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PubMed1999

Developmental pathways to antisocial behavior: the delayed-onset pathway in girls.

Recent research has suggested that there are two distinct trajectories for the development of antisocial behavior in boys: a childhood-onset pathway and an adolescent-onset pathway. After reviewing the limited available research on antisocial girls, we propose that this influential method of conceptualizing the development of severe antisocial behavior may not apply to girls without some important modifications. Antisocial girls appear to show many of the correlates that have been associated with the childhood-onset pathway in boys, and they tend to show impaired adult adjustment, which is also similar to boys in the childhood-onset pathway. However, antisocial girls typically show an adolescent-onset to their antisocial behavior. We have proposed that these girls show a third developmental pathway which we have labeled the "delayed-onset" pathway. This model rests on the assumption that many of the putative pathogenic mechanisms that contribute to the development of antisocial behavior in girls, such as cognitive and neuropsychological deficits, a dysfunctional family environment, and/or the presence of a callous and unemotional interpersonal style, may be present in childhood, but they do not lead to severe and overt antisocial behavior until adolescence. Therefore, we propose that the delayed-onset pathway for girls is analogous to the childhood-onset pathway in boys and that there is no analogous pathway in girls to the adolescent-onset pathway in boys. Although this model clearly needs to be tested in future research, it highlights the need to test the applicability of current theoretical models for explaining the development of antisocial behavior in girls.

Adolescent↗
PubMed1977

Spatial propagation of associations in a cortex-like neural network model.

A neural network model is studied, having associative memory properties and allowing retrieved associations to propagate within the network. It is intended as a tentative description of the cerebral cortex consisting of "pyramidal cells" with modifiable synapses and "stellate cells" providing feedback through excitatory and inhibitory recurrent pathways. The model is based on some general assumptions: Learning occurs through facilitation of synapses which depends on simultaneous pre- and postsynaptic activity (two-conditional facilitation). Connections within the network are realizations of a random process, implying that nearby cells are more likely to be connected than distant one. The two-conditional facilitation makes it possible for an output signal pattern which occurred in conjunction with a certain input pattern to be retrieved later by reapplying the particular input, the model working as an associative memory. The random connections and the operation of the stellate cell models as linear threshold units give rise to pattern separation in the feedback link. This, in addition to the fact that patterns form associations with themselves, is of importance during the associative recall enabling the network to attain alternative stable modes of activity each corresponding to a learned association. It is shown that a learned pattern of activity which is retrieved, ie, a stable mode, can propagate across the surface of the network. The mode of activity evoked through a certain association may get into contact with modes originating from different associations, forming a stable or slowly moving boundary between the interacting modes. The model is discussed in relation to some properties of the visual system.

Association↗
PubMed1998

Influence of the permeation enhancers 1-alkyl-2-pyrrolidones on permeant partitioning into the stratum corneum.

In a previous study, the enhancing effects of a series of 1-alkyl-2-pyrrolidones (APs; 1-ethyl, 1-butyl, 1-hexyl, and 1-octyl-2-pyrrolidone) on the transport of steroidal permeants across hairless mouse skin were investigated via a parallel pathway skin model. Isoenhancement concentration conditions were deduced under which different APs induce essentially the same transport enhancement for the lipoidal pathway of the stratum corneum (s.c.). As a continuing effort to understand the mechanism of action of permeation enhancers, the influence of the APs on permeant partitioning into hairless mouse s.c. was investigated under the isoenhancement concentration conditions using beta-estradiol (E2 beta) as the model permeant. The amount of E2 beta uptake into s.c. was found to be essentially the same for all the APs under these isoenhancement conditions. This result suggests that inducing a higher partitioning tendency for E2 beta into the lipoidal pathway of hairless mouse s.c. is a principal mechanism of action of the APs in enhancing transdermal transport. The uptake of the APs into s.c. lipoidal domains was also determined, and the results show only a modest (approximately 2-fold) increase in the uptake of the APs in going from 1-ethyl-to 1-octyl-2-pyrrolidone under isoenhancement conditions. This indicates the potency of the APs as permeation enhancers is only very modestly dependent upon the alkyl chain length in this chain length region when compared at concentrations in the microenvironment where the action occurs in the lipid domains.

Animals↗
PubMed2006

The Path-A metabolic pathway prediction web server.

Pathway Analyst (Path-A) is a publicly available web server (http://path-a.cs.ualberta.ca) that predicts metabolic pathways. It takes a FASTA format file containing a set of query protein sequences from a single organism (a partial or complete proteome) and identifies those sequences that are likely to participate in any of its supported metabolic pathways (currently 10). Path-A uses a number of machine-learning and sequence analysis techniques (e.g. SVM, BLAST and HMM) to predict pathways. Each machine-learned classifier exploits similarity between sequences in the pathways of its model organisms and sequences in the query set. It predicts the pathways that are present in the query organism and annotates each predicted reaction and catalyst, using the appropriate sequences from the query set. Path-A also provides a browsable and searchable database of the pathways for the model organisms that are used to make its predictions. Path-A's predictor sets (using different classifier technologies) have been evaluated using standard cross-validation techniques on a dataset of 10 metabolic pathways across 13 model organisms--a total of 125 organism-specific pathways. The most accurate classifier technology obtained a mean precision of 78.3% and a mean recall of 92.6% in predicting all catalyst proteins, of all reactions, in all pathways present in the dataset. Although Path-A currently only supports metabolic pathways, the underlying prediction techniques are general enough for other types of pathways. Consequently, it is our intent to extend Path-A to predict other types of pathways, including signalling pathways.

Algorithms↗
PubMed2006

Evaluation of clinically relevant glutamate pathway inhibitors in in vitro model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, inherited and fatal neurodegenerative disorder for which there is, at present, no effective treatment or cure. Striatal medium spiny neurons (MSN) are the most sensitive in HD. Dysregulation of glutamate/calcium signaling pathway emerges as a possible cause of striatal MSN neurodegeneration in HD. Here we evaluated five clinically relevant glutamate pathway inhibitors using previously developed in vitro HD model. We found that folic acid, gabapentin and lamotrigine did not protect HD neurons from glutamate-induced cell death, but memantine and riluzole were protective. Our results provide further support to potential use of memantine and riluzole for treatment of HD.

Amines↗
PubMed2002

The organization of visual object representations: a connectionist model of effects of lesions in perirhinal cortex.

We have developed a simple connectionist model based on the idea that perirhinal cortex has properties similar to other regions in the ventral visual stream, or 'what' pathway. The model is based on the assumption that representations in the ventral visual stream are organized hierarchically, such that representations of simple features of objects are stored in caudal regions of the ventral visual stream, and representations of the conjunctions of these features are stored in more rostral regions. We propose that a function of these feature conjunction representations is to help to resolve 'feature ambiguity', a property of visual discrimination problems that can emerge when features of an object predict a given outcome (e.g. reward) when part of one object, but predict a different outcome when part of another object. Several recently reported effects of lesions of perirhinal cortex in monkeys have provided key insights into the functions of this region. In the present study these effects were simulated by comparing the performance of connectionist networks before and after removal of a layer of units corresponding to perirhinal cortex. The results of these simulations suggest that effects of lesions in perirhinal cortex on visual discrimination may be due not to the impairment of a specific type of learning or memory, such as declarative or procedural, but to compromising the representations of visual stimuli. Furthermore, we propose that attempting to classify perirhinal cortex function as either 'perceptual' or 'mnemonic' may be misguided, as it seems unlikely that these broad constructs will map neatly onto anatomically defined regions of the brain.

Animals↗
PubMed1996

Resolving the apparent discrepancy between the incongruency effect and the expectancy-based illusory correlation effect: the TRAP model.

The incongruency effect and the expectancy-based illusory correlation effect seem contradictory because they describe apparently contrasting consequences of previously held expectancies: better recall of incongruent than congruent items but overestimation of congruent items. This article resolves this dilemma by presenting a model that is able to simultaneously predict both of these effects. The Twofold Retrieval by Associative Pathways (TRAP) model adopts the encoding assumptions of person memory models but distinguishes between two different retrieval processes, exhaustive and heuristic, hypothesized to underlie recall and frequency estimation, respectively. Experiment 1 showed that expectancy-based illusory correlation effects and incongruency effects are compatible in that they were produced simultaneously. Experiments 2 and 3 tested and rejected alternative explanations for the obtained pattern of results.

Adult↗
PubMed1992

Phosphatidylcholine synthesis in castor bean endosperm : free bases as intermediates.

The methylation steps in the biosynthesis of phosphatidylcholine by castor bean (Ricinus communis L.) endosperm have been studied by pulse-chase labeling. Endosperm halves were incubated with [methyl-(14)C]S-adenosyl-l-methionine, [2-(14)C]ethanolamine, [(14)C]ethanolamine phosphate, or [(14)C]serine phosphate. The kinetics of appearance were followed in the free, phospho-, and phosphatidyl-bases. The initial methylation utilized ethanolamine as a substrate to form methylethanolamine, which was then converted to dimethylethanolamine, choline, and phosphomethylethanolamine. Subsequent methylations occurred at the phospho-base and, to a lesser extent, the phosphatidyl-base levels, after which the radioactivity either remained constant or decreased in these compounds and accumulated in phosphatidylcholine. Although the precursors tested did support the synthesis of choline, the kinetics of the labeling make them unlikely to be the major sources of free choline to be utilized for the nucleotide pathway. A model with two pools of choline is proposed, and the implications of these results for the pathways leading to phosphatidylcholine biosynthesis are discussed.

Journal Article↗
PubMed1990

The reactions of pindolol, mepindolol, carazolol, and related model compounds with triethyl orthoformate: pathways and products of a new colour reaction.

The acid-catalysed electrophilic tandem substitutions of pindolol, mepindolol, and carazolol and some related model compounds with triethyl ortho formate give rise to new derivatives from the trishetaryl methane series. In some cases also further functionalized heterocycles were isolated. The structural aspects of the new trishetarylmethanes were discussed as C3-symmetric molecular propellers, respectively. The importance of the described reaction as colour reaction was mentioned.

Adrenergic beta-Antagonists↗
PubMed2006

Administration of levetiracetam after prolonged status epilepticus does not protect from mitochondrial dysfunction in a rodent model.

Neuronal death and dysfunction occur after status epilepticus (SE), and is associated with mitochondrial enzyme damage. We previously showed, using the rat perforant pathway stimulation model, that levetiracetam administration (LEV; 1000 mg/kg intraperitoneal) during established SE reduces seizure severity and prevents mitochondrial dysfunction. We now show that administration of the same dose of LEV after 5h SE, does not protect from mitochondrial dysfunction.

Animals↗
PubMed2003

Pathways of cholesterol crystallization in model bile and native bile.

Hypersecretion of hepatic cholesterol, chronic supersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles represent the primum movens in cholesterol gallstone formation. Physical-chemical factors and pathways leading to cholesterol crystallization can be investigated in artificial model biles and ex vivo in fresh human bile. Depending on modulatory factors (i.e., lipid concentration, bile salt or phospholipid species, humidity, mucins, etc.), cholesterol can precipitate in several forms (i.e., monohydrate, anhydrous) and habits (i.e., plate-like, needle-like, intermediate arcs, filaments, tubules, spirals). Careful analysis of biliary cholesterol crystals includes biochemical analysis of precipitated crystals, polarizing quantitative light microscopy, and turbidimetric methods. In this paper, recent concepts on cholesterol crystallization in artificial model biles as well as in human bile will be reviewed.

Bile↗
PubMed2006

Startle and prepulse inhibition as a function of background noise: a computational and experimental analysis.

Schmajuk and Larrauri [Schmajuk NA, Larrauri JA. Neural network model of prepulse inhibition. Behav Neurosci 2005;119:1546-62.] introduced a real-time model of acoustic startle, prepulse inhibition (PPI) and facilitation (PPF) in animals and humans. The model assumes that (1) positive values of changes in noise level activate an excitatory and a facilitatory pathway, and (2) absolute values of changes in noise level activate an inhibitory pathway. The model describes many known properties of the phenomena and the effect of brain lesions on startle, PPI, and PPF. The purpose of the present study is to (a) establish the magnitude of startle and PPI as a function of pulse, prepulse, and background intensity, and (b) test the model predictions regarding an inverted-U function that relates startle to the intensity of the background noise.

Acoustic Stimulation↗
PubMed2006

Directing adenovirus across the blood-brain barrier via melanotransferrin (P97) transcytosis pathway in an in vitro model.

Adenovirus serotype 5 (Ad5) is widely used in the development of gene therapy protocols. However, current gene therapy strategies involving brain are mostly based on intra-cranial injection. A major obstacle for systemically administered vectors to infect brain tissue is the blood-brain barrier (BBB). One strategy to cross the BBB is transcytosis, a transcellular transport process that shuttles a molecule from one side of the cell to the other side. Recently, melanotransferrin (MTf)/P97 was found to be able to cross the BBB and accumulate in brain. We thus hypothesize that re-directing Ad5 vectors to the MTf transcytosis pathway may facilitate Ad5 vectors to cross the BBB. To test this hypothesis, we constructed a bi-specific adaptor protein containing the extracellular domain of the coxsackie-adenovirus receptor (CAR) and the full-length melanotransferrin (sCAR-MTf), and investigated its ability to re-direct Ad5 vectors to the MTf transcytosis pathway. We found this adaptor protein could re-direct Ad5 to the MTf transcytosis pathway in an in vitro BBB model, and the transcytosed Ad5 viral particles retained their native infectivity. The sCAR-MTf-mediated Ad5 transcytosis was temperature- and dose dependent. In addition, we examined the directionality of sCAR-MTf-mediated Ad5 transcytosis, and found the efficiency of apical-to-basal transcytosis was much higher than that of basal-to-apical direction, supporting a role of this strategy in transporting Ad5 vectors towards the brain. Taken together, our study demonstrated that re-directing Ad5 to the MTf transcytosis pathway could facilitate gene delivery across the BBB.

Adenoviridae↗
PubMed1995

Release of iron from C-terminal monoferric transferrin to phosphate and pyrophosphate at pH 5.5 proceeds through two pathways.

Iron release fro C-terminal monoferric transferrin at pH 5.5 and 37 degrees C was studied as a function of chloride, phosphate, and pyrophosphate concentration. The rate constant for iron release depends linearly on chloride concentration, confirming that anion binding is mandatory for iron release, not only at pH 7.4 as has been previously reported, but also at pH 5.5. The extent of iron release is relatively small (< 20% for 1.0 M chloride). Concentrations of > 0.2 M phosphate are required for complete iron removal, but millimolar concentrations of pyrophosphate effect complete removal. The observed rate constants for iron release to phosphate and pyrophosphate change from one linear dependence to another less steep linear dependence on the concentration of these ligands, providing quantitative evidence that the two-pathway mechanism that we previously proposed for iron release at pH 7.4 persists at pH 5.5. According to this model, the pathway of iron release is determined by the nature of the anion occupying a kinetically significant anion binding site on the protein. The qualitative similarity of the current data with that recently reported for iron release from the transferrin-transferrin receptor complex provides strong support for the contention that the two-pathway mechanism also persists in this complex at low pH and is hence likely to be operative in vivo.

Chlorides↗
PubMed2005

Quantitative assessment of the glyoxalase pathway in Leishmania infantum as a therapeutic target by modelling and computer simulation.

The glyoxalase pathway of Leishmania infantum was kinetically characterized as a trypanothione-dependent system. Using time course analysis based on parameter fitting with a genetic algorithm, kinetic parameters were estimated for both enzymes, with trypanothione derived substrates. A K(m) of 0.253 mm and a V of 0.21 micromol.min(-1).mg(-1)for glyoxalase I, and a K(m) of 0.098 mm and a V of 0.18 micromol.min(-1).mg(-1) for glyoxalase II, were obtained. Modelling and computer simulation were used for evaluating the relevance of the glyoxalase pathway as a potential therapeutic target by revealing the importance of critical parameters of this pathway in Leishmania infantum. A sensitivity analysis of the pathway was performed using experimentally validated kinetic models and experimentally determined metabolite concentrations and kinetic parameters. The measurement of metabolites in L. infantum involved the identification and quantification of methylglyoxal and intracellular thiols. Methylglyoxal formation in L. infantum is nonenzymatic. The sensitivity analysis revealed that the most critical parameters for controlling the intracellular concentration of methylglyoxal are its formation rate and the concentration of trypanothione. Glyoxalase I and II activities play only a minor role in maintaining a low intracellular methylglyoxal concentration. The importance of the glyoxalase pathway as a therapeutic target is very small, compared to the much greater effects caused by decreasing trypanothione concentration or increasing methylglyoxal concentration.

Animals↗
PubMed2001

Using model-system genetics for drug-based target discovery.

The combination of medicinal chemistry and model-organism genetics is emerging as a powerful tool for the discovery and validation of drug targets. Model systems can be used to identify the cognate target for compounds that demonstrate in vivo efficacy but have unknown mechanisms of action. Alternatively, drugs with known cognate targets can be used to probe biochemical pathways in model organisms, revealing new targets and mechanisms within these pathways. In both cases, the availability of human genomic sequence data is opening up new opportunities for accelerating target discovery.

Journal Article↗
PubMed2003

Dehalogenation potential of municipal waste incineration fly ash. II. Comparison of dehalogenation pathways of fly ash and model fly ash with thermodynamic calculations.

BACKGROUND, AIMS AND SCOPE: In the first part of this paper the main principles which control the dehalogenation of polychlorinated aromatic compounds on municipal waste incineration fly ash (MWI-FA) have been discussed and the model fly ash of similar dehalogenation activity has been proposed. Even if both systems show comparable dehalogenation properties, the main question concerning the postulated identical reaction mechanism in both cases is left unanswered. The other very important point is to what extent is this dechlorination mechanism thermodynamically controlled. The same problem is often discussed in the literature also for the de novo synthetic reactions. From the data it is clear that metallic copper plays a decisive role in the mechanism of the dehalogenation reaction. Although the results reported in the first part strongly support the idea that copper acts in this dechlorination as the reaction component, in contrast to its generally accepted catalytic behaviour, we believed that additional support for this conclusion can be obtained with the help of a thermodynamic interpretation of the mechanism of the reaction. RESULTS AND DISCUSSION: The pathways of hexachlorobenzene dechlorination on MWI-FA and model fly ash were studied in a closed system at 260-300 degrees C under nitrogen atmosphere. These pathways were the same for both systems, with the following prevailing sequences: hexachlorobenzene --> pentachlorobenzene --> 1,2,3,5-tetrachlorobenzene --> 1,3,5-trichlorobenzene --> 1,3-dichlorobenzene. Thermodynamic calculations were carried out by using the method of minimization total Gibbs energy of the whole system. In the calculations, the following reaction components were taken into account: all gaseous chlorinated benzenes, benzene, hydrogen chloride, a gaseous trimer Cu3Cl3, and also Cu2O and CuCl2 as solid components. The effect of the reaction temperature and the amount of copper and water vapour were considered as well. The effect of reaction temperature was determined from the data calculated for the 500 to 750 K temperature region. The effect of the initial composition was determined for the molar amounts of copper = 0.01-3 moles and water vapour = 0.2 to 3 moles per mole of chlorobenzene isomer CONCLUSIONS: The results of hexachlorobenzene dechlorination by MWI-FA and model fly ash under comparable reaction conditions allow us to conclude that both dechlorinations proceed via the same dechlorination pathways, which can be taken as an evidence of the identical dehalogenation mechanism for both systems. The relative percentual distribution of the dehalogenated products depends on the temperature, but not on the initial amount of water vapour or copper metal. On the other hand, the initial amount of copper substantially affects the conversion of the dehalogenation as well as the molar ratio of Cu3Cl3 to HCl in the equilibrium mixture. Comparison of the experimental with thermodynamic results supports the idea that dehalogenation reactions are thermodynamically controlled. RECOMMENDATIONS AND OUTLOOK: Thermodynamic analysis of the dehalogenation reactions may prove useful for a wide range of pollutants. The calculations concerning polychlorinated biphenyls and phenols are under study.

Carbon↗