scholarly journals An experimental design tool to optimize inference precision in data-driven mathematical models of bacterial infections in vivo

2020 ◽  
Vol 17 (173) ◽  
pp. 20200717
Author(s):  
Myrto Vlazaki ◽  
David J. Price ◽  
Olivier Restif
Keyword(s):  
Experimental Design ◽  
Mathematical Models ◽  
High Precision ◽  
Bacterial Infections ◽  
Parameter Estimate ◽  
Fixed Number ◽  
Inoculum Size ◽  
Design Tool ◽  
Detailed Knowledge

The management of bacterial diseases calls for a detailed knowledge about the dynamic changes in host–bacteria interactions. Biological insights are gained by integrating experimental data with mechanistic mathematical models to infer experimentally unobservable quantities. This inter-disciplinary field would benefit from experiments with maximal information content yielding high-precision inference. Here, we present a computationally efficient tool for optimizing experimental design in terms of parameter inference in studies using isogenic-tagged strains. We study the effect of three experimental design factors: number of biological replicates, sampling timepoint selection and number of copies per tagged strain. We conduct a simulation study to establish the relationship between our optimality criterion and the size of parameter estimate confidence intervals, and showcase its application in a range of biological scenarios reflecting different dynamics patterns observed in experimental infections. We show that in low-variance systems with low killing and replication rates, predicting high-precision experimental designs is consistently achieved; higher replicate sizes and strategic timepoint selection yield more precise estimates. Finally, we address the question of resource allocation under constraints; given a fixed number of host animals and a constraint on total inoculum size per host, infections with fewer strains at higher copies per strain lead to higher-precision inference.

scholarly journals In vitro and in vivo antibacterial activities of CS-940, a new 6-fluoro-8-difluoromethoxy quinolone.

1996 ◽  
Vol 40 (5) ◽  
pp. 1201-1207 ◽  
Author(s):  
N Masuda ◽  
Y Takahashi ◽  
M Otsuki ◽  
E Ibuki ◽  
H Miyoshi ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Oral Treatment ◽  
Horse Serum ◽  
Antibacterial Activities ◽  
Inoculum Size ◽  
The Other ◽  
Gram Positive Bacteria ◽  
Systemic Infections

The in vitro and in vivo activities of CS-940, a new 6-fluoro-8-difluoromethoxy quinolone, were compared with those of ciprofloxacin, tosufloxacin, sparfloxacin, and levofloxacin. The in vitro activity of CS-940 against gram-positive bacteria was nearly equal to or greater than those of the other quinolones tested. In particular, CS-940 was two to eight times more active against methicillin-resistant Staphylococcus aureus than the other quinolones, at the MIC at which 90% of the clinical isolates are inhibited. Against gram-negative bacteria, the activity of CS-940 was comparable to or greater than those of tosufloxacin, sparfloxacin, and levofloxacin, while it was lower than that of ciprofloxacin. The activity of CS-940 was largely unaffected by medium, inoculum size, or the addition of horse serum, but it was decreased under acidic conditions, as was also seen with the other quinolones tested. CS-940 showed potent bactericidal activity against S. aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. In oral treatment of mouse systemic infections caused by S. aureus, Streptococcus pneumoniae, Streptococcus pyogenes, E. coli, K. pneumoniae, Serratia marcescens, and P. aeruginosa, CS-940 was more effective than ciprofloxacin, sparfloxacin, and levofloxacin against all strains tested. Against experimental pneumonia with K. pneumoniae in mice, CS-940 was the most effective of all the quinolones tested. These results suggest that CS-940 may be effective in the therapy of various bacterial infections.

scholarly journals Live cell imaging of Salmonella Typhimurium interaction with zebrafish larvae after injection and immersion delivery methods

2016 ◽  
Author(s):  
Macarena A Varas ◽  
Alonso Fariña ◽  
Francisco Díaz-Pascual ◽  
Javiera Ortíz-Severín ◽  
Andrés E Marcoleta ◽  
...  
Keyword(s):  
Immune Response ◽  
Bacterial Infections ◽  
Inoculum Size ◽  
Live Cell ◽  
Transgenic Zebrafish ◽  
Human Pathogens ◽  
Zebrafish Model ◽  
Zebrafish Larvae ◽  
Serovar Typhimurium

Surrogate host models have been employed to study bacterial virulence mechanisms of important human pathogens. Particularly, zebrafish (Danio rerio) has been used to determine the role of vertebrate innate immunity during bacterial infections. The easy-to-obtain large number of embryos and optical transparency of larvae allow live cell imaging of the infection progress and the major cellular types of the innate immune system that develop during the first days of embryogenesis. In zebrafish model, microinjecting bacteria into embryos and/or larvae can cause infection. Alternatively, an infection can be generated by static immersion of larvae on a microbial suspension. Both methods differ in the mode and time of infection, inoculum size and host response. In this work, we compare the in vivo immune response induced by Salmonella enterica serovar Typhimurium (S. Typhimurium) inoculated by immersion and microinjection in zebrafish larvae. To this end, an immersion protocol using transgenic zebrafish larvae was developed for in vivo monitoring of GFP-tagged S. Typhimurium infection progress and immune response during 72 h. The infection progress was compared to that of zebrafish larvae inoculated by microinjection. Our results in zebrafish corroborate previous Salmonella virulence studies in murine models and reveal that host-pathogen interaction not only depends on the virulence of the strain, but also on the inoculation method and host conditions.

scholarly journals Integrating mathematical models with experimental data to investigate the within-host dynamics of bacterial infections

2019 ◽  
Vol 77 (8) ◽  
Author(s):  
Myrto Vlazaki ◽  
John Huber ◽  
Olivier Restif
Keyword(s):  
Experimental Data ◽  
Mathematical Models ◽  
Bacterial Infections ◽  
Vaccine Development ◽  
Bacterial Colonization ◽  
Experimental Techniques ◽  
Efficient Design ◽  
Mortality And Morbidity ◽  
Bacterial Dynamics

ABSTRACT Bacterial infections still constitute a major cause of mortality and morbidity worldwide. The unavailability of therapeutics, antimicrobial resistance and the chronicity of infections due to incomplete clearance contribute to this phenomenon. Despite the progress in antimicrobial and vaccine development, knowledge about the effect that therapeutics have on the host–bacteria interactions remains incomplete. Insights into the characteristics of bacterial colonization and migration between tissues and the relationship between replication and host- or therapeutically induced killing can enable efficient design of treatment approaches. Recently, innovative experimental techniques have generated data enabling the qualitative characterization of aspects of bacterial dynamics. Here, we argue that mathematical modeling as an adjunct to experimental data can enrich the biological insight that these data provide. However, due to limited interdisciplinary training, efforts to combine the two remain limited. To promote this dialogue, we provide a categorization of modeling approaches highlighting their relationship to data generated by a range of experimental techniques in the area of in vivo bacterial dynamics. We outline common biological themes explored using mathematical models with case studies across all pathogen classes. Finally, this review advocates multidisciplinary integration to improve our mechanistic understanding of bacterial infections and guide the use of existing or new therapies.

scholarly journals A data-based mathematical modelling study to quantify the effects of ciprofloxacin and ampicillin on the within-host dynamics of Salmonella enterica during treatment and relapse

2020 ◽  
Vol 17 (168) ◽  
pp. 20200299
Author(s):  
Myrto Vlazaki ◽  
Omar Rossi ◽  
David J. Price ◽  
Callum McLean ◽  
Andrew J. Grant ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Bacterial Infections ◽  
Post Treatment ◽  
Lymphoid Tissues ◽  
Detailed Knowledge ◽  
Antibiotic Administration ◽  
Mesenteric Lymph Nodes ◽  
Bacterial Populations ◽  
Spatio Temporal

Antibiotic therapy has drastically reduced the mortality and sequelae of bacterial infections. From naturally occurring to chemically synthesized, different classes of antibiotics have been successfully used without detailed knowledge of how they affect bacterial dynamics in vivo . However, a proportion of patients receiving antimicrobial therapy develop recrudescent infections post-treatment. Relapsing infections are attributable to incomplete clearance of bacterial populations following antibiotic administration; the metabolic profile of this antibiotic-recalcitrant bacterial subpopulation, the spatio-temporal context of its emergence and the variance of antibiotic–bacterial interactions in vivo remain unclear. Here, we develop and apply a mechanistic mathematical model to data from a study comparing the effects of ciprofloxacin and ampicillin on the within-host dynamics of Salmonella enterica serovar Typhimurium in murine infections. Using the inferential capacity of our model, we show that the antibiotic-recalcitrant bacteria following ampicillin, but not ciprofloxacin, treatment belong to a non-replicating phenotype. Aligning with previous studies, we independently estimate that the lymphoid tissues and spleen are important reservoirs of non-replicating bacteria. Finally, we predict that post-treatment, the progenitors of the non-growing and growing bacterial populations replicate and die at different rates. Ultimately, the liver, spleen and mesenteric lymph nodes are all repopulated by progenitors of the previously non-growing phenotype in ampicillin-treated mice.

scholarly journals Multimodal Imaging Techniques for the Extraction of Detailed Geometrical and Physiological Information for Use in Multi-Scale Models of Colorectal Cancer and Treatment of Individual Patients

2006 ◽  
Vol 7 (2-3) ◽  
pp. 177-188 ◽  
Author(s):  
Joe Pitt-Francis ◽  
Dan Chen ◽  
Mark Slaymaker ◽  
Andrew Simpson ◽  
Michael Brady ◽  
...  
Keyword(s):  
Mathematical Models ◽  
Imaging Techniques ◽  
Detailed Knowledge ◽  
Treatment Regimes ◽  
Multi Scale ◽  
Building Models ◽  
Wide Range ◽  
Spatio Temporal ◽  
Cancer Specialists

A vast array of mathematical models have been proposed for all stages of cancer formation across a wide range of spatio–temporal scales. Attention is now turning to coupling these models across scales and building models of “virtual tumours” for use inin silicotesting of novel drugs and treatment regimes. This leads naturally to the requirement for detailed knowledge of the underlying geometry and physiological properties of individual tumours for use in: (i) multi-scale mathematical models ofin vivotumour growth and development; (ii) fusion of multi-scale, multimodal medical imaging techniques to improve the diagnosis and treatment of individual patients; and (iii) training of cancer specialists and surgeons.

scholarly journals Live cell imaging of Salmonella Typhimurium interaction with zebrafish larvae after injection and immersion delivery methods

2016 ◽  
Author(s):  
Macarena A Varas ◽  
Alonso Fariña ◽  
Francisco Díaz-Pascual ◽  
Javiera Ortíz-Severín ◽  
Andrés E Marcoleta ◽  
...  
Keyword(s):  
Immune Response ◽  
Bacterial Infections ◽  
Inoculum Size ◽  
Live Cell ◽  
Transgenic Zebrafish ◽  
Human Pathogens ◽  
Zebrafish Model ◽  
Zebrafish Larvae ◽  
Serovar Typhimurium

Surrogate host models have been employed to study bacterial virulence mechanisms of important human pathogens. Particularly, zebrafish (Danio rerio) has been used to determine the role of vertebrate innate immunity during bacterial infections. The easy-to-obtain large number of embryos and optical transparency of larvae allow live cell imaging of the infection progress and the major cellular types of the innate immune system that develop during the first days of embryogenesis. In zebrafish model, microinjecting bacteria into embryos and/or larvae can cause infection. Alternatively, an infection can be generated by static immersion of larvae on a microbial suspension. Both methods differ in the mode and time of infection, inoculum size and host response. In this work, we compare the in vivo immune response induced by Salmonella enterica serovar Typhimurium (S. Typhimurium) inoculated by immersion and microinjection in zebrafish larvae. To this end, an immersion protocol using transgenic zebrafish larvae was developed for in vivo monitoring of GFP-tagged S. Typhimurium infection progress and immune response during 72 h. The infection progress was compared to that of zebrafish larvae inoculated by microinjection. Our results in zebrafish corroborate previous Salmonella virulence studies in murine models and reveal that host-pathogen interaction not only depends on the virulence of the strain, but also on the inoculation method and host conditions.

Phospholipid-Protein Interactions in the Formation of Prothrombin Activator

1965 ◽  
Vol 14 (03/04) ◽  
pp. 431-444 ◽  
Author(s):  
E. R Cole ◽  
J. L Koppel ◽  
J. H Olwin
Keyword(s):  
Complex Formation ◽  
Protein Interactions ◽  
Calcium Ions ◽  
Fixed Number ◽  
Factor V ◽  
Clotting Factors ◽  
Number Of Binding Sites ◽  
C Complex ◽  
Autoprothrombin C

SummarySince Ac-globulin (factor V) is involved in the formation of prothrombin activator, its ability to complex with phospholipids was studied. Purified bovine Ac-globulin was complexed to asolectin, there being presumably a fixed number of binding sites on the phospholipid micelle for Ac-globulin. In contrast to the requirement for calcium ions in the formation of complexes between asolectin and autoprothrombin C, calcium ions were not required for complex formation between asolectin and Ac-globulin to occur ; in fact, the presence of calcium prevented complex formation occurring, the degree of inhibition being dependent on the calcium concentration. By treating isolated, pre-formed aso- lectin-Ac-globulin complexes with calcium chloride solutions, Ac-globulin could be recovered in a much higher state of purity and essentially free of asolectin.Complete activators were formed by first preparing the asolectin-calcium- autoprothrombin C complex and then reacting the complex with Ac-globulin. A small amount of this product was very effective as an activator of purified prothrombin without further addition of calcium or any other cofactor. If the autoprothrombin C preparation used to prepare the complex was free of traces of prothrombin, the complete activator was stable for several hours at room temperature. Stable preparations of the complete activator were centrifuged, resulting in the sedimentation of most of the activity. Experimental evidence also indicated that activator activity was highest when autoprothrombin C and Ac-globulin were complexed to the same phospholipid micelle, rather than when the two clotting factors were complexed to separate micelles. These data suggested that the in vivo prothrombin activator may be a sedimentable complex composed of a thromboplastic enzyme, calcium, Ac-globulin and phospholipid.

DIFFRACTION ANALYSIS OF DEFORMED METALS: Theory, Methods, Programs

2019 ◽  
Author(s):  
Faina Satdarova
Keyword(s):  
Experimental Design ◽  
Dislocation Density ◽  
Mathematical Models ◽  
Diffraction Analysis ◽  
Experimental Research ◽  
Russian Federation ◽  
Statistical Estimation ◽  
X Rays ◽  
National University ◽  
The Russian Federation

General analysis of the distribution of crystals orientation and dislocation density in the polycrystalline system is presented. Recovered information in diffraction of X-rays adopting is new to structure states of polycrystal. Shear phase transformations in metals — at the macroscopic and microscopic levels — become a clear process. Visualizing the advances is produced by program included in package delivered. Mathematical models developing, experimental design, optimal statistical estimation, simulation the system under study and evolution process on loading serves as instrumentation. To reduce advanced methods to research and studies problem-oriented software will promote when installed. Automation programs passed a testing in the National University of Science and Technology “MISIS” (The Russian Federation, Moscow). You score an advantage in theoretical and experimental research in the field of physics of metals.

Ethanol Extract Of Centella Asiatica (L.) Urban Leaves Effectively Inhibit Streptococcus pyogenes and Pseudomonas aeruginosa by Invitro Test

2020 ◽  
Vol 2 (2) ◽  
pp. 69-76
Author(s):  
Dini Aulia Azmi ◽  
Nurlailah Nurlailah ◽  
Ratih Dewi Dwiyanti
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Streptococcus Pyogenes ◽  
Bacterial Infections ◽  
Herbal Medicines ◽  
Centella Asiatica ◽  
Ethanol Extract ◽  
Dilution Method ◽  
Initial Stage ◽  
Independent Variable

Streptococcus pyogenes and Pseudomonas aeruginosa are some of the causes of infectious diseases. Centella asiatica (L.) Urban has many benefits for humans, including overcoming fever, anti-bacterial, and anti-inflammatory. This study aims to determine the inhibition of Centella asiatica (L.) Urban leaves ethanol extract on the growth of Streptococcus pyogenes and Pseudomonas aeruginosa. This research is the initial stage of the development of herbal medicines to treat Streptococcus pyogenes and Pseudomonas aeruginosa infections. The independent variable was the concentration of ethanol extract of Centella asiatica (L.) Urban leaves and the dependent variable was the growth of Streptococcus pyogenes and Pseudomonas aeruginosa. The anti-bacterial activity test was carried out by the liquid dilution method. The concentrations used are 20%, 40%, 60%, 80%. 100% The results showed that the minimum inhibitory concentration (MIC) against Streptococcus pyogenes: 40% and Pseudomonas aeruginosa: 40%. Minimum bactericidal concentration (MBC) results for Streptococcus pyogenes: 60% and Pseudomonas aeruginosa: 60%. So it can be concluded that there is inhibition of the ethanol extract of Centella asiatica (L.) Urban leaves on the growth of Streptococcus pyogenes and Pseudomonas aeruginosa. Centella Asiatica (L.) Urban extract has potential as herbal medicine against bacterial infections but requires further research to determine its effect in vivo.

Garlic Extract (Allium sativum L.) Effectively Inhibits Staphylococcus aureus and Escherichia coli by Invitro Test

2020 ◽  
Vol 2 (2) ◽  
pp. 61-68
Author(s):  
Agnina Listya Anggraini ◽  
Ratih Dewi Dwiyanti ◽  
Anny Thuraidah
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Bacterial Infections ◽  
Allium Sativum ◽  
Antibacterial Properties ◽  
Herbal Medicines ◽  
Garlic Extract ◽  
Dilution Method ◽  
Initial Stage

Infection is a disease caused by the presence of pathogenic microbes, including Staphylococcus aureus and Escherichia coli. Garlic (Allium sativum L.) has chemical contents such as allicin, alkaloids, flavonoids, saponins, tannins, and steroids, which can function as an antibacterial against Staphylococcus aureus and Escherichia coli. This study aims to determine the antibacterial properties of garlic extract powder against Staphylococcus aureus and Escherichia coli. This research is the initial stage of the development of herbal medicines to treat Staphylococcus aureus and Escherichia coli infections. The antibacterial activity test was carried out by the liquid dilution method. The concentrations used were 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL and 70 mg/mL. The results showed that the Minimum Inhibitory Concentration (MIC) against Staphylococcus aureus and Escherichia coli was 40 mg/mL and 50 mg / mL. Minimum Bactericidal Concentration (MBC) results for Staphylococcus aureus and Escherichia coli are 50 mg/mL and 70 mg/mL. Based on the Simple Linear Regression test, the R2 value of Staphylococcus aureus and Escherichia coli is 0.545 and 0.785, so it can be concluded that there is an effect of garlic extract powder on the growth of Staphylococcus aureus and Escherichia coli by 54.5% and 78.5%. Garlic (Allium sativum L.) extract powder has potential as herbal medicine against bacterial infections but requires further research to determine its effect in vivo.

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