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PubMed1999

Evolution and development of a central pattern generator for the swimming of a lamprey.

This article describes the design of neural control architectures for locomotion using an evolutionary approach. Inspired by the central pattern generators found in animals, we develop neural controllers that can produce the patterns of oscillations necessary for the swimming of a simulated lamprey. This work is inspired by Ekeberg's neuronal and mechanical model of a lamprey [11] and follows experiments in which swimming controllers were evolved using a simple encoding scheme [25, 26]. Here, controllers are developed using an evolutionary algorithm based on the SGOCE encoding [31, 32] in which a genetic programming approach is used to evolve developmental programs that encode the growing of a dynamical neural network. The developmental programs determine how neurons located on a two-dimensional substrate produce new cells through cellular division and how they form efferent or afferent interconnections. Swimming controllers are generated when the growing networks eventually create connections to the muscles located on both sides of the rectangular substrate. These muscles are part of a two-dimensional mechanical simulation of the body of the lamprey in interaction with water. The motivation of this article is to develop a method for the design of control mechanisms for animal-like locomotion. Such a locomotion is characterized by a large number of actuators, a rhythmic activity, and the fact that efficient motion is only obtained when the actuators are well coordinated. The task of the control mechanism is therefore to transform commands concerning the speed and direction of motion into the signals sent to the multiple actuators. We define a fitness function, based on several simulations of the controller with different commands settings, that rewards the capacity of modulating the speed and the direction of swimming in response to simple, varying input signals. Central pattern generators are thus evolved capable of producing the relatively complex patterns of oscillations necessary for swimming. The best solutions generate traveling waves of neural activity, and propagate, similarly to the swimming of a real lamprey, undulations of the body from head to tail propelling the lamprey forward through water. By simply varying the amplitude of two input signals, the speed and the direction of swimming can be modulated.

Algorithms↗
PubMed2003

A functional genomic analysis of cell morphology using RNA interference.

BACKGROUND: The diversity of metazoan cell shapes is influenced by the dynamic cytoskeletal network. With the advent of RNA-interference (RNAi) technology, it is now possible to screen systematically for genes controlling specific cell-biological processes, including those required to generate distinct morphologies. RESULTS: We adapted existing RNAi technology in Drosophila cell culture for use in high-throughput screens to enable a comprehensive genetic dissection of cell morphogenesis. To identify genes responsible for the characteristic shape of two morphologically distinct cell lines, we performed RNAi screens in each line with a set of double-stranded RNAs (dsRNAs) targeting 994 predicted cell shape regulators. Using automated fluorescence microscopy to visualize actin filaments, microtubules and DNA, we detected morphological phenotypes for 160 genes, one-third of which have not been previously characterized in vivo. Genes with similar phenotypes corresponded to known components of pathways controlling cytoskeletal organization and cell shape, leading us to propose similar functions for previously uncharacterized genes. Furthermore, we were able to uncover genes acting within a specific pathway using a co-RNAi screen to identify dsRNA suppressors of a cell shape change induced by Pten dsRNA. CONCLUSIONS: Using RNAi, we identified genes that influence cytoskeletal organization and morphology in two distinct cell types. Some genes exhibited similar RNAi phenotypes in both cell types, while others appeared to have cell-type-specific functions, in part reflecting the different mechanisms used to generate a round or a flat cell morphology.

Animals↗
PubMed2006

Kdo2-Lipid A of Escherichia coli, a defined endotoxin that activates macrophages via TLR-4.

The LIPID MAPS Consortium (www.lipidmaps.org) is developing comprehensive procedures for identifying all lipids of the macrophage, following activation by endotoxin. The goal is to quantify temporal and spatial changes in lipids that occur with cellular metabolism and to develop bioinformatic approaches that establish dynamic lipid networks. To achieve these aims, an endotoxin of the highest possible analytical specification is crucial. We now report a large-scale preparation of 3-deoxy-D-manno-octulosonic acid (Kdo)(2)-Lipid A, a nearly homogeneous Re lipopolysaccharide (LPS) sub-structure with endotoxin activity equal to LPS. Kdo(2)-Lipid A was extracted from 2 kg cell paste of a heptose-deficient Escherichia coli mutant. It was purified by chromatography on silica, DEAE-cellulose, and C18 reverse-phase resin. Structure and purity were evaluated by electrospray ionization/mass spectrometry, liquid chromatography/mass spectrometry and (1)H-NMR. Its bioactivity was compared with LPS in RAW 264.7 cells and bone marrow macrophages from wild-type and toll-like receptor 4 (TLR-4)-deficient mice. Cytokine and eicosanoid production, in conjunction with gene expression profiling, were employed as readouts. Kdo(2)-Lipid A is comparable to LPS by these criteria. Its activity is reduced by >10(3) in cells from TLR-4-deficient mice. The purity of Kdo(2)-Lipid A should facilitate structural analysis of complexes with receptors like TLR-4/MD2.

Animals↗
PubMed1998

Patients with Cushing's disease secrete adrenocorticotropin and cortisol jointly more asynchronously than healthy subjects.

We examined serum concentration time-series for ACTH and cortisol in 20 patients with pituitary-dependent ACTH excess (Cushing's disease) and in 29 age- and gender-matched controls. For each subject, blood samples were obtained at 10-min intervals for 24 h. Joint ACTH-cortisol synchrony was quantified using the recently introduced cross-approximate entropy (cross-ApEn) statistic. In patients, cross-ApEn was greater than in controls (1.686 +/- 0.051 vs. 1.077 +/- 0.039, P = 3.45 x 10(-16), giving a sensitivity of 85%. In control subjects, but not in patients, cross-ApEn was correlated positively with age (r = 0.465, P = 0.011) There was no gender difference in cross-ApEn, nor a relationship between cross-ApEn and the 24-h ACTH and cortisol secretion, in patients or controls. In contrast, the maximal cross-correlation coefficient for the ACTH and cortisol series after detrending the series was 0.394 +/- 0.033 in controls and 0.297 +/- 0.034 in patients with considerable overlap of the subgroups, giving a sensitivity for this index of only 5%. In addition to previous findings of increased individual irregularity of ACTH and cortisol release in Cushing's disease, we can now also demonstrate greater joint asynchrony of the circulating concentrations of these hormones. Thus, Cushing's disease disrupts ensemble network secretory dynamics over individual hormone output. We conclude that, like GH-secreting pituitary and aldosterone-secreting adrenal tumors, ACTH-secreting pituitary tumors exhibit significant loss of orderly hormone release patterns. Moreover, Cushing's disease is marked further by deterioriation of bihormonal synchrony between ACTH and cortisol release, thus suggesting further erosion of within-axis feedback control.

Adolescent↗
PubMed2005

Cooperative requirement of the Gli proteins in neurogenesis.

The Gli proteins are critical components of multiple processes in development, homeostasis and disease, including neurogenesis and tumorigenesis. However, it is unclear how the Gli code, the sum of their combinatorial positive and negative functions, dictates cell fate and behavior. Using an antisense approach to knockdown gene function in vivo, we find that each of the three Gli proteins is required for the induction of all primary neurons in the amphibian neural plate and regulates the bHLH/Notch neurogenic cascade. Analyses of endogenous Gli function in Gli-mediated neurogenesis and tumorigenesis, and in animal cap assays, reveal specific requirements that are context specific. Nuclear colocalization and binding studies suggest the formation of complexes, with the first two zinc fingers of the Gli five zinc-finger domain acting as a protein-protein interaction site. The Gli proteins therefore appear to form a dynamic physical network that underlies cooperative function, greatly extending the combinatorial possibilities of the Gli code, which may be further fine-tuned in cell fate specification by co-factor function.

Animals↗
PubMed2002

Active ammonia excretion across the gills of the green shore crab Carcinus maenas: participation of Na(+)/K(+)-ATPase, V-type H(+)-ATPase and functional microtubules.

Although aquatic animals are generally believed to export nitrogenous waste by diffusion of NH(3) or NH(4)(+) across external epithelia, evidence for active ammonia excretion has been found in a number of species. In the euryhaline green shore crab Carcinus maenas, active excretion of ammonia across isolated gills is reduced by inhibitors of the Na(+)/K(+)-ATPase and vacuolar-type H(+)-ATPase. In addition, a functional dynamic microtubule network is necessary, since application of colchicine, taxol or thiabendazole leads to almost complete blockage of active and gradient-driven ammonia excretion. Actin filaments seem not to play a role in the excretory process. The NH(4)(+)-dependent short-circuit current and the conductance of the isolated cuticle were reduced in a dose-dependent manner by amiloride, a non-specific inhibitor of the Na(+)/H(+) exchanger and Na(+) channels. Combined with an analysis of gill morphology, the strong intracellular but weak apical abundance of V-type H(+)-ATPase and the fact that ammonia flux rates are equal under buffered and unbuffered experimental conditions, our observations suggest a hypothetical model of transepithelial ammonia movement that features active uptake across the basolateral membrane, sequestration in acidified vesicles, vesicle transport via microtubules and exocytosis at the apical membrane.

Amino Acid Sequence↗
PubMed1998

Nuclear matrix proteins and osteoblast gene expression.

The molecular mechanisms that couple osteoblast structure and gene expression are emerging from recent studies on the bone extracellular matrix, integrins, the cytoskeleton, and the nucleoskeleton (nuclear matrix). These proteins form a dynamic structural network, the tissue matrix, that physically links the genes with the substructure of the cell and its substrate. The molecular analog of cell structure is the geometry of the promoter. The degree of supercoiling and bending of promoter DNA can regulate transcriptional activity. Nuclear matrix proteins may render a change in cytoskeletal organization into a bend or twist in the promoter of target genes. We review the role of nuclear matrix proteins in the regulation of gene expression with special emphasis on osseous tissue. Nuclear matrix proteins bind to the osteocalcin and type I collagen promoters in osteoblasts. One such protein is Cbfa1, a recently described transcriptional activator of osteoblast differentiation. Although their mechanisms of action are unknown, some nuclear matrix proteins may act as "architectural" transcription factors, regulating gene expression by bending the promoter and altering the interactions between other trans-acting proteins. The osteoblast nuclear matrix is comprised of cell- and phenotype-specific proteins including proteins common to all cells. Nuclear matrix proteins specific to the osteoblast developmental stage and proteins that distinguish osteosarcoma from the osteoblast have been identified. Recent studies indicating that nuclear matrix proteins mediate bone cell response to parathyroid hormone and vitamin D are discussed.

Antigens, Nuclear↗
PubMed2006

A master relation defines the nonlinear viscoelasticity of single fibroblasts.

Cell mechanical functions such as locomotion, contraction, and division are controlled by the cytoskeleton, a dynamic biopolymer network whose mechanical properties remain poorly understood. We perform single-cell uniaxial stretching experiments on 3T3 fibroblasts. By superimposing small amplitude oscillations on a mechanically prestressed cell, we find a transition from linear viscoelastic behavior to power law stress stiffening. Data from different cells over several stress decades can be uniquely scaled to obtain a master relation between the viscoelastic moduli and the average force. Remarkably, this relation holds independently of deformation history, adhesion biochemistry, and intensity of active contraction. In particular, it is irrelevant whether force is actively generated by the cell or externally imposed by stretching. We propose that the master relation reflects the mechanical behavior of the force-bearing actin cytoskeleton, in agreement with stress stiffening known from semiflexible filament networks.

3T3 Cells↗
PubMed2006

Dynamical analysis of the regulatory network defining the dorsal-ventral boundary of the Drosophila wing imaginal disc.

The larval development of the Drosophila melanogaster wings is organized by the protein Wingless, which is secreted by cells adjacent to the dorsal-ventral (DV) boundary. Two signaling processes acting between the second and early third instars and between the mid- and late third instar control the expression of Wingless in these boundary cells. Here, we integrate both signaling processes into a logical multivalued model encompassing four cells, i.e., a boundary and a flanking cell at each side of the boundary. Computer simulations of this model enable a qualitative reproduction of the main wild-type and mutant phenotypes described in the experimental literature. During the first signaling process, Notch becomes activated by the first signaling process in an Apterous-dependent manner. In silico perturbation experiments show that this early activation of Notch is unstable in the absence of Apterous. However, during the second signaling process, the Notch pattern becomes consolidated, and thus independent of Apterous, through activation of the paracrine positive feedback circuit of Wingless. Consequently, we propose that appropriate delays for Apterous inactivation and Wingless induction by Notch are crucial to maintain the wild-type expression at the dorsal-ventral boundary. Finally, another mutant simulation shows that cut expression might be shifted to late larval stages because of a potential interference with the early signaling process.

Animals↗
PubMed2002

Statistical methods for analysis of time course gene expression data.

Since many biological systems or regulatory networks are dynamic systems, gene expression levels measured over different time points during a given biological process can often provide more insights about the underlying system. These gene expression data measured over time are often called the time-course gene expression data. One unique feature of such data is the time dependency of the gene expression levels for a given gene at different times or between two different genes. Statistical analysis needs to account for such dependency in order to make valid inferences. This paper presents several statistical methods for analyzing such time-course gene expression data, including the time-lagged correlation coefficient for analyzing the relationship between genes, a mixed-effects model with splines for clustering genes and for estimating missing gene expression data, and a new method for aligning gene expression profiles obtained under two experimental conditions and for identifying gene clusters that show significant changes between two experimental conditions. We used the yeast cell cycle gene expression data sets to illustrate these methods and obtained the biologically meaningful conclusions from these analyses.

Cell Cycle Proteins↗
PubMed2002

Decreased neuronal synchronization during experimental seizures.

Synchronization between CA1 pyramidal neurons was studied using dual-cell patch-clamp techniques simultaneous with an extracellular measurement of network activity. We explored various linear and nonlinear methods to detect weak synchronization in this network, using cross-correlation, mutual information in one and two dimensions, and phase correlation in both broad and narrow band. The linear and nonlinear methods demonstrated different patterns of sensitivity to detect synchrony in this network, depending on the dynamical state of the network. Bursts in 4-amino-pyridine (4AP) were highly synchronous events. Unexpectedly, seizure-like events in 4AP were desynchronous events, both in comparison with interictal periods preceding the seizure without bursts (cut Schaffer collateral tract) and in comparison with bursts preceding the seizures (intact Schaffer collateral tract). The finding that seizure-like events are associated with desynchronization in such networks is consistent with recent theoretical work, suggesting that asynchrony is necessary to maintain a high level of activity in neuronal networks for sustained periods of time and that synchrony may disrupt such activity.

4-Aminopyridine↗
PubMedDate not supplied

The use of decision support systems in health facility allocation problems.

Employing Kitchener's Freeport Hospital as a case study, the author introduces decision support systems as possible aids for allocating public health care facilities. The study found that the Dynamic Interactive Network Analysis System (DINAS) was useful in determining Kitchener as the most suitable location for Freeport, based upon a comparison of need throughout Ontario.

Catchment Area, Health↗
PubMed2001

Sequestration of aggregated LDL by macrophages studied with freeze-etch electron microscopy.

The detailed morphology of macrophages involved in the uptake and intracellular processing of low density lipoprotein (LDL) and, ultimately, formation of macrophage-derived foam cells of atherosclerotic lesions has long fascinated investigators. This study examined localization of LDL in subcellular compartments of macrophage-derived intimal foam cells in cardiac valves isolated from rabbits by diet-induced hypercholesterolemia and, as an in vitro model of formation of foam cells, in cultured human monocyte-macrophages incubated for 2;-120 h with aggregated LDL produced by vortexing or phospholipase C lipolysis. The quasi-three-dimensional morphology of macrophages involved in endocytosis was preserved by ultrarapid freezing and freeze-etch microscopy in conjunction with thin-section electron microscopy. This approach produced unique images of subcellular compartments in human monocyte-macrophages involved in the uptake and processing of aggregated LDL with a clarity not previously reported. Three-dimensional ultrastructural analyses revealed a complex network of coated and uncoated vesicles, surface-connected saclike compartments, and endosomal/lysosomal compartments including the labyrinth of vesicular/tubular lysosomes all enmeshed in the microtubular, microfilament cytoskeletal network. These dynamic views of subcellular structures at the high resolution of the electron microscope provide an additional framework to better understand how lipoprotein particles are transported into, and processed within, macrophages during foam cell formation in atherogenesis.

Animals↗
PubMed2003

[Correlation between transcriptional activity of vascular endothelial growth factor (VEFG) and transcriptional activity of its receptors (FLT-1 and FLK-1) in low-grade squamous intraepithelial lesions (LSIL) of uterine cervix].

OBJECTIVES: In this report we focus on angiogenesis, as one component of a complex molecular relations in the process of neovascularisation in the low-grade intraepithelial changes (LSIL). Increasing number of publications indicates that the interrelation between isoforms of VEGF (VEGF121, VEGF145, VEGF165, VEGF183, VEGF189, VEGF206) but not total VEGF is responsible for angiogenesis, both in physiological and pathological processes. The molecular co-operation of the said isoforms and their receptors results in morphological presentation of "de novo" created vascular network that dynamically involves the entire connective tissue stroma of the uterine cervix. METHOD: The selection of intraepithelial pathology 38 cases to assess molecular activity of the given genes was based on colposcopy examination. Tissue specimens were taken for pathological investigation and to analyse transcriptional activity and mRNA alternative splicing of the angiogenesis genes. VEGF, Flt-1, Flk-1. To analyse quantitative gene expression RT-PCR TaqMan was performed. To estimate the dependence transcriptional activity of Flt-1 and Flk-1 on VEGF gene expression Spearman's correlation rank was performed. Differences with p < 0.05 were considered significant. RESULTS: The comparison of transcriptional activity of VEGF and its receptors revealed significant correlation between increase in the number of Flt-1 mRNA copies and enhanced mRNA expression of VEGF121 (p < 0.05), VEGF145 (p < 0.05), VEGF165 (p < 0.05), VEGF183 (p < 0.05), VEGF189 (p < 0.05), and VEGF206 (p < 0.05). Significant increase in the number of Flk-1 mRNA copies was observed in case of enhanced mRNA expression of VEGF121 (p < 0.05), VEGF145 (p < 0.05), VEGF183 (p < 0.05), VEGF189 (p < 0.05) and VEGF206 (p < 0.05). The number of sFlt-1 mRNA copies significantly correlated only with enhanced VEGF145 mRNA expression (p < 0.05). CONCLUSION: Changing intensification of transcriptional activity of VEGF gene and its receptors indicates on autocrine mechanism regulation of angiogenic genes activity in the first steep of carcinogenesis--LSIL.

Carcinoma, Squamous Cell↗
PubMed2003

The development of geriatric psychiatry services in Singapore.

Singapore is ageing rapidly and the need to develop a comprehensive range of psychiatric services for the elderly is urgent. To cater to the increase in the number of elderly with mental health problems, a multi-pronged, collaborative approach to developing services is necessary. Over the last decade, the development of such services has been initiated by the Department of Geriatric Psychiatry, Woodbridge Hospital and Institute of Mental Health, and effected through dynamic elderly networks consisting of health, social and voluntary organisations. This has facilitated the integration of psychogeriatric services within the overall framework of elderly services. With the establishment of the Integrated Framework of Healthcare of the Elderly by the Ministry of Health in 2000, the importance and effectiveness of building partnerships in service provision have been demonstrated. The challenge for the future is to attract and retain geriatric-trained healthcare professionals, enhance their training in the early diagnosis and management of psychiatric disorders in the elderly, improve the support of family caregivers and expand the range of quality psychogeriatric services.

Aged↗
PubMed1987

Integrating management and expertise in a computerised system for hypertensive patients.

An expert system has been integrated to the data management system of the ARTEMIS programme for hypertensive patients. The patient database, which has been used since 1975, contains the medical records of about 20,000 patients. Information is interactively entered by physicians, nurses and secretaries on video display units. The computerised medical record has replaced the traditional handwritten medical record. The database management system is used to produce different summary reports (inpatient and outpatient care) and personalized recall letters which are mailed to the patients before their appointments. Suggestions provided by the expert system include additional information to be obtained (complementary patient interrogation, biological or radiological investigations, etc.), possible causes of hypertension, and medical prescriptions. The information base allows the description of both static knowledge (in the form of a semantic network) and dynamic knowledge (in the form of production rules). The inference system sequentially uses a combination of forward and backward chaining and performs both exact and approximate reasoning. The diagnostic performance of the expert system was evaluated in 100 cases of hypertension (50 of essential hypertension and 50 of secondary hypertension. Concordance between the diagnosis proposed by the expert system and the one proposed by the specialist was achieved in 92% of secondary hypertension cases and 88% of essential hypertension cases. It is suggested that the integration of data and knowledge management might enhance the overall acceptance by medical staff of a computerised system, and facilitate the validation of a knowledge base.

Database Management Systems↗
PubMed1983

Unresponsiveness in hapten-specific cytotoxic T lymphocytes. IV. Functional deletion of T cell subsets required for trinitrophenyl (TNP)-specific cytotoxic T cell generation after acute or chronic treatment with trinitrobenzene sulfonic acid (TNBS).

The generation of cytotoxic T cell responses requires the interaction of a network of immunocompetent cells. Within this network, a dynamic balance of positive and negative immunoregulatory cells and their products modulate the cytotoxic T cell response. We have developed protocols which shift the balance to favor negative immunoregulation and thus result in antigen-specific unresponsiveness. In this report, a variety of approaches have been utilized to examine the effects of acute and chronic tolerance protocols on specific T cell subsets, namely amplifier helper T cells and precursor cytotoxic T cells. The results to be detailed show differential effects on these T cell subsets which are related to the tolerance protocol employed and the strains of mice tested.

Animals↗
PubMed1994

A hybrid knowledge based system for therapy adjustment in gestational diabetes.

This poster describes a system to analyze self-monitoring data of gestational diabetic patients, for obtaining an assessment of their metabolic control with the final goal of supporting decision-making in therapy adjustment. The system is able to manage incomplete data and to make temporal reasoning under uncertainty, the two most important constraints when analyzing ambulatory monitoring data. Two different formalism have been used to represent and manage the knowledge: a dynamic Bayesian network and a production system based on rules. The outcomes provided by the whole system are: information on possible patient transgressions of the prescribed treatment and recommendations of treatment adjustments.

Artificial Intelligence↗