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PubMed1998

Sphingomyelinase activity in human platelets.

The sphingolipid metabolites, ceramide, sphingosine, and sphingosine-1-phosphate, may be involved in several signalling pathways and may regulate cell functions such as cell growth, secretion, differentiation, and apoptosis. During activation of human platelets by thrombin, sphingosine-1-phosphate is released from platelets and can potentiate their aggregation. Thrombin also causes an increase in platelet sphingosine levels. Since these molecules can be derived from sphingomyelin, we have determined whether platelets possess sphingomyelinase and whether this enzyme is regulated during platelet function. Using radioactive sphingomyelin as substrate, we assayed sphingomyelinase activity over the range of pH 4 to 10 and observed optimal activity at pH 5.0-5.5. Little activity was found at neutral or alkaline pH, and the presence of Mg++, Ca++, Zn++, or EDTA in the reaction mixture had little effect on the pH profile. Activation of platelets by thrombin or ADP had no effect on sphingomyelinase activity, but thrombin caused secretion of the acid-sphingomyelinase activity into the media. Thus, human platelets contain an acid-sphingomyelinase which is secreted during thrombin-induced platelet activation.

Acid-Base Equilibrium↗
PubMed1982

Purification and characterization of a nicotinamide adenine dinucleotide-dependent secondary alcohol dehydrogenase from Candida boidinii.

From the yeast Candida boidinii grown on glucose a new secondary alcohol dehydrogenase was purified 426-fold by heat treatment, column chromatography on DEAE-Sephacel, affinity chromatography on Blue Sepharose Cl-6b, and gel filtration on Sephacryl S-300. The purified enzyme was homogeneous as judged by analytical polyacrylamide gel electrophoresis. The molecular weight was found to be 150000 by sedimentation equilibrium as well as by gel filtration. The enzyme appears to be composed of four identical subunits (Mr=38000) as determined by SDS-gel electrophoresis. The enzyme catalyzes the oxidation of isopropanol to acetone in the presence of NAD+ as an electron acceptor. The Km values were found to be 0.099 mM for isopropanol and 0.14 mM for NAD+. Besides isopropanol also other secondary alcohols like butan-2-ol, pentan-2-ol, pentan-3-ol, hexan-2-ol, cyclobutanol, cyclopentanol, and cyclohexanol served as a substrate and were oxidized to the corresponding ketones. Isopropanol seems to be the best substrate for this enzyme which we therefore call isopropanol dehydrogenase. Primary alcohols are not oxidized by the enzyme. The optimum pH for enzymatic activity in the oxidation reaction was found to be 9.0, the optimal temperature is 45 degrees C. The isoelectric point of the isopropanol dehydrogenase was found to be pH 4.9. The enzyme is inactivated by mercaptide-forming reagents and chelating agents, 2-mercaptoethanol is an inhibitor. Zinc ions appear necessary for enzyme production.

Alcohol Oxidoreductases↗
PubMed2003

Translational stiffness of the replaced shoulder joint.

Results after a total shoulder arthroplasty in rheumatoid patients are poor, indicated by loosening of especially the glenoid component, bad joint functionality and the possibility of a joint dislocation. The failure mechanisms behind this are multiple, including patient, surgical and design factors. These results must be improved. At present, the optimal geometrical prosthesis component design, focused on joint conformity and constraint, still has to be investigated. Proper understanding of the effect of geometrical design parameters on the theoretical relationship between joint translations and joint forces may contribute to improved designs. The main objective of this study is to theoretically describe this relationship and to investigate the joint translational stiffness, which can be used to investigate the effect of design parameters on joint motion. Joint translational stiffness is the gradient of the subluxation force with respect to the humeral head displacement. For this static analysis a potential field is introduced, as the result of a joint compressive force (muscle forces) and a subluxation force (external forces). The positive and negative stiffness during articulation inside and subluxation outside the glenoid cavity, lead to stable and unstable equilibrium joint positions, respectively. A most lateral position of the humeral head centre coincides with a zero subluxation force; at this position the humerus is dislocated and a restoring force is needed to relocate the humeral head. Joint conformity and compression force influence the joint translational stiffness during articulation inside the glenoid cavity, whereas during articulating outside the glenoid cavity this is influenced by the joint compression force and humeral radius of curvature. The glenoid radius of curvature influences the contact point and, in combination with the glenoid superior-inferior chord length, it also influences the constraintness angle, which influences the maximum allowable subluxation load to prevent a joint dislocation. This constraintness angle together with the joint conformity also influences maximum joint translations before articulation outside the glenoid cavity. Furthermore, the sign of the joint translational stiffness determines the stability of shoulder motion, which is stable and unstable if this stiffness is positive and negative, respectively.

Computer Simulation↗
PubMed1993

Optimization of a recombinant von Willebrand factor fragment as an antagonist of the platelet glycoprotein Ib receptor.

The binding of von Willebrand factor (vWF) to platelet glycoprotein (GP) Ib receptor is one of the initial events in thrombus formation. Previous studies have shown that RG12986, a reduced and alkylated recombinant fragment of vWF (Ser445-Val733), can inhibit binding of native vWF to GP Ib and offers potential as an anti-thrombotic agent. We have now evaluated a series of deletion mutants of RG12986 and found that reduced and alkylated rvWF508-704 is close to the minimal sequence with optimal RG12986-like activity (IC50 for inhibition of GP Ib-dependent platelet aggregation in the absence of modulators: 0.022 microM +/- 0.01, n = 3) and that it too binds directly to GP Ib. Under in vitro conditions, with no exogenous modulators present and in the absence of shear stress, oxidized rvWF508-704 (containing a disulfide bond between Cys508 and Cys659) is approximately 5-fold less active than reduced and alkylated rvWF508-704; the two fragments, however, display comparable activity in the presence of the modulator botrocetin. The smaller rvWF508-704 fragment offers distinct advantages over RG 12986. In particular, removal of non-active NH2 and COOH terminal sequences may reduce the risk of antigenicity and may contribute to rendering the molecule mostly monomeric in solution, as opposed to the monomer-dimer equilibrium previously described for RG12986.

Chromatography, High Pressure Liquid↗
PubMed2005

Evolution of the electronic structure of Be clusters.

Using a modified symbiotic genetic algorithm approach and many-body interatomic potential derived from first principles, we have calculated equilibrium geometries and binding energies of the ground-state and low-lying isomers of Be clusters containing up to 41 atoms. Molecular-dynamics study was also carried out to study the frequency of occurrence of the various geometrical isomers as these clusters are annealed during the simulation process. For a selected group of these clusters, higher-energy isomers were more often found than their ground-state structures due to large catchment areas. The accuracy of the above ground-state geometries and their corresponding binding energies were verified by carrying out separate ab initio calculations based on molecular-orbital approach and density-functional theory with generalized gradient approximation for exchange and correlation. The atomic orbitals were represented by a Gaussian 6-311G** basis, and the geometry optimization was carried out using the GAUSSIAN 98 code without any symmetry constraint. While the ground-state geometries and their corresponding binding energies obtained from ab initio calculations do not differ much from those obtained using the molecular-dynamics approach, the relative stability of the clusters and the energy gap between the highest occupied and the lowest unoccupied molecular orbitals show significant differences. The energy gaps, calculated using the density-functional theory, show distinct shell closure effects, namely, sharp drops in their values for Be clusters containing 2, 8, 20, 34, and 40 electrons. While these features may suggest that small Be clusters behave free-electron-like and, hence, are metallic, the evolution of the structure, binding energies, coordination numbers, and nearest-neighbor distances do not show any sign of convergence towards the bulk value. We also conclude that molecular-dynamics simulation based on many-body interatomic potentials may not always give the correct picture of the evolution of the structure and energetics of clusters although they may serve as a useful tool for obtaining starting geometries by efficiently searching a large part of the phase space.

Journal Article↗
PubMed2003

Changes in 3D joint kinematics support the continuous use of orthoses in the management of painful rearfoot deformity in rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy of custom foot orthoses for the management of painful rearfoot valgus in patients with rheumatoid arthritis (RA). METHODS: Patients were randomized to receive custom-manufactured rigid carbon graphite foot orthoses (RA-orthosis) or enter a control group (RA-control) receiving no orthotic intervention. Three-dimensional (3D) kinematics were measured at the ankle joint complex (AJC) using an electromagnetic tracking (EMT) system under barefoot, shod, and orthosis walking conditions. Previously established normal 3D kinematic data were used to descriptively compare motion patterns in both RA groups and statistical analyses were performed on integrals of motion-time for each axis of rotation from data collected at baseline, 3, 6, 12, 18, 24, and 30 months. RESULTS: Compared with healthy control subjects, all patients with RA demonstrated excessive subtalar joint eversion motion through the stance phase of gait (p < 0.0001) coupled with excessive internal leg rotation (p < 0.0001). Custom-manufactured orthoses significantly reduced eversion through stance (p = 0.009) and re-established equilibrium of motion relative to neutral joint position. Correcting the frontal plane component of the deformity did not lead to a significant reduction in internal leg rotation (p = 0.294). The devices had no effect on tibiotalar dorsiflexion/plantarflexion (p = 0.960). Prospectively, the rigid orthoses maintained and then improved the reduction in cumulative subtalar eversion motion (p < 0.0001). Minimal changes in cumulative subtalar component eversion and internal leg rotation were recorded for both RA groups when walking barefoot but the effect was significantly less for the RA-control group. From 12 months onwards, internal leg rotation started to decrease, suggesting re-coupling of motion, but the overall motion pattern remained abnormal in comparison with normal reference values. CONCLUSION: These results support the continuous use of custom-manufactured foot orthoses to correct deformity and optimize AJC function in RA patients with early painful deformity of the rearfoot.

Arthritis, Rheumatoid↗
PubMed1990

Characterization of the equilibrium binding of Xenopus transcription factor IIIA to the 5 S RNA gene.

A nitrocellulose filter-binding assay has been developed to study the interaction of Xenopus transcription factor IIIA (TFIIIA) with its specific binding site on the 5 S RNA gene. The protein binds to a DNA restriction fragment containing a Xenopus oocyte 5 S RNA gene (5 S DNA) with an apparent association constant of 1.90 x 10(9) M-1 in 0.1 M salt, pH 7.5, at 22 degrees C. Under these assay conditions, the protein has approximately a 100-fold lower binding affinity for DNA fragments that do not contain a 5 S RNA gene. Analysis of the temperature dependence of the binding of TFIIIA to 5 S DNA indicates that the interaction is largely enthalpy driven at temperatures above 19 degrees C, while it is largely entropy driven at lower temperatures. One molecule of TFIIIA binds per 5 S RNA gene, and this bimolecular complex dissociates with first order kinetics, having a half-life of 15.6 min. The DNA binding activity of the protein exhibits a broad pH optimum from 6.0 to 8.0, and is optimal at 5 mM MgCl2 decreasing rapidly at higher divalent ion concentrations. The specific binding of TFIIIA to 5 S DNA is insensitive to the identity of the monovalent cation present in the binding buffer. In comparison, the anion effects on DNA binding are dramatic, with a 100-fold decrease in binding affinity observed to follow the lyotropic series. This result suggests that there are several specific anion-binding sites on TFIIIA. Determination of the monovalent salt dependence of the association constant revealed that as many as 8 lysine-phosphate type ionic bonds are formed in the TFIIIA-DNA complex.

Animals↗
PubMedDate not supplied

Relation between unbound plasma concentrations and toxicity in a prolonged oral etoposide schedule.

OBJECTIVE: This study was undertaken in order to evaluate the impact of pharmacokinetics on the toxicity of oral etoposide administered daily for 21 days. METHODS: The daily dose was 50 mg/m2. Thirty-two patients 24 males and eight females, 36 76 years old, treated for various tumour types), were evaluated. Blood samples were obtained on day 1 for all patients, and on day 21 for 16 patients. Plasma etoposide concentrations were determined by high-performance liquid chromatography, and etoposide plasma protein binding by equilibrium dialysis. RESULTS: On day 1, the mean value (with coefficient of variation for interindividual variability) for the unbound fraction (fu), area under the concentration versus time curve (AUC), and unbound AUC was 9.8% (59%), 34 mg x h/l (39%), and 3.5 mg x h/l (92%), respectively. The ratio between AUC on day 1 and day 21 ranged between 0.5 and 1.8 (mean 0.9, with CV 33%). The plasma trough unbound concentrations and the unbound AUCs both corresponding to the first administration were significantly higher in the 11 patients who had a severe neutropenia than in the 21 patients who had no or moderate toxicity. However, total etoposide concentrations did not differ between these two groups. A limited sampling strategy using the NONMEM program and a database of 89 patients previously studied was performed. The optimal sampling schedule (i.e. 1, 4, and 24 h after oral etoposide administration) allowed to obtain the AUC accurately on day 1. CONCLUSION: Individual adjustment of oral etoposide based on unbound pharmacokinetics after the first administration appears relevant and feasible.

Adult↗
PubMed1993

Thrombin-fibrinogen interaction: pH dependence and effects of the slow-->fast transition.

A recently developed strategy capable of measuring the equilibrium dissociation constant for thrombin-fibrinogen interaction has been used to explore the pH dependence of the interaction and the effects of thrombin conformational transitions. The dependence of fibrinogen binding to thrombin in the pH range 6-10 is bell-shaped and remarkably similar to that obtained in the case of the small synthetic amide substrate tosyl-Gly-Pro-Arg-p-nitroanilide-AcOH. Since the synthetic substrate contains no groups that can ionize in the pH range 6-10, the bell-shaped curve must reflect ionization reactions of two groups of the enzyme with pK1 = 7.53 +/- 0.09 and pK2 = 8.80 +/- 0.09. These groups can be identified as the catalytic histidine, His57, and the amino terminus of the B chain, Ile16, respectively. Deprotonation of His57 in the acidic region is important for optimal binding, while protonation of Ile16 in the alkaline region is critical for the formation of a salt bridge with Asp194, which guarantees the conformational stability of the enzyme. The loss of binding free energy at low (< 7.0) and high (> 9.0) pH values is linked to protonation of His57 and deprotonation of Ile16, respectively. The first 51 residues of the A alpha chain of fibrinogen are known to be necessary and sufficient for optimal recognition by thrombin, but none of them contributes to the pH dependence of fibrinogen binding in the pH range examined. Hence, the two possible ionizable groups of the A alpha chain, i.e., the amino terminus Alal and His24, make no contacts with the thrombin surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗
PubMed1992

Use of protein unfolding studies to determine the conformational and dimeric stabilities of HIV-1 and SIV proteases.

The free energies of dimer dissociation of the retroviral proteases (PRs) of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) were determined by measuring the effects of denaturants on the protein fluorescence upon the unfolding of the enzymes. HIV-1 PR was more stable to denaturation by chaotropes and extremes of pH and temperature than SIV PR, indicating that the former enzyme has greater conformational stability. The urea unfolding curves of both proteases were sigmoidal and single phase. The midpoints of the transition curves increased with increasing protein concentrations. These data were best described by and fitted to a two-state model in which folded dimers were in equilibrium with unfolded monomers. This denaturation model conforms to cases in which protein unfolding and dimer dissociation are concomitant processes in which folded monomers do not exist [Bowie, J. U., & Sauer, R. T. (1989) Biochemistry 28, 7140-7143]. Accordingly, the free energies of unfolding reflect the stabilities of the protease dimers, which for HIV-1 PR and SIV PR were, respectively, delta GuH2O = 14 +/- 1 kcal/mol (Ku = 39 pM) and 13 +/- 1 kcal/mol (Ku = 180 pM). The binding of a tight-binding, competitive inhibitor greatly stabilized HIV-1 PR toward urea-induced unfolding (delta GuH2O = 19.3 +/- 0.7 kcal/mol, Ku = 7.0 fM). There were also profound effects caused by adverse pH on the protein conformation for both HIV-1 PR and SIV PR, resulting in unfolding at pH values above and below the respective optimal ranges of 4.0-8.0 and 4.0-7.0

Aspartic Acid Endopeptidases↗
PubMedDate not supplied

Kinetic measurements of protein conformation in a microchip.

This paper presents a microchip-based system for collecting kinetic time-based information on protein refolding and unfolding. Dynamic protein conformational change pathways were studied in microchannel flow using a microfluidic device. We present a protein-conserving approach for quantifying refolding by dynamically varying the concentration of the chemical denaturants, guanidine hydrochloride and urea. Short diffusion distances in the microchannel result in rapid equilibrium between protein and titrating solutions. Dilutions on the chip were tightly regulated using pressure controls rather than syringe-based flow, as verified with extensive on-chip tracer dye controls. To validate this protein assay method, folding transition experiments were performed using two well-characterized proteins, human serum albumin (HSA) and bovine carbonic anhydrase (BCA). Transition events were monitored through fluorescence intensity shifts of the protein dye 8-anilino-1-naphthalenesulfonic acid (ANS) during dilutions of protein from urea or guanidine hydrochloride solutions. The enzymatic activity of refolded BCA was measured by UV absorption through the conversion of p-nitrophenyl acetate (p-NPA). The microchip protein refolding transitions using ANS were well-correlated with conventional plate-based experiments. The microfluidic platform enables refolding studies to identify rapidly the optimal folding strategy for a protein using small quantities of material.

Animals↗
PubMed1990

Synthesis and pharmacological evaluation of a series of new 3-methyl-1,4-disubstituted-piperidine analgesics.

The synthesis and intravenous analgesic activity of a series of 3-methyl-4-(N-phenyl amido)piperidines, entries 34-79, is described. The methoxyacetamide pharmacophore produced a series of compounds with optimal analgesic potency and short duration of action. cis-42 was 13,036 times more potent than morphine and 29 times more potent than fentanyl; however, the corresponding diastereomer 43 was only 2778 and 6 times more potent, respectively. Compounds 40, 43, 47, and 57 are extremely short acting; all had durations of action of about 2 min, which was about 1/5 of that of fentanyl in the mouse hot-plate test at a dose equivalent to 2 times the ED50 analgesic dose. Among the many compounds that displayed exceptional analgesic activity, duration of action was one of the main factors for choosing a candidate for further pharmacological investigation. At present, cis-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-3-meth yl-4- [N-in equilibrium 2-fluorophenyl)methoxyacetamido]piperidine hydrochloride (40) (Anaquest, A-3331.HCl, Brifentanil) is in clinical evaluation. Opiate analgesics that possess short duration of action are excellent candidates for short surgical procedures in an outpatient setting where a rapid recovery is required.

Analgesics↗
PubMed2004

One site mutation disrupts dimer formation in human DPP-IV proteins.

DPP-IV is a prolyl dipeptidase, cleaving the peptide bond after the penultimate proline residue. It is an important drug target for the treatment of type II diabetes. DPP-IV is active as a dimer, and monomeric DPP-IV has been speculated to be inactive. In this study, we have identified the C-terminal loop of DPP-IV, highly conserved among prolyl dipeptidases, as essential for dimer formation and optimal catalysis. The conserved residue His750 on the loop contributes significantly for dimer stability. We have determined the quaternary structures of the wild type, H750A, and H750E mutant enzymes by several independent methods including chemical cross-linking, gel electrophoresis, size exclusion chromatography, and analytical ultracentrifugation. Wild-type DPP-IV exists as dimers both in the intact cell and in vitro after purification from human semen or insect cells. The H750A mutation results in a mixture of DPP-IV dimer and monomer. H750A dimer has the same kinetic constants as those of the wild type, whereas the H750A monomer has a 60-fold decrease in kcat. Replacement of His750 with a negatively charged Glu (H750E) results in nearly exclusive monomers with a 300-fold decrease in catalytic activity. Interestingly, there is no dynamic equilibrium between the dimer and the monomer for all forms of DPP-IVs studied here. This is the first study of the function of the C-terminal loop as well as monomeric mutant DPP-IVs with respect to their enzymatic activities. The study has important implications for the discovery of drugs targeted to the dimer interface.

Adenosine Deaminase↗
PubMed1988

Prescheduling graphic displays for optimal cancer therapies to reveal possible tumor regression or stabilization.

The paper describes an adaptive control approach to the problem of the treatment of solid tumors. The evolution with time t of the state of a tumor is modelled by a two-compartment system, governed by two differential equations forming an autonomous system under therapy control u, (formula; see text) where y1 and y2 are the number of proliferating and nonproliferating cells, respectively. The output is analyzed in the phase plane y1y2. The control problem is that of restricting the tumor state to a predetermined region of the plane by selecting a suitable change in therapy control u, e.g., modality and dosage, when the state solution intersects the boundary of this region and the ratio y1/y2 of proliferating to nonproliferating cells is displayed together with an elapsed time scale. Then, consequent selection of a suitable therapeutic sequence may be assisted by the use of a data base as part of an expert system. The process is repeated at each intersection of the prescribed boundary. Such sequences may lead to stabilization of the system through the appearance on a computer display screen of a stable equilibrium point or a limit cycle.

Cell Division↗
PubMed1976

[Conditions for the efficacy of nutritional therapy].

This is to discuss regulatory mechanisms which enable the organism to respond optimally to special nutritive conditions. Those regulatory mechanisms are often in disorder with patients who need nutritive therapy. However, normal functions of the body are required for nutrition. Disarrangements in microcirculation, oxygen supply, water and electrolyte metabolism and acid-base metabolism are described and the way they will influence nutrition therapy. Furthermore, we try to describe special conditions of metabolism in stress and its influence to efficiency of nutritive therapy.

Acid-Base Equilibrium↗
PubMed2005

Sorption and desorption of arsenic to ferrihydrite in a sand filter.

Elevated arsenic concentrations in drinking water occur in many places around the world. Arsenic is deleterious to humans, and consequently, As water treatment techniques are sought. To optimize arsenic removal, sorption and desorption processes were studied at a drinking water treatment plant with aeration and sand filtration of ferrous iron rich groundwater at Elmevej Water Works, Fensmark, Denmark. Filter sand and pore water were sampled along depth profiles in the filters. The sand was coated with a 100-300 microm thick layer of porous Si-Ca-As-contaning iron oxide (As/Fe = 0.17) with locally some manganese oxide. The iron oxide was identified as a Si-stabilized abiotically formed two-line ferrihydrite with a magnetic hyperfine field of 45.8 T at 5 K. The raw water has an As concentration of 25 microg/L, predominantly as As(II). As the water passes through the filters, As(III) is oxidized to As(V) and the total concentrations drop asymptotically to a approximately 15 microg/L equilibrium concentration. Mn is released to the pore water, indicating the existence of reactive manganese oxides within the oxide coating, which probably play a role for the rapid As(III) oxidation. The As removal in the sand filters appears controlled by sorption equilibrium onto the ferrihydrite. By addition of ferrous chloride (3.65 mg of Fe(II)/L) to the water stream between two serially connected filters, a 3 microg/L As concentration is created in the water that infiltrates into the second sand filter. However, as water flow is reestablished through the second filter, As desorbs from the ferrihydrite and increases until the 15 microg/L equilibrium concentration. Sequential chemical extractions and geometrical estimates of the fraction of surface-associated As suggest that up to 40% of the total As can be remobilized in response to changes in the water chemistry in the sand filter.

Adsorption↗
PubMed1985

A theoretical investigation of atmospheric sulfur chemistry. 1. The HSO/HOS energy separation and the heat of formation of HSO, HOS, and HS2.

The energy separation between the ground-state structures of HSO and HOS has been determined by using two independent ab initio methods. In the first method, the optimized geometry of all species was obtained at the HF/6-31G(d) level, as were harmonic vibrational frequencies for zero-point energy corrections. The energies were calculated by using fourth-order Moller-Plesset perturbation theory and a 6-31G(d,p) basis set. After corrections for extrapolation of the Moller-Plesset series to infinite order and extension of the basis set to include diffuse sp-, extra d-, and f-type Gaussian functions, the predicted energy separation, including zero-point vibrational effects, is 2.5 kcal/mol. HOS is the more stable isomer. The second method uses a double-zeta basis augmented with an extra set of p functions and two sets of d functions on the sulfur and oxygen atoms and a double-zeta + p basis on hydrogen. With this basis, equilibrium structures of HSO and HOS were obtained from MCSCF calculations; the energy separation between these structures was corrected by using large scale configuration interaction. In good agreement with the first method, HOS is the more stable isomer by 3.1 kcal/mol. Through calculation of the energy change in the reaction HO2 + XY --> O2 + HXY, the first method predicts the heats of formation of HXY = HSO, HOS, and HS2 to be -0.4, -2.9, and 26.7 kcal/mol, respectively.

Atmosphere↗
PubMed1993

Memory to antigenic challenge of the immune system: synergy of idiotypic interactions and memory B cells.

Memory to antigenic challenge of the immune system is described as a synergy of two components: cycles of interacting B cells in a dynamic equilibrium which store an internal image of an antigen, and long-lived memory B cells which stabilize the cycle that generates them. Small cycles are most relevant to the immune system's memory. The network is globally stable and supports Jerne's idea that suppression is important. Our model allows for exponential increase of antigens during the initial stage of infection. It has a number of stable fixed points, viz the virgin state, the healthy immunized state, and a state of chronic infection, the last occurring if the antigen is virulent enough. Numerical simulations show a difference between primary and secondary response and exhibit both predator-prey and intracycle oscillations. In the case of a chronic infection, the simulations suggest a specific stimulation therapy triggered by repeatedly injecting the antigens, thus making the infection acute. An optimal therapy is indicated.

Antigens↗