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PubMed2002

Combined quantum chemical and RRKM modeling of the main fragmentation pathways of protonated GGG. II. Formation of b(2), y(1), and y(2) ions.

Quantum chemical and RRKM calculations were performed on protonated GGG in order to determine the atomic details of the main fragmentation pathways leading to formation of b(2),y(1), and y(2) ions. Formation of y(1) ions on the "diketopiperazine" pathway is initiated from relatively high-energy C-terminal amide nitrogen protonated species for which the N-terminal amide bond is in the cis isomerization state. The reaction goes through a transition structure which is only slightly less favored than the reactive configuration itself. RRKM calculations indicate that this reaction is extremely fast as soon as the fragmenting species have more internal energy than the reaction threshold. The calculated energetics suggests that y(1) ions are formed on the "diketopiperazine" pathway with a non-negligible (6-10 kcal/mol) reverse activation barrier. Investigation of species occurring during the formation of b(2) ions having an oxazolone structure indicates that y(1) ions can be formed also from intermediates previously thought to result in only b(2) ions. As the first step of the "b(x)-y(z)" pathway proposed here the extra proton must reach the nitrogen of the C-terminal amide bond. Attack of the N-terminal amide oxygen on the carbon center of the C-terminal amide bond results in formation of the oxazolone ring while the detaching G leaves the precursor ion. Under low-energy collision conditions the complex of protonated 2-aminomethyl-5-oxazolone and G can rearrange to form a proton-bonded dimer of these species. In such circumstances the extra proton is shared by the two monomers and dissociation of the dimer will be determined by the thermochemistry involved. Based on the "b(x)-y(z)" pathway one can easily explain the linear relationship between the logarithm of the y(1)/b(2) ion abundance ratio and the proton affinity of the C-terminal amino acid substituent for the series of H-Gly-Gly-Xxx-OH tripeptides where Xxx was varied (Morgan DG, Bursey MM. Org. Mass. Spectrom. 1994; 29: 354). The calculated energetics indicates that both y(1) and b(2) ions are formed with no reverse activation barrier on the "b(x)-y(z)" pathway.

Diketopiperazines↗

PubMed2005

Specific in vivo binding of activator of G protein signalling 1 to the Gbeta1 subunit.

Activator of G protein signalling 1 (AGS1) is a Ras-like protein that affects signalling through heterotrimeric G proteins. Previous in vitro studies suggest that AGS1 can bind to G(alpha)-GDP subunits and promote nucleotide exchange, leading to activation of intracellular signalling pathways. This model is consistent with in vivo evidence demonstrating that AGS1 activates both G(alpha)- and G(betagamma)-dependent pathways in the absence of ligand. However, it does not easily explain how AGS1 blocks G(betagamma)-dependent, but not G(alpha)-dependent, signalling following receptor activation. We have used yeast two hybrid analysis and co-immunoprecipitation studies in mammalian cells to demonstrate a direct interaction between AGS1 and the G(beta1) subunit of heterotrimeric G proteins. The interaction is specific for G(beta1) and involves the cationic region of AGS1 and the C-terminal region of G(beta1). Possible implications of this novel interaction for the activity of AGS1 are discussed.

Binding Sites↗

PubMed1993

Requirement for the polymerization and 5'-->3' exonuclease activities of DNA polymerase I in initiation of DNA replication at oriK sites in the absence of RecA in Escherichia coli rnhA mutants.

In previous studies, we found that the requirement for RecA protein in constitutive stable DNA replication (cSDR) can be bypassed by derepression of the LexA regulon and that DNA polymerase I (DNA PolI) is essential for this Rip (RecA-independent process) pathway of cSDR (Y. Cao, R. R. Rowland, and T. Kogoma, J. Bacteriol. 175:7247-7253, 1993). In this study, the role of DNA PolI in the Rip pathway was further examined. By using F' plasmids carrying different parts of the polA gene, a series of complementation tests was carried out to investigate the requirement for the three enzymatic activities, polymerization, 3'-->5' exonuclease, and 5'-->3' exonuclease activities, of DNA PolI. The result indicated that both the 5'-->3' exonuclease and polymerization activities of DNA PolI are essential for bypassing the requirement for RecA in cSDR but that the 3'-->5' exonuclease activity can be dispensed with. Complementation experiments with rat DNA Pol beta also supported the hypothesis that a nick translation activity is probably involved in cSDR in the absence of RecA. An analysis of DNA synthesis suggested that DNA PolI is involved in the initiation but not the elongation stage of cSDR. Moreover, the dnaE293(Ts) mutation was shown to render the bypass replication temperature sensitive despite the presence of active DNA PolI, suggesting that DNA PolIII is responsible for the elongation stage of the Rip pathway. A model which describes the possible roles of RecA in cSDR and the possible function of DNA PolI in the Rip pathway is proposed.

DNA Polymerase I↗

PubMed2001

Photodegradation of the pharmaceutical drug diclofenac in a lake: pathway, field measurements, and mathematical modeling.

Vertical concentration profiles of diclofenac were measured in Lake Greifensee (Switzerland) under mixed (February/December) and stratified (July) lake conditions. The concentrations ranged from 1 to 12 ng/L and were lower in summer than in winter, especially near the lake surface, pointing to an efficient elimination of diclofenac by photodegradation in the lake. Laboratory experiments confirmed the rapid photodegradation of diclofenac in water when exposed to sunlight. First-order reaction rates varied seasonally according to actual solar radiation (half-lives, tau = 0.2-1.7 h). The initial photoproduct was 8-chlorocarbazole-1-acetic acid, which photodegraded even faster than the parent compound. Carbazole-1-acetic acid, previously reported as the main photoproduct, was only formed in the presence of a H-source, such as methanol. In the absence of a H-source and of air, hydroxycarbazole-1-acetic acid was formed. However, hydroxycarbazole-1-acetic acid was not observed in the presence of air and, thus, under conditions similar to those in a lake, likely because of its rapid further photooxidation. Computer simulations using a one-dimensional lake model taking actual solar radiation and flushing data of the lake into account confirmed that photolysis is the predominant elimination pathway for diclofenac in Lake Greifensee. These calculations further showed that the expected concentrations of the photoproduct 8-chlorocarbazole-1-acetic acid are less than the current detection limits of approximately 3 ng/L.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2026

Molecular Pathways, Target Landscape, and Translational Models in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a substantial global health burden and the greatest unmet medical need for cardiovascular diseases. It is marked by pronounced clinical heterogeneity and complex multi-system pathophysiology with limited therapeutic options. Progress in developing effective therapeutics is constrained by the inadequacy of experimental models to fully recapitulate the multifactorial nature of the disease. Recent evidence underscores the significant involvement of inflammatory, oxidative, and mitochondrial pathways in the pathogenesis of HFpEF, with non-coding RNAs and epigenetic regulation serving as crucial modulators and prospective therapeutic targets. This review maps the HFpEF target landscape, while critically assessing the mechanistic contributions, translational fidelity, and limitations of existing in vivo and in vitro models. Further, advances are noted among the in vitro technologies, including human cardiac organoids and engineered heart tissues integrated with high-throughput multi-omics and computational modeling, enabling in-depth examination of HFpEF mechanisms. Finally, we underscore the necessity of integrative, systems-level approaches and multi-marker strategies to enhance translational relevance, improve risk stratification, and accelerate development of mechanism-based therapies. Collectively, this review supports phenotypic-guided and mechanism-informed therapeutic development for HFpEF, and provides a roadmap for next generation model development and therapeutic innovation.

Humans↗

PubMed1996

Complete mapping of crystallization pathways during cholesterol precipitation from model bile: influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems.

Using complementary physical-chemical techniques we defined five different crystallization pathways as functions of time (30 days) and increasing lecithin (egg yolk) content in pathophysiologically relevant model biles super-saturated (cholesterol saturation indices, 1.2 - 2.7) by dilution of approximately equal to 29 g/dl bile salt-lecithin-cholesterol micellar solutions. As evidenced by quasi-elastic light-scattering spectroscopy, supersaturation was heralded by the appearance of unilamellar vesicles. With the lowest lecithin contents, arc-like crystals with habit and density (d 1.030 g/mL) consistent with anhydrous cholesterol appeared first and evolved via helical and tubular crystals to form plate-like cholesterol monohydrate crystals (d 1.045 g/mL). With higher lecithin fractions, cholesterol monohydrate crystals appeared earlier than arc and other transitional crystals. With typical physiological lecithin contents, early liquid crystals (d 1.020 g/mL) were followed by cholesterol monohydrate crystals and subsequent appearances of arc and other intermediate crystals. With higher lecithin contents, liquid crystals were followed by cholesterol monohydrate crystals only, and at the highest lecithin mole fractions, liquid crystals appeared that did not generate solid crystals. Added calcium increased solid crystal number in proportion to its concentration (5 - 20 mM) but did not influence appearance times, crystallization pathways, or micellar cholesterol solubilities. Decreases in temperature (37 degrees --> 4 degrees C), total lipid concentration (7.3 --> 2.4 g/dL), and bile salt hydrophobicity (3 alpha, 12 alpha --> 3 alpha, 7 alpha, 12 alpha --> 3 alpha, 7 beta hydroxylated taurine conjugates) progressively shifted all crystallization pathways to lower lecithin contents, retarded crystallization, and decreased micellar cholesterol solubilities. The lecithin content of mother biles decreased markedly during crystallization especially where liquid crystals were a coexisting phase at equilibrium. This systematic study provides a framework for understanding cholesterol crystallization in human and animal biles and for examining factors that influence the kinetics of phase separation.

Bile↗

PubMed1994

Molecular models that may account for nitrous acid mutagenesis in organisms containing double-stranded DNA.

Nitrous acid (NA) is often presumed to cause base substitutions in organisms with double-stranded DNA as a direct consequence of oxidative deamination of adenine and of cytosine residues. Here we summarize evidence indicating that other mechanisms are involved in the case of NA-induced G/C-->A/T transition mutations. We present several models for pathways of NA mutagenesis that may account for our experimental results and overlapping data noted in the literature. One model proposes that the base substitution mutations observed are due to DNA alkylation damage mediated via nitrosation of polyamines and/or other ubiquitous cellular molecules. Other models assume that predisposing lesions, such as G-to-G cross-links, are first formed. The cross-links are pictured as leading to perturbations in DNA structure that allow subsequent opportunity for NA-induced deaminations of cytosine residues in their immediate vicinity. The deaminations preferentially result in G/C-->A/T transition mutations at sites highly dependent on adjoining base sequence context (i.e., in NA "mutational hotspots"). A final model proposes that NA-induced G/C-->A/T transition mutations arise mainly from oxidative deamination of guanosine residues and not from deamination of cytosine residues in duplex DNA.

Adenine↗

PubMed1999

Horizontal vestibuloocular reflex evoked by high-acceleration rotations in the squirrel monkey. I. Normal responses.

The horizontal angular vestibuloocular reflex (VOR) evoked by high-frequency, high-acceleration rotations was studied in five squirrel monkeys with intact vestibular function. The VOR evoked by steps of acceleration in darkness (3,000 degrees /s(2) reaching a velocity of 150 degrees /s) began after a latency of 7.3 +/- 1.5 ms (mean +/- SD). Gain of the reflex during the acceleration was 14.2 +/- 5.2% greater than that measured once the plateau head velocity had been reached. A polynomial regression was used to analyze the trajectory of the responses to steps of acceleration. A better representation of the data was obtained from a polynomial that included a cubic term in contrast to an exclusively linear fit. For sinusoidal rotations of 0.5-15 Hz with a peak velocity of 20 degrees /s, the VOR gain measured 0.83 +/- 0.06 and did not vary across frequencies or animals. The phase of these responses was close to compensatory except at 15 Hz where a lag of 5.0 +/- 0.9 degrees was noted. The VOR gain did not vary with head velocity at 0.5 Hz but increased with velocity for rotations at frequencies of >/=4 Hz (0. 85 +/- 0.04 at 4 Hz, 20 degrees /s; 1.01 +/- 0.05 at 100 degrees /s, P < 0.0001). No responses to these rotations were noted in two animals that had undergone bilateral labyrinthectomy indicating that inertia of the eye had a negligible effect for these stimuli. We developed a mathematical model of VOR dynamics to account for these findings. The inputs to the reflex come from linear and nonlinear pathways. The linear pathway is responsible for the constant gain across frequencies at peak head velocity of 20 degrees /s and also for the phase lag at higher frequencies being less than that expected based on the reflex delay. The frequency- and velocity-dependent nonlinearity in VOR gain is accounted for by the dynamics of the nonlinear pathway. A transfer function that increases the gain of this pathway with frequency and a term related to the third power of head velocity are used to represent the dynamics of this pathway. This model accounts for the experimental findings and provides a method for interpreting responses to these stimuli after vestibular lesions.

Acceleration↗

PubMed1992

A comparative investigation of hepatic clearance models: predictions of metabolite formation and elimination.

Liver clearance models serve to improve our understanding of the relationships between the physiological determinants and hepatic clearance and predict changes in the disposition of substrates when homeostasis of the organ is perturbed. Their ability to describe metabolism was presently extended to the sequential formation and elimination of primary (M1), secondary (M2), and tertiary (M3) metabolites during a single passage of drug (P) across the liver, under steady state and first-order conditions. The well-stirred model is distinct from other models in that metabolite formation and elimination is independent of enzymic distributions, the number of steps involved in metabolite formation, and the intrinsic clearances of the precursors. This model predicts that the extraction ratio of a formed primary metabolite derived from drug (E[M1, P]) is identical to that for the preformed primary metabolite (E[M1]), and that the extraction ratios of a secondary metabolite derived from drug (E[M2, P]) and primary metabolite (E[M2, M1]) or preformed secondary metabolite (E[M2]) are identical. For the more physiologically acceptable, parallel-tube and dispersion models, metabolite sequential elimination is highly influenced by the intrinsic clearances of the precursors and the enzymic distributions that mediate removal of precursor species and the metabolites. Furthermore, the extent of sequential metabolism recedes as the number of steps involved for metabolite formation increases. These models predict that E[M1, P] less than E[M1], and E[M2, P] less than E[M2, M1] less than E[M2], with the magnitude of the changes being less for the dispersion model than for the parallel-tube model. Competing pathways that divert substrate from entering the sequential pathway were found to exert only minimal influence on the sequential pathway.

Liver↗

PubMed2006

Trends in sea ice cover within habitats used by bowhead whales in the western Arctic.

We examined trends in sea ice cover between 1979 and 2002 in four months (March, June, September, and November) for four large (approximately 100,000 km2) and 12 small (approximately 10,000 km2) regions of the western Arctic in habitats used by bowhead whales (Balaena mysticetus). Variation in open water with year was significant in all months except March, but interactions between region and year were not. Open water increased in both large and small regions, but trends were weak with least-squares regression accounting for < or =34% of the total variation. In large regions, positive trends in open water were strongest in September. Linear fits were poor, however, even in the East Siberian, Chukchi, and Beaufort seas, where basin-scale analyses have emphasized dramatic sea ice loss. Small regions also showed weak positive trends in open water and strong interannual variability. Open water increased consistently in five small regions where bowhead whales have been observed feeding or where oceanographic models predict prey entrainment, including: (1) June, along the northern Chukotka coast, near Wrangel Island, and along the Beaufort slope; (2) September, near Wrangel Island, the Barrow Arc, and the Chukchi Borderland; and (3) November, along the Barrow Arc. Conversely, there was very little consistent change in sea ice cover in four small regions considered winter refugia for bowhead whales in the northern Bering Sea, nor in two small regions that include the primary springtime migration corridor in the Chukchi Sea. The effects of sea ice cover on bowhead whale prey availability are unknown but can be modeled via production and advection pathways. Our conceptual model suggests that reductions in sea ice cover will increase prey availability along both pathways for this population. This analysis elucidates the variability inherent in the western Arctic marine ecosystem at scales relevant to bowhead whales and contrasts basin-scale depictions of extreme sea ice retreats, thinning, and wind-driven movements.

Animals↗

PubMedDate not supplied

A neural model of foveal light adaptation and afterimage formation.

Psychophysical research has documented the existence of three processes in light adaptation: a fast subtractive process, a divisive process that is fast at light onset and slower at light offset, and a very slow subtractive process (Hayhoe et al., 1987). In the neural model developed here, the fast subtractive process is identified with horizontal cell feedback onto cones and the divisive process with amacrine cell feedback onto bipolar cells. The very slow subtractive process is identified with the modulatory feedback circuit from amacrines via interplexiform cells to horizontal cells. A nonlinear dynamical model is developed incorporating these aspects of retinal circuitry along with both ON- and OFF-center M and P pathways. This model is shown to account for many aspects of foveal light adaptation, including negative afterimage formation, and to explain a number of the physiological differences between M and P ganglion cells, including their differing contrast-response functions.

Adaptation, Physiological↗

PubMed2007

An oncogenetic tree model in gastrointestinal stromal tumours (GISTs) identifies different pathways of cytogenetic evolution with prognostic implications.

To model the cytogenetic evolution in gastrointestinal stromal tumour (GIST), an oncogenetic tree model was reconstructed using comparative genomic hybridization data from 203 primary GISTs (116 gastric and 87 intestinal GISTs, including 151 newly analysed cases), with follow-up available in 173 cases (mean 40 months; maximum 133 months). The oncogenetic tree model identified three major cytogenetic pathways: one initiated by -14q, one by -1p, and another by -22q. The -14q pathway mainly characterized gastric tumours with predominantly stable karyotypes and more favourable clinical course. On the other hand, the -1p pathway was more characteristic of intestinal GISTs, with an increased capacity for cytogenetic complexity and more aggressive clinical course. Loss of 22q, more closely associated with -1p than -14q, appeared to initiate the critical transition to an unfavourable cytogenetic subpathway. This -22q pathway included accumulation of +8q, -9p, and -9q, which could all predict disease-free survival in addition to tumour site. Thus, insights into the cytogenetic evolution obtained from oncogenetic tree models may eventually help to gain a better understanding of the heterogeneous site-dependent biological behaviour of GISTs.

Chromosome Aberrations↗

PubMed1996

13C isotopomer model for estimation of anaplerotic substrate oxidation via acetyl-CoA.

A previous model using 13C nuclear magnetic resonance isotopomer analysis provided for direct measurement of the oxidation of 13C-enriched substrates in the tricarboxylic acid cycle and/or their entry via anaplerotic pathways. This model did not allow for recycling of labeled metabolites from tricarboxylic acid cycle intermediates into the acetyl-CoA pool. An extension of this model is now presented that incorporates carbon flow from oxaloacetate or malate to acetyl-CoA. This model was examined using propionate metabolism in the heart, in which previous observations indicated that all of the propionate consumed was oxidized to CO2 and water. Application of the new isotopomer model shows that 2 mM [3-13C]propionate entered the tricarboxylic acid cycle as succinyl-CoA (an anaplerotic pathway) at a rate equal to 52% of tricarboxylic acid cycle turnover and that all of this carbon entered the acetyl-CoA pool and was oxidized. This was verified using standard biochemical analysis; from the rate (mumol.min-1.g dry wt-1) of propionate uptake (4.0 +/- 0.7), the estimated oxygen consumption (24.8 +/- 5) matched that experimentally determined (24.4 +/- 3).

Acetyl Coenzyme A↗

PubMed2003

Dynamical clustering of red blood cells in capillary vessels.

We have modeled the dynamics of a 3-D system consisting of red blood cells (RBCs), plasma and capillary walls using a discrete-particle approach. The blood cells and capillary walls are composed of a mesh of particles interacting with harmonic forces between nearest neighbors. We employ classical mechanics to mimic the elastic properties of RBCs with a biconcave disk composed of a mesh of spring-like particles. The fluid particle method allows for modeling the plasma as a particle ensemble, where each particle represents a collective unit of fluid, which is defined by its mass, moment of inertia, translational and angular momenta. Realistic behavior of blood cells is modeled by considering RBCs and plasma flowing through capillaries of various shapes. Three types of vessels are employed: a pipe with a choking point, a curved vessel and bifurcating capillaries. There is a strong tendency to produce RBC clusters in capillaries. The choking points and other irregularities in geometry influence both the flow and RBC shapes, considerably increasing the clotting effect. We also discuss other clotting factors coming from the physical properties of blood, such as the viscosity of the plasma and the elasticity of the RBCs. Modeling has been carried out with adequate resolution by using 1 to 10 million particles. Discrete particle simulations open a new pathway for modeling the dynamics of complex, viscoelastic fluids at the microscale, where both liquid and solid phases are treated with discrete particles. Figure A snapshot from fluid particle simulation of RBCs flowing along a curved capillary. The red color corresponds to the highest velocity. We can observe aggregation of RBCs at places with the most stagnant plasma flow.

Animals↗

PubMed2002

Regional radiation risk and vulnerability assessment by integration of mathematical modelling and GIS analysis.

The Kola Peninsula, Russian Arctic exceeds all other regions in the world in the number of nuclear reactors. The study was aimed at estimating possible radiation risks to the population in the Nordic countries in case of a severe accident in the Kola Peninsula. Two approaches were tested: (1) probabilistic analysis of modelled possible pathways of radionuclide transport and precipitation and (2) deterministic approach (case studies) for most possible or worst-case scenarios of modelled transport and deposition of radionuclides. For the general population, Finland is at most risk with respect to the Kola nuclear power plant (NPP) because of (a) relatively high population density or proximity to the radiation-risk sites and (b) rather high probability of an airflow trajectory there and precipitation. After considering the critical group, northern counties in Norway, Finland and Sweden appear to be most vulnerable. The case scenarios demonstrate that population in many counties in each country, both near and far away from a nuclear site, might be subject to high risk depending on the meteorological situation.

Air Movements↗

PubMed2000

Risk factors for depression in later life; results of a prospective community based study (AMSTEL).

BACKGROUND: Depression in the elderly was found to be associated with a variety of risk-factors in cross sectional designs. Based on the vulnerability-stress model, etiologic pathways for depression have been suggested, with vulnerability modifying the effect of stress factors. The current prospective study tests an etiologic model for depression incidence, by assessing modifying effects of three types of vulnerability: genetic/familial vulnerability, organic vulnerability, and environmental vulnerability. METHODS: 1940 non-depressed community-living elderly were interviewed at baseline, and at follow-up three years later. Bivariate and multivariate relationships between risk factors and incident depression (GMS-AGECAT) were studied. RESULTS: Higher age, personal history of depression, death of spouse, health related factors and comorbid organic or anxiety syndrome showed significant bivariate associations with depression incidence. In multivariate analysis, the effect of stress factors on incident depression was not modified by a genetic/familial vulnerability, nor by an organic vulnerability. Effect modification by environmental factors was however evident; having a marital partner, and if unmarried having social support, significantly reduced the impact of functional disabilities on the incidence of depression. LIMITATIONS: The study consisted of two measurements with a three years interval, depressive episodes with a short duration may be under-represented. CONCLUSIONS: In the elderly, the effect of stress on incident depression is modified by environmental vulnerability. No evidence was found of effect modification by either genetic/familial or organic vulnerability. The results have implications for both recognition and treatment of late-life depression.

Age Factors↗

PubMed1996

Fluorescent probe studies of the interactions of 1-alkyl-2-pyrrolidones with stratum corneum lipid liposomes.

Previously, the effects of a series of 1-alkyl-2-pyrrolidones (APs; C2-C8) on the lipoidal pathway of hairless mouse skin (HMS) were studied with a parallel pathway skin model. At their isoenhancement concentrations, these 1-alkyl-2-pyrrolidones induce the same transport enhancement (isoenhancement factor, EHMS) on the lipoidal pathway of the stratum comeum for the probe permeants studied. In the present study, the fluidizing effects of APs upon the stratum comeum lipid liposome (SCLL) bilayer were investigated under these isoenhancement conditions using steady state anisotropy and fluorescence lifetime studies with fluorescent probes 2-, 6-, and 9-(9-anthroyloxy)stearic acids, 16-(9-anthroyloxy)palmitic acid, and 1,6-diphenyl-1,3,5-hexatriene to examine a possible correlation between the fluidizing properties of APs and their enhancement effects on transdermal drug transport. Time-resolved fluorescence decay studies were also conducted to further investigate the fluidizing properties of APs and add support to the steady-state fluorescence results. Under an isoenhancement condition of EHMS = 10, these APs fluidized the alkyl chains of the lipids at intermediate depths (C6-C9) in the SCLL bilayer (a 40-50% decrease in the rotational correlation times) but did not significantly change the fluidity in the deep hydrophobic region of the bilayer. Three rotational correlation times were deduced from the global simultaneous analysis in time-resolved fluorescence decay measurements. The slowest of these (greater than 1000 ns) was attributed to the global motion of SCLLs and is probably related to the static component of steady-state anisotropy. The other two rotational correlation times (on the order of nanoseconds) were in the range expected for the local motion of the fluorophores and may correspond to their vibrational and rotational motions. When the concentrations of APs were increased (increasing the EHMS value), the static component (alpha) decreased. This suggests that APs might induce a general fluidizing effect upon the lipid bilayer (i.e., a decrease in the order of the lipid bilayer). The decrease in the longer rotational correlation time (on the order of nanoseconds) with increasing EHMS value, on the other hand, indicates a possible increase in the "cavity volume" for the hindered motions of the fluorophores (i.e., an increase in the free volume at intermediate depths in the bilayer).

Animals↗

PubMed1994

A model for the tissue factor pathway to thrombin. II. A mathematical simulation.

A mathematical simulation of the tissue factor pathway to the generation of thrombin has been developed using a combination of empirical, estimated, and deduced rate constants for reactions involving the activation of factor IX, X, V, and VIII, in the formation of thrombin, as well as rate constants for the assembly of the coagulation enzyme complexes which involve factor VIIIa-factor IXa (intrinsic tenase) and factor Va-Xa (prothrombinase) assembled on phospholipid membrane. Differential equations describing the fate of each species in the reaction were developed and solved using an interactive procedure based upon the Runge-Kutta technique. In addition to the theoretical considerations involving the reactions of the tissue factor pathway, a physical constraint associated with the stability of the factor VIIIa-factor IXa complex has been incorporated into the model based upon the empirical observations associated with the stability of this complex. The model system provides a realistic accounting of the fates of each of the proteins in the coagulation reaction through a range of initiator (factor VIIa-tissue factor) concentrations ranging from 5 pM to 5 nM. The model is responsive to alterations in the concentrations of factor VIII, factor V, and their respective activated species, factor VIIIa and factor Va, and overall provides a reasonable approximation of empirical data. The computer model permits the assessment of the reaction over a broad range of conditions and provides a useful tool for the development and management of reaction studies.

Blood Coagulation Factors↗