Motion detection, noise reduction, texture suppression, and contour enhancement by spatiotemporal Gabor filters with surround inhibition

We study the orientation and speed tuning properties of spatiotemporal three-dimensional (3D) Gabor and motion energy filters as models of time-dependent receptive fields of simple and complex cells in the primary visual cortex (V1). We augment the motion energy operator with surround suppression to model the inhibitory effect of stimuli outside the classical receptive field. We show that spatiotemporal integration and surround suppression lead to substantial noise reduction. We propose an effective and straightforward motion detection computation that uses the population code of a set of motion energy filters tuned to different velocities. We also show that surround inhibition leads to suppression of texture and thus improves the visibility of object contours and facilitates figure/ground segregation and the detection and recognition of objects.     

A computational model of visual marking using an inter-connected network of spiking neurons: the spiking search over time & space model (sSoTS).

In the real world, visual information is selected over time as well as space, when we prioritise new stimuli for attention. Watson and Humphreys [Watson, D., Humphreys, G.W., 1997. Visual marking: prioritizing selection for new objects by top-down attentional inhibition of old objects. Psychological Review 104, 90-122] presented evidence that new information in search tasks is prioritised by (amongst other processes) active ignoring of old items - a process they termed visual marking. In this paper we present, for the first time, an explicit computational model of visual marking using biologically plausible activation functions. The "spiking search over time and space" model (sSoTS) incorporates different synaptic components (NMDA, AMPA, GABA) and a frequency adaptation mechanism based on [Ca(2+)] sensitive K(+) current. This frequency adaptation current can act as a mechanism that suppresses the previously attended items. We show that, when coupled with a process of active inhibition applied to old items, frequency adaptation leads to old items being de-prioritised (and new items prioritised) across time in search. Furthermore, the time course of these processes mimics the time course of the preview effect in human search. The results indicate that the sSoTS model can provide a biologically plausible account of human search over time as well as space.     

Tyrosinase inhibition by isophthalic acid: kinetics and computational simulation

Using inhibition kinetics and computational simulation, we studied the reversible inhibition of tyrosinase by isophthalic acid (IPA). IPA inhibited tyrosinase in a complex manner with K(i)=17.8 ± 1.8mM. Measurements of intrinsic and ANS-binding fluorescence showed that IPA induced no changes in tertiary protein structure. For further insight, we predicted the 3D structure of tyrosinase and used a docking algorithm to simulate binding between tyrosinase and IPA. Simulation was successful (binding energies for Dock6.3: -25.19 kcal/mol and for AutoDock4.2: -4.28 kcal/mol), suggesting that IPA interacts with PRO175 or VAL190. This strategy of predicting tyrosinase inhibition based on hydroxyl group number and orientation may prove useful for the screening of potential tyrosinase inhibitors.     

A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910

Diarylquinolines (DARQs) are a new class of potent inhibitors of the ATPase of Mycobacterium tuberculosis. We have created a homology model of a binding site for this class of compounds located on the contact area of the a-subunit (gene atpB) and c-subunits (gene atpE) of Mycobacterium tuberculosis ATPase. The binding pocket that was identified from the analysis of the homology model is formed by 4 helices of three c-subunits and 2 helices of the a-subunit. The lead compound of the DARQ series, R207910, was docked into the pocket using a simulated annealing, multiple conformer, docking algorithm. Different stereoisomers were treated separately. The best docking pose for each stereoisomer was optimized by molecular dynamics simulation on the 5300 atoms of the binding region and ligand. The interaction energies in the computed complexes enable us to rank the different stereoisomers in order of interaction strength with the ATPase binding pockets. We propose that the activity of R207910 against Mycobacterium tuberculosis is based on interference of the compound with the escapement geometry of the proton transfer chain. Upon binding the compound mimics the conserved Arg-186 residue of the a-subunit and interacts in its place with the conserved acidic residue Glu-61 of the c-subunit. This mode of action is corroborated by the good agreement between the computed interaction energies and the observed pattern of stereo-specificity in the model of the binding region.     

Inhibition of mushroom tyrosinase by a newly synthesized ligand: inhibition kinetics and computational simulations

Alterations in the synthesis of melanin contribute to a number of diseases; therefore, the design of new tyrosinase inhibitors is very important. Mushroom tyrosinase (MT) is a metalloenzyme, which plays an important role in melanin biosynthesis. In this study, the inhibitory effect of a novel designed compound, i.e. 2-((1Z)-(2-(2,4-dinitrophenyl)hydrazin-1-ylidene)methyl)phenol, as a specific ligand which can bind to the copper ion of MT, has been assessed. The ligand was found to competitively inhibit both the cresolase and catecholase activities of MT, with small inhibition constants of 2.8 and 2.6?μM, respectively. Intrinsic fluorescence studies were performed to gain more information on the binding constants. Docking results indicated that the ligand binds to copper ions in the active site of MT via the OH group of the ligand. The ligand makes four hydrogen bonds with aspartic acid and one hydrogen bond with the histidine residue in the active site. Molecular dynamics results show that ligand binds to the MT via both electrostatic and hydrophobic interactions with its different parts.     

Hydrolysis of nerve agents by model nucleophiles: a computational study

Density functional theory calculations were employed to study the reaction of five nerve agents with model nucleophiles, including EtX(-) and EtXH (X=O, S, Se) for serine, cysteine and selenocysteine, respectively. Calculations at the B3LYP/6-311++G(2d,p) level of theory predict an exothermic reaction between ethoxide and all of the nerve agents studied. As compared to EtO(-) as a nucleophile, these reactions become approximately 30kcal/mol more endothermic for EtS(-), and by approximately 40kcal/mol for EtSe(-). The equivalent reactions with the neutral nucleophiles (EtXH) were more endothermic. The effect of solvation on the reaction thermochemistry was determined using a polarizable continuum model simulating the dielectric constant of chloroform. While there was a large exothermic shift for reactions involving charged nucleophiles with solvation modeling, the corresponding shift was minimal for the reaction with neutral nucleophiles.     

Inhibition of mushroom tyrosinase by a newly synthesized ligand: inhibition kinetics and computational simulations

Alterations in the synthesis of melanin contribute to a number of diseases; therefore, the design of new tyrosinase inhibitors is very important. Mushroom tyrosinase (MT) is a metalloenzyme, which plays an important role in melanin biosynthesis. In this study, the inhibitory effect of a novel designed compound, i.e. 2-((1Z)-(2-(2,4-dinitrophenyl)hydrazin-1-ylidene)methyl)phenol, as a specific ligand which can bind to the copper ion of MT, has been assessed. The ligand was found to competitively inhibit both the cresolase and catecholase activities of MT, with small inhibition constants of 2.8 and 2.6?μM, respectively. Intrinsic fluorescence studies were performed to gain more information on the binding constants. Docking results indicated that the ligand binds to copper ions in the active site of MT via the OH group of the ligand. The ligand makes four hydrogen bonds with aspartic acid and one hydrogen bond with the histidine residue in the active site. Molecular dynamics results show that ligand binds to the MT via both electrostatic and hydrophobic interactions with its different parts.     

Reactivation of model cholinesterases by oximes and intermediate phosphyloximes: a computational study

Phosphyloximes (POX) are generated upon the reactivation of organophosphorus (OP)-inhibited cholinesterases (ChEs) by pyridinium oximes. These POXs are known to be potent inhibitors of the ChEs following reactivation. However, they can also decompose to give an OP derivative and a cyano derivative of the oxime when a base abstracts the benzylic proton. Using density functional theory, thermodynamic properties were calculated for the reactivation and decomposition pathways of three different oximes (2-PAM, 3-PAM and 4-PAM) with six different OPs (cyclosarin, paraoxon, sarin, tabun, VR and VX). For reactivation purposes, 2-PAM is predicted to be more efficient than 3- and 4-PAM. Based on atomic charges and relative energies, 2-POXs were found to be more inclined towards the decomposition process.     

An integrated study of tyrosinase inhibition by rutin: progress using a computational simulation

Tyrosinase inhibition studies have recently gained the attention of researchers due to their potential application values. We simulated docking (binding energies for AutoDock Vina: -9.1 kcal/mol) and performed a molecular dynamics simulation to verify docking results between tyrosinase and rutin. The docking results suggest that rutin mostly interacts with histidine residues located in the active site. A 10 ns molecular dynamics simulation showed that one copper ion at the tyrosinase active site was responsible for the interaction with rutin. Kinetic analyses showed that rutin-mediated inactivation followed a first-order reaction and mono- and biphasic rate constants occurred with rutin. The inhibition was a typical competitive type with K(i) = 1.10±0.25 mM. Measurements of intrinsic and ANS-binding fluorescences showed that rutin showed a relatively strong binding affinity for tyrosinase and one possible binding site that could be a copper was detected accompanying with a hydrophobic exposure of tyrosinase. Cell viability testing with rutin in HaCaT keratinocytes showed that no toxic effects were produced. Taken together, rutin has the potential to be a potent anti-pigment agent. The strategy of predicting tyrosinase inhibition based on hydroxyl group number and computational simulation may prove useful for the screening of potential tyrosinase inhibitors.     

Energy and phase orientation mechanisms: a computational model

A computational model is proposed for spatial orientation processing beyond the initial stage of linear filtering in visual cortex. The model accounts for orientation pop-out, edge location and orientation, and bar location and orientation. It naturally extends to higher order orientation symmetries. The model is consistent with much of the current understanding of early processing in mammalian visual cortex. It builds on the notions of orientation and spatial frequency specific simple cells, any subsequent non-linearity, and orientation 'pooling'. The processing treats simple cell energy, real, and imaginary responses in a unified way to generate 'feature maps'. The 'pooling' operation in each case is a discrete Fourier transform of the simple cell responses over orientation. The suggested processing has implications for psychophysics (e.g. providing an explanation of why orientation discrimination thresholds are more than an order of magnitude less than simple cell orientation bandwidths), provides some understanding of the variety of 'complex-cell' properties found in visual cortex, and provides a plausible starting point for subsequent processing.     

A computational model to link psychophysics and cortical cell activation patterns in human texture processing

The human visual system uses texture information to automatically, or pre-attentively, segregate parts of the visual scene. We investigate the neural substrate underlying human texture processing using a computational model that consists of a hierarchy of bi-directionally linked model areas. The model builds upon two key hypotheses, namely that (i) texture segregation is based on boundary detection--rather than clustering of homogeneous items--and (ii) texture boundaries are detected mainly on the basis of a large scenic context that is analyzed by higher cortical areas within the ventral visual pathway, such as area V4. Here, we focus on the interpretation of key results from psychophysical studies on human texture segmentation. In psychophysical studies, texture patterns were varied along several feature dimensions to systematically characterize human performance. We use simulations to demonstrate that the activation patterns of our model directly correlate with the psychophysical results. This allows us to identify the putative neural mechanisms and cortical key areas which underlie human behavior. In particular, we investigate (i) the effects of varying texture density on target saliency, and the impact of (ii) element alignment and (iii) orientation noise on the detectability of a pop-out bar. As a result, we demonstrate that the dependency of target saliency on texture density is linked to a putative receptive field organization of orientation-selective neurons in V4. The effect of texture element alignment is related to grouping mechanisms in early visual areas. Finally, the modulation of cell activity by feedback activation from higher model areas, interacting with mechanisms of intra-areal center-surround competition, is shown to result in the specific suppression of noise-related cell activities and to improve the overall model capabilities in texture segmentation. In particular, feedback interaction is crucial to raise the model performance to the level of human observers.     

Generating oscillatory bursts from a network of regular spiking neurons without inhibition

Avian nucleus isthmi pars parvocellularis (Ipc) neurons are reciprocally connected with the layer 10 (L10) neurons in the optic tectum and respond with oscillatory bursts to visual stimulation. Our in vitro experiments show that both neuron types respond with regular spiking to somatic current injection and that the feedforward and feedback synaptic connections are excitatory, but of different strength and time course. To elucidate mechanisms of oscillatory bursting in this network of regularly spiking neurons, we investigated an experimentally constrained model of coupled leaky integrate-and-fire neurons with spike-rate adaptation. The model reproduces the observed Ipc oscillatory bursting in response to simulated visual stimulation. A scan through the model parameter volume reveals that Ipc oscillatory burst generation can be caused by strong and brief feedforward synaptic conductance changes. The mechanism is sensitive to the parameter values of spike-rate adaptation. In conclusion, we show that a network of regular-spiking neurons with feedforward excitation and spike-rate adaptation can generate oscillatory bursting in response to a constant input.     

Maturation of the immune response: a computational model

Experimental studies of the effect on antibody affinity of antigen dose and time after immunization show that average affinity increases progressively with time after immunization, and that this increase is greater at lower doses of antigen. In this paper we describe a polyclonal computer model of the immune system that yields all the essential phenomena of affinity maturation, including dose-dependency. Our main findings are (1) the dose-dependency relationship is not produced when typical assumptions regarding B-cell populations and binding reactions are employed, and (2) it is possible to reproduce this dependency by assuming two classes of lymphocytes: generalists and specialists. Generalists have a low threshold for response and produce antibody of low effectiveness, whereas specialists have a high threshold for response, and produce highly effective antibody. We make an analogy between the generalists and a pioneer species in ecological succession, and suggest how the generalists may contribute to a more effective defense against real infections.     

Binding and uptake of single and dual-opsonized targets by macrophages

Our current understanding of phagocytosis is largely derived from studies of individual receptor-ligand interactions and their downstream signaling pathways. Because phagocytes are exposed to a variety of ligands on heterogeneous target particles in vivo, it is important to observe the engagement of multiple receptors simultaneously and the triggered involvement of downstream signaling pathways. Potential crosstalk between the two well-characterized opsonic receptors, FcγR and CR3, was briefly explored in the early 1970s, where macrophages were challenged with dual-opsonized targets. However, subsequent studies on receptor crosstalk were primarily restricted to using single opsonins on different targets, typically at saturating opsonin conditions. Beyond validating these initial explorations on receptor crosstalk, we identify the early signaling mechanisms that underlie the binding and phagocytosis during the simultaneous activation of both opsonic receptors, through the presence of a dual-opsonized target (immunoglobulin G [IgG] and C3bi), compared with single receptor activation. For this purpose, we used signaling protein inhibitor studies as well as live cell brightfield and fluorescent imaging to fully understand the role of tyrosine kinases, F-actin dynamics and internalization kinetics for FcγR and CR3. Importantly, opsonic receptors were studied together and in isolation, in the context of sparsely opsonized targets. We observed enhanced particle binding and a synergistic effect on particle internalization during the simultaneous activation of FcγR and CR3 engaged with sparsely opsonized targets. Inhibition of early signaling and cytoskeletal molecules revealed a differential involvement of Src kinase for FcγR- vs CR3- and dual receptor-mediated phagocytosis. Src activity recruits Syk kinase and we observed intermediate levels of Syk phosphorylation in dual-opsonized particles compared with those opsonized with IgG or C3bi alone. These results likely explain the intermediate levels of F-actin that is recruited to sites of dual-opsonized particle uptake and the notoriously delayed internalization of C3bi-opsonized targets by macrophages.     

UniDrug-target: a computational tool to identify unique drug targets in pathogenic bacteria

Background

Targeting conserved proteins of bacteria through antibacterial medications has resulted in both the development of resistant strains and changes to human health by destroying beneficial microbes which eventually become breeding grounds for the evolution of resistances. Despite the availability of more than 800 genomes sequences, 430 pathways, 4743 enzymes, 9257 metabolic reactions and protein (three-dimensional) 3D structures in bacteria, no pathogen-specific computational drug target identification tool has been developed.

Methods

A web server, UniDrug-Target, which combines bacterial biological information and computational methods to stringently identify pathogen-specific proteins as drug targets, has been designed. Besides predicting pathogen-specific proteins essentiality, chokepoint property, etc., three new algorithms were developed and implemented by using protein sequences, domains, structures, and metabolic reactions for construction of partial metabolic networks (PMNs), determination of conservation in critical residues, and variation analysis of residues forming similar cavities in proteins sequences. First, PMNs are constructed to determine the extent of disturbances in metabolite production by targeting a protein as drug target. Conservation of pathogen-specific protein''s critical residues involved in cavity formation and biological function determined at domain-level with low-matching sequences. Last, variation analysis of residues forming similar cavities in proteins sequences from pathogenic versus non-pathogenic bacteria and humans is performed.

Results

The server is capable of predicting drug targets for any sequenced pathogenic bacteria having fasta sequences and annotated information. The utility of UniDrug-Target server was demonstrated for Mycobacterium tuberculosis (H37Rv). The UniDrug-Target identified 265 mycobacteria pathogen-specific proteins, including 17 essential proteins which can be potential drug targets.

Conclusions/Significance

UniDrug-Target is expected to accelerate pathogen-specific drug targets identification which will increase their success and durability as drugs developed against them have less chance to develop resistances and adverse impact on environment. The server is freely available at http://117.211.115.67/UDT/main.html. The standalone application (source codes) is available at http://www.bioinformatics.org/ftp/pub/bioinfojuit/UDT.rar.     

Latent learning,shortcuts and detours: a computational model

Voicu and Schmajuk (Rob. Auto. Syst. 35 (2001a) 23) described a model of spatial navigation and exploration that includes an action system capable of guiding, with the help of a cognitive system, the search for specific goals as determined by a motivation system. Whereas in the original model the cognitive map stores information about the connectivity between places in the environment, in the present version the cognitive map also stores information about the paths traversed by the agent. Computer simulations show that the network correctly describes experimental results including latent learning in a maze, detours in a maze, and shortcuts in an open field. In addition, the model generates novel predictions about detours and shortcuts in an open field.     

Spontaneous spiking and synaptic depression underlie noradrenergic control of feed-forward inhibition

Inhibitory interneurons across diverse brain regions commonly exhibit spontaneous spiking activity, even in the absence of external stimuli. It is not well understood how stimulus-evoked inhibition can be distinguished from background inhibition arising from spontaneous firing. We found that noradrenaline simultaneously reduced spontaneous inhibitory inputs and enhanced evoked inhibitory currents recorded from principal neurons of the mouse dorsal cochlear nucleus (DCN). Together, these effects produced a large increase in signal-to-noise ratio for stimulus-evoked inhibition. Surprisingly, the opposing effects on background and evoked currents could both be attributed to noradrenergic silencing of spontaneous spiking in glycinergic interneurons. During spontaneous firing, glycine release was decreased due to strong short-term depression. Elimination of background spiking relieved inhibitory synapses from depression and thereby enhanced stimulus-evoked inhibition. Our findings illustrate a simple yet powerful neuromodulatory mechanism to shift the balance between background and stimulus-evoked signals.     

Haemodynamics and wall remodelling of a growing cerebral aneurysm: a computational model

We have developed a computational simulation model for investigating an often postulated hypothesis connected with aneurysm growth. This hypothesis involves a combination of two parallel and interconnected mechanisms: according to the first mechanism, an endothelium-originating and wall shear stress-driven apoptotic behavior of smooth muscle cells, leading to loss of vascular tone is believed to be important to the aneurysm behavior. Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All resistance and capacitance vessels under basal conditions exhibit some degree of smooth muscle contraction that determines the diameter, and hence tone, of the vessel. The second mechanism is connected to the arterial wall remodeling. Remodeling of the arterial wall under constant tension is a biomechanical process of rupture, degradation and reconstruction of the medial elastin and collagen fibers. In order to investigate these two mechanisms within a computationally tractable framework, we devise mechanical analogues that involve three-dimensional haemodynamics, yielding estimates of the wall shear stress and pressure fields and a quasi-steady approach for the apoptosis and remodeling of the wall. These analogues are guided by experimental information for the connection of stimuli to responses at a cellular level, properly averaged over volumes or surfaces. The model predicts aneurysm growth and can attribute specific roles to the two mechanisms involved: the smooth muscle cell-related loss of tone is important to the initiation of aneurysm growth, but cannot account alone for the formation of fully grown sacks; the fiber-related remodeling is pivotal for the latter.