scholarly journals Growth-mediated negative feedback shapes quantitative antibiotic response

2020 ◽  
Author(s):  
S. Andreas Angermayr ◽  
Guillaume Chevereau ◽  
Tobias Bollenbach
Keyword(s):  
Negative Feedback ◽  
Dose Response ◽  
Response Curve ◽  
Feedback Loop ◽  
Dose Response Curve ◽  
Specific Response ◽  
Growth Responses ◽  
Response Curves ◽  
Resistance Evolution ◽  
General Response

AbstractSlow growth and persistence are common strategies bacteria use to survive antibiotic treatment. Bacterial growth responses to antibiotics are quantitatively characterized by dose-response curves. The shape of the dose-response curve varies drastically between antibiotics and plays a key role in drug treatments, interactions, and resistance evolution. Understanding the mechanisms that shape the dose-response curve is a major challenge. Here we show in Escherichia coli that the distinctly shallow dose-response curve of the antibiotic trimethoprim is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth, which in turn weakens the effect of this antibiotic. At the molecular level, this feedback is caused by the upregulation of the drug target dihydrofolate reductase (FolA/DHFR). We show that target upregulation is not a specific response to trimethoprim but a general response to slower growth, regardless of cause. Quantitatively, folA expression follows a universal trend line that only depends on growth rate and converges to a fixed maximum value at zero growth. Synthetically breaking the negative feedback loop or reversing it to positive feedback drastically steepens the dose-response curve; a similar steepening occurs under conditions of slower growth. A general mathematical model that captures growth-mediated feedback explains these phenomena. Our results indicate that growth-mediated feedback loops shape drug responses and could be exploited to design evolutionary traps that enable selection against drug resistance.

OVARIAN ASCORBIC ACID DEPLETION TEST FOR LUTEINIZING HORMONE

1967 ◽  
Vol 56 (4) ◽  
pp. 619-625 ◽  
Author(s):  
Hans Jacob Koed ◽  
Christian Hamburger
Keyword(s):  
Ascorbic Acid ◽  
Luteinizing Hormone ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Human Origin ◽  
Response Curves ◽  
Significant Difference ◽  
The Mean ◽  
Different Levels

ABSTRACT Comparison of the dose-response curves for LH of ovine origin (NIH-LH-S8) and of human origin (IRP-HMG-2) using the OAAD test showed a small, though statistically significant difference, the dose-response curve for LH of human origin being a little flatter. Two standard curves for ovine LH obtained with 14 months' interval, were parallel but at different levels of ovarian ascorbic acid. When the mean ascorbic acid depletions were calculated as percentages of the control levels, the two curves for NIH-LH-S8 were identical. The use of standards of human origin in the OAAD test for LH activity of human preparations is recommended.

Method for testing antiserum titer and avidity in nephelometric systems.

1981 ◽  
Vol 27 (11) ◽  
pp. 1838-1844 ◽  
Author(s):  
G A Hudson ◽  
R F Ritchie ◽  
J E Haddow
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Direct Evidence ◽  
Reaction Rates ◽  
Dose Response Curve ◽  
Antigen Concentration ◽  
Response Curves ◽  
Binding Strength ◽  
Antiserum Dilution ◽  
Antiserum Titer

Abstract Antiserum performance in a nephelometric system can be characterized by parameters derived from measuring reaction rates. The characterization process is derived from a series of dose-response curves (elicited nephelometric response vs antigen concentration) generated from various dilutions of the antiserum being tested. Antiserum titer can then be calculated by plotting the antigen concentration found at one-half the maximum nephelometric response (Hmax) of each dose-response curve (C50) vs the corresponding antiserum dilution. Antiserum avidity can be calculated by plotting Hmax against its corresponding antiserum concentration. After general expressions are determined for C50 and Hmax vs antiserum concentration, a single dose-response curve suffices for characterizing antisera with respect to titer and avidity. Direct evidence is provided for the validity of C50 and Hmax as measures of titer and avidity by correlating these parameters with antiserum binding strength and with the number of antibodies eluted from immobilized antigen. This method can be applied to evaluate and compare different antiserum lots having the same specificity, to identify reagent inadequacies by comparing antisera of different specificity, and to predict the optimal antiserum dilution to use in performing an assay.

Oxytocin as an antidiuretic hormone. II. Role of V2 vasopressin receptor

1995 ◽  
Vol 269 (1) ◽  
pp. F78-F85 ◽  
Author(s):  
C. L. Chou ◽  
S. R. DiGiovanni ◽  
A. Luther ◽  
S. J. Lolait ◽  
M. A. Knepper
Keyword(s):  
Dose Response ◽  
Water Permeability ◽  
Response Curve ◽  
Collecting Duct ◽  
Oxytocin Receptor ◽  
Dose Response Curve ◽  
Vasopressin Receptor ◽  
Response Curves ◽  
V2 Receptor ◽  
V2 Vasopressin Receptor

We conducted this study to determine what receptor mediates the effect of oxytocin to increase osmotic water permeability (Pf) in the rat inner medullary collecting duct (IMCD). Reverse transcription-polymerase chain reaction (RT-PCR) experiments demonstrated that mRNA for both the oxytocin receptor and the V2 receptor is present in the rat terminal IMCD. In isolated perfused IMCD segments, we found that the V2 vasopressin receptor antagonist [d(CH2)5(1),D-Ile2,Ile4,Arg8]vasopressin, but not oxytocin receptor antagonists, blocked the hydrosmotic response to 200 pM oxytocin. The selective oxytocin receptor agonist [Thr4,Gly7]oxytocin did not increase water permeability. Oxytocin also increased urea permeability in IMCD segments. Studies in IMCD suspensions showed that oxytocin increases adenosine 3',5'-cyclic monophosphate production in a dose-dependent fashion with a half-maximal (EC50) response at 5.2 nM. The dose-response curves were virtually identical for IMCD suspensions from Sprague-Dawley rats and Brattleboro rats. The oxytocin dose-response curve was displaced to the right of the vasopressin dose-response curve (EC50, 0.44 nM). From these results, we conclude that the V2 receptor mediates the hydrosmotic action of oxytocin in rat IMCD.

Implications of hormesis on the bioassay and hazard assessment of chemical carcinogens

1998 ◽  
Vol 17 (5) ◽  
pp. 254-258 ◽  
Author(s):  
Justin G Teeguarden ◽  
Yvonne P Dragan ◽  
Henry C Pitot
Keyword(s):  
Hazard Assessment ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Low Doses ◽  
Response Curves ◽  
Large Numbers ◽  
Carcinogenic Agents ◽  
Assessment Guidelines ◽  
Study Designs

Hormesis has been defined as a dose-response relationship which depicts improvement in some endpoint (increased metabolic rates, reduction in tumor incidence, etc.) at low doses of a toxic compound followed by a decline in the endpoint at higher doses. The existence of hormetic responses to carcinogenic agents has several implications for the bioassay and hazard assessment of carcinogens. To be capable of detecting and statistically testing for hormetic or other nonlinear dose-response functions, current study designs must be modified to include lower doses and sufficiently large numbers of animals. In addition, improved statistical methods for testing nonlinear dose-response relationships will have to be developed. Research integrating physiologically-based pharmacokinetic model descriptions of target dose with mechanistic data holds the greatest promise for improving the description of the dose-response curve at low doses. The 1996 Proposed Carcinogen Risk Assessment Guidelines encourage the use of mechanistic data to improve the descriptions of the dose-response curve at low doses, but do not distinguish between the types of nonlinear dose-response curves. Should this refined approach lead to substantial support for hormesis in carcinogenic processes, future guidelines will need to provide guidance on establishing safe doses and communicating the results to the public.

The Influence of Sodium Intake on the Pressor Response to Angiotensin II in the Unanaesthetized Rat

1976 ◽  
Vol 50 (4) ◽  
pp. 285-291
Author(s):  
Barbara L. Slack ◽  
J. M. Ledingham
Keyword(s):  
Angiotensin Ii ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Response Curves ◽  
High Sodium ◽  
Sodium Diet ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
High Sodium Diet

1. Dose—response curves for the pressor activity of angiotensin II have been determined in unanaesthetized rats receiving diets containing 2·5% (w/w) or 0·007% (w/w) sodium; the different diets were administered in various sequences. 2. In comparison with those from rats receiving a low sodium diet, the dose—response curves were displaced to the left on the high sodium diet, indicating a greater response to angiotensin, and this displacement persisted for a period of approximately 7 days after the diet was changed from high to low sodium. The dose—response curve subsequently shifted to the right when the low sodium diet was maintained for longer. 3. There was a negative correlation between the slope of the dose—response curve and the basal blood pressure in all groups; the correlation was significant in three out of the five different treatment groups. 4. Basal blood pressures were significantly raised in rats on the high sodium diet for 7 days. 5. A number of possible mechanisms have been considered to explain both the parallel shift of the dose—response curve and alteration in its slope. It is concluded that the observed findings are compatible with an action of sodium-loading on the sensitivity of the smooth muscle cell to angiotensin, on the resting of the renin—angiotensin system, on the rate of in-activation of angiotensin and on a change in initial length of the muscle fibre.

The sensitivity of prolactin secretion to dopamine changes during pregnancy in mice

1986 ◽  
Vol 111 (4) ◽  
pp. 567-571
Author(s):  
Stacey R. Swartz ◽  
Linda Ogren ◽  
Frank Talamantes
Keyword(s):  
Dose Response ◽  
Anterior Pituitary ◽  
Response Curve ◽  
Prolactin Secretion ◽  
Dose Response Curve ◽  
Serum Prolactin ◽  
Response Curves ◽  
Dopamine Concentration ◽  
Pituitary Glands ◽  
Low Levels

Abstract. Pituitary responsiveness to dopamine was investigated on several days of pregnancy in the mouse. Sera and anterior pituitary glands were obtained at 09.00 and 18.00 h on day 5 of pregnancy and at 09.00 h on days 12 and 18, and the pituitaries were incubated for 5 h in several concentrations of dopamine (0, 5 × 10−10—5 × 10−7 m). Serum prolactin (Prl) concentration was the highest on day 5 (18.00 h sample), followed by day 18 (09.00 h), day 5 (09.00 h) and day 12 (09.00 h). Pituitary responsiveness to dopamine was assessed on each day of pregnancy by determining the slopes of dose-response curves in which the Prl concentration of the medium was plotted as a function of dopamine concentration. The slope of the dose-response curve for pituitaries from day 12 or pregnancy was significantly steeper than the slopes of the curves for pituitaries from days 5 and 18, which did not differ from each other. These data suggest that the Prl secretion mechanism is more sensitive to inhibition by dopamine on day 12 of pregnancy, when serum Prl concentration is very low, than on days 5 or 18, when serum Prl concentrations are higher. One of the mechanisms by which circulating Prl concentrations are reduced to very low levels during midpregnancy in the mouse may be increased pituitary sensitivity to dopamine.

scholarly journals Interim In vitro Dose-Response Curve for the Dicentric Biodosimeter Assay from a Philippine Radiotherapy Facility using a Linear Accelerator

2021 ◽  
Vol 55 (1) ◽  
Author(s):  
Antonio Carlo D. De Guzman ◽  
Carmencita D. Padilla ◽  
Henri Cartier S. Co ◽  
Elrick T. Inocencio ◽  
Edsel Allan G. Salonga
Keyword(s):  
Radiation Exposure ◽  
Dose Response ◽  
Linear Accelerator ◽  
Response Curve ◽  
Dose Response Curve ◽  
Quadratic Model ◽  
Linear Quadratic ◽  
Response Curves ◽  
Energy Agency

Background. Accidental radiation exposure can occur anytime. Biodosimeters help in quantifying the absorbed dose of individuals who are not equipped with personal dosimeters during radiation exposure. The dicentric assay can quantify radiation damage by correlating radiation dose exposure with the frequency of dicentric chromosomes in the peripheral lymphocytes extracted from exposed individuals. Objective. The study aims to present the interim results of the reference dose-response curve for a Philippine radiotherapy facility constructed using a 6MV linear accelerator (ClinacX, Varian). Methods. Samples of peripheral blood from healthy volunteers were irradiated in a customized water phantom of doses 0.10 to 5.0 Gray using a linear accelerator. The irradiated samples were cultured and analyzed following the International Atomic Energy Agency Cytogenetic Dosimetry Protocol (2011) with modifications. Linear-quadratic model curve fitting and further statistical analysis were done using CABAS (Chromosome Aberration Calculation Software Version 2.0) and Dose Estimate (Version 5.2). Interim results of the samples were used to generate these curves. Results. The dose-response curve generated from the preliminary results were comparable to published dose response curves from international cytogenetic laboratories. Conclusion. The generated dose-response calibration curve will be useful for medical triage of the public and radiologic staff accidentally exposed to radiation during medical procedures or in the event of nuclear accidents.

Role of Endothelial K + Channels in NO-Dependent Vasorelaxant Responses to Acetylcholine in Rat Aorta.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 698-698
Author(s):  
John Quilley ◽  
Yue Qiu
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Rat Aorta ◽  
Dose Response Curve ◽  
Response Curves ◽  
K Channels ◽  
Voltage Dependent ◽  
The Right ◽  
Stimulation Of

P30 Endothelium-dependent vasorelaxant responses to acetylcholine (Ach) in rat aorta are mediated solely by NO. Rings precontracted with U46619 were used to investigate the role of endothelial K + channels. Thus, any effect of K + channel inhibitors on Ach responses in the absence of an effect on those to nitroprusside (NP) can be attributed to interference with Ach-induced stimulation of NO. Vasorelaxant responses to Ach (log EC 50 -7.29M) were abolished by removal of the endothelium or inhibition of NO synthesis with nitroarginine (100μM) which potentiated responses to NP (log EC 50 -9.41M vs -8.47M for control). In the presence of TEA (10mM) to inhibit K + channels, the dose-response curve for Ach, but not NP, was shifted to the right (log EC 50 -6.06). Elevation of extracellular K + (25mM KCl)also shifted the dose-response curve for Ach to the right. Inhibitors of specific types of K + channels: BaCl 2 (30μM), apamin (100nM), glibenclamide (10μM), charybdotoxin (50nM) and iberiotoxin (100nM) were without effect on dose-response curves to either Ach or NP. However, the combination of apamin (100nM) and charybdotoxin (50nM) but not apamin plus iberiotoxin, reduced relaxant responses to Ach (log EC 50 -6.95M) without affecting those to NP.These results confirm that Ach-induced relaxation of rat aorta is mediated entirely by endothelium-derived NO, the release of which apparently involves hyperpolarization of the endothelium. This effect is dependent on activation of a K + channel that is blocked by a combination of apamin/charybdotoxin but neither agent alone, possibly indicating characteristics of both Ca 2+ - activated and voltage-dependent K + channels.

Nanomolar ouabain augments caffeine-evoked contractions in rat arteries

1993 ◽  
Vol 265 (5) ◽  
pp. C1443-C1448 ◽  
Author(s):  
D. N. Weiss ◽  
D. J. Podberesky ◽  
J. Heidrich ◽  
M. P. Blaustein
Keyword(s):  
Dose Response ◽  
Mesenteric Artery ◽  
Response Curve ◽  
Dose Response Curve ◽  
Response Curves ◽  
Low Concentrations ◽  
Vascular Responsiveness ◽  
Subunit Isoforms ◽  
Evoked Contractions ◽  
Small Mesenteric Artery

Chronic parenteral administration of ouabain to normal rats raises plasma ouabain concentrations to low nanomolar levels and induces hypertension [C. M. Yuan, P. Manunta, J. M. Hamlyn, S. W. Chen, E. Bohen, J. Yeun, F. J. Haddy, and M. B. Pamnani. Hypertension 22: 178-187, 1993 and see also M. P. Blaustein. Am. J. Physiol. 264 (Cell Physiol. 33): C1367-C1387, 1993]. To determine whether rat arteries are sensitive to these low ouabain levels, we tested the effects of various ouabain concentrations on caffeine-evoked contractions (CEC) in rat aortic and small mesenteric artery rings. CEC amplitude was used as a measure of the sarcoplasmic reticulum (SR) Ca2+ content. Ouabain increased CEC in aortic as well as mesenteric artery rings, but the effects in the aorta were difficult to quantitate because the CEC were often oscillatory. Mesenteric artery, under control conditions and after sensitization with 10-30 nM phenylephrine (PE), exhibited biphasic ouabain dose-CEC response curves. Low concentrations of ouabain (0.1-10 nM) caused small significant increases in CEC, but a further effect was observed only with > or = 10 microM ouabain. PE shifted the ouabain dose-response curve toward lower ouabain concentrations; conversely, ouabain shifted the PE dose-response curve toward lower PE concentrations. It appears that nanomolar concentrations of ouabain can influence vascular responsiveness to vasoconstrictors. We conclude that rat vascular smooth muscle contains both high- and low-affinity ouabain receptors, possibly corresponding to Na+ pumps with alpha 3- and alpha 1-subunit isoforms, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine dose-response curves in guinea pigs

1985 ◽  
Vol 58 (2) ◽  
pp. 625-634 ◽  
Author(s):  
W. C. Hulbert ◽  
T. McLean ◽  
B. Wiggs ◽  
P. D. Pare ◽  
J. C. Hogg
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Dynamic Compliance ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Mechanically Ventilated ◽  
Dose Response Curves ◽  
The Right

Histamine dose-response curves were performed on anesthetized tracheostomized guinea pigs that were paralyzed and mechanically ventilated at a constant tidal volume and breathing frequency. The dose was calculated by generating an aerosol of known concentration and measuring the volume delivered to the lung. Increasing the dose was accomplished by increasing the number of breaths of aerosol delivered. The response to each dose was determined by measuring the change in airway resistance (RL) and dynamic compliance (Cdyn) using the method of Von Neergaard and Wirz (Z. Klin. Med. 105: 51–82, 1927). With increasing doses of histamine, RL increased and reached a plateau at approximately five times the base-line value and Cdyn fell to approximately 20% of its initial value. The variability in the base-line and maximum response as well as the calculated sensitivity and reactivity was less than that previously reported. Propranolol pretreatment increased resting RL and shifted the dose-response curve for RL to the left of the controls, increasing reactivity but not sensitivity. Atropine shifted the dose-response curve to the right of the control, decreasing sensitivity but without changing reactivity. The data for Cdyn showed that atropine pretreatment caused a higher resting value and propranolol pretreatment a lower value at the highest histamine dose but no differences in either sensitivity or reactivity.

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