerically or analyzed analytically. Systems biology integrates quantitative molecular data acquisition with mathematical models to design new experiments, discriminate between alternative mechanisms and explain the molecular basis of cellular properties. At the heart of this approach are mechanistic models of molecular networks. We focus on the articulation and development of mechanistic models, identifying five constraints which guide the articulation of models in molecular systems biology. These constraints are not independent of one another, with the result that modeling becomes an iterative process. We illustrate the use of these constraints in the modeling of the mechanism for bistability in the lac operon.     

An experiment to evaluate methods for estimating fossil fuel resources

Estimates of petroleum and natural gas resources vary substantially, both over time and across estimation methods. This paper develops a simulation model of global oil resources to evaluate different resource estimation techniques. Protocols for the Hubbert life cycle and USGS geological analogy methods are developed and applied to synthetic data generated by the model. It is shown that the Hubbert method can generate an accurate estimate as early as twenty years before the peak of global production, but the geological analogy approach overestimates the true resource base over the life cycle of the resource. The results show the applicability of simulation and the synthetic data approach to the problem of evaluating forecasting methods.     

Examination of the potential mutagenicity of hair dye constituents using the micronucleus test

Summary 12 compounds which are constitutents of hair dyes or chemically related aromatic amines, aminophenols, their nitroderivatives and aromatic hydroxyderivatives were examined for evidence of mutagenic potential by means of the micronucleus test. None of the compounds tested caused an increase in the incidence of micronucleated erythrocytes after oral dosing.Acknowledgment. These investigations were conducted on behalf and with the assistance of Elida-Gibbs GmbH, Hamburg, Goldwell GmbH, Darmstadt, Thera-Chemie GmbH, Dusseldorf, L'Oreal-Haarkosm, und Parf. GmbH, Karlsruhe, Kadus-Werk K.G., Lenzkirch, Hans Schwarzkopf GmbH, Hamburg, Wella AG, Darmstadt.     

A soluble CD4 protein selectively inhibits HIV replication and syncytium formation

The CD4 (T4) molecule is expressed on a subset of T lymphocytes involved in class II MHC recognition, and is probably the physiological receptor for one or more monomorphic regions of class II MHC (refs 1-3). CD4 also functions as a receptor for the human immunodeficiency virus (HIV) exterior envelope glycoprotein (gp120) (refs 4-9), being essential for virus entry into the host cell and for membrane fusion, which contributes to cell-to-cell transmission of the virus and to its cytopathic effects. We have used a baculovirus expression system to generate mg quantities of a hydrophilic extracellular segment of CD4. Concentrations of soluble CD4 in the nanomolar range, like certain anti-CD4 monoclonal antibodies, inhibit syncytium formation and HIV infection by binding gp120-expressing cells. Perhaps more importantly, class II specific T-cell interactions are uninhibited by soluble CD4 protein, whereas they are virtually abrogated by equivalent amounts of anti-T4 antibody. This may reflect substantial differences in CD4 affinity for gp120 and class II MHC.     

A topographically forced asymmetry in the martian circulation and climate

Large seasonal and hemispheric asymmetries in the martian climate system are generally ascribed to variations in solar heating associated with orbital eccentricity. As the orbital elements slowly change (over a period of >104 years), characteristics of the climate such as dustiness and the vigour of atmospheric circulation are thought to vary, as should asymmetries in the climate (for example, the deposition of water ice at the northern versus the southern pole). Such orbitally driven climate change might be responsible for the observed layering in Mars' polar deposits by modulating deposition of dust and water ice. Most current theories assume that climate asymmetries completely reverse as the angular distance between equinox and perihelion changes by 180 degrees. Here we describe a major climate mechanism that will not precess in this way. We show that Mars' global north-south elevation difference forces a dominant southern summer Hadley circulation that is independent of perihelion timing. The Hadley circulation, a tropical overturning cell responsible for trade winds, largely controls interhemispheric transport of water and the bulk dustiness of the atmosphere. The topography therefore imprints a strong handedness on climate, with water ice and the active formation of polar layered deposits more likely in the north.     

Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture

The various cell types in a multicellular animal differentiate on a predictable schedule but the mechanisms responsible for timing cell differentiation are largely unknown. We have studied a population of bipotential glial (O-2A) progenitor cells in the developing rat optic nerve that gives rise to oligodendrocytes beginning at birth and to type-2 astrocytes beginning in the second postnatal week. Whereas, in vivo, these O-2A progenitor cells proliferate and give rise to postimitotic oligodendrocytes over several weeks, in serum-free (or low-serum) culture they stop dividing prematurely and differentiate into oligodendrocytes within two or three days. The normal timing of oligodendrocyte development can be restored if embryonic optic-nerve cells are cultured in medium conditioned by type-1 astrocytes, the first glial cells to differentiate in the nerve: in this case the progenitor cells continue to proliferate, the first oligodendrocytes appear on the equivalent of the day of birth, and new oligodendrocytes continue to develop over several weeks, just as in vivo. Here we show that platelet-derived growth factor (PDGF) can replace type-1-astrocyte-conditioned medium in restoring the normal timing of oligodendrocyte differentiation in vitro and that anti-PDGF antibodies inhibit this property of the appropriately conditioned medium. We also show that PDGF is present in the developing optic nerve. These findings suggest that type-1-astrocyte-derived PDGF drives the clock that times oligodendrocyte development.