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PubMed2005

A hybrid approach for efficient and robust parameter estimation in biochemical pathways.

Developing suitable dynamic models of biochemical pathways is a key issue in Systems Biology. Predictive models for cells or whole organisms could ultimately lead to model-based predictive and/or preventive medicine. Parameter estimation (i.e. model calibration) in these dynamic models is therefore a critical problem. In a recent contribution [Moles, C.G., Mendes, P., Banga, J.R., 2003b. Parameter estimation in biochemical pathways: a comparison of global optimisation methods. Genome Res. 13, 2467-2474], the challenging nature of such inverse problems was highlighted considering a benchmark problem, and concluding that only a certain type of stochastic global optimisation method, Evolution Strategies (ES), was able to solve it successfully, although at a rather large computational cost. In this new contribution, we present a new integrated optimisation methodology with a number of very significant improvements: (i) computation time is reduced by one order of magnitude by means of a hybrid method which increases efficiency while guaranteeing robustness, (ii) measurement noise (errors) and partial observations are handled adequately, (iii) automatic testing of identifiability of the model (both local and practical) is included and (iv) the information content of the experiments is evaluated via the Fisher information matrix, with subsequent application to design of new optimal experiments through dynamic optimisation.

Algorithms↗

PubMed2006

Robustness and regularity of oscillations in neuronal populations.

We study a biologically plausible but computationally simplified integrate-and-fire neuronal model. Oscillatory activity is analyzed in the networks with and without self-connections. We perform a detailed scan of four major parameters that represent the properties of neurons and synapses: connection ratio, connection strengths, post-synaptic potential decay rate and soma's potential decay rate. It is observed that networks with different properties exhibit different periods and different patterns of synchrony. We find that generally these oscillations are robust against changes of parameters, meanwhile we also locate the parametric boundaries where oscillations break down.

Electrophysiology↗

PubMed2006

A bio-inspired visual collision detection mechanism for cars: combining insect inspired neurons to create a robust system.

The lobula giant movement detector (LGMD) of locusts is a visual interneuron that responds with an increasing spike frequency to an object approaching on a direct collision course. Recent studies involving the use of LGMD models to detect car collisions showed that it could detect collisions, but the neuron produced collision alerts to non-colliding, translating, stimuli in many cases. This study presents a modified model to address these problems. It shows how the neurons pre-synaptic to the LGMD show a remarkable ability to filter images, and only colliding and translating stimuli produce excitation in the neuron. It then integrates the LGMD network with models based on the elementary movement detector (EMD) neurons from the fly visual system, which are used to analyse directional excitation patterns in the biologically filtered images. Combining the information from the LGMD neuron and four directionally sensitive neurons produces a robust collision detection system for a wide range of automotive test situations.

Accidents, Traffic↗

PubMed2006

Protein folding and the robustness of cells.

The intricate intracellular infrastructure of all known life forms is based on proteins. The folded shape of a protein determines both the protein's function and the set of molecules it will bind to. This tight coupling between a protein's function and its interconnections in the molecular interaction network has consequences for the molecular course of evolution. It is also counter to human engineering approaches. Here we report on a simulation study investigating the impact of random errors in an abstract metabolic network of 500 enzymes. Tight coupling between function and interconnectivity of nodes is compared to the case where these two properties are independent. Our results show that the model system under consideration is more robust if function and interconnection are intertwined. These findings are discussed in the context of nanosystems engineering.

Cells↗

PubMed2026

Robust error-minimization in the genetic code across physicochemical metrics and variant codes: A graph-theoretic analysis in GF(2)6.

The standard genetic code reduces the impact of point mutations, but the robustness of this property across physicochemical metrics, naturally occurring variant codes, and codon-reassignment mechanisms remains incompletely quantified. Embedding the 64 codons in GF(2)6 represents the hypercube Q6 as a coordinate-dependent subgraph of the encoding-independent single-nucleotide mutation graph H(3,4), and enables continuous ρ-interpolation between the two. Under a quartet-pattern shuffle null (n=10,000), the standard code is significantly low-cost across four established, code-independent physicochemical distance metrics with partially overlapping content (Grant ham p=0.0062; Miyata p<0.001; Woese polar requirement p=0.003; Kyte-Doolittle hydropathy p=0.001), and the signal strengthens monotonically as ρ moves Q6→H(3,4). A structure-aware sensitivity analysis under the alignment-derived ProtSub matrix (Jia & Jernigan 2021) yields the most extreme percentile of any measure tested (p=0.0004; all five p-values pass Bonferroni at α=0.05). Across the 27 NCBI translation tables, near-optimality is preserved: 11 of 12 informative-distance variants retain top-5% placement after BH-FDR correction. Natural codon reassignments avoid disrupting codon-family connectivity: under the encoding-independent H(3,4) adjacency, observed events are topology-breaking at relative risk 0.32 versus the candidate landscape (permutation p≤10-4). The H(3,4) result is stable by construction; the Q6 decomposition is representation-specific and fails to show depletion under 8 of 24 base-to-bit encodings, so we report H(3,4) as the primary test and Q6 as a sensitivity. Event-level conditional-logit modelling shows that topology avoidance and local physicochemical cost provide complementary, only weakly correlated signal (rs=0.15), and that topology adds explanatory value beyond physicochemistry under both Q6 and encoding-independent H(3,4) adjacency. Retrospective reanalysis of nine genome-recoding datasets is consistent with codon-family topology operating as an evolutionary-trajectory constraint distinct from acute engineering fitness. The contribution is the second axis: code evolution is jointly constrained by physicochemical smoothness and codon-family topological integrity, and these two constraints are partly independent.

Codon reassignment↗

PubMed2006

A fast and robust 19F NMR-based method for finding new HIV-1 protease inhibitors.

The human immunodeficiency virus (HIV) which encodes, among other indispensable enzymes, an aspartic protease that is essential for viral maturation and replication. Numerous inhibitors of the protease have been developed. However, the eventual resistance of HIV-1 to these drugs implies a continuous battle to develop new inhibitors. Proposed herein is a robust, fast, and reliable method employing (19)F NMR for the evaluation of the inhibitory activity of new compounds against HIV-1 protease.

Binding Sites↗

PubMed2005

On the robustness of complex heterogeneous gene expression networks.

We analyze a continuous gene expression model on the underlying topology of a complex heterogeneous network. Numerical simulations aimed at studying the chaotic and periodic dynamics of the model are performed. The results clearly indicate that there is a region in which the dynamical and structural complexity of the system avoid chaotic attractors. However, contrary to what has been reported for Random Boolean Networks, the chaotic phase cannot be completely suppressed, which has important bearings on network robustness and gene expression modeling.

Computer Simulation↗

PubMed2004

Nicotine-mediated plasticity in robust nucleus of the archistriatum of the adult zebra finch.

Activation of neuronal nicotinic acetylcholine receptors (nAChRs) modulates the induction of long-term potentiation (LTP), a possible cellular mechanism for learning. This study was undertaken to determine the effects of activation of nAChRs by nicotine on long-term plasticity in the songbird zebra finch, which is a valuable model to study synaptic plasticity and its implications to behavioral learning. Electrophysiological recordings in the robust nucleus of the archistriatum (RA) in adult zebra finch brain slices reveal that tetanic stimulation alone does not produce LTP. However, LTP is induced by such stimulation in the presence of nicotine. The nicotine-mediated LTP is blocked by dihydro-beta-erythroidine (DHbetaE, 1 microM), an antagonist having a greater effect against nAChRs containing the alpha 4 subunit. In the presence of methyllcaconitine (MLA, 10 nM), an antagonist of nAChRs containing the alpha 7 subunit, a long-term depression (LTD) is unmasked, implicating a bi-directional type of plasticity in the zebra finch RA, which is modulated by differential activation of nAChR subtypes. Intracellular recordings from single neurons show a depression of the afterhyperpolarization (AHP) and an increase in frequency of evoked and spontaneous action potentials in the presence of nicotine. These results suggest that nicotinic cholinergic mechanisms may play a critical role in synaptic plasticity in the zebra finch song system and thereby influence song learning and plasticity.

Acetylcholine↗

PubMed2006

Inhibitory synaptic transmission in area postrema neurons of the rat showing robust presynaptic facilitation mediated by nicotinic ACh receptors.

Inhibitory synaptic transmission and its modulation in neurons of the area postrema (AP), one of autonomic nuclei in the medulla, were studied using whole-cell patch-electrodes applied to slices from rats on postnatal days 10-24. When glycine (100 microM) or GABA (10 microM) was applied to AP neurons from a "Y tube", large outward currents that showed reversal potential of - 67 mV (approximate Cl- equilibrium potential estimated) were induced. At a holding potential of - 10 mV, application of high K+ to the AP neurons evoked massive inhibitory postsynaptic currents (IPSCs) in the neurons. Most of the evoked synaptic currents were blocked by bicuculline, while the remaining currents were sensitive to strychnine, indicating that the major inhibitory transmission in the area postrema was GABAergic. When nicotine (5-100 microM) was applied to AP neurons, robust IPSCs having GABAergic identity were evoked. Even in the presence of tetrodotoxin, nicotine could induce GABAergic IPSCs, most of which, however, disappeared in the presence of 5 mM Mg2+. Presynaptic facilitation was also induced by other nicotinic agonists, including cytisine, 1,1-dimethyl-4-phenyl-piperazinium iodide, ACh and choline. The nicotine-induced presynaptic facilitation was inhibited by mecamylamine and slightly inhibited by dihydro-beta-erythroidine or alpha-Bungarotoxin. These results indicate that nicotinic receptors are expressed at GABAergic presynaptic terminals in the area postrema and induce Ca2+ influx to trigger vesicular release. The major nicotinic receptors involved are thought to be heteromeric subtypes such as alpha3beta4 receptors, which may regulate inhibitory transmission potently responding to endogenous or exogenous nicotinic agents appeared in this area.

Animals↗

PubMed2005

Minimum evolution using ordinary least-squares is less robust than neighbor-joining.

The method of minimum evolution reconstructs a phylogenetic tree T for n taxa given dissimilarity data d. In principle, for every tree W with these n leaves an estimate for the total length of W is made, and T is selected as the W that yields the minimum total length. Suppose that the ordinary least-squares formula S(W)(d) is used to estimate the total length of W. A theorem of Rzhetsky and Nei shows that when d is positively additive on a completely resolved tree T, then for all W not =T it will be true that S(W)(d)>S(T)(d). The same will be true if d is merely sufficiently close to an additive dissimilarity function. This paper proves that as n grows large, even if the shortest branch length in the true tree T remains constant and d is additive on T, then the difference S(W)(d) - S(T)(d) can go to zero. It is also proved that, as n grows large, there is a tree T with n leaves, an additive distance function d(T) on T with shortest edge epsilon, a distance function d, and a tree W with the same n leaves such that d differs from d(T) by only approximately epsilon/4, yet minimum evolution incorrectly selects the tree W over the tree T. This result contrasts with the method of neighbor-joining, for which Atteson showed that incorrect selection of W required a deviation at least epsilon/2. It follows that, for large n, minimum evolution with ordinary least-squares can be only half as robust as neighbor-joining.

Biological Evolution↗

PubMed2006

A robust small-molecule microarray platform for screening cell lysates.

Herein we report the expanded functional group compatibility of small-molecule microarrays to include immobilization of primary alcohols, secondary alcohols, phenols, carboxylic acids, hydroxamic acids, thiols, and amines on a single slide surface. Small-molecule "diversity microarrays" containing nearly 10,000 known bioactive small molecules, natural products, and small molecules originating from several diversity-oriented syntheses were produced by using an isocyanate-mediated covalent capture strategy. Selected printed bioactive compounds were detected with antibodies against compounds of interest. The new surface of the diversity microarrays is highly compatible with approaches involving cellular lysates. This feature has enabled a robust, optimized screening methodology using cellular lysates, allowing the detection of specific interactions with a broad range of binding affinity by using epitope-tagged or chimeric fluorescent proteins without prior purification. We believe that this expanded research capability has considerable promise in biology and medicine.

Cell Line↗

PubMed2003

Robust isocratic liquid chromatographic separation of functional poly(methyl methacrylate).

The separation of telechelic poly(methyl methacrylate) (PMMA) prepolymers based on the number of end-groups under critical liquid chromatography (LC) conditions has been studied using a bare-silica column, which can interact with polar functional groups. The critical solvent compositions for non-functional, mono-functional and bi-functional PMMAs were determined in normal-phase LC using mixtures of acetonitrile and dichloromethane (DCM) of varying composition as the mobile phase. The telechelic prepolymers were successfully separated according to hydroxyl (OH) functionality (with zero, one, or two OH groups, respectively) under the critical conditions, in which fast (5 min), base-line separations were obtained independent of molecular weight. Changing the column temperature, flow rate, and mobile-phase composition within a certain range did not affect the functionality separation. Therefore this isocratic LC separation method is quite robust. Evaporative light-scattering detector (ELSD) calibration curves were used for the quantitative analysis of functional PMMA prepolymers.

Calibration↗

PubMed2004

Fast and robust simultaneous determination of three veterinary antibiotics in groundwater and surface water using a tandem solid-phase extraction with high-performance liquid chromatography-UV detection.

A simple and robust analytical method is presented in which the three veterinary antibiotics oxytetracycline (OTC), sulfachloropyridazine (SCP) and tylosin (TYL) were simultaneously determined in surface water and groundwater. The three compounds were simultaneously extracted from the water samples using a mixture of methanol, EDTA and McIlvaine buffer (citric acid and sodium orthophosphate) and then cleaned-up and pre-concentrated by solid-phase extraction using sacrificial Isolute strong anion-exchange cartridges, to remove interfering organic material, and Waters Oasis hydrophilic-liphophilic balance polymer cartridges, to retain the compounds, in tandem. Analysis was performed using liquid chromatography with ultraviolet detection. Recoveries for river water samples spiked at 10 and 1 microgl(-1) were respectively 99.6+/-4.6 and 99.4+/-8.4% for OTC; 99.9+/-2.2 and 105.0+/-5.7% for SCP; and 94.9+/-2.4 and 71.6+/-8.2% for TYL. Overall limits of detection based on pre-concentrating 400 ml of sample were 0.35 microgl(-1) for OTC and TYL and 0.25 microgl(-1) for SCP.

Anti-Bacterial Agents↗

PubMed2005

Novel, highly robust method of carbohydrate pre-purification by two-dimensional liquid chromatography prior to liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry.

We describe a novel two-dimensional liquid chromatography (2D-LC) method for fast and robust isolation and concentration of low abundant carbohydrates (sorbitol, glycerol) from biological matrices (plasma and urine). Off-line pre-purified fractions, enriched by analyte of interest, were analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS-MS). Initial 2D-LC automated sample pre-purification improved MS detection, eliminated matrix effects, and achieved high sensitivity (picogram detection limit) with a 6 min runtime and increased column lifetime. Using this method we have analyzed more than 1300 samples from biological matrices without column replacement.

Carbohydrates↗

PubMed2005

Highly selective solid-phase extraction and large volume injection for the robust gas chromatography-mass spectrometric analysis of TCA and TBA in wines.

A reliable solid-phase extraction (SPE) method for the simultaneous determination of 2,4,6-trichloroanisole (TCA) and 2,4,6-tribromoanisole (TBA) in wines has been developed. In the proposed procedure 50 mL of wine are extracted in a 1 mL cartridge filled with 50 mg of LiChrolut EN resins. Most wine volatiles are washed up with 12.5 mL of a water:methanol solution (70%, v/v) containing 1% of NaHCO3. Analytes are further eluted with 0.6 mL of dichloromethane. A 40 microL aliquot of this extract is directly injected into a PTV injector operated in the solvent split mode, and analysed by gas chromatography (GC)-ion trap mass spectrometry using the selected ion storage mode. The solid-phase extraction, including sample volume and rinsing and elution solvents, and the large volume GC injection have been carefully evaluated and optimized. The resulting method is precise (RSD (%) < 6% at 100 ng L(-1)), sensitive (LOD were 0.2 and 0.4 ng/L for TCA and TBA, respectively), robust (the absolute recoveries of both analytes are higher than 80% and consistent wine to wine) and friendly to the GC-MS system (the extract is clean, simple and free from non-volatiles).

Anisoles↗

PubMed2006

Development of a robust method for the quantitative determination of disaccharides in honey by gas chromatography.

An iterative method for the GC quantitative determination of TMS-oxime disaccharides in honey has been developed. This approach takes into account possible positive systematic errors caused by unidentified compounds which overlap with the expected disaccharides. The results of its application to the determination of 15 disaccharides in simulated honey samples indicate that the iterative method is more robust that methods based on least-squares regression, improves the accuracy of the quantitative analysis and allows to detect the possible presence of disaccharides not identified.

Chromatography, Gas↗

PubMed2006

Robust segmentation and analysis of DNA microarray spots using an adaptative split and merge algorithm.

Microarray images push to their limits classical analysis methods, since gene spots are often poorly contrasted, ill defined and of irregular shapes. These characteristics hinder a robust quantification of corresponding values for red and green intensities as well as their R/G ratio. New approaches are thus needed to ensure accurate data extraction from these images. Herein we present an automatic non-supervised algorithm for a fast and accurate spot data extraction from DNA microarrays. The method is based on a split and merge algorithm, relying on a Delaunay triangulation process, allowing an incremental partition of the image into homogeneous polygons. Geometric properties of triangles as well as homogeneity criteria are defined according to the specificities of microarray image signals. The method is first assessed on simulated data, and then compared with GenePix and Jaguar Softwares. Results in segmentation and quantification are superior to those obtained from a number of standard techniques for spot extraction.

Algorithms↗

PubMed2006

Robust regression for high throughput drug screening.

Effective analysis of high throughput screening (HTS) data requires automation of dose-response curve fitting for large numbers of datasets. Datasets with outliers are not handled well by standard non-linear least squares methods, and manual outlier removal after visual inspection is tedious and potentially biased. We propose robust non-linear regression via M-estimation as a statistical technique for automated implementation. The approach of finding M-estimates by Iteratively Reweighted Least Squares (IRLS) and the resulting optimization problem are described. Initial parameter estimates for iterative methods are important, so self-starting methods for our model are presented. We outline the software implementation, done in Matlab and deployed as an Excel application via the Matlab Excel Builder Toolkit. Results of M-estimation are compared with least squares estimates before and after manual editing.

Algorithms↗