Closed-loop learning control of bio-networks.

A general goal of systems biology is to acquire a detailed quantitative understanding of the life-sustaining interactions between genes and proteins. There arises an interesting question of whether these network dynamics can be controlled externally. In the open-loop approach to experimental biology, a control design would be chosen based on a desired target response and modeling with all the available knowledge about the system. If the system is not completely understood or disturbances occur, then unexpected deviations from the desired response can arise. A means to circumvent this difficulty is to optimize the controls in a closed-loop operation by modifying successive input controls based on the performance of previous controls. This paper presents a simulation of closed-loop learning control applied to biological systems in order to generate a desired response. The most powerful advantage of this technique is that the controls are deduced based on experimental results and the process can operate without a model for the underlying biochemical network. This feature eliminates the problem of faulty predictions as well as the need for a detailed understanding of the underlying molecular pathways, suggesting that biological systems can be controlled even before the post-systems biology era.     

Genetic Mapping of the Coding Regions for Three Heat-Shock Proteins in DROSOPHILA MELANOGASTER

We describe variants of three heat-shock proteins of Drosophila melanogaster and their use to map the chromosome regions that contain the coding sequences for these proteins. All three map to a region on chromosome 3L that includes only one heat-shock puff, designated as 67B. The results imply that the genes coding for at least three heat-shock proteins are included within the 67B region.     

Dyslexia revisited

Summary Specific developmental dyslexia, a condition characterized by reduced reading, spelling, and writing abilities combined with normal intellectual capacity, has challenged geneticists and environmentalists. Although most of the strikingly controversial results can be traced to differences concerning diagnostic decision-making, there are many hints of a genetic contribution. Twin studies and extensive pedigree analysis substantiate this view, but it is too early to infer a definite mode of inheritance from the available data.     

Mechanism of intraoral transport in macaques

All mammals have the same divisions of cyclic movement of tongue and hyoid during mastication: a protraction or forward phase that begins at minimum gape, and a retraction or return phase. Nonanthropoid mammals transport food from the oral cavity to the oropharynx during the return phase; food on the dorsal surface of the tongue moves distally while the tongue is retracted. Macaques, however, transport food during the protraction phase of tongue/hyoid movement. Food is squeezed posteriorly by contact between the tongue surface and the palate anterior to the food. This mechanism of transport is occasionally seen in nonanthropoid mammals when they are transporting liquids from the oral cavity to the oropharynx. It has, however, not been seen when these mammals transport solid food. One morphological basis for this difference is the reduction in height of the rugae of the palate of macaques. In most mammals these rugae are pronounced ridges that are able to hold food in place during protraction as the tongue slides forward beneath the food. Anthropoids and other mammals differ in the way they store food prior to swallowing. When macaques transport food to the oropharynx, usually they swallow in the next cycle, but always in the next 2 or 3 cycles. Most mammals transport and store food in the oropharynx for several cycles before a swallow clears that region of food. This behavior is correlated with differences in morphology of the oropharynx; anthropoids have reduced valleculae, the area in which other mammals store food prior to swallowing.     

Quiescent fibroblasts exhibit high metabolic activity

Many cells in mammals exist in the state of quiescence, which is characterized by reversible exit from the cell cycle. Quiescent cells are widely reported to exhibit reduced size, nucleotide synthesis, and metabolic activity. Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes. In contrast, we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition. By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data, we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells, with greater overflow flux from the pentose phosphate pathway back to glycolysis. Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts. By feeding the cells labeled glutamine, we also detected a "backwards" flux in the tricarboxylic acid cycle from α-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis. The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid, and in part toward excretion of extracellular matrix proteins. Thus, reduced metabolic activity is not a hallmark of the quiescent state. Quiescent fibroblasts, relieved of the biosynthetic requirements associated with generating progeny, direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole.     

Biological Effects of Incomplete Destratification of Hypertrophic Freshwater Reservoir

This paper describes results of partial destratification of a large reservoir with complex morphology. In order to reduce phytoplankton growth by light limitation, the upper 20 m of the water column were destratified in the Bleiloch Reservoir (Thuringia, Germany). Temperatures, phytoplankton, and zooplankton were investigated before and during aeration to determine the effects of the partial destratification on plankton. The measure induced an increase of phytoplankton dynamics. Since 1991 nuisance cyanobacteria blooms increased in the hypertrophic Bleiloch reservoir (Thuringia, Federal Republic of Germany), as light conditions improved due to a reduction of coloured wastewaters supplied by a cellulose mill. Warm inflowing water formed an upper layer, which reached the bubble plume near the dam, and was only weakly affected by the deeper mixed water body. The water column stability decreased, which caused an overturn 2–3 weeks earlier, because the hypolimnion warmed up faster. These physical effects of the destratification delayed the seasonal succession of phytoplankton. Cyanobacteria were suppressed but diatoms and chlorophytes became more abundant. Copepods maintained higher population densities throughout the summer. During artificial mixing, the algal diversity increased, not only because k-strategists selected a stratified water column, but also because episodic thermal instability enabled r- and k-strategists to co-exist in a competitive environment.     

Metabolomics‐driven quantitative analysis of ammonia assimilation in E. coli

Despite extensive study of individual enzymes and their organization into pathways, the means by which enzyme networks control metabolite concentrations and fluxes in cells remains incompletely understood. Here, we examine the integrated regulation of central nitrogen metabolism in Escherichia coli through metabolomics and ordinary‐differential‐equation‐based modeling. Metabolome changes triggered by modulating extracellular ammonium centered around two key intermediates in nitrogen assimilation, α‐ketoglutarate and glutamine. Many other compounds retained concentration homeostasis, indicating isolation of concentration changes within a subset of the metabolome closely linked to the nutrient perturbation. In contrast to the view that saturated enzymes are insensitive to substrate concentration, competition for the active sites of saturated enzymes was found to be a key determinant of enzyme fluxes. Combined with covalent modification reactions controlling glutamine synthetase activity, such active‐site competition was sufficient to explain and predict the complex dynamic response patterns of central nitrogen metabolites.     

Biclustering via optimal re-ordering of data matrices in systems biology: rigorous methods and comparative studies

Background  

The analysis of large-scale data sets via clustering techniques is utilized in a number of applications. Biclustering in particular has emerged as an important problem in the analysis of gene expression data since genes may only jointly respond over a subset of conditions. Biclustering algorithms also have important applications in sample classification where, for instance, tissue samples can be classified as cancerous or normal. Many of the methods for biclustering, and clustering algorithms in general, utilize simplified models or heuristic strategies for identifying the "best" grouping of elements according to some metric and cluster definition and thus result in suboptimal clusters.     

Descriptor-free molecular discovery in large libraries by adaptive substituent reordering

Molecular discovery often involves identification of the best functional groups (substituents) on a scaffold. When multiple substitution sites are present, the number of possible substituent combinations can be very large. This article introduces a strategy for efficiently optimizing the substituent combinations by iterative rounds of compound sampling, substituent reordering to produce the most regular property landscape, and property estimation over the landscape. Application of this approach to a large pharmaceutical compound library demonstrates its ability to find active compounds with a threefold reduction in synthetic and assaying effort, even without knowing the molecular identity of any compound.