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At least 37 records · Page 2Linked to original sources
PubMed1979

Zinc metabolism in humans: a kinetic model.

A quantitative model is developed that describes the kinetics of the early phases of zinc metabolism in humans. The model is based on averaged data obtained over 5 days from 17 atients with smell and/or taste dysfunction who were given 69mZn in trace amounts orally and intravenously. A function describing the rate of entry of 69mZn into systemic plasma following ingestion of the isotope is derived showing that about 37% of the ingested zinc enters plasma. Gastrointestinal absorption is essentially completed by 4 h. Sixty-seven percent of the absorbed zinc in the portal circulation is extracted by the liver before being released into the systemic circulation and agrees with the calculated extraction efficiency from the systemic circulation. There are both rapid and slow exchnage phases between plasma and liver and between plasma and red cells. The calculated steady-state zinc values for plasma, red cells, and liver agree with previously reported measured values implying there are no additional zinc pools in these tissues. The tracer data, however, account for only 10% of total body zinc, the remaining 90% in tissues whose kinetics are too slow to be resolved from a 5-day study.

Adult↗
PubMed1978

The multicellular spheroid as a model tumor allograft. I. Quantitative assessment of spheroid destruction in alloimmune mice.

A quantitative model for the assessment of in situ immunity to solid tumor allografts has been developed. Multicellular spheroids of murine EMT6 mammary sarcoma cells were implanted in the peritoneal cavity of normal or specifically alloimmune mice. Damage to spheroids was quantitatively assessed at various times by trypsinizing the recovered spheroids and assaying for surviving EMT6 cells by a cloning technique. In alloimmune mice, significant destruction of spheroids was observed within 24 hr of implantation, and a 99% reduction in the number of clonogenic MT6 cells in spheroids was consistently found after 48 hr. In contrast, little or no cytotoxic effect was observed when spheroids were implanted for 48 hr in nonimmune mice or in mice immunized against unrelated alloantigens. Implantation of spheroids in alloimmune athymic (nu/nu) mice did not result in appreciable spheroid damage as compared with littermate controls. Histological analysis of spheroids taken from alloimmune mice at the time of maximum tumor cell destruction indicated that large numbers of mononuclear cells had infiltrated the spheroid. These results suggests that multicellular spheroids will be a useful model for quantitative studies of the cellular mechanisms responsible for tissue-damaging reactions in vivo.

Animals↗
PubMed1976

Inhibition of T cell activity in vivo: a test model for quantitative evaluation.

A test model is presented which, in comparison with the conventional models of skin transplantation or graft-versus-host (GvH) reaction in mice, permits a more sensitive quantitative evaluation of T cell inhibition in vivo. Prospective donors (type AA) are immunized with prospective recipient material (type AB); the resulting T cell reaction of A versus B is inhibited by consecutive treatment. Extent of inhibition can be evaluated after transfer of the pretreated AA material onto AB recipients by calculation of remaining GvH reactivity, if compared to adequate control tranfers. In this model the target animal for T cell reactivity (the AB recipient) remains untouched from immunosuppressive regimen.

Animals↗
PubMed2025

A single-locus quantitative genetic model incorporating DNA methylation.

We describe a single-locus quantitative genetic model that incorporates effects due to DNA methylation. Extending Fisher's decomposition of the genotypic value, we distinguish two quantities to predict an individual's phenotypic or genetic values: the "basic genetic value" and the "expressed genetic value". We show how these quantities relate to the concept of breeding value and derive their corresponding formulas, along with those for phenotypic variance and covariance between relatives. The resulting parameters are influenced by several factors, including the population distribution of DNA methylation levels, the functional relationship between methylation and phenotype, the magnitudes of genetic and methylation effects, and allele frequencies. We show that under the conditions modeled, the presence of DNA methylation does not bias estimated breeding values.

DNA Methylation↗
PubMed1978

Systems-matching by degeneration. II. Interpretation of the generation and degeneration of retinal ganglion cells in the chicken by a mathematical model.

Quantitative data on generation and degeneration of retinal ganglion cells during development (Rager and Rager, 1978) are interpreted in terms of a mathematical model which consists of a system of differential equations. By these equations we attempt to describe the formation of retinal ganglion cells and their termination domains in the tectum. Since ganglion cells seem not to degenerate before their axons have arrived at their termination site and start branching, from the arrival time on they may become competent either to continue to mature or to die. Therefore, to find the actual number of competent cells the extension of the fiber pathway between the retina and the optic tectum had also to be measured and computed. The differential equations are united by the principle that at any given time cells in excess of the number of termination domains have to die. By this model the mathematical function was determined. Several parameter values of this function were optimized with the Gauss-Newton method by which the curve was fitted to the measured values. The high correlation obtained by this method allows to conclude that, to a first approximation, the model may be satisfactory. The evidence of competition for termination sites and of systems-matching by cell death is discussed.

Age Factors↗
PubMed2026

Dual β-lactam therapy against high-risk Pseudomonas aeruginosa isolates: a dynamic in-vitro infection model study integrating population genomics with quantitative systems pharmacology modelling and simulations.

BACKGROUND: Pseudomonas aeruginosa has an extraordinary capacity for resistance emergence during treatment, even with newer antipseudomonals. There is a gap in understanding how resistance mechanisms affect the time-course of bacterial response to these newer agents. Traditional approaches for predicting pathogen response to an antibiotic do not apply to combination therapy. We aimed to develop a modelling framework to predict treatment response based on resistome information, using isolates of the worldwide-disseminated high-risk clone sequence type (ST) 235 and β-lactam antibiotics as the example. METHODS: In this hollow-fibre in-vitro infection study, we used three extensively drug-resistant ST235 clinical isolates from the national collection of the Clinical Microbiology Department of the Hospital Son Espases (Palma de Mallorca, Spain) that were hospital-acquired, were isolated following routine microbiological procedures from different patients between 2017 and 2022, were susceptible to ceftolozane-tazobactam, and had different levels of meropenem resistance. The selected isolates (ST235-05, ST235-09, and ST235-10) showed classical β-lactam resistance mechanisms pre-treatment. The isolates were investigated in 240-h dynamic hollow-fibre in-vitro infection models (HFIMs). The studies exposed the isolates to pharmacokinetic profiles of ceftolozane-tazobactam (simulating 1 g of ceftolozane and 0·5 g of tazobactam as a 3-h infusion every 8 h) and meropenem (simulating 6 g per day continuous infusion) as observed in hospitalised patients, as monotherapy and in combination. Treatment response was assessed through the quantification of the time-courses of viable total and resistant bacteria. Whole-genome sequencing identified the mechanisms of emerging resistance. A quantitative systems pharmacology (QSP) approach was used to model total and resistant bacterial counts and corresponding pharmacokinetic data from the HFIM. Monte Carlo simulations were used to predict treatment responses in 1000 virtual infected patients treated with ceftolozane-tazobactam and meropenem as monotherapies or in combination over 10 days. FINDINGS: In the HFIMs, each antibiotic alone amplified resistance by approximately 48 h for all isolates; that is, monotherapies resulted in a higher concentration of resistant bacteria compared with the control treatment at the respective time, except ceftolozane-tazobactam against ST235-10. Combination of ceftolozane-tazobactam and meropenem was synergistic (bacterial counts ≥2 log10 colony forming units [CFU] per mL lower than the best performing monotherapy and initial inoculum) against all isolates and suppressed resistance. Against ST235-10, ceftolozane-tazobactam monotherapy reduced counts to less than 1 log10 CFU per mL from 192 h onwards, whereas the combination reached less than 1 log10 CFU per mL by 24 h. Across strains, population genomics confirmed monotherapy failures were associated with emerging resistance mechanisms (ceftolozane-tazobactam: ampC Ω-loop mutations; meropenem: ftsl mutation). The developed QSP model incorporated baseline resistance mechanisms and those emerging in resistant mutant subpopulations. The model explained and predicted the monotherapy failures involving amplification of these subpopulations, and synergistic killing and resistance suppression by the combination. Simulations using the model predicted bacterial regrowth above the initial inoculum for more than 90% of patients after 0 to approximately 3 days for meropenem monotherapy across all strains and for ceftolozane-tazobactam monotherapy against ST235-05 and ST235-09. For ceftolozane-tazobactam monotherapy against ST235-10, regrowth was predicted for approximately 30% of patients. In contrast, the simulations predicted sustained bacterial killing of at least 2 log10 CFU per mL compared with the initial inoculum by the combination for more than 89% of patients across all strains. INTERPRETATION: To our knowledge, this model is the first to characterise and predict the time-course of responses of clinical isolates to antibiotics only by the resistance mechanisms present and their complex interplay, representing a step towards pathogen-specific, personalised medicine. FUNDING: Australian National Health and Medical Research Council.

Pseudomonas aeruginosa↗
PubMed1978

An immunoprecipitation-dissociation technique for large scale antibody purification and an antigen consumption electroimmunoassay for antibody quantitation. A model study with antibodies to pregnancy zone protein.

A simple immunoprecipitation--dissociation technique for large scale purification of antibodies is described, which comprises selective denaturation of the antigen and recovery of the antibody fraction by exclusion chromatography at low pH. Its use is illustrated by the purification of antibodies to pregnancy zone protein. A purification factor of about 60 was achieved. An antigen consumption electroimmunoassay was also developed which permits quantitative determination of the antigen binding activity of antibodies with a given specificity. The methods have general application.

Antibodies↗
PubMed1979

Multifactorial genetic models for quantitative traits in humans.

Quantitative traits measured in human families can be analyzed to partition the total population variance into genetic and environmental components, or to elucidate the genetic mechanism involved. We review the estimation of variance components directly from human pedigree data, or in the form of path coefficients from correlations between pairs of relatives. To elucidate genetic mechanisms, a mixed model that allows for segregation at a major locus, a polygenic effect and a sibling environmental correlation is described for nuclear families. In each case appropriate likelihoods are derived as a basis, using numerical maximum likelihood methods, for parameter estimation and hypothesis testing. A general model is then described that allows for several familial sources of environmental variation, assortative mating, and both major gene and polygenic effects; and an algorithm for calculating the likelihood of a pedigree under this model is indicated. Finally, some of the remaining problems in this area of biometric analysis are pointed out.

Genetic Variation↗
PubMed1975

Interactions between K+ and ATP binding to the (Na+ + K+)-dependent ATPase.

K+ appears to decrease the affinity of the (Na+ + K+)-dependent ATPase (ATP phosphohydrolase, EC 3.6.1.3) for its substrate, Mg2+ - ATP, and Mg2+ - ATP, in turn, appears to decrease the affinity of the enzyme for K+. These antagonisms have been investigated in terms of a quantitative model defining the magnitude of the effects as well as identifying the class of K+ sites on the enzyme involved. K+ increased the apparent Km for Mg2+ - ATP, an effect that was antagonized competitively by Na+. The data can be fitted to a model in which Mg2+ - ATP binding is prevented by occupancy of alpha-sites on the enzyme by K+ (i.e. sites of moderate affinity for K+ accessible on the "free" non-phosphorylated enzyme, in situ on the external membrane surface). By contrast, occupancy of these alpha-sites by Na+ has no effect on Mg2+ - ATP binding to the enzyme. On the other hand, Mg2+ - ATP decreased the apparent affinity of the enzyme for K+ at the alpha-sites, in terms of (i) the KD for K+ measured by K+-accelerated inactivation of the enzyme by F-, and (ii) the concentration of K+ for half-maximal activation of the K+-dependent phosphatase reaction (which reflects the terminal hydrolytic steps of the overall ATPase reaction). These data fit the same quantitative model. Although this formulation does not support schemes in which ATP binding effects the release of transported K+ from discharge sites, it is consistent with observations that K+ can inhibit the enzyme at low substrate concentrations, and that Li+, which has poor efficacy when occupying these alpha-sites, can stimulate enzymatic activity at high K+ concentrations by displacing the inhibitory K+.

Adenosine Triphosphatases↗
PubMed1977

A quantitative rotational model for studying serotonergic function in the rat.

Unilateral injection of 5,7-dihydroxytryptamine (4 mug/4 mul) into the medial forebrain bundle of rats produced serotonin depletions of 65% and 70% in the ipsilateral corpus striatum and ipsilateral forebrain, respectively. These animals showed a dose-dependent increase in contralateral turning (rotational behavior) when pretreated with a peripheral decarboxylase inhibitor and then injected with L-5-hydroxytryptophan in doses ranging from 5 to 100 mg/kg i.p. Injections of p-chloroamphetamine, which releases endogenous stores of serotonin, produced ipsilateral turning which could be blocked by prior serotonin depletion. Systemic administration of the catecholamine drugs L-DOPA, apomorphine and D-amphetamine never elicited consistent turning in either direction in these animals. These data indicate that the turning response of rats with unilateral destruction of brain serotonin nerve terminals provides a sensitive tool for quantifiably studying changes in serotonergic function.

5-Hydroxytryptophan↗
PubMed2026

Quantitative molecular cartography of emergency myelopoiesis reveals conserved modules of hematopoietic activation.

Hematopoietic stem and progenitor cells (HSPCs) respond to infections, inflammation, and regenerative challenges using emergency myelopoiesis (EM) pathways to amplify myeloid cell production. However, it remains unclear how various EM inducers regulate HSPCs using shared or distinct molecular mechanisms. Here, we generate a comprehensive and generalizable cell annotation method (HemaScribe) and a refined quantitative model of hematopoietic differentiation (HemaScape) using single-cell RNA sequencing (scRNA-seq) of murine HSPCs, which we apply to a broad range of EM modalities. We uncover multiple strategies for enhancing myelopoiesis that act at different levels of the HSPC hierarchy and are associated with both unique and shared transcriptional response modules. In particular, we identify a myeloid progenitor-based EM activation module across diverse inflammatory challenges that is conserved in humans and informs outcomes in adult and pediatric acute myeloid leukemia. Our work illuminates fundamental regulatory mechanisms in hematopoietic regeneration that have direct translational applications in disease contexts.

Animals↗
PubMed2024

Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.

PURPOSE: Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. METHODS: A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. RESULTS: The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. CONCLUSION: Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.

Humans↗
PubMed1978

[An in vitro model for the quantitative study of E. histolytica virulence].

An experimental model for the quantitative study of the cytopathic effect of E. histolytica is described. Confluent cultures of the MDCK cell line, which form a monolayer with morphological and electrophysiological features of an epithelium were used. Trophozoites of the strains HM1:IMSS, HM2:IMSS and HM3:IMSS, axenic produced variable degrees of cytopathic effects of MDCK cultures each one characteristic for a given strain. The degree of damage induced by the different strains of amebas was measured quantitatively. The results demonstrate that the degree of the cytopathic effect produced in vitro by the various strains tested correlates with the virulence shown in vivo by the same strains, judged as the size of the inoculum required to induce liver cytopathic effect in newborn hamsters.

Animals↗
PubMed2026

Coarse-grained resource allocation modeling for decoding and rewiring microbial metabolism.

Microbial metabolism is a complex, emergent system driven by the coordinated interplay of intricate and dynamic molecular processes. To elucidate cellular behavior and enable biotechnological applications, quantitative models that address the inherent complexity of metabolism have been developed from a resource allocation perspective. Here, we synthesize recent advances in coarse-grained resource allocation frameworks and their applications in understanding microbial physiology and guiding gene circuit design. These frameworks reveal global regulatory constraints and predict cellular adaptation to nutrient and environmental changes. In addition, they enable the quantification of metabolic costs, the dissection of circuit-host interactions, and the development of strategies for burden mitigation. Collectively, these modeling frameworks provide a powerful platform for uncovering quantitative principles of microbial growth and engineering robust synthetic biological systems.

coarse-grained modeling↗
PubMed1979

[Quantitative exercise scintigraphy of the myocardium with 201Tl--methods and normal values (author's transl)].

Quantitative myocardial scintigraphy was performed in 20 normal individuals after maximum exercise and after two hours of rest. A mobile Anger camera with converging collimator and a Data-General computer with a 128 x 128 matrix were used. Quantitative analysis of data was performed on the basis of a 14-halfsegment model. Quantitative normal values after exercise and after redistribution of activity during rest are presented.

Adult↗
PubMed1979

Pattern generation in the lobster (Panulirus) stomatogastric ganglion. II. Pyloric network simulation.

1. Results from the companion paper were incorporated into a physiologically realistic computer model of the three principal cell types (PD/AB, LP, PY) of the pyloric network in the stomatogastric ganglion. Parameters for the model were mostly calculated (sometimes estimated) from experimental data rather than fitting the model to observed output patterns. 2. The initial run was successful in predicting several features of the pyloric pattern: the observed gap between PD and LP bursts, the appropriate sequence of the activity periods (PD, LP, PY), and a substantial PY burst not properly simulated by an earlier model. 3. The major discrepancy between model and observed patterns was the too-early occurrence of the PY burst, which resulted in a much shortened LP burst. Motivated by this discrepancy, additional investigations were made of PY properties. A hyperpolarization-enabled depolarization-activated hyperpolarizing conductance change was discovered which may make an important contribution to the late phase of PY activity in the normal burst cycle. Addition of this effect to the model brought its predictions more in line with observed patterns. 4. Other discrepancies between model and observation were instructive and are discussed. The findings force a substantial revision in previously held ideas on pattern production in the pyloric system. More weight must be given to functional properties of individual neurons and less to properties arising purely from network interactions. This shift in emphasis may be necessary in more complicated systems as well. 5. An example has been provided of the value quantitative modeling can be to network physiology. Only through rigorous quantitative testing can qualitative theories of how the nervous system operates be substantiated.

Animals↗
PubMed2026

Multiscale Modeling Primer: Focus on Chromatin and Epigenetics.

A central challenge in modern biology is to understand how molecular interactions produce cellular and organismal functions across vast spatiotemporal scales. Nowhere is this challenge more apparent than in the study of chromatin, where meters of DNA compact into a micron-sized nucleus. How this polymer folds is a dynamic process, regulated by epigenetic modifications-chemical changes to DNA and histones that involve only a handful of atoms. These small changes cooperate to produce emergent, higher-order structures that define cellular identity and function. To explain this system, we must integrate static, high-resolution snapshots from techniques like cryo-EM with dynamic, lower-resolution data from microscopy and genomics. Multiscale computational models are essential tools that bridge these experimental gaps and reveal the mechanisms of emergent behavior. However, the communication divide between experimental biologists and quantitative modelers often hampers progress. This primer addresses that gap. It first introduces the fundamental biology of chromatin and epigenetics at an introductory level for non-biologists audiences. We then survey the landscape of computational approaches, from atomistic to systems-level models, and connect them to the experimental data that inform and validate them at an introductory level for non-computationalists. We argue that the next frontier will require us to build integrative models that can predict how molecular perturbations mechanistically alter cellular phenotypes, which will open a new era of chromatin-targeted therapeutics.

Chromatin Dynamics↗
PubMed1975

Studies of energy transport in heart cells. Mitochondrial isoenzyme of creatine phosphokinase: kinetic properties and regulatory action of Mg2+ ions.

1. The kinetic properties of mitochondrial creatine phosphokinase (Km for all substrates and maximal rates of the forward and reverse reaction) have been studied. Since (a) Km value for MgADP- (0.05 mM) and creatine phosphate (0.5 mM) are significantly lower than Km for MgATP2- (0.7 mM) and creatine (5.0 mM) and (b) maximal rate of the reverse reaction (creatine phosphate + ADP leads to ATP + creatine) equal to 3.5 mumol times min-1 times mg-1 is essentially higher than maximal rate of the forward reaction (0.8 mumol times min-1 times mg-1), ATP synthesis from ADP and creatine phosphate is kinetically preferable over the forward reaction. 2. A possible regulatory role of Mg2+ ions in the creatine phosphokinase reaction has been tested. It has been shown that in the presence of all substrates and products of the reaction the ratio of the rates of forward and reverse reactions can be effectively regulated by the concentration of Mg2+ ions. At limited Mg2+ concentrations creatine phosphate is preferably synthesized while at high Mg2+ concentrations (more ATP in the reaction medium) ATP synthesis takes place. 3. The kinetic (mathematical) model of the mitochondrial creatine phosphokinase reaction has been developed. This model accounts for the existence of a variety of molecular forms of adenine nucleotides in solution and the formation of their complexes with magnesium. It is based on the assumption that the mitochondrial creatine phosphokinase reactions mechanism is analogous to that for soluble isoenzymes. 4. The dependence of the overall rate of the creatine phosphokinase reaction on the concentration of total Mg2+ ions calculated from the kinetic model quantitatively correlates with the experimentally determined dependence through a wide range of substrates (ATP, ADP, creatine and creatine phosphate) concentration. The analysis of the kinetic model demonstrates that the observed regulatory effect of Mg2+ on the overall reaction rate can be expained by (a) the sigmoidal variation in the concentration of the MgADP- complex resulting from the competition between ATP AND ADP for Mg2+ and (b) the high affinity of the enzyme to MgADP-. 5. The results predicted by the model for the behavior of mitochondrial creatine phosphokinase under conditions of oxidative phosphorylation point to an intimate functional interaction of mitochondrial creatine phosphokinase and ATP-ADP translocase.

Adenosine Diphosphate↗