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Showing papers by "University of Pennsylvania published in 1973"


Journal ArticleDOI
TL;DR: It is postulated that in addition to the well-known flavin reaction, formation of H( 2)O(2) may be due to interaction with an energy-dependent component of the respiratory chain at the cytochrome b level.
Abstract: 1. Pigeon heart mitochondria produce H(2)O(2) at a maximal rate of about 20nmol/min per mg of protein. 2. Succinate-glutamate and malate-glutamate are substrates which are able to support maximal H(2)O(2) production rates. With malate-glutamate, H(2)O(2) formation is sensitive to rotenone. Endogenous substrate, octanoate, stearoyl-CoA and palmitoyl-carnitine are by far less efficient substrates. 3. Antimycin A exerts a very pronounced effect in enhancing H(2)O(2) production in pigeon heart mitochondria; 0.26nmol of antimycin A/mg of protein and the addition of an uncoupler are required for maximal H(2)O(2) formation. 4. In the presence of endogenous substrate and of antimycin A, ATP decreases and uncoupler restores the rates of H(2)O(2) formation. 5. Reincorporation of ubiquinone-10 and ubiquinone-3 to ubiquinone-depleted pigeon heart mitochondria gives a system in which H(2)O(2) production is linearly related to the incorporated ubiquinone. 6. The generation of H(2)O(2) by pigeon heart mitochondria in the presence of succinate-glutamate and in metabolic state 4 has an optimum pH value of 7.5. In states 1 and 3u, and in the presence of antimycin A and uncoupler, the optimum pH value is shifted towards more alkaline values. 7. With increase of the partial pressure of O(2) to the hyperbaric region the formation of H(2)O(2) is markedly increased in pigeon heart mitochondria and in rat liver mitochondria. With rat liver mitochondria and succinate as substrate in state 4, an increase in the pO(2) up to 1.97MPa (19.5atm) increases H(2)O(2) formation 10-15-fold. Similar pO(2) profiles were observed when rat liver mitochondria were supplemented either with antimycin A or with antimycin A and uncoupler. No saturation of the system with O(2) was observed up to 1.97MPa (19.5atm). By increasing the pO(2) to 1.97MPa (19.5atm), H(2)O(2) formation in pigeon heart mitochondria with succinate as substrate increased fourfold in metabolic state 4, with antimycin A added the increase was threefold and with antimycin A and uncoupler it was 2.5-fold. In the last two saturation of the system with oxygen was observed, with an apparent K(m) of about 71kPa (0.7-0.8atm) and a V(max.) of 12 and 20nmol of H(2)O(2)/min per mg of protein. 8. It is postulated that in addition to the well-known flavin reaction, formation of H(2)O(2) may be due to interaction with an energy-dependent component of the respiratory chain at the cytochrome b level.

2,535 citations


Journal ArticleDOI
04 Apr 1973-Nature
TL;DR: The pathogenesis of metastasis begins with the invasion of tissues, blood vessels and/or lymphatics by cells originating from a primary cancer, and most tumour emboli are initially arrested in the first capillary bed encountered, but some recirculate and are trapped in other organs.
Abstract: The pathogenesis of metastasis begins with the invasion of tissues, blood vessels and/or lymphatics by cells originating from a primary cancer. Following their release into the circulation, most tumour emboli are initially arrested in the first capillary bed encountered, but some recirculate and are trapped in other organs. After their initial arrest, tumour cells must invade the parenchyma, establish a micro-environment, escape host defence mechanisms and finally grow into secondary tumours1.

1,367 citations


Book ChapterDOI
01 Jan 1973

490 citations


Journal ArticleDOI
TL;DR: Seven types of microtubules were analyzed: those in the heliozoan axoneme, the mitotic apparatus, the contractile axostyle, repolymerized microtubule derived from the chick brain, the central pair in Flagella, and the A tubules of flagella and the basal body.
Abstract: When microtubules are fixed in glutaraldehyde in the presence of tannic acid and thin sections cut, the subunit structure of the microtubule is readily observed without the need of image reinforcement. Seven types of microtubules were analyzed: those in the heliozoan axoneme, the mitotic apparatus, the contractile axostyle, repolymerized microtubules derived from the chick brain, the central pair in flagella, and the A tubules of flagella and the basal body. In all cases microtubules were composed of 13 equally spaced protofilaments. The B tubules in flagella and the basal body appear to be composed of 11 subunits. The connections of the B to the A and the C to the B are described. A model of a microtubule is presented.

460 citations


Journal ArticleDOI
TL;DR: Research with 125IUDR‐labelled melanoma cells indicates that thrombocytopenia does not affect the initial vascular arrest of tumor cells but seems to influence their subsequent retention by the lung, and formation of platelet aggregates not only enhances but also seems to change the distribution of metastases.
Abstract: Thrombocytopenia reduces the number of metastases produced by a wide variety of murine tumors. Studies aimed at investigating interactions between tumors and platelets reveal that many tumors aggregated platelets in vitro and/or produced thrombocytopenia in vivo. In some instances, tumor-cell-induced thrombocytopenia in vivo was accompanied by accumulation of platelets in the lung. Thrombocytopenia was most active against metastases produced by tumors with the capacity to aggregate platelets in vitro and/or in vivo but it was also effective against metastases produced by tumors lacking such a capacity. Further studies, aimed at increasing platelet aggregation in vivo, as when fibroblasts were added to the tumor inoculum, or decreasing the platelet response to aggregating agents, as when aspirin was administered to mice, strongly support the role of platelet aggregation and the platelet release reaction in metastasis. As expected, fibroblasts enhanced while aspirin decreased tumor spread, the latter being equally effective against both artificially induced and spontaneously-occurring metastases. Formation of platelet aggregates not only enhances but also seems to change the distribution of metastases. Tumors with platelet aggregating capacities usually give lung metastases while those devoid of such a capacity may show metastases of widespread distribution. Research with 125IUDR-labelled B16 melanoma cells indicates that thrombocytopenia does not affect the initial vascular arrest of tumor cells but seems to influence their subsequent retention by the lung.

459 citations


Journal ArticleDOI
30 Nov 1973-Science
TL;DR: Muscle carnitine palmityltransferase activity, measured by three different methods, was very low in a patient with a familial syndrome of recurrent myoglobinuria, suggesting a more severe defect of carnityl transferase I than transferase II, due to a genetic defect of lipid metabolism in skeletal muscle.
Abstract: Muscle carnitine palmityltransferase activity, measured by three different methods, was very low (0 to 20 percent of controls) in a patient with a familial syndrome of recurrent myoglobinuria. Long-chain fatty acyl CoA synthetase activity was normal; acetylcarnitine transferase activity was decreased by 40 percent, and carnitine content was 1.7 times higher than the mean control value. Utilization of palmitate by isolated mitochondria was more impaired than utilization of palmitylcarnitine, suggesting a more severe defect of carnitine palmityltransferase I than transferase II. Thus, myoglobinuria may be due to a genetic defect of lipid metabolism in skeletal muscle.

437 citations


Journal ArticleDOI
TL;DR: In this paper, a general scheme for calculating the surface density of states change and the interaction energy of one and two single-level adatoms is presented, and contact (and a correction) is made with Grimley's formulation.
Abstract: The indirect interaction between adatom pairs on the (100) surface of a simple-cubic tight-binding solid is investigated within a molecular-orbital approach. A general scheme for calculating the surface-density-of-states change and the interaction energy of one and two single-level adatoms is presented, and contact (and a correction) is made with Grimley's formulation. The method permits binding above surface atoms, at bridge sites, or at centered positions, and yields interaction energy as a function of band filling, adatom energy level, and a general hopping potential $V$ between an adatom and the nearest surface atom(s). Calculations have been carried out for $\frac{V}{{W}_{b}}$ in the range 1/12-1/2, the upper limit giving split-off states (${W}_{b}\ensuremath{\equiv}\mathrm{bandwidth}$). The single-atom interaction shows little dependence on binding type, in all three cases being most attractive when the Fermi energy equals the noninteracting adatom level, with a strongly $V$-dependent strength. For the pair interaction, one finds a strength at nearest-neighbor separation of about an order of magnitude smaller than the absorption energy of a single adatom. This interaction has an exponentiallike dropoff and sign alternations as one moves along the $〈10〉$ direction. Under reasonable conditions, the nearest-neighbor interaction is often repulsive while the next nearest, third nearest, or fourth nearest is attractive, suggesting the patterns $c(2\ifmmode\times\else\texttimes\fi{}2)$, (2 \ifmmode\times\else\texttimes\fi{} 2), and $c(4\ifmmode\times\else\texttimes\fi{}2)$, respectively, which are frequently observed in the adsorption of simple gases on the (100) surfaces of transition metals. On the basis of two-dimensional Ising-model calculations including second-neighbor interactions, one can estimate the strength of $V$ from the observed disordering temperature of the adatom lattice; the result is similar to that obtained from estimates based on the heat of adsorption.

384 citations


Journal ArticleDOI
TL;DR: A model of the E.-C Coupling Mechanism in Mammalian Heart Muscle and a Mechanism for the Altered Inotropic State (the Interval Strength Relation) are presented.
Abstract: III. EXCITATION-CONTRACT/ON COUPLING PROCESSES IN THE MAMMALIAN VENTRICLE A. Structure 1. Transverse-tubular system 2. Sarcoplasmic reticulum B. Functional Implications of the Structure of the Mammalian Myocardium C. Action Potential Control of Contraction D. Membrane Potential and Development of Tension in Mammalian Ventricle E. Potassium Chloride Contracture Studies F. Ionic and Drug Dependence of the Two Components of Tension in Mammalian Heart 1. The phasic response 2. The tonic response G. The Mechanism of Development of the Tonic Tension H. The Mechanism of the Triggered Release of the Phasic Store 1. Secondary inward current and activation of contraction 2. Other observations concerning the secondary inward current I. Replenishment of the Phasic Store 1. Depletion of the activator store 2. Beat-dependent kinetics 3. Quantity of activator in the phasic store and the concept of recirculation 4. An estimate of the magnitude of the recirculated fraction of activator 5. Delay in availability of activator 6. Anatomical correlates 7, Plateau and replenishment J. A Model of the E.-C Coupling Mechanism in Mammalian Heart Muscle K. Events Leading to a Normal Contraction L. A Mechanism for the Altered Inotropic State (the Interval Strength Relation) 1. Post-extrasystolic potentiation 2. Treppe 3. Other theories (a) Inotropic mediator hypothesis (b) Sodium-lag hypothesis

340 citations



Journal ArticleDOI
TL;DR: There still remains much to be done to clarify the systematics of Cannabis, which has been associated with man for so long, and botanical studies alone are inadequate to ascertain the origin of cultivation.
Abstract: Although Cannabis is generally believed to be of Asiatic origin, within this vast geographical area, there is no general agreement as to where the domestication really came about. Alphonse de Candolle (1884), the first authority on the origin of cultivated plants, ascribed a very extensive range to the plant. He asserted that "the species has been found wild, beyond a doubt, to the south of the Caspian Sea, near the Irtysch, in the desert of Kirghiz, beyond Lake Baikal in Dahuria (government of Irlkutsch). Authors mention it throughout southern and central Russia and to the south of the Caucasus, but its wild nature is here less certain, seeing that these are populous countries, and that the seeds of the hemp are easily diffused from gardens. The antiquity of the cultivation of hemp in China leads me to believe that its area extends further to the east, although this has not yet been proved by botanists. " Later workers, mostly working on field collections, either have accepted this very general and extensive area, or favor specific regions, such as the Himalayas, central Asia, India, Pakistan or China (Vavilov, 1926; Zhukovskii, 1962). It is a difficult problem to differentiate truly wild plants from spontaneous, escaped or semicultivated plants. There still remains much to be done to clarify the systematics of Cannabis. Moreover, in the case of Cannabis, which has been associated with man for so long, botanical studies alone are inadequate to ascertain the origin of cultivation. As one author states (Schultes, 1972), "It would seem that historical and ethnobotanical evidence

290 citations


Journal ArticleDOI
TL;DR: The measurement of rate versus inhibitor concentration leads to the determination of the fluxes of reducing equivalents in each of the two pathways of electron transport in both State 3 and State 4, where the alternate, cyanide-insensitive pathway is regulated by the activity of the normal cytochrome pathway.

Journal ArticleDOI
TL;DR: The results have ranged from the production of severe and occasionally fatal Li to use as a psychoactive agent in the treatment of manic-depressive disorders.
Abstract: LITHIUM first attracted medical attention in the 19th century when A. B. Garrod attempted to treat gout with Li+ because Li+ urate was found to be more soluble than Na+ or K+ urate. However, the ub...

Journal ArticleDOI
TL;DR: The general conclusion is that, the body regulates the intracellular H2O2 level below about 10−7 m, and with this level biological oxidations of considerable significance are possible through the catalase system.

Journal ArticleDOI
TL;DR: A review of the literature which reflects the imprisoning of women in their biological entities and envisions motherhood as the normal destiny of all women is given in this article, where women who lived beyond their normal biologically-based roles would produce inferior offspring.
Abstract: Social characteristics that were considered ideal for the Victorian woman--morality domesticity and passivity--were assumed to be rooted in biology. The economic and social forces which began to change social roles in 19th-century Europe and America led women to demand more education and to practice fertility control against their previous traditional role. Men within the power structure used biological and medical arguments to rationalize traditional sex roles and oppose these deviations. This is a review of the literature which reflects the imprisoning of women in their biological entities and envisions motherhood as the normal destiny of all women. It was feared that women who lived beyond their normal biologically-based roles would produce inferior offspring. The so-called weakness of American women as compared to their European counterparts was seen to be the result of too much education for girls during puberty and adolescence. Women were eager to begin practicing fertility control in earnest because of the dangers of childbirth the drudgery which too many children caused for them and their desire to move beyond the home. The often-voiced fears of "race suicide" as a result of contraceptive practice were really reflections of the social changes occurring at that time and reflections of the tensions surrounding changing gender roles.

Journal ArticleDOI
TL;DR: It appears that, at least in mammalian hearts, the energy-linked transport of Ca++ by mitochondria is inadequate for regulating the beat-to-beat Ca++ cycle.
Abstract: Initial velocities of energy-dependent Ca++ uptake were measured by stopped-flow and dual-wavelength techniques in mitochondria isolated from hearts of rats, guinea pigs, squirrels, pigeons, and frogs. The rate of Ca++ uptake by rat heart mitochondria was 0.05 nmol/mg/s at 5 µM Ca++ and increased sigmoidally to 8 nmol/mg/s at 200 µM Ca++. A Hill plot of the data yields a straight line with slope n of 2, indicating a cooperativity for Ca++ transport in cardiac mitochondria. Comparable rates of Ca++ uptake and sigmoidal plots were obtained with mitochondria from other mammalian hearts. On the other hand, the rates of Ca++ uptake by frog heart mitochondria were higher at any Ca++ concentrations. The half-maximal rate of Ca++ transport was observed at 30, 60, 72, 87, 92 µM Ca++ for cardiac mitochondria from frog, squirrel, pigeon, guinea pig, and rat, respectively. The sigmoidicity and the high apparent Km render mitochondrial Ca++ uptake slow below 10 µM. At these concentrations the rate of Ca++ uptake by cardiac mitochondria in vitro and the amount of mitochondria present in the heart are not consistent with the amount of Ca++ to be sequestered in vivo during heart relaxation. Therefore, it appears that, at least in mammalian hearts, the energy-linked transport of Ca++ by mitochondria is inadequate for regulating the beat-to-beat Ca++ cycle. The results obtained and the proposed cooperativity for mitochondrial Ca++ uptake are discussed in terms of physiological regulation of intracellular Ca++ homeostasis in cardiac cells.

Journal ArticleDOI
TL;DR: Evidence is given for the presence of two NADH dehydrogenase systems accessible to exogenous NADH in mitochondria from mung bean hypocotyls, one of which contains a flavoprotein and cytochrome b555 and is insensitive to antimycin A and specific for the 4α hydrogen atom of NADH.


Journal ArticleDOI
TL;DR: A series of nine procollagen samples in which the hydroxyproline content varied from indicated that the polymethine content of these samples varied from 0.1 to 0.2 parts per million.

Journal ArticleDOI
TL;DR: In this article, the formulation of international marketing strategies is requiring more sophisticated management approaches due to the increasing importance of international business operations, and the authors examine the impact of such approaches on international marketing.
Abstract: The formulation of international marketing strategies is requiring more sophisticated management approaches due to the increasing importance of international business operations. The authors examin...

Journal ArticleDOI
16 Mar 1973-Science
TL;DR: The chromosomes of two human males were identified by fluorescent banding, restained, and measured by scanning microscopy and computer analysis and the two variables, DNA content and DNA-based centromeric index, provided almost complete discrimination of chromosome types.
Abstract: The chromosomes of two human males were identified by fluorescent banding, restained, and measured by scanning microscopy and computer analysis. The two variables, DNA content and DNA-based centromeric index, provided almost complete discrimination of chromosome types. Some chromosomes showed significant differences in DNA content between the men, and for one man two pairs of chromosomes showed significant differences between homologs.

Journal ArticleDOI
TL;DR: The data on cyanide-insensitive respiration previously presented as well as additional results are discussed from the point of view of control of respiration in plant mitochondria and it is shown that the results are inconsistent with certain mechanisms for control of the alternate pathway rate.

Journal ArticleDOI
TL;DR: The results reported show that the experimental results in the study on the ;microsomal ethanol-oxidation system' may be reinterpreted and the catalase ;peroxidatic' reaction provides a quantitative explanation for the activity hitherto attributed to the ; microsomal Ethanol-Oxidation system'.
Abstract: Ethanol oxidation by rat liver catalase (the ‘peroxidatic’ reaction) was studied quantitatively with respect to the rate of H2O2 generation, catalase haem concentration, ethanol concentration and the steady-state concentration of the catalase–H2O2 intermediate (Compound I). At a low ratio of H2O2-generation rate to catalase haem concentration, the rate of ethanol oxidation was independent of the catalase haem concentration. The magnitude of the inhibition of ethanol oxidation by cyanide was not paralleled by the formation of the catalase–cyanide complex and was altered greatly by varying either the ethanol concentration or the ratio of the rate of H2O2 generation to catalase haem concentration. The ethanol concentration producing a half-maximal activity was also dependent on the ratio of the H2O2-generation rate to catalase haem concentration. These phenomena are explained by changes in the proportion of the ‘catalatic’ and ‘peroxidatic’ reactions in the overall H2O2-decomposition reaction. There was a correlation between the proportion of the ‘peroxidatic’ reaction in the overall catalase reaction and the steady-state concentration of the catalase–H2O2 intermediate. Regardless of the concentration of ethanol and the rate of H2O2 generation, a half-saturation of the steady state of the catalase–H2O2 intermediate indicated that about 45% of the H2O2 was being utilized by the ethanol-oxidation reaction. The results reported show that the experimental results in the study on the ‘microsomal ethanol-oxidation system’ may be reinterpreted and the catalase ‘peroxidatic’ reaction provides a quantitative explanation for the activity hitherto attributed to the ‘microsomal ethanol-oxidation system’.

Journal ArticleDOI
TL;DR: This finding suggests that the presence of hydroxyproline in the molecule contributes significantly to the thermal stability of collagen, and suggests that triple strand formation may be required for normal secretion.

Journal ArticleDOI
TL;DR: A two-allele diploid model is described in which the fitnesses of the three genotypes are stationary stochastic processes and it is shown that a stable polymorphism will occur if the geometric mean fitness of the heterozygote exceeds that of both homozygotes.

Journal ArticleDOI
TL;DR: This field experiment tested the hypothesis that social labeling influences an actor's self-concept and his perception of the consequences of his behavior bylabeling subjects charitable or not labeled.


Book ChapterDOI
TL;DR: To indicate my empathy with polarographic techniques as they have been developed at the Johnson Foundation, I wish to recall the pioneering works of Bronk, Brink, Davies, Davies and Remond that stand as landmarks in the exploration of tissue oxygen tension by microelectrode methods.
Abstract: The importance of measuring intracellular oxygen concentrations in tissues has, over the years, emerged as a basic parameter in the physiology and biochemistry of living tissues. The credibility of oxyhemoglobin determinations, even as refined A/V differences, is taxed especially in cases where inhomogeneous tissues with variable oxygen demands and oxygen supply are served. The formation of lactic acid in the venous blood is often used as a criterion of anoxia, but it also lacks credibility where inhomogeneous circulatory pathways are served and in addition, is questionable from the standpoint of whether the appearance of excess lactate is an unequivocal criterion of oxygen insufficiency. To indicate my empathy with polarographic techniques as they have been developed at the Johnson Foundation, I wish to recall the pioneering works of Bronk(1) Brink (2), Davies and Remond (3) that stand as landmarks in the exploration of tissue oxygen tension by microelectrode methods. I served my apprenticeship with them.

Journal ArticleDOI
TL;DR: A model, which takes into account previous and present data, is presented for the uptake of Ca++ and Mn++ in liver mitochondria and the proposed mechanism is discussed in terms of the physiological regulation of cellular [Ca++] homeostasis in liver cells.

Journal ArticleDOI
TL;DR: In this paper, an exact treatment is given for the stochastic behavior of the frequency of haploid genotypes in an infinite population when the absolute fitnesses of the two genotypes vary at random over generations.
Abstract: In this paper an exact treatment is given for the stochastic behaviour of the frequency of haploid genotypes in an infinite population when the absolute fitnesses of the two genotypes vary at random over generations. The main qualitative result from this treatment is that natural selection will favour that allele with the largest geometric mean fitness. A diffusion equation is derived whose solution is identical to the exact solution. The drift coefficient for this equation is of the form − μp(1 − p) + σ2(½ − p)p(l − p). This differs from the drift coefficient used in previous treatments of this problem and reduces the rate of quasi-fixation. Various waiting time problems are solved using this diffusion equation.

Journal ArticleDOI
TL;DR: Variations in teriiperatui-e i n the ordinary test environment cont r i hut c' I i t t I e to v a r i a t i o 11 5 i n conduction 1182 Neurology 1 Volume 23 /November 1973 appa r en t I y s low.
Abstract: The nieitsurement ot nerve conduction vc I (1 c i t y is n ow a st an ci a r d e I ect r o d iag ii o s t i c procedure i n clinical neurology. The m o s t commonly used technics estimate the conduction rates o f fast fibers o n l y , ' but newer methods allow study o f the slower-conducting sensory'\" and motor4-\" fibers. Several sources of 'error are inherent in the c I i i i i cul d ct er iii i 11 at io n o t lie rve co nd uct ion velocity., Among these. variabi I i tY in tissue temperature has been m o s t t horoughly studied. Motor nerve conduction velocity decreases ahout 2.4 m per second per degree between 38 mid 29\" C\" a n d sensory nerve conduction velocity drops about 2.0 111 per second per degree between 36 and 2 I O C.!' Distal n i o t o r latcnc) ~ ;I coniposite measure o f terminal nerve conduct i o n an cl 11 eu r o m usc u 1211' _i u iict io n tririismission. increases by 0.2 iiisec per. degree o f d r o p i n teniperaturc hetween 35 arid 25\" C.\"' These factors are uset'ul clinically i n evil I u ;it i n g c o n d u ct io 11 velocities of' fast fibers when l i m b temperature is k i i own but not con t r o I I ed. S i i i i i l a r co r rection Iwtors have not yet been detcrmined f o r s I o \\ ~ . sensory and m o t o r fibers. Linlh temperature ol'ten is not controlled u 11 tl e r pro hab I y becausc o f the opinion that variations in teriiperatui-e i n the ordinary test environment cont r i hut c' I i t t I e to v a r i a t i o 11 5 i n conduction 1182 Neurology 1 Volume 23 /November 1973 appa r en t I y s low