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Lengths and patterns of transcriptional units in the amplified nucleoli of oocytes of Xenopus laevis.

Transcriptionally active chromatin from peripheral amplified nucleoli of lampbrush-chromosome stage oocytes of Xenopus laevis was dispersed and spread in various solutions of low salt concentrations (including some with additions of detergents) and examined by electron microscopy. Nucleolar material from oocytes of animals with normal (2-nu) and mutant (1-nu) genetical constitution of nucleolus organizers was compared. Histograms showing the distributions of the length of matrix units, apparent spacer intercepts, and the total repeating units of the rDNA containing chromatin axes revealed a significant degree of heterogeity, with indications of subclasses and predominant repeat unit size classes of 3.3 amd 3.8 micron length. The correspondence of matrix unit length to the molecular weight of the first stable product of rDNA transcription was studied using gel electrophoresis of labelled pre-rRNA under non-denaturing and denaturing conditions. Evaluations of individual strands of nucleolar chromatin further demonstrated the existence of both (i) strands with obviously homogeneous repeating units of and (ii) strands with intra-axial heterogeneity of rDNA subunits. "Prelude complexes", i.e. groups of transcriptional complexes in apparent spacer intercepts, were not infrequently noted. The data are compared with the measurements of lengths of repeating units in fragments of rDNA obtained by digestion with EcoRI endonuclease as described by Morrow et al.(1974) and Wellauer et al. (1974,1976a, b). The results are discussed in relation to problems of variations in the modes of arrangement of the pre-rRNA genes, the state of packing of rDNA during transcription, and possible mechanisms of the amplification process.

Animals↗

The size and curvature of synapses in the cerebellar cortex of the cat.

At the supra Purkinje layer and the subpial level in the molecular layer of lobules V and VI of the cerebellar cortex of the cat, synaptic profiles were measured in ultrathin serial sections treated with either osmium tetroxide (OsO4) or ethanolic phosphotungstic acid (E-PTA). From trace and chord lengths of the intercepts of synaptic profiles the curvature and the mean caliper diameter of the synapse was calculated. In OsO4-material the curvature of synapses yielded an average angle of about 47 degrees and about 36 degrees in E-PTA material. Although these values are contrary to the assumption of a flat disc, which is commonly required in stereological procedures to estimate caliper diameter, the effect of the curvature on the estimation of the mean caliper diameter is limited. This is shown by serial reconstruction analysis of the largest diameter of synapses from maximal arc and chord length measurements at the subpial and supra Purkinje level. The results provide quantitative data concerning synaptic size, curvature and the frequency of intercepts per synapse at the subpial and supra Purkinje level in the cerebellar cortex in OsO4 and E-PTA material. In addition the advantages and disadvantages of E-PTA and osmiumtetroxide staining in quantitative analysis are discussed.

Animals↗

Eubacteria have 3 growth modes keyed to nutrient flow. Consequences for the concept of maintenance and maximal growth yield.

Aerobic growth of Escherichia coli and Paracoccus denitrificans has been studied in chemostat, fed batch, and recycling fermentor modes under carbon and energy limitation. Two abrupt drops or discontinuities in molar growth yield, Y, have been found that occur over relatively short ranges in the value of specific growth rate. Before the first discontinuity, Y is constant and maximal. After the first discontinuity, at a doubling time of 33 h, Y becomes constant again and independent of mu until the second discontinuity appears at a doubling time of about 50 h, corresponding to a mu of about 0.014. At this point, Y drops to a lower value that is constant at doubling times longer than 100 h, corresponding to a mu of about 0.007. The second discontinuity is associated in Paracoccus with elevated levels of guanosine tetraphosphate (ppGpp) that impose stringent regulation as has been found previously with Bacillus and Escherichia species. It is thus likely that the stringent response generally occurs in bacteria in vivo at a doubling time of about 50 h. The cause of the first discontinuity is unknown. All experiments indicate that Pirt-type calculations relating mu, Y, and maintenance energy demand are no longer valid. In chemostat experiments, the intercept of the relationship between specific substrate utilization and specific growth rate is defined as maintenance. However, this intercept most probably is caused by stringent regulation at low dilution rates. Three regions of bacterial growth rates are defined by this study, corresponding to doubling times of 0.5 to 15 h, 33 to 50 h, and greater than 100 h. Some growth behavior in each region is unique to that region.

Chromatography, Thin Layer↗

The relation of ventilation to metabolic rate during moderate exercise in man.

To characterize more precisely the relationship between ventilation (VE) and CO2 output (VCO2) during incremental exercise, 35 healthy males were studied at rest and during upright cycle ergometry, with the work rate incremented every 4 min up to each subject's anaerobic threshold (Oan). Twenty-one subjects had arterial blood sampled at rest and in the steady state at each work rate to determine the relationship between physiological dead space ventilation (VD) and VCO2. At these work rates arterial PCO2 was regulated at the resting, control value. VE (BTPS) was linearly related to VCO2 from rest Oan with a slope of 24.6. However, the regression had a significant positive intercept of 3.2 L/min-1. This causes the ventilatory equivalent for CO2 (i.e., VE/VCO2) to decrease with increasing work rates. VD also increased linearly with increasing VCO2. However, this was consequent to increased breathing frequency as VD remained constant. Thus, the observed fall in VE/VCO2 with increasing work rates is due to the positive intercept but the inherent relationship between VE and VCO2, reflected by the linear regression slope, remains unchanged from rest through moderate exercise.

Adult↗

Effect of diazepam on the speed of mental rotation.

The effect of diazepam on spatial visualization was studied using a double-blind crossover design. Diazepam 10 mg (or placebo) was given orally to 12 healthy young men at bedtime, followed again by 10 mg (or placebo) the next morning. One hour after the administration of the morning dose, the subjects performed a mental rotation task. Diazepam effects were analyzed in terms of an information processing model previously constructed to account for performance of the task. Using this method, the slope and intercept parameters of a linear function relating reaction time to task condition (i.e., angular difference in orientation between two identical stimulus figures) were computed for diazepam and placebo conditions. Diazepam significantly increased the slope and intercept of the mental rotation function (P less than 0.05). These results suggest that diazepam impairs spatial visualization ability.

Adult↗

An error in interpretation of double-reciprocal plots and Scatchard plots in the studies of binding of fluorescent probes to proteins, and alternative proposals for determining binding parameters.

One of the objects of experiments in which fluorochrome is added to suspensions of cell membranes is to determine the parameters n and Kp, the capacity of unit mass of protein to bind fluorochrome and the dissociation constant, respectively. Currently, these are estimated from Scatchard plots, construction of which first requires that observed fluorescence intensity be converted to moles of bound fluorochrome. This in turn is said to be possible by analysis of the intercept of a plot of reciprocal fluorescence intensity against reciprocal protein concentration. However, analysis of the classical mass action equilibrium equation, upon which the foregoing procedures are said to be based, reveals that the intercept of the double-reciprocal plot always underestimates the desired value. The error is formalized and shown to increase without bound with fluorochrome concentration. The error in turn leads to erroneous assessment of n and Kp. Alternative methods for calculating the desired parameters are proposed, based on direct plots of fluorescence intensity.

Anilino Naphthalenesulfonates↗

Heart rate and oxygen uptake relationship: a comparison of loaded marching and running in women.

Heart rate (beats.min-1; fc) measured during marching with a load is often used to predict the oxygen cost (l.min-1; VO2) of the activity. The prediction comes from the fc/VO2 relationship determined from laboratory measures of fc and VO2 during treadmill running. Studies in men have suggested that this may not be appropriate although this has yet to be examined in women. This study, therefore, compared the fc/VO2 relationship between loaded marching and maximal running protocols in women. Sixteen female subjects [mean (SD), age 21.9 (2.3) years, height 6 (0.06) m, weight 62.6 (7.6) kg] had their fc (from three-lead chest electrodes) and VO2 measured first during standard treadmill run protocols, and again 1 week later during loaded marching protocols. The slopes and intercepts determined from linear regression of fc on VO2 for each individual for each protocol were compared as were the maximal fc(fcmax), VO2 and ratings of perceived exertion (RPE) from the last work period of each protocol in paired t-tests. The fc/VO2 slopes (P < 0.01) and intercepts (P < 0.05) differed significantly between loaded marching and running. fcmax for loaded marching were 90% of fcmax for running (P < 0.01) and VO2peak for loaded marching were 80% of those for running (P < 0.01). However, RPE at the final levels for the two protocols were not significantly different. The data suggest that in women the fc/VO2 relationships for loaded marching and for running are different. This difference is similar to that found in men when speed is held constant and the load and gradient are varied. The results suggest that it would be erroneous to use fc and VO2 measured during running protocols in the laboratory to estimate energy expenditure and work intensity during loaded marching in the field.

Adult↗

Apparent volumes of distribution and drug binding to plasma proteins and tissues.

A pharmacokinetic model that incorporates linear binding of drug to plasma proteins and tissue indicates the same relationship between apparent volume of distribution and drug binding as that proposed by Gillette (1971) based on a simple distribution model. Apparent volume of distribution (V) is directly proportional to free fraction of drug in plasma (fp) and indirectly proportional to free fraction of drug in tissue (fT). In the case of a constant fT, a plot of V versus fp will be linear with an intercept equal to plasma volume (Vp). If fT changes with fp, an apparently linear plot may result but the intercept will exceed Vp. An approach to the calculation of fT, a composite binding parameter, is presented and illustrated by comparing the tissue binding of tolbutamide in patients during acute viral hepatitis and upon recovery.

Blood Proteins↗

Effects of beta-adrenoceptor blocking agents of N-tertiary butyl derivatives on maximum upstroke velocity of action potential in guinea-pig papillary muscles.

The effects of bufetolol (27.8-138.9 mumol/l), bunitrolol (70.2-351.1 mumol/l), bupranolol (16.2-100 mumol/l), carteolol (60.7-607 mumol/l), D32 (17.3-100 mumol/l), penbutolol (1.5-29.4 mumol/l) and timolol (115.5 and 231.2 mumol/l) on action potentials were investigated in isolated guinea-pig papillary muscles. All these beta-adrenoceptor blocking agents of teritary butyl aminopropranol derivatives produced a concentration-dependent reduction of Vmax at driving rates of 1 Hz, 0.027 Hz and 4 Hz. The reduction was frequency-dependent but at all the rates penbutolol was highest in potency, as estimated by ED30 (0.027 Hz) and ED 50 values (1 and 4 Hz), followed by bupranolol, D-32, bufetolol and bunitrolol. These were followed in turn by timolol and carteolol in ED30 at 0.027 Hz and ED50 at 1 Hz, but by carteolol and timolol in ED50 at 4 Hz. Each log (1/ED) value is a linear function of log n-octanol/water partition coefficient (log P). The slope and intercept (the value at log P = 0) of the line of log (1/ED50) at 4 Hz are steeper and higher, respectively, than those of the lines at the other frequencies. The time course of recovery of Vmax during diastole was studied by assessing Vmax in premature responses at 0.027 Hz, being approximated by a single exponential function. The time constants of recovery (tau) and intercepts (Ao: the value extrapolated to the time of APD90 of the conditioning responses) at the level of ED50 and at 100 mumol/l of the drugs were thus estimated.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

Noninvasive continuous blood pressure measurement from the finger: optimal measurement conditions and factors affecting reliability.

We recorded finger arterial blood pressure (FINAP) in 50 male patients during various types of surgical operations. Three different types of cuffs were used on four fingers of each patient. Measurements were made by the arterial volume-clamp method of Penaz. The FINAP measurements were compared with pressure data obtained ipsilaterally from a radial artery catheter-transducer system (intraarterial pressure [IAP]) to find optimal recording conditions and to document factors affecting FINAP readings. The thumb, with a specially designed cuff, gave the most accurate results. The mean FINAP - IAP difference for the thumb was -4.8 mm Hg for systolic pressure, 1.49 mm Hg for diastolic pressure, and 0.29 mm Hg for mean pressure. The differences were statistically significant for systolic and diastolic pressure but not for mean pressure. The regression slope for thumb systolic FINAP/IAP was 0.979, that for thumb diastolic FINAP/IAP was 0.963, and that for mean thumb FINAP/IAP was 0.996, whereas the intercepts were 7.499 for systolic pressure, 0.802 for diastolic pressure, and 0.083 for mean pressure. The correlation coefficients were 0.945 (systolic), 0.884 (diastolic), and 0.949 (mean). The correlation coefficients with the other fingers ranged from 0.502 to 0.922 for systolic pressure, 0.757 to 0.932 for diastolic pressure, and 0.767 to 0.892 for mean pressure. The slopes for the various finger-cuff combinations ranged from 0.537 to 0.996, and the intercepts ranged from 0.083 to 32.387 from mean pressure. In 3 patients (6%) the FINAP measurement was not possible because of insufficient peripheral circulation. In 9 other patients (18%) the FINAP measurements were not accurate during some periods of time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

The mechanical effects of contractions on blood flow to the muscle.

To determine whether muscle contractions can increase muscle blood flow independently from metabolic factors, we isolated the vasculature of the left diaphragm or gastrocnemius muscle of anesthetized and mechanically ventilated dogs. Arterial blood flow was controlled with a constant pressure source and the arterial pressure (Pa) was decreased in steps to obtain pressure-flow relationships (P-Q). The local vasculatures were maximally dilated with nitroprusside [mean (SD) 114.0 (32.0) micrograms.min-1], adenosine [1.43 (0.41) mmol.l-1.min-1], and acetylcholine [1.43 (0.41) mmol.l-1.min-1] and the P-Q with and without spontaneous contractions (n = 6), stimulated twitches (n = 12, 2-4 Hz), or tetanic trains (n = 7, 25 Hz) in the diaphragm and stimulated twitches (n = 6, 2-4 Hz), or tetanic contractions (n = 6, 12-16 trains) in the gastrocnemius were compared. The pressure axis intercept decreased (P < 0.5) with spontaneous contractions in the diaphragm and the slope did not change. At Pa of 13.3 kPa, flow increased from 36.2 (34.9) to 43.9 (38.2) ml.min-1.100 g-1 (P < 0.05). During twitch contractions, the slope and intercept of the P-Q were not significantly different from vasodilatation alone, but the flow at a pressure of 13.3 kPa increased slightly. In the gastrocnemius (n = 6), continuous and intermittent tetanic contractions did not affect P-Q or flow at Pa of 100 mmHg (n = 6). Furthermore, increasing venous pressure to 6.7 kPa did not affect flow in this muscle. We conclude that the muscle pump has only a small direct effect on muscle blood flow and its main effect is to reduce venous pressures.

Animals↗

Oxygen cost of internal work during cycling.

The energy cost of internal work and its relationships with lower limb mass and pedalling frequency were studied in four male subjects [age 22.2 (SD 1.5) years, body mass 81.0 (SD 5.1) kg, maximal O2 uptake (VO2max) above resting 3.06 (SD 0.4) l.min-1]. The subjects cycled at 40, 60, 80 and 100 rpm and at five different exercise intensities for every pedalling frequency (unloaded condition, UL); the same exercises were repeated after having increased the lower limbs' masses by 40% (loaded condition, L). The exercise intensities were chosen so that the oxygen consumption (VO2) did not exceed 75% of VO2max. For all the subjects and all the conditions, the rate of VO2 above resting increased linearly with the mechanical power (W). The y-intercepts of the linear regressions of VO2 on W, normalised per kilogram of overall lower limbs mass were the same in both UL and L and increased with the 4.165 power of pedalling frequency (fp). These intercepts were taken to represent the metabolic counterpart of the internal power dissipation in cycling; they amounted to 0.78, 0.34, 3.29 and 10.30 W.kg-1 for pedalling frequencies of 40, 60, 80 and 100 rpm respectively. The slope of the regression lines (delta W/delta VO2) represents the delta efficiency of cycle ergometer exercise; this was also affected by fp, ranging, on average, from 22.9% to 32.0%. These data allowed us to obtain a comprehensive description of the effects of fp (per minute), exercise intensity (W, watts) and lower limbs' mass with or without added loads (mL, kg), on VO2 (ml.min-1) during cycling: VO2 = [mL.(4.3.10(-8).fp4.165/0.35)] + (1/[(3.594.10(-5).fp2 - 0.003.fp + 0.326).0.35]).W. The mean percentage error between the VO2 predicted from this equation and the actual value was 12.6%. This equation showed that the fraction of the overall VO2 due to internal work, for a normal 70-kg subject pedalling at 60 rpm and 100 W was of the order of 0.2.

Adult↗

Quantification of the ease of removal of bacteria from surfaces.

This paper describes a technique which reproducibly quantifies the ease of removal of microorganisms from surfaces. Tiles (22 mm x 22 mm) of various materials were colonised with Staphylococcus epidermidis NCTC 11047, Escherichia coli K12 HB101 or Pseudomonas aeruginosa PaWH, by submersion, for various times (2 min-48 h), in inoculated Tryptone Soya broth (37 degrees C). Colonised tiles were blotted onto a Tryptone Soya agar plate for 1 min and the process was repeated through a succession of agar plates. The final plate contained tetrazolium salts (0.05% w/v) and was incubated in situ with the tile. Tetrazolium plates indicated that very few organisms remained on the tiles after 15 successive blots. In all instances, the number of recovered colonies per plate decreased exponentially with plate succession number, according to the relationship, CFU = A.10-kN, where CFU is the number of colonies transferred, k is the removal exponent, A is the intercept and N is the plate succession number. Removal exponents differed significantly between organisms (P > 0.95), depended on the nature of the test surface, and decreased as the inital attachment and colonisation time was increased from 2 min-48 h. Intercept values (A) but not the gradients were dependent upon the initial numbers of bacteria in suspension. These data indicate that the gradients derived from counting recoverable viable cells from successive blots of test tiles onto agar is a measure of the strength of attachment of the organisms to the surface.

Bacteria↗

Calorimetric validation of 13C bicarbonate and doubly labeled water method for determining the energy expenditure in goats.

The purpose of the present study was to validate the 13C bicarbonate method (13C-M) and the doubly labeled water method (DLWM) for the estimation of the CO2 production R(CO2) in goats as a ruminant model. Indirect calorimetry was chosen as the reference method. Studies were carried out in 2 male African dwarf goats at 3 different developing stages (age: 5, 10, and 14 months, body mass: 14.6, 20.3, and 21.7 kg). Animals were fed a balanced feed 14 days before and during the studies. The isotope tracers (4 mg/kg NaH13CO3, 120 mg/kg 2H2O, and 75 mg/kg H218O; 99 AT.-%) were simultaneously given as a single pulse injection into the jugular vein. Thereafter, the animals were kept for 8 days in two respiration chambers (volume of chamber: 2.85 m3, air flow rate: 25 1/min) for the estimation of CO2 production and O2 consumption. For the determination of R(CO2) using the 13C-M samples of exhaled breath were drawn from the respiration chambers. The 13C enrichment and CO2 concentration of breath samples were measured by means of an infrared isotope analyzer. In order to determine R(CO2) by means of the DLWM, blood serum was used. The 2H and 18O enrichments were measured by an isotope ratio mass spectrometer. Urine samples were collected over 24 h to quantify renal water losses. The R(CO2) was calculated by means of the 13C-M using the area under the 13C enrichment-time curve. The determination of R(CO2) by means of the DLWM was based on the slopes of the 2H and 18O disappearance curves and the body water pool obtained from the zero time intercept of the isotope curves. The values of R(CO2) resulting from the 13C-M were found to be comparable with those from the calorimetric measurement. Smaller (not statistically significant) values of R(CO2)--92% from 13C-M and 87% from DLWM--compared to the indirect calorimetry could indicate the incorporation of 13C and 2H into metabolites other than CO2 and H2O, respectively. The body water contents calculated from the zero time intercepts of the 2H and 18O disappearance curves amounted to 66% and 63%, respectively. The body water content was found to be not related to the age of animals. The renal water loss was calculated to be 35% of the total water loss (0.76 l/d.

Aging↗

Model for the physics and physiology of fluid administration.

This article describes a model designed to provide an understanding of fluid flow in intravenous systems and human subjects. Experiments were developed which demonstrate that the model can represent common clinical situations. The model depicts physical devices as ideal resistors, pressure sources, and flow sources. The patient's venous system is depicted as a combination of ordinary and Starling resistors. For flows between 0 and 300 ml/hr, both physical devices and patients are adequately represented by a straight line representing the pressure-flow relationship (PFR): pressure = opening pressure + flow X resistance, where the slope is the resistance to fluid flow and the intercept is the opening pressure. The PFR for a normal vein is characterized by a flat slope (vein resistance = 22 +/- 20 mm Hg/L/hr, mean +/- SD) and a low intercept (opening pressure = 15 +/- 8 mm Hg). The PFR for a partially obstructed vein has a resistance equal to that of an unobstructed vein and an opening pressure elevated approximately equal to the pressure obstructing the vein. For perivascular tissue, the PFR has a steep slope (tissue resistance = 1,125 +/- 1,376 mm Hg/L/hr), while tissue opening pressure depends on the amount of fluid infused. At the onset of fluid extravasation (infiltration), tissue pressure usually is lower than venous pressure (8 +/- 8 versus 15 +/- 8 mm Hg), until fluid fills the distensible tissue compartment. In clinical practice, when infiltration or obstruction occurs, flow decreases and the clinician adjusts the roller clamp until correct flow resumes; no problem is obvious. The combined model for the intravenous tubing and venous systems explains the behavior of current clinical infusion devices.

Biophysical Phenomena↗

Regional myocardial function curve of the ventricle.

To understand the pathophysiology of diseased hearts, we devised a new regional myocardial function curve and investigated its properties. Regional work per unit volume of the myocardium (RWM) was calculated by integrating mean wall stress (sigma) with respect to the natural logarithm of the reciprocal of wall thickness [ln(1/H)] over a cardiac cycle. Regarding the end-diastolic ln(1/H) as the preload for the region of concern on the assumption that the myocardium is incompressible, we defined the relation between RWM and end-diastolic ln(1/H) as the regional myocardial function curve. In ten mongrel dogs, we measured left ventricular pressure, left ventricular internal diameter, and wall thickness with a catheter-tip micromanometer and ultrasonic dimension gauges during volume loading to obtain the regional myocardial function curve. We examined the sensitivity of the regional myocardial function curve to changes in contractile state (isoproterenol, propranolol) and changes in afterload (pressure loading by a balloon-occlusion catheter). The linear fit to the data points of the regional myocardial function curve under each condition always achieved a very good correlation coefficient (greater than 0.62). Isoproterenol increased the slope of the regional myocardial function curve from 9.7 +/- 0.9 (SEM) mJ/cm3 to 14.4 +/- 1.0 mJ/cm3 (P < 0.01), with no significant changes in the x-intercept, while propranolol decreased it to 5.6 +/- 1.2 mJ/cm3 (P < 0.01) with no significant changes in the x-intercept.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

A thermodynamic analysis of the correlation between active Na+ transport and the rate of oxygen consumption in epithelia.

Active transport in epithelia is discussed in terms of the relationships between oxygen consumption and sodium flux as affected by each of the two corresponding thermodynamic forces. Analysis is presented of the use of nonequilibrium thermodynamics as a total in elucidating coupling and stoichiometry, and in evaluating drug action in the system. The analysis leads to the quantitative characterization of active transport in "two-flow" systems in terms of two plots: oxygen consumption nad sodium flow, each as a function of electrical potential difference, at constant affinity and constant concentrations. The relevant characteristic parameters are then shown to be represented by the slopes and intercepts of the two plots, the ratios of the slopes and of the intercepts, and by the difference--as well as the ratio--of the ratios. Distinction is made between experimental conditions in which the phenomenological coefficients remain constant and those in which these coefficients undergo appreciable changes. In terms of the above analysis, and examination is made of the effect of commonly used drugs. It is shown that while drugs may effect both the affinity and the phenomenological coefficients, they invariably affect the latter--at least in the cases hitherto reported.

Animals↗

Initial charge distribution and capacity transients in frog skeletal muscle.

The effect of prior charge transfers on intramembrane charge movements was investigated in voltage-clamped frog skeletal muscle fibres. 10 mV steps between fixed prepulse and test voltages were imposed at varying intervals after a 5 mV prepulse step made from a previous conditioning level. The amount of charge transfer prior to the test step was varied by altering the extent to which the test step intercepted slow (q gamma) currents elicited in the prepulse. The greater the prior charge transfer, the more rapid the transients in the subsequent test step. In contrast, where the prepulse had not reached the threshold of slow currents, or at larger depolarizations where the then faster charging currents were not intercepted, charge movements induced by the test step had a constant size and form. Charging kinetics thus varied with preceding charge transfer, consistent with higher-order cooperative (Huang, 1984), or sequential (Almers, 1978) schemes for the nonlinear charge.

Animals↗