scholarly journals Beyond non-integer Hill coefficients: A novel approach to analyzing binding data, applied to Na+-driven transporters

2015 ◽  
Vol 145 (6) ◽  
pp. 555-563 ◽  
Author(s):  
Silvia Ravera ◽  
Matthias Quick ◽  
Juan P. Nicola ◽  
Nancy Carrasco ◽  
L. Mario Amzel
Keyword(s):  
Hill Equation ◽  
Integer Coefficient ◽  
Novel Approach ◽  
Binding Data ◽  
Na Ions ◽  
Hill Coefficients ◽  
Integer Exponent ◽  
The Individual ◽  
The Hill ◽  
Analyze Data

Prokaryotic and eukaryotic Na+-driven transporters couple the movement of one or more Na+ ions down their electrochemical gradient to the active transport of a variety of solutes. When more than one Na+ is involved, Na+-binding data are usually analyzed using the Hill equation with a non-integer exponent n. The results of this analysis are an overall Kd-like constant equal to the concentration of ligand that produces half saturation and n, a measure of cooperativity. This information is usually insufficient to provide the basis for mechanistic models. In the case of transport using two Na+ ions, an n < 2 indicates that molecules with only one of the two sites occupied are present at low saturation. Here, we propose a new way of analyzing Na+-binding data for the case of two Na+ ions that, by taking into account binding to individual sites, provides far more information than can be obtained by using the Hill equation with a non-integer coefficient: it yields pairs of possible values for the Na+ affinities of the individual sites that can only vary within narrowly bounded ranges. To illustrate the advantages of the method, we present experimental scintillation proximity assay (SPA) data on binding of Na+ to the Na+/I− symporter (NIS). SPA is a method widely used to study the binding of Na+ to Na+-driven transporters. NIS is the key plasma membrane protein that mediates active I− transport in the thyroid gland, the first step in the biosynthesis of the thyroid hormones, of which iodine is an essential constituent. NIS activity is electrogenic, with a 2:1 Na+/I− transport stoichiometry. The formalism proposed here is general and can be used to analyze data on other proteins with two binding sites for the same substrate.

Effect of osmotic swelling and shrinkage on Na(+)-K+ pump activity in mammalian cardiac myocytes

1993 ◽  
Vol 265 (5) ◽  
pp. C1201-C1210 ◽  
Author(s):  
D. W. Whalley ◽  
L. C. Hool ◽  
R. E. Ten Eick ◽  
H. H. Rasmussen
Keyword(s):  
Ventricular Myocytes ◽  
Pump Current ◽  
Hill Equation ◽  
Cell Swelling ◽  
Intracellular Na Activity ◽  
Single Ventricular Myocytes ◽  
Hyperosmolar Solutions ◽  
Hill Coefficients ◽  
The Hill ◽  
The Relationship

The effect on the sarcolemmal Na(+)-K+ pump of exposure to anisosmolar solutions was examined using whole cell patch clamping and ion-selective microelectrodes. Na(+)-K+ pump currents were measured in single ventricular myocytes by using pipette Na+ concentrations ([Na]pip) of 0-70 mM. The relationship between [Na]pip and pump current was well described by the Hill equation. The [Na]pip for half-maximal pump current (K0.5) was 21.4 mM in isosmolar (310 mosM) solution. K0.5 was 12.8 mM during cell swelling in hyposmolar solution (240 mosM) and 39.0 mM during cell shrinkage in hyperosmolar solution (464 mosM). The maximal pump currents, derived from the best fit of the Hill equation, and the Hill coefficients were similar in isosmolar, hyposmolar, and hyperosmolar solutions. A sustained (> 20 min) decrease in the intracellular Na+ activity developed during exposure of intact papillary muscles to hyposmolar solutions, and a sustained increase developed during exposure to hyperosmolar solutions. We conclude that osmotic myocyte swelling stimulates the sarcolemmal Na(+)-K+ pump at near-physiological levels of intracellular Na+, whereas shrinkage inhibits the pump. These changes are due to increases and decreases, respectively, in the apparent affinity of the pump for Na+.

scholarly journals A Novel Approach to Analyzing Binding Data from Na+ Driven Transporters: Beyond Non-Integer Hill Coefficients

2015 ◽  
Vol 108 (2) ◽  
pp. 308a
Author(s):  
Silvia Ravera ◽  
Matthias Quick ◽  
Juan P. Nicola ◽  
Nancy Carrasco ◽  
Mario L. Amzel
Keyword(s):  
Novel Approach ◽  
Binding Data ◽  
Hill Coefficients

Using hidden Markov models to find discrete targets in continuous sociophonetic data

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Daniel Duncan
Keyword(s):  
Hidden Markov Models ◽  
Markov Models ◽  
Hidden Markov ◽  
Abstract Representation ◽  
Language Variation And Change ◽  
Novel Approach ◽  
Single Target ◽  
The Individual ◽  
Individual Speaker

Abstract Advances in sociophonetic research resulted in features once sorted into discrete bins now being measured continuously. This has implied a shift in what sociolinguists view as the abstract representation of the sociolinguistic variable. When measured discretely, variation is variation in selection: one variant is selected for production, and factors influencing language variation and change are influencing the frequency at which variants are selected. Measured continuously, variation is variation in execution: speakers have a single target for production, which they approximate with varying success. This paper suggests that both approaches can and should be considered in sociophonetic analysis. To that end, I offer the use of hidden Markov models (HMMs) as a novel approach to find speakers’ multiple targets within continuous data. Using the lot vowel among whites in Greater St. Louis as a case study, I compare 2-state and 1-state HMMs constructed at the individual speaker level. Ten of fifty-two speakers’ production is shown to involve the regular use of distinct fronted and backed variants of the vowel. This finding illustrates HMMs’ capacity to allow us to consider variation as both variant selection and execution, making them a useful tool in the analysis of sociophonetic data.

scholarly journals HPM: A Hybrid Model for User’s Behavior Prediction Based on N-Gram Parsing and Access Logs

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Sonia Setia ◽  
Verma Jyoti ◽  
Neelam Duhan
Keyword(s):  
Web Mining ◽  
Contextual Information ◽  
Hybrid Approach ◽  
Web Pages ◽  
Continuous Growth ◽  
Novel Approach ◽  
Content Mining ◽  
Long Access ◽  
N Gram ◽  
The Individual

The continuous growth of the World Wide Web has led to the problem of long access delays. To reduce this delay, prefetching techniques have been used to predict the users’ browsing behavior to fetch the web pages before the user explicitly demands that web page. To make near accurate predictions for users’ search behavior is a complex task faced by researchers for many years. For this, various web mining techniques have been used. However, it is observed that either of the methods has its own set of drawbacks. In this paper, a novel approach has been proposed to make a hybrid prediction model that integrates usage mining and content mining techniques to tackle the individual challenges of both these approaches. The proposed method uses N-gram parsing along with the click count of the queries to capture more contextual information as an effort to improve the prediction of web pages. Evaluation of the proposed hybrid approach has been done by using AOL search logs, which shows a 26% increase in precision of prediction and a 10% increase in hit ratio on average as compared to other mining techniques.

scholarly journals Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James M. Kidd ◽  
Kamilia Abdelraouf ◽  
Tomefa E. Asempa ◽  
Romney M. Humphries ◽  
David P. Nicolau
Keyword(s):  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Hill Equation ◽  
Infection Model ◽  
Free Drug Concentration ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
The Hill ◽  
Susceptibility Breakpoint

ABSTRACT The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 μg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 μg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium. We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 μg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0–24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0–24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0–24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0–24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 μg/ml and 0/3 E. faecium isolates with MICs of ≥4 μg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint.

Perspective on the relationship between GABAA receptor activity and the apparent potency of an inhibitor

2021 ◽  
Vol 19 ◽  
Author(s):  
Allison L. Germann ◽  
Spencer R. Pierce ◽  
Alex S. Evers ◽  
Joe Henry Steinbach ◽  
Gustav Akk
Keyword(s):  
Gabaa Receptor ◽  
Hill Equation ◽  
Response Relationship ◽  
Inhibition Concentration ◽  
Level Of Activity ◽  
Control Response ◽  
The Hill ◽  
The Relationship ◽  
Inhibition Curve ◽  
Receptor Channel

Background : In electrophysiological experiments inhibition of a receptor-channel, such as the GABAA receptor, is measured by co-applying an agonist producing a predefined control response with an inhibitor to calculate the fraction of the control response remaining in the presence of the inhibitor. The properties of the inhibitor are determined by fitting the inhibition concentration-response relationship to the Hill equation to estimate the midpoint (IC50) of the inhibition curve. Objective: We sought to estimate here the sensitivity of the fitted IC50 to the level of activity of the control response. Methods: The inhibition concentration-response relationships were calculated for models with distinct mechanisms of inhibition. In Model I, the inhibitor acts allosterically to stabilize the resting state of the receptor. In Model II, the inhibitor competes with the agonist for a shared binding site. In Model III, the inhibitor stabilizes the desensitized state. Results: The simulations indicate that the fitted IC50 of the inhibition curve is sensitive to the degree of activity of the control response. In Models I and II, the IC50 of inhibition was increased as the probability of being in the active state (PA) of the control response increased. In Model III, the IC50 of inhibition was reduced at higher PA. Conclusions: We infer that the apparent potency of an inhibitor depends on the PA of the control response. While the calculations were carried out using the activation and inhibition properties that are representative of the GABAA receptor, the principles and conclusions apply to a wide variety of receptor-channels.

scholarly journals A Genetic Algorithm Approach for Group Recommender System Based on Partial Rankings

2018 ◽  
Vol 29 (1) ◽  
pp. 653-663 ◽  
Author(s):  
Ritu Meena ◽  
Kamal K. Bharadwaj
Keyword(s):  
Genetic Algorithm ◽  
Recommender Systems ◽  
Rank Aggregation ◽  
Partial Ranking ◽  
Novel Approach ◽  
Kendall Tau Distance ◽  
Ultimate Objective ◽  
Aggregation Technique ◽  
The Individual ◽  
Group Recommender

Abstract Many recommender systems frequently make suggestions for group consumable items to the individual users. There has been much work done in group recommender systems (GRSs) with full ranking, but partial ranking (PR) where items are partially ranked still remains a challenge. The ultimate objective of this work is to propose rank aggregation technique for effectively handling the PR problem. Additionally, in real applications, most of the studies have focused on PR without ties (PRWOT). However, the rankings may have ties where some items are placed in the same position, but where some items are partially ranked to be aggregated may not be permutations. In this work, in order to handle problem of PR in GRS for PRWOT and PR with ties (PRWT), we propose a novel approach to GRS based on genetic algorithm (GA) where for PRWOT Spearman foot rule distance and for PRWT Kendall tau distance with bucket order are used as fitness functions. Experimental results are presented that clearly demonstrate that our proposed GRS based on GA for PRWOT (GRS-GA-PRWOT) and PRWT (GRS-GA-PRWT) outperforms well-known baseline GRS techniques.

scholarly journals Kinetic studies on two isoforms of acetyl-CoA carboxylase from maize leaves

1996 ◽  
Vol 318 (3) ◽  
pp. 997-1006 ◽  
Author(s):  
Derek HERBERT ◽  
Lindsey J PRICE ◽  
Claude ALBAN ◽  
Laure DEHAYE ◽  
Dominique JOB ◽  
...  
Keyword(s):  
Kinetic Studies ◽  
Product Inhibition ◽  
Hill Equation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Maize Leaves ◽  
Ic50 Values ◽  
A Minor ◽  
The Hill

The steady-state kinetics of two multifunctional isoforms of acetyl-CoA carboxylase (ACCase) from maize leaves (a major isoform, ACCase1 and a minor isoform, ACCase2) have been investigated with respect to reaction mechanism, inhibition by two graminicides of the aryloxyphenoxypropionate class (quizalofop and fluazifop) and some cellular metabolites. Substrate interaction and product inhibition patterns indicated that ADP and Pi products from the first partial reaction were not released before acetyl-CoA bound to the enzymes. Product inhibition patterns did not match exactly those predicted for an ordered Ter Ter or a random Ter Ter mechanism, but were close to those postulated for an ordered mechanism. ACCase2 was about 1/2000 as sensitive as ACCase1 to quizalofop but only about 1/150 as sensitive to fluazifop. Fitting inhibition data to the Hill equation indicated that binding of quizalofop or fluazifop to ACCase1 was non-cooperative, as shown by the Hill constant (napp) values of 0.86 and 1.16 for quizalofop and fluazifop respectively. Apparent inhibition constant values (K´ from the Hill equation) for ACCase1 were 0.054 µM for quizalofop and 21.8 µM for fluazifop. On the other hand, binding of quizalofop or fluazifop to ACCase2 exhibited positive co-operativity, as shown by the napp values of 1.85 and 1.59 for quizalofop and fluazifop respectively. K´ values for ACCase2 were 1.7 mM for quizalofop and 140 mM for fluazifop. Kinetic parameters for the co-operative binding of quizalofop to maize ACCase2 were close to those of another multifunctional ACCase of limited sensitivity to graminicide, ACC220 from pea. Inhibition of ACCase1 by quizalofop was mixed-type with respect to acetyl-CoA or ATP, but the concentration of acetyl-CoA had the greater effect on the level of inhibition. Neither ACCase1 nor ACCase2 was appreciably sensitive to CoA esters of palmitic acid (16:0) or oleic acid (18:1). Approximate IC50 values were 10 µM (ACCase2) and 50 µM (ACCase1) for both CoA esters. Citrate concentrations up to 1 mM had no effect on ACCase1 activity. Above this concentration, citrate was inhibitory. ACCase2 activity was slightly stimulated by citrate over a broad concentration range (0.25–10 mM). The significance of possible effects of acyl-CoAs or citrate in vivo is discussed.

scholarly journals Rates of reactions catalysed by a dimeric enzyme. Effects of the reaction scheme and the kinetic parameters on co-operativity

1991 ◽  
Vol 280 (1) ◽  
pp. 131-137 ◽  
Author(s):  
H Ishikawa ◽  
H Ogino ◽  
H Oshida
Keyword(s):  
Substrate Inhibition ◽  
Reaction Scheme ◽  
Rate Equations ◽  
Kinetic Behaviour ◽  
Hill Coefficients ◽  
S Curve ◽  
Almost All ◽  
The Hill ◽  
Rate Behaviour ◽  
Reaction Schemes

For the reaction S in equilibrium P catalysed by a dimeric enzyme, the reaction schemes are considered on the basis of the KNF model. For each of the ten possible schemes, the rate equation is derived on the basis of the combined steady-state and rapid-equilibrium assumptions. The curves of the plots of initial velocity v versus the substrate concentration [S] and the Hill coefficients h calculated from the rate equations depend strongly on the reaction scheme and the parameter X1. This parameter is defined by log (KS2/KS1) and is a measure of the relative affinities of the first and second protomers for the substrate. When X1 less than 0, v-[S] curves for some schemes exhibit negative co-operativity (h less than 1.0) and v-[S] curves for other schemes are similar to that of the Michaelis-Menten scheme, indicating that, even if there is interaction between the distinct protomers, sigmoidal rate behaviour is not necessarily observed. When X1 greater than 0, all the reaction schemes except one, which shows substrate-inhibition kinetic behaviour, exhibit sigmoidal kinetic behaviour (h greater than 1.0), and at the limit of X1 much greater than 0 the Hill coefficients attain the maximum possible value of 2.0. Furthermore, we have found that, even if X1 = 0, the v-[S] curve for almost all the schemes considered in the present work does not necessarily agree with that for the Michaelis-Menten scheme. This means that the deviation of the v-[S] curve from a hyperbola can be observed even if there is no interaction between the distinct protomers.

scholarly journals All fingers are not the same: Handling variable-length sequences in a discriminative setting using conformal multi-instance kernels

2017 ◽  
Author(s):  
Sarvesh Nikumbh ◽  
Peter Ebert ◽  
Nico Pfeifer
Keyword(s):  
Binary Classification ◽  
Positional Information ◽  
Weight Vector ◽  
Variable Length ◽  
Genomic Sequences ◽  
String Kernels ◽  
Promoter Sequences ◽  
Novel Approach ◽  
The Individual ◽  
Visualization Techniques

AbstractMost string kernels for comparison of genomic sequences are generally tied to using (absolute) positional information of the features in the individual sequences. This poses limitations when comparing variable-length sequences using such string kernels. For example, profiling chromatin interactions by 3C-based experiments results in variable-length genomic sequences (restriction fragments). Here, exact position-wise occurrence of signals in sequences may not be as important as in the scenario of analysis of the promoter sequences, that typically have a transcription start site as reference. Existing position-aware string kernels have been shown to be useful for the latter scenario.In this work, we propose a novel approach for sequence comparison that enables larger positional freedom than most of the existing approaches, can identify a possibly dispersed set of features in comparing variable-length sequences, and can handle both the aforementioned scenarios. Our approach, CoMIK, identifies not just the features useful towards classification but also their locations in the variable-length sequences, as evidenced by the results of three binary classification experiments, aided by recently introduced visualization techniques. Furthermore, we show that we are able to efficiently retrieve and interpret the weight vector for the complex setting of multiple multi-instance kernels.

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