Negative feedback regulation of intracellular Ca2+and the slope of the dose-response curve

1987 ◽  
Vol 130 (1) ◽  
pp. 77-81 ◽  
Author(s):  
E. BÁRÁNY
Keyword(s):  
Negative Feedback ◽  
Dose Response ◽  
Response Curve ◽  
Feedback Regulation ◽  
Dose Response Curve ◽  
Negative Feedback Regulation

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.

HYPERTROPHIC ADRENALS AND THEIR RESPONSE TO STRESS AFTER LESIONS IN THE MEDIAN EMINENCE OF TOTALLY HYPOPHYSECTOMIZED PIGEONS

1961 ◽  
Vol 37 (4) ◽  
pp. 565-576 ◽  
Author(s):  
Richard A. Miller
Keyword(s):  
Dose Response ◽  
Median Eminence ◽  
Response Curve ◽  
Liver Parenchyma ◽  
Dose Response Curve ◽  
Pars Distalis ◽  
Adrenal Enlargement ◽  
Response To Stress ◽  
Lethal Doses ◽  
Chromaffin Tissue

ABSTRACT Four per cent formaldehyde, insulin, or epinephrine in oil was injected for 5 days into pigeons subjected to varying degrees of hypophysectomy alone or together with large lesions in the median eminence and hypothalamus. Adrenals atrophied after the removal of the pars distalis alone or together with the neurohypophysis in untreated pigeons but showed markedly hypertrophic interrenal tissue (cortex in mammals) after treatment with formaldehyde or insulin. The slope of the dose-response curve was similar in operated and unoperated pigeons. The accumulation of bile in the liver parenchyma, which may occur after removal of the pars distalis, is an endogenous stress which was associated regularly with adrenal hypertrophy. After very large lesions of the median eminence and ventral hypothalamus in addition to total hypophysectomy, adrenals hypertrophied rather than atrophied, and the response to formaldehyde paralleled that in intact and »hypohysectomized« pigeons. Interrenal tissue was stimulated regularly; chromaffin tissue was partially degranulated, sometimes showed hyperplasia with colchicine, but only occasionally appeared hypertrophied. Epinephrine in nearly lethal doses caused only minimal adrenal enlargement. After adrenal denervation followed by hypophysectomy, the adrenals were still stimulated by formaldehyde. It appears that the interrenal tissue of the pigeon responds to a humoral stimulus not of hypophyseal origin in the absence of the hypophyseal-hypothalamic system.

ANTI-OVULATORY ACTIVITY OF STEROIDS ADMINISTERED BY GAVAGE IN THE ADULT OESTRUS RABBIT

1963 ◽  
Vol 42 (2_Suppl) ◽  
pp. S17-S30
Author(s):  
Fred A. Kind ◽  
Ralph I. Dorfman
Keyword(s):  
Dose Response ◽  
Active Compound ◽  
Subcutaneous Injection ◽  
Response Curve ◽  
Parent Compound ◽  
Dose Response Curve ◽  
Relative Potency ◽  
Reference Standard ◽  
Highly Active ◽  
Dose Levels

ABSTRACT Thirty-seven steroids have been studied as orally effective inhibitors of ovulation in the mated oestrus rabbit. Norethisterone served as the reference standard and a dose response curve was established between the 0.31 and 1.25 mg dose levels. Nine highly active anti-ovulatory compounds are described listed in a decreasing order of potency with norethisterone having the arbitrary value of one: 6-chloro-Δ6-dehydro-17α-acetoxyprogesterone (35), 6α-methyl-Δ1-dehydro-17α-acetoxyprogesterone (≥ 10), 6-fluoro-Δ6-dehydro-17α-acetoxyprogesterone(9), 6-methyl-Δ6-dehydro-17α-acetoxyprogesterone (5), Δ6-dehydro-17α-acetoxyprogesterone (≥ 3), 6α-methyl-17α-acetoxyprogesterone (2.6), 6-chloro-Δ1,6-bisdehydro-17α-acetoxyprogesterone (≥ 2), 2-hydroxymethyl-17α-methyl-17β-hydroxyandrostan-3-one (≥ 2), and 6α-fluoro-16α-methyl-17α-acetoxyprogesterone (≥ 1.25). The anti-ovulatory activity of a compound was not related necessarily to the progestational activity of a compound nor to the anti-gonadotrophic activity as measured in parabiotic rats. 6-Chloro-Δ60dehydro-17-acetoxyprogesterone was as effective by gavage as previously shown by subcutaneous injection. 2-Hydroxymethyl-17α-methyl-17β-hydroxyandrostan-3-one was at least 2.5 times more active by gavage than by injection. While 17α-acetoxyprogesterone was a very weak anti-ovulatory steroid, modifications of the structure by addition of methyl or halogen at the 6α position with or without unsaturation greatly increased the activity. 6-Chloro-Δ6-dehydro-27α-acetoxyprogesterone was the most active compound in this series showing a relative potency of 3500 times that of the parent compound 17α-acetoxyprogesterone.

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