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Biomedical subjects

G N Ling

Publications and source records attributed to G N Ling.

At least 19 recordsLinked to original sources
PubMed1994

The new cell physiology: an outline, presented against its full historical background, beginning from the beginning.

The primary objective of this review is to present a brief outline of the new cell physiology. First introduced in 1962 under the title of the association-induction hypothesis, the theory is now confirmed in its essence, after more than thirty years of world-wide experimental testing. While minor, and even more than minor, improvements and revisions may yet be needed, the weight and scope of the confirmatory evidence have left little doubt that a comprehensive and coherent new theory of cell physiology is established. For the first time in history we have available a realistic cell physiology, awaiting to unite and to guide future biomedical research and teaching. The review also demonstrates in passing how, as well as why, the old cell physiology has fizzled so miserably. Instead of providing the guiding light for all biomedical research it has degenerated into a fairy tale of make-believe. This degradation began with a wrong theory. The situation has grown steadily worse with time by the impact of premature progressive fragmentation on something inherently indivisible; and by the universal adoption of the peer-review system which gives to those with strong vested interests in the preservation of the status quo absolute power in determining who prospers and who is cast out (see Endnote 9). It is thus hardly surprising that up to now, despite superlative chemical engineering know-how available and the lure of great financial awards, not a single drug has been designed from understanding, an understanding that will remain forever beyond reach as long as the guiding theory of the cell physiology is basically wrong. In contrast, in its brief history, and despite its minuscule list of subscribers and their endless debilitating struggle merely to stay alive (see Endnote 9), the new cell physiology has already generated one mankind-enhancing medical technology of major proportions, magnetic resonance imaging or MRI (see Ling, 1984, p. vii; 1992, p. xxv). To this day, most biomedical research scientists, teachers as well as students, still operate under the delusion that the old cell physiology, a little battered perhaps, is still basically sound. By far the greatest majority of them simply do not know enough; and it is hard for them to find a convenient source of relevant information that will help in this regard. A second purpose of the present review is to fill this need. To a few "true believers" of the old cell physiology the preservation of the status quo is of overriding importance.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

A quantitative theory of solute distribution in cell water according to molecular size.

A quantitative theory (based on polarized multilayer (PM) theory of cell water, a subsidiary of the association-induction (AI) hypothesis) for the distribution in cell water of solutes of different molecular size is presented. From this theory, three predictions are derived: (1) linear distribution: when the equilibrium concentration of a solute in cell or model water is plotted against its concentration in the external solution, a straight line is obtained, with a slope equal to the equilibrium distribution coefficient or q-value of that solute in the cell water.(2): the size rule; the q-value is, as a rule, size-dependent: the larger the solute, the lower the q-value.(3): solutes with exceptionally high q-value may act as cryoprotectants. Earlier published data on the distribution of various nonelectrolytes in solutions of 15% poly(ethylene oxide)(PEO), 20% NaOH-denatured hemoglobin and 18% gelatin gel agree in general with the predictions of the theory. They demonstrate linear distribution and obey the size rule. The q-value vs. molecular volume plots can be fitted by theoretical curves after correction had been made for a minor fraction of free water in the system. The new theory has made it possible for the first time to estimate quantitatively the intensities of (bulk-phase) water polarization. In the 20% solution of NaOH-denatured bovine hemoglobin, 18% gelatin gel, 15% PEO solution, and 39% native bovine hemoglobin solution, the intensities of polarization of the bulk-phase water (over and above the vastly greater water-to-water interaction in normal liquid water) are respectively estimated at 16.5, 14.9, 11.7, and 3.8 cal per mole of water. The intensity of water polarization is higher in sulfonate ion exchange resin in the Li+ form (55.2 cal/mole) than in the Rb+ form (26.6 cal/mole). The theory has also made it possible to demonstrate that from 72% to 75% of the water in gelatin gel and in solution of NaOH-denatured hemoglobin, and of the PEO are polarized and are endowed with solvency properties quite different from normal liquid water. It has also been demonstrated that each polar site in the model system polarizes all water molecules in the first and second layer and at least some water molecules in the third layer of water surrounding each polar site. The multiplicity in the number of layers of water molecules polarized is thus established in these model systems.

Animals↗
PubMed1993

Predictions of polarized multilayer theory of solute distribution confirmed from a study of the equilibrium distribution in frog muscle of twenty-one nonelectrolytes including five cryoprotectants.

We determined the equilibrium distribution of twenty-one nonmetabolized nonelectrolytes in frog muscle cells. In all cases, plots of the equilibrium intracellular concentrations of a solute in the cell water against the external concentrations of the solute yielded straight lines in agreement with the prediction of such a rectilinear plot by the polarized multilayer (PM) theory. The slopes of these straight lines yield the equilibrium distribution coefficients or q-value of that solute. It was shown that, again in agreement with the PM theory, the q-values of fourteen nonelectrolytes vary with the molecular volumes of the nonelectrolytes, obeying the "size rule", i.e., the larger the solute, the lower its q-value. The q-values of the remaining seven nonelectrolytes also decrease with their molecular volumes but on a separate curve. These q-value vs. molecular volume plots (q-v plots) show strong resemblance to similar q-v plots of solutes in dialysis sacs containing proteins and polymers assuming the fully-extended conformation (extrovert models) but no, or only weak, resemblance to q-v plots of solutions containing native globular proteins (introvert models). These findings also support the PM theory, according to which some protein(s) pervasively present in cells are in the fully-extended conformation; and that these fully extended cell protein(s) polarize(s) in multilayers all or virtually all cell water. The relationship between the q-values of the nonelectrolytes and the solutes' respective molecular volume are described by two sets of theoretical curves, calculated from an equation introduced in the preceding paper. Both curves were computed on the basis of the same exclusion intensity (Uvp = 126 cal/mole). This factor measures the extra water-to-water interaction of the polarized water which acts to keep solute out of the cell water in degree according to the size of the solute. The two curves are computed on the basis of two different values of U(s), which represents the surface or solute component of the polarization energy, describing the affinity of the solute for the dynamic water structure: one curve which roughly predicts the q-value of fourteen of the nonelectrolytes studied was computed with a U(s) equal to 119 cal/mole. The second curve which roughly predicts the q-value of the remaining seven solutes was computed on the basis of a higher U(s) (156 cal/mole).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Can we see living structure in a cell?

Colloid chemistry (kappa o lambda lambda alpha: glue, or gelatin) was introduced in 1861 after the discovery of protoplasm which exhibits gelatin-like properties. Some 80 years later, colloid chemistry (and with it, the concept of protoplasm) was largely abandoned. The membrane (pump) theory, according to which cell water and cell solute like K+ are free as in a dilute KCl solution, became dominant. Later studies revealed that rejecting the protoplasmic approach to cell physiology was not justified. Evidence against the membrane (pump) theory, on the other hand, has stood the test of time. In a new theory of the living cell called the association-induction (AI) hypothesis, the three major components of the living cell (water, proteins and K+) are closely associated; together they exist in a high-(negative)-energy-low entropy state called the living state. The bulk of cell water is adsorbed as polarized multilayers on some fully extended protein chains, and K+ is adsorbed singly on beta- and gamma-carboxyl groups carried on aspartic and glutamic residues of cell proteins. Extensive evidence in support of the AI hypothesis is reviewed. From an extension of the basic concepts of the AI hypothesis and the new knowledge on primary structure of the proteins, one begins to understand at long last what distinguishes gelatin from other proteins; in this new light, new definitions of protoplasm and of colloid chemistry have been introduced. With the return of the concept of protoplasm, living structure takes on renewed significance, linking cell anatomy to cell physiology. Finally, evidence is presented showing that electron microscopists have come close to seeing cell structure in its living state.

Animals↗
PubMed1991

The majority of potassium ions in muscle cells is adsorbed on beta- and gamma-carboxyl groups of myosin: potassium-ion-adsorbing carboxyl groups on myosin heads engage in cross-bridge formation during contraction.

High-molecular weight poly(ethylene glycol) (PEG-8000) in the bathing medium prolongs the survival of 2-mm-wide frog muscle segments with open ends. In a PEG-8000-containing medium Rb+, K+, and Na+ in the muscle segments reached new diffusion equilibrium in 2-4 hours. At this new equilibrium, the cell's preference of K+ over Na+ was preserved but very much weakened. Studies of the influence of pH on the equilibrium distribution of labelled Na+ in 2-mm-wide muscle segments confirmed the prediction that beta- and gamma-carboxyl groups, carried respectively on aspartic and glutamic acid residues of intracellular proteins, adsorb K+, Na+ and other monovalent cations. These carboxyl groups have a characteristic pKa between 3.65 and 4.25. A pKa of 3.85 was observed. These findings, when seen in the light of other relevant information available, led to the conclusion that beta- and gamma-carboxyl groups on myosin molecules adsorb--in a close contact one-ion-one-site fashion--the majority (67% to 80%) of K+ in resting muscle cells. Other evidence suggests that in muscle contraction, the K(+)-adsorbing beta- and gamma-carboxyl groups on myosin heads form salt linkages with cationic sites on actin, displacing and releasing the adsorbed K+. Present and earlier findings together offer support for an earlier suggestion that the formation and dissociation of these salt-linkages may underlie the force-generating, cyclic formation and dissociation of cross-bridges during muscle contraction.

Animals↗
PubMed1990

Theory of active transport across frog skin and other bifacial cell systems: a subsidiary of the association-induction hypothesis.

This review presents the theory of solute transport across frog skin, epithelial cells of the intestine, the kidney tubules, and other similar systems. This theory is a part of a broader theory of the living cell, called the association-induction hypothesis. The central pumping mechanism is the cyclic activity of a sponge-like cytoplasmic protein(s), which alternately sop-up (by adsorption) the solute being transported and squeeze it out again (by desorption) into the cytoplasmic water at a high concentration level. The uptake phase begins with the adsorption of ATP on key cardinal sites of the protein involved; the release phase is triggered by the desorption of ATP through its dephosphorylation during a transitory activation of an ATPase. The theory recognizes the different nature of the two surfaces of the epithelial cells and assigns to each a key role in the active transport. The surface facing the "source solution" has a higher permeability to the solute being transported, while the surface facing the "sink solution" has a low permeability to the solute. This asymmetry in permeability insures that the solute sopped up by the cytoplasmic protein(s) comes primarily from the source solution. Depolarization of the water of the cell surface facing the sink solution (but not that facing the source solution) insures that the solute released into the cytoplasmic water during the squeezing phase leaves the cell only through the opposite surface as that where the solute has entered the cell.

Animals↗
PubMed1990

The physical state of potassium ion in the living cell.

This review summarizes more than 30 years of experimental testing (and confirmation) of a key postulate of the association-induction (AI) hypothesis: most K+ ions in resting cells are adsorbed on beta- and gamma-carboxyl group of cell proteins in a close-contact one ion-one site manner. Failure of healthy, cytoplasm-free, squid axon-membrane sacs to selectively accumulate K+ over Na+ and success of muscle cells without a functional cell membrane (and postulated pumps) to achieve the same, point to the cytoplasm as the seat of selective K+ accumulation. Four independent techniques unanimously confirmed the predicted localization in striated muscle cells, of the bulk of cell K+ in the A-bands where 65% of the beta- and gamma-carboxyl groups are located. Strict adherence to the Langmuir adsorption isotherm in the equilibrium distribution of K+ in muscle cells in the absence and presence of competing ions, proved one ion-one site, close contact adsorption of cell K+ on anionic groups. The "effectively membrane-pumpless open-ended cell" (EMOC) technique, further helped to establish close contact adsorption of K+ to take place in the cytoplasm rather than the cell membrane. A pK, of 3.9 obtained by titration of the cytoplasmic anions groups and a sensitivity to specific carboxyl group-reagent, 1-ethyl-3-(3-dimethylamino-propyl) carbodimide HCl combine to establish that the cytoplasmic anionic sites adsorbing K+ are indeed beta- and gamma-carboxyl groups.

Animals↗
PubMed1990

Low paramagnetic-ion content in cancer cells: its significance in cancer detection by magnetic resonance imaging.

In previous publications, one of us demonstrated that variation in paramagnetic-ion contents is a major contributing factor to the different NMR relaxation times, T1 and T2, of water protons among normal mouse tissues; and between normal tissues and cancer cells. The nature of the paramagnetic ions involved was not determined. In the present communication, we report results of analysis of the contents of three biologically prominent paramagnetic ions (manganese, iron and copper) in 9 normal mouse tissues (brain, heart, small intestine, kidney, liver, lung, voluntary muscle, spleen and stomach); one strain of rat cancer cells (As-30, rat hepatoma); and 6 strains of mouse cancer cells (Ehrlich mammary adenocarcinoma, LSA lymphoma, Krebs carcinoma of the inguinal region; sarcoma 180; Klein TA3 mammary adenocarcinoma; P815 mast cell leukemia). Our data indicate that manganese and iron are by far the two most important paramagnetic ions contributing to the diversity of NMR relaxation times. The average manganese content of all the normal mouse tissues studied (29.6 +/- 4.99 mu mole/kg) is 24 times higher than the average manganese contents of all the cancer cells studied (1.22 +/- 0.27 mu moles/kg) and there is essentially no overlap between the two groups of data. The average iron content of the normal mouse tissues (281.6 +/- 51.2 mumoles/kg) is 4 times the average in cancer cells (66.7 +/- 7.74 mumoles/kg) but there is some overlap here. The observed differences in both the manganese and iron contents are statistically highly significant, with P's below 0.0001. The copper contents of the cancer cells is lower than the average of normal mouse tissues but only by some 20%. The difference is statistically insignificant at the 0.05 level but significant at the 0.2 level.

Animals↗
PubMed1989

The physical state of water in living cells and model systems. XII. The influence of the conformation of a protein on the solubility of Na+ (sulfate), sucrose, glycine and urea in the water in which the protein is also dissolved.

In this report, we describe the result of an extensive investigation of the effects of the conformations of proteins on the solvency of the bulk-phase water in which the proteins are dissolved. The concentrations of the proteins used were usually between 20 to 40%; the temperature was 25 degrees +/- 1 degree C. To probe the solvency of the water, the apparent equilibrium distribution coefficients (or p-values) of 4 solutes were studied: Na+ (sulfate), glycine, sucrose, and urea. From 8 to 14 isolated proteins in three types of conformations were investigated: native; denatured by agents that unravel the secondary structure (e.g., alpha-helix, beta-pleated sheet) of the protein (i.e., 9 M urea, 3 M guanidine HCl); denatured by agents that only disrupt the tertiary structure but leave the secondary structure intact or even strengthened (i.e., 0.1 M sodium dodecylsulfate or SDS, 2 M n-propanol). The results are as follows: (1) as a rule, native proteins have no or weak effect on the solvency of the water for all 4 probes; (2) exposure to 0.1 M SDS and to 2 M n-propanol, as a rule, does not significantly decrease the p-value of all 4 probes; (3) exposure to 9 M urea and to 3 M guanidine HCl consistently lowers the p-values of sucrose, glycine and Na+ (sulfate) and equally consistently produces no effect on the p-value of urea. Sucrose, glycine, and Na+ are found in low concentrations in cell water while urea is not. These experiments were designed and carried out primarily to test two subsidiary theories of the AI hypotheses: the polarized multilayer (PM) theory of cell water; and the theory of size-dependent solute exclusion.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Propanol↗
PubMed1988

Solute exclusion by polymer and protein-dominated water: correlation with results of nuclear magnetic resonance (NMR) and calorimetric studies and their significance for the understanding of the physical state of water in living cells.

According to the polarized multilayer (PM) theory of cell water proteins with their backbones fully extended and their NHCO groups directly exposed to bulk water, polarize water in multilayers. Experimental testing of the theory led to a new understanding of the uniqueness of gelatin, due to its permanently maintained fully extended conformation and its ability to polarize the bulk phase water in multilayers with reduced solubilities for solutes in a size dependent manner ("size rule"). Other models which behave like gelatin are urea-denatured proteins, synthetic polymers like polyethylene oxide (PEO), and polyvinylpyrrolidine (PVP), but not native proteins. NMR studies showed that the majority of water molecules dominated by these polymers does indeed suffer rotational (and translational) motional restriction as predicted by the PM theory. In conjunction with ultra-high frequency dielectric studies but particularly quasielastic neutron scattering of both model systems (e.g., PEO) and living cells (i.e., brine shrimp cysts and frog muscle), this finding offers confirmation of the PM theory of living cell water and model systems. Studies of the freezing point depression showed that the presence of as much as 50% of native proteins had no effect on the freezing point of water while inclusion of gelatin, PEO, etc., caused concentration-dependent lowering of the freezing temperature. These findings demonstrate the key role of polarized water in the phenomena of freezing point depression and the unusual ice forms seen in living cells.

Biopolymers↗
PubMed1988

Studies on the physical state of water in living cells and model systems: IX. Theoretical significance of a straight line relationship between intracellular concentration of a partially excluded solute and its concentration in the bathing medium.

The experimentally observed steady-level distribution of Na+ (25 degrees) and of D-glucose (0 degree c) in frog muscle were chosen as examples of solute distribution patterns observed in living cells, for comparison with those predicted by two theoretical models: one derived from the membrane-pump theory and the other from the association-induction (AI) hypothesis. Neither the distribution of Na+ nor that of D-glucose follows the pattern predicted by the membrane-pump models for solutes maintained at lower level than in the external medium, in which the plot of intracellular solute concentration as ordinate against different external concentrations as abscissa bends upward with increasing external solute concentration. Instead, both Na+ and D-glucose exhibit either straight line distribution with unchanging (below unity) slopes, or that of a hyperbola superimposed on such a straight line, both in agreement with the AI hypothesis.

Animals↗
PubMed1988

Studies on the physical state of water in living cells and model systems. X. The dependence of the equilibrium distribution coefficient of a solute in polarized water on the molecular weights of the solute: experimental confirmation of the "size rule" in model studies.

The equilibrium distribution of 14 sugars, sugar alcohols, and other nonelectrolytes in solutions of polyethylene oxide (PEO) and of native and alkali-denatured bovine hemoglobin were studied over wide concentration ranges. The results show that the equilibrium concentrations of all the solutes studies are rectilinearly related to their external concentrations. This straight-line relationship demonstrates the existence of these solutes entirely or almost entirely in the aqueous phase of these systems. Therefore the slope of each of these straight lines equals the equilibrium distribution coefficient or q-value of the solute involved. In general, the q-values decrease with increasing molecule weights (M.W.) of the solutes in 15% solutions of PEO, 20% solutions of alkali-denatured hemoglobin (and in 18% gelatin) but not in 39% solution of native hemoglobin. In solutions of PEO, of alkali-denatured hemoglobin studied (and of gelatin) a fraction of the water (20% to 30%) appears to have solvency similar to that of normal liquid water. The experimental findings of M.W.-dependent solute exclusion were discussed in the light of four alternative theories that have been offered to explain this type of phenomena. Among these four theories only the polarized multilayer theory agrees with most, if not all the facts known.

Animals↗
PubMed1988

Studies on the physical state of water in living cells and model systems. XI. The equilibrium distribution coefficients of pentoses in muscle cell water: their dependence primarily on the molecular weights of the pentoses and lesser dependence on their stereospecificity.

Studies of the metabolism of four pentoses (D-, and L-arabinose; D-, and L-xylose) in frog muscle at 0 degree C revealed that all are metabolized at extremely slow rates. As a result, the metabolic degradation of these pentoses does not significantly affect their equilibrium distribution in muscle cells at this temperature at least. Of the four stereoisomers, three (L-xylose, D-arabinose, L-arabinose) were found exclusively or almost exclusively in the cell water, demonstrating a rectilinear distribution pattern; the equilibrium distribution coefficients (q-values) obtained from the slopes of these rectilinear distribution curves are 0.256, 0.274, and 0.271 respectively. The fourth pentose, D-xylose, is apparently partially adsorbed. With the aid of the equation for solute distribution according to the association-induction (AI) hypothesis, the data for this sugar can also be fitted with a theoretical curve calculated on the basis of a q-value close to those for the other three pentoses. The close similarity of the q-values of pentoses which are sterically different, but have identical molecular weights, provides further confirmation of the "size rule", a prediction of the polarized multilayer (PM) theory of cell water, according to which, the q-values are as a rule primarily determined by the molecular weights of the solute and to a lesser extent dependent on its stereospecificity.

Animals↗
PubMed1988

A physical theory of the living state: application to water and solute distribution.

This review begins with a summary of the disproof of the membrane-pump theory and the alternative theory of the living cell, the association-induction (AI) hypothesis. Being alive in the AI hypothesis represents the maintenance of a high (negative) energy-low entropy state in which the two major components K+ and water of the living cell are closely associated with the third major component of the living cells, proteins. K+ is adsorbed singly on beta- and gamma- carboxyl groups and the bulk of cell water in multilayers on the exposed NHCO groups of fully extended polypeptide chains of cell proteins. These adsorptions account for both the constancy of cell K+ and cell water per unit of cell proteins. ATP plays a key role in the maintenance of the cooperatively linked protein-ion-water assembly at the living state by its adsorption on key protein site and exercises the controlling influence through its strong inductive effects. Water polarized in multilayers demonstrates size-dependent exclusion of solutes, e.g., large (hydrated) Na+ is excluded from water in living cells or model systems while smaller urea that fits into the dynamic water structure is not excluded. The confirmation of the polarized multilayer theory of cell water by nuclear magnetic resonance (NMR), dielectric, neutron scattering, and other studies not only reverses the conventional belief of the existence of the cell water as normal liquid water; it also gives a new definition to colloids.

Adsorption↗
PubMed1988

An electronic mechanism in the action of drugs, ATP, transmitters and other cardinal adsorbents. II. Effect of ouabain on the relative affinities for Li+, Na+, K+, and Rb+ of surface anionic sites that mediate the entry of Cs+ into frog ovarian eggs.

Ouabain enhanced the inhibitory effects of Li+, Na+, and K+ on the rate of Cs+ permeation into frog ovarian eggs while it reduced the inhibiting effect of Rb+. The data agree with earlier demonstrated effects of ouabain on the rank order of selective accumulation of the five alkali-metals in frog muscles and on the relative effectiveness of glycine, Li+, Na+, K+, Rb+, and Cs+ in inhibiting the rate of entry of Cs+ into frog sartorius muscle. In all three cases, the ouabain behaved as an electron-donating cardinal adsorbent (EDC) causing a rise of the electron density (c-value) of the beta- and gamma-carboxyl groups in the cell cytoplasm (for selective accumulation) and on the cell surface (for selective ion permeation). Explanations based on the association-induction hypothesis were offered why an EDC like ouabain does not initiate cell activation (like veratridine does) and why Ca++ and tetradotoxin delays or inhibits physiological and artificial cell activation.

Animals↗
PubMed1987

Studies on the physical state of water in living cells and model systems. VI. Concentration-dependent sustained volume changes of dialysis sacs containing aqueous solution of native and denatured protein, gelatin, and oxygen-containing polymers immersed in solutions of Na salt and of sugar and sugar alcohol.

In this paper we studied the volume changes of dialysis sacs containing concentrated solutions of native and denatured proteins and of oxygen-containing polymers after immersion in aqueous solution of Na-citrate, D-glucose, and sorbitol of varying concentration. The results confirm the theory of cell volume regulation: volume changes of living cells in different solutions represent a balance between the tendency of intracellular proteins -- which exist in the fully extended conformation -- to polarize, sorb, and draw into the sac or cell more water and the opposite tendency to lose water from the sac or cell created by the lower level of the solutes in the cell or sac water than in the external medium. The lower level of the solutes is the consequence of the reduced solvency of the polarized water in the sac or cell water for large and complex solutes like sugar and free amino acids. This study adds another important physico-chemical attribute of the living cell that can be duplicated by aqueous solutions of gelatin, oxygen-containing polymers like PEO and PEG as well as urea-denatured proteins but not, or only weakly so, by aqueous solutions of native proteins or SDS-denatured proteins.

Animals↗