Oscillations and waves of cytosolic calcium: insights from theoretical models.

Oscillations in cytosolic Ca2+ occur in a wide variety of cells, either spontaneously or as a result of external stimulation. This process is often accompanied by intracellular Ca2+ waves. A number of theoretical models have been proposed to account for the periodic generation and spatial propagation of Ca2+ signals. These models are reviewed and their predictions compared with experimental observations. Models for Ca2+ oscillations can be distinguished according to whether or not they rely on the concomitant, periodic variation in inositol 1,4,5-trisphosphate. Such a variation, however, is not required in models based on Ca(2+)-induced Ca2+ release. When Ca2+ diffusion is incorporated into these models, propagating waves of cytosolic Ca2+ arise, with profiles and rates comparable to those seen in the experiments.     

On the octagonal structure of the nuclear pore complex: insights from coarse-grained models

The basic structure of the nuclear pore complex (NPC), conserved across almost all organisms from yeast to humans, persists in featuring an octagonal symmetry involving the nucleoporins that constitute the NPC ring. In this article, we seek to understand and evaluate the potential biomechanical reasons for this eightfold symmetry. Our analytical investigation shows that the eightfold symmetry maximizes the bending stiffness of each of the eight NPC spokes while our computational analyses identify the most likely deformation modes, frequencies, and associated kinetic energies of the NPC. These modes have energies close to other published findings using membrane analysis of the nuclear membrane pore opening, and deformation states in agreement with experimental observations. A better understanding of NPC mechanics is essential for characterizing the nucleocytoplasmic transport, which has a central importance in cell biology.     

Experimental models of Parkinson's disease: insights from many models.

Toxin-induced and genetic experimental models have been invaluable in investigating idiopathic Parkinson's disease (PD). The neurotoxins--reserpine, 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and methamphetamine--have been used to develop parkinsonian models in a wide variety of species. Both 6-OHDA and MPTP can replicate the neurochemical, morphologic, and behavioral changes seen in human disease. The unilateral 6-OHDA rat model is an excellent model for testing and determining modes of action of new pharmacologic compounds. The nonhuman primate MPTP-induced parkinsonian model has behavioral features that best approximate idiopathic PD. These induced and genetic models have been used to study the pathophysiology of the degenerating nigrostriatal system and to evaluate novel therapeutic strategies. Important differences within these models provide insights into various aspects of the dopaminergic phenotype and its role as a target in disease. These models provide an avenue to evaluate many anti-parkinsonian compounds, such as levodopa, which was first evaluated in an animal model and is the gold standard of parkinsonian treatment today.     

Glycosphingolipid functions: insights from engineered mouse models

Glycosphingolipids are remarkable for their structural complexity and their distinctive patterns that mark different tissues and stages of development. The physiological functions of glycosphingolipids are likely to be profound and are only beginning to emerge. Much of this new information is due to the study of mutant mice lacking specific sets of glycosphingolipids, the topic of this review.     

Excitation dynamics: insights from simplified membrane models

Excitable nerve membranes and models for their electrical activity exhibit a broad repertoire of dynamic behavior. To reveal these behaviors the theoretician seeks a model that is simple enough to analyze yet one that retains adequate biophysical realism. Here we strike such a balance by describing a two-variable simplification of the Hodgkin-Huxley (HH) model, which exhibits many membrane phenomena and reproduces, with good agreement, many HH responses. Comparisons and illustrations are presented for the single spike response, repetitive firing (and its cessation by a brief current pulse), and bistable behavior for increased extracellular K+ concentrations.     

Iron homeostasis: insights from genetics and animal models

Disorders that perturb iron balance are among the most prevalent human diseases, but until recently iron transport remained poorly understood. Over the past five years, genetic studies of patients with inherited iron homeostasis disorders and the analysis of mutant mice, rats and zebrafish have helped to identify several important iron-transport proteins. With information being mined from the genomes of four species, the study of iron metabolism has benefited enormously from positional-cloning efforts. Complementing the genomic strategy, targeted mutagenesis in mice has produced new models of human iron diseases. The animal models described in this review offer valuable tools for investigating iron homeostasis in vivo.     

PKB/AKT: functional insights from genetic models

Since its discovery 10 years ago, the potential functions of protein kinase B (PKB)/AKT have been catalogued with increasing efficiency. The physiological relevance of some of the proposed mechanisms by which PKB/AKT mediates many of its effects has been questioned, and recent work using new reagents and approaches has revealed some cracks in our understanding of this important molecule, and also hinted that these effects may involve other players.     

Protein folding cooperativity: basic insights from minimalist models

Basic concepts about two-state, cooperative protein folding and its relation to first-order phase transitions are reviewed. Minimalist models capable of reproducing the required free energy barrier between folded and unfolded macroscopic states are described. A significantly more restrictive "calorimetric" criterion is also discussed, which is based on direct comparison between model and experimental heat capacities with additional assumptions about conformational enthalpy variation in the unfolded state.     

Mammary gland neoplasia: insights from transgenic mouse models

Current theories of breast cancer progression have been greatly influenced by the development and refinement of mouse transgenic and gene targeting technologies. Early transgenic mouse models confirmed the involvement of oncogenes, previously implicated in human breast cancer, by establishing a causal relationship between overexpression or activation of these genes and mammary tumorigenesis. More recently, the importance of genes located at sites of loss of heterozygosity in human breast cancer have been examined in mice by their targeted disruption via homologous recombination. The union of these two approaches allows the generation of complex animal models that more accurately reflect the multistep nature of human breast cancer. This review will examine how the study of transgenic mice has increased our understanding of the molecular events responsible for oncogenic transformation of the mammary gland. BioEssays 22:554-563, 2000.     

Understanding fragile X syndrome: insights from animal models

The fragile X mental retardation syndrome is caused by large methylated expansions of a CGG repeat in the FMR1 gene leading to the loss of expression of FMRP, an RNA-binding protein. FMRP is proposed to act as a regulator of mRNA transport or translation that plays a role in synaptic maturation and function. To study the physiological function of the FMR1 protein, mouse and Drosophila models have been developed. The loss-of-function mouse model shows slightly enlarged testes, a subtle behavioral phenotype, and discrete anomalies of dendrite spines similar to those observed in brains of patients. Studies in Drosophila indicate that FXMR plays an important role in synaptogenesis and axonal arborization, which may underlie the observed deficits in flight ability and circadian behavior of FXR mutant flies. The relevance of these studies to our understanding of fragile X syndrome is discussed.     

Understanding autoimmune diabetes: insights from mouse models.

Type 1 or insulin-dependent diabetes is an autoimmune disease that causes the selective destruction of insulin-secreting beta cells in the pancreatic islets. Although this is a polygenic disease, with at least 20 genes implicated, the dominant susceptibility locus maps to the major histocompatibility complex (MHC), both in humans and in rodent models. However, in spite of progress on several fronts, the molecular pathology of autoimmune diabetes remains incompletely defined. Major areas of research include environmental trigger factors, the identification and role of beta-cell antigens in inducing and maintaining the autoimmune response, and the nature of the pathogenic and protective lymphocytes involved. In this review, we will focus on these areas to highlight recent advances in understanding the pathogenesis of autoimmune diabetes, drawing extensively on insights gained by studying the non-obese diabetic (NOD) mouse.     

Mechanisms of cigarette smoke-induced COPD: insights from animal models

Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.     

Sensory rhodopsin II: functional insights from structure

Atomic resolution structures of a sensory rhodopsin phototaxis receptor in haloarchaea (the first sensory member of the widespread microbial rhodopsin family) have yielded insights into the interaction face with its membrane-embedded transducer and into the mechanism of spectral tuning. Spectral differences between sensory rhodopsin and the light-driven proton pump bacteriorhodopsin depend largely upon the repositioning of a conserved arginine residue in the chromophore-binding pocket. Information derived from the structures, combined with biophysical and biochemical analysis, has established a model for receptor activation and signal relay, in which light-induced helix tilting in the receptor is transmitted to the transducer by lateral transmembrane helix-helix interactions.     

Zigzagging: theoretical insights on climbing strategies

Human and animal trails on steep hillsides often exhibit dramatic switchbacks and shortcuts. Helbing et al. have recently examined the emergence of human trail systems on flat terrains while Minetti and Margaria established the effect of gradients on human metabolic efficiency. In this paper we use these ideas to develop a semi-quantitative theoretical model of the behaviour of humans moving on a terrain with relief. The model determines the direction of movement by minimising metabolic cost per unit of distance in a desired direction. The structure of the theory resembles the Landau Theory of Phase Transitions, much used in theoretical physics. We find that both hairpin bends (switchbacks) and shortcuts appear as efficient strategies for downhill walkers, while uphill walkers retain switchbacks. For weakly inclined slopes, the best strategy involves walking directly uphill or downhill. For sufficiently steep slopes, however, we find that the best strategy should undergo a transition to a broken symmetry solution corresponding to the switchback trail patterns typical of rugged environments. The critical slope at which this transition takes place should be less steep for uphill and downhill walkers. The theory should be amenable to empirical investigation. Amongst other applications, this model will enable us to generalize the work of previous authors to real landscapes, eventually permitting the reconstruction of ancient patterns of movement in archaeological landscapes.     

Opinion: Building epithelial architecture: insights from three-dimensional culture models

How do individual cells organize into multicellular tissues? Here, we propose that the morphogenetic behaviour of epithelial cells is guided by two distinct elements: an intrinsic differentiation programme that drives formation of a lumen-enclosing monolayer, and a growth factor-induced, transient de-differentiation that allows this monolayer to be remodelled.