A model-based optimization framework for the inference on gene regulatory networks from DNA array data

MOTIVATION: Identification of the regulatory structures in genetic networks and the formulation of mechanistic models in the form of wiring diagrams is one of the significant objectives of expression profiling using DNA microarray technologies and it requires the development and application of identification frameworks. RESULTS: We have developed a novel optimization framework for identifying regulation in a genetic network using the S-system modeling formalism. We show that balance equations on both mRNA and protein species led to a formulation suitable for analyzing DNA-microarray data whereby protein concentrations have been eliminated and only mRNA relative concentrations are retained. Using this formulation, we examined if it is possible to infer a set of possible genetic regulatory networks consistent with observed mRNA expression patterns. Two origins of changes in mRNA expression patterns were considered. One derives from changes in the biophysical properties of the system that alter the molecular-interaction kinetics and/or message stability. The second is due to gene knock-outs. We reduced the identification problem to an optimization problem (of the so-called mixed-integer non-linear programming class) and we developed an algorithmic procedure for solving this optimization problem. Using simulated data generated by our mathematical model, we show that our method can actually find the regulatory network from which the data were generated. We also show that the number of possible alternate genetic regulatory networks depends on the size of the dataset (i.e. number of experiments), but this dependence is different for each of the two types of problems considered, and that a unique solution requires fewer datasets than previously estimated in the literature. This is the first method that also allows the identification of every possible regulatory network that could explain the data, when the number of experiments does not allow identification of unique regulatory structure.     

Insights into the relation between mRNA and protein expression patterns: I. Theoretical considerations

Translation is a central cellular process in every organism and understanding translation from the systems (genome-wide) perspective is very important for medical and biochemical engineering applications. Moreover, recent advances in cell-wide monitoring tools for both mRNA and protein levels have necessitated the development of such a model to identify parameters and conditions that influence the mapping between mRNA and protein expression. Experimental studies show a lack of correspondence between mRNA and protein expression profiles. In this study, we describe a mechanistic genome-wide model for translation that provides mapping between changes in mRNA levels and changes in protein levels. We use our model to study the system in detail and identify the key parameters that affect this mapping. Our results show that the correlation between mRNA and protein levels is a function of both the kinetic parameters and concentration of ribosomes at the reference state. In particular, changes in concentration of free and total ribosomes in response to a perturbation; changes in initiation and elongation kinetics due to competition for aminoacyl tRNAs; changes in termination kinetics; average changes in mRNA levels in response to the perturbation; and changes in protein stability are all important determinants of the mapping between mRNA and protein expression.     

A memorial review of Jay Bailey's contribution in prokaryotic metabolic engineering

When mentioning prokaryotic metabolic engineering, most people will immediately think of Jay Bailey. Jay's contribution to this fast-growing field is evident and familiar to many. Therefore, instead of a detailed technical review, we attempt in this article to summarize his contribution and dissect reasons for his success in this area from a standpoint of one of his former students (VH) and of a colleague in the field (JCL). This short review is by no means complete and provides only a partial view of Jay's contribution to the metabolic engineering of prokaryotes.     

Muscle electrolyte measurements during and after hypokinesia in determining muscle electrolyte depletion during hypokinesia in the rat

Hypokinesia (diminished movement) induces muscle mineral depletion. However, the mechanism of muscle mineral depletion during hypokinesia (HK) remains unknown. Measuring electrolyte retention and electrolyte values in muscle, plasma, and urine during and after HK, the aim of this study was to discover if HK could depress mineral retention and lead to muscle mineral depletion. Studies were done on 204 13-wk-old male Wistar rats (370–390 g) during 10 d pre-HK period, 98 d HK period, and 15 d post-HK period. Rats were equally divided into two groups: vivarium control rats (VCR) and hypokinetic rats (HKR). All hypokinetic rats were kept for 98 d in small individual cages, which restricted their movements in all directions without hindering food and water intakes. All control rats were housed for 98 d in individual cages under vivarium control conditions. Both groups of rats were pair-fed. During the HK period skeletal muscle sodium (Na), potassium (K), magnesium (Mg), calcium (Ca), and water content and electrolyte retention decreased significantly (p < 0.05), while urinary and plasma electrolyte levels increased significantly (p < 0.05) in HKR compared with their pre-HK values and their respective VCR. During the initial days of the post-HK period, mineral retention increased significantly (p < 0.05), plasma and urinary electrolyte level decreased significantly (p < 0.05), while muscle electrolyte and water content remained significantly (p < 0.05) depressed in HKR compared with VCR. Muscle mineral and water content, electrolyte retention, plasma, and urinary electrolyte values did not change in VCR compared with their pre-HK values. It was concluded that during HK decreased muscle mineral content may suggest muscle mineral depletion, while increased urinary electrolyte loss and muscle mineral depletion may demonstrate reduced mineral retention. Reduced electrolyte excretion and depressed muscle mineral content during post-HK may indicate skeletal muscle mineral depletion during HK. Dissociation between electrolyte retention and muscle mineral depletion may demonstrate the presence of decreased electrolyte retention as the mechanism of muscle electrolyte depletion during prolonged HK.     

Comparative analysis of RNA regulatory elements of amino acid metabolism genes in Actinobacteria

Background  

Formation of alternative structures in mRNA in response to external stimuli, either direct or mediated by proteins or other RNAs, is a major mechanism of regulation of gene expression in bacteria. This mechanism has been studied in detail using experimental and computational approaches in proteobacteria and Firmicutes, but not in other groups of bacteria.     

Morphomechanics: goals, basic experiments and models

Morphomechanics is a branch of developmental biology, studying the generation, space-time patterns and morphogenetic role of mechanical stresses (MS) which reside in embryonic tissues. All the morphogenetically active embryonic tissues studied in this respect have been shown to bear substantial mechanical stresses of tension or pressure. MS are indispensable for organized cell movements, expression of a number of developmentally important genes and the very viability of cells. Even a temporary relaxation of MS leads to an increase in the morphological variability and asymmetry of embryonic rudiments. Moreover, MS may be among the decisive links of morphogenetic feedback required for driving forth embryonic development and providing its regular space-time patterns. We hypothesize that one such feedback is based upon the tendency of cells and tissues to hyperrestore (restore with an overshoot) their MS values after any deviations, either artificial or produced by neighboring morphogenetically active tissues. This idea is supported by a number of observations and experiments performed on the tissue and individual cell levels. We describe also the models demonstrating that a number of biologically realistic stationary shapes and propagating waves can be generated by varying the parameters of the hyperrestoration feedback loop. Morphomechanics is an important and rapidly developing branch of developmental and cell biology, being complementary to other approaches.     

Morphological characterization and molecular phylogeny of Portunoidea Rafinesque, 1815 (Crustacea Brachyura): Implications for understanding evolution of swimming capacity and revision of the family-level classification

Cheliped construction, in particular the teeth pattern on chelae fingers is considered as most important character suit (along with burrowing/swimming apparatus) for the diagnosis of Portunoidea. Heterochelic and heterodontic chelipeds with the molariform tooth in the larger chela and multi-lobed serial teeth are presumably ancestral and most common pattern for the group. New material (mostly species of Thalamitinae Paulson, 1875, Lupocyclus Adamd and White, 1848 and Portunus Weber, 1795 sensu lato) have been combined with the existing sequences from the GenBank to produce molecular phylogenetic reconstructions based on the histone H3 gene fragment and a multi-gene tree (for smaller set of species) based on partial sequences of H3, D1 region of 28S gene and mitochondrial COI gene. These reconstructions have not provided necessary support to the monophyly of Portunoidea sensu lato but indicated the presence of several monophyletic lineages, i.e. Portunidae sensu stricto, Polybiidae + Thiidae + Carcinidae + Pirimelidae, Benthochascon + Geryonidae (to lesser extent), and Ovalipes. Monophyly of the Portunidae sensu stricto is supported by both the H3 and multigene trees and morphological evidence. Swimming capacity probably evolves as a result of parallel evolution in at least three different lineages of portunoids. A new version of the family level classification of Portunoidea and a key to their families are provided with the following taxa: Geryonidae (Geryoninae + Benthochasconinae subfam. nov.), Ovalipidae fam. nov., Brusiniidae Štev?i?, 1991, Thiidae, Pirimelidae, Carcinidae McLeay, 1838 (Carcininae + Portumninae Ortmann, 1893), Polybiidae Ortmann, 1893, and Portunidae Rafinesque, 1815 sensu stricto. The most radical change in the systematics of Portunidae sensu stricto is the final recognition of the polyphyly of Portunus sensu lato and the need for revalidization and re-diagnozing of several taxa that were synonymized by Stephenson and Campbell (1959) and Stephenson (1972) under Portunus. While some subfamilies of the Portunidae (Podophthalminae Dana, 1851, Thalamitinae, and Lupocyclinae Alcock, 1895) are well supported by molecular phylogenies and the presence of morphological synapomorphies, the others need re-assessment.