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At least 775 records · Page 43Linked to original sources

PubMed2004

Robust global sensitivity in multiple enzyme cascade system explains how the downstream cascade structure may remain unaffected by cross-talk.

A steady-state framework was applied to the ubiquitous tricyclic enzyme cascade structure, as seen in the mitogen-activated protein (MAP) kinase system, to analyze the effect of upstream kinase concentrations on final output response. The results suggest that signal amplification achieved by the cascade structure ensured that the modifying enzymes at various steps of the cascade were nearly saturated. Thus, there was no change in the response sensitivity with increasing upstream kinase concentration. Analysis was also extended to branching of a signaling pathway as an example of cross-talk. It was observed that the cascade structure confers a larger share of the signal transduction properties to its last kinase. This phenomenon in enzyme cascades may explain how the response of the terminal MAP kinase is unaffected by cross-talk of upstream kinases.

Adenosine Triphosphate↗

PubMed1995

Some cases of human male infertility are explained by abnormal in vitro human sperm activation.

OBJECTIVE: To determine if a human sperm activation assay can be used to evaluate males exhibiting otherwise unexplained infertility. DESIGN: Sperm from age-matched fertile and idiopathic infertile males were assayed in the human sperm activation assay and the results were compared. A portion of the sperm from the idiopathic infertile males also was used in assisted reproductive technology (ART) attempts at pregnancy. PATIENTS: Idiopathic infertile couples who had extensive fertility testing with no identified problems that would explain their infertility. Fertile males that had fathered one or more children. MAIN OUTCOME MEASURES: Sperm nuclear decondensation-recondensation and DNA synthesis. Pregnancies resulting from ART using semen from a male whose sperm responded abnormally in the human sperm activation assay. RESULTS: Thirteen (22%) of 59 idiopathic infertile males produced sperm that responded abnormally in the human sperm activation assay. Only 1 (1.7%) of 59 fertile males produced sperm that responded abnormally in the human sperm activation assay. The percentage of abnormal responders in the patient group exhibiting unexplained infertility was significantly higher than in the fertile male group. No sperm samples that responded abnormally in the human sperm activation assay resulted in pregnancies when used in ART. CONCLUSIONS: The human sperm activation assay is a new and independent indicator for some cases of infertility that otherwise would be unexplained. The human sperm activation assay appears to have utility in determining a sperm sample's efficacy for fertilization in ART attempts at pregnancy.

Cell Nucleus↗

PubMed1997

Does an acidic pH explain why low density lipoprotein is oxidised in atherosclerotic lesions?

The oxidation of low density lipoprotein (LDL) within atherosclerotic lesions may be involved in atherogenesis. LDL oxidation by cells in the presence of iron is faster at acidic pH. In addition, LDL oxidation by iron alone or iron cysteine in the absence of cells is much faster at acidic pH, even at mildly acidic pH (pH 6.5). The effect of pH on LDL oxidation by copper ions is more complex, in that acidity slows down the initial oxidation, as measured by conjugated dienes, hydroperoxides and thiobarbituric acid-reactive substances, but can increase the later stages of LDL oxidation as measured by increased macrophage uptake. Extensive LDL oxidation by cells in atherosclerotic lesions probably requires a source of iron or copper as catalysts for the oxidation. Iron in plasma is carried by the protein transferrin. Lowering the pH releases some of the iron from transferrin so that it can catalyse LDL oxidation. Copper is carried in plasma on caeruloplasmin and becomes more effective in catalysing LDL oxidation when the caeruloplasmin is preincubated at acidic pH, or even at pH 7.0. These effects can be seen with concentrations of caeruloplasmin and transferrin below those present in plasma. By analogy to other inflammatory and ischaemic sites, atherosclerotic lesions may well have an acidic extracellular pH, particularly within clusters of macrophages where the oxidative stress may also be high. This localised acidic pH may help to explain why atherosclerotic lesions are one of the few sites in the body where extensive LDL oxidation occurs.

Arteriosclerosis↗

PubMed2000

Tensegrity architecture explains linear stiffening and predicts softening of living cells.

The problem of theoretical explanation of the experimentally observed linear stiffening of living cells is addressed. This explanation is based on Ingber's assumption that the cell cytoskeleton, which enjoys tensegrity architecture with compressed microtubules that provide tension to the microfilaments, affects the mechanical behavior of the living cell. Moreover, it is shown that the consideration of the extreme flexibility of microtubules and the unilateral response of microfilaments is crucial for the understanding of the living cell overall behavior. Formal nonlinear structural analysis of the cell cytoskeleton under external mechanical loads is performed. For this purpose, a general computer model for tensegrity assemblies with unilateral microfilaments and buckled microtubules is developed and applied to the theoretical analysis of the mechanical response of 2D and 3D examples of tensegrity cells mimicking the behavior of real living cells. Results of the computer simulations explain the experimentally observed cell stiffening. Moreover, the theoretical results predict the possible existence of a transient softening behavior of cells, a phenomenon, which has not been observed in experiments yet.

Biomechanical Phenomena↗

PubMed2002

A curve-fitting procedure to explain changes in muscle force-velocity relationship induced by hyperactivity.

Experiments have shown that a period of hyperactivity induces changes in the muscle force-velocity relationship. The goal of this study was to explain such changes by taking into account that the myosin heavy chain (MHC) composition of a muscle is a primary determinant of its shortening velocity. For this purpose a mathematical model was developed where the force-velocity relationship of the whole muscle was built by summing the force contributions of individual components at each of a series of shortening velocities. An individual force-velocity relationship was assigned to each component, i.e. each type of MHC. Experimental data were obtained on control and hyperactivated epitrochlearis muscles from rats. In the controls rats, fitting of the model with experimental data was satisfactory. In hyperactivated muscles, parameters of the fastest MHC component had to be modified. This improved the fit between model and experimental data and accounted for possible changes in myosin light chain composition.

Animals↗

PubMed2003

A rate-dependent microcrack-bridging model that can explain the strain rate dependency of cortical bone apparent yield strength.

Although there are empirical correlations between strain rate, cortical and cancellous bone apparent stiffness, apparent yield strength, apparent ultimate strength and cortical bone fracture toughness, a mechanistic description for these phenomena is lacking. Microcracking is a major mechanism in cortical and cancellous bone failure, however, microdamage content alone cannot explain the strain rate dependence of bone strength without considering time-dependent behavior of the crack. Using a rate-dependent model of a fiber-bridged microcrack and data from the literature, we demonstrate that the experimental apparent yield strength of bone can be predicted directly from measurements of apparent moduli of elasticity of bone constituents and failure strain of the collagenous matrix. Yield strength predictions for estrogen depleted bone were made using the model and data from ovariectomized sheep. It was predicted that the yield strength of estrogen-deficient bone is comparable to that of normal bone within strain rates associated with physiological activities. For high strain rates, however, the strength of estrogen-depleted bone was predicted to be much weaker than normals suggesting a higher fracture risk due to impact from falls, for individuals with estrogen-depleted bones such as in post-menopausal osteoporosis.

Bone and Bones↗

PubMed1997

Compressive behavior of articular cartilage is not completely explained by proteoglycan osmotic pressure.

It has been hypothesized that applied mechanical or osmotic loads which decrease cartilage volume by 5% or more are sufficient to relieve all collagen tensile forces, and that further changes in the applied load are completely supported by changes in proteoglycan osmotic pressure. In this view, cartilage should behave mechanically like a concentrated solution of proteoglycans. We tested this hypothesis by measuring the equilibrium axial and radial stresses in bovine articular cartilage during uniaxial confined compression. If the hypothesis is correct, the observed changes in the radial and axial stresses in confined compression should be equal for compression greater than 5%. However, the observed change in axial stress was always substantially greater than the change in radial stress over the range of strains (5-26%) and saline concentrations (0.05-0.15 M) tested. This indicates that the mechanical behavior of cartilage in confined compression cannot solely be explained by changes in proteoglycan osmotic pressure even for strains as large as 26%. A linear isotropic model was found to describe the observed equilibrium behavior adequately. In addition, the inferred shear modulus was found to be independent of saline concentration and similar to measurements by others of the flow-independent shear modulus. Our results have implications regarding the relative contribution of the proteoglycans and collagen to the mechanical properties of the tissue in compression, and suggest that tensile forces in the collagen network may play an important role in determining tissue behavior in confined compression even for relatively large volume changes.

Animals↗

PubMed1999

Correlation between pre-operative periprosthetic bone density and post-operative bone loss in THA can be explained by strain-adaptive remodelling.

Periprosthetic adaptive bone remodelling after total hip arthroplasty can be simulated in computer models, combining bone remodelling theory with finite element analysis. Patient specific three-dimensional finite element models of retrieved bone specimens from an earlier bone densitometry (DEXA) study were constructed and bone remodelling simulations performed. Results of the simulations were analysed both qualitatively and quantitatively. Patterns of predicted bone loss corresponded very well with the DEXA measurements on the retrievals. The amount of predicted bone loss, measured quantitatively by simulating DEXA on finite element models, was found to be inversely correlated with the initial bone mineral content. It was concluded that the same clinically observed correlation can therefore be explained by mechanically induced remodelling. This finding extends the applicability of numerical pre-clinical testing to the analysis of interaction between implant design and initial state of the bone.

Absorptiometry, Photon↗

PubMed1999

Compression data on bovine bone confirms that a "stressed volume" principle explains the variability of fatigue strength results.

The literature contains many measurements of the fatigue properties of compact bone, but these experimental results have been difficult to interpret and use due to a large amount of apparent scatter: variation in the number of cycles to failure for a given cyclic stress or strain range. Recently Taylor (1998a, Journal of Orthopaedic Research, 16, 163-169) showed that much of this scatter could be explained using a statistical model which took into account specimen size, or more specifically stressed volume. The present paper describes an attempt to test this model by using it to predict some new data, for bovine bone tested in compressive loading at room temperature at physiological loading rates. Twenty specimens were tested at the same applied load range (100 MPa). The theory was able to predict the mean behaviour of the specimens very well, with an accuracy (expressed in terms of stress) of 2%. It was also able to predict the degree of scatter (i.e. the variation of Nf), which was shown to be similar to that measured by other workers.

Animals↗

PubMed2002

Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains.

Protease inhibitors (PIs) are an important class of drugs for the treatment of HIV infection. However, in the course of treatment, resistant viral variants with reduced sensitivity to PIs often emerge and become a major obstacle to successful control of viral load. On the basis of a compound equipotently inhibiting HIV-1 and 2 proteases (PR), we have designed a pseudopeptide inhibitor, QF34, that efficiently inhibits a wide variety of PR variants. In order to analyze the potency of the inhibitor, we constructed PR species harboring the typical (signature) mutations that confer resistance to commercially available PIs. Kinetic analyses showed that these mutated PRs were inhibited up to 1,000-fold less efficiently by the clinically approved PIs. In contrast, all PR species were effectively inhibited by QF34. In a clinical study, we have monitored 30 HIV-positive patients in the Czech Republic undergoing highly active antiretroviral therapy, and have identified highly PI resistant variants. Kinetic analyses revealed that QF34 retained its subnanomolar potency against multi-drug resistant PR variants. X-ray crystallographic analysis and molecular modeling experiments explained the wide specificity of QF34: this inhibitor binds to the PR in an unusual manner, thus avoiding contact sites that are mutated upon resistance development, and the unusual binding mode and consequently the binding energy is therefore preserved in the complex with a resistant variant. These results suggest a promising route for the design of second-generation PIs that are active against a variety of resistant PR variants.

Amino Acid Substitution↗

PubMedDate not supplied

Critical analysis of the theories advanced to explain short REM sleep latencies and other sleep anomalies in several psychiatric conditions.

One of the most consistent and most studied sleep modifications in several psychiatric conditions is the shortening of the rapid eye movement (REM) sleep latency. While its clinical usefulness is still to be proven and its meaning relatively obscure, the appearance of a short REM latency continues to be a daily fact in sleep laboratories. Many theories compete to explain what is observed, the most important being the circadian rhythm hypotheses, the homeostatic model and the reciprocal interaction model. These three are summarised and their pros and cons are exposed in a systematic manner. Points of conflict, possible convergences and limitations are discussed in the light of recent developments on the general theories of sleep regulation.

Body Temperature↗

PubMed2001

Low affinity of beta1-adrenergic receptor for beta-arrestins explains the resistance to agonist-induced internalization.

It has been reported that beta-arrestin is essential for the internalization of many G protein-coupled receptors. Since beta1-adrenergic receptor (beta1AR) shows the resistance to agonist-induced internalization, we examine the interaction of beta-arrestin with beta1AR with three different approaches: translocation of beta-arrestin to the plasma membrane, direct binding of in vitro translated beta-arrestin to intracellular domains of beta1- and beta2ARs, inhibition of beta1- and beta2AR-stimulated adenylyl cyclase activities by beta-arrestin. The enhanced green fluorescent protein (EGFP)-tagged beta-arrestin 2 (beta-arrestin 2-GFP) translocates to and stays at the plasma membrane by beta2AR stimulation. Beta-arrestin 2-GFP also translocates to the plasma membrane upon beta1AR stimulation. However, it returns to the cytoplasm 10 - 30 min after agonist stimulation. The amount of beta-arrestin bound to the third intracellular loop and the carboxyl tail of beta1AR is lower than that of beta2AR. The fusion protein of beta-arrestin 1 with glutathione-S-transferase inhibits the beta1- and beta2AR-stimulated adenylyl cyclase activities. However, inhibition of the beta1AR-stimulated activity requires a higher amount of the fusion protein than that of the beta2AR-stimulated activity. These results suggest that affinity of beta1AR for beta-arrestins is lower than that of beta2AR, and explains the resistance to agonist-induced internalization. This conclusion is further supported by the finding that beta-arrestin can induce internalization of beta1AR when beta-arrestin 1 fused to the carboxyl tail of beta1AR.

Adenylyl Cyclase Inhibitors↗

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↗

PubMed2000

Mechanisms to explain pancreatic dysfunction in cystic fibrosis.

This article focuses on three potential mechanisms by which pancreatic dysfunction occurs in cystic fibrosis. These include (1) obstruction of pancreatic ducts by inspissated plugs, (2) inhibition of endocytosis in acinar cells, and (3) imbalance in membrane lipids in cystic fibrosis regulated cells. Any of these abnormalities alone or in combination may explain the development of pancreatic exocrine insufficiency.

Cystic Fibrosis↗

PubMed1997

Explaining category-related effects in the retrieval of conceptual and lexical knowledge for concrete entities: operationalization and analysis of factors.

Category-related effects in the retrieval of conceptual and lexical knowledge for concrete entities have been well documented in lesion studies, and also with functional imaging and electrophysiological approaches. For example, brain-damaged subjects may be impaired in the ability to recognize or to name animals but not tools, or the opposite pattern may obtain. One reason for these dissociations is that different patterns of defects tend to be caused by distinct lesion profiles, suggesting a relative tendency for certain neural systems to be involved in category-related knowledge. But we and others have also hypothesized that a variety of traits of concrete entities co-determine category-related dissociations. Such traits ('factors') include homomorphy (similarity of form), familiarity, value to perceiver, manipulability, characteristic motion, characteristic sensory modality of transaction (vision, touch, hearing), and typical age of acquisition. It is our view that the mix of factors relative to different conceptual categories plays a key role in the neuroanatomical distribution of records for those different categories, and is thus behind the systematic correlations between certain retrieval defects and damage to certain neural systems [12, 52]. In this study, we operationalized these factors and analyzed their intercorrelations. Stimuli were slides of 215 items from the conceptual categories of animals, fruits/vegetables, tools/utensils, vehicles, and musical instruments. The factors were operationalized on the basis of ratings obtained from 227 normal control subjects and on the basis of computer analyses of the digitized outlines of the stimuli. Principal components analysis revealed that 81% of the variability across items could be accounted for by three components: Component 1 (practically useful, common items): high value to perceiver, tactile mode of transaction, high familiarity, low age of acquisition; Component 2 (homomorphic, non-manipulable items): high homomorphy, low characteristic motion and manipulability; Component 3 (items with characteristic sound): hearing mode of transaction, highly distinctive sounds. In another analysis, we found that the categories of animals versus tools/utensils differed significantly on the factors of homomorphy, familiarity, value, manipulability, characteristic motion, and touch. The factor structure we identified in this study may help explain category-related performance defects in brain-damaged subjects. The results lend support to our proposal that systematic differences in physical characteristics and contextual specification of concrete entities constitute a driving force behind the regionalization of neural systems related to the acquisition and retrieval of conceptual and lexical knowledge.

Adolescent↗

PubMedDate not supplied

A hypothesis to explain the substrate reactivity of ribosomal and stem-loop RNA with ricin A-chain.

A hypothesis is proposed which explains the low catalytic efficiency of ricin A-chain on artifical stem-loop RNA substrates, relative to the high catalytic efficiency found on intact mammalian ribosomes. The enzymatic binding energy required to reach the transition state is greater than that to stabilize the stem structure of stem-loop RNA molecules. When artifical stem-loop complexes bind, the base-pairing of the stem is lost rapidly relative to catalysis. Loss of secondary structure causes movement of the susceptible adenine to a catalytically unfavorable geometry and most of the enzyme-substrate complexes dissociate without catalysis. The protein architecture of intact ribosomes, when bound to ricin A-chain, is proposed to stabilize the stem-loop structure to maintain adenine 4324 in a configuration external to the RNA phosphodiester backbone. The slow catalysis observed with small stem-loop structures is a consequence of the relative probabilities for stem-melting induced by the enzyme and for reaching the transition state. Catalysis with a ten-base stem-loop RNA shows product formation at a rate of up to 0.02 hr-1, but fails to achieve a full catalytic turnover with long incubations. The substoichiometry of product formation with small stem-loops is proposed to be a consequence of the competing rates of catalysis and enzyme denaturation under in vitro assay conditions. Rates for these processes are estimated from the kinetic parameters for ricin A-chain hydrolysis of ribosomes and stem-loop structures.

Humans↗

PubMed2001

Can contrast sensitivity functions in dyslexia be explained by inattention rather than a magnocellular deficit?

We examined whether data demonstrating contrast sensitivity losses in dyslexia that have been interpreted as evidence for loss of magnocellular visual function could be explained by inattention. Computer simulations of observers with poor concentration yielded inflated estimates of threshold that were a constant proportion of the true threshold across spatial frequencies. Data from many, but not all, studies supporting the magnocellular deficit theory are well described by these simulations, which predicted no interaction between observer group and spatial frequency. Some studies have reported significant interactions, but suffer from statistical deficiencies. This compromises some of the evidence for a magnocellular deficit in dyslexia derived from studies of threshold contrast sensitivity.

Analysis of Variance↗

PubMed2001

Is second-order spatial loss in amblyopia explained by the loss of first-order spatial input?

The purpose of the study was to determine whether amblyopes show detection loss for second-order spatial information, and if present, whether the loss is explained by the loss of first-order spatial input. We psychophysically determined detection thresholds for the amblyopic and non-amblyopic eyes of five adult amblyopes and the dominant eyes of three control observers. We found that four amblyopic eyes and two non-amblyopic eyes showed second-order loss relative to the control eyes. The second-order loss was greater than the first-order loss at the carrier spatial frequency (first-order input). The extra second-order loss indicates an early amplification of cortical neural loss that we speculate is due to deficient binocular input to second-order neurons.

Adult↗