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PubMed1985

Subcortical functions in language: a working model.

The current paper explains a model of subcortical language functions that focuses on dynamic interactions between the cortex, the thalamus, and the basal ganglia in the production of spoken language. The model was derived from (a) studies of subcortical lesions and language, (b) studies of subcortical stimulation and language, (c) knowledge regarding neural pathways between various cortical and subcortical structures, and (d) indications that preverbal monitoring of language occurs. In the current model, the thalamus plays roles in cortical arousal and activation and in preverbal semantic monitoring. The basal ganglia function to regulate the degree of excitation conveyed from the thalamus to the cortex and to time the release of formulated language for motor programming. Consistency with classical syndromes of aphasia and potential applications to other areas in the neurosciences are discussed. The current theory, unlike previous formulations, is specific enough that testable hypotheses can be derived.

Aphasia↗
PubMed2002

Modeled channel distributions explain extracellular recordings from cultured neurons sealed to microelectrodes.

Amplitudes and shapes of extracellular recordings from single neurons cultured on a substrate embedded microelectrode depend not only on the volume conducting properties of the neuron-electrode interface, but might also depend on the distribution of voltage-sensitive channels over the neuronal membrane. In this paper, finite-element modeling is used to quantify the effect of these channel distributions on the neuron-electrode contact. Slight accumulation or depletion of voltage-sensitive channels in the sealing membrane of the neuron results in various shapes and amplitudes of simulated extracellular recordings. However, estimation of channel-specific accumulation factors from extracellular recordings can be obstructed by co-occuring ion currents and defect sealing. Experimental data from cultured neuron-electrode interfaces suggest depletion of sodium channels and accumulation of potassium channels.

Action Potentials↗
PubMed2004

Variation in antimicrobial activity of lactoferricin-derived peptides explained by structure modelling.

Antimicrobial peptides bovine lactoferricin (LfcinB) and human lactoferricin (LfcinH) are produced from the respective lactoferrin, but are more active than their precursors. Despite sequence homology, the bovine peptide and its derivatives are more active than their human homologs. Such differences between not only the peptides and their precursor but also between the bovine and the human peptides could relate to structural differences. Upon sequence alignment of both peptides with their parental proteins, the structural differences observed between the bovine lactoferrin (BLf) and LfcinB were also found between the human lactoferrin (HLf) and the LfcinH. The helical structures in HLf are replaced by beta-strands separated by a strong turn in LfcinH suggesting an antiparallel beta-sheet structure similar to LfcinB. MIC assays with HLP-2 and BLP-2, 11-residue peptides derived from the active core of both Lfcins, against Escherichia coli, showed that the bovine derivative, BLP-2, is more active than its human homolog HLP-2. Both 3D models for HLP-2 and BLP-2 showed that the beta-strand is centred between the aromatic residues giving both side chains the same orientations. The displacement towards the N-terminus observed for the beta-strand in HLP-2, compared with its central location in BLP-2, could be less favourable to membrane interaction and therefore responsible for the decrease in activity. Such a model suggests for LfcinH a mechanism similar to the one observed for LfcinB, where the absence of long-range interaction, present in lactoferrin, destabilises the first alpha helix, as observed in solution and, upon interaction with the membrane, could result in the formation of a beta-strand, as observed in the presence of LPS. The location of the beta-strand in relation to the positive charges, seems to define the efficiency of the activity of the peptide and may explain the difference in activity obtained between HLP-2 and BLP-2.

Amino Acid Sequence↗
PubMed2006

Comparison of migration models for acidic solutes in micellar electrokinetic chromatography.

The validity of two models that explain the migration of ionisable solutes in micellar electrokinetic chromatography (MEKC), mobility model and retention factor model, has been tested. For this purpose, the mobility (mu) and retention factor (k) of a set of 10 phenolic compounds with different hydrophobicity and pKa values have been determined for several sodium dodecyl sulphate (SDS) concentrations and pH values, and fitted to the models. Results show that in general the retention factor model explains better the retention of ionisable solutes, although for hydrophilic compounds at low SDS concentration, mobility model can give better fits. The different drawbacks pointed out by several authors in relation to both models have been checked, and a deep evaluation of each one has been done. As a result we have observed that, while in the retention factor model the variation of k with pH and [SDS] always follows the same trend, the variation of mu with these variables mainly depends on the value of the binding constant of the neutral form of the solutes to the micelles, KHA(m), which plays a critical role in the fit of the mobility model. Also we provide rules and advices to set up the experimental conditions to apply each model to a particular solute.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed1989

Sequences linked to prokaryotic promoters can affect the efficiency of downstream termination sites.

The efficiency of transcription termination at certain well-defined prokaryotic rho-independent terminators depends on the promoter unit from which transcription is initiated. Some promoter units allow substantial readthrough of strong termination signals, a phenomenon we term "factor-independent antitermination". This observation is not easily explained by current models for prokaryotic terminator function that consider the terminator to be a "cassette" involving only sequences and RNA transcript structures in the immediate region of the terminator or directly upstream. When transcription is carried out in vitro employing only purified Escherichia coli RNA polymerase, up to 20 times as many RNA polymerase molecules pass through a particular terminator when transcription is initiated from the E. coli tac promoter unit, as compared to transcription initiated from the T7A1 or rrnB P2 promoters. This effect cannot be attributed to antitermination factors separate from the core RNA polymerase. Similar differences in termination efficiency are found for the same promoters in vivo. These termination differences are affected by sequences just downstream from the start site for transcription, including those in the +25 region of the nascent transcript. These early transcribed sequences can confer factor-independent antitermination onto a heterologous promoter, but only when the sequences are precisely positioned relative to the start site for transcription. We have considered several possible models to explain how early transcribed sequences might affect termination, including those in which the 5' end of the transcript interacts with either the terminator RNA or the polymerase. We favor an alternative model in which these sequences interact with the core RNA polymerase to convert the enzyme from a termination-proficient state (T-state) to a conformation resistant to termination (R-state). Such enzyme conformations may be an important component of factor-dependent antitermination systems.

Base Sequence↗
PubMed1997

Depletion of nigrostriatal and forebrain tyrosine hydroxylase by S-adenosylmethionine: a model that may explain the occurrence of depression in Parkinson's disease.

The loss of nigrostriatal tyrosine hydroxylase (TH), dopamine and dopaminergic neurons are the major pathology of Parkinson's disease (PD). These catecholaminergic changes are responsible for the symptoms of tremor, hypokinesia and rigidity. Depression is also a major symptom in PD, but the cause is unknown. The impairments of catecholaminergic fibers in the frontal lobe may be involved, because the frontal lobe of the cerebrum is involved in the regulation of mood, and decreased catecholaminergic activity in the frontal lobe is related to behavioral depression. The changes that damage the nigrostriatal dopamine system and induce motor impairments may also damage the forebrain catecholamine fibers and induce depression. It means that manipulations that damage the nigrostriatum (NS) and induce parkinsonism may also deplete TH in the frontal cortex. Such an effect would suggests a basis for the depression seen in PD. The injection of S-adenosyl-L-methionine (SAM), the biological methyl donor, into the brain of rats damaged the NS, depleted TH and caused tremor and hypokinesia. SAM may interfere also with the forebrain TH, which may help to explain the occurrence of depression in PD. Experiments were designed to test such a hypothesis. The results showed that SAM caused a loss of immunoreactive nerve fibers and it decreased the intensity of TH-immunoreactivity (IR) in the frontal cortex. These changes were accompanied with the loss of cells and the depletion of TH-IR from nerve fibers in the SN and the caudate nucleus. Other studies showed that SAM depletes DA and since SAM induces PD-like changes the results may be relevant to the co-occurrence of PD symptoms and depression. A single biological manipulation may impair the nigrostriatal dopaminergic neurons as well as the frontal cortex catecholaminergic fibers.

Animals↗
PubMed1998

A computational model of depth perception based on headcentric disparity.

It is now well established that depth is coded by local horizontal disparity and global vertical disparity. We present a computational model which explains how depth is extracted from these two types of disparities. The model uses the two (one for each eye) headcentric directions of binocular targets, derived from retinal signals and oculomotor signals. Headcentric disparity is defined as the difference between headcentric directions of corresponding features in the left and right eye's images. Using Helmholtz's coordinate systems we decompose headcentric disparity into azimuthal and elevational disparity. Elevational disparities of real objects are zero if the signals which contribute to headcentric disparity do not contain any errors. Azimuthal headcentric disparity is a 1D quantity from which an exact equation relating distance and disparity can be derived. The equation is valid for all headcentric directions and for all binocular fixation positions. Such an equation does not exist if disparity is expressed in retinal coordinates. Possible types of errors in oculomotor signals (six) produce global elevational disparity fields which are characterised by different gradients in the azimuthal and elevational directions. Computations show that the elevational disparity fields uniquely characterise both the type and size of the errors in oculomotor signals. Our model uses a measure of the global elevational disparity field together with local azimuthal disparity to accurately derive headcentric distance throughout the visual field. The model explains existing data on whole-field disparity transformations as well as hitherto unexplained aspects of stereoscopic depth perception.

Computational Biology↗
PubMed2003

Migration of poly-L-lysine through a lipid bilayer.

When a giant vesicle, composed of neutral and anionic lipid (90:10 mol %), comes into contact with various poly-l-lysines (MW 500-29 300), ropelike structures form within the vesicle interior. By using fluorescence lipids and epi-fluorescence microscopy, we have shown that both neutral and anionic lipids are constituents of the ropes. Evidence that the ropes are also comprised of poly-l-lysine comes from two experiments: (a) direct microinjection of poly(acrylic acid) into rope-containing vesicles causes the ropes to contract into small particles, an observation consistent with a polycation/polyanion interaction; and (b) direct microinjection of fluorescein isothiocyanate (a compound that covalently labels poly-l-lysine with a fluorescent moiety) into rope-containing vesicles leads to fluorescent ropes. The results may be explained by a model in which poly-l-lysine binds to the vesicle exterior, forms a domain, and enters the vesicle through defects or at the domain boundary. The model helps explain the ability of poly-l-lysine to mediate the permeation of a cancer drug, doxorubicine, into the vesicle interior.

Lipid Bilayers↗
PubMed1997

A simplified quantitative cervical mucus penetration test.

A simplified quantitative cervical mucus penetration test was developed and applied to the semen of 21 prospective donors in order to evaluate its performance. Analysis of the data using stepwise multiple regression revealed that the concentration of spermatozoa in mucus was related primarily to the concentration of progressive spermatozoa in the semen (63% of variance explained), and secondarily to the average path velocity of spermatozoa in semen (70% of variance explained by a model incorporating both variables). However, consistent with previous studies, the derived indices of penetration efficiency including the percentage successful collisions (PSC), percentage successful entries (PSE) and the motile density ratio (MDR) were not significantly correlated with any of the semen variables examined, although multiple regression did derive models which explained 27-31% of the variance in these three dependent variables. The strong correlation and correspondence between the PSC and the MDR suggests that the latter may provide a simplified index of penetration efficiency for routine clinical use and further research in this area.

Cervix Mucus↗
PubMed2003

Relation between cerebral blood flow and metabolism explained by a model of oxygen exchange.

The cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRo(2)) are major determinants of the contrast in functional magnetic resonance imaging and optical imaging. However, the coupling between CBF and CMRo(2) during cerebral activation remains controversial. Whereas most of the previous models tend to show a nonlinear coupling, experimental studies have led to conflicting conclusions. A physiologic model was developed of oxygen transport through the blood-brain barrier (BBB) for dynamic and stationary states. Common model simplifications are proposed and their implications for the CBF/CMRo(2) relation are studied. The tissue oxygen pool, the BBB permeability, and the hemoglobin dissociation curve are physiologic parameters directly involved in the CBF/CMRo(2) relation. We have been shown that the hypothesis of a negligible tissue oxygen pool, which was admitted by most of the previous models, implies a tight coupling between CBF and CMRo(2). By relaxing this hypothesis, a real uncoupling was allowed that gives a more coherent view of the CBF/CMRo(2) relation, in better agreement with the hypercapnia data and with the variability reported in experimental works for the relative changes of those two variables. This also allows a temporal mismatch between CBF and CMRo(2), which influences the temporal shape of oxygenation at the capillary end.

Brain↗
PubMed2006

Explaining the explosion: modelling hybrid invasions.

The emergence of hybrids between native and introduced species is an increasingly widespread problem which can alter entire ecosystems. We present a general model for the hybridization of two plant species to investigate the conditions under which hybrid invasions can occur, and the ecological and genetic consequences of such hybridizations. We find that parental compatibility and fecundity are important determinants of whether (and at what rate) hybrid genotypes emerge. Enhanced hybrid fitness traits affect both the population's genetic structure and total rate of increase, with rapid selection for the fittest genotype. Conversely, if different genotypes maximize different life-history characteristics, the ensuing population can be genetically very variable. The model provides a novel approach to evaluate the contributions of population dynamic and genetic processes in the study of hybrid invasions.

Computational Biology↗
PubMed2000

Sex-limited mutations and the evolution of sexual dimorphism.

Although the developmental and genetic mechanisms underlying sex differences are being elucidated in great detail in a number of species, there remains a breach between proximate and evolutionary studies of sexual dimorphism. More precisely, the evolution of sex-limited gene expression at autosomal loci has not been well reasoned using either theoretical or empirical methods. Here, I show that a Mendelian genetic model including elementary details of sexual differentiation provides novel insight into the evolution of sex differences via sex limitation. This model indicates that the nature of allelic effects and the pattern of selection must be known in both sexes to predict the evolution of sex differences. That is, selection interacts with genetic variation for sexual dimorphism to produce unanticipated patterns of trait divergence or convergence between the sexes. Ultimately, this model may explain why previous models for the evolution of sexual dimorphism do not predict the erratic behavior of the sex difference during artificial selection experiments.

Alleles↗
PubMed1993

Perceptual organization and the judgment of brightness.

The perceived brightness of a gray patch depends on the surrounding context. For example, a medium-gray patch appears darker when placed on a bright background and brighter when placed on a dark background. Models to explain these effects are usually based on simple low-level mechanisms. A new set of brightness illusions cannot be explained by such models. In these illusions, the brightness percept is strongly influenced by the perceptual organization of the stimuli. Simple modifications of the stimuli that should have little effect on low-level mechanisms greatly alter the strength of the illusion. These effects may be ascribed to more complex mechanisms occurring later in the visual system.

Contrast Sensitivity↗
PubMed1988

Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome.

This study examines the relationship between impaired fatty acid oxidation and the pathogenesis of Reye syndrome. We present a hypothesis proposing that many clinical signs of this childhood disease are caused by accumulation of unusual acyl CoA esters, precursors to deacylated metabolites found in the patients' blood and urine. A new method was developed to measure acyl CoA compounds in small human liver biopsy samples, offering several advantages over previous techniques. A major finding was an accumulation in Reye syndrome patients of short- and medium-chain acyl CoA intermediates of fatty acid and branched-chain amino acid oxidation. These metabolites included octanoyl, isovaleryl, butyryl, isobutyryl, propionyl, and methylmalonyl CoA esters. The findings were explained in a model of hepatic fatty acid oxidation involving three interrelated pathways: mitochondrial beta-oxidation, peroxisomal beta-oxidation, and omega-oxidation in the endoplasmic reticulum. The results suggest that pathogenesis in Reye syndrome stems from generalized mitochondrial damage resulting in accumulation of acyl CoA esters. High levels of these compounds lead to inhibition of mitochondrial pathways for ureogenesis, gluconeogenesis, and fatty acid oxidation. The inhibited pathways, in turn, could cause the hyperammonemia, hypoglycemia, and hypoketonemia observed in patients. The model also explains underlying biochemical differences between patients with Reye syndrome and medium-chain acyl CoA dehydrogenase deficiency, another disorder of fatty acid metabolism. Acetyl CoA levels, in the latter disease, were dramatically decreased, compared with both human controls and Reye syndrome patients.

Acyl Coenzyme A↗
PubMed2026

Development and external validation of an explainable machine learning model for predicting chronic kidney disease progression in the Korean population.

BACKGROUND: Current risk stratification models, such as the Kidney Failure Risk Equation (KFRE), exhibit variable performance across ethnic groups and fail to capture dynamic clinical trajectories. This study aimed to develop and validate a Korean-specific machine learning (ML) model for predicting chronic kidney disease (CKD) progression using an ensemble approach. METHODS: We used electronic health records from Seoul National University Hospital for model development (n = 28,209) and the Korean Genome and Epidemiology Study (KoGES) CKD cohort for external validation (n = 3,960). The primary outcome was a composite of ≥40% decline in estimated glomerular filtration rate (eGFR) or progression to end-stage renal disease within 2 years. A soft-voting ensemble of four ML algorithms (XGBoost, LightGBM, CatBoost, and Random Forest) was developed. RESULTS: The ensemble model demonstrated robust discrimination in internal validation (area under the receiver operating characteristic curve [AUROC], 0.939; 95% confidence interval [CI], 0.934-0.944), significantly exceeding the KFRE (AUROC, 0.879-0.884). External validation in the KoGES cohort showed comparable discrimination (AUROC, 0.859; 95% CI, 0.798-0.914) versus KFRE (four-variable AUROC, 0.882; 95% CI, 0.818-0.935). Shapley Additive exPlanations (SHAP) analysis identified baseline eGFR, serum creatinine, eGFR slope, albumin, and hemoglobin as key prognostic features, supporting a complementary framework using KFRE for community screening and the ML model for hospital-based risk stratification. CONCLUSION: The ensemble ML model accurately predicts short-term CKD progression in Korean patients. By incorporating longitudinal features and ensemble learning, it provides a precise alternative to Western-derived equations, particularly in tertiary care settings.

Chronic kidney failure↗
PubMed1993

Information metabolism as a model of consciousness.

Kepinski's model of "information metabolism" is a biological model which is based on the structural organization of the cell and which attempts to describe information processing in analogy to energy metabolism. The terms of control center, information transmission and transformation, energy requirements and boundaries are considered. The principles of this model are explained. The original model is extended by addition of an integrated model of the main states of consciousness and a developmental model of information metabolism. Concepts of protective mechanisms of information metabolism are developed.

Consciousness↗
PubMed1993

Color stereopsis: a model for depth reversals based on border contrast.

Color stereopsis refers to the effect of stimulus color on perceived depth of stimuli viewed binocularly. It is well established and well understood that the wavelength of a stimulus affects its perceived depth in color stereopsis by prismatic effects in human optics, with long-wavelength stimuli normally seen in front of short-wavelength stimuli. It is less well known, and not well understood, that the background of the stimulus affects depth order as well. We demonstrate experimentally, using a long-wavelength orange stimulus and a short-wavelength blue stimulus, that a change from black to white in the background at the border (a change in border contrast) of the stimulus changes the perceived depth order from orange in front of blue to blue in front of orange (a color reversal). We present a descriptive model to explain reversals in color stereopsis when stimuli are displayed on a white background and suggest that it may account for instances of color reversals that are currently unexplained or questionably explained by other models.

Adult↗