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PubMed2006

Polyoxyethylene fatty acid esters as potential promotors of transdermal absorption for morphine hydrochloride and sulphate.

The presence of opioid receptors mu in pathologically changed skin and mucosa justifies application of preparations with morphine salts to obtain topical analgesic activity. Numerous factors associated with the vehicle and therapeutic agent physiochemical properties affect the capability and rate of penetration of a therapeutic substance in the form of a drug into dermis. Promotors of transcutaneous absorption, which weaken the integrity of epidermal corneal layer and thus, increase therapeutic substance penetration play more and more important role. In this study non-ionic macromolecular surface active compounds from Rokacets group were suggested as potential promotors of transdermal absorption for morphine sulphate and hydrochloride. The aim of the study was to work out prescription composition of ointment with morphine salts of optimal rheological and morphological parameters and high pharmaceutical availability of the therapeutic agent (morphine sulphate, hydrochloride). Three model emulsive ointment vehicles were prepared and selected promoters of transdermal absorption were introduced into them. On the basis of the formed vehicles ointments were made with morphine sulphate and hydrochloride. The obtained vehicles and ointment preparations were subjected to rheological tests. Spreadness was determined by extensometric method and viscosity with digital cone-plate rheometer. Morphological parameters of the vehicles and ointments, such as: pH and pharmacopeal density were estimated. Carrying out direct diffusion from the surface of the preparation to acceptor fluid (to water), the amount of the released therapeutic substance in time function was determined by spectrophotometric method. The performed tests demonstrated that the investigated vehicles and ointments are non-Newtonian systems, viscoelastic and highly thixotropic. The kind of morphine salt affects the spreadness and viscosity of model ointments. Preparations with morphine hydrochloride have higher spreadness than viscosity and more alkaline pH. From among the investigated non-ionic surface active compounds Rokacet R-40 appeared to be the most beneficial promotor of transdermal absorption for both pharmacopeal morphine salts. Pharmaceutical availability of morphine sulphate and hydrochloride is the highest from ointments with its content in the vehicle prescription.

Administration, Cutaneous↗
PubMed2004

External optimal control of self-organisation dynamics in a chemotaxis reaction diffusion system.

Detailed quantitative understanding and specific external control of cellular behaviour are general long-term goals of modem bioscience research activities in systems biology. Pattern formation and self-organisation processes both in single cells and in distributed cell populations are phenomena which are highly significant for the functionality of life, because life requires to maintain a highly organised spatiotemporal system structure. In particular chemotaxis is crucial for various biological aspects of intercellular signalling and cell aggregation. As an example for model based control of self-organising biological systems, we describe numerical optimal control of E. coli bacterial chemotaxis based on a 1-D two-component partial differential equation (PDE) model of reaction diffusion type. We present a numerical scheme to force cell aggregation patterns to particular desired results by applying a boundary influx control of chemoattractant without interfering with the system itself. Optimal controls are numerically computed by using a specially tailored interior point optimisation technique applied to a direct collocation discretisation of the control function and the PDE constraint. The objective to be minimised is the deviation of a desired cell distribution from the cell density, which results from the dynamics of the controlled system.

Bacterial Proteins↗
PubMed1999

Mathematical models for peritoneal transport characteristics.

Four mathematical models and for the description of peritoneal transport of fluid solutes are reviewed. The membrane model is usually applied for (1) separation of transport components, (2) formulation of the relationship between flow components and their driving forces, and (3) estimation of transport parameters. The three-pore model provides correct relationships between various transport parameters and demonstrates that the peritoneal membrane should be considered heteroporous. The extended three-pore model discriminates between heteroporous capillary wall and tissue layer, which are assumed to be arranged in series; the model improves and modifies the results of the three-pore model. The distributed model includes all parameters involved in peritoneal transport and takes into account the real structure of the tissue with capillaries distributed at various distances from the surface of the tissue. How the distributed model may be applied for the evaluation of the possible impact of perfusion rate on peritoneal transport, as recently discussed for clinical and experimental studies, is demonstrated. The distributed model should provide theoretical bases for the application of other models as approximate and simplified descriptions of peritoneal transport. However, an unsolved problem is the theoretical description of bi-directional fluid transport, which includes ultrafiltration to the peritoneal cavity owing to the osmotic pressure of dialysis fluid and absorption out of the peritoneal cavity owing to hydrostatic pressure.

Biological Transport↗
PubMedDate not supplied

Biomaterial calcification without direct material-cell interaction.

This report summarizes 1) features of the local redistribution of calcium ions and formation of complexes with calcium (Ca) in the presence of polymer samples; 2) the adsorption of Ca ions and Ca containing complexes onto biomaterial surfaces; 3) the character and composition of Ca containing deposits; and 4) the role of cellular and humoral factors in calcification. All experiments were done with three types of medical grade polymer material (from USSR): silicone rubber (SR), polyurethane "Vitur" (PU), and polyethylene (PE). Biochemical, radioisotopic, SEM, and EDAX methods were used in in vitro and in vivo experiments. The diffusion chamber model was used in animal experiments. SR was shown to induce greater changes in complex formation processes and to adsorb more Ca containing complexes than PE or PU. In addition to the degree of SR calcification seen after 21 days, implantation accentuated these findings. The possibility of calcification of polymer materials without direct contact of material and cells was observed. Combining the in vitro and in vivo experimental data, the authors propose a hypothetical scheme of biomaterial calcification.

Adsorption↗
PubMed2003

Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium.

PURPOSE: The purpose of this work was to elucidate the asymmetric effect of P-gp on modulation of absorptive and secretory transport of compounds across polarized epithelium, to develop experimental parameters to quantify P-gp-mediated modulation of absorptive and secretory transport, and to elucidate how P-gp-mediated modulation of transport is affected by passive diffusion properties, interaction of the substrate with P-gp, and P-gp expression. METHODS: The permeability of a set of P-gp substrates was determined in absorptive and secretory directions in Madine-Darby Canine kidney (MDCK), Caco-2, and MDR-MDCK monolayers. The transport was also determined in the presence of GW918, a non-competitive P-gp inhibitor, to quantify the permeability without the influence of P-gp. From these two experimental permeability values in each direction, two new parameters, absorptive quotient (AQ) and the secretory quotient (SQ), were defined to express the functional activity of P-gp during absorptive and secretory transport, respectively. Western blot analysis was used to quantify P-gp expression in these monolayers and in normal human intestinal. RESULTS: P-gp expression in Caco-2 and MDR-MDCK monolayers was comparable to that in normal intestine, and much less in MDCK cells. For all models, the substrates encompassed a wide range of apparent permeability due to passive diffusion (PPD). The parameters AQ and SQ, calculated for all compounds, assessed the attenuation in absorptive and enhancement of secretory transport, respectively, normalized to the permeability due to passive diffusion. Analysis of these parameters showed that 1) P-gp affected absorptive and secretory transport differentially and 2) compounds could be stratified into distinct groups with respect to the modulation of their absorptive and secretory transport by P-gp. Compounds could be identified whose absorptive transport was either strongly affected or poorly affected by changes in P-gp expression. For certain compounds, AQ values showed parabolic relationship with respect to passive diffusivity, and for others AQ was unaffected by changes in passive diffusivity. CONCLUSIONS: The relationship between attenuation of absorptive transport and enhancement of secretory transport of compounds by P-gp is asymmetric, and different for different sets of compounds. The relationship between attenuation of absorption by P-gp and passive diffusivity of compounds, their interaction potential with P-gp, and levels of P-gp expression is complex; however, compounds can be classified into sets based on these relationships. A classification system that describes the functional activity of P-gp with respect to modulation of absorptive and secretory transport was developed from these results.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Survival, neuronal differentiation, and fiber outgrowth of propagated human neural precursor grafts in an animal model of Huntington's disease.

Expanded neural precursor cells provide an attractive alternative to primary fetal tissue for cell replacement therapies in neurodegenerative diseases. In this study we transplanted epigenetically propagated human neural precursor cells into a rat model of Huntington's disease. Neural precursors survived transplantation and large numbers differentiated to express neuronal antigens, including some that expressed DARPP-32, indicating a mature striatal phenotype had been adopted. Neuronal fibers from the grafts projected diffusely throughout the host brain, although there was no evidence that outgrowth was specifically target directed. This study supports the contention that propagated human neural precursors may ultimately be of use in therapeutic neural transplantation paradigms for diseases such as Huntington's disease.

Acetylcholinesterase↗
PubMed2000

What is the precise role of human MDR 1 protein in chemotherapeutic drug resistance?

Elucidating the molecular function of hu MDR 1 protein (also called P-glycoprotein or P-gp 1) and the precise role this protein plays in clinically relevant tumor drug resistance remains a perplexing problem. Hundreds of reports over the past decades summarize a dizzying array of observations relevant to hu MDR 1 protein function. A dominant model in the MDR literature that is used to explain many observations is the well known "drug pump" model first suggested by Keld Dano in 1973 [1]. Although this model has proved useful in conceptualizing additional experiments, it violates fundamental laws of biology and chemistry and in well over a decade of intense effort, active outward drug pumping via hu MDR 1 protein has still never been unequivocally measured. Also, in recent years it has become clear that the drug pump model cannot explain several important phenomena that are highly relevant to the cancer clinic. Thus, other models have also proved increasingly popular. One is the altered partitioning model, which does not violate fundamental laws, is consistent with the vast majority of available data, and has important predictive ability. This newer model has several novel facets that are relevant for cancer pharmacology, and that help explain phenomena not explained by the drug pump model. The basic principle of this model is that MDR proteins do not directly transport drugs, but that their altered expression leads to altered regulation of ion transport or signal transduction that is critical for setting key biophysical parameters of the cell (e.g. compartmental pH and membrane potentials) that dictate relative passive diffusion of drugs as well as important signal transduction linked to the cytotoxic actions of these drugs. Along with debate over the molecular details of hu MDR 1 function, additional controversy surrounds the precise role of hu MDR 1 in the clinic. Many investigators now debate the significance of its function (regardless of precise mechanism) with regard to "real" drug resistance phenotypes exhibited in the clinic. I believe that thorough debate on the pros and cons of various molecular models for hu MDR 1 function will help to address confusion over the clinical relevance of hu MDR1. In the current atmosphere of disappointment over the relative success of clinical trials based in large part on the logic of the drug pump model, it is important that we not lose sight of critical points. Namely, hu MDR 1 protein remains an extremely important window in on the complex pathways that lead to induced chemotherapeutic drug resistance. Exploring the rationale behind newer models for hu MDR 1 function leads to key predictions that can be tested.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

[Overgrowth and DNA synthesis of neuroepithelium in embryonic stages of induced Long-Evans rat myeloschisis].

Overgrowth of the myeloschisis, namely the excessive amount of the neural plate tissue, has been reported in the human myeloschisis. However, it is still debatable how the overgrowth develops and whether the overgrowth is the cause, or the secondary effect of spinal dysraphism. The author induced myeloschisis in the fetuses of Long-Evans rats by the administration of ethylenethiourea (ETU) to pregnant rats on day 10 of gestation. The fetuses were removed 1 hour after the treatment with bromodeoxyuridine (BrdU) to the dams on day 14 and 21. The fetuses were fixed in alcohol and embedded in paraffin. H-E staining and the immunohistologic examination were performed on the staining patterns to anti-neurofilament (NFP), anti-glial fibrillary acidic protein (GFAP) and anti-BrdU antibody by ABC method. On day 14, the lateral portion of everted neural plate showed a loose arrangement of cells and there was rosette formation in the mesoderm. On day 21, cell necrosis was observed at the dorsolateral portion of myeloschisis, although the ventral portion showed almost normal cytoarchitecture and was positive to NFP and GFAP. The cause of myeloschisis in this model is supposed to be the local and direct cytotoxic effect of ETU to neuro-ectodermal junction. On day 14, control animals contained few BrdU-incorporated cells at the basal plate of neural tube. In contrast, everted neural plate showed an active uptake of BrdU diffusely in the subependymal matrix layer cells. Overgrowth was not yet identified. On day 21, overgrowth of myeloschisis was found in spite of a few positive cells to BrdU which was identical to the control animals. These findings seem to suggest that cells in the myeloschisis retain their ability of DNA synthesis for longer periods of development and overgrowth found on day 21 is possibly a secondary effect of spinal dysraphism in this model.

Animals↗
PubMed1999

Re-evaluation of the oxygen diffusion model for predicting minimum contact lens Dk/t values needed to avoid corneal anoxia.

PURPOSE: (1) To update Fatt's mathematical model of the distribution of oxygen tension (pO2) across the cornea and contact lens (CL) to include the recent finding that corneal oxygen consumption increases with the acidification that occurs with CL wear. (2) To estimate the minimum transmissibility (CL Dk/t) to avoid epithelial anoxia or to avoid stromal anoxia. METHODS: A five-layer static and one-dimensional mathematical model of oxygen diffusion through the cornea based on Fatt's models was used. The relationships between acidosis and increased QO2, and acidosis and CL Dk/t were used to estimate corneal QO2 for a given CL Dk/t. RESULTS: (1) Revised model predictions are in agreement with direct tear pO2 measurements beneath CLs in the rabbit. (2) For the human eye, the minimum CL Dk/t for oxygen delivery to the basal epithelial cells was determined to be 23 for the open eye and 89 for the closed eye. To prevent anoxia throughout the entire corneal thickness the Dk/t requirements are 35 for the open eye and 125 for the closed eye. CONCLUSIONS: (1) Model predictions of the oxygen distribution beneath contact lenses are significantly lower than previous models that did not include the effect of acidosis on corneal QO2. (2) Minimum Dk/t values that allow oxygen delivery to the basal epithelium are in agreement with the Dk/t needed to avoid corneal edema.

Acidosis↗
PubMed2006

A three-dimensional model of myxobacterial fruiting-body formation.

Myxobacterial cells are social; they swarm by gliding on surfaces as they feed cooperatively. When they sense starvation, tens of thousands of cells change their movement pattern from outward spreading to inward concentration and form aggregates that become fruiting bodies. Cells inside fruiting bodies differentiate into round, nonmotile, environmentally resistant spores. Traditionally, cell aggregation has been considered to imply chemotaxis, a long-range cell interaction that shares many features of chemical reaction-diffusion dynamics. The biological evidence, however, suggests that Myxococcus xanthus aggregation is the consequence of direct cell-contact interactions that are different from chemotaxis. To test whether local interactions suffice to explain the formation of fruiting bodies and the differentiation of spores within them, we have simulated the process. In this article, we present a unified 3D model that reproduces in one continuous simulation all the stages of fruiting-body formation that have been experimentally observed: nonsymmetric initial aggregates (traffic jams), streams, formation of toroidal aggregates, hemispherical 3D mounds, and finally sporulation within the fruiting body.

Cell Communication↗
PubMed2005

Colloid filtration theory and the Happel sphere-in-cell model revisited with direct numerical simulation of colloids.

The transport of colloids and bacterial cells through saturated porous media is a complex phenomenon involving many interrelated processes that are often treated via application of classical colloid filtration theory (CFT). This paper presents a numerical investigation of CFT from the Lagrangian perspective, to evaluate the role of some of the classical assumptions underlying the theory and to demonstrate a means to include processes relevant to bacterial transport that were inadequately characterized or neglected in the original formulation, including Brownian diffusion and potentially hysteretic potential functions. The methodology is based on conducting a Lagrangian trajectory analysis within Happel's sphere-in-cell porous media model to obtain the collection efficiency (eta), the frequency at which colloids or bacteria make contact with the solid phase of the porous medium. The Lagrangian framework of our model lends itself to mechanistic modeling of the biological processes that may be important in subsurface bacterial transport. The numerical study presented here focuses on the size range of bacterial colloids and smaller (down to 10 nm). Results of our model runs are in good agreement with the deterministic trajectory analysis of Rajagopalan and Tien (when diffusion is neglected) and in excellent agreement with the analytical solution to the Smoluchowski-Levich approximation of the convective-diffusion equation (when external forces and interception are neglected). Simple addition of our result for the deterministic eta to our result for the Smoluchowski-Levich eta matches the overall Rajagopalan and Tien eta to within 5% error or less for all cases studied. When we simulate diffusion and the deterministic forces together, our results diverge from the Rajagopalan and Tien eta as the particle size decreases, with discrepancies as large as 73%. These results suggest that accurate prediction of eta values for bacteria-sized (and all submicrometer) colloids requires simultaneous consideration of the primary transport mechanisms.

Journal Article↗
PubMed1990

Mathematical modeling of the excitation process in myocardial tissue: influence of fiber rotation on wavefront propagation and potential field.

In our macroscopic model the heart tissue is represented as a bidomain coupling the intra- and extracellular media. Owing to the fiber structure of the myocardium, these media are anisotropic, and their conductivity tensors have a principal axis parallel to the local fiber direction. A reaction-diffusion system is derived that governs the distribution and evolution of the extracellular and transmembrane potentials during the depolarization phase of the heart beat. To investigate frontlike solutions, the system is rescaled and transformed into a system dependent on a small parameter. Subsequently a perturbation analysis is carried out that yields zero- and first-order approximations called eikonal equations. The effects of the transmural fiber rotation on wavefront propagation and the corresponding potential field, elicited by point stimulations, are investigated by means of numerical simulations.

Animals↗
PubMed1994

Free concentrations of intracellular fluorescent anions determined by cytoplasmic dialysis of isolated hepatocytes.

Intracellular organic ions exist in free solution bound to cytoplasmic proteins, partitioned within intracellular membranes, and enclosed in intracellular vesicles and organelles. The aim of this study was to develop a method for measurement of the free cytosolic concentration of organic ions. This was accomplished by measuring initial rates of diffusion between patch-clamp pipettes and cell cytoplasm and determining the null-point concentration of this process. Carboxydimethylfluorescein (CF) was used as a model compound. It readily diffused between cytoplasm and pipette, and there was a linear relationship between concentration in the pipette and equilibrium cell fluorescence. When cells previously loaded with CF were patched, intracellular fluorescence rapidly changed in a positive or a negative direction, depending on the concentration of CF in the pipette. The null point, defined as the concentration at which cells neither gained nor lost fluorescence, described the same relationship between free concentration and total cell fluorescence as that determined by direct loading of the cells to equilibrium. In hepatocytes preloaded with a fluorescent bile acid derivative, cholylglycylamidofluorescein (CGamF), by exposure (0.05 microM) for 30 min, the null point occurred at a CGamF concentration in the pipette of 0.6 microM. This value is 12 times greater than that in the bath. In conclusion, a new method is described that can measure free cytosolic concentrations of fluorescent molecules. It should prove useful in determining the intracellular location and state of transported organic ions.

Animals↗
PubMed1994

Utilization of antidrug antibody fragments for the optimization of intraperitoneal drug therapy: studies using digoxin as a model drug.

The direct administration of chemotherapeutic agents into the peritoneal cavity has been investigated as a method to treat cancers residing within the peritoneum. The benefits of i.p. drug administration are limited, however, by the systemic toxicity of antineoplastic drugs which diffuse out of the peritoneum and into the general circulation. We propose that antidrug antibody fragments may be useful in binding chemotherapeutics in the general circulation, thereby reducing the systemic tissue exposure and toxicity resulting from such i.p. therapy. Inasmuch as antibody fragments directed against antineoplastic agents are not available, we tested our hypothesis by using i.v. administered ovine antidigoxin Fab fragments and determined their ability to limit digoxin tissue exposure and toxicity in mice after an i.p. digoxin injection. The rate of digoxin disappearance from the peritoneal cavity and the fraction of digoxin unbound in the peritoneal cavity were also assessed to determine the effect of the antibody fragments on peritoneal exposure. Our results showed that the antidigoxin antibody fragments can greatly decrease digoxin tissue exposure and toxicity without affecting peritoneal exposure, unbound fraction of digoxin in the peritoneum or peritoneal digoxin disappearance rate. Although the utility of drug-binding antibodies and antibody fragments for the treatment of drug intoxication is well known, these results demonstrated the potential ability of antidrug antibody fragments to improve the site-specificity of drug therapy.

Animals↗
PubMed1997

Activin has direct long-range signalling activity and can form a concentration gradient by diffusion.

BACKGROUND: Activin has strong mesoderm-inducing properties in the early Xenopus embryo, and has a long-range signalling activity that activates genes in cells distant from a source in a concentration-dependent way. It has not yet been established what mechanism of signal transmission accounts for this and other examples of long-range signalling in vertebrates. Nor is it known whether activin itself acts on distant cells or whether other kinds of molecules are used for long-range signalling. Here we have used a well characterised model system, involving animal caps of Xenopus blastulae treated with activin or transforming growth factor beta, to analyze some fundamental properties of long-range signalling and of the formation of a morphogen gradient. RESULTS: We find that cells distant from the source of activin require functional activin receptors to activate Xbrachyury, a result suggesting that activin itself acts directly on distant cells and that other secondary signalling molecules are not required. We also find that the signals can be transmitted across a tissue that cannot respond to it; this argues against a relay process. We provide direct evidence that labelled activin forms a concentration gradient emanating from its source and extending to the distant cells that express Xbrachyury. Lastly, we show that there is no inherent polarity in the responding tissue that influences either the direction or rate of signalling. CONCLUSIONS: The long-range signalling mechanism by which activin initiates the transcription of genes in a concentration-dependent manner depends on a process of rapid diffusion and the establishment of an activin gradient across the tissue. It cannot be explained by a relay or wave propagation mechanism. Activin itself is the signalling molecule to which distant cells respond.

Activins↗
PubMed1990

An in vivo quantitative angiogenesis model using tumor cells entrapped in alginate.

A new in vivo system of monitoring tumor cell induced blood vessel growth using a sodium alginate entrapment process was developed. The alginate polymer of guluronic and mannuronic acids surrounds and sequesters cells from direct contact with their immediate environment, but permits diffusible angiogenic factors to pass through to induce neovascularization in the host. The alginate beads containing tumor cells were injected subcutaneously into animals and coalesced as a point source. The tumor cells are protected from direct contact with the host's immune system, so that various tumor types may be evaluated for their angiogenic potential across histocompatibility or species barriers. C57BI/6, BALB/c and nude mice as well as squirrel monkeys were used as host animals. This provided tumor cell testing in a syngeneic, allogeneic, or xenogeneic system. We found that alginate-Lewis lung carcinoma cells were potent inducers of blood vessel growth. As few as 100 alginate-Lewis lung carcinoma cells were needed to induce macroscopically visible blood vessels by 3 days. Dose-response experiments with alginate-Lewis lung carcinoma cells showed a greater level of blood vessel induction as cell numbers increased. Neovascularization was monitored qualitatively by macroscopic photography and microscopic histologic evaluation. Also, neovascularization was monitored quantitatively by measuring the level of hemoglobin at the injection site of alginate or by measuring the amount of radioactive red blood cells pooled at the injection site of the alginate beads. Both the measured levels of hemoglobin and radiolabeled red blood cells increased at the alginate site with each log increase of tumor cells delivered, which paralleled our findings at the macroscopic and microscopic level. This in vivo angiogenesis model was relatively simple and the procedures technically easy to perform. Most importantly, this model allowed both a qualitative and quantitative assessment of tumor-induced blood vessel growth.

Alginates↗
PubMed2004

Characterizing non-Gaussian diffusion by using generalized diffusion tensors.

Diffusion tensor imaging (DTI) is known to have a limited capability of resolving multiple fiber orientations within one voxel. This is mainly because the probability density function (PDF) for random spin displacement is non-Gaussian in the confining environment of biological tissues and, thus, the modeling of self-diffusion by a second-order tensor breaks down. The statistical property of a non-Gaussian diffusion process is characterized via the higher-order tensor (HOT) coefficients by reconstructing the PDF of the random spin displacement. Those HOT coefficients can be determined by combining a series of complex diffusion-weighted measurements. The signal equation for an MR diffusion experiment was investigated theoretically by generalizing Fick's law to a higher-order partial differential equation (PDE) obtained via Kramers-Moyal expansion. A relationship has been derived between the HOT coefficients of the PDE and the higher-order cumulants of the random spin displacement. Monte-Carlo simulations of diffusion in a restricted environment with different geometrical shapes were performed, and the strengths and weaknesses of both HOT and established diffusion analysis techniques were investigated. The generalized diffusion tensor formalism is capable of accurately resolving the underlying spin displacement for complex geometrical structures, of which neither conventional DTI nor diffusion-weighted imaging at high angular resolution (HARD) is capable. The HOT method helps illuminate some of the restrictions that are characteristic of these other methods. Furthermore, a direct relationship between HOT and q-space is also established.

Anisotropy↗
PubMedDate not supplied

The electron microscope band pattern of human fibrin: various stains, lateral order, and carbohydrate localization.

Human fibrin negatively contrasted with a variety of heavy metal compounds and examined by electron microscopy displays a distinctive, nonpolar band pattern with a repeat of 22.5 nm. These results together with a reversal of contrast observed in images of positively stained fibrin, indicate that the striations reflect the protein density along the fiber. All major features of the band pattern can be accounted for directly in terms of a model for the structure of fibrinogen. Optical and computed diffraction patterns of micrographs of fibrin show that most specimens are highly ordered along the fiber axis but have only diffuse equatorial reflections arising from the average spacing of the protofibrils, although occasional fibers have discrete reflections at about 19 nm. Finally, the resulting change in negative staining pattern upon binding of lectins to the carbohydrate moieties is distinctive and allows the carbohydrate-containing beta domain of the molecule to be localized.

Fibrin↗