Optimal blood glucose regulation of diabetic patients using single network adaptive critics

Diabetes is a long-term disease during which the body's production and use of insulin are impaired, causing glucose concentration level to increase in the bloodstream. Regulating blood glucose levels as close to normal as possible leads to a substantial decrease in long-term complications of diabetes. In this paper, an intelligent online feedback-treatment strategy is presented for the control of blood glucose levels in diabetic patients using single network adaptive critic (SNAC) neural networks (which is based on nonlinear optimal control theory). A recently developed mathematical model of the nonlinear dynamics of glucose and insulin interaction in the blood system has been revised and considered for synthesizing the neural network for feedback control. The idea is to replicate the function of pancreatic insulin, i.e. to have a fairly continuous measurement of blood glucose and a situation-dependent insulin injection to the body using an external device. Detailed studies are carried out to analyze the effectiveness of this adaptive critic-based feedback medication strategy. A comparison study with linear quadratic regulator (LQR) theory shows that the proposed nonlinear approach offers some important advantages such as quicker response, avoidance of hypoglycemia problems, etc. Robustness of the proposed approach is also demonstrated from a large number of simulations considering random initial conditions and parametric uncertainties. Copyright (C) 2009 John Wiley & Sons, Ltd.

Genetic regulation of flower development

Flower development provides a model system to study mechanisms that govern pattern formation in plants. Most flowers consist of four organ types that are present in a specific order from the periphery to the centre of the flower. Reviewed here are studies on flower development in two model species: Arabidopsis thaliana and Antirrhinum majus that focus on the molecular genetic analysis of homeotic mutations affecting pattern formation in the flower. Based on these studies a model was proposed that explains how three classes of regulatory genes can together control the development of the correct pattern of organs in the flower. The universality of the basic tenets of the model is apparent from the analysis of the homologues of the Arabidopsis genes from other plant species

The precision of regulation in Dictyostelium discoideum: implications for cell-type proportioning in the absence of spatial pattern

We have made careful counts of the exact number of spore, stalk and basal disc cells in small fruiting bodies of Dictyostelium discoideum (undifferentiated amoebae are found only rarely and on average their fraction is 4.96 x 10(-4)). (i) Within aggregates of a given size, the relative apportioning of amoebae to the main cell types occurs with a remarkable degree of precision. In most cases the coefficient of variation (c.v.) in the mean fraction of cells that form spores is within 4.86%. The contribution of stalk and basal disc cells is highly variable when considered separately (c.v.'s upto 25% and 100%, respectively), but markedly less so when considered together. Calculations based on theoretical models indicate that purely cell-autonomous specification of cell, fate cannot account for die observed accuracy of proportioning. Cell-autonomous determination to a prestalk or prespore condition followed by cell type interconversion, and stabilised by feedbacks, suffices to explain the measured accuracy. (ii) The fraction of amoebae that differentiates into spores increases monotonically with the total number of cells. This fraction rises from an average of 73.6% for total cell numbers below 30 and reaches 86.0% for cell numbers between 170 and 200 (it remains steady thereafter at around 86%). Correspondingly, the fraction of amoebae differentiating into stalk or basal disc decreases viith total size. These trends are in accordance with evolutionary expectations and imply that a mechanism for sensing the overall size of the aggregate also plays an essential role in the determination of cell-type proportions.

In vitro and in vivo regulation of assimilatory nitrite reductase from Candida utilis

The nitrate assimilation pathway in Candida utilis, as in other assimilatory organisms, is mediated by two enzymes: nitrate reductase and nitrite reductase. Purified nitrite reductase has been shown to be a heterodimer consisting of 58- and 66-kDa subunits. In the present study, nitrite reductase was found to be capable of utilising both NADH and NADPH as electron donors. FAD, which is an essential coenzyme, stabilised the enzyme during the purification process. The enzyme was modified by cysteine modifiers, and the inactivation could be reversed by thiol reagents. One cysteine was demonstrated to be essential for the enzymatic activity. In vitro, the enzyme was inactivated by ammonium salts, the end product of the path way, proving that the enzyme is assimilatory in function. In vivo, the enzyme was induced by nitrate and repressed by ammonium ions. During induction and repression, the levels of nitrite reductase mRNA, protein, and enzyme activity were modulated together, which indicated that the primary level of regulation of this enzyme was at the transcriptional level. When the enzyme was incubated with ammonium salts in vitro or when the enzyme was assayed in cells grown with the same salts as the source of nitrogen, the residual enzymatic activities were similar. Thus, a study of the in vitro inactivation can give a clue to understanding the mechanism of in vivo regulation of nitrite reductase in Candida utilis.

Regulation of progesterone biosynthesis in the human placenta by estradiol 17 beta and progesterone

Ex vivo addition of estradiol 17 beta to first trimester or term human placental minces caused a significant increase in the quantity of progesterone produced. Addition of an aromatase inhibitor, CGS 16949 A or the estrogen receptor antagonist, ICI 182780, significantly inhibited progesterone production confirming the role of estradiol 17 beta in the regulation of progesterone synthesis in human placenta. RU 486 and ZK 98299, which are antagonists of progesterone receptor, significantly modulated progesterone synthesis in the human placenta but exhibited paradoxical effects on the first trimester and term placenta We conclude that progesterone synthesis in the human placenta is regulated by estradiol 17 beta and progesterone. This is the first report providing evidence for autoregulation of progesterone synthesis in the human placenta.

Regulation of an 8-kDa peptide involved in testosterone production by luteinizing hormone in rat Leydig cells

Results of Western blot analysis carried out with an interstitial cell extract from male guinea pig and ovarian extract from immature female rats administered equine chorionic gonadotropin (eCG) provide supportive evidence to our earlier suggestion that an 8-kDa peptide is involved in acquisition of steroidogenic capacity by the rat Leydig cells. It was found that though the signal was observed in other tissues such as liver, kidney and lung which do not produce gonadal hormones, the peptide was modulated only by lutenizing hormone (LH) in the rat Leydig cells.

Conformational basis for substrate recognition and regulation of catalytic activity in Staphylococcus aureus nucleoside di-phosphate kinase

Nucleoside diphosphate kinases (NDK) are characterized by high catalytic turnover rates and diverse substrate specificity. These features make this enzyme an effective activator of a pro-drug an application that has been actively pursued for a variety of therapeutic strategies. The catalytic mechanism of this enzyme is governed by a conserved histidine that coordinates a magnesium ion at the active site. Despite substantial structural and biochemical information on NDK, the mechanistic feature of the phospho-transfer that leads to auto-phosphorylation remains unclear. While the role of the histidine residue is well documented, the other active site residues, in particular the conserved serine remains poorly characterized. Studies on some homologues suggest no role for the serine residue at the active site, while others suggest a crucial role for this serine in the regulation and quaternary association of this enzyme in some species. Here we report the biochemical features of the Staphylococcus aureus NDK and the mutant enzymes. We also describe the crystal structures of the apo-NDK, as a transition state mimic with vanadate and in complex with different nucleotide substrates. These structures formed the basis for molecular dynamics simulations to understand the broad substrate specificity of this enzyme and the role of active site residues in the phospho-transfer mechanism and oligomerization. Put together, these data suggest that concerted changes in the conformation of specific residues facilitate the stabilization of nucleotide complexes thereby enabling the steps involved in the ping-pong reaction mechanism without large changes to the overall structure of this enzyme. (C) 2011 Elsevier B.V. All rights reserved.

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-beta (TGF-beta)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Dendritic cells (DCs) as sentinels of the immune system are important for eliciting both primary and secondary immune responses to a plethora of microbial pathogens. Cooperative stimulation of a complex set of pattern-recognition receptors, including TLR2 and nucleotide-binding oligomerization domain (NOD)-like receptors on DCs, acts as a rate-limiting factor in determining the initiation and mounting of the robust immune response. It underscores the need for ``decoding'' these multiple receptor interactions. In this study, we demonstrate that TLR2 and NOD receptors cooperatively regulate functional maturation of human DCs. Intriguingly, synergistic stimulation of TLR2 and NOD receptors renders enhanced refractoriness to TGF-beta- or CTLA-4-mediated impairment of human DC maturation. Signaling perturbation data suggest that NOTCH1-PI3K signaling dynamics assume critical importance in TLR2- and NOD receptor-mediated surmounting of CTLA-4- and TGF-beta -suppressed maturation of human DCs. Interestingly, the NOTCH1-PI3K signaling axis holds the capacity to regulate DC functions by virtue of PKC delta-MAPK-dependent activation of NF-kappa B. This study provides mechanistic and functional insights into TLR2-and NOD receptor-mediated regulation of DC functions and unravels NOTCH1-PI3K as a signaling cohort for TLR2 and NOD receptors. These findings serve in building a conceptual foundation for the design of improved strategies for adjuvants and immunotherapies against infectious diseases.

A System-C based Micro architectural Exploration Framework for Latency, Power and Performance Trade-offs of On-Chip Interconnection

We describe a System-C based framework we are developing, to explore the impact of various architectural and microarchitectural level parameters of the on-chip interconnection network elements on its power and performance. The framework enables one to choose from a variety of architectural options like topology, routing policy, etc., as well as allows experimentation with various microarchitectural options for the individual links like length, wire width, pitch, pipelining, supply voltage and frequency. The framework also supports a flexible traffic generation and communication model. We provide preliminary results of using this framework to study the power, latency and throughput of a 4x4 multi-core processing array using mesh, torus and folded torus, for two different communication patterns of dense and sparse linear algebra. The traffic consists of both Request-Response messages (mimicing cache accesses)and One-Way messages. We find that the average latency can be reduced by increasing the pipeline depth, as it enables higher link frequencies. We also find that there exists an optimum degree of pipelining which minimizes energy-delay product.

NETGEM: Network Embedded Temporal GEnerative Model for gene expression data

Background: Temporal analysis of gene expression data has been limited to identifying genes whose expression varies with time and/or correlation between genes that have similar temporal profiles. Often, the methods do not consider the underlying network constraints that connect the genes. It is becoming increasingly evident that interactions change substantially with time. Thus far, there is no systematic method to relate the temporal changes in gene expression to the dynamics of interactions between them. Information on interaction dynamics would open up possibilities for discovering new mechanisms of regulation by providing valuable insight into identifying time-sensitive interactions as well as permit studies on the effect of a genetic perturbation. Results: We present NETGEM, a tractable model rooted in Markov dynamics, for analyzing the dynamics of the interactions between proteins based on the dynamics of the expression changes of the genes that encode them. The model treats the interaction strengths as random variables which are modulated by suitable priors. This approach is necessitated by the extremely small sample size of the datasets, relative to the number of interactions. The model is amenable to a linear time algorithm for efficient inference. Using temporal gene expression data, NETGEM was successful in identifying (i) temporal interactions and determining their strength, (ii) functional categories of the actively interacting partners and (iii) dynamics of interactions in perturbed networks. Conclusions: NETGEM represents an optimal trade-off between model complexity and data requirement. It was able to deduce actively interacting genes and functional categories from temporal gene expression data. It permits inference by incorporating the information available in perturbed networks. Given that the inputs to NETGEM are only the network and the temporal variation of the nodes, this algorithm promises to have widespread applications, beyond biological systems. The source code for NETGEM is available from https://github.com/vjethava/NETGEM

The beta-Glucoside (bgl) Operon of Escherichia coli Is Involved in the Regulation of oppA, Encoding an Oligopeptide Transporter

We report that the bgl operon of Escherichia coli, encoding the functions necessary for the uptake and metabolism of aryl-beta-glucosides, is involved in the regulation of oligopeptide transport during stationary phase. Global analysis of intracellular proteins from Bgl-positive (Bgl(+)) and Bgl-negative (Bgl(-)) strains revealed that the operon exerts regulation on at least 12 downstream target genes. Of these, oppA, which encodes an oligopeptide transporter, was confirmed to be upregulated in the Bgl(+) strain. Loss of oppA function results in a partial loss of the growth advantage in stationary-phase (GASP) phenotype of Bgl(+) cells. The regulatory effect of the bgl operon on oppA expression is indirect and is mediated via gcvA, the activator of the glycine cleavage system, and gcvB, which regulates oppA at the posttranscriptional level. We show that BglG destabilizes the gcvA mRNA in vivo, leading to reduced expression of gcvA in the stationary phase. Deletion of gcvA results in the downregulation of gcvB and upregulation of oppA and can partially rescue the loss of the GASP phenotype seen in Delta bglG strains. A possible mechanism by which oppA confers a competitive advantage to Bgl(+) cells relative to Bgl(-) cells is discussed.